BP601T Unit 1-3

BP601T Medicinal Chemistry III (Theory)
UNIT II
Prepared by-
Mrs. Sneha Kushwaha
Assistant Professor
Rama University
Kanpur
Unit II 10 Hours
Antibiotics
Historical background, Nomenclature, Stereochemistry, Structure activity relationship

Chemical degradation classification and important products of the following classes
Macrolide: Erythromycin, Clarithromycin, Azithromycin.
Miscellaneous: Chloramphenicol*, Clindamycin.
Prodrugs: Basic concepts and application of prodrug design.
Antimalarials: Etiology of malaria.
Quinolines: SAR, Quinine sulphate, Chloroquine*, Amodiaquine, Primaquine phosphate,

Pamaquine*, Quinacrine hydrochloride, Mefloquine.
Biguanides and dihydro triazines: Cycloguanil pamoate, Proguanil.
Miscellaneous: Pyrimethamine, Artesunete, Artemether, Atovoquone.
Antibiotics
B.Pharma – 3rd Year VI Sem. UNIT II – Antibiotics
By - Sneha Kushwaha (Asst. Professor) Subject – Medicinal Chemistry (BP601 T)
Macrolide Antibiotics
Introduction
 The macrolides are a class of natural products that consist of a large macrocyclic lactone ring to which one
or more deoxy sugars, usually cladinose and desosamine, may be attached.
 The lactone rings are usually 14-, 15-, or 16-membered.
 Macrolides belong to the polyketide class of natural products
History
 The first macrolide discovered was erythromycin, which was first used in 1952.
 Erythromycin was widely used as a substitute to penicillin in cases where patients were allergic to
penicillin or had penicillin-resistant illnesses.
 Later macrolides developed, including azithromycin and clarithromycin, stemmed from chemically
modifying erythromycin; these compounds were designed to be more easily absorbed and have fewer
side-effects (erythromycin caused gastrointestinal side-effects in a significant proportion of users).
Classification
Mechanism of action
 Macrolides are protein synthesis inhibitors.

 The mechanism of action of macrolides is inhibition of bacterial protein biosynthesis, and they are thought
to do this by preventing peptidyltransferase from adding the growing peptide attached to tRNA to the next
amino acid (similarly to chloramphenicol as well as inhibiting bacterial ribosomal translation. Another
potential mechanism is premature dissociation of the peptidyl-tRNA from the ribosome.
 Macrolide antibiotics do so by binding reversibly to the P site on the 50S subunit of the bacterial ribosome.
This action is considered to be bacteriostatic.
 Macrolides are actively concentrated within leukocytes, and thus are transported into the site of infection.
Uses
They are used to treat infections caused by Gram-(+) bacteria (Streptococcus pneumoniae) and limited Gram-(-)
bacteria (Bordetella pertussis, Hoemophilus influenzae), and some respiratory tract and soft-tissue infections,
Legionella pneumophila, mycoplasma, mycobacteria, some rickettsia, and chlamydia.
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(2)
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Lyncomycins
 Lincomycin is a lincosamide antibiotic that comes from the actinomycete Streptomyces lincolnensis.
 A related compound, clindamycin, is derived from lincomycin by using thionyl chloride to replace the 7-
hydroxy group with a chlorine atom with inversion of chirality
Structure
Mechanism of Action
 The lincosamides inhibit protein synthesis in susceptible bacteria by binding to the 50s subunits of
bacterial ribosomes.
 Thus, inhibiting peptidyltransferases, interference with the incorporation of amino acids into peptides
occurs thereby.
SAR
Variation of the substituents on pyrrolidine portion and C -5 side-chain affects the activity. e.g.
(1) N-demethylation imparts activity against gram-negative bacteria.
(2) Increase in chain length of the propyl substituent at 4 position in pyrrolidine moiety upto n-hexyl increases in-
vivo activity about 1.5 times than parent compound.
(3) The thiomethyl ether of a-thiolincosamide moiety is essential for activity
(4) Structural modifications at C-7, like introduction of 7S chloro or 7R- OCH; changes the physicochemical
parameters of the drug (i.e., partition coefficient) and thus alters activity spectrum and pharmacokinetic
properties. The ability of lincomycin to penetrate into bone, adds to its qualities and it gets promoted in
chemotherapy of bone and joint infections by penicillin resistant strains of Staphylococcus aureus.
Uses
 Although similar in antibacterial spectrum and mechanism of action to macrolides, lincomycin is also
effective against other organisms including actinomycetes and some species of Mycoplasma and
Plasmodium.
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 However, because of its adverse effects and toxicity, it is rarely used today and reserved for patients
allergic to penicillin or where bacteria have developed resistance.

Chloramphenicol
 Chloramphenicol is an antibiotic useful for the treatment of a number of bacterial infections.

 This includes use as an eye ointment to treat conjunctivitis.
 By mouth or by injection into a vein, it is used to treat meningitis, plague, cholera, and typhoid fever.
History
 Chloramphenicol was first isolated from Streptomyces venezuelae in 1947 and in 1949 a team of scientists
at Parke-Davis including Mildred Rebstock published their identification of the chemical structure and their
synthesis, making it the first antibiotic to be made instead of extracted from a microorganism.
 In 2007, the accumulation of reports associating aplastic anemia and blood dyscrasia with chloramphenicol
eye drops lead to the classification of “probable human carcinogen” according to World Health
Organization criteria, based on the known published case reports and the spontaneous reports submitted
to the National Registry of Drug-Induced Ocular Side Effects.
Structure
Mechanism of Action
 Chloramphenicol is a bacteriostatic by inhibiting protein synthesis.

 It prevents protein chain elongation by inhibiting the peptidyl transferase activity of the bacterial
ribosome.
 It specifically binds to A2451 and A2452 residues in the 23s rRNA of the 50s ribosomal subunit, preventing
peptide bond formation.
 Chloramphenicol directly interferes with substrate binding in the ribosome, as compared to macrolides,
which sterically block the progression of the growing peptide.
Uses
 Chloramphenicol is an antibiotic.
 It's mainly used to treat eye infections (such as conjunctivitis) and sometimes ear infections.
 Chloramphenicol comes as eye drops or eye ointment.
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Antimalarials
Etiology
 Malaria is a mosquito born infectious disease of human and other animals caused by eukaryotic protists of
the genus plasmodium.
 The disease results from the multiplication of plasmodium parasites within RBC
 Main species plasmodium falciparum (severe disease), plasmodium vivax, plasmodium ovale.
Life cycle of malaria
 Incubation period of the parasite species Incubation period (Liver cycle) P. falciparum 7-14 days P. vivax
12-17 days ( with relapse up to 3 years) P. ovale 9-18 days ( with relapse up to 20 years) P. malaria 13-40
days.
 The time between the fever episodes can be characteristics of the infecting plasmodium species.
 Duration of fever (erythrocytic cycle)-
a. P. falciparum 36-48 h, Malignant tertian malaria.
b. P. vivax 48h, Benign tertian malaria.
c. P. ovale 48h, Ovale tertian malaria.
d. P. malaria 72h, Quartan malaria.
Pathophysiology of malaria-
 Showers of new merozoites are released from the RBCs at intervals of approximately 48h for P.vivax,
P.ovale and P.falciparum and 72h for P.malaria.
 The episodic shaking, chills, and fever coincide with this release.
 The parasites destroy large numbers of infected RBC, thereby causing a hemolytic anemia.
 A characteristic brown malaria pigment derived from hemoglobin, called hematin is released from
ruptured RBCs and produces discoloration of the spleen, liver, lymph nodes and bone marrow.
 Activation of defense mechanisms in the host leads to a marked hyperplasia of mononuclear phagocytes,
producing massive splenomegaly and occasional hepatomegaly.
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Classification
Mechanim of Action
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Quinolines
Artemisinin
 SAR Of Artemisinin
a. Artemisinin serve as a lead compound for the development of new antimalarials with improved properties
b. The lactone group can be reduced & form dihydroartemisinin which is used to prepare semi synthetic
prodrug that are more water & oil soluble
c. The hydroxyl group can be alkylated to give oil soluble ether derivatives such as artemether & arteether
d. Esterification of the hydrooxyl with succinic acid gives the water soluble derivative , artesunate
e. 19. SAR Of Artemisinin
f. Studies of artemisinin analogues such as deoxyartemisinin which do not contain the endoperoxide bridge,
showed vastly reduced biological activity.
g. Moreover, derivatisation at the carbonyl lactone demonstrated that it is a possible region of modification
that can be manipulated in order to improve pharmacokinetic properties.
h. This was demonstrated by the semisynthetic prodrugs.
i. Compared to artemisinin itself, artemether, artesunate and dihydroartemisinin are more active.
Quinine & Related Compounds
 Quinine
a. The bark of the cinchona tree contains antimalarial compounds, most notably the highly fluorescent
compound, quinine.
b. The bark of the cinchona tree, if made into an aqueous solution was able to treat most cases of malaria.
c. The active principle quinine was first isolated from the bark during the early 19th century.
d. Quinine is the compound that contributes to the bitter taste of tonic water.
 4-aminoquinolines
a. Increasing concern about cinchona supplies and the desire to find quinine alternatives with reduced side
effects led to a massive search for novel antimalarials.
b. Chloroquine was one of the drugs successfully developed.
c. The drug was first used during the 1950s.
d. Chloroquine is effective against erythrocytic forms of the Plasmodium parasite. Like chloroquine, the drugs
amodiaquine and hydroxychloroquine belong to a class of quinine analogues called 4-aminoquinolines.
e. Drug designed of Chloroquine as prototype drug
f. It consists of 4- aminoquinoline pharmacophore.
g. The structural analogues of chloroquine have been designed in such a way that it will show more drug
likeness score than the prototype molecule but having the same pharmacophore essential for the
antimalarial activity.
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SAR of Quinolines
 The side chain present at 4 position of chloroquine have been modified with alteration of halogen atom in
some cases at position 8 to get increased drug likeness score.
 In case of designed molecules the chlorine molecule at position 8 have been replaced by –F atom to
increase the drug likeness score than the prototype molecule chloroquine.
 The position of R1 and R2 in the 4- aminoquinolone ring are modified in these designed molecules to get
increased drug likeness score
 8-aminoquinolines-
a. Drugs in this group have amino group at position 8 of quinoline ring
b. Such drugs have OCH3 group at position 6
c. Pamaquine, primaquine, and tafenoquine are antimalarial drugs that belong to a family named 8-
aminoquinolines.
d. Pamaquine is closely related to primaquine.
e. Compared to primaquine, pamaquine is more toxic and less effacacious.
f. Tafenoquine is currently in late clinical trials.
 When side chain is introduced at amino group antimalarial activity is intensified. It causes hemolysis of
RBCs Diethyl amino pentyl side chain Pamaquine
 It contains tertiary amino group and when it is converted into primary amino group the compound is called
primaquine, which is – Less toxic – Well tolerated It is the most commonly used agent in this group in the
treatment of malaria Primaquine
 -OCH3 is not necessary for antimalarial activity but when replaced by OC2H5 the compound became – less
active – Toxic in nature
 -OCH3 when replaced by CH3 the compound become inactive
 Introduction of halogens increases toxicity
 Presence of quinoline ring is necessary for antimalarial activity. When pyridine ring is converted to
piperidine (saturated) the compound became inactive
 Pentyl side chain gives maximum activity, increase or decrease of chain result is reduction of activity.
 The branched side chain when converted into straight chain pentaquine is obtained
 It has less antimalarial activity as compared to both pamaquine and primaquine
Other Quinine Analogues
 Mefloquine is an orally administered 4- methanolquinoline drug used to prevent and treat malaria.
 Like the other drugs, the halo substituents deter Phase I metabolism (hydroxylation) of the rings and also
contribute to enhanced lipophilicity.
 Halofantrine contains a phenanthrene ring. The absorption of halofantrine is enhanced when taken with
fatty food.
 Lumefantrine is usually taken in combination with the artemisinin based drug, artemether.
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Piperaquine-
 Resistance to chloroquine is a major problem which continues to drive the need for new antimalarials
structurally similar to chloroquine.
 Resistance to the drug was first documented during the 1950s. The compound has two of the bicyclic 4-
aminoquinoline group.
 Piperaquine showed excellent activity against resistant parasites. However, the use of piperaquine
declined during the 1980s as a result of the emergence of resistant strains of P. falciparum.
Isoquine-
 One disadvantage of amodiaquine is the formation of toxic amodiaquine quinone imine (AQQI)
metabolites. Isoquine as a less toxic variant of amodiaquine.
 In fact isoquine is an isomer of amodiaquine, differing only in the positions of the hydroxyl and the
diethylamine. Isoquine’s hydroxyl group is located in the meta position rather than the para position.
 When OH is in the meta-position, AQQI does not form.
 Isoquine has been described as a new lead compound for less toxic 4- aminoquinolines.
Fluoroamodiaquine (FAQ)-
 Fluorine is commonly used in drug design.

 Substitution with fluorine also contributes to increased lipophilicity.
 In terms of metabolism, fluorine is used to block parts of the drug that are susceptible to metabolism such
as the para-position of benzene rings.
 Due to the formation of the toxic amodiaquine metabolite, a series of fluoro-substituted variants of
amodiaquine designed and found the desired metabolic stability.
Medicinal Chemistry of Other Antimalarial Drugs
Pyronaridine
 Pyronaridine is an antimalarial compound exhibits high potency towards P. falciparum and some
chloroquine-resistant strains.
 When used in combination with other antimalarials such as artesunate, the emergence of resistance
appears to be slowed down considerably.
 Pyronaridine is an ideal candidate for combination therapy with artemisinins.
 Pyronaridine's core structure is similar to mepacrine (quinacrine). The drug is typically administered orally
as pyronaridine tetraphosphate which appears yellowish and has a bitter taste.
 The drug can also be administered via the intramuscular or intravenous route.
Pyrimethamine
 Often used in combination with other sulfonamide antimalarial drugs, pyrimethamine is also an antifolate
drug. Pyrimethamine acts on the dihydrofolate reductase enzyme.
 Pyrimethamine is administered through the oral route and is well-absorbed.
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 This drug is also used in the treatment of Toxoplasma gondii infections in immunocompromised patients.
 Pyrimethamine is also currently being investigated as a treatment for Amyotrophic Lateral Sclerosis (ALS),
also known as Lou Gehrig's disease.
Sulfadoxine or sulphadoxine
 It is a sulfonamide drug that was used in combination with pyrimethamine to treat or prevent malaria.
 Due to the emergence of resistance, its use has been reduced.
 Sulfadoxine acts by competitively inhibiting plasmodial dihydropteroate synthase, an enzyme not
biosynthesised by most eukaryotes including humans.
Synthesis of Chloroquine
Synthesis of Pamaquine
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Biguanides
 Biguanides are a class of medications used to treat type 2 diabetes and other conditions.
 They work by reducing the production of glucose that occurs during digestion.
 Metformin is the only biguanide currently available in most countries for treating diabetes
Structure
Mechanism of Action
a. Activate AMP activated protein kinase (AMPA-PK)

b. Reduce hepatic glucose production Lower blood glucose level
c. Impairment of renal gluconeogenesis
d. Slowing of glucose absorption from the gastrointestinal tract
e. Increased glucose to lactate conversion by enterocytes
f. Direct stimulation of glycolysis in tissues
g. Increased glucose removal from blood
h. Reduction of plasma glucagon levels
Cycloguanil Pamoate
Proguanil
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Prodrugs
 A prodrug is a medication or compound that, after administration, is metabolized (i.e., converted within
the body) into a pharmacologically active drug.
 Instead of administering a drug directly, a corresponding prodrug can be used to improve how the drug is
absorbed, distributed, metabolized, and excreted (ADME).
 Prodrugs are often designed to improve bioavailability when a drug itself is poorly absorbed from the
gastrointestinal tract.
 A prodrug may be used to improve how selectively the drug interacts with cells or processes that are not
its intended target. This reduces adverse or unintended effects of a drug, especially important in
treatments like chemotherapy, which can have severe unintended and undesirable side effects.
Classification
 Prodrugs can be classified into two major types, based on how the body converts the prodrug into the final
active drug form:
 Type I prodrugs are bioactivated inside the cells (intracellularly).
Examples of these are anti-viral nucleoside analogs that must be phosphorylated and the lipid-lowering
statins.
 Type II prodrugs are bioactivated outside cells (extracellularly), especially in digestive fluids or in the body's
circulatory system, particularly in the blood.
Examples of Type II prodrugs are salicin (described above) and certain antibody-, gene- or virus-directed
enzyme prodrugs used in chemotherapy or immunotherapy.
 Both major types can be further categorized into subtypes, based on factors such as (Type I) whether the
intracellular bioactivation location is also the site of therapeutic action, or (Type 2) whether or not
bioactivation occurs in the gastrointestinal fluids or in the circulation system.
Applications of Prodrug design
1. Taste or Odour
 Undesirable taste arises due to adequate solubility and interaction of drug with taste receptors. It can be
solved by lowering the solubility of drug or prodrug in saliva. Eg: chloramphenicol palmitate is the sparingly
soluble of prodrug of chloramphenicol, which is practically tasteless due to its low aqueous solubility, as
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well as it is hydrolysed to active chloramphenicol by the action of pancreatic lipase. Eg:Ethyl mercaptan
has a boiling point of 25ºC and a strong disagreeable odour. But diethyl dithio isophthalate, prodrug of
ethyl mercaptan has a higher boiling point and is relatively odourless.
2. Reduction of gastric irritation
Eg: Aspirin is a prodrug of salicylic acid designed to reduce gastric irritation
Drug Prodrug Salicylic acid, Aspirin Diethyl stilbestrol, Fosfestrol, Kanamycin, Kanamycin pamoate,
Phenylbutazone, N-methyl piperazine salt, Nicotinic acid, Nicotinic acid hydrazide, Oleandrin, oleandrin acetate
3. Reduction in Pain at Site of Injection
 Pain caused by intramuscular injection is mainly due to the weakly acidic nature or poor aqueous solubility
of drugs. Eg: IM injection of antibiotics like clindamycin and anti convulsant like phenytoin was found to be
painful due to poor solubility. So, prodrugs are produced like 2’phosphate ester of clindamycin and
hydantoic ester prodrug of phenytoin (fosphenytoin) an aqueous soluble form of phenytoin respectively.
Fosphenytoin Phenytoin
4. Enhancement of drug solubility and dissolution rate
 The prodrug approach can be used to increase or decrease the solubility of a drug, depending on its
ultimate use. Eg: chloramphenicol succinate and chloramphenicol palmitate, ester prodrugs of
chloramphenicol, have enhanced and reduced aqueous solubility respectively.
 On the basis of altered solubility, chloramphenicol sodium succinate prodrug is found suitable for
parenteral administration.
 The prodrug approach is also made useful for better gastrointestinal absorption. Eg: sulindac, a prodrug of
sulindac sulfide being more water soluble with sufficient lipophilicity, makes this drug suitable for oral
administration Testosterone - testosterone phosphate ester Tetracycline - tetralysine ,Diazepam -
diazepam L-lysine ester
5. Enhancement of chemical stability
 Chemical stability is an utmost necessary parameter for every therapeutic agent.

 The prodrug approach is based on the modification of the functional group responsible for the instability
or by changing the physical properties of the drug resulting in the reduction of contact between the drug
and the media in which it is unstable. Eg: Inhibiting the auto aminolysis, which occur due to capability of
NH2 group of side chain to attach β lactam ring of other molecule, in ampicillin molecule in concentrated
solution it generates polymeric species of ampicillin. By making hetacillin, a prodrug of ampicillin formed
by the reaction of acetone and ampicillin „ties up‟ the amine group and thus inhibits auto aminolysis
6. Pharmacokinetic Applications
 Improvement of Bioavailablity and Enhancement of Oral Bioavailablity
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 Various therapeutic agents such as water soluble vitamins, structural analogues of natural purine and
pyrimidine nucleoside, dopamine, antibiotics like ampicillin and carbenicillin, phenytoin and cardiac
glycoside such as gitoxin suffers with poor gastrointestinal absorption.
 The prime cause of the poor absorption of these agents is their highly polar nature, poor lipophilicity
and/or metabolism during the absorption process.
 On contrary gitoxin, a cardiac glycoside has very poor oral bioavailability due to limited aqueous solubility
7. Absorption of water soluble vitamin was enhanced by derivatization of thiolate ion to form lipid soluble
prodrugs .
 Dopamine was made useful by making its precursor L-Dopa. Though L- Dopa is highly polar, it is actively
transported through specific L–amino acid active transport mechanism and regenerates dopamine by
decarboxylation.
 Penta acetyl prodrug of gitoxin has four to five times more aqueous solubility. To increase aqueous
solubility esterification with amino acids is done.
 Examples of such prodrugs are valacyclovir and valgancyclovir, which are valine esters of the antiviral
drugs acyclovir and gancyclovir, respectively.
8. Prevention of Presystemic metabolism
 Following oral administration, a drug must pass through two metabolizing organs i.e., liver and
gastrointestinal mucosa, before reaching the general circulation.
 Phenolic moiety, oxidative N– and O– dealkylation, ester cleavage and peptide degradation are responsible
for the pre-systemic metabolism of various drugs.
 Two types of drugs fall into this category. The first are drugs rapidly degraded by the acid condition of the
stomach and the Drugs of second category degrade due to enzymes present in the gastrointestinal mucosa
and liver.
9. Prodrugs may protect a drug from presystemic metabolism
 Naltrexone (treatment of opioid addiction) and is readily absorbed from GIT and hence undergoes
Presystemic metabolism.
 Ester prodrugs such as O- nitrobenzoate and acetylsalicylate increased bioavilablity 45 and 28 fold
respectively.
 Drug Prodrug Propranolol Propranolol hemisuccinate Dopamine L-DOPA Morphine Heroin
10. Prolongation of duration of action
 Drugs with short half life require frequent dosing with conventional dosage forms to maintain adequate
plasma concentration of the particular drug.
 In plasma level time profile and consequently patient compliance is often poor. Prolongation of duration of
action of a drug can be accomplished by the prodrug .
 Prodrug can be formed by two approaches- Control the release of the drug from complex Control the
conversion of prodrug in to the parent drug.
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 Drug Prodrug Testosterone Testosterone propionate Estradiol Estradiol propionate Fluphenazine

Fluphenazine deaconate
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β-Lactam antibiotics
Prepared by
Dr. Sanjeev Kumar Sahu
Assistant Professor
Department of Pharmaceutical Chemistry
Lovely professional University, Phagwara, Punjab
Introduction
• The name “Lactam” is given to cyclic amides and is analogous to
the name “Lactone” which is given to cyclic esters .
• Antibiotics that contains the β-lactam (a four membered cyclic

amide) ring structure constitute the dominant class of agent
currently employed for the chemotherapy of bacterial
infections.
• β-lactam are the most widely used group of antibiotics available.

HISTROICAL BACKGROUND
The first synthetic β-Lactam was prepared
by HERMANN STAUDINGER in 1907
by reaction of the schiff base of aniline and
benzaldehyde with diphenylketone in a
cycloaddition.
Upto 1970, most β-Lactam research was
concerned with the penicillin and cephalosporin
groups, but since then a wide variety of structures have been
described.
BETA-LACTAM ANTIBIOTICS
(inhibitors of cell wall synthesis)
• Their structure contains a beta-lactam ring.
The major subdivisions are:
(a)penicillins whose official names usually include or end in “cillin”

(b)cephalosporins which are recognized by the inclusion of “cef” or
“ceph” in their official names.
(c) carbapenems (e.g. meropenem, imipenem)
(d) monobactams (e.g. aztreonam)
(e) beta-lactamase inhibitors (e.g. clavulanic acid, sulbactam).

CLASSFICATION OF β-LACTAM ANTIBIOTICS
PENICILLINS
• The penicillins were the first antibiotics discovered as natural
products from the mold Penicillium.
• 1928 - Sir Alexander Fleming, professor of bacteriology at St.
Mary's Hospital in London, was culturing Staphylococcus aureus.
He noticed zones of inhibition where mold spores were growing.
He named the mold Penicillium rubrum. It was determined that a
secretion of the mold was effective against Gram-positive
bacteria.
• It was isolated from fungus Penicillium notatum.

• Florey and Chain isolated penicillin by freeze drying and
chromatography.
• Penicillin was effective even when it is diluted up to 800 times.
Chemistry
•Penicillin nucleus consists of
• Thiazolidine ring (Ring A) - Sulphur containing with COOH
(Carboxyl group).
• Beta lactam ring (Ring B) – (Broken by Beta-lactamase)
Side chain is attached at position – 6- (NHCOR)
• Side chains attached through amide linkage. (Broken by

Amidase)
• Beta Lactam ring is broken by –
• Penicillinase (Beta Lactamase), and by gastric acid.

• Resultant Product is Penicilloic acid with No anti-bacterial
activity but Acts as antigenic determinant (Major
determinant)
Instability of beta-lactams
Instability of penicillins in acid. Hydrolysis involves the C-6 side chain.
BASIC STRUCTURE OF PENICILLIN
Basic chemistry:Beta lactum ring+Thiazolidine ring
Cis stereochemistry
Thiazolidine ring
H H S CH 3
R C HN C C
Variable group C CH 3
O C N
C H
O
Beta lactum ring
COO- Free carboxylate
Bicyclic ring system sysyem is essential
Site of Penicillinase action

Most reactive carbonyl group
PENICILLIN DERIVATIVES
PENICILLIN G (BENZYL PENICILLIN)
•Acid unstable.
•Parenteral route.
•Self destructive mechanism in its structure because of influence of
acyl side chain.
• PENICILLIN-V
• More acid stable than Penicillin G.
• Administered by oral route.
• Electron withdrawing group is present in acyl side chain.

• METHICILLIN
• Has no electron withdrawing group on the side chain.
• Acid sensitive and has to be injected.
• Steric shields can be added to penicillins to protect from
penicillinase enzyme.
• AMPICILLIN
• If hydrophilic groups like (NH2, OH , COOH ) are attached to the
carbon that is α to the carbonyl group on the side chain then α
hydrophilic group aids the passage of penicillins through porins of
gram –ve bacteria.
• Acid stable.
• AMOXICILLIN
• β-hydroxy ampicillin.
• Same spectrum of activity as that of penicillin G but more active
against gram–ve bacteria.
• Acid resistant hence given orally.
• Non toxic.
Other Derivatives
Ticarillin
Piperacillin Carbenicillin
Mezlocillin
Azlocillin
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Unsaturated lactone- essential for biological activity

Allylic primary alcohol at C-26 for potent activity. 24
27
23 25
H
Decreased cytotoxicity due to removal of double 21 26
bond between C2 & C3 22
18 20 O O
12
17
11
O 13
19
H 16
9 14
1
2
4-hydroxy-5(6)-epoxy-2-en-1-one moiety: Essential 10 8 15
for biological activity H H
5
3 7
4
Abolish its therapeutic activity due
6 to removal or substitution of epoxy
O group at C-(5,6).
Cell viability inhibition of withanolides is basically contributed to the
hydroxyl group OH Acts as an acceptor of nucleophile
Enhancing the activity to constrain and disrupt interaction of Hsp90- and interfere with Hsp90 client
Cdc37 that results for potential action. protein.
Carbonyl group addition increases the activity of withanolides.
STRUCTURAL ACTIVITY RELATIONSHIP
Resistance against Penicillin
•Natural
•Target enzymes and PBPs are deeply located (Lipoprotein barrier in –ve)
•PBPs of organisms have low affinity for penicillin
•Acquired
•Production of Penicillinase (Beta-Lactamase) enzyme, (>300 subtypes).
Common organisms producing Beta-Lactamase are
•Staphylococcus
•Bacillus subtilis
•Gonococci
•E. coli
•Enterococci
•Haemophilus influenza
•Loss or alteration of Porin channels in gram negative
•Modification of penicillin binding proteins (PBPs)- having low affinity .
•Activation of antibiotic efflux mechanism- Some gram negative bacteria
Adverse effects
General
•Hypersensitivity reactions (including Anaphylaxis)
•More with procaine penicillin,
•Intradermal Skin sensitivity test
•Major Determinant (Penicilloyl moiety in terms of amount) is responsible for
hypersensitivity other than anaphylaxis
•Minor determinants( Penicillamine and Penicillenate) are responsible for
anaphylaxis.
• The Penicilloyl moiety or major determinant results from reaction of beta-

lactam ring with endogenous proteins. The Beta lactam ring spontaneously
opens in the body forming a hapten-protein complex, the most abundant but
not necessarily most immunogenic.
• Super infections (Ampicillin)
• Nephrotoxicity (Methicillin causing interstitial nephritis)
• Increase in Prothrombin time leading to bleeding
• Jarisch -Herxheimer Reaction-
 Common in secondary syphilis,
 Release of Spirochetal lytic products (Heat stable proteins,

endotoxins)
 Characterized by fever, myalgia, exacerbation of lesions,
 Usually occurs within 2 hours of first dose
 Treatment- NSAIDs and Corticosteroids
 Also in Borelliosis, Leptospirosis, and Brucelosis

 Adolf Jarisch an Austrian and Karl Herxheimer a German
dermatologist
β-LACTAMASE INHIBITORS
 Has negligible antibacterial activity.
 Given with Penicillins which increases spectrum of activity.
 Microbial resistance to beta lactam antibiotics.
S Beta-lactamse S
N N
O O OH H
• Clavulanic acid:
Isolated from Streptomyces clavuligerus.
1stnaturally occurring β-lactam ring that
was not fused to a ‘S’ containing ring.
• Sulbactum:
 β-lactamase disabiling agent.
 Prepared by partial chemical synthesis
from penicillins.
Tazobactum:
Co-administered with Piperacillin.
Has little or no antibacterial activity.
Cephalosporins
• Cephalosporins were discovered shortly after penicillin entered
into widespread product, but not developed till the 1960’s.
• Cephalosporins are similar to penicillins but have a 6 member

dihydrothiazine ring instead of a 5 member thiazolidine ring.
• 7-aminocephalosporanic acid (7-ACA) can be obtained from

bacteria, but it is easier to expand the ring system of 7-APA
because it is so widely produced.
• They were isolated from cultures of Cephalosporium acremonium

by italian scientist Giuseppe Brotzu in 1945.
• In 1948, Abraham and his colleagues have isolated three principle
antibiotic components from cultures of fungus.
Cephalosporin P
Cephalosporin N
Cephalosporin C
• 1964 ,the first semi synthetic cephalosporin i.e. cefalothin was

launched in the Market by Eli Lilly and company.
• Unlike penicillin, cephalosporins have two side chains which can be

easily modified. Cephalosporins are also more difficult for β-
lactamases to hydrolyze.
1ST Generation Cephalosporins
cephalothin
cephaloridine
cefadroxil
cefalexin cefradine
 These drugs are very active against Gram-positive cocci (such as
Pneumococci, Streptococci, and Staphylococci).
 They do not cross BBB.
2nd Generation Cephalosporins
Cefachlor
Cefamycin
They have a greater gram-negative

spectrum while retaining some activity
against gram-positive bacteria.
 They are also more resistant
to β-lactamase.
No BBB Penetration. Cefuroxime
3rd Generation Cephalosporins
Cefixime
Ceftriaxone Cefotaxime
Third-generation drugs exhibit the lest activity against gram-positive
bacteria, but most potent activity against gram-negative bacteria :
(a) Extended antibacterial spectrum, include Pseud. aeruginosa;

(b)Less activity on gram-positive bacteria than first and second
generation;
(c) Most active on gram-negative bacteria;
(d) High stability with β-lactamase;

(e)Easy penetrate to different tissues, and then have broad
distribution;
(f) Little kidney toxicity.

4th Generation Cephalosporins
Cefpirome
Cefepime
 Zwitterionic compounds.
 Good affinity for the transpeptidase enzyme.
 Low affinity for some β-lactamases.
 Cross BBB and effective in meningitis.
5th Generation Cephalosporins
Ceftobiprole
 Active against
• Methicillin-resistant -Staphylococcus aureus
• Penicillin-resistant - Streptococcus pneumoniae
Cephalosporins advantages over penicillins
 Increased acid stability compare to penicillins.
 Most of the drugs have better absorption than penicillins.
 Broad antimicrobial spectrum.
 Increased activity against resistant microorganisms.
 Decreased allergenicity.
 Increased tolerence than penicillins.

Carbapenam
• Introduction
 Carbapenems are a class of β-lactam antibiotics with a broad
spectrum of antibacterial activity.
 They have a structure that renders them highly resistant to most
β-lactamases.
 Carbapenem antibiotics were originally developed from the
carbapenem thienamycin, a naturally derived product of
Streptomyces cattleya
Examples: Imipenem, Meropenem, Ertapenem

IMIPENEM:
 IMIPENEM has a wide spectrum with
good activity many gram negative rods
incluiding P.aeruginosa, gram positive organisms and anaerobes.

 Imipenem is inactivated by dehydropeptidases in renal tubules, result in
low urinary concentrations.
Monobactam
 Introduction:
 Monobactams are drugs with a monocyclic β-lactam ring.
 They are relatively resistant to beta-lactamases and active

aganist Gram-negative rods (including Pseudomonas and Serratia).
 They have no activity against Gram-positive bacteria or anaerobes.
Examples: Aztreonam, Tigemonam.

Aztreonam
 Aztreonam is given i.v.
 The half-life is 1–2 hours and is greatly prolonged in renal
failure.
 Penicillin-allergic patients tolerate aztreonam
without reaction
(Aztreonam)
Reference
 William O. Foye.,Textbook of Medicinal Chemistry, Pg. no: 1089 -1106
 Sriram., Medicinal Chemistry, Pg. no: 295-309.
 Kadam., Textbook of Medicinal Chemistry, Pg. no: 68-82.
 Ilango., Principles of Medicinal chemistry(vol.1), Pg. no: 121-143.

 Good man And GilMan’s; The Pharmacology Basis Of Therapeutics Tenth
Edition, pg. no 1189-1225.
 JH Block & JM Beale., Wilson & Giswold’s Textbook of Organic Medicinal

Chemistry & pharmaceutical chemistry 12th Edition, 2011, pg. No. 260-294.
LEARNING MATERIAL
COURSE: B.PHARMACY, 6th Sem, Medicinal Chemistry, BP -601T
Module 02: Antibiotics
Unit 2.1 Macrolides
2.2 Prodrug
2.3 Anti malarials
Ms. Baljeet Kaur

Assistant Professor
ASBASJSM College of Pharmacy, Bela (Ropar)
Objectives:
1. Understand the chemistry of drug with respect to their
biological activity.
2. Know the Importance of SAR of Drugs
3. Know the metabolism, Adverse Effect and therapeutic
value of drugs.
4. Understand the importance of Drug design.
Learning Outcomes:
1. Students will Learn about the structures and Medicinal
uses of Drugs.
2. Students will learn about relation of structure with its
activity.
3. Students will Learn about the designing of drugs.
Macrolides
The macrolides are a group of antibiotics produced by
various strains of Streptomyces and having a macrolide
ring structure linked to one or more sugars. They act by
inhibiting protein synthesis, specifically by blocking the
50S ribosomal subunit. They are broad spectrum
antibiotics.
Examples: Erythromycin, Azithromycin, Clarithromycin,

Roxithromycin etc……………
SOURCE:
These Are Produced By Streptomyces species.
CHEMISTRY:
 A macro cyclic lactone, usually having 12 to 17 atoms.

 A ketone group.
 One or two amino sugars linked to the nucleus.
 A neutral sugar linked either to amino sugar or to
lactone ring.
 The presence of the dimethyl amino moiety on the
sugar residue, which explains the basicity of these
compounds and consequently formationsalts.
General structure of macrolide
As macrolide are unstable in acidic pH, a no. of strategies have been
utilized to improve the acidic stability of erythromycin.
The addition of hydroxylamine
to the ketone to formoxime
e.g. roxithromycin
Alteration of c-6 hydroxyl
group: nucleophilic
functionality which
initiates erythromycindegradation.
The azalides (azithromycin)are
semisynthetic 15 -membered
congeners in which a nitrogen atom
has been introduced to expanda
14-membered precursor-leads to an extended spectrum of action.
Physical & Chemical properties
 Water insoluble molecules.
 Occurs as crystallinepowders.
Stable in aqueous solutions at or bellow
room temperature.
Unstable in acidic conditions and forms
internal cyclic ketal.
Macrolide is a protein synthesisinhibitor:
Macrolide bind to 50S ribosomal subunit
Inhibit polypeptide chain elongation &

protein synthesis inhibition
Result in inhibition of growth &

multiplication
 Erythromycin
Physical
Yellow to white crystalline powder.
properties:
Soluble in alcohol, slightlysoluble in water.
Stable at neutral pH.
• Dosage forms:
Oral and topical dosage forms.
Enteric coted and delayed realesedosage forms.
• Drug interactions:
Anticoagulants
Benzodiazepines
It is used in,
 Streptococcal pharyngitis
 Tonsillitis
 Respiratory infection
 Diphtheria
 Tetanus
 Syphilis & gonorrhoea
 Whooping cough
 Abdominal cramps
 Epigastric distress
 Jaundice
 Transient deafness
 Hypersensitivity rashes
 Hearing impairment
Therapeutic agents of erythromycin
 Erythromycin ethylsuccinate
 Erythromycin estolate
 Erythromycin gluceptate
 Erythromycin lactobionate
Advantages
Cannot undergo cyclic ketal formation, sodoesn’t
cause cramp in GI
 Higher blood concentrations.
 More lipophyl.
 Lower doses with lessintervals.
Uses:
 Atypical mycobacterial infection
 Resistant leprosy
 Toxoplasmosis
 H.Pylori induced peptic ulcers
 In the treatment of Urogenital infections caused by
N.gonorrhoeae and Chlamydia trachomatis.
 For the treatment of respiratory tract infections.
Pregnant women infected with scrub typhus:

Azithromycin can suitable for doxycyclin.
Miscellaneous
Structure and Synthesis of Chloramphenicol
Clindamycin
• P
PRODRUG
Introduction
• Almost all drugs possess some undesirable physicochemical and
biological properties.
• Drug candidates are often discontinued due to issues of poor

pharmacokinetic properties or high toxicities
• Their therapeutic efficacy can be improved by eliminating the

undesirable properties while retaining the desirable ones.
• This can be achieved through biological, physical or chemical means.

• The Biological approach is to alter the route of administration
which may or may not be acceptable to patient.
• The Physical approach is to modify the design of dosage form

such as controlled drug delivery of drug.
• The best approach in enhancing drug selectivity while minimizing

toxicity, is the chemical approach for design of prodrugs.
Definition
• The term prodrug, introduced in 1958 by Adrien Albert, relates to
“Biologically inert derivatives of drug molecules that undergo an
enzymatic and/or chemical conversion in vivo to release the
pharmacologically active parent drug.”
• A prodrug is a chemically modified inert drug precursor, which upon

biotransformation liberates the pharmacologically active parent
compound.
History of Prodrugs
• The first compound fulfilling the classical criteria of a prodrug was acetanilide,
introduced into the medical practice by Cahn and Hepp in 1867 as an antipyretic
agent. Acetanilide is hydroxylated to biologically active acetaminophen.
• Another historical prodrug is Aspirin (acetylsalicylic acid), synthesized in 1897

by Felix Hoffman (Bayer, Germany), and introduced into medicine by Dreser in
1899.
• The prodrug concept was intentionally used for the first time by the Parke-Davis
company for modification of chloramphenicol structure in order to improve the
antibiotic’s bitter taste and poor solubility in water. Two prodrug forms of
chloramphenicol were synthesized: chloramphenicol sodium succinate with a
good water solubility, and chloramphenicol palmitate used in the form of
suspension in children.
Objectives of Prodrug Design
• There are three basic, overlapping objectives in prodrug research:

1. Pharmaceutical Objectives:
o To improve solubility, chemical stability, and organoleptic properties
o To decrease irritation and/or pain after local administration,
oTo reduce problems related with the pharmaceutical technology of the

active agent.
2. Pharmacokinetic Objectives:
oTo improve absorption (oral and by non-oral routes).
oTo decrease presystemic metabolism to improve time profile.
oTo increase organ/ tissue-selective delivery of the active agent.
3. Pharmacodynamic Objectives:
oTo decrease toxicity and improve therapeutic index.
oTo design single chemical entities combining two drugs (co-drugs
strategy.
Prodrug
concept
• The awareness that the onset, intensity and duration of drug action are greatly
affected by the physicochemical properties of drug has promoted the
emergence of various prodrugs.
• Most of the limitations can be overcame by prodrug approach, but after

overcoming the various barriers, the prodrug should rapidly convert into active
moiety after reaching the target site.
• The design of an efficient, stable, safe, acceptable and aesthetic way to target a
drug to its site of action while overcoming various physical, chemical and
social barriers is certainly the utilization of the prodrug approach holds great
potential.
Barrier
Classification of Prodrugs
Carrier linked prodrug
Carrier linked prodrug consists of the attachment of a carrier group to
the active drug to alter its physicochemical properties.
The subsequent enzymatic or non-enzymatic mechanism releases the

active drug moiety.
Active Drug Drug
Chemical Prodrug Formation
Covalent Bond
Chemical/Enzymatic cleavage
Inert Carrier in vivo
Inert carrier
Bipartite
prodrug
• It is composed of one carrier (group) attached to the drugs.
• Such prodrugs have greatly modified lipophilicity due to the attached
carrier. The active drug is released by hydrolytic cleavage either chemically
or enzymatically.
• E.g. Tolmetin-glycine prodrug.
Glycine Tolmetin
12
Tripartite prodrug
The carrier group is attached via linker/spacer to drug.

Mutual Prodrugs
• A mutual prodrug consists of two pharmacologically active agents
coupled together so that each acts as a promoiety for the other agent and
vice versa.
• A mutual prodrug is a bipartite or tripartite prodrug in which the carrier
is a synergistic drug with the drug to which it is linked.
• Benorylate is a mutual prodrug aspirin and paracetamol.
• Sultamicillin, which on hydrolysis by an esterase produces ampicillin &
sulbactum.
Paracetamol Aspirin Ampicillin
Sulbactum
Benorylate Sultamicillin
Bioprecursors
• The bioprecursor does not contain a temporary linkage between the active
drug and carrier moiety, but designed from a molecular modification of an
active principle itself.
• Eg: phenylbutazone. Phenylbutazone gets metabolized to oxyphenbutazone
that is responsible for the anti inflammatory activity of the parent drug
• Polymeric Prodrugs
• Also known as macromolecular prodrug, the drug is dispersed or
incorporated into the polymer (both naturally occurring and synthetically
prepared) system without formation of covalent bond between drug and
polymer.
• Eg: p–phenylene diamine mustard is covalently attached to polyamino
polymer backbone polyglutamic acid.
Novel Classification
 Type I Prodrugs
 Type II Prodrugs
• Type I prodrugs are bioactivated inside the cells (intracellularly). Examples

of these are anti-viral nucleoside analogs that must be phosphorylated and
the lipid-lowering statins.
• Type II prodrugs are bioactivated outside cells (extracellularly), especially

in digestive fluids or in the body's circulation system,
Tissue location of
Type Bioactivation site Subtype Examples
bioactivation
Aciclovir, fluorouracil, cyclophosphamide

Therapeutic target , diethylstilbestrol diphosphate, L-
Type IA
tissues/cells DOPA,mercaptopurine, mitomycin, zidov
udine
Type I Intracellular
Carbamazepine, captopril, carisoprodol,
Metabolic tissues (liver, GI heroin, molsidomine, leflunomide, palipe
Type IB
mucosal cell, lung etc.) ridone,phenacetin, primidone, psilocybin
, sulindac, fursultiamine, codeine
Loperamide
Type IIA GI fluids
oxide, oxyphenisatin, sulfasalazine
Acetylsalicylate, bacampicillin, bambuter

Systemic circulation and
Type II Extracellular ol, chloramphenicol
Type IIB other extracellular fluid
succinate, dipivefrin, fosphenytoin,lisdex
compartments
amfetamine, pralidoxime
Therapeutic target
Type IIC ADEPTs, GDEPs, VDEPs
tissues/cells
Applications of Prodrugs
Pharmaceutical applications
 Masking Taste or Odour

 Undesirable taste arises due to adequate solubility and interaction of drug
with taste receptors.
 It can be solved by lowering the solubility of drug or prodrug in saliva.
 Eg: chloramphenicol palmitate is the sparingly soluble of prodrug of
chloramphenicol, which is practically tasteless due to its low aqueous
solubility, as well as it is hydrolysed to active chloramphenicol by the action
of pancreatic lipase.
 Eg:Ethyl mercaptan has a boiling point of 25ºC and a strong disagreeable
odour. But diethyl dithio isophthalate, prodrug of ethyl mercaptan has a
higher boiling point and is relatively odourless.
 Reduction of gastric irritation
Eg: Aspirin is a prodrug of salicylic acid is designed to reduce gastric irritation
Drug Prodrug
Salicylic acid Aspirin
Diethyl stilbestrol Fosfestrol
Kanamycin Kanamycin pamoate
Phenylbutazone N-methyl piperazine salt
Nicotinic acid Nicotinic acid hydrazide
Oleandrin oleandrin acetate
 Reduction in Pain at Site of Injection
 Pain caused by intramuscular injection is mainly due to the weakly acidic nature
or poor aqueous solubility of drugs.
 Eg: IM injection of antibiotics like clindamycin and anti convulsant like phenytoin
was found to be painful due to poor solubility. So, prodrugs are produced like
2’phosphate ester of clindamycin and hydantoic ester prodrug of phenytoin
(fosphenytoin) an aqueous soluble form of phenytoin respectively.
Fosphenytoin
Phenytoin
Clindamycin–2 dihydrogen phosphate
 Enhancement of drug solubility and dissolution rate
• The prodrug approach can be used to increase or decrease the solubility of a
drug, depending on its ultimate use.
• Eg: chloramphenicol succinate and chloramphenicol palmitate, ester
prodrugs of chloramphenicol, have enhanced and reduced aqueous
solubility respectively. On the basis of altered solubility, chloramphenicol
sodium succinate prodrug is found suitable for parenteral administration.
• The prodrug approach is also made useful for better gastrointestinal
absorption.
• Eg: sulindac, a prodrug of sulindac sulfide being more water soluble with
sufficient lipophilicity, makes this drug suitable for oral administration
• Testosterone - testosterone phosphate ester
• Tetracycline - tetralysine
• Diazepam - diazepam L-lysine ester
 Enhancement of chemical stability
• Chemical stability is an utmost necessary parameter for every therapeutic

agent.
• The prodrug approach is based on the modification of the functional group

responsible for the instability or by changing the physical properties of the
drug resulting in the reduction of contact between the drug and the media in
which it is unstable.
• Eg: Inhibiting the auto aminolysis, which occur due to capability of NH2
group of side chain to attach β lactam ring of other molecule, in ampicillin
molecule in concentrated solution it generates polymeric species of
ampicillin. By making hetacillin, a prodrug of ampicillin formed by the
reaction of acetone and ampicillin „ties up‟ the amine group and thus
inhibits auto aminolysis
Ampicillin
Hetacillin
Pharmacokinetic Applications
 Improvement of Bioavailablity
 Enhancement of Oral Bioavailablity

 Various therapeutic agents such as water soluble vitamins, structural
analogues of natural purine and pyrimidine nucleoside, dopamine,
antibiotics like ampicillin and carbenicillin, phenytoin and cardiac glycoside
such as gitoxin suffers with poor gastrointestinal absorption.
 The prime cause of the poor absorption of these agents is their highly polar
nature, poor lipophilicity and/or metabolism during the absorption process.
 On contrary gitoxin, a cardiac glycoside has very poor oral bioavailability

due to limited aqueous solubility
• Absorption of water soluble vitamin was enhanced by derivatization of
thiolate ion to form lipid soluble prodrugs .
• Dopamine was made useful by making its precursor L-Dopa. Though L-

Dopa is highly polar, it is actively transported through specific L–amino
acid active transport mechanism and regenerates dopamine by
decarboxylation.
• Penta acetyl prodrug of gitoxin has four to five times more aqueous
solubility.
• To increase aqueous solubility esterification with amino acids is done.

Examples of such prodrugs are valacyclovir and valgancyclovir, which are
valine esters of the antiviral drugs acyclovir and gancyclovir, respectively.
 Enhancement of ophthalmic bioavailability
oEpinephrine - dipivalyl derivative
oLatanoprost and travoprost - isopropyl esters of latanoprost acid and
travoprost acid
 Enhancement of percutaneous bioavailability

oMefenide - mefenide hydrochloride/acetate
 Enhancement of topical administration

o Ketolac - Esters of ketolac
 Prevention of Presystemic metabolism
 Following oral administration, a drug must pass through two metabolizing organs
i.e., liver and gastrointestinal mucosa, before reaching the general circulation.
 Phenolic moiety, oxidative N– and O– dealkylation, ester cleavage and peptide

degradation are responsible for the pre-systemic metabolism of various drugs.
 Two types of drugs fall into this category.
 The first are drugs rapidly degraded by the acid condition of the stomach and the
 Drugs of second category degrade due to enzymes present in the gastrointestinal

mucosa and liver.
 Prodrugs may protect a drug from presystemic metabolism.
 Naltrexone (treatment of opioid addiction) and is readily absorbed from GIT

and hence undergoes Presystemic metabolism. Ester prodrugs such as O-
nitrobenzoate and acetylsalicylate increased bioavilablity 45 and 28 fold
respectively.
Drug Prodrug
Propranolol Propranolol hemisuccinate
Dopamine L-DOPA
Morphine Heroin
 Prolongation of duration of action
• Drugs with short half life require frequent dosing with conventional dosage
forms to maintain adequate plasma concentration of the particular drug.
• In plasma level time profile and consequently patient compliance is often
poor.
• Prolongation of duration of action of a drug can be accomplished by the
prodrug . Prodrug can be formed by two approaches-
 Control the release of the drug from complex
 Control the conversion of prodrug in to the parent drug.
Drug Prodrug
Testosterone Testosterone propionate
Estradiol Estradiol propionate
Fluphenazine Fluphenazine deaconate
 Reduction Local and Systemic Toxicity of Drugs
• An important objective of drug design is to develop a moiety with high activity and
low toxicity.
• Gastric irritation and ulcerogenicity associated with aspirin use due to presence of
free carboxylic group. Esterification of aspirin(R = alkyl) and other nonsteroidal
anti-inflammatory agents (NSAIDs) greatly suppresses gastric ulcerogenic activity.
• Another example is the bioprecursor Sulindac, as it is a sulphoxide, it doesn’t cause

any gastric irritation and also better absorbed.
• The prodrug Ibuterol is iisobutyrate ester of Terbutaline (a selective β-agonist useful)

in glaucoma. This prodrug, is 100 times more potent, has longer duration of action
and is free from both local and systemic toxicity.
 Site specific drug delivery
• After its absorption into the systemic circulation, the drug is distributed to the various
parts of the body including the target site as well as the non-target tissue.
• These problems can be overcome by targeting the drug specifically to its site of action by
prodrug design
• The prodrug is converted into its active form only in the target organ/tissue by utilizing
either specific enzymes or a pH value different from the normal pH for activation e.g. 5-
amino salicylic acid.
• Tumour cells contain a higher concentration of phosphates and amidases than do normal
cells. Consequently a prodrug of cytotoxic agent could be directed to tumour cells if
either of these enzymes was important to prodrug activation process. Diethylstilbestrol
diphosphate was designedfor site-specific delivery of diethylstilbestrol to prostatic
carcinoma tissue.
 Site specific Drug Delivery in Chemotherapy
Directed Enzyme Prodrug Therapy (DEPT)
 Many chemotherapy drugs for cancer lack tumour specificity and the doses
required to reach therapeutic levels in the tumour are often toxic to other
tissues.
 (DEPT) uses enzymes artificially introduced into the body to
convert Prodrugs, which have no or poor biological activity, to the active
form in the desired location within the body.
 DEPT strategies are an experimental method of reducing the systemic

toxicity of a drug, by achieving high levels of the active drug only at the
desired site.
 Antibody-directed enzyme prodrug therapy (ADEPT)
 Gene-directed enzyme prodrug therapy (GDEPT)
 Virus-directed enzyme prodrug therapy (VDEPT)
 Polymer-directed enzyme prodrug therapy (PDEPT)
 Clostridia-directed enzyme prodrug therapy (CDEPT)

 Antibody-directed enzyme prodrug therapy (ADEPT)
 ADEPT is a strategy to overcome the problems of lack

of tumour selectivity.
 An antibody designed/developed against a tumor antigen is linked to

an enzyme and injected to the blood, resulting in selective binding of the
enzyme in the tumor.
 A prodrug is administrated into the blood circulation, which is converted to

an active cytotoxic drug by the enzyme, only within the tumor.
 Selectivity is achieved by the tumor specificity of the antibody and by

delaying prodrug administration until there is a large differential between
tumor and normal tissue enzyme levels.
Schematic presentation of antibody-directed enzyme prodrug therapy (ADEPT).
mAb-enzyme conjugate is given first, which binds to antigens expressed on tumor surfaces. Prodrug is
given next, which is converted to active drug by the pre-targeted enzyme.
Antibody Prodrug Drug Tumor target
Mitomycin C Lung
phosphate adenocarcinoma
L6 Mitomycin C
Etoposide
phosphate
BW413 Etoposide Colon carcinoma
Doxorubicin Lung
phosphate adenocarcinoma
L6 Doxorubicin
 Gene-directed enzyme prodrug therapy - GDEPT
 GDEPT, is a two-step process.
 In the first step, the gene for a foreign enzyme is delivered to tumor cells.
 In the second step, a non-toxic agent is administered systematically and

converted by the enzyme to its cytotoxic metabolite.
Enzyme Prodrug Drug

Cytochrome p450 Cyclophosphamide, Phosphamide
ifosfamide mustard, acrolein
Cytosine deaminase 5-Fluorocytosine 5-Fluorouracyl
5-Fluorouridine
Nitroreductase 5-(Aziridin-1-yl)-2,4- 5-(Aziridin-1-yl)-4-
dinitrobenzamide hydroxylamino-2-
nitrobenzamide
Schematic presentation of gene-directed enzyme prodrug therapy (GDEPT).
Gene for foreign enzyme is transfected to tumor cells, which express the enzyme to activate
the systemically administered prodrug
 Virus-directed enzyme prodrug therapy (VDEPT)
VDEPT is the term given to the use of a virus to deliver the gene for GDEPT.
VDEPT can potentially be used to enhance the therapeutic potential
of oncolytic viruses.
 Polymer-directed enzyme prodrug therapy (PDEPT)
PDEPT uses polymer-drug conjugates, drugs contained within a polymer

'shell' such as pHPMA and designed to be released only by a specific
enzyme.
 Clostridia-directed enzyme prodrug therapy (CDEPT)
 CDEPT is the use of Clostridia to convert prodrugs into active drug agents.
CDEPT exploits the hypoxic environment of solid tumors to target drugs to
tumors using anaerobic bacteria resident in the tumour to convert the pro-drug to
the active form.
 Solid tumours, in contrast to normal tissues, grow rapidly. As a result, the

cancerous tissues may suffer from inadequate blood and oxygen supply. Therefore,
clostridia can grow in tumor and destroy it specifically.
 In CDEPT, a prodrug-converting enzyme expressed by a clostridial expression

plasmid converts a prodrug into an active drug form within the tumor.
 While the prodrug is the inactive form and can be administrated to the blood, the
products of the prodrug cleavage are highly cytotoxic and show their effect only in
the vicinity of tumor cells.
CONCLUSION
Prodrug design is a part of the general drug discovery process, in which a
unique combination of therapeutically active substances is observed to have
desirable pharmacological effects.
In human therapy prodrug designing has given successful results in overcoming

undesirable properties like absorption, nonspecificity, and poor bioavailability
and GI toxicity.
Thus, prodrug approach offers a wide range of options in drug design and
delivery for improving the clinical and therapeutic effectiveness of drug.
ANTIMALARIAL AGENT
INTRODUCTION
• Malaria, one of the most widespread diseases, is caused
parasite and is transmitted to humans by the female an
Plasmodium belongs to the class of protozoa known as sporoz
• Mainly four species of plasmodium typically cause hu

plasmodium falciparum, p. Vivax, P. Malariae and P. Ovale .
• A 5th species, P. Knowlesi, is primarily a pathogen of monkeys,
been recognized to cause illness, including severe disease, in h
• Although all species may cause significant illness, p. Falciparum

for the majority of serious complications and death.
LIFE CYCLEOF THE MALARIAL PARASITE
• An anopheles mosquito inoculates plasmodium sporozoites
infection. Circulating sporozoites rapidly invade liver cells, a
stage tissue schizonts mature in the liver. Merozoites are sub
from the liver and invade erythrocytes.
• Only erythrocytic parasites cause clinical illness. Sexual stage

develop in erythrocytes before being taken up by mosquitoes,
into infective sporozoites.
THERAPEUTIC CLASSIFICAT
1. Causal prophylaxis: (primary tissue schizonticides)
• Drugs prevent the maturation of or destroy the sporozoites
hepatic cell- thus prevent erythrocytic invasion
• Primaquine, proguanil
• Primaquine – for all species of malaria but not used due to it

• Proguanil- primarily for P. Falciparum and not effective aga
activity), rapid development of resistance
2. Supressives prophylaxis:
• Supress the erythrocytic phase and thus attack of malarial fe
prophylactics
• Chloroquine, proguanil, mefloquine, doxycycline

3. Clinical cure: Erythrocytic Schizonticides
• Erythrocytic schizontocides are used to terminate episodes of
• Fast acting high efficacy drugs:
• Chloroquine, quinine, mefloquine, halofantrine, artemicin
• Used singly to treat malaria fever

• Faster acting, preferably used in falciparum malaria where
may lead to death even if parasites are clear from blood
• Slow acting low efficacy drugs:
• Proguanil, pyrimethamine, sulfonamides, tetracyclines
• Used only in combination

4. Radical curatives:
• Drug attack exoerythrocytic stage (hypnozoites) given with cl
the total eradication of the parasite from the patient’s body
• Radical cure of the P. Falciparum malaria can be achieved by
• For radical cure of P. Vivax infection, primaquine and progua
5. Gametocidal:
• Removal of male and female gametes of plasmodia form

blood
• It has no benefit for treated patient

• Primaquine and artemisinins are highly effective against
species
CHEMICAL CLASSIFICATIO
Classes Drugs
1. 4-aminoquinolines Chloroquine (CQ), amodiaquine

Piperaquine
2. Quinoline-methanol Mefloquine
3. Cinchona alkaloid Quinine, quinidine
4. Biguanide Proguanil (chloroguanide)
5. Diaminopyrimidine Pyrimethamine
6. 8-aminoquinoline Primaquine, tafenoquine

7. Sulfonamides and Sulfadoxine, sulfamethopyrazin
sulfone dapsone
8. Amino alcohols Halofantrine, lumefantrine
9. Sesquiterpine lactones Artesunate, artemether, arteeth
10. Naphthyridine Pyronaridine
11. Naphthoquinone Atovaquone

12. Antibiotics Tetracycline, Doxycycline, Clind
1. 4-AMINOQUINOLINES
CH3
CH3 C2H5
N HN
HN C2H5
Cl N
Cl N
Hydrox
Chloroquine
OH
C2H5
NH
HN C2H5
Cl N
Amodiaquine
CHLOROQUINE:
• It has activity against the blood stages of plasmodium ovale
susceptible strains of P. Vivax and P. Falciparum.
• Widespread resistance in most malaria-endemic countries has led

use for the treatment of p. Falciparum, although it remains effecti
P. Ovale, P. Malariae and, in most regions, P. Vivax.
• Mechanism of action :
• Binds to and inhibits dna and rna polymerase; interferes wi

hemoglobin utilization by parasites; inhibits prostaglandin effect
• The parasite digests the human hemoglobin in order to get a

problem here is that the heme part of hb is toxic to the parasite.
• To overcome this obstacle, the parasite has developed an enzy
polymerization of heme. To form insoluble crystals called he
collected in vacuoles.
• Chloroquine enters parasite cell by simple diffusion. Chloroqu

protonated as the digestive vacuole is known to be acidic (pH
then cannot leave by diffusion. Chloroquine inhibits polymeriz
accumulation of heme.
• Chloroquine binds to heme (or fp) to form what is known as

complex, this complex is highly toxic to the cell and disrupts m
Action of the toxic compound results in cell lysis and ultim
autodigestion.
MECHANISM OF ACTION
MECHANISM OF ACTION :
• RESISTANCE RESULTS FROM ENHANCED EFFLUX OF THE
EXPRESSION OF THE HUMAN MULTI DRUG RESISTANCE
GLYCOPROTEIN.
THERAPEUTIC USES
1. HEPATIC AMOEBIASIS
2. GIARDIASIS
3. CLONORCHIS SINENSIS
4. RHEUMATOID ARTHRITIS
5. DISCOID LUPUS ERYTHEMATOSUS
6. CONTROL MANIFESTATION OF LEPRA REACTION
7. INFECTIOUS MONONUCLEOSIS
• Hydroxy chloroquine:
 Less toxic, properties &uses similar
• Amodiaquine:
 As effective as chloroquine
 Pharmacological actions similar
 Chloroquine resistant strains may be effective
 Adverse events: GIT, headache , photosensitivity, rarely agra
 Not recommended for prophylaxis

• Contraindications:
1. Psoriasis or porphyria
2. Visual field abnormalities or myopathy
3. Ca and mg containing antacid interfere with absorption
4. Used with caution in liver disease or neurologic or hemato

SAR of 4-aminoquinolines
Dialkylaminoalkyl side chain

1. 2-5 carbon atoms between the nitrogen atoms,particula
1-methylbutylamino side chain is optimal for activity as
2. The tertiary amine is important.
3. Introduction of unsaturation in the side chain was not d
4. Substitution of a hydroxy on one of the ethyl groups in te
(hydroxy quinoline) generally reduces toxicity and increa
concentration. This is one of the metabolites of chloroqu
5. Incorporation of an aromatic ring in the side chain e.g. in
gives a compound with reduced toxicity and toxicity.
Introduction of chloro
group at this position is Introductio
NHR group at th
optimal for activity 5 4 reduces ac
R1
6
3
2
Cl 7
8
N
1
d-Isomer of chloroquine is somewhat less toxic than l-isomer

2. QUINOLINE-METHANOL
 Mefloquine, is marketed as the R,S-isomer.
 Mefloquine's effectiveness in the treatment and prophylaxis o
malaria is due to the destruction of the asexual blood forms o
the malarial pathogens that affect humans, Plasmodium
falciparum, P. vivax, P. malariae, P. ovale.
 Used in chloroquine-resistant strains of P. falciparum and
other species.
 Has strong blood schizonticidal activity against P. falciparum
and P. vivax, it is not active against hepatic stages o
gametocytes.
Adverse effects
 Mefloquine is bitter in taste
 At high doses: Nausea, vomiting, diarrhea, abdominal pain
CONTRAINDICATIONS
• Hypersensitivity to mefloquine, related compounds (eg, qu

or any component of the formulation; prophylactic use in p
of seizures or severe psychiatric disorder (including active
depression, generalized anxiety disorder, psychosis, or schiz
Drug interactions
• Cardiac arrests are possible if mefloquine is taken concurr

quinidine.
Uses
• Effective for multidrug resistant p. Falciparum
• However its use is restricted due to its toxicity, cost and lon
3. CINCHONA ALKALOIDS
4
3 R2
7
6
8 5
HO 9 2
N
5 4 H 1
R1 6
3
7 2
N
8 1
• Quinine is a l-isomer of alkaloid obtained from cinchona bark a

(antiarrhythmic) is its d-isomer.
• An effective erythrocytic schizontocide as suppressive and u
terminate attacks of vivax, ovale, malariae, sensitive falciparum
more toxic than chloroquine.
• Moderately effective against hepatic form (pre-exoerythrocyte and
1. M odification of the secondary alcohol at C -9,
through oxidation, esterification dim inishes
activity.
2.T he configuration at positions 8 and 9 affects
the juxtaposition of the hydroxyl group and Assym m etry a
the non-arom atic nitrogen atom , a relationship for antim alaria
that is associated with antim alarial activity.
SAR Of Quinine
H 5 3 Q uin
H 6 for a
HO 2 am in
9
8 N
5' 1
R1
4' 3'
6'
7' 2'
8'
N Activi
1' introd
positi
Q uinoline Ring
1. Presence of m ethoxy group in quinine is not
essential.
2. R eplacem ent of m ethoxy group by a halogen,
especially chlorine, enhances activity.
3. A further increase in activity resulted from
the introduction of a phenyl group at position 2'.
4. It was discovered that high activity without
phototoxicity could be attained by blocking
position 2' with a trifluorom ethyl group, a finding
that eventually led to developm ent of m efloquine.
4. BIGUANIDES
 It is an early example of a prodrug.
 It is a slow-acting erythrocytic schizontocide which also
inhibits the preerythrocytic stage of P. falciparum.
Gametocytes exposed to proguanil are not killed but fail to
develop properly in the mosquito.
 It is cyclized in the body to a triazine derivative
(cycloguanil) which inhibits plasmodial DHFRase in
preference to the mammalian enzyme.
 Resistance to proguanil develops rapidly due to mutational
changes in the plasmodial DHFRase enzyme.
Conversion of proguanil to cycloguanil by CYP2C19
Adverse effects
• Mild abdominal upset, vomiting
• Occasional stomatitis
• Haematuria, rashes and transient loss of hair
• Note : safe during pregnancy

Mechanism of action of anti folates
5. DIAMINOPYRIMIDIN
MeO H2 N C2 H5
N
MeO C NH2 Cl
H2
N
MeO H2 N
Trimethoprim Pyrimetham
 Slow acting erythrocytic schizontocide

 Direct inhibitor of plasmodial dihydrofolate reductase (DHFRas
 Conversion of dihydrofolic acid to tetrafolic acid is inhibited
 High doses inhibits Toxoplasma gondi
 Resistance develops by mutation in DHFRase enzyme
 Diaminopyrimidine more potent than proguanil & effective
forms of all species.
Pyrimethamine
Adverse effects
• Occasional nausea and rashes
• Folate deficiency rare
• Megaloblastic anaemia and granulocytopenia with higher do
• Can be treated with folinic acid
• Combined with a sulfonamide (S/P) or dapsone for treatmen

malaria
SULFADOXINE - PYRIMETHAM
• Sequential blockade
• Sulfadoxine 500 mg + pyrimethamine 25 mg, 3

tablets once for acute attack
• Not recommended for prophylaxis
• Effective blood schizontocide against plasmodium

falciparum
• Treatment and prophylaxis of falciparum malaria

resistant to chloroquine
Adverse effects
• Mild GIT upset
• Megaloblastic anemia, bone marrow depletion
• Rashes, urticaria, serum sickness, drug fever
• Exfoliative dermatitis, stevens johnson syndrome
• Nephrotoxicity
Uses:
• Single dose treatment of uncomplicated chloroquine resistant falci
• Patients intolerant to chloroquine
• First choice treatment for toxoplasmosis

6. 8-AMINOQUINOLINE
MeO MeO
MeO
N N
NH NH HN
H3C CHCH2CH 2CH 2NH 2 H3C CHCH2CH2CH2N(C2H5)2
Pent
Primaquine Pamaquine
MeO
N
HN CH3
NH2
Quinocide
Primaquine:
• It is the only 8-aminoquinoline in clinical use.
• It is largely used to prevent relapse of p. Ovale and P. Vivax m

dormant hypnozoites, and it also has activity against the pr
and gametocytes of P. Falciparum.
• It is not used for prophylaxis. Its spectrum of activity is one of

currently used antimalarial drugs being indicated only for exoe
malaria
Mechanism of action primaquine:
• Not clear, its converted & produces active oxygen interfere with
mitochondrial function
Uses of primaquine
1. Radical cure
A) P.Vivax & ovale :
• Given in acute attack or throughout incubation period
• Prevents relapse
Prophylactically: before & after leaving the endemic area to eradic
• Effective vector control is possible or used in areas of low transm
B) falciparum malaria:
• 45mg with chloroquine used like gametocidal & cut down t

effective control is needed.
Adverse drug reaction
Therapeutic doses:
• Haemolysis & methaemoglobinaemia commonly seen in g6pd def
• Causes nausea, headache, epigastric pain &abdominal cramps on
• Rarely : leucopenia, leucocytosis & agranulocytosis
• Precaution – primaquine
• Should not be given during pregnancy because fetus is gluc

dehydrogenase ( g-6-pd) deficient
9. SESQUITERPINE LACTON
• The artemisinin series are the newest
PLANT- ARTE
of the antimalarial drugs and are
structurally unique when compared
with the compounds previously and
currently used.
• The parent compound, artemisinin, is
a natural product extracted from the
dry leaves of artemisia annua (sweet
wormwood).
• All of the compounds given in figure
are active against the plasmodium
genera that cause malaria.
• The key structure characteristic
appears to be a “trioxane” consisting
of the endoperoxide and dioxepin
oxygens.
• Note that the stereochemistry at

position 12 is not critical.
• These are the artimisinin derivatives

used in malaria:
1. Artesunate
2. Artemether
3. Arteether
4. Arterolane
MECHANISM OF ACTION
• These compounds contains endoperoxide bridge.
• Endoperoxide bridge interacts with heme in parasite.
• Heme iron cleaves this endoperoxide bridge.
• There is generation of highly reactive free radicals which

membrane by covalently binding to membrane proteins.
• They act rapidly, killing blood stages of all plasmodium specie
parasite biomass.
• Artemisinins have the fastest parasite clearance times of any a
• Artemisinins are active against gametocytes, the parasite form

mosquitoes, and their use has been associated with reduced m
• Safe & 10-100 times potent compared to other antimalarials.

ANTIMALARIAL ACTION
ARTEMISININ-BASED COMBINATION TH
• In general, artemisinins should not be used as a single
emergence of drug resistance and to avoid the need for prolon
• Artemisinin-based combination therapy (acts) combine the hi

acting artemisinins with a longer-acting partner to protect
resistance and to facilitate dosing convenience.
• Acts are typically administered for 3 days and are often ava
tablets.
• Four acts are recommended by the who for the treatmen

malaria: artemether-lumefantrine, artesunate-amodiaq
mefloquine and artesunate-sulfadoxine-pyrimethamine.
ARTEMISININS
• Intravenous artesunate is used for the treatment of severe ma
• It is superior to quinine for treatment of severe malaria with

parasitemia and reducing mortality.
• Given the short half-life of artemisinins, intravenous therap

by a longer acting agent once the patient is able to tolerate or
• If used alone (via the parenteral, rectal or oral route), a

administered for 5-7 days.
• Treatment for less than 5 days results in recurrent parasit

after therapy due to the very short duration of action, rather
resistance.
• Artemisinins are generally well tolerated.
• Type 1 hypersensitivity to the artemisinin compounds has been
• Adverse effects of orally-administered artemisinins dem

neurological abnormalities (nystagmus and disturbances in ba
resolved without lasting sequelae.
Advantages of act
• Rapid clinical and parasitological cure
• High cure rates(>95%) and low recrudescence rate
• Absence of parasite resistance
• Good tolerability profile
• Dosing schedule is simpler

1. ARTESUNATE - SULFADOXINE + PYRI
(AS-S/P)
• First line drug for uncomplicated falciparum malaria.
• Not effective against multidrug-resitant strains which are n

s/p.
• Fewe2r.siAderetefescutsntahtaena/sm/meqf.loquine (AS/MQ)
• Highly effective and well tolerated in uncomplicated falciparum
m a lar ia
3. Artemether - l u m e fantrine (AS/LF)
 Clinical efficacy: 95-99%
 Must be administered with fatty food or milk to allow absor
adequate blood level of AS/LF
 Quickly reduces parasite biomass, resolve symptoms, prevent recrud
gametocyte population
4. DIHYDROARTEMISININ (DHA)-PIPERAQUINE
• Used in dose ratio of 8:1 for multidrug resistant plasmodium falcip
• Good safety profile and even tolerated by children (>98% response

5. ARTESUNATE-AMODIAQUINE(AS/AQ)
• First line therapy of uncomplicated falciparum malaria

•To be taken twice daily for three day treatment
Other recently developed ACT are:
6. ARTEROLANE-PIPERAQUINE
• Acts rapidly at all stages of asexual schizogony of malaria
multidrug resistant P. Falciparum
7. ARTESUNATE-PYRONARIDINE
• Under clinical trial
10. NAPHTHYRIDINE
 Newer drug from Mepacrine developed in china.
 Mechanism similar to chloroquine.
 High effective erythrocytic schizonticide, effective against
chloroquine sensitive & resistant vivax & falciparum malaria.
 Slow onset & long duration of action, concentrated in RBC.
 Water soluble, t1/2 : 7days
 Orally & parenterally used , well tolerated
 At high dose used analgesic/anti pyretic
11. NAPHTHOQUINONE
 Hydroxy naphthoquinone antiparasitic drug active against all

Plasmodium species.
 Rapid acting erythrocytic schizontocide & inhibits pre-
erythrocytic stage of falciparum.
 Also active against pneumocystis jiroveci & Toxoplasma
gondii.
 Combined with proguanil Where its resistant, reduces relapse
& which is synergistic.
 Collapses mitochondrial membrane interferes with
cytochrome electron transport.
12. ANTIBIOTICS
Tetracycline & doxycycline
 Erythrocytic schizonts are inhibited by all malarial parasite.
 Tetracycline used in combination with quinine in treatme

resistant as well vivax malaria.
 Avoid in children & pregnant women.
 Doxycycline used in places where high resistance present.
 200mg doxycycline combined with artesuna

mefloquine/chloroquine/s-p resistant malaria.
 100mg/day of doxycycline used 2nd line prophylactic fo

chloroquine resistant p. Falciparum.
CLINDAMYCIN:
• Slow erythrocytic schizontocide, bacteriostatic
• With quinine used in treatment of resistant P.Falciparum
• Its used where tetracyclines can not be used in pregna

than 8 years old
INTRODUCTION TO PRODRUG
DESIGN
DR. SANJEEV KUMAR SAHU
Lovely Professional University, Phagwara, Punjab
©1
Prodrugs
Definition:
Pharmacologically inactive compounds which are converted
to active compounds in the body through biotranformation.
Uses:
• Improving membrane permeability
• Prolonging activity
• Masking toxicity and side effects
• Varying water solubility
• Drug targeting
• Improving chemical stability
• ‘Sleeping agents’
©1
History of Prodrugs
• The first compound fulfilling the classical criteria of a prodrug was
acetanilide, introduced into the medical practice by Cahn and Hepp in
1867 as an antipyretic agent. Acetanilide is hydroxylated to biologically
active acetaminophen.
• Another historical prodrug is Aspirin (acetylsalicylic acid), synthesized

in 1897 by Felix Hoffman (Bayer, Germany), and introduced into
medicine by Dreser in 1899.
• The prodrug concept was intentionally used for the first time by the
Parke-Davis company for modification of chloramphenicol structure
in order to improve the antibiotic’s bitter taste and poor solubility in
water. Two prodrug forms of chloramphenicol were synthesized:
chloramphenicol sodium succinate with a good water solubility, and
chloramphenicol palmitate used in the form of suspension in children.
©1
Classification of Prodrugs
©1
Carrier linked prodrug
Carrier linked prodrug consists of the attachment of a carrier group to the active
drug to alter its physicochemical properties.
The subsequent enzymatic or non-enzymatic mechanism releases the active drug

moiety.
Active Drug Drug
Chemical Prodrug Formation
Covalent Bond
Chemical/Enzymatic cleavage in
Inert Carrier vivo Inert carrier
©1
Bipartite prodrug
• It is composed of one carrier (group) attached to the drugs.
• Such prodrugs have greatly modified lipophilicity due to the attached carrier. The
active drug is released by hydrolytic cleavage either chemically or enzymatically.
• E.g. Tolmetin-glycine prodrug.
Glycine Tolmetin
12
©1
Tripartite prodrug
The carrier group is attached via linker/spacer to drug.
©1
Mutual Prodrugs
• A mutual prodrug consists of two pharmacologically active agents coupled
together so that each acts as a promoiety for the other agent and vice versa.
• A mutual prodrug is a bipartite or tripartite prodrug in which the carrier is a

synergistic drug with the drug to which it is linked.
• Benorylate is a mutual prodrug aspirin and paracetamol.
• Sultamicillin, which on hydrolysis by an esterase produces ampicillin &

sulbactum.
©1
Paracetamol Aspirin Ampicillin
Sulbactum
Benorylate Sultamicillin
©1
Bioprecursors
• The bioprecursor does not contain a temporary linkage between the active drug and
carrier moiety, but designed from a molecular modification of an active principle
itself.
• Eg: phenylbutazone. Phenylbutazone gets metabolized to oxyphenbutazone that is
responsible for the anti inflammatory activity of the parent drug
• Polymeric Prodrugs
• Also known as macromolecular prodrug, the drug is dispersed or incorporated into the
polymer (both naturally occurring and synthetically prepared) system without
formation of covalent bond between drug and polymer.
• Eg: p–phenylene diamine mustard is covalently attached to polyamino
polymer backbone polyglutamic acid.
©1
Novel Classification
 Type I Prodrugs
 Type II Prodrugs
• Type I prodrugs are bioactivated inside the cells (intracellularly). Examples of these
are anti-viral nucleoside analogs that must be phosphorylated and the lipid-lowering
statins.
• Type II prodrugs are bioactivated outside cells (extracellularly), especially in

digestive fluids or in the body's circulation system,
©1
Tissue location of
Type Bioactivation site Subtype Examples
bioactivation
Aciclovir, fluorouracil, cyclophosphamide

Therapeutic target , diethylstilbestrol diphosphate, L-
Type IA
tissues/cells DOPA,mercaptopurine, mitomycin, zidov
udine
Type I Intracellular
Carbamazepine, captopril, carisoprodol,
Metabolic tissues (liver, GI heroin, molsidomine, leflunomide, palipe
Type IB
mucosal cell, lung etc.) ridone,phenacetin, primidone, psilocybin
, sulindac, fursultiamine, codeine
Loperamide
Type IIA GI fluids
oxide, oxyphenisatin, sulfasalazine
Acetylsalicylate, bacampicillin, bambuter ol,

Systemic circulation and
Type II Extracellular chloramphenicol
Type IIB other extracellular fluid
succinate, dipivefrin, fosphenytoin,lisdex
compartments
amfetamine, pralidoxime
Therapeutic target
Type IIC ADEPTs, GDEPs, VDEPs
tissues/cells
©1
1 Prodrugs to improve membrane permeability
1.1 Esters
• Used to mask polar and ionisable carboxylic acids
• Hydrolysed in blood by esterases
• Used when a carboxylic acid is required for target binding
• Leaving group (alcohol) should ideally be non toxic
Example:
Enalapril for enalaprilate (antihypertensive)
CH3
RO N
N
H
O O CO2H
R=Et Enalapril
R=H Enalaprilit
©1
Example:
Candoxatril for Candoxatrilat (protease inhibitor)
OMe
OMe
O
O
H
H O N
HO N
O O
O O CO2H
CO2H Candoxatril
Candoxatrilat 5-indanyl group
• Varying the ester varies the rate of hydrolysis

• Electron withdrawing groups increase rate of hydrolysis
(e.g. 5-indanyl)
• Leaving group (5-indanol) is non toxic
©1
1.2 N-Methylation of amines
• Used to reduce polarity of amines

• Demethylated in liver
Example: O
Hexobarbitone Me
N NH
O O
Me
©1
1.3 Trojan Horse Strategy
• Prodrug designed to mimic biosynthetic building block
• Transported across cell membranes by carrier proteins
Example: Levodopa for dopamine

HO CH2 HO CH2 CO2H
CH2 C
H
NH2 NH2
HO HO
Dopamine Levodopa
• Useful in treating Parkinson’s Disease • More polar but is an amino acid
• Too polar to cross cell membranes • Carried across cell membranes
and BBB by carrier proteins for amino
acids
• Decarboxylated in cell to
dopamine
©1
Blood Brain
supply cells
H2N COOH
H2N COOH
L-Dopa Enzyme
H2N
Dopamine
BLOOD BRAIN
BARRIER
©1
2 Prodrugs to prolong activity
2.1 Mask polar groups
• Reduces rate of excretion
Example:
Azathioprine for 6-mercaptopurine
O2N
N
SH
N S N
N
N Me
N
N N
H
N N
H
6-Mercaptopurine Azathioprine
(suppresses immune response) • Slow conversion to 6-mercaptopurine
• Short lifetime - eliminated too quickly • Longer lifetime
©1
Example:
Valium for nordazepam
Me H
O O
N N
Cl N N-Demethylation Cl N
Valium Nordazepam
©1
2.2 Add hydrophobic groups
• Drug concentrated in fat tissue
• Slow removal of hydrophobic group
• Slow release into blood supply
Example:
Cycloguanil pamoate (antimalarial) CO2
Cl
NH3
OH
N N CH2
Me
OH
H3N N Me
CO2
Cycloguanil Pamoate
Lipophilic
©1
Example:
Hydrophobic esters of fluphenazine (antipsychotic)
fatty ester
N
N O (CH2)8CH3
H
N CF3
• Given by intramuscular injection

• Concentrated in fatty tissue
• Slowly released into the blood supply
• Rapidly hydrolysed in the blood supply ©1
3 Prodrugs to mask toxicity and side effects
• Mask groups responsible for toxicity/side effects
• Used when groups are important for activity
Example:
Aspirin for salicylic acid
O
OH
CO2H H3C O
CO2H
Salicylic acid Aspirin

• Analgesic, but causes stomach • Phenol masked by ester
ulcers due to phenol group • Hydrolysed in body
©1
Example:
Cyclophosphoramide for phosphoramide mustard
(anticancer agent)
NH
Phosphoramidase H2N O
O Cl Cl
(liver)
P P
HO N
O N
Cl Cl
Cyclophosphoramide Phosphoramide mustard

• Non toxic • Alkylating agent
• Orally active
©1
Example:
Antiviral drugs
N N
N N N
N
HO Viral PO
N N N NH2 P P PO
N NH2 thymidine N N NH2
kinase
Cell kinases
Penciclovir
OH OH
OH
©1
Example:
LDZ for diazepam
Ar O
CH3 O
H a) Aminopeptidase N
N NH2 Ar
N b) Cyclisation O
H
O N
Cl CH3
LDZ Cl
NH2
LDZ Diazepam
• Avoids drowsy side effects of diazepam
©1
Ar O H
CH3 O H
H N
N NH2 Ar O Ar
N CH3 NH2 O
H Enz -H HO
O N N
Cl -lysine CH3
O
LDZ Cl Cl
NH2
H H
N N N
H2O Ar Ar
O O O
+H Ar -H
N N N
CH3 CH3 CH3
Cl Cl Cl
Diazepam
©1
4 Prodrugs to lower water solubility
• Used to reduce solubility of foul tasting orally active drugs
• Less soluble on tongue
• Less revolting taste
Example:
Palmitate ester of chloramphenicol (antibiotic)
Palmitate ester OH Cl
H H
N
Cl
O O Cl O
OH
H H Esterase H
N
Cl
O2N
O
H
OH Chloramphenicol
O2N
©1
5 Prodrugs to increase water solubility
• Often used for i.v. drugs
• Allows higher concentration and smaller dose volume
• May decrease pain at site of injection
Example:
Succinate ester of chloramphenicol (antibiotic)
HO O
Succinate ester OH Cl
H H
N
Cl
O O Cl
H H O
N OH
Cl Esterase H
O O2N
OH
H Chloramphenicol
O2N
©1
Example:
Phosphate ester of clindamycin (antibacterial)
CH3CH2CH2 Me H
N
Cl H
H
C C CH3
H O N C
H
HO O H
OH H
H SCH3
H OPO32-
• Less painful on injection
©1
Example:
Lysine ester of oestrone
O O
Me Me
H H H H H H
NH2 NH2
H + H
H2N H2N
O O O OH HO
Prodrug Lysine Oestrone
• Lysine ester of oestrone is better absorbed orally than oestrone

• Increased water solubility prevents formation of fat globules in gut
• Better interaction with the gut wall
• Hydrolysis in blood releases oestrone and a non toxic amino acid
©1
6. Prodrugs used to target drugs
Example:
Hexamine
N
N
N
N
• Stable and inactive at pH>5

• Stable at blood pH
• Used for urinary infections where pH<5
• Degrades at pH<5 to form formaldehyde (antibacterial agent)
©1
7. Prodrugs to increase chemical stability
Example:
Hetacillin for ampicillin
Ph O Ph O
Ampicillin
HN N CH3 H2N HN
S S CH3
'Locked' CH3 CH3
Nitrogen H3C CH3
N O N
O O
OH OH
O H 3C CH3
Hetacillin O
• Ampicillin is chemically unstable in solution due to the a-

NH2 group attacking the b-lactase ring
• ‘N’ in heteracillin is locked up within a heterocyclic ring
©1
8. Prodrugs activated by external influences: sleeping agents
Example: Photodynamic therapy - Foscan

HO
OH
NH N
Porphyrins or
chlorins are
H N HN photosensitizing
HO
H agents used in
H
H cancer therapy
OH
• Inactive and accumulates in cells
• Activated by light - method of targeting tumour cells
• Foscan is excited and reacts with oxygen to produce toxic singlet
oxygen
• Cell destruction is caused by singlet oxygen 1 ©
ANTIMALARIAL AGENTS
PREPARED BY:
Assistant Professor
Lovely Professional University Phagwara Punjab
INTRODUCTION
• Malaria, one of the most widespread diseases, is caused by a plasmodium
parasite and is transmitted to humans by the female anopheles mosquito.
Plasmodium belongs to the class of protozoa known as sporozoa.
• Mainly four species of plasmodium typically cause human malaria are

plasmodium falciparum, p. Vivax, P. Malariae and P. Ovale .
• A 5th species, P. Knowlesi, is primarily a pathogen of monkeys, but has recently
been recognized to cause illness, including severe disease, in humans in asia.
• Although all species may cause significant illness, p. Falciparum is responsible

for the majority of serious complications and death.
LIFE CYCLE OF THE MALARIALPARASITE
• An anopheles mosquito inoculates plasmodium sporozoites to initiate human
infection. Circulating sporozoites rapidly invade liver cells, and exoerythrocytic
stage tissue schizonts mature in the liver. Merozoites are subsequently released
from the liver and invade erythrocytes.
• Only erythrocytic parasites cause clinical illness. Sexual stage gametocytes also
develop in erythrocytes before being taken up by mosquitoes, where they develop
into infective sporozoites.
THERAPEUTIC CLASSIFICATION
1. Causal prophylaxis: (primary tissue schizonticides)
• Drugs prevent the maturation of or destroy the sporozoites within the infected
hepatic cell- thus prevent erythrocytic invasion
• Primaquine, proguanil
• Primaquine – for all species of malaria but not used due to its toxic potential
• Proguanil- primarily for P. Falciparum and not effective against P. Vivax (weak
activity), rapid development of resistance
2. Supressives prophylaxis:
• Supress the erythrocytic phase and thus attack of malarial fever can be used as
prophylactics
• Chloroquine, proguanil, mefloquine, doxycycline

3. Clinical cure: Erythrocytic Schizonticides
• Erythrocytic schizontocides are used to terminate episodes of malarial fever
• Fast acting high efficacy drugs:
• Chloroquine, quinine, mefloquine, halofantrine, artemicinin
• Used singly to treat malaria fever

• Faster acting, preferably used in falciparum malaria where delayed treatment
may lead to death even if parasites are clear from blood
• Slow acting low efficacy drugs:
• Proguanil, pyrimethamine, sulfonamides, tetracyclines
• Used only in combination

4. Radical curatives:
• Drug attack exoerythrocytic stage (hypnozoites) given with clinical curative for
the total eradication of the parasite from the patient’s body
• Radical cure of the P. Falciparum malaria can be achieved by suppressives only
• For radical cure of P. Vivax infection, primaquine and proguanil are effective
5. Gametocidal:
• Removal of male and female gametes of plasmodia formed in the patient’s

blood
• It has no benefit for treated patient

• Primaquine and artemisinins are h ighly effective against gametocytes o f all
species
CHEMICAL CLASSIFICATION
Classes Drugs
Cinchona alkaloid Quinine, Cinchonine,
Quinoline-methanol Mefloquine
4-aminoquinolines Chloroquine (CQ), amodiaquine (AQ),

Piperaquine
8-aminoquinoline Primaquine, tafenoquine
9-aminoacridines Quinacrine
Sulfonamides and Sulfadoxine, sulfamethopyrazine,

sulfone dapsone
Diaminopyrimidine Pyrimethamine
Biguanides Proguanil (chloroguanide)

Amino alcohols Halofantrine, lumefantrine
10.Sesquiterpine Artesunate, artemether, arteether
lactones
11. Naphthyridine Pyronaridine
12. Naphthoquinone Atovaquone

13. Antibiotics Tetracycline, Doxycycline,
Clindamycin
1. CINCHONA ALKALOIDS
4
3 R2
7
6
8 5
HO 9 2
N
5 4 H 1
R1 6
3
7 2
N
8 1
• Quinine is a l-isomer of alkaloid obtained from cinchona bark and quinidine

(antiarrhythmic) is its d-isomer.
• An effective erythrocytic schizontocide as suppressive and used to prevent or
terminate attacks of vivax, ovale, malariae, sensitive falciparum. less effective and
more toxic than chloroquine.
• Moderately effective against hepatic form (pre-exoerythrocyte and gametocytes).
1. M odification of the secondary alcohol at C -9,
through oxidation, esterification dim inishes
activity.
2.T he configuration at positions 8 and 9 affects
the juxtaposition of the hydroxyl group and Assym m etry at this positions is not essential
the non-arom atic nitrogen atom , a relationship for antim alarial activity
that is associated with antim alarial activity.
7
H 5 3 Q uinuclidine portion is not necessary
SAR Of Quinine HO
H
8
6
N
2
for activity; however, an alkyl tertiary
am ine attached at C -9 is im portant
9
5' 1
R1
4' 3'
6'
7' 2'
8'
N Activity usually enhanced by the
1' introduction of a halogen at this
position.
Q uinoline Ring
1. Presence of m ethoxy group in quinine is not
essential.
2. R eplacem ent of m ethoxy group by a halogen,
especially chlorine, enhances activity.
3. A further increase in activity resulted from
the introduction of a phenyl group at position 2'.
4. It was discovered that high activity without
phototoxicity could be attained by blocking
position 2' with a trifluorom ethyl group, a finding
that eventually led to developm ent of mefloquine.
2. QUINOLINE-METHANOL
 Mefloquine, is marketed as the R,S-isomer.
 Mefloquine's effectiveness in the treatment and prophylaxis of
malaria is due to the destruction of the asexual blood forms of HN
the malarial pathogens that affect humans, Plasmodium HO
falciparum, P. vivax, P. malariae, P. ovale. H
 Used in chloroquine- resistant strains o f P. falciparum and

other species. N CF3
 Has strong blood schizonticidal activity against P. falciparum CF3

Mefloquine
and P. vivax, it is not active against hepatic stages or
gametocytes.
Adverse effects
 Mefloquine is bitter in taste
 At high doses: Nausea, vomiting, diarrhea, abdominal pain,
4-AMINOQUINOLINES
CH3 C2 H5
CH3 C2H5
N
N HN C2 H4 OH
HN C2H5
Cl N
Cl N
Hydroxychloroquine
Chloroquine
OH
C2H5
NH
HN C2H5
Cl N
Amodiaquine
MECHANISM OF ACTION
MECHANISM OF ACTION :
• RESISTANCE RESULTS FROM ENHANCED EFFLUX OF THE PARASITE VESICLE
EXPRESSION OF THE HUMAN MULTI DRUG RESISTANCE TRANSPORTER P-
GLYCOPROTEIN.
Adverse drug reactions
• Retinopathy:
• Constriction of arteries, edema, blue black pigmentation, constricted field of

vision.
• CNS:
•Insomnia, transient depression seizures, rarely neuromyopathy &

ototoxicity
• CVS:
• ST & T wave abnormalities, abrupt fall in bp & cardiac arrest in children

reported
THERAPEUTIC USES
1. HEPATIC AMOEBIASIS
2. GIARDIASIS
3. CLONORCHIS SINENSIS
4. RHEUMATOID ARTHRITIS
5. DISCOID LUPUS ERYTHEMATOSUS
6. CONTROL MANIFESTATION OF LEPRAREACTION
7. INFECTIOUS MONONUCLEOSIS
• Hydroxy chloroquine:
 Less toxic, properties &uses similar
• Amodiaquine:
 As effective as chloroquine
 Pharmacological actions similar
 Chloroquine resistant strains may be effective
 Adverse events: GIT, headache , photosensitivity, rarely agranulocytosis
 Not recommended for prophylaxis

• Contraindications:
1. Psoriasis or porphyria
2. Visual field abnormalities or myopathy
3. Ca and mg containing antacid interfere with absorption
4. Used with caution in liver disease or neurologic or hematologic disorders.

SAR of 4-aminoquinolines
Dialkylaminoalkyl side chain
1. 2-5 carbon atoms between the nitrogen atoms,particularly 4-diethylamino-
1-methylbutylamino side chain is optimal for activity as in chloroquine.
2. The tertiary amine is important.
3. Introduction of unsaturation in the side chain was not detrimental to activity.
4. Substitution of a hydroxy on one of the ethyl groups in tertiary amine
(hydroxy quinoline) generally reduces toxicity and increases the plasma
concentration. This is one of the metabolites of chloroquine.
5. Incorporation of an aromatic ring in the side chain e.g. in Amodiaquine,
gives a compound with reduced toxicity and toxicity.
Introduction of chloro
group at this position is Introduction of methyl
NHR group at this position
optimal for activity 5 4 reduces activity
R1
6
3
2
Cl 7 N
8 1
d-Isomer of chloroquine is somewhat less toxic than l-isomer

8-AMINOQUINOLINE
MeO MeO
MeO
N N
N
NH NH HN CH(CH3)2
H3C CHCH2CH 2CH 2NH 2 H3C CHCH2CH2CH2N(C2H5)2 N
H
Pentaquine
Primaquine Pamaquine
MeO
N
HN CH3
NH2
Quinocide
Pyrimethamine
Adverse effects
• Occasional nausea and rashes
• Folate deficiency rare
• Megaloblastic anaemia and granulocytopenia with higher dose
• Can be treated with folinic acid
• Combined with a sulfonamide (S/P) or dapsone for treatment o f falciparum

malaria
Primaquine:
• It is the only 8-aminoquinoline in clinical use.
• It is largely used to prevent relapse of p. Ovale and P. Vivax malaria by eliminating

dormant hypnozoites, and it also has activity against the pre-erythrocytic stage
and gametocytes of P. Falciparum.
• It is not used for prophylaxis. Its spectrum of activity is one of the narrowest of the
currently used antimalarial drugs being indicated only for exoerythrocytic P. Vivax
malaria
Mechanism of action primaquine:
• Not clear, its converted & produces active oxygen interfere with plasmodial
mitochondrial function
Uses of primaquine
1. Radical cure
A) P.Vivax & ovale :
• Given in acute attack or throughout incubation period
• Prevents relapse
Prophylactically: before & after leaving the endemic area to eradicate hepatic forms
• Effective vector control is possible or used in areas of low transmission
B) falciparum malaria:
• 45mg with chloroquine used like gametocidal & cut down transmission or where
effective control is needed.
Adverse drug reaction
Therapeutic doses:
• Haemolysis & methaemoglobinaemia commonly seen in g6pd deficiency
• Causes nausea, headache, epigastric pain &abdominal cramps on empty stomach
• Rarely : leucopenia, leucocytosis & agranulocytosis
• Precaution – primaquine
• Should not be given during pregnancy because fetus is glucose-6-phosphate

dehydrogenase ( g - 6 - p d ) deficient
BIGUANIDES H
H2N N NH2
HN N
 It is an early example of a prodrug. H
CH
 It is a slow- acting erythrocytic schizontocide which also
(CH3)2
inhibits the preerythrocytic stage of P. falciparum.
Proguanil
Gametocytes exposed to proguanil are not killed but fail to
develop properly in the mosquito.
 It is cyclized in the body to a triazine derivative
(cycloguanil) which inhibits plasmodial DHFRase in
preference to the mammalian enzyme.
 Resistance to proguanil develops rapidly due to mutational
changes in the plasmodial DHFRase enzyme.
Conversion of proguanil to cycloguanil by CYP2C19
Adverse effects
• Mild abdominal upset, vomiting
• Occasional stomatitis
• Haematuria, rashes and transient loss of hair
• Note : safe during pregnancy

Mechanism of action of anti folates
SULFONAMIDES AND SULFONE
O N
H2N S N N
H
O
MeO OMe
Sulfadoxine
Dapsone
DIAMINOPYRIMIDINE
MeO H2N C2 H5
N N
MeO C NH2 Cl NH2
H2
N N
MeO H2 N
Trimethoprim Pyrimethamine
 Slow acting erythrocytic schizontocide

 Direct inhibitor of plasmodial dihydrofolate reductase (DHFRase)
 Conversion of dihydrofolic acid to tetrafolic acid is inhibited
 High doses inhibits Toxoplasma gondi
 Resistance develops by mutation in DHFRase enzyme
 Diam inopyrimidine more potent th an proguanil & effective against erythrocytic
forms of all species.
SULFADOXINE - PYRIMETHAMINE
• Sequential blockade
• Sulfadoxine 500 mg + pyrimethamine 25 mg, 3

tablets once for acute attack
• Not recommended for prophylaxis
• Effective blood schizontocide against plasmodium

falciparum
• Treatment and prophylaxis o f falciparum malaria

resistant to chloroquine
Amino alcohols
• Structurally, halofantrine differs from all other antimalarial drugs. It is a good
example of drug design that incorporates bioisosteric principles as evidenced by
the trifluromethyl moiety.
• Halofantrine is a schizonticide and has no affect on the sporozoite, gametocyte,or

hepatic stages.
• It is active against strains resistant to chloroquine, pyrimethamine, quinine.
• Cross-resistance in falicparum infection occurred .
• Erratic bioavailability, lethal cardio toxicity & cross resistance to mefloquine limited
its use.
• Now a days used only when no other alternative available

ADR:-
• Abdominal pain, headache, transient increase in hepatic enzymes, cough,

pruritus, lengthening of qt interval. May cause hemolytic anemia &
convulsions. Reserved for infection caused by resistant organisms.
Contraindications: with mefloquine.
• Patients with cardiac conduction defects.
• In pregnancy → embriotoxic in animals

SESQUITERPINE LACTONES
• The artemisinin series are the newest
PLANT- ARTEMISIA ANNUA
of the antimalarial drugs and are
structurally unique when compared
with the compounds previously and
currently used.
• The parent compound, artemisinin, is
a natural product extracted from the
dry leaves of artemisia annua (sweet
wormwood).
• All of the compounds given in figure
are active against the plasmodium
genera that cause malaria.
• The key structure characteristic
appears to be a “trioxane” consisting
of the endoperoxide and dioxepin
oxygens.
• Note that the stereochemistry at

position 12 is not critical.
• These are the artimisinin derivatives

used in malaria:
1. Artesunate
2. Artemether
3. Arteether
4. Arterolane
MECHANISM OF ACTION
• These compounds contains endoperoxide bridge.
• Endoperoxide bridge interacts with heme in parasite.
• Heme iron cleaves this endoperoxide bridge.
• There is generation of highly reactive free radicals which damage parasite

membrane by covalently binding to membrane proteins.
• They act rapidly, killing blood stages of all plasmodium species and reducing the
parasite biomass.
• Artemisinins have the fastest parasite clearance times of any antimalarial.
• Artemisinins are active against gametocytes, the parasite form that is infectious to
mosquitoes, and their use has been associated with reduced malaria transmission.
• Safe & 1 0 -1 0 0 times potent compared to other antimalarials.

ANTIMALARIAL
ACTION
ARTEMISININ-BASED COMBINATION THERAPIES
• In general, artemisinins should not be used as a single agent, to prevent
emergence of drug resistance and to avoid the need for prolonged therapy.
• Artemisinin-based combination therapy (acts) combine the highly effective short-

acting artemisinins with a longer-acting partner to protect against artemisinin
resistance and to facilitate dosing convenience.
• Acts are typically administered for 3 days and are often available in fixed-dose
tablets.
• Four acts are recommended by the who for the treatment of uncomplicated
malaria: artemether-lumefantrine, artesunate-amodiaquine, artesunate-
mefloquine and artesunate-sulfadoxine-pyrimethamine.
ARTEMISININ
• S the treatment of severe malaria.
Intravenous artesunate is used for
• It is superior to quinine for treatment of severe malaria with respect to clearing

parasitemia and reducing mortality.
• Given the short half-life of artemisinins, intravenous therapy must be followed

by a longer acting agent once the patient is able to tolerate oral medication.
• If used alone (via the parenteral, rectal or oral route), artesunate must be
administered for 5 - 7 days.
• Treatment for less than 5 days results in recurrent parasitemia several weeks
after therapy due to the very short duration of action, rather than to artemisinin
resistance.
• Artemisinins are generally well tolerated.
• Type 1 hypersensitivity to the artemisinin compounds has been reported.
• Adverse effects of orally-administered artemisinins demonstrated transient

neurological abnormalities (nystagmus and disturbances in balance); these effects
resolved without lasting sequelae.
Advantages of act
• Rapid clinical and parasitological cure
• High cure rates(>95%) and low recrudescence rate
• Absence of parasite resistance
• Good tolerability profile
• Dosing schedule is simpler

1. ARTESUNATE - SULFADOXINE +
PYRIMETHAMINE (AS-S/P)
• First line drug for uncomplicated falciparum malaria.
• Not effective against multidrug- resitant strains which are non responsive to
s/p .
• Fewe2r.siAderetefescutsntahtaena/sm/meqf.loquine (AS/MQ)
• Highly effective and well tolerated in uncomplicated falciparum
m a lar ia
3. Artemether - l u m e fantrine(AS/LF)
 Clinical efficacy: 95-99%
 Must be adm inistered with fatty food or m ilk to allow absorption and ensure
adequate blood level of AS/LF
 Quickly reduces parasite biomass, resolve symptoms, prevent recrudescence, check
gametocyte population
4. DIHYDROARTEMISININ (DHA)-PIPERAQUINE
• Used in dose ratio of 8:1 for multidrug resistant plasmodium falciparum.
• Good safety profile and even tolerated by children (>98% response rate).
5. ARTESUNATE-AMODIAQUINE(AS/AQ)
•First line therapy of uncomplicated falciparum malaria

•To be taken twice daily for three day treatment
Other recently developed ACT are:
6. ARTEROLANE-PIPERAQUINE
• Acts rapidly at all stages of asexual schizogony of malarial parasite including
multidrug resistant P. Falciparum
7. ARTESUNATE-PYRONARIDINE
• Under clinical trial
10. NAPHTHYRIDINE
 Newer drug from Mepacrine developed in china.
 Mechanism similar to chloroquine.
 High effective erythrocytic schizonticide, effective against
chloroquine sensitive & resistant vivax & falciparum malaria.
 Slow onset & long duration of action, concentrated in RBC.

 Water soluble, t 1 / 2 : 7days
 Orally & parenterally used , well tolerated
 At high dose used analgesic/anti pyretic
11.
NAPHTHOQUINONE
 Hydroxy naphthoquinone antiparasitic drug active against all
Plasmodium species.
 Rapid acting erythrocytic schizontocide & inhibits pre-
erythrocytic stage of falciparum.
 Also active against pneumocystis jiroveci & Toxoplasma
gondii.
 Combined with proguanil Where its resistant, reduces relapse
& which is synergistic.
 Collapses mitochondrial membrane interferes with

cytochrome electron transport.
12.
Tetracycline & doxycycline ANTIBIOTI
CS
 Erythrocytic schizonts are inhibited by all malarial parasite.
 Tetracycline used in combination with quin ine in treatment o f chloroquine
resistant as well vivax malaria.
 Avoid in children & pregnant women.
 Doxycycline used in places where high resistance present.

 200mg doxycycline combined with artesunate to treat
mefloquine/chloroquine/s-p resistant malaria.
 100m g/day o f doxycycline used 2nd line prophylactic for short travels to
chloroquine resistant p. Falciparum.
CLINDAMYCIN:
• Slow erythrocytic schizontocide, bacteriostatic
• With quinine used in treatment of resistant P.Falciparum
• Its used where tetracyclines can not be used in pregnancy & children less
than 8 years old
Synthesis of Primaquine
See discussions, stats, and author profiles for this publication at: https://www.researchgate.net/publication/349607732
B Pharm VI Sem MEDICINAL CHEMISTRY – III (Theory) BP601T UNIT – I
Presentation · February 2021

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BP 601T: MEDICINAL CHEMISTRY – III UNIT-II: Antimalarials
Antimalarials: Etiology of malaria.

Quinolines: SAR, Quinine sulphate, Chloroquine*, Amodiaquine, Primaquine phosphate, Pamaquine*, Quinacrine
hydrochloride, Mefloquine.
Biguanides and dihydro triazines: Cycloguanil pamoate, Proguanil.
Miscellaneous: Pyrimethamine, Artesunete, Artemether, Atovoquone.
❖ Definition
- Antimalarials are antiparasitic chemotherapeutic drugs that are used to prevent and cure
malaria. Plasmodium falciparum, Plasmodium malariae, Plasmodium ovale, and Plasmodium
vivax are four Plasmodium species that cause malaria.
❖ On a blood stain, how to determine the form of malaria

- Malaria may be diagnosed in a variety of ways, but one of the quickest is to examine a patient's
blood smear under a microscope. This helps one to decide whether or not malaria is present, as
well as the form of malaria.
▪ Identifying Plasmodium falciparum on a blood smear

- The following are the key features of Plasmodium falciparum that can be identified by examining
a blood stain under a microscope:
o High-grade parasitemia
o Crescent-shaped gametocytes
Plasmodium falciparum can be characterized from a high proportion of infected red blood
cells and crescent-shaped gametocytes in a blood smear under a microscope.
▪ Identifying Plasmodium malariae on a blood smear
- Plasmodium malariae can be identified by its three unique characteristics:
o Senescent RBC infection
o Band-like trophozoites
o Rosette forms
Plasmodium malariae can be identified using a microscope by looking for infection in the smallest red
blood cells, band-like trophozoites, and rosette schizonts.
Dr. S. Mondal_Lecture Notes_ B. Pharm 6th Semester_GITAM (Deemed to be University) 1|Page
▪ Identifying Plasmodium ovale on a blood smear

- Let's take Plasmodium ovale as an example. When examining a blood stain, there are four major
characteristics to keep in mind:
o Reticulocyte infection
o Schuffner’s dots
o Oval shape
o Feathering
When finding Plasmodium ovale in a blood smear, look for infection in large red blood cells,
Schuffner's dots in the cytoplasm, oval-shaped cells, and feathering around the cell's edges.
▪ Identifying Plasmodium vivax on a blood smear

- There are three things to look for in blood smears with P. vivax infection:
o Reticulocyte infection
o Schuffner’s dots
o Absence of RBC shape changes
The blood smear will reveal low-grade parasitemia with contaminated reticulocytes only in
Plasmodium vivax infections. There will be Schuffner's dots, but the red blood cells will be oval and
without feathered edges.
❖ Etiology of Malaria
- Malaria can occur if a mosquito infected with the Plasmodium parasite bites you. There are four
kinds of malaria parasites that can infect humans: Plasmodium vivax, P. ovale, P. malariae, and
P. falciparum.
- P. falciparum causes a more severe form of the disease and those who contract this form of
malaria have a higher risk of death. An infected mother can also pass the disease to her baby at
birth. This is known as congenital malaria.
- Malaria is transmitted to humans by female mosquitoes of the genus Anopheles. Female
mosquitoes take blood meals for egg production, and these blood meals are the link between the
human and the mosquito hosts in the parasite life cycle.

- Whereas, Culicine mosquitoes such as Aedes spp. and Culex spp. are important vectors of
other human pathogens including viruses and filarial worms, but have never been observed to
transmit mammalian malarias.
- Malaria is transmitted by blood, so it can also be transmitted through: (i) an organ transplant;
(ii) a transfusion; (iii) use of shared needles or syringes.
▪ The Symptoms of Malaria
- The symptoms of malaria typically develop within 10 days to 4 weeks following the infection. In
some cases, symptoms may not develop for several months. Some malarial parasites can enter
the body but will be dormant for long periods of time.
- Common symptoms of malaria include:
o Shaking chills that can range from moderate to severe
o High fever
o Profuse sweating
o Headache
o Nausea
o Vomiting
o Abdominal pain
o Diarrhea
o Anemia
o Muscle pain
o Convulsions
o Coma
o Bloody stools
▪ Life-threatening complications of malaria
- Malaria can cause a number of life-threatening complications.
- The following may occur:
o Swelling of the blood vessels of the brain, or cerebral malaria
o An accumulation of fluid in the lungs that causes breathing problems, or pulmonary edema
o Organ failure of the kidneys, liver, or spleen
o Anemia due to the destruction of red blood cells
o Low blood sugar
▪ Transmission
- Transmission can also occur by way of blood transfusion, organ transplant, the sharing of
needles with contaminated blood, or by congenital means when a mother passes the infection to
her unborn baby. Furthermore, “Airport” Malaria can occur when infected mosquitos are
transported from a Malarious region to an area not affected by Malaria. Subsequently, civilians
of the non-endemic region can be infected by Malaria without having travelled to a foreign
country.
- Once the parasites are inside your body, they travel to the liver, where they mature. After
several days, the mature parasites enter the bloodstream and begin to infect red blood cells.
- Within 48 to 72 hours, the parasites inside the red blood cells multiply, causing the infected
cells to burst open.
- The parasites continue to infect red blood cells, resulting in symptoms that occur in cycles that
last two to three days at a time.

▪ Life Cycle of Plasmodium

- Two important phases of the parasite life cycle are the following:
1. Asexual cycle: occurs in the infected host.
2. Sexual cycle: occurs in the mosquito.
▪ Mosquito Transmission Cycle
- Uninfected mosquito: A mosquito becomes infected by feeding on a person who has malaria.
- Transmission of parasite: If this mosquito bites you in the future, it can transmit malaria
parasites to you.
- In the liver: Once the parasites enter your body, they travel to your liver — where some types can
lie dormant for as long as a year.
- Into the bloodstream: When the parasites mature, they leave the liver and infect your red blood
cells. This is when people typically develop malaria symptoms.
- On to the next person: If an uninfected mosquito bites you at this point in the cycle, it will
become infected with your malaria parasites and can spread them to the other people it bites.
Malaria spreads when a mosquito becomes infected with the disease after biting an infected person, and
the infected mosquito then bites a noninfected person. The malaria parasites enter that person's
bloodstream and travel to the liver. When the parasites mature, they leave the liver and infect red blood
cells.

❖ Classification of Antimalarial Drugs

▪ According to anti-malarial activity:
(i) Tissue schizonticides for causal prophylaxis: These drugs act on the primary tissue
forms of the plasmodia which after growth within the liver, initiate the erythrocytic stage.
By blocking this stage, further development of the infection can be theoretically prevented.
Pyrimethamine and Primaquine have this activity. However since it is impossible to predict
the infection before clinical symptoms begin, this mode of therapy is more theoretical than
practical.
(ii) Tissue schizonticides for preventing relapse: These drugs act on the hypnozoites of P.
vivax and P. ovale in the liver that cause relapse of symptoms on reactivation. Primaquine is
the prototype drug; pyrimethamine also has such activity.
(iii) Blood schizonticides: These drugs act on the blood forms of the parasite and thereby
terminate clinical attacks of malaria. These are the most important drugs in anti-malarial
chemotherapy. These include chloroquine, quinine, mefloquine, halofantrine,
pyrimethamine, sulfadoxine, sulfones, tetracyclines etc.
(iv) Gametocytocides: These drugs destroy the sexual forms of the parasite in the blood and
thereby prevent transmission of the infection to the mosquito. Chloroquine and quinine
have gametocytocidal activity against P. vivax and P. malariae, but not against P.
falciparum. Primaquine has gametocytocidal activity against all plasmodia, including P.
falciparum.
(v) Sporontocides: These drugs prevent the development of oocysts in the mosquito and thus
ablate the transmission. Primaquine and chloroguanide have this action.
▪ Currently available antimalarials fall into three broad categories
according to their chemical structure and mode of action:
(i) Aryl aminoalcohol compounds: Quinine, Quinidine, Chloroquine, Amodiaquine, Mefloquine,
Halofantrine, Lumefantrine, Piperaquine, Tafenoquine.
(ii) Antifolate compounds (“antifols”): Pyrimethamine, Proguanil, Chlorproguanil, Trimethoprim
(iii) Artemisinin compounds: Artemisinin, Dihydroartemisinin, Artemether, Artesunate.
▪ Chemical classification of antimalarials agents:
Sl. No. Derivatives Example
(-) Quinine; (+) Cinchonine; (-) Cinchonidine.
I. Cinchona alkaloids
Quinidine [(+) isomer (used as antiarrhythmic)]
Cholorquine; Amodiaquine; Hydroxychloroquine;
II. 7-Chloro-4-Amino Quinolines
Sontoquine; Amopyroquine
Primaquine; Pamaquine; Pentaquine phosphate;
III. 8-Amino Quinolines
Isopentaquine; Quinocide HCl.
Acridine derivatives
IV. Quinacrine; Acriquine
(9-amino acridine derivatives)
V Biguanids Proguanil; Chloro proguanil; Bromoguanil; Nitroguanil
VI Diamino pyrimidines Pyrimethamine; Trimethoprim
Sulphonamides and Sulphadoxine; Sulphadiazine; Sulphamethoxazole;
VII
Sulphones Sulphalene
Halofantrine; Mefloquine; Dapsone; Artemether,
VII Miscellaneous drugs
Artemotil; Artesunate
“Mosquitoes are like family: They are annoying, but they carry your blood.”

Drug Target
An antiparasitic drug used in the prevention and treatment of toxoplasmosis
Pyrimethamine
and malaria.
An antimalarial agent used in the prophylaxis and treatment of malaria
Mefloquine
caused by Plasmodium falciparum and Plasmodium vivax.
Quinine An alkaloid used to treat uncomplicated Plasmodium falciparum malaria.
Amodiaquine For treatment of acute malarial attacks in non-immune subjects.
Primaquine An antimalarial indicated to prevent relapse of vivax malaria.
A medication indicated for prophylaxis and treatment of Plasmodium
Proguanil
falciparum malaria.
Halofantrine An antimalarial used for the treatment of severe malaria.
An antimalarial medication used to treat uncomplicated cases of malaria and
Hydroxychloroquine for chemoprophylaxis in specific regions. Also, for treatment of rheumatoid
arthritis and lupus erythematosus.
An antimalarial agent used in combination with lumefantrine for the
Artemether
treatment of acute uncomplicated malaria caused by P. falciparum.
An antimalarial agent used in combination with artemether for the treatment
Lumefantrine
of acute uncomplicated malaria caused by P. falciparum.
Artesunate is an artemesinin derivative indicated for the initial treatment of
Artesunate
severe malaria.
For the treatment of uncomplicated Plasmodium falciparum infection in
Artenimol
adults, children, and infants aged 6 months.
Pyronaridine Pyronaridine has been investigated for the treatment of Malaria.
Artemotil, also known as β-arteether, is a semi-synthetic derivative of
Artemotil artemisinin and a fast-acting blood schizonticide specifically indicated for
the treatment of chloroquine-resistant P. falciparum and cerebral malaria.
Atovaquone For the prevention and treatment of Plasmodium falciparum malaria.
For the treatment of uncomplicated P. falciparum infection in adults,
Piperaquine
children, and infants aged 6 months.
A medication used to restore normal sinus rhythm, treat atrial fibrillation
Quinidine
and flutter, and treat ventricular arrhythmias.
For the treatment of giardiasis and cutaneous leishmaniasis and the
Quinacrine
management of malignant effusions.
Sulfadoxine A long-acting sulphonamide used for the treatment or prevention of malaria.
An antiparasitic agent used for the treatment and prevention of relapse of
Tafenoquine
Vivax malaria.
Chlorproguanil has been used in trials studying the treatment of malaria. It
Chlorproguanil
is a dichloro-derivative of chloroguanide.
Artemisinin has been used in trials studying the treatment of Schizophrenia,
Artemisinin
Malaria, Falciparum, and Plasmodium Falciparum.
A sulfone drug used to treat acne vulgaris, Hansen's disease, and dermatitis
Dapsone
herpetiformis.
An antimalarial drug used to treat susceptible infections with P. vivax, P.
Chloroquine malariae, P. ovale, and P. falciparum. It is also used for second line treatment
for rheumatoid arthritis.
Betulinic Acid has been used in trials studying the treatment of Dysplastic
Betulinic Acid
Nevus Syndrome.
Cycloguanil Cycloguanil is the active metabolite of proguanil.
Artefenomel Artefenomel has been investigated for the treatment of Malaria.

❖ Structure–Activity Relationship of Antimalarial Agents
- At C-4 position, the dialkylaminoalkyl side chain has 2-5 carbon atoms between the nitrogen
atoms, particularly the 4-diethylaminomethyl butyl amino side chain that is optimal for activity,
as in chloroquine and quinacrine.
- The substitution of a hydroxyl group on one of the ethyl groups on the tertiary amine (hydroxy
quinoline), reduces toxicity.
- Incorporation of an aromatic ring in the side chain (e.g., amodiaquine) gives a compound with
reduced toxicity and activity.
- The tertiary amine in the side chain is important.
- The introduction of an unsaturated bond in the side chain was not detrimental to activity.
- The 7-chloro group in the quinoline nucleus is optimal, the methyl group in position 3 reduces
activity, and an additional methyl group in position 8 abolishes activity.
- The D-isomer of chloroquine is less toxic than its L-isomer.


❖ What is Haemozoin?
- Haemozoin or hemozoin is formed by blood-feeding parasites as the end product of their
digestion. It is usually formed by the digestion of blood. Parasites, after digesting haemoglobin,
release large amounts of free-heme, and free-heme is toxic to cells.
- So, the parasites convert the free-heme into an insoluble, crystalline form called hemozoin.
Hence, haemozoin appears to have a crystalline structure when observed under a microscope.
- Haemozoin is important for the survival of parasites, hence present and emerging antibiotics
inhibit the formation of haemozoin, thereby killing the parasites.
Hemoglobin degradation by Plasmodium falciparum in RBC.
Chemical structure of heme, hematin, and hemozoin.

❖ Antimalarial Drugs
➢ Quinine and Quinidine
- Quinine is the chief alkaloid of cinchona bark (known as ‘Fever Bark’).

- Quinine and Quinidine are a pair of optical isomers marked as (–) and (+). The only difference
between the two isomers is their configuration on the C9 carbon atom.
- The dextrorotatory stereoisomer of Quinine is both internally more active and more cardiotoxic
than the opposite stereoisomer.
- Whereas Quinine is used for the treatment of malaria, Quinidine is an important class
Ia antiarrhythmic drug. But In the USA, quinidine is used to treat severe falciparum malaria.
- Most cases of falciparum infection in pregnancy will be treated with quinine.
- Mechanism of Action
o In Plasmodium falciparum quinine has been found to inhibit nucleic acid synthesis, protein
synthesis, and glycolysis; it also binds with hemazoin in parasitized erythrocytes.
o It also has gametocytocidal activity against P. vivax, P. malariae and P. ovale but not
P. falciparum.
o Quinine blocks cardiac K & Na channels similar to quinidine.
- Side Effects
o Cinchonism: tinnitus, headache, nausea, dizziness, visual disturbances.
o Increased risk for cardiac arrhythmias (Torsade de pointes) due to block of cardiac K
(causing prolonged QTc) & Na channels (conduction slowing).
o Antimuscarinic side effects (blurred vision)
- Dosage:
o Quinine: In uncomplicated malaria, the standard oral dose of quinine is 10mg/kg of salt 8
hourly for 7 days for both children and adults.
o Quinidine: should be given in a loading dose (10 mg/kg gluconate in 1 hour) followed by a
maintenance infusion of 0.02 mg/kg/minute during the acute phase of severe infection.
Conversion to oral quinidine can take place when it is tolerated.
Dr. S. Mondal_Lecture Notes_ B. Pharm 6th Semester_GITAM (Deemed to be University) 10 | P a g e

➢ Chloroquine
- Chloroquine is the prototype anti-malarial drug, most widely used to treat all types of malarial
infections. It is also the cheapest, time tested and safe anti-malarial agent.
- It is highly effective against erythrocytic forms of P. vivax, P. ovale and P. malariae, sensitive
strains of P. falciparum and gametocytes of P. vivax.
- Antidiarrheal agents (kaolin) & calcium- and magnesium-containing antacids interfere with
chloroquin absorption.
- Mechanism of action:
o The mechanism of action of chloroquine is unclear. Being alkaline, the drug reaches high
concentration within the food vacuoles of the parasite and raises its pH.
o It is found to induce rapid clumping of the pigment. Chloroquine inhibits the parasitic
enzyme heme polymerase that converts the toxic heme into non-toxic hemazoin, thereby
resulting in the accumulation of toxic heme within the parasite.
o It may also interfere with the biosynthesis of nucleic acids. Other mechanisms suggested
including formation of drug-heme complex, intercalation of the drug with the parasitic DNA
etc.
- Adverse effects:
o Chloroquine is a relatively safer anti-malarial. At therapeutic doses, it can cause dizziness,
headache, diplopia, disturbed visual accommodation, dysphagia, nausea, malaise, and
pruritus of palms, soles and scalp.
o It can also cause visual hallucinations, confusion, and occasionally frank psychosis. These
side effects do not warrant stoppage of treatment.
o Intramuscular injections of chloroquine can cause hypotension and cardiac arrest, particularly
in children.
o Long term use of high doses (typically for treating rheumatologic diseases) can cause:
✓ Irreversible ototoxicity
✓ Retinal damage
✓ Myopathy
✓ Peripheral neuropathy.

- Synthesis of Chloroquine
o Step I: Synthesis of 4,7-dichloro quinoline.
o Step-II: Preparation of 1-diethyl amino-4-amino pentane

o Step III: Condensation of the products of Step I and Step II
- Dose:
o Oral: 10mg/kg stat., then three doses of 5 mg/kg, over 36-48 hours.
o Intra-venous infusion: 10 mg / kg (max.600mg) in isotonic fluid, over 8 hours; followed by
15 mg / kg (max.900mg) over 24 hours.
o Intra-muscular or sub-cutaneous injections: 3.5 mg of base/ kg (max.200 mg) every 6
hours or 2.5 mg of base/ kg (max.150mg) every 4 hours. (Intramuscular injection can cause
fatal hypotension, especially in children).

➢ Amodiaquine
- Amodiaquine is a 4-aminoquinoline similar to chloroquine in structure and activity, has been
used as both an antimalarial and an anti-inflammatory agent.
- Amodiaquine has also been found to work against chloroquine-resistant P. falciparum strains of
malaria.
- It is also used in combination with sulfadoxine/pyrimethamine and artensunate.
- Amodiaquine is readily absorbed from the gastrointestinal tract and rapidly converted by the
cytochrome P450 (CYP) enzyme CYP2C8 into Desethylamodiaquine (DEAQ), which contributes
nearly all the antimalarial effect. While amodiaquine is eliminated rapidly, desethylamodiaquine
is eliminated more slowly, with a terminal half-life of 4–10 days.
- Mechanism of action:
o Amodiaquine is converted to its active metabolite desethylamodiaquine and is thought to act
by accumulating inside the parasite food vacuole and interfering with haem detoxification.
- Therapeutic dosage
o For the treatment of acute malarial attacks in non-immune subjects: 600 mg of the base,
followed by 200 mg after 6 hours, then 400 mg daily on each of the subsequent two days.
- Adverse effects:
o Overdoses of Amodiaquine causes headache, drowsiness, visual disturbances, vomiting,
hypokalaemia, cardiovascular collapse, and cardiac and respiratory arrest.

➢ Mefloquine
[(R*,S*)-2,8-Bis(trifluoromethyl)quinolin-4-yl]-(2-piperidyl)methanol
- Mefloquine was born during the Vietnam war, because of research into newer anti malarials, to
protect the American soldiers from the multi drug resistant falciparum malaria.
- It is effective against the chloroquine resistant types.
- Mechanism of Action:
o Mefloquine may inhibit merozoite invasion and interact with proteins involved with parasite
membrane lipid trafficking and nutrient uptake.
o Mefloquine mediates killing of the malaria parasite by inhibition of parasite protein synthesis
through direct binding to the cytoplasmic ribosome (Pf80S) of P. falciparum.
- Absorption, fate and excretion:
o Mefloquine is available for oral administration only because parenteral preparations cause
severe local reactions.
o It is absorbed rapidly and is extensively bound to plasma proteins. Elimination half-life is
about 2-3 weeks. It is mainly excreted in the faeces.
- Adverse effects:
o Nausea, vomiting
o Dizziness
o Neuropsychiatric side effects (rare sometimes severe): anxiety/depression/psychosis/
seizures.
- Dose:
o It is available as 250 mg tablets and in combikits with artesunate.
o 15 mg/kg in a single dose. If the dose exceeds 1000 mg, the second dose can be given after
4-8 hours to minimise gastric irritation. Total dose should not exceed 1500 mg.

➢ Quinacrine
(RS)-N′-(6-Chloro-2-methoxy-acridin-9-yl)-N,N-diethylpentane-1,4-diamine
- Quinacrine, also called Mepacrine, which is acridine derivative formerly widely used as an
antimalarial
- Quinacrine is a derivative of quinine, synthesized from the bark of the cinchona tree.
- Quinacrine has been used as an antimalarial drug and as an antibiotic. It is used to treat
giardiasis, a protozoal infection of the intestinal tract, and certain types of lupus erythematosus,
an inflammatory disease that affects the joints, tendons, and other connective tissues and
organs.
- Mechanism of action
o The exact mechanism of antiparasitic action is unknown; however, quinacrine binds to
deoxyribonucleic acid (DNA) in-vitro by intercalation between adjacent base pairs, inhibiting
transcription and translation to ribonucleic acid (RNA).
o It also inhibits NF-κB and activates p53.
o In addition, by binding to nucleoproteins, quinacrine suppress the lupus erythematous
cell factor and acts as a strong inhibitor of cholinesterase.
o It is known to act as a histamine N-methyltransferase inhibitor.
✓ Lupus Erythematosus cell
▪ It is a neutrophil or macrophage that has phagocytized (engulfed) the denatured nuclear
material of another cell. The denatured material is an absorbed hematoxylin body.
▪ Systemic lupus erythematosus (lupus) is a disease that causes your body's immune
system to attack its own cells and tissues.
✓ NF-κB is a protein complex that controls transcription of DNA, cytokine production and
cell survival.
✓ Tumor protein P53, also known as p53, cellular tumor antigen p53, the Guardian of the
Genome, phosphoprotein p53, tumor suppressor p53, antigen NY-CO-13, or
transformation-related protein 53 (TRP53).
✓ Histamine N-methyltransferase is an enzyme involved in the metabolism of histamine.
- Adverse effects:
o Common side effects: Skin Discoloration, Dizziness, Decreased Appetite, Headache,
Nausea, Vomiting, Diarrhea, Stomach Cramps.
o Rare side effects: Mental Problems, Mood Changes, Nightmares, Inflammation of the Skin
due to an Allergy, Abnormal Peeling of Skin, Erythema or Skin Redness, Itching, Mental
Status Changes, Hallucinations, A Skin Rash, Irritability.
- Dose:
o Quinacrine is dispensed as 100 mg tablets. The recommended maintenance dose is 100 mg
orally daily, or on alternate days in fair-skinned patients due to possible skin discoloration.
o Quinacrine is often combined with hydroxychloroquine, when hydroxychloroquine alone is
ineffective (eg, hydroxychloroquine 200–400 mg daily with 50–100 mg quinacrine every
second day).

➢ Cycloguanil pamoate & Proguanil
Cycloguanil is a dihydrofolate reductase inhibitor and is a metabolite of the antimalarial drug.
- Proguanil and its triazine metabolite cycloguanil.

- Proguanil is a prodrug that is metabolized to its main active metabolite, cycloguanil, mostly via
Cytochrome P450 2C19 (CYP2C19).
- Proguanil is oxidized to two major metabolites, cycloguanil (active) and an inactive
4-chlorophenylbiguanide.
- Proguanil, also known as chlorguanide.
- In sensitive P. falciparum malaria, proguanil exerts activity against both the primary liver stages
and the asexual red cell stages, thus adequately controlling the acute attack and usually
eradicating the infection. Proguanil also is active against acute P. vivax malaria.
- Proguanil is slowly but adequately absorbed from the GI tract. After a single oral dose, peak
plasma concentrations of the drug usually are attained within 5 hours. The mean plasma
elimination t1/2 is ~12–20 hour.
o The proguanil selectively inhibits the bifunctional dihydrofolate reductase–thymidylate
synthetase of sensitive plasmodia.
o Inhibiting DNA synthesis and depleting folate cofactors.
- Adverse effects:
o In prophylactic doses (200–300 mg/day) causes few side effects except occasional nausea
and diarrhea.
o Large doses (1 g or more daily) may cause vomiting, abdominal pain, diarrhea, hematuria,
and transient appearance of epithelial cells and casts in the urine.

➢ Primaquine
- Primaquine is an antimalarial agent and is the essential co-drug with chloroquine in treating all
cases of malaria and to treat Pneumocystis pneumonia. Specifically, it is used for malaria due
to Plasmodium vivax and Plasmodium ovale.
o Primaquine kills the intrahepatic form of Plasmodium vivax and Plasmodium ovale, and
thereby prevents the development of the erythrocytic forms that are responsible for relapses
(it also kills gametocytes).
o Primaquine acts by interfering with a part of the parasite (mitochondria) that is responsible
for supplying it with energy. Without energy the parasite dies.
o Primaquine's may be acting by generating reactive oxygen species or by interfering with the
electron transport in the parasite. Also, although its mechanism of action is unclear,
primaquine may bind to and alter the properties of protozoal DNA.
- Dose:
o World Health Organization (WHO)-recommended primaquine regimen of 15 mg to 30 mg per
day for 14 days.
- Adverse effects:
o Common side effects of primaquine administration include nausea, vomiting, and stomach
cramps.
o In persons with cytochrome b5 reductase deficiency, primaquine causes methemoglobinemia.
o Overdosing can reduce the number of functions of various kinds of blood cells, including loss
of red blood cells, methemoglobinemia, and loss of white blood cells. Persons with glucose-6-
phosphate dehydrogenase deficiency (G6PD) may develop hemolytic anemia from primaquine.

➢ Pamaquine
- Pamaquine is an 8-aminoquinoline drug formerly used for the treatment of malaria.
- Pamaquine was first introduced for treatment of malaria in 1926 and has been replaced with
primaquine.
- Pamaquine also active against latent tissue forms of P. vivax and P. ovale and is active against
the hepatic stages of P. falciparum.
- The drug is not active against erythrocytic stages of the parasite but does possess gametocidal
activity against all strains of plasmodium.
- It is recommended to be combined with chloroquine to eradicate the erythrocytic stages of
malaria.
- Synthesis of Pamaquine
o Pamaquine act against erythrocytic parasites is believed to be similar to that of 4-
aminoquinolines, but an alternate mechanism involving interference with mitochondrial
function could be involved in its activity against liver stage parasites and gametocytes.
- Adverse effects:
o Common side effects of primaquine administration include nausea, vomiting, and stomach
cramps.
o Pamaquine causes haemolytic anemia.
- Dose:
o Pamaquine was given as a malaria prophylactic twice weekly (adult dose, 40 mg daily).
➢ Artesunate & Artemether (Artemisinin analogs)

- Artemisinin is derived from the leaves and flowers of the annual mugwort (Artemisia annua)
and has been used in traditional Chinese medicine for centuries. Artemisinin and its semi-
synthetic derivatives - collectively known as Artesunate and Artemether - are used to treat the
tropical infectious disease malaria specially in the treatment of uncomplicated Plasmodium
falciparum malaria.
o Artesunate and Artemether contain an unusual peroxide bridge that undergoes an iron-
catalyzed cleavage within the parasite food vacuole, producing free radicals that kill the
malarial parasite.
o They are rapidly acting blood schizonticides, with some activity against gametocytes, but no
activity against the hepatic stages of the malarial parasite.
- Pharmacokinetics:
o Artesunate is water soluble and is administered either orally (30% bioavailability) or
parenterally (IV or IM).
o Artemether is a lipid soluble analog.
o Artesunate and Artemether are prodrugs that are easily converted to dihydroartemisinin,
the active form (DHA).
o Half life 1-3 hrs (relatively short), making them unsuitable for prophylactic use.
- Side Effects: Generally, well tolerated but can produce nausea & vomiting.
- Dose:
o Artemether (oral formulation): The recommended dose schedule is 3.2 mg/kg on day 1,
followed by 1.6 mg/kg daily for up to 7 days. An oral dose of approximately 2 mg/kg daily,
for up to 7 days has also been suggested for the treatment of uncomplicated malaria.
o Artesunate - IV/IM formulation: Children weighing less than 20 kg should receive a higher
parenteral dose of artesunate (3 mg/kg/dose) than larger children and adults (2.4
mg/kg/dose).

➢ Pyrimethamine
- Pyrimethamine, a Diamino pyrimidines analog, is an antiparasitic agent used to prevent and
cure toxoplasmosis and malaria.
- Pyrimethamine also used as an adjunct in the treatment of uncomplicated, chloroquine
resistant.
- It is also used with dapsone as a second-line option to prevent Pneumocystis jiroveci
pneumonia in people with HIV/AIDS.
- It was previously used for malaria but is no longer recommended due to resistance.
o Pyrimethamine inhibits the dihydrofolate reductase of plasmodia and thereby blocks the
biosynthesis of purines and pyrimidines, which are essential for DNA synthesis and cell
multiplication.
o This leads to failure of nuclear division at the time of schizont formation in erythrocytes and
liver.
- Side Effects:
o Pyrimethamine can cause symptoms such as nausea, vomiting, glossitis, anorexia,
diarrhea. skin rashes, erythema multiforme, Stevens-Johnson syndrome and toxic
epidermal necrolysis.
- Doses Recommendations:
o Loading dose: 100 mg orally on the first day
o Maintenance dose: 25 to 50 mg orally per day
o Duration of therapy: 4 to 6 weeks
Stevens-Johnson syndrome (SJS) is a rare, serious disorder of the skin and mucous membranes.
It's usually a reaction to medication that starts with flu-like symptoms, followed by a painful rash
that spreads and blisters. Then the top layer of affected skin dies, sheds and begins to heal after
several days.
Toxic epidermal necrolysis (TEN) is a rare and serious skin condition. Often, it's caused by an
adverse reaction to medication like anticonvulsants or antibiotics. The main symptom is severe
skin peeling and blistering. The peeling progresses quickly, resulting in large raw areas that may
ooze or weep.
Glossitis refers to inflammation of the tongue.
Anorexia: An eating disorder characterized by markedly reduced appetite or total aversion to food.
Erythema multiforme is a skin immune reaction that an infection or medication can trigger. Its
name combines the Latin “erythema” (redness), “multi” (many), and “forme” (shapes) and describes
the main symptom, which is a rash on the body where each mark resembles a bullseye.

➢ Atovaquone
- Atovaquone is a hydroxynaphthoquinone, or ubiquinone derivative, of antibacterial and
antipneumocystis properties. It's used in antimalarial treatments.
- Atovaquone is a particularly lipophilic treatment that can help people who have had bone
marrow transplants.
o Inhibition of electron transport by atovaquone will result in indirect inhibition of these
enzymes.
o The ultimate metabolic effects of such blockade may include inhibition of nucleic acid and
ATP synthesis.
o Atovaquone also has been shown to have good in vitro activity against Toxoplasma gondii.
- Side Effects:
o Pyrimethamine can cause symptoms such as nausea, vomiting, glossitis, anorexia,
diarrhea. skin rashes, erythema multiforme, Stevens-Johnson syndrome and toxic
epidermal necrolysis.
- Doses Recommendations:
o Single oral doses of 225 mg to 750 mg was 70 to 84 hours.
o Treatment and prophylaxis of Pneumocystis carinii Pneumonitis

✓ The recommended dose is 1500mg daily, taken in two divided doses for 21 days for
treatment and as a single dose of 1500mg for prevention taken with food.
o Treatment and prophylaxis of Plasmodium falciparum Malaria

✓A fixed dose combination tablet, containing atovaquone 250mg and proguanil
hydrochloride 100mg, has been specifically developed. For the treatment of adults, four
tablets should be taken daily as a single dose at the same time each day for three
consecutive days.
Toxoplasma gondii is an obligate intracellular parasitic protozoan eukaryote (specifically an
apicomplexan) that causes the infectious disease toxoplasmosis.
“Mosquitoes bite you as if they are in some kind of love with you.”
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ANTIMYCOBACTERIAL
Definition
• An antimycobacterial is a
type of drug used to treat
mycobacteria infections.
• Types include:
1. Tuberculosis
treatments
2. Leprostatic agents
TB
• is a common, and in many cases
lethal, infectious disease caused
by various strains of
mycobacteria, usually
Mycobacterium tuberculosis.
• Tuberculosis usually attacks the
lungs but can also affect other
parts of the body.
TB
• It is spread through the air

when people who have an
active MTB infection
cough, sneeze, or otherwise
transmit their saliva through
the air.
Symptoms
chest pain, coughing up
blood, and a
productive, prolonged cough for
more than three weeks.
Systemic symptoms include
fever, chills, nigh
sweats, appetite loss, weight
loss, pallor, and fatigue.
First line
• All first-line anti-tuberculous drug
names have a standard three-letter
and a single-letter abbreviation:
– Ethambutol is EMB or E,
– isoniazid is INH or H,
– pyrazinamide is PZA or Z,
– rifampicin is RMP or R,
– Streptomycin
Never use a single drug
therapy
– Isoniazid –rifampicin combination
administered for 9 months will
cure 95-98% of cases .
– Addition of pyrazinamide for this
combination for the first 2
months allows total duration to
be reduced to 6 months.
isoniazid
MOA
–Bacteriostatic at low conc. &
bacteriocidal at high conc.
Especially against actively
growing bacteria.
– Inhibits synthesis of mycolic
acid is an essential
components of mycobacterial
cell wall.
–Readily absorbed from GIT.
MOA
–Diffuse into all body fluids and
tissues
–Penetrates caseous material
and macrophages so it is
effective against intra and
extracellular organisms.
–Metabolized in liver by
acetylation
–Excreted mainly in urine
Chemistry
1-Substitutionof
hydrazine portion of
INH with alkyl and ar-
alkyl substitution
resulted in a series of
active and inactive
derivatives.
2-Substitution on the
N2 position (R
1,R2=alkyl,R3=H)----
active compounds.
2-Substitution on the
N2 position (R
1,R2=alkyl,R3=H)----
active compounds.
3-Any Substitution at
N1-
hydrogen(R3=alkyl)--
----------destroy the
activity.
4-Any Substitution---
not superior than
INH.
Uses
– Mycobacterial infections (it is
recommended to be given with
pyridoxine to avoid neuropathy).
– Latent tuberculosis in patients
with positive tuberculin skin test
– Prophylaxis against active TB in
individuals who are in great risk as
very young or
immunocompromised individuals.
Side effects
– Peripheral neuritis
– Optic neuritis.
– Allergic reactions ( fever,skin
rash,systemic lupus
erythematosus )
– Hepatitis
– Gastric upset
– Haemolytic anaemia
– Enzyme inhibitor
– CNS toxicity.
Ethambutol
MOA
– Inhibits mycobacterial cell wall
synthesis by inhibiting arabinosyl
transferase .
– Bacteriostatic
– Active against intra&extracellular
bacilli .
– Well absorbed from gut.
– 20% excreted in feces and 50% in
urine in unchanged form.
– Crosses BBB in meningitis
Chemistry
– Ethylene diamine chain --↑this chain length --↓or

destroy.
– Replacement of either N--↓or destroy.
– Increasing the size of Nitrogen substituents--↓or
destroy.
– Moving the location of alcohol groups--↓or
destroy.
Uses
– Used only in mycobacterial

infections.
Side effects
– Retrobulbar (optic) neuritis
causing loss of visual acuity and
red-green colour blindness.
– It is relatively contraindicated in
children.
– GIT .upset .
– Hyperuricemia
Pyrazinamide or Z,
Rifampicin or R
Streptomycin
2nd line
• Indication of 2nd line treatment :
– Resistance to the drugs of 1st
line.
– Failure of clinical response
– Increase of risky effects.
– Patient is not tolerating the
drugs first line drugs.
– Ethionamide
– Aminosalicylic Acid (PAS)
– Capreomycin
– Cycloserine
– Rifabutin
Ethionamide
MOA
– As isoniazid blocks synthesis of mycolic
acid .
– Available only in oral form.
– Metabolized by the liver ,excreted by
kidney.
– It is poorly tolerated because of :
• intense gastric irritation
• neurologic symptoms
• hepatotoxicity
Uses
Used in TB & leprosy.

Cycloserine
Cycloserine is an analog of the amino
acid D-alanine. It interferes with an early
step in bacterial cell wall synthesis in the
cytoplasm by competitive inhibition of two
enzymes, L-alanine racemase, which forms
D-alanine from L-alanine, and D-
alanylalanine synthetase, which
incorporates D-alanine into the
pentapeptide necessary for peptidoglycan
formation and bacterial cell wall synthesis

P-amino salicylic acid
Capreomycin
Fluoroquinolones
CIPROFLOXACIN LEVOFLOXACIN
MOA
– Broad
spectrum,antibacterial,but
also active for
M.tuberculosis,
– binding to DNA gyrase-DNA
complex (gyrA and gyrB )

– inhibiting bacterial DNA
replication and
transcription, bactericidal.
Synthesis of Isoniazid
4-picoline
Synthesis of Prazinamide
Leprosy
• Leprosy or Hansen's disease (HD) is a
chronic disease caused by the bacteria
Mycobacterium leprae and
Mycobacterium lepromatosis.
• granulomatous disease of the
peripheral nerves and mucosa of the
upper respiratory tract; skin lesions
are the primary external sign.
Leprosy
• Secondary infections, in turn, can
result in tissue loss causing fingers
and toes to become shortened and
deformed, as cartilage is absorbed
into the body
• usually spread from person to
person in respiratory droplets
Drugs used in leprosy
• Dapsone
• Clofazimine
Dapsone
MOA
Inhibits folate synthesis.
– Well absorbed orally,widely
distributed .
– Half-life 1-2 days,tends to be
retained in skin,muscle,liver and
kidney.
– Excreted into bile and reabsorbed in
the intestine.
– Excreted in urine as acetylated.
– It is well tolerated.
Chemistry
– Relpcemnet of 1 benzene ring results in thiazosulfones—

less active than DDS
– Substitution on benzene ring results in acetosulphone--↓
activity, ↓g.i.t irritation(bz increase solubility)
– Substitution by methanesulfinate (CH2SO2)-gives
sulfoxone Na, which is water soluble, ↓g.i.t irritation(bz
increase solubility) –this drug is preferred who can’t
tolerate DDS-but given 3times of DDS bz of its hydrolysis.
Uses
– Tuberculoid leprosy.
– Lepromatous leprosy in
combination with rifampin &
clofazimine.
– To prevent & treat Pneumocystis
pneumonia in AIDS caused by
Pneumocystis jiroveci (
Pneumocystis carinii).
Side effects
– Haemolytic anaemia
– Methemoglobinemia
– Gastrointestinal intolerance
– Fever,pruritus,rashes.
– Erythema nodosum leprosum
Clofazimine
MOA
– It is a phenazine dye.
– Unknown mechanism of
action ,may be DNA
binding.
– Antiinflammatory effect.
– Absorption from the gut is
variable.
– Given orally , once daily.
Chemistry
– Basic nucleus –phenazine
– Halogen substitution at P-
position of two phenyls at
C-3, and C-10-enhance
activity but are not
essential for activity.
– Br > Cl > CH3 >C2H5OH > H
>F
Uses
– Multidrug resistance TB.
– Lepromatous leprosy
– Tuberculoid leprosy in :
• patients intolerant to
sulfones
– dapsone-resistant bacilli.
– Chronic skin ulcers caused by
M.ulcerans.
Side effects
– Skin discoloration ranging from
red-brown to black.
– Gastrointestinal intolerance.
– Red colour urine.
– Eosinophilic enteritis
Thank you
Antitubercular Agents
Dr. Rajendra Nath

Professor
• Tuberculosis is a chronic granulomatous
disease
• In developing countries it is a major
health problem
• ≈ 30% of world population is infected
with Myc. Tuberculosis infection
• In India > 2 million people develop active
disease every year & half million die.
Tuberculosis
Mycobacterium tuberculosis
It is an infection difficult to
treat ??
Typical growth characteristics
Peculiar cell wall structure

(waxy appearance ) due to mycolic acid.
Resistance to infection emerges quickly.

Antitubercular Drugs
Mycobacterium Infections
Common infection sites
• Lung (primary site) - Intestines
• Brain - Lymph nodes
• Bone
• Liver
• Kidney
• Aerobic bacillus
• Passed from infected:
– Humans
– Cows (bovine) and birds (avian)
• Much less common
Mycobacterium Infections
• Tubercle bacilli are conveyed by droplets
• Droplets are expelled by coughing or sneezing, then

gain entry into the body by inhalation
• Tubercle bacilli then spread to other body organs

via blood and lymphatic systems
• Tubercle bacilli may become dormant, or walled off

by calcified or fibrous tissue
Tuberculosis - Pathophysiology
• M. tuberculosis – gram-positive, acid-fast
bacillus
• Spread from person to person via airborne

droplets
– Coughing, sneezing, speaking – disperse organism
and can be inhaled
– Not highly infectious – requires close, frequent, and
prolonged exposure
– Cannot be spread by hands, books, glasses, dishes,
or other fomites
Tuberculosis – Clinical Manifestations
• Early stages – free of symptoms
– Many cases are found incidentally
• Systemic manifestations:
– Fatigue, malaise, anorexia, weight loss, low-grade fevers, night
sweats
– Weight loss – occurs late
– Characteristic cough – frequent & produces mucoid or
mucopurulent sputum
– Dull or tight chest pain
• Some cases: acute high fever, chills, general flulike
symptoms, pleuritic pain, productive cough
• HIV Pt with TB: Fever, cough, weight loss –
– Pneumocystic carinii pneumonia (PCP)
Tuberculosis – Diagnostic Studies
• Tuberculin Skin Testing -- + reaction 2-12 weeks after the initial
infection
– PPD – Purified protein derivative – used to detect delayed
hypersensitivity response
• Two-step testing – health care workers
• 5mm > induration – Immunosuppressed patients
• 10 mm> “at risk” populations & health care workers
• 15 mm> Low risk people
– Chest X-ray -- used in conjunction with skin testing
• Multinodular lymph node involvement with cavitation in the upper
lobes of the lungs
• Calcification – within several years after infection
– Bacteriologic Studies –
• Sputum, gastric washings –early morning specimens for acid-fast
bacillus -- three consecutive cultures on different days
• CSF or pus from an abscess
M. tuberculosis: peculiar features
• Rapid growers: In the wall of cavitary lesion,

extracellular.
• Slow growers: intracellular, within the
macrophages at inflamed sites.
• Spurters: intermittent growth spurts.
• Dormant: Do not grow for long time, become
active at times of low host resistance.
Bacilli continuously shift from one to other subpopulation.

Mycobacterial cell wall
Baron S (ed.) Medical Microbiology. 4th edition. Chapter 33

Chemotherapy in tuberculosis
• Goals of anti-tubercular chemotherapy
• Kill dividing bacilli: Patient is non-
contagious : transmission of TB is
interrupted.
• Kill persisting bacilli: To effect cure and
prevent relapse.
• Prevent emergence of resistance: so that
the bacilli remain susceptible to the drugs.
• Now there is emergence of multidrug
resistant ( MDR ) TB . More than 0.4
million cases globally .
History
• First successful drug for treating TB was
PAS (Para- aminosalicylic acid) developed
by Lehman in 1943.
• Dramatic success came when Waksman
& Schutz discovered Streptomycin which

has made remarkable progress.
• Followed by Thiacetazone by Domagk in
in 1946
• In 1952 Isoniazid came into being
• Pyrazinamide by Kushner & colleagues
in 1952 & later on Rifampicin in 1957
by S. Margalith has totally changed the
strategy in the chemotherapy.
• Ethambutol came in 1961 by Lederle -
laboratories
• Fluoroquinolones , newer macrolides &
congener of Rifampicin →Rifabutin are
recent addition in antimycobacterial drugs
First line drugs:
Ionized ( H)
Rifampicin (R)
Ethambutol (E)
Pyrazinamide ( Z)
Streptomycin ( S) now reserved drug in
first line
Second line drugs:
Thiacetazone
Para aminosalicylic acid (PAS)
Ethionamide ( Etm)
Kanamycin
Cycloserine
Amikacin
Capreomycin
Newer Second Line drugs:
Ciprofloxacin
Ofloxacin
Levofloxacin
Clarithromycin
Azithromycin
Rifabutin
Drugs used in Tuberculosis
1st line drugs 2nd line drugs

high efficacy, low toxicity Low efficacy, high toxicity or both
• Isoniazid (INH) • Ethionamide

• Rifampin • Para aminosalicylic acid
• Pyrazinamide • Cycloserine
• Ethambutol • Amikacin/ Capreomycin
• Fluoroquinolones
• Streptomycin
• Rifabutin
Isoniazid (Isonicotinic acid hydrazide,H):
Essential component of all anti TB regimen
(except intolerance to H or resistance)
-It is tuberculocidal , kills fast multiplying
organism & inhibit slow acting organism
-Acts both on intracellular ( present in
macrophages ) & extracellular bacilli
-It
It is the cheapest AT Agent
-Atypical mycobacteria are not inhibited by
INH.
Not active against any other micro-orgs.
Mechanism of Action :
Inhibit synthesis of mycolic acid ( unique
fatty acid component of mycobacterial cell
wall .)
-INH enters the bacilli by passive diffusion.
It
must be activated to become toxic to bacilli.
It became toxic by Kat G (multifunctional
Catalase - peroxidase , a bacterial enzyme )
which catalyzes the product from INH an
Isonicotinoyl radical that subsequently
inter-acts with mycobacterial NAD & NADP
to produce dozen of adducts , one of these
a nicotinoyl NAD isomer which ↓ the activity
of enoyl acyl carrier protein reductase
(Inh A) & β- ketoacyl carrier protein
synthase ( Kas A) , inhibition of these
enzymes↓ the synthesis of mycolic acid an
essential component of the mycobacterial
cell wall & causes cell death.
st
MOA of 1 line drugs
Isoniazid
Ethambutol
-
Mycolic Acid
-
Arabinogalactan
Peptidoglycan
Cell membrane
- Mitochondria
(ATP)
Rifampin
Pyrazinamide -
- Streptomycin
Cytoplasm
A N A erase
R ym
-
DN l
po
R
NA I Protein
mR B
O
S
O
M
e
(another adduct , a nicotinoyl –NADP isomer potentially mycobacterial

dihydrofolate reductase → interfere with nucleic acid synthesis .
These adducts also produce H2O2 , NO radical & other free radicals which
are toxic to bacilli )
- If INH is given alone , inherent resistant bacilli

proliferate selectively & after 2-3 months an
apparently resistant infection emerges .
(Mutation of the catalase –peroxidase gene in bacilli do
not generate the active metabolite of INH )
- Combination therapy with INH has good
resistance preventing action .
- There is no cross resistance .
Pharmacokinetics :
-Completely absorbed orally , penetrate all
body tissues, tubercular cavities , placenta
& meninges .
- Metabolized in liver by acetylation &
metabolites are excreted in urine .
- Rate of acetylation shows genetic
variation
( fast acetylators > 30% Indians - t½ -1 hr
Slow acetylators >60% Indians -t ½- 3 hrs)
(daily regimen is not affected but biweekly
regimens are less effective in fast
acetylators )
Dose – 4-6 mg/ kg for >50 kg – 300 mg daily
- 600 mg bi-wkly
ISONIAZID (INH):
Pharmacokinetics
INH
Acetylation
(Phase II) N-acetyl transferase
N-acetyl Isoniazid
Hydrolysis
(Phase I) Isonicotinic acid Acetyl hydrazine
Genetic polymorphism affects INH metabolism

Slow acetylators are at higher risk of developing
neuritis
ADRs -
Well tolerated drug
1.Peripheral neuritis & other neurological
manifestations- parasthesia , numbness,
mental disorientation & rarely convulsion
( due to interference with utilization of
pyridoxine & ↑ excretion in urine )
Due to this Pyridoxine given prophylactically
-10
10 mg/day which prevents neurotoxicities
(INH neurotoxicity treated with Pyridoxine-100
100 mg/ day )
2. Hepatitis – more common in older
patients & alcohlics ( reversible)
3. Rashes , fever , acne & arthralgia .
Rifampin ( Rifampicin , R ):
-Semisynthetic derivative of Rifamycin B
from Streptomyces mediterranei
-Bactericidal to M. Tuberculosis & others –
S. aureus Klebsiella
N. meningitidis Pseudomonas
H. influenzae Proteus
E. coli & Legionella
- Best action on slowly or intermittently
dividing bacilli on extracellular as well as
intracellular organisms
-Also act on many atypical mycobacteria
-Have good resistance preventing action
Mechanism:
Inhibit DNA dependant RNA Synthesis
(by ↓ bact RNA polymerase , selective because does not
↓ mammalian RNA polymerase )
- TB patient usually do not get primary
Rifampicin resistance – If occurs is due
to
mutation in the repo -B gene (β subunit of
RNA polymerase ).
- No cross resistance
PKT –
Well absorbed orally widely distributed in the
body , penetrate cavities , caseous mass,
placenta & meninges .
-Metabolized in liver
-Excreted mainly in bile & some in urine
-t½- 2-5 hrs
ADR’s
1. Hepatitis – mainly in pts having
preexisting liver disease & is dose
related- Jaundice req. stoppage of drug
2. Respiratory syndrome –breathlessness
shock & collapse .
3. Purpura , hemolysis , shock , renal failure
4. Cutaneous syndrome – flushing , pruritis
& rashes ( face & scalp ), redness &
watering of eyes.
5. Flue syndrome – Nausea , vomiting,
abdominal cramps
( Urine & secretions may become red – which are
harmless & Pt should be told about this effect)
D/I
Rifampicin is microsomal enzyme inducer
-↑ several CYP 450 isoezymes
-↑ its own metabolism as well as of others
e.g.-Oral contraceptive Digoxin
Warfarin Theophylline
Steroids Metoprolol
Sulphonyl urea Fluconazole & Ketoconazole
etc.
(contraceptive failure can occur if given
simultaneously in child bearing age women taking
oral contraceptive)
Other uses –1. Atypical myc. Inf. (M. kansasii,
marinum , avium & intracellulare )
2. Leprosy
3. Prophylaxis of meningococcal & H. infl.
meningitis
4. MRSA , Diphtheroids & legionella inf.
5. Along with Doxycycline –first line therapy
in Brucellosis
Dose-
Dose 10 mg ( 8-12 mg / kg), for > 50 kg = 600 mg OD
3. Pyrazinamide ( Z)
Chemically≡ INH
-Weak tuberculocidal more active in acidic
medium
-More lethal to intracellular bacilli & to those
at sites showing an inflammatory response
( Therefore effective in first two months of therapy where
inflammatory changes are present )
-Good sterilizing activity
-It’s use enabled total duration of therapy to
be shortened & risk of relapse to be
reduced.
Mechanism ≡ INH - ↓ fatty acid synthesis
but
by interacting with a different fatty acid
synthesis encoding gene .
PZA is thought to enter M. tub. by passive
diffusion and converted to pyrazinoic acid
(its active metabolite) by bact. pyrazinamidase
enz. .This metabolite inhibits mycobact.
fatty
acid synthase -I enz. and disrupts mycolic
acid synthesis needed for cell wall
synthesis
-Mutation in the gene (pcn A) that encodes
pyrazinamidase enzyme is responsible for drug resistance
PKT :
-Absorbed orally, widely distributed ,Good
penetration in CSF.
-Metabolized in liver & excreted in urine.
-t½ -6-10 hrs
ADRs :
-Hepatotoxic -dose related
-Arthralgia , hyperuricaemia, flushing ,
rashes , fever & anaemia
-Loss of diabetic control
Dose – 20-30 mg /kg daily , 1500 mg if > 50 kg
Ethambutol ( E) :
-Tuberculostatic , clinically active as
Streptomycin
-Fast multiplying bact.s are more sensitive
-Also act against atypical mycobacteria
-If added in triple regimen (RHZ) it is found
to hasten the rate of sputum conversion &
to prevent development of resist.
Mech. :
Not well understood . Found to ↓arabinosyl
transferase III involved in arabinogalactone
synthesis & also interfere with mycolic acid
incorporation in mycobacterial cell wall (this
is encoded by emb AB genes )
-Resistance develop slowly
- No cross resistance
PKT:
-3/4th of an oral dose of Ethm. is absorbed
-Distributed widely but penetrates in
meninges incompletely
-½ metabolized , excreted in urine
-caution is required in pts of renal disease
-Pts acceptability is good & S/Es are low
ADRs:
-Loss of visual acquity / color vision due to
optic neuritis ,which is most impt. dose &
duration dependent toxicity.
(children can not report this complaint easily therefore not
given below 6 yrs of age)
-Early recognition –reversible
Others- Nausea , rashes & fever
-Neurological changes
-Hyper uricaemia is due to interference
with urate excretion
Dose – 15-20 mg/kg , > 50kg -1000mg
Streptomycin (S):
-It was 1st clinically useful antibiotic drug
-It is protein synthesis inhibitor by
combining
with 30S ribosome
-It is tuberculocidal , but less effective than
INH / Rifampicin
-Acts on extracellular bacilli only ( poor
penetration in the cells )
-It penetrates tubercular cavities but does
not cross BBB
- Resistance when used alone (in average
popul.1 in 10 to the power 8 bacilli are resistant to
streptomycin –they multiply & cause relapse therefore
stopped at the earliest .)
- Atypical mycobact.s are ineffective
- Popularity ↓ due to need of IM inj. & lower
margin of safety ( because of ototox. & nephrotox.).
- Dose-
Dose 15 ( 12-18 ) mg/kg, >50 mg- 1000mg
Thiacetazone (TZN) :
-First AT drug tested but weak
-Discarded due to hepatotoxicity
-In India revived in 1960s for oral use along
with INH as a substitute to PAS
-Tuberculostatic , does not add to the
therapeutic effect of H,S, R, E
ADRs -
Hepatotoxic
Exfoliative dermatitis
Stevenson Johnson’s syndrome
Can cause bone marrow depression
Others- Nausea , anorexia , abd. discomfort
Loose motions
Mild anemia
Pruritis
Dose-
Dose 150 mg OD (2-5 mg/ kg ) ,used in combined tablet
with INH
The Basis for Multi-Drug Therapy
• Prevent emergence of resistance

The Basis for Multi-Drug Therapy
2 INH Antibacterial attack
Rifampin against all
Streptomycin subpopulations
of bacilli.
INH, Rifampin
Rapid Ethambutol, PZ
growers
Rifampin
Slow
growers No drug
is effective
Spurters
Mitchison, Tubercle 66: 219-226, 1985

Mechanism of Resistance
Relative activity of first line Drugs
• INH: potent bactericidal Combination is synergistic
• Rifampin: potent bactericidal
• Pyrazinamide: Weak bactericidal, active against
intracellular bacilli.
• Ethamutol: bacterisostatic, prevents resistance
development.
• Streptomycin: bactericidal, active against
extracellular rapid growers.
Never use a single drug for chemotherapy in

tuberculosis, a combination of two or more
drugs must be used.
PAS – Paraaminosalicylic acid:
-Related to sulfonamides chemically as well
as in mech. of action.
-Tuberculostatic , not add to therapeutic
value , only delay resistance
-Interfere with absorption of Rifampicin
S/E - Acceptability is poor due to frequent
anorexia , nausea & epigastric pain
Other use- Goitre
Liver dysfunction
& Blood dyscrasias
Dose-
Dose 10- 12 gm ( 200 mg/ kg) / day
Rarely used now

Ethionamide :
-Tuberculostatic , having moderate efficacy
-Acts both on extra as well as intracellular
bacterias
(Mycobacterial EthaA, an NADPH specific FAD- containing
mono- oxygenases converts Ethionamide to a sulfoxide, it ↓
mycobacterial growth by ↓ the activity of the inh A gene product,
the enoyl acyl reductase of fatty acid synthase II ,the same
enzyme which is ↓ by INH )
-Resistance develop readily & some cross
resistance to TZN
-Absorbed orally ,distributed all over including CSF
S/E-
S/E Anorexia
Nausea & vomiting,
Rashes
Hepatitis ,
Peripheral/ Optic neuritis
Dose-
Dose 1 gm / day, but more than 0.5 gm not tolerated.
- seldom used now , only used in resistance
cases .
Cycloserine (Cycs):
- Obtained from S. archidacces & is a chemical
analogue of D- alanine
-↓ Bacterial cell wall synthesis
-Tuberculostatic & ↓ other G -ve organisms
( E. coli , Chlamydia)
-Resistance develop slowly , no cross resist.
CNS toxicity is high , sleepiness , headache
tremor , psychosis & convulsions
-Rarely used (only in resistance cases)
Dose – 250 mg BD
Kanamycin , Amikacin & Capreomycin:
Used as reserved drug in severe cases not
responding to usual therapy
Newer drugs :
Ciprofloxacin
Ofloxacin
Levofloxacin
( all are used in TB & MAC )
Clarithromycin
Azithromycin
( used in MAC )
Rifabutin - > in MAC < in TB
Antitubercular Therapy
Treatment of Tuberculosis :
Remarkable change, conventional 1-1½yr
Tt – is replaced by more effective & less
toxic 6 month-8 month therapy
a) Rapidly growing with higher bacillary
load e.g. wall of the cavity region- highly
suscep. to INH & lesser extent to R,E,S
b) Slow growing – intracellular & at
inflamed sites – vulnerable to Z while H,
R,E are lesser active
c) Spurturs - with in caseous material
(where O2 tension is less ) the bacilli
grow intermittently.
R- is most active in this sub population
d) Dormant –bacilli remain totally inactive
for
prolonged periods- No ATT is effective
Goals-
1. Killing of dividing bacilli- drugs with
bactericidal activity rapidly reduce the
bact. load in the Pt & achieve quick
sputum clearance – Pt become non con-
tageous to the community
- Transmission is interrupted
2. Killing of persistent bacilli for effective
cure & prevention of relapse
3. Prevent emergence of resistance
(Drug combination are selected to maximize the
above action together with consideration of cost &
convenience )
- H & R are most efficacious drugs ,their
combination is synergistic
Duration of therapy shortened from 12 to 9
months.
Addition of Z for initial 2 months further
reduces duration of treatment to 6 months
DOTs –Directly observed treatment short
course ,was recommended by the
WHO in 1995
Short course chemotherapy-
Regimen of 6-9 months treatment
In 1997 WHO framed clear cut guidelines
for different category of TB treatment .
All regimen have initial intensive phase -2
3 months to rapidly kill the TB bacilli & bring
sputum conversion & afford symptomatic
relief followed by continuation phase last
4-6 months for elementary remaining bacilli
t
Categories:
Category I
–New
New ( untreated ) smear +ve pulmonary TB
-New
New smear –ve pulmonaryTB with extensive
parenchymal involvement
-New cases of severe forms of extrapulmonary
TB e.g.- meningitis , miliary TB , pericarditis
-B/L or extensive pl. effusion , intestinal or
genitourinary TB
(Revised National Tub. Control programme
In India in 1997— DOTs –follow thrice wkly
regimen to ↓ cost & it is more practical )
WHO :
- 2HRZE(S) (initial phase)-daily
- 4HR or 6HE (continuation phase,)daily
total duration 6-8 months
RNTCP :
2H3R3Z3E3 + 4H3R3 -total
- duration- 6month
Category II
-Smear +ve failure ,relapse & interrupted Tt cases
-Relapse- cured TB Patient again become sputum +ve
-Tt after interruption –interrupted Tt x 2month →return to
sputum + ve case
WHO: Initial phase –daily 2 HRZES +1 HRZE
Continuation phase –5HRE
5HRE - total
otal 8 month
RNTCP:
Initial phase -2H3R3Z3E3S3
2H3R3Z3E3S3 +1H3R3Z3E3
Continuation phase -5H3R3E3
5H3R3E3 –total 8 months
Category III
New cases of smear –ve pulmonary TB with limited
parenchymal involvement or severe form of extra
pulmonary TB .
e.g.-Lymph node TB
Unilateral pleural effusion
Bone (excluding spine )
Peripheral joint & skin TB
WHO : Initial phase -2HRZ (daily)
Continuation phase - 4HR or 6HE (daily)
Total duration-6-8 months
RNTCP :
Initial phase -2H3R3Z3
- ( daily )
Continuation phase -4H3R3
- ( daily )
Total duration- 6 months
CATEGORY-WISE TREATMENT
(WHO1997 & RNTCP1997)
RNTCP1997
TB Initial Phase Continuation Total
Category (daily /3xper week) Phase Duration
(daily/3xper week)
i. 2 HRZE(S)/ 4 HR/ 4H3R3 or 6HE 6

2H3R3Z3E3 8
ii. 2 HRZES+ 5 HRE or 5H3R3E3 8

1HRZE / 8
2H3R3Z3E3S3+1H3R3Z3E
3
iii. 2 HRZ/ 4 HR/4 H3R3 or 6 HE 6
2H3R3Z3 8
DOTS PLUS:
Refers to DOTS programme which includes
component for multidrug resistance (MDR)
tuberculosis , its diagnosis , management &
treatment.
(It began in 2000 by WHO & implemented in India in 2010
created .
& thus category IV is created)
Cat IV –
Chronic cases who have remained or become smear +ve
after completing fully supervised Tt / close contact of
most likely MDR cases
MDR –TB –Resistant to both H& R & many
other anti -TB drugs
Tt difficult because –one or more 2nd line drugs are to be
(Tt
given for 12-24 months & they are less efficacious , less
convenient & more toxic & expensive )
Chronic – presence of association of
AIDS /Diabetes / Leukemia /Silicosis
-If sensitivity of drugs known then resistant
drugs are excluded
-For H resistance – RZE X 12 months
- For H+ R resistance- ZE+ S / Kanamycin / Capreomycin/
+ Ciprofloxacin or Ofloxacin ± Ethionamide could be
used
Extremely drug resistant ( XDR) TB :
Term applied to bacilli that are resistant to at
least 4 most effective cidal drugs i.e. H ,R
Ofloxacin , one of Kanamycin / Amikacin/
Capreomycin.
Global survey –reveals 20% TB isolates are
MDR out of which 2% are XDR .
TB in pregnant women :
WHO – H,R,Z –safe
(Recommended - – 2HRZ + 6HR regimen -8 month
-E
E can be added late
-S
S is C/I
In India Z is avoided
-(2HRE +7HR total 9 month regimen )
Breast feeding mother:
All ATT drugs are compatible ,baby should
be watched ,the infant should receive BCG
vaccination & INH prophylaxis
Indication of Glucocorticoids in TB:
-In TB Pts, glucocorticoids if at all used are always used
with AT drugs, they are considered in –
- Miliary TB
- Tuberculous Meningitis
- Rapidly filling Pleural effusion &
- Renal TB ( to reduce exudation & stricture formation)
formation
( Its administration should be withdrawn gradually when
the G.C. of Pts improved ).
RECENT DRUGS
Three novel drugs currently under clinical
development which are active against MDR-
TB-
TB
1. Linezolid
2. OPC-67683, a nitroimidazole
3. TMC207, a diarylquinoline
Newer Antitubercular Drugs in
Clinical Trials
1.LINEZOLID (Also known as 3rd line agent)
agent
• Linezolid is an oxazolidinone used primarily for the
treatment of drug-resistant gram-positive infections.
• Also active against M. tuberculosis
• Mechanism of action is disruption of protein synthesis
by binding to the 50S bacterial ribosome.
• Linezolid has nearly 100% oral bioavailability, with
good penetration into tissues and fluids, including CSF.
• Adverse effects may include optic and peripheral
neuropathy, pancytopenia, and lactic acidosis .
Clinical Trials
2.TMC207 (R207910 ) by Andries etal
in 2005 :
• TMC207 is a new diarylquinoline with a novel
mechanism of action: inhibition of the mycobacterial
ATP synthetase proton pump.
• TMC207 is bactericidal for drug-susceptible and MDR
strains of M. tuberculosis.
• Resistance has been reported and is due to point
mutations in the gene coding for the ATP synthetase
proton pump.
• A phase 2 randomized controlled clinical trial
demonstrated substantial improvement in rates of 2-
month culture conversion, with improved clearance of
mycobacterial cultures, for MDR-TB patients.
Clinical Trials
• This drug is metabolized by the hepatic
cytochrome CYP3A4.
• Rifampin lowers TMC207 levels by 50%, and
protease inhibitors also interact significantly
with this drug.
• The dosage is 400 mg/d for the first 2 weeks
and then 200 mg thrice weekly.
• Adverse effects are reported to be minimal,
with nausea and slight prolongation of the
QTc interval.
Clinical Trials
3. OPC-67683 AND PA 824 :
• The prodrugs OPC-67683 and PA 824 are
novel nitro- dihydro- imidazoxazole
derivatives.
• Antimycobacterial activity is due to
inhibition of mycolic acid biosynthesis.
biosynthesis
• Early clinical trials of these compounds
are ongoing.
CHANGES IN RNTCP
GUIDELINES IN
2010-11
Changes in RNTCP Guidelines
• Discontinuation of Cat III Regimen under
RNTCP
• The programme has now revised its
categorization of patients from the earlier
3 categories (Cat I, Cat II and Cat III) to 2
categories (New and Previously treated
cases)
NEW (CAT I)
New Sputum smear-positive
New Sputum smear-negative
New Extra-pulmonary
New Others
PREVIOUSLY TREATED (CAT II)

Smear-positive relapse
Smear-positive failure
Smear-positive treatment after default
Others
TREATMENT
Category Initial Phase Continuation Phase
• New (Cat I) 2H3R3Z3E3 4H3R3
• Previously 2H3R3Z3E3S3/ 5H3R3E3

Treated 1H3R3Z3E3
(Cat II)
CHEMOPROPHYLAXIS
Chemoprophylaxis of TB:
Prevention of active disease from latent inf.
& It is indicated by +ve Mantuox test.
test
Mantuox test / Tuberculin test – In this test purified protein derivative
(PPD) is injected by intradermal route . In normal person i.e. in
immunocompetent pts induration of > 5 mm & in immunocompromised Pts >10
mm induration is considered positive after giving 5 units of PPD .
Subjects require prophylaxis are –
- PPD +ve pts but no active disease
- -ve PPD but in close contact with TB Pts
-Immunocompromised Pts ( having leukemia ,HIV, taking corticosteroid) with
+ve MT
- HIV inf. Pts . exposed to MDR TB cases
Chemoprophylaxis
Standard drug is INH daily for 6-12 months.

OR: INH + Rifampin daily for 6 months.
If INH can not be used: Rifampin (4 months)/R+Z (2 months).
MDR: E+Z + FQ.
THE DEVELOPMENT PIPELINE FOR
NEW DRUGS, 2010
• Rifaximin : Newer non systemic rifamycin
approved for :
- Traveler's diarrhea,
- Hepatic encephalopathy
- Irritable bowel syndrome,
syndrome
- Small intestinal bacterial overgrowth &
- Clostridium difficile infection
The goal of the new drugs component of the
Global
Plan to Stop TB 2011–2015
• To develop and introduce new TB drugs
and drug combinations that will result in-
 Shorter, safer, more effective and accessible
treatment regimens
Cure all forms of TB
Compatible with ART
Suitable for children
Easily managed in the field.
ACHIEVEMENTS EXPECTED BY
2015
• A new four-month TB treatment regimen
• Two new drugs will be approved by regulatory
authorities for drug sensitive TB
• At least one new drug for the treatment of drug
resistant TB will be introduced into the market
• A nine-month regimen for the treatment of drug
resistant TB including at least one new drug
ACHIEVEMENTS EXPECTED BY
2015
• Fixed-dose combinations (FDCs) for first-
line drugs (including new drugs) will be
available and in use
• Child-friendly first-line TB drug
formulations will be under development
Anti- Leprotic agents
• Also known as Hansen’s disease
• It is a chronic granulomatous infection
caused by Mycobacterium leprae
• Attacks superficial tissues e.g. skin &
peripheral nerves
• Organism grow very slowly ( org.s can not
be cultured in artificial media but grows in
foot pad of Armedillon.)
Armedillon
• Disease is still considered as social
stigma
but it needs a change in the attitude of
public to consider it just like any other
disease .
• Important is early diagnosis & Tt. which
makes it non infectious & prevents compl.s
Anti- Leprotic drugs :
Classification-
-Sulfone-
Sulfone- Dapsone (DDS)
-Phenazine
Phenazine derivatives- Clofazimine
-Antitubercular
Antitubercular drugs- Rifampicin
Ethionamide
-Other
Other Antibiotics -
Ofloxacin , Minocycline & Clarithromycin
Sulfones -
Derivative of 4-4’ diamino diphenyl sulfone
(DDS)
Dapsone:
-Bacteriostatic
-High risk of resistance if used alone
Mechanism:
Similar to sulfonamide i.e. ↓ of dihydrofolate
synthase enzyme.( Anti-inflammatory effect occurs via ↓ of
tissue damage by neutrophils by ↓ neutrophil myeloperoxidase activity
,↓activity of neutrophil lysosomal enzyme , free radical scavanger ,↓ of
migration of neutrophils to the inflammatory sites )
ADRs:
-Nausea , vomiting , anorexia
-Allergic reaction
-Hemolysis in pts with G6PD deficiency
-Methemoglobinaemia
• Neurotoxicity & Psychosis
Sulphone Syndrome:
After 5/6 wks of Tt. in malnourished
patients
there may be exacerbation of Lepromatous
Leprosy similar to Jerisch Hexheimer
reaction (seen with Penicillin ) ,
characterized
by fever, malaise , exfoliative dermatitis ,
lymphadenopathy, Jaundice etc.
Indication –
-Leprosy
-Resistant Malaria ( with pyrimethamine)
-Toxoplasma encephalitis in AIDS
-Pneumocystis jirovecii in AIDS
Clofazimine :
It is a dye , weak bactericidal by ↓ the
function of DNA.
( membrane disruption ,↓of mycobacterial Phospholipase A2 , ↓ of
mycobacterial K+ transport , generation of H2O2 , interference with
the bacterial electron transport chain via ↓ of macrophages , T cells,
neutrophils & complement )
- Also having anti- inflammatory activity so
prevents Lepra reaction.
reaction
-used for common skin ulcers & MAC
S/E-
S/E Red discolouration of skin
- Eosinophilic enteritis
Rifampicin :
- Important antiTb drug also bactericidal to
M. Leprae.
- Rapidly make leprosy Pts noncontagious
- However not satisfactory if used alone-
some bacilli persist after prolonged Tt –
can cause resistance .
( The congener of Rifampicin - Rifabutin is
also bactericidal against M. leprae but not
superior to Rifampicin)
Ethionamide - Has significant antileprotic
activity but is hepatotoxic . It can be used
as an alternative to Clofazimine but other
substitutes are preferred.
Other Antibiotics:
-Fluoroquinolones
Fluoroquinolones : Ofloxacin , Pefloxacin,
Gatifloxacin are highly active against
M. leprae ( but not Ciprofloxacin )
-Minocycline:
Minocycline due to high lipophilicity, it is
active against M. leprae. , antibacterial
activity is less than Rifampicin but more
than that of Clarithromycin .
Clarithromycin :
Only macrolide antibiotic having
significant activity against M. leprae . It is
being included in alternative MDT
regimens.
regimens
Diagnosis of Leprosy:
Diagnosed with any of the following-
- Skin lesions ( hypopigmented patches )
- Impaired or loss of sensation
- Acid fast bacilli in skin smears
- Nerve thickening
Treatment of Leprosy
• Leprosy primarily affect skin , mucous
membranes & nerves
• Prevalent in poors ( low socioeconomic
strata ) .
• National Leprosy Control Programme
launched in 1955
• It was changed to National Leprosy
Eradication Programme ( NLEP) in 1982
• India achieved elimination of Leprosy as
a public health problem .
• Incidence is less than 1 case/ 10,000
population .
Classification:
1. Indeterminate
2. Tuberculoid
3. Borderline
4. Lepromatous
5. Pure neuritis ( no skin lesion )
Tuberculoid:
Well defined skin lesion
-anesthetic patches
-Organism may or may not be found in skin
lesions.
-Lepromine
Lepromine test is positive (diagnostic
diagnostic for
Leprosy. It evaluate the immune system of
the patient & classify the type of disease.)
disease
-prolonged remission occurs
Lepromatous:
-Ill defined skin lesions
-Skin is thickened , glossy & corrugated
-Disease progresses – large nerve trunks
get involved – anesthetic patches
-Atrophy of skin & muscles & absorption of
small bones e.g. phalanges of extremities,
ulceration & spontaneous amputation
occurs
-Lepromine
Lepromine test is –ve ( as cell mediated
immunity is absent )
-Smear
Smear is +ve for organism .
For treatment purpose –leprosy is classified
as-
Multibacillary - It includes lepromatous,
borderline cases with +ve skin smear test
Tt- Rifampicin - 600 mg / month supervised
Dapsone-100 mg / day self administration
Clofazimine – 300 mg/ month supervised
+ 50 mg/ day self administration
X 2 years- relapse – repeat
Paucibacillary : ( small no. of organism)-
It includes indeterminate & tuberculoid
Tt- Rifampicin – 600 mg / month supervised
Dapsone – 100 mg / day self administration
X minimum for 6 months-repeat if relapse
Single lesion paucibacillary –single dose
ROM- Rifampicin-600 mg + Ofloxacin - 400mg +
Minocycline-100 mg
(MDT was introduced by the WHO in 1981& was implemented under
the NLEP ( National Leprosy Eradication Programme).
Programme It includes
Dapsone , Rifampicin & Clofazimine . The WHO in 1994
recommended a fixed duration therapy( FDT) of 2 years for MBL & 6
months for PBL . WHO expert committee On Leprosy in 1995
recommended shortening of MDT in MBL to 12 months & this was
implemented in our country since 1999 . The purpose of this is to
render the Pts noncontiguous & therefore cut down transmission
Alternative regimens :
Incorporating newer antileprotic drugs , but these are
used only in case of Rifampicin resistance or when MDT is
not advisable e.g.-
Clofazimine + any two of Ofloxacin / Minocycline/ Clarithromycin
for 6 months followed by Clofazimine + any one of Ofloxacin /
Minocycline x additional 18 months .
(PBL cases having few bacteria in the body & only one Skin lesion can
be treated with single dose of Rifampicin -600 mg + Ofloxacin-400
Ofloxacin- mg
+ Minocycline -100 mg. This has been recommended by the WHO for
solitary lesion of PBL.)
Two types of reactional state may occur
with therapy
1. Type I : Lepra reaction (reversal reaction)
In borderline leprosy due to increased in host
immunity- skin lesion & nerves become swollen
& tender without systemic manifestation –
Tt. –
Prednisolone (Thalidomide
Thalidomide not effective)
effective
Type II :Lepra reaction ( erythema nodosum
leprosum) –observed in lepromatous
leprosy – there is skin & nerve
manifestation with fever & systemic
involvement.
Tt.- by analgesic /antipyretic for mild cases,
in severe cases-Prednisolone
Prednisolone or Thalidomide.
-Chloroquine
Chloroquine & cytotoxic drugs are also
effective.
-Clofazimine
Clofazimine require 3-4 wks so not suitable
for acute cases, but useful in chronic
cases & prevention of this reaction .
- No need to stop the antileprotic drugs .
MCQs
• 1. A middle aged man with chronic renal failure is diagnosed to have sputum +ve
• Pulmonary tuberculosis. His creatinine clearance is 25 mg/ min. All of the following
• Drugs need modification in doses EXCEPT :
• a) Isoniazid
• b) Streptomycin
• c) Rifampicin
• d) Ethambutol
• ( Ans- c ,Ref : Katzung 11/e p826)
•
• 2. A 30 year old pregnant women develops Tuberculosis. Which of the following
• antitubercular drug should not be given ?
• a) Rifampicin
• b) INH
• c) Streptomycin
• d) Ethambutol
• ( Ans- b ,Ref : KDT 6/e p748)
•
MCQs
• 3. A patient suffering from AIDS is on Zidovudine ,Lamivudine and Indinavir therapy.
• He develops Pulmonary tuberculosis for which treatment is started. Which of the
• Following should be avoided in him ?
• a) INH
• b) Ethambutol
• c) Pyrazinamide
• d) Rifampicin ( Ans- d ,Ref : KDT 6/e p741)
• 4. A patient of multidrug resistant Tuberculosis is on antitubercular drugs. After a few Months he
develops an inability to distinguish between red & green color. Most likely drug causing these
symptoms is :
• a) Rifampicin
• b) Ethambutol
• c) Cycloserine
• d) Ethionamide ( Ans -b ,Ref : KDT 6/e p742)
• 5. In multidrug resistant strains of M. tuberculosis which of the following drugs is likely
• to be effective, including those resistant to Streptomycin?
• a) Amikacin
• b) Gentamicin
• c) Spectinomycin
• d) Clarithromycin ( Ans- a ,Ref: Katzung 11/e p825)
•
MCQs
• 6. In atypical mycobacterial infection which of the following drug is active?
• a) Ethionamide
• b) Streptomycin
• c) INH
• d) Clarithromycin ( Ans- d , Ref: KDT 6/e p750)
• 7. Which of the following antitubercular drug DOES NOT cross blood brain barrier?
• a) Isoniazid
• b) Pyrazinamide
• c) Rifampicin
• d) Streptomycin ( Ans- d , Ref: KDT 6/e p743 )
• 8. Which of the following anti-tubercular drug is implicated in the causation of transient
• memory loss?
• a) Ethambutol
• b) Ethionamide
• c) Pyrazinamide
• d) Isoniazid ( Ans –d , Ref : Goodman & Gilman 10/e p1277 )
MCQs
• 9. Most effective drug for extracellular mycobacteria is:
• a) Ethambutol
• b) Rifampicin
• c) Isoniazid
• d) Pyrazinamide
• ( Ans –c , Ref : Goodman & Gilman 11/e p1205 ,1208,1211 )
• 10. In severe liver disease which of the following combination of antitubercular drug can
• be used ?
• a) Isoniazid + Streptomycin
• b) Rifampicin + Isoniazid
• c) Rifampicin + Ethambutol
• d) Streptomycin + Ethambutol
• ( Ans -d , Ref: KDT 6/e p 742-743 )
• 11. In Leprosy , the best bactericidal agent is :
• a) Rifampicin
• b) Clofazimine
• c) Dapsone
• d) Ethionamide
• ( Ans-a ,Ref : KDT 6/e p753)
MCQs
• 12. What is the side effect of Dapsone apart from hemolytic anaemia ?
• a) Infective mononucleosis like syndrome
• b) Flu like syndrome
• c) Lichenoid eruptions
• d) G-6-PD deficiency
• ( Ans -a , Ref: KDT 6/e p752 )
• 13. Dapsone is used in all EXCEPT :
• a) Dermatitis herpitiformis
• b) Leprosy
• c) Pneumocystis jiroveci pneumonia
• d) Tuberculosis
• ( Ans -d , Ref: KDT 6/e p752 )
• 14. In Lepra reaction , the drug useful is :
• a) Penicillins
• b) Clofazimine
• c) Dapsone
• d) Rifampicin
• ( Ans -a , Ref: KDT 6/e p752 )
•
MCQs
• 15. Treatment of Lepromatous leprosy is :
• a) Rifampicin + Dapsone
• b) Rifampicin + Clofazimine
• c) Rifampicin + Dapsone + Clofazimine
• d) Rifampicin + Ofloxacin + Minocycline
• ( Ans -c , Ref: KDT 6/e p755 )
•
Bibliography
1.Goodman & Gilman’s ,The Pharmacological Basis of
Therapeutics (12th Edition).
2. A complete Textbook of Medical Pharmacology by
S. K. Srivastava ( Latest Edition )
3.. Essentials of Medical Pharmacology by K. D. Tripathi
(7th edition)
QUINOLONES
STRUCTURE OF SPARFLOXACIN :
NH2 O
5 4
F 3 COOH
6
H3C 2
7
N 8 N
1
HN F
CH3
Sparfloxacin
SAR of Quinolones
 1,4-dihydro-4-oxo-3-pyridinecarboxylic acid
portion is necessary for the antibacterial activity.
 The pyridone ring must be attached to an
aromatic ring, in which isosteric substitution of
carbon with nitrogen still remaines the activity.
O O
4 5 4
3 COOH 3 COOH
5 6
6 2 7 2
N1 N
8 1
R R
Substituted 1,4-dihydro-4-oxo- Substituted quinolone 3-carboxylic
3-pyridinecarboxylic acid
acid
SAR continued...
 Isosteric substitution of carbon with nitrogen still
remains the activity.
O O
5 4 5 4
3 COOH N 3 COOH
6 6
7 N2 7 2
N N
8 1 8 1
R R
Cinnolines 1,5-Naphthyridines
O O
5 4 5 4
3 COOH 3 COOH
6N 6
7 2 7 2
N N N
8 1 8 1
R R
1,6-Naphthyridines 1,8-Naphthyridines
SAR continued...
 N1-Substitution is necessary for antibacterial
activity. Small alkyl or cycloalkyl groups increase it:
cyclopropyl>ethyl>methyl
O O
5 4 5 4
F 3 COOH F 3 COOH
6 6
2 2
7 7
N N N N
8 1 8 1
HN HN
CH3
Ciprofloxacin Norfloxacin
SAR continued...
 Substitution at C2 position decreases the activity
remarkably or changes the antibacterial characters.
 Substitution at C5 , C6 , C7 and especially at C8 has
good effects on the activity.
 C6 fluorine substitution increases the activity
prominently, That’s why quinolones are also called
fluoroquinolones.
 Substituted or unsubstituted piperazinyl or
pyrolidinyl groups at C7 increase the activity against
p.aeroginosa O
5 4
3 COOH
6
7 2
N
8 1
R
SAR continued...
 Ring fusion at C1and C8; C5 and C6; C6 and C7

or C7and C8 introduces active compounds:
O O
5 4 5 4
F 3 COOH COOH
O 3
6 6
2 X2
7 O 7
N 8 N N1
1 8
H3CN O
CH3 CH3
H
Ofloxacin X: N = Cinoxacin
Levofloxacin (-)S X: CH = Oxolinic acid
Why Fluoroquinolones cause CNS
toxicity?
O
F COOH
N N
HN
COOH
CH2
CH2
CH2
H2N
 Tremor, sleep disorders, anxiety, and convulsions

because of GABA antagonism at the receptor.
 Because of low penetration to brain this toxicity is rare.
Chapter 2
Anti-infective Agents
Author: Beatriz Manzor Mitrzyk, PharmD, BCPS, BCAP
Editor: Amy L. Wojciechowski, PharmD, BCPS-AQ ID, BCCCP
Learning Objectives
■■ Identify current pharmacologic agents that are appropriate for each condition/diagnosis.
■■ Recommend optimal pharmacologic interventions based on patient-specific characteristics.
■■ Provide appropriate patient-specific counseling points and optimal overall medication management.
Key Terms: anthelmintics, antibacterials, aminoglycosides, cephalosporins, beta-lactams, carbapenems, cephamycins,
monobactams, chloramphenicols, macrolides, erythromycins, ketolides, penicillins, aminopenicillins, penicillinase-
resistant penicillins, extended-spectrum penicillins, quinolones, sulfonamides, tetracyclines, glycylcyclines,
bacitracins, cyclic lipopeptides, glycopeptides, lincomycins, oxazolidinones, polymyxins, rifamycins, streptogramins,
antifungals, allylamines, azoles, echinocandins, polyenes, pyrimidines, antimycobacterials, antituberculosis agents,
antivirals, adamantanes, antiretrovirals, HIV entry and fusion inhibitors, HIV protease inhibitors, HIV integrase
inhibitors, HIV non-nucleoside reverse transcriptase inhibitors, HIV nucleoside and nucleotide reverse transcriptase
inhibitors, interferons, monoclonal antibodies, neuraminidase inhibitors, nucleosides and nucleotides, HCV antivirals,
HCV polymerase inhibitors, HCV protease inhibitors, HCV replication complex inhibitors, antiprotozoals
Overview of Anti-infective Agents

Antimicrobials are medications that prevent and treat infections; they are vital to the health and well-being of society.
Often assisting the body’s defenses, this wide variety of medications has been developed to manage infections caused
by bacteria, viruses, and parasites. The clinical course of any infection is dependent on the interaction between the
pathogen and a complex set of host defenses.
The first consideration in selecting antimicrobial therapy is whether an antimicrobial agent is truly needed. The
differential diagnosis should indicate whether the cause requires treatment with an antimicrobial drug or whether the
infection is self-limiting and will resolve without antimicrobial therapy. For self-limiting infections, supportive treat-
ment and symptom management are recommended. If possible, antimicrobial use should be limited to highly suspi-
cious, empiric, and definitive diagnoses of infection to avoid toxicity and the development of antimicrobial resistance.
Prior to beginning antimicrobial therapy, specimens for culture and sensitivity testing should be obtained. The
exceptions to this care are septic patients, in whom prompt antimicrobial therapy should not be delayed if culture
specimens cannot be obtained in a timely manner, because early administration of antibiotics in sepsis has shown to
reduce mortality. Empiric antimicrobial therapy selection is based on the likely pathogens for the site or type of infec-
tion; the patient’s medical, medication, and social history; prior antibiotic use; and local susceptibility patterns.
17
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9781284110562_CH02_Pass01.indd 17 30/11/16 6:38 PM

18 Pharmacotherapeutics for Advanced Nursing Practice
Monitoring includes assessing for resolution of signs and symptoms of infection (e.g., normalization of body
temperature and white blood cell [WBC] count) and watching for adverse drug events. Ideally, the antibiotic with the
narrowest effective spectrum of activity should be selected. The route of administration should be evaluated daily,
and conversion to oral therapy should be made once the patient is clinically improving and able to tolerate it (i.e.,
functioning gastrointestinal [GI] tract; general exceptions are endocarditis and central nervous system [CNS] infec-
tions). Patients not responding to therapy within 2–3 days should be reevaluated to assess the diagnosis, determine
whether therapeutic drug concentrations are being achieved, and identify if the patient is immunosuppressed. In ad-
dition, further investigation should be conducted to determine if there is an isolated infection (i.e., abscess, foreign
body) or if resistance to the therapy has developed.
It is recommended that practitioners follow a systematic approach when selecting an antimicrobial regimen. This
approach minimizes the development of resistance, the likelihood of superinfections, and the use of more expensive
and potentially more toxic agents.
Systematic Approach for Selection of Antimicrobials

■■ Confirm the presence of infection.
■■ Perform a careful history and physical examination.
■■ Identify signs and symptoms.
■■ Identify predisposing factors.
■■ Identify the pathogen.
■■ Collect infected material.
■■ Perform Gram stain.
■■ Perform serologies.
■■ Perform culture and sensitivity tests.
■■ Select an empiric therapy considering every infected site.
■■ Assess host factors.
■■ Assess drug factors.
■■ Monitor therapeutic response.
■■ Perform clinical assessment.
■■ Perform laboratory tests.
■■ Assess for therapeutic failure.
Initial selection of antimicrobial therapy is typically empiric, meaning before the causative pathogen has been
identified. Infections are usually acute cases, and delaying treatment can result in serious morbidity or possibly death.
Patient-specific factors such as allergy history, age, pregnancy, renal function, liver function, type of infection, infec-
tion site, and the cost of medication must be considered when deciding which antimicrobial agent to use. The classic
signs and symptoms of infection include fever, elevated WBCs, and pain; however, they may not always be present.
Older adults, for example, may experience altered mental status with a urinary tract infection (UTI), so clinicians
must always look past the expected and seemingly obvious symptoms.
After beginning antimicrobial therapy, the patient must be monitored for a therapeutic response. Tissue and
fluid cultures should be obtained for infections such as pneumonia, meningitis, bacteremia, and pyelonephritis. Cul-
tures can take days to weeks for results to become available, depending on the pathogen. Once a pathogen is con-
firmed, the patient can be switched to narrower-spectrum antimicrobial therapy based on the susceptibility results. If
anaerobic bacteria are suspected but not identified, anaerobic therapy should be continued, as commonly used labo-
ratory culture techniques are often unsuccessful in isolating and identifying anaerobic organisms. Patient monitoring
should include similar parameters used for diagnosis. The WBC count and temperature should begin to normalize
within 24 to 48 hours. Physical complaints from the patient should also begin to diminish (i.e., decreased pain, short-
ness of breath, cough, or sputum production) and appetite (if reduced) should improve. Resolution of radiologic
changes may lag behind the patient’s clinical improvement.
Serum (or other fluid) concentrations of antimicrobials may guide efficacy assessments and prevent toxicity. An-
timicrobials that require serum concentration monitoring in patient-specific situations include the aminoglycosides,
vancomycin, flucytosine, and some azole antifungals. More efficacious outcomes have been associated with therapeu-
tic aminoglycoside concentrations; for example, for a gram-negative infection, therapeutic peak concentrations have
been correlated with better clinical outcomes.
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Chapter 2 Anti-infective Agents 19
Patient education is critical to optimize efficacy, minimize adverse effects, and prevent the development of an-
tibiotic resistance. If the infection worsens, the patient should report this status to the prescriber, who will then de-
termine whether a different therapy is needed. Patients should be instructed to finish the entire medication regimen,
even if they are feeling better, to prevent recurrence and/or the development of antibiotic resistance. They should also
report any significant effects or possible “new” secondary infections such as yeast infection or severe diarrhea. They
should report serious adverse effects and not stop taking the medication unless instructed to do so. Excess medica-
tion should be disposed of properly and not shared or saved for later. Clinicians should explain to their patients that
antibiotic resistance is an increasing societal problem and educate them on the rationale for using antimicrobials ex-
actly as prescribed. In addition, they should explain why prescribers reserve the use of these medications for patients
who have a suspected or documented bacterial infection and do not prescribe them for self-limiting viral infections.
Prescribing practices involving antibiotics have changed significantly with the rise of antibiotic resistance and
the emergence of “superbugs.” Clinicians have begun to reserve use of antibiotics for cases where bacterial infection is
most likely, and to avoid indiscriminate use in a patient with a suspected viral infection. Because antibiotic resistance
is a growing public health issue, prescribers should reserve use of these medications for patients with true infections to
avoid contributing to this problem. Antimicrobial stewardship programs have been implemented at hospitals and some
outpatient settings, with the goals of optimizing treatment of infections and reducing inappropriate use of antibiotics.
2.1 Anthelmintics
Infections with helminths or parasitic worms affect more than 2 billion people worldwide. Worms pathogenic for
humans are classified as roundworms (intestinal and tissue nematodes) or as one of two types of flatworms, flukes
(trematodes) and tapeworms (cestodes). Worldwide, several types of soil-transmitted helminths infect millions of peo-
ple in developing countries and can negatively impact the health and well-being of school-aged children. Simultane-
ous infection with more than one type of helminth is common in tropical, poor, rural areas. In the United States, the
most common helminthic infections are caused by intestinal nematodes: Enterobius vermicularis (pinworm), Trichuris
trichiura (whipworm), Ascaris lumbricoides (roundworm), Strongyloides stercoralis (threadworm), and Ancylostoma
duodenale and Necator americanus (hookworms). Anthelmintics are drugs that treat infections with parasitic worms.
Anthelmintics act either locally within the gut lumen to cause expulsion of worms from the GI tract or sys-
temically against helminths residing outside the GI tract. Broad-spectrum anthelmintics, initially developed for
veterinary use, are also used in humans. Unfortunately, treatment for many tissue-dwelling worms, such as filarial
parasites, is not completely effective.
Anthelmintics are separated into classes on the basis of their chemical structure and mode of action. Anthel-
mintic resistance has been widely reported in livestock, and it may be only a matter of time before it emerges in hu-
man parasites.
Ascariasis
Ascariasis is caused by Ascaris lumbricoides, a giant roundworm that can grow to be 35 cm long. Endemic areas in
the United States include the southeastern parts of the Appalachian range, the Gulf Coast states, and areas with poor
sanitation. Symptoms of ascariasis include abdominal discomfort, abdominal obstruction, vomiting, and appendici-
tis; many patients, however, are asymptomatic. During migration of the larvae through the lungs, patients can present
with pneumonitis, fever, cough, eosinophilia, and pulmonary infiltrates on chest x-ray.
Diagnosis is made by identifying the characteristic egg in the stool. Because of a very high egg burden, sample
concentration techniques are generally not needed to make the diagnosis. Eosinophilia is marked during worm mi-
gration but may be absent during intestinal infection. Treatment of ascariasis is one dose of albendazole or pyrantel
pamoate (refer to companion drug grid for detailed drug regimens).
Enterobiasis
Enterobiasis is caused by the small, threadlike pinworm, Enterobius vermicularis, which is approximately 1 cm long. It
is a common helminthic infection and primarily affects children. Infection is manifested by a perianal cutaneous irrita-
tion caused by the migrating female worm or presence of eggs, which may result in dermatitis and secondary bacterial
infections. Children may be restless and have difficulty sleeping. Appendicitis and intestinal perforation occur rarely.
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Pinworm can be diagnosed by perianal swab using adhesive tape that is examined microscopically for eggs.
Treatment includes two doses of pyrantel pamoate or albendazole with the second dose administered 2 weeks
later. Following treatment, all bedding, underclothes, bathroom rungs, and toilet accessories should be sterilized
by steaming or washing in the hot-water cycle of a regular washing machine to eradicate eggs. It is critical for
all those in the household and those in close contact with the infected person be evaluated and also treated for
infection.
Trichuriasis
Infections caused by Trichuris trichiura (whipworm) are typically asymptomatic, but heavy infections may cause
gastrointestinal symptoms, malnourishment, and rectal prolapse. Such infections are most common among poor
children from resource-poor regions. Trichuris worms live in the colon and cecum. Lemon-shaped eggs are easily de-
tected on stool examination. Adult worms, which are typically 3–5 cm long, may be seen on proctoscopy.
The treatment of choice in the United States is albendazole (400 mg daily for 3 doses), which produces cure rates
of 70% to 90%. Ivermectin (200 μg/kg daily for 3 doses) may also be used, but has a lower cure rate.
Anthelmintics
Albendazole
Ivermectin
Praziquantel
Pyrantel
Case Studies and Conclusions

A 5-year-old boy presents for care, accompanied by his mother. The child is scratching between his legs and has
been unable to sleep for the past 2 days. His perianal area is red and irritated and the prescriber has diagnosed
the patient with pinworm (Enterobius vermicularis) infection. The mother describes she is experiencing similar
symptoms.
1. What is the appropriate intervention for this mother once the pediatrician treats the child?
a. One-time dose of pyrantel pamoate or albendazole
b. One-time dose of mebendazole or albendazole
c. One dose of pyrantel pamoate or albendazole, then a second dose 2 weeks later
d. One dose of mebendazole or albendazole, then a second dose 2 weeks later
Answer C is correct. One dose of pyrantel pamoate or albendazole is given, then a second dose is administered 2 weeks later.
Mebendazole is also an effective treatment but is no longer available in the United States.
2. The prescriber selects the optimal drug regimen. What common side effect should you warn the
mother of?
a. Confusion
b. Behavior changes
c. Abdominal pain
d. Seizures
Answer C is correct. Patients on pyrantel pamoate commonly develop abdominal pain and nausea (mild adverse effects).
3. What administration recommendation would you make for taking the drug selected?
a. May take with food or juice
b. Must take on empty stomach
c. Must take only at night
d. Must take every other day
Answer A is correct. May take with food or juice and none of the other factors are required for appropriate medication
administration.
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4. Should anyone else be treated for pinworm infection?

a. No one else needs to be treated.
b. Only household contacts should be treated.
c. All individuals in close contact with an infected person should be treated.
d. All individuals with any contact with an infected person should be treated.
Answer C is correct. All individuals in close contact with the infected person should be treated, including family members.
A 23-year-old female has just returned from her visit to Panama City, Florida, after volunteering with a medical
mission group for a month. She has abdominal discomfort and she reports that she ate some undercooked pork and
also went swimming in dark, dirty (brackish) water. She is concerned she may have contracted an infection involving
pork tapeworm (Taenia solium [Ascaris lumbricoides]), which is a fear that is confirmed upon diagnosis by her
healthcare provider.
1. What is the appropriate treatment for this patient’s condition?

a. Albendazole 400 mg, single dose
b. Mebendazole 500 mg, daily for 3 days
c. Pyrantel pamoate 2 g, single dose
d. Albendazole 400 mg once, then repeat 2 weeks later
Answer A is correct. Albendazole 400 mg as a single dose is the appropriate treatment in the United States.
2. The prescriber selects the optimal drug regimen. What common side effect would you want to
prepare the family to observe for based on your previous answer?
a. Confusion
b. Behavior problems
c. Abdominal pain
d. Seizures
Answer C is correct. Patients on albendazole commonly develop abdominal pain and nausea (mild adverse effects). More
common side effects include elevated liver enzymes and hepatotoxicity, which may also be associated with abdominal pain.
Prescribers should monitor LFTS and discontinue therapy if liver enzymes are more than 2 times the upper limit of normal.
3. What administration recommendation would you make for taking the drug selected?
a. Must take with high fat meal
b. Must take on empty stomach
c. Must take only at night
d. Must take every other day
Answer A is correct. Optimal absorption of albendazole occurs in the presence of a high fat meal.
2.2 Antibacterials
The development of new antibiotics has also evolved to “keep up” with bacterial mutations; thus the different cate-
gories of antibiotics described in this section have different mechanisms of action that are responsible for their bac-
tericidal (and sometimes bacteriostatic) effects. As is the case with the cephalosporin antibiotics, the mechanism of
action may be similar for drug classes, but progressive “generations” of the antibiotic may be developed to increase
potency and/or reduce chances of bacterial resistance through mutation of the organism. Antibiotics are unique in
their concentration and in the time of exposure required for bacterial killing. While each antibiotic category has a
somewhat unique mechanism of action, generally all of these drugs target critical survival mechanisms of the bacte-
ria (such as altering the cell wall or disrupting protein synthesis), resulting in death of the pathogenic organism. One
example of recent resistance includes the ability of some bacteria to produce the enzyme penicillinase, which destroys
the chemical structure of certain antibiotics (β-lactam ring). Penicillinase-resistant penicillins are an effective tool in
our clinical toolbox; however we are aware of current and evolving resistance to these agents. Penicillinase-resistant
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penicillins include oxacillin, dicloxacillin, and nafcillin, and are the agents of choice for most staphylococcal disease.
However, the recent emergence of methicillin-resistant (MRSA) organisms has reminded the clinical community of
the need for heightened efforts to use antibiotics responsibly.
The absorption, distribution, metabolism, and elimination (ADME) of a medication are all critical elements
for drug action with the body. One key aspect associated with the ADME process is the amount of drug found in
the blood at any given time. Certain medications have a lower safety “tolerance” for large fluctuations of drug in the
blood and are termed narrow therapeutic agents. Therapeutic drug monitoring is the process of using ADME pre-
dictions to estimate a safe range between efficacy and toxicity. It is critical that the ADME of antibacterial agents is
accurately predicted to ensure the prescribed drug concentrations remain at therapeutic levels. Therapeutic levels
of antibacterial agents are established during clinical trials and are based on specific microbiologic end points—
including measurements such as the area under the curve (AUC):minimal inhibitory concentration (MIC) ratio,
peak:MIC ratio, and time (T) that the concentration remains greater than MIC (T > MIC).
Aminoglycosides exhibit concentration-dependent bactericidal effects. High-dose, extended-interval aminogly-
coside dosing maximizes the peak:MIC ratio through administration of a large dose once daily. Aminoglycosides have
a postantibiotic effect (persistent suppression of organism growth after concentrations decrease to less than the MIC),
which facilitates the efficacy of this regimen. Fluoroquinolones also exhibit concentration-dependent killing activity.
For these antibiotics, the bactericidal effect is characterized by the AUC:MIC ratio. In contrast, beta-lactams (β-lactams)
display time-dependent bactericidal effects. Bactericidal activity is most likely when the drug concentration is greater
than the MIC (T > MIC) for at least 40% to 50% of the dosing interval. To achieve this effect, the antibiotic is typically
administered as a continuous infusion, as a prolonged infusion, or as a series of small, frequent doses.
Many antimicrobials require dosage adjustment in patients with renal dysfunction (if the renal system is a sub-
stantial source of elimination) to minimize toxicity, and some may require dosage adjustment in patients with liver
dysfunction. Food–drug or drug–drug interactions with certain antibacterial medications (such as occurs with the
quinolones and calcium-containing foods or aluminum/magnesium-containing antacids) may decrease absorption of
the antibacterial medication. This interaction is usually addressed by separating the administration times or avoiding
the combination.
Patients with delayed dermatologic reactions (i.e., rash) to penicillin generally can receive cephalosporins with-
out adverse effects. Patients with type I hypersensitivity reactions (i.e., anaphylaxis) to penicillins should not receive
cephalosporins. Although the likelihood of cross-reactivity is low, the severe consequences of an anaphylactic reac-
tion outweigh the benefits of using another β-lactam antibiotic. Non-β-lactam options (depending on the targeted
pathogen) include aztreonam, quinolones, sulfonamides, and vancomycin.
Renal function (typically creatinine clearance or estimated glomerular filtration rate) should be calculated for
each patient receiving antibiotics; for renally eliminated antibiotics, the dose amount or dosing interval should be
adjusted accordingly. Hepatic function should be assessed in each patient receiving medications metabolized via the
hepatobiliary system, such as clindamycin, erythromycin, and metronidazole. All concomitant drugs and nutritional
supplements should be reviewed to avoid drug–drug interactions. Combination antibiotic therapy may be indicated
for polymicrobial infections (e.g., intra-abdominal, gynecologic infections), to produce synergistic killing (such as
β-lactam plus aminoglycoside regimens in enterococcal endocarditis), or to prevent the emergence of resistance.
Aminoglycosides
Amikacin
Gentamicin
Neomycin
Streptomycin
Tobramycin
Paromomycin (see also the Antiprotozoals section)
Cephalosporins
First-Generation Cephalosporins
Cefadroxil
Cefazolin
Cephalexin
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Second-Generation Cephalosporins
Cefaclor
Cefprozil
Cefuroxime
Cefotetan (see also the Cephamycins section)
Cefoxitin (see also the Cephamycins section)
Third-Generation Cephalosporins
Cefdinir
Cefditoren
Cefixime
Cefotaxime
Cefpodoxime
Ceftazidime
Ceftazidime and avibactam
Ceftibuten
Ceftolozane and tazobactam
Ceftriaxone
Fourth-Generation Cephalosporins
Cefepime
Fifth-Generation Cephalosporins
Ceftaroline
Miscellaneous Beta Lactams

Carbapenems
Doripenem
Ertapenem
Imipenem and cilastatin sodium
Meropenem
Cephamycins
Cefotetan
Cefoxitin
Monobactams
Aztreonam
Chloramphenicols
Chloramphenicol
Macrolides
Erythromycins
Erythromycin
Erythromycin estolate
Erythromycin ethylsuccinate
Erythromycin lactobionate
Erythromycin stearate
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Ketolides
Telithromycin
Other Macrolides
Azithromycin
Clarithromycin
Fidaxomicin
Penicillins
Natural Penicillins
Penicillin G (benzathine, potassium, procaine)
Penicillin V potassium
Aminopenicillins
Amoxicillin
Amoxicillin and clavulanate
Ampicillin
Ampicillin and sulbactam
Penicillinase-Resistant Penicillins
Dicloxacillin
Nafcillin
Oxacillin
Extended-Spectrum Penicillins
Piperacillin and tazobactam
Quinolones
Ciprofloxacin
Finafloxacin
Gemifloxacin
Levofloxacin
Moxifloxacin
Ofloxacin
Sulfonamides
Co-trimoxazole
Sulfadiazine
Sulfamthoxazole/Trimethoprim
Sulfasalazine
Tetracyclines
Demeclocycline
Doxycycline
Minocycline
Tetracycline
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Glycylcyclines
Tigecycline
Antibacterials: Miscellaneous Agents

Bacitracins
Bacitracin
Cyclic Lipopeptides
Daptomycin
Glycopeptides
Dalbavancin
Oritavancin
Telavancin
Vancomycin
Lincomycins
Clindamycin
Lincomycin
Oxazolidinones
Linezolid
Tedizolid
Polymyxins
Colistimethate/colistin
Polymyxin B
Rifamycins
Rifaximin
Rifabutin (see also the Antimycobacterials section)
Rifampin (see also the Antimycobacterials section)
Rifapentine (see also the Antimycobacterials section)
Streptogramins
Quinupristin and dalfopristin
Miscellaneous Urinary Anti-infectives

Fosfomycin
Methenamine
Nitrofurantoin
Trimethoprim

A 56-year-old man diagnosed with a MRSA infection expresses concern that he has never “not finished” an antibiotic
and has always followed the instructions.
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1. Why is he now experiencing antibiotic resistance?

a. He shares the societal problem of progressive mutation.
b. His body must just be “born” to be resistant.
c. He may grow out of resistance, so keep trying penicillin.
d. He may never use penicillin again.
Answer A is correct. Antibacterial resistance is on the rise. The mechanism of penicillin resistance is as follows: β-Lactam
antibiotics are capable of being inactivated by β-lactamases that are present in large quantities. The β-lactamases are
grouped into four classes. Some Class A and D enzymes are inhibited by β-lactamase inhibitors such as clavulanate and
tazobactam. Bacterial resistance to the β-lactam antibiotics may also develop by mechanisms other than destruction by
β-lactamases.
A 68-year-old woman has contracted an S. epidermidis infection that is methicillin sensitive. An infectious diseases
consultant recommends the use of a penicillinase-resistant penicillin. The patient wants to know which medications
are included in this category so she can determine if they are “covered by her health plan.”
1. Which of the following agents do you advise as being the list of potential penicillinase-resistant
penicillins?
a. Amoxicillin
b. Dicloxacillin
c. Moxifloxacin
d. Azithromycin
Answer B is correct. The penicillinase-resistant penicillins (oxacillin, dicloxacillin, and nafcillin) are resistant to hydroly-
sis by staphylococcal penicillinase. These semisynthetic penicillins are effective against penicillinase-producing strains of
Staphylococcus.
Your patient inquires further about which types of infections might be resistant to dicloxacillin.
2. Which infection type is resistant to penicillinase-resistant penicillins?

a. Candida infections
b. MSSA infections
c. MRSA infections
d. C. difficile infections
Answer C is correct. The role of these penicillins as the agents of choice for most staphylococcal disease is changing with the
increasing incidence of isolates of MRSA microorganisms. MRSA strains demonstrate resistance to all penicillinase-resistant
penicillins and cephalosporins. Hospital-acquired strains usually are resistant to the aminoglycosides, tetracyclines, erythro-
mycin, and clindamycin as well. Vancomycin is considered the drug of choice for hospital-acquired resistant strains, although
resistance to vancomycin is also emerging.
2.3 Antifungals
Fungal infections are becoming more common. Organ and bone marrow transplantation, cytotoxic chemotherapy,
long-term indwelling IV catheters, and the increased use of potent broad-spectrum antibiotic agents have contrib-
uted to the increase in fungal infections. Immunocompromised patients are at increased risk for fungal infections.
Systemic fungal infections include histoplasmosis, coccidioidomycosis, cryptococcosis, blastomycosis, paracoc-
cidioidomycosis, and sporotrichosis. Most systemic fungal infections are acquired via inhalation. Fungi are eukary-
otes with unique cell walls containing glucans and chitin, and their eradication requires different strategies than those
used for treatment of bacterial infections. Antifungals work by inhibiting synthesis of cell wall components, synthesis
of nucleic acids, or microtubule/mitotic spindle function. As with most infections, host factors contribute greatly to
the clinical outcome for patients with fungal infections. An antifungal agent may provide for cure of an infection de-
spite in vitro resistance because the immune system may eradicate the infection, or the antifungal agent may achieve
high concentrations at the infection site, allowing the drug to overcome high MICs.
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Resistance can be categorized as clinical or microbiological. Clinical resistance refers to treatment failure because
of factors other than microbial resistance; microbial resistance can refer to either primary or secondary resistance, as
determined by in vitro susceptibility testing using standardized methodology. Primary (intrinsic) resistance is pres-
ent prior to drug exposure. Secondary (acquired) resistance develops after exposure to an antifungal agent; it can be
reversible in some cases. The clinical consequences of antifungal resistance can take the form of treatment failure and
changes in the prevalence of the fungal species causing disease. Antifungal resistance has been reported in Candida
albicans as well as C. glabrata, C. tropicalis, and C. krusei isolates.
Several antifungal classes are available. Amphotericin B, a polyene, binds to sterols in the fungal cell mem-
brane, leading to alterations in cell permeability and cell death. It is available in four formulations; each has relative
advantages and disadvantages. Newer liposomal formulations are associated with less toxicity than the older ones,
however, renal toxicity remains one of the most prominent clinical concerns. Imidazoles and triazoles have a similar
spectrum of activity and mechanism of action. The azoles are agents that require significant hepatic metabolism and
often strongly compete with other drugs using the same pathway through the liver. For this reason, these agents are
associated with drug–drug interactions that may limit their use. The echinocandins are used primarily for invasive
candidiasis and aspergillosis. Griseofulvin is used for mycotic disease of the skin, hair, and nails due to Microsporum,
Trichophyton, or Epidermophyton species. Topical antifungal treatment is useful for superficial infections that are
confined to the stratum corneum, squamous mucosa, or cornea. In addition, creams for vaginal use are available to
treat vaginal candidiasis.
Allylamines
Terbinafine
Azoles
Efinaconazole
Fluconazole
Isavuconazonium sulfate
Itraconazole
Ketoconazole
Luliconazole
Posaconazole
Voriconazole
Echinocandins
Anidulafungin
Caspofungin
Micafungin
Oxaboroles
Tavaborole
Polyenes
Amphotericin B
Nystatin
Pyrimidines
Flucytosine
Miscellaneous Antifungal Agents

Griseofulvin
Potassium iodide (see also the Thyroid Hormones section in the Hormones and Synthetic Substitutes chapte)
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A 56-year-old woman is diagnosed with mucormycoses involving the maxillary sinuses. An infectious diseases con-
sultant recommends that she be treated with amphotericin B.
1. Which formulations of amphotericin B are available for her treatment?

a. C-AMB, L-AMB, ABLC, ABCD
b. C-AAB, L-AAB, ABBC, AAAD
c. C-BBA, LBBB, ABBA, ADDA
d. CAAA, LAAB, ABBL, ADDD
Answer A is correct. Four formulations of amphotericin B are commercially available: conventional amphotericin B (C-AMB),
liposomal amphotericin B (L-AMB), amphotericin B lipid complex (ABLC), and amphotericin B colloidal dispersion (ABCD).
2. The patient requests more information about the amphotericin options available to her. What
would you advise her about the major difference in these formulations?
a. Degree of infusion reaction
b. Blood concentration achieved
c. Indications for use
d. All of these are major differences.
Answer D is correct. C-AMB is insoluble in water, but is formulated for intravenous use by complexing it with a bile salt, de-
oxycholate. ABCD forms a colloidal solution when dispersed in water and is present in much lower blood concentrations than
C-AMB. Infusion reactions of chills and fever are more commonly noted with ABCD than with C-AMB. L-AMB is supplied as a lyo-
philized powder and achieves blood concentrations equivalent to those for C-AMB. L-AMB is approved for empirical therapy of
fever in the neutropenic host not responding to appropriate antibacterial agents, as well as for salvage therapy in patients with
aspergillosis and candidiasis. ABLC provides blood concentrations of amphotericin B that are much lower than those achieved
with the same dose of C-AMB. ABLC is approved for salvage therapy of deep mycoses. The lipid formulations appear to reduce
the risk of nephrotoxicity during therapy. The costs of the lipid formulations of amphotericin B greatly exceed the cost of C-AMB.
3. The patient requests information on how these medications will “fight her infection.” How would
you describe the mechanism of action of amphotericin?
a. Binds to the membranes of fungi, increasing permeability
b. Decreases permeability of the fungal membrane, causing fungal dehydration
c. Forms a calcified cell membrane
d. Triggers preprogrammed cell death
Answer A is correct. The antifungal activity of amphotericin B depends principally on its binding to a sterol moiety, primarily
ergosterol, in the membrane of sensitive fungi. By virtue of their interaction with these sterols, polyenes appear to form pores
or channels that increase the permeability of the membrane, allowing the outward leakage of a variety of small molecules.
4. The patient is concerned about side effects of amphotericin B. Which serious, untoward effects
should be watched for in this patient?
a. Hepatic impairment
b. Renal impairment
c. Hair loss
d. Constipation
Answer B is correct. Major untoward effects of amphotericin B are infusion-related reactions such as fever and chills. These are
most severe with ABCD, slightly less severe with C-AMB, even less severe with ABLC, and least severe with L-AMB. Nephrotoxicity,
a major concern with amphotericin B use, is dose dependent, usually transient, and increased by concurrent therapy with other
nephrotoxic agents such as aminoglycosides or cyclosporine. Permanent functional renal impairment is uncommon in adults
with normal renal function prior to treatment. Hypochromic, normocytic anemia commonly occurs during treatment with C-AMB.
A 19-year-old woman with coccidioidal meningitis is being treated with fluconazole. Her parents (who have received
HIPAA clearance from the patient) and she request information about why fluconazole was chosen instead of am-
photericin B.
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1. Which of the following statements is the best response?

a. Fluconazole is the least expensive antifungal drug available.
b. Fluconazole is the drug of choice for this type of fungal infection.
c. Fluconazole has less potential to cause stomach irritation.
d. Fluconazole will not interfere with the patient’s oral contraceptive.
Answer B is correct. Fluconazole is the drug of choice for the treatment of coccidioidal meningitis because of its good pene-
tration into cerebrospinal fluid and its much lower morbidity compared to intrathecal amphotericin B.
2. The patient is a new pharmacy technician and is learning about medication side effects as she
works in the pharmacy. She wants to know which major issues and limitations are involved with
the use of fluconazole, an azole antifungal. What do you tell her?
a. There are none; fluconazole is 100% safe to use.
b. Fluconazole has numerous drug interactions that must be considered.
c. Fluconazole should not be used in patients older than age 50.
d. Fluconazole is not covered by most insurance plans and is expensive.
Answer B is correct. Fluconazole competes with other drugs that are metabolized through the liver and for this reason
drug–drug interactions limit its use.
2.4 Antimycobacterials
Agents used for the treatment of mycobacterial infections, including tuberculosis (TB), leprosy, and infections due to
nontuberculous mycobacteria (NTM), are administered in multiple-drug regimens for prolonged courses. Because
these pathogenic organisms grow slowly, treatment requires a much longer course of therapy compared with most
bacterial infections. Combination therapy is needed because of the high rate of intrinsic resistance mutations as well
as mutations that develop during treatment.
The incidence of TB (i.e., Mycobacterium tuberculosis infection) has been declining in the United States;
however, TB remains a leading cause of morbidity and mortality in developing countries. In addition to effective
drug regimens, a well-organized infrastructure for diagnosis and treatment of TB, including both therapeutic
and control efforts, is needed to ensure successful individual and public health outcomes. Infections with NTM
have become more common because of the increased number of immunocompromised hosts and persons with
structural lung disease.
Even though a multiple-drug regimen is used, typically 3–6 months of treatment is required to e radicate
drug-susceptible TB. Latent TB infection (LTBI) and active TB disease are diagnosed based on the patient’s
history, physical examination, radiographic imaging, tuberculin skin test (TST), interferon-γ release assays
(IGRA), acid-fast staining, and/or mycobacterial cultures. Active TB disease is treated with regimens that
include an initial phase of 2 months (daily isoniazid, rifampin, pyrazinamide and ethambutol), followed by
a choice of several options for the continuation phase—either 4 or 7 months (typically the combination of
isoniazid and rifampin is used for drug susceptible TB) for a total of 6 or 9 months of treatment. Multiple drug
combination treatment has decreased the risk of resistance and has also led to a reduction in total treatment
duration. LTBI is treated with isoniazid (optimally given daily or twice weekly for 6–9 months), rifampin (daily
for 4 months), or isoniazid plus rifapentine (weekly for 3 months). Any regimen with weekly or twice-weekly
dosing (anything less frequent than daily) requires directly observed therapy (DOT) to ensure adequate adher-
ence to the regimen. If significant clinical improvement does not occur or the patient’s clinical status worsens,
then treatment failure due to nonadherence, poor medication absorption, or development of resistance should
be considered. If resistance is documented or strongly suspected, at least two efficacious drugs to which the
isolate is susceptible or which the patient has not already taken should be added to the therapeutic regimen.
Due to the high risk of drug–drug interactions with both isoniazid and rifamin, any exaggerated side effects or
suboptimal therapeutic responses should be evaluated based on the potential for interaction in light of other
medications the patient is taking.
Multidrug-resistant TB (MDR-TB) is caused by a strain of M. tuberculosis that is resistant to both isoniazid
and rifampin. The risk of MDR-TB is elevated in patients presenting from specific geographic areas in which 5% or
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more of incident cases involve MDR-TB and in patients previously treated for TB. Treatment regimens for MDR-TB
generally include a susceptible fluoroquinolone and an injectable second-line agent (such as capreomycin or amika-
cin). Regimens of at least five drugs are recommended for the treatment of MDR-TB. Extensively drug-resistant TB
(XDR-TB) is MDR-TB with additional resistance to any fluoroquinolone and at least one of the second-line injectable
agents. Treatment of XDR-TB is individualized on the basis of complete phenotypic and, if possible, genotypic an-
timicrobial susceptibility testing. Therapeutic regimens for either MDR-TB or XDR-TB should be constructed with
input from experienced clinicians, who should continue the management of the disease.
Antimycobacterial Agents
Antituberculosis Agents
Aminosalicylic acid
Bedaquiline
Capreomycin
Cycloserine
Ethambutol
Ethionamide
Isoniazid
Pyrazinamide
Rifabutin
Rifampin
Rifapentine
Amikacin (see also the Antibacterials section)
Ciprofloxacin (see also the Antibacterials section)
Clarithromycin (see also the Antibacterials section)
Levofloxacin (see also the Antibacterials section)
Moxifloxacin (see also the Antibacterials section)
Streptomycin (see also the Antibacterials section)
Miscellaneous Antimycobacterial Agents

Dapsone

A 55-year-old male has returned from traveling to India for 3 months. He returns with a productive cough and chest
x-ray indicative of TB.
1. Which medication(s) should be initiated in this patient?

a. Isoniazid for 9 months
b. Isoniazid and rifampin for 6 months
c. Isoniazid, rifampin, and pyrazinamide for 6 months
d. Isoniazid, rifampin, pyrazinamide, and ethambutol for up to 9 months
Answer D is correct. Regimens for treating TB disease are based on an initial phase lasting 2 months (daily isoniazid, rifampin,
pyrazinamide, and ethambutol), followed by a choice of several options for the continuation phase—either 4 or 7 months
(typically the combination of isoniazid and rifampin is used for drug-susceptible TB), for a total of 6 or 9 months for treatment.
Combination anti-TB therapy is recommended for treatment of TB because resistance quickly develops when these medica-
tions are used alone. The probability that resistance will emerge when the regimen includes more than 2 drugs is small. Multi-
drug therapy has also led to a reduction in the length of therapy to 6–9 months.
When TB bacteria become active (multiplying in the body) and the immune system cannot stop the bacteria
from growing, the condition is called TB disease. People with TB disease may spread the bacteria to people with
whom they spend many hours. TB medication adherence is important to prevent treatment failure, TB spread, and
resistance. MDR-TB is more difficult and more expensive to treat compared with susceptible strains.
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2. Which drug interaction education should this patient be warned about with isoniazid?
a. Isoniazid is a potent competitor (inhibitor) of drug metabolism and is responsible for many drug
interactions.
b. Isoniazid is not metabolized by the liver and therefore is not subject to drug interactions.
c. Isoniazid is only a potential drug interaction problem when taken with rifampin.
d. Isoniazid should never be taken with any other drug because it is dangerous to do so.
Answer A is correct. Isoniazid is a potent inhibitor of specific liver enzymes well known to be responsible for numerous drug
interactions. Drugs metabolized by competing liver enzymes will potentially be affected by the patient’s use of isoniazid.
A 37-year-old respiratory therapist with no past medical history has a positive (more than 10 mm) tuberculin skin
test (TST) and normal chest x-ray. She is employed full time at the university hospital.
1. Which medication therapy, if any, should this patient receive?

a. Isoniazid for 3 months
b. Isoniazid for 9 months or rifampin for 4 months
c. Isoniazid, rifampin, and pyrazinamide for 6 months
d. No therapy is needed since TST < 15 mm.
Answer B is correct. People with latent TB infection do not have symptoms, and they cannot spread TB bacteria to others.
These individuals should receive treatment to prevent them from developing active TB disease—a step that is essential for
controlling and eliminating TB. Groups who should be given high priority for latent TB infection treatment (not a complete
list) include HIV-infected persons, organ transplant recipients, and persons with a positive IGRA result or a TST reaction of 10
mm or more, including residents and employees of high-risk congregate settings (e.g., correctional facilities, nursing homes,
homeless shelters, hospitals, and other healthcare facilities). Persons with no known risk factors for TB may be considered for
treatment of LTBI if they have a positive IGRA result or if their reaction to the TST is 15 mm or greater. For patients with a pos-
itive TST, no symptoms, and normal chest x-ray, drug therapy with isoniazid for 6–9 months, rifampin for 4 months, or combi-
nation isoniazid plus rifapentine for 3 months is appropriate for treatment of their latent TB.
2. What is a potential adverse effect of isoniazid therapy in this otherwise healthy woman with
adequate nutrition?
a. Nephrotoxicity
b. Cardiac toxicity
c. Hepatotoxicity
d. Peripheral neuropathy
Answer C is correct. Isoniazid is converted to acetyl isoniazid, which can be converted to acetyl hydrazine and hepatotoxic
metabolites. Rapid acetylators will form diacetyl hydrazine, which is nontoxic; slow acetylators or CYP2E1 induction will lead
to more hepatotoxic metabolites. Rifampin, a potent inducer of CYP2E1, potentiates isoniazid hepatotoxicity. Isoniazid also
can cause a peripheral neuropathy in patients who are deficient in vitamin B6 (pyridoxine).
3. Which adverse effect(s) from rifampin use should this patient be warned about?
a. Orange-tan discoloration of skin, urine, and contact lenses
b. Peripheral neuritis
c. Cardiac toxicity
d. Nephrotoxicity
Answer A is correct. Orange-tan discoloration of the skin, urine, feces, saliva, tears, and contact lenses is possible with rifampin.
2.5 Antivirals
Viruses replicate intracellularly and often use host cell enzymes, macromolecules, and organelles to make viral parti-
cles. Therefore, useful antiviral compounds must discriminate between host and viral functions with a high degree of
specificity; agents without such selectivity would be too toxic for clinical use.
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Viruses are simple microorganisms made up of double- or single-stranded DNA or RNA enclosed in a protein
coat (capsid). Effective antiviral agents inhibit virus-specific replicative events or inhibit virus-directed nucleic acid
or protein synthesis. Nonspecific antiviral agents (e.g., interferons) have multiple mechanisms of action that include
modulation of the host’s immune responses. DNA viruses include poxviruses (smallpox), herpesviruses (chickenpox,
shingles, herpes), adenoviruses (conjunctivitis, sore throat), hepadnaviruses (hepatitis B [HBV]), and papillomavi-
ruses (warts). Antiviral agents work best when administered early (when infection is first recognized). As is the case
with antibiotics, antiviral agents are also susceptible to mutation and resistance. For example, with some miscella-
neous antivirals, such as foscarnet, resistant clinical isolate of herpes viruses have emerged during therapeutic use
and may be associated with poor clinical response.
Interferons
Interferons (IFNs) are biological response modifiers with antiviral and immunomodulatory activity. IFN-α (leuko-
cyte interferon) and IFN-β (fibroblast interferon) are released by human cells infected with certain viruses, whereas
IFN-γ (immune interferon) is produced by natural killer cells (T-cell lymphocytes) in response to antigen exposure.
These cytokines then act on uninfected host tissue cells to induce a state of relative resistance to viral infections. IFNs
bind to cell-surface receptors that initiate the induction of certain enzymes, inhibition of cell proliferation, enhance-
ment of immune activities (including increased phagocytosis by macrophages), and augmentation of cytotoxicity
by T cells. IFNs are not absorbed orally because of their large amino acid sequence, which is digested by proteolytic
enzymes in the digestive tract.
IFN-α is rapidly absorbed after both intramuscular and subcutaneous injection, and frequent injections are
needed to maintain adequate serum concentrations. The available products are now chemically modified with poly-
ethylene glycol (PEG) to extend their half-life and allow for once-weekly dosing. In addition, adverse effects are re-
duced because of the lowered peak concentration. IFN-α is used to treat chronic hepatitis C infections.
IFN-β products have antiviral properties but are used for multiple sclerosis, not infections. IFN-γ1b injection is
used for prevention of infections in patients with chronic granulomatous disease in combination with antibacterials
and antifungals. In rare cases, IFN-γ is used as salvage therapy for mycobacterial infections.
Topical imiquimod creams do not have inherent antiviral activity alone, but instead induce IFN-α, IFN-β, and
IFN-γ plus tumor necrosis factor alpha (TNF-α). Local application of these medications to external genital and peri-
anal warts stimulates an immunomodulatory response that produces cytokines, which have antiviral action and re-
duce viral load and wart size.
Monoclonal Antibodies
Antibodies (immunoglobulins) are produced by B cells of the immune system. Antibodies neutralize and eliminate
the infectious agents and toxins produced by pathogens. They are found in blood, plasma, and extracellular fluids.
Antibodies’ Y-shaped structures contain two identical variable-region antigen binding sites, with the lower (constant)
region being responsible for the initiation of effector functions that lead to the removal and destruction of the patho-
gen or cells harboring the pathogen. The antigen binding sites on an antibody can bind to and neutralize bacterial
toxins and viruses, thereby preventing them from binding to their target cells or receptors and thereby causing toxic
effects or spread of the infection.
Antibodies being developed for treatment of diseases in humans are highly purified and are mostly fully human
monoclonal antibodies. The term monoclonal antibody (mAb) refers to the cell cultures used—that is, a single cell line
that produces one specific antibody. Antibodies are specific to a single virus, bacterium, or bacterial subtype. Muta-
tions can render the antibody ineffective; however, the mutation would not affect other similar agents and would not
cause resistance to spread. Only one monoclonal antibody, palivizumab, is approved for treatment of infection—that
is, for the prevention and treatment of respiratory syncytial virus (RSV) infection in high-risk children.
Antiretroviral Agents
Infection with human immunodeficiency virus (HIV) may occur through a sexual, parenteral, or perinatal route.
Sexual intercourse, primarily receptive anal and vaginal intercourse, is the most common method for HIV trans-
mission. HIV infects cells expressing cluster of differentiation 4 (CD4) receptors, such as T-helper lymphocytes,
monocytes, macrophages, dendritic cells, and brain microglia. Untreated HIV infection leads to depletion of CD4 T
lymphocytes and immunosuppression that increases the patient’s risk of opportunistic infections (OIs). Untreated
OIs and a lack of effective antiretroviral therapy (ART) are the main causes of HIV morbidity and mortality.
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The current goal of ART is to achieve maximum and durable suppression of HIV replication or a level of HIV
RNA in plasma (viral load) less than the lower limit of quantification. Another, equally important outcome is an
increase in CD4 lymphocytes, as their number closely correlates with the risk for developing OIs. Prophylaxis with
antiretroviral agents in at-risk persons lowers HIV acquisition risk.
Clinical use of antiretroviral agents is complicated by drug–drug interactions. Some interactions are beneficial
and used purposely; others may be harmful, leading to dangerously elevated or inadequate drug concentrations.
For these reasons, clinicians involved in the pharmacotherapy of HIV infection must exercise constant vigilance
and maintain a current knowledge of drug interactions. Current recommendations for the initial treatment of HIV
advocate the use of a minimum of three active antiretroviral agents from at least two drug classes.
The typical HIV regimen consists of two nucleoside/nucleotide analogues plus either a “boosted” prote-
ase inhibitor (PI)—utilizing a purposeful drug interaction that results in an increased blood concentration of the
PI—a non-nucleoside reverse transcriptase inhibitor, or an integrase strand transfer inhibitor (InSTI). Inadequate
suppression of viral replication allows HIV to select for antiretroviral-resistant HIV variants; this possibility is a ma-
jor factor limiting the ability of antiretroviral drugs to inhibit virus replication. Current recommendations for treating
drug-resistant HIV include choosing at least two drugs (preferably three) to which the patient’s virus is susceptible.
Susceptibility can be assessed using either virtual genotypic or phenotypic resistance testing.
The longer life span conferred by antiretroviral treatment has given rise to other medical issues. Complications
associated with older age have become common, some of which are adverse effects from antiretroviral drugs.
Hepatitis C virus (HCV) coinfection is an important cause of morbidity and mortality in these patients. Medical
management of these contemporary HIV complications is constantly evolving.
Adamantanes
Amantadine
Rimantadine
Antiretrovirals
HIV Entry and Fusion Inhibitors
Enfuvirtide
Maraviroc
HIV Protease Inhibitors

Atazanavir
Darunavir
Fosamprenavir
Indinavir
Lopinavir and ritonavir
Nelfinavir
Ritonavir
Saquinavir
Tipranavir
HIV Integrase Inhibitors

Dolutegravir
Elvitegravir and cobicistat
Raltegravir
HIV Non-nucleoside Reverse Transcriptase Inhibitors

Delavirdine
Efavirenz
Etravirine
Nevirapine
Rilpivirine
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HIV Nucleoside and Nucleotide Reverse Transcriptase Inhibitors

Abacavir
Didanosine
Emtricitabine
Lamivudine
Stavudine
Tenofovir
Zidovudine
Interferons
Interferon alfa
Peginterferon alfa
Neuraminidase Inhibitors
Oseltamivir
Peramivir
Zanamivir
Nucleosides and Nucleotides

Acyclovir
Adefovir
Cidofovir
Entecavir
Famciclovir
Ganciclovir
Ribavirin
Telbivudine
Valacyclovir
Valganciclovir
HCV Antivirals
NS5B Polymerase inhibitors
Dasabuvir
Sofosbuvir
NS3/4A Protease Inhibitors

Grazoprevir
Paritaprevir
Simeprevir
NS5A Replication Complex Inhibitors

Daclatasvir
Elbasvir
Ledipasvir
Ombitasvir
Antivirals: Miscellaneous
Foscarnet
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A 73-year-old man with no other health issues developed a rash on his back yesterday. He now complains of
considerable pain in the area. You suspect varicella zoster virus (VZV) infection (shingles).
1. What is the best treatment option for this patient?

a. Acyclovir within 7 days of rash presentation
b. Valacyclovir within 24 hours of rash presentation
c. Penciclovir within 5 days of rash presentation
d. Famciclovir within 3 days of rash presentation
Answer B is correct. The two drugs most commonly used for VZV infections are acyclovir and penciclovir, or their pro-
drugs, valacyclovir and famciclovir, respectively. Both drugs are most effective if started within 24 hours of the rash’s
appearance.
A 23-year-old man with AIDS has begun to develop blurred vision in his left eye. The diagnosis of cytomegalovirus
(CMV) retinitis is made. The patient is started on intravenous foscarnet.
1. Regardless of the initial choice of IV foscarnet, which treatment option is not recommended for the
treatment of CMV retinitis?
a. Ganciclovir
b. Famciclovir
c. Fomivirsen
d. Cidofovir
Answer B is correct. The treatment options for CMV retinitis include foscarnet, ganciclovir, fomivirsen, and cidofovir. Fomi-
virsen is given by intravitreal injection for patients intolerant of or unresponsive to other therapies.
2. Which of the following statements is true regarding development of resistance to foscarnet?

a. R esistant clinical isolates of adenoviruses have emerged during therapeutic use of foscarnet and may be
associated with poor clinical response.
b. CMV strains that are resistant to foscarnet have point mutations in the viral DNA polymerase and are
associated with 3- to 7-fold reductions in foscarnet activity in vitro.
c. Herpesviruses that are resistant to foscarnet have point mutations in the viral DNA polymerase and are
associated with 3- to 7-fold reductions in foscarnet activity in vitro.
d. Resistant clinical isolates of noroviruses have emerged during therapeutic use of foscarnet and may be
associated with poor clinical response.
Answer C is correct. Resistant clinical isolates of herpesviruses have emerged during therapeutic use of foscarnet and may be
associated with poor clinical response. Herpesviruses resistant to foscarnet have point mutations in the viral DNA polymerase
and are associated with 3- to 7-fold reductions in foscarnet activity in vitro.
3. This patient should be monitored for which major adverse effects while on foscarnet?
a. Nephrotoxicity and symptomatic hypocalcemia
b. Nephrotoxicity and hyponatremia
c. Hepatoxicity and hyponatremia
d. Hepatoxicity and symptomatic hypocalcemia
Answer A is correct. The dose-limiting toxicities associated with foscarnet are nephrotoxicity and symptomatic
hypocalcemia. Acute tubular necrosis, crystalline glomerulopathy, nephrogenic diabetes insipidus, and interstitial nephritis
have been described. Saline loading may reduce the risk of nephrotoxicity. Foscarnet is highly ionized at physiological pH,
and metabolic abnormalities are common—for example, increases or decreases in calcium and phosphate, hypomagnese-
mia, and hypokalemia. Decreased serum ionized calcium may cause paresthesia, arrhythmias, tetany, seizures, and other CNS
disturbances.
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2.6 Antiprotozoals
Antiprotozoal drugs are a class of medications used to treat infections caused by protozoa (single-cell organisms)
that can act as parasites. Amebiasis, giardiasis, trichomoniasis, toxoplasmosis, cryptosporidiosis, trypanosomiasis,
and leishmaniasis are common protozoal infections seen worldwide. Protozoa multiply rapidly, and effective vaccines
against them are not available. Therapy of protozoal infections often requires multiple drugs, but antiprotozoal drugs
have severe toxicities that require careful monitoring.
Giardiasis is the most commonly reported protozoal infection in the United States. Trichomoniasis is a sexually
transmitted disease that is common in the United States. Treatment of patients with giardiasis or trichomoniasis us-
ing either metronidazole or tinidazole is usually successful.
Malaria is transmitted by the bite of an infected Anopheles mosquito that introduces the sporozoites (tissue para-
sites) of the plasmodia (Plasmodium falciparum, P. vivax, P. malariae, P. ovale, and P. knowlesi) into the bloodstream.
P. vivax and P. ovale have life stages that can remain in the liver, and specific antiparasitic drugs are necessary to treat
the liver stages of these organisms.
Giardiasis
The acute presentation of giardiasis is characterized by diarrhea, cramping abdominal pain, bloating, flatulence, mal-
aise, anorexia, nausea, and belching. Chronic presentation includes diarrhea (foul-smelling, copious, light-colored,
fatty stools) and weight loss. Periods of diarrhea may alternate with constipation. Steatorrhea, lactose intolerance, and
vitamin B12 and fat-soluble vitamin deficiencies may also be present. For patients with prolonged diarrhea and mal-
absorption with a history of recent travel to an endemic area, rapid identification based on ova and parasites exam-
ination or an antigen detection test should be performed so as to institute appropriate therapy.
Giardiasis can be prevented with good personal hygiene and avoiding potentially contaminated food and drink. All
symptomatic adults and children (older than 8 years) with giardiasis can be treated with metronidazole 250 mg 3 times
daily for 5–10 days or tinidazole 2 g once or nitazoxanide 500 mg twice daily for 3 days. Metronidazole cures 80% to
90% of cases and is the agent most commonly used to treat giardiasis. This treatment regimen also prevents the infected
person from shedding infection to others which is described as the development of a carrier state. Diarrhea should cease
within 2–3 days, although it may take as long as 2 weeks to end. Patients who do not respond to the initial therapy with
metronidazole should be switched to a drug from a different class, such as nitazoxanide (500 mg twice daily for 3 days).
Malaria
Malaria is a devastating disease in terms of its burden of human suffering and economics. As many as 500 million new
infections and 2 million deaths are reported annually worldwide. Deaths occur in patients because of lack of access to or
failure to take chemoprophylaxis, inappropriate chemoprophylaxis, delay in seeking medical care, or misdiagnosis. In
the United States, most cases of malaria are reported in immigrants from endemic areas and in travelers to these areas.
Symptoms of malaria vary based on the course of the disease. At their initial presentation, patients may com-
plain of nonspecific fever, chills, rigors, diaphoresis, malaise, vomiting, and lightheadedness. During the erythrocytic
phase (when the plasmodia attack erythrocytes), patients may complain of headache, anorexia, malaise, fatigue, and
myalgia as well as abdominal pain, diarrhea, chest pain, and arthralgia. Complications such as hypoglycemia, pulmo-
nary edema, and renal failure are associated with increased mortality. Blood smears should be obtained every 12–24
hours for 3 consecutive days. The presence of parasites in the blood 3–5 days after initiation of therapy suggests drug
resistance. Recent advances in detecting malaria parasite have included DNA or RNA probes that utilize polymerase
chain reaction (PCR) and rapid dipstick tests. The dipstick is reported to have a sensitivity of 88% and a specificity of
97%; however, microscopy is still considered the optimal test.
Chemoprophylaxis has traditionally consisted of chloroquine phosphate 300 mg (base) once weekly beginning
1–2 weeks prior to departure to the endemic areas and continued for 4 weeks after leaving the endemic area. When
departing an area where P. vivax or P. ovale is endemic, primaquine phosphate 30 mg (base) daily for 14 days, begin-
ning during the last 2 weeks of chloroquine prophylaxis, should be added to the regimen. When advising potential
travelers on prophylaxis for malaria, be aware of the incidence of chloroquine-resistant P. falciparum (CRPF) and the
countries where in which this variant is prevalent. In these areas, commonly recommended drugs for malaria pro-
phylaxis include mefloquine, atovaquone/proguanil, or doxycycline.
The adult dose of mefloquine is 250 mg once weekly, beginning 1 week prior to departure and continuing for
the full period of exposure, followed by 250 mg for 4 weeks after last exposure. Treatment regimens require different
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doses and schedules, however, chloroquine is still currently the recommended drug of choice for most cases of un-
complicated malaria (refer to drug grid for further detail). All patients receiving mefloquine should receive the FDA
Medication Guide; note that this agent is contraindicated in patients with a history of cardiac conduction problems.
Patients may experience neuropsychiatric reactions (seizures, psychosis, anxiety, sleep disturbances, insomnia, and
dizziness) from mefloquine and should be monitored closely.
Doxycycline is an alternative option for chemoprophylaxis that avoids the central nervous system side effects.
However, it requires daily dosing, can increase sun sensitivity, and should be avoided in children and pregnant women.
Atovaquone/proguanil is generally well tolerated and preferred by many travelers. This regimen is more expen-
sive than most malaria prophylaxis medications, which may be a barrier to its use.
Detailed recommendations for prevention of malaria may be obtained by checking the Centers for Disease Con-
trol and Prevention’s (CDC) website: www.cdc.gov/travel.
Amebicides
Iodoquinol
Paromomycin
Metronidazole (see also Miscellaneous Antiprotozoals section)
Antimalarials
Artemether and lumefantrine
Atovaquone and proguanil
Chloroquine
Hydroxychloroquine
Mefloquine
Primaquine
Pyrimethamine
Quinine
Quinidine (see also the Cardiac Drugs section in the Cardiovascular Agents chapter)
Miscellaneous Antiprotozoals
Atovaquone
Metronidazole
Nitazoxanide
Pentamidine
Tinidazole
Co-trimoxazole (see also the Antibacterials section)
Dapsone (see also the Antimycobacterials section)

A 35-year-old woman presents with a history of diarrhea and abdominal pain for the past 3 days. She recently re-
turned from a whitewater rafting trip. During the trip, she fell out of the boat; although she had a life preserver on,
she swallowed considerable amounts of river water. She is diagnosed with giardiasis, and treatment should begin after
obtaining appropriate specimens.
1. How is the diagnosis of giardiasis made?

a. Identification of cysts or trophozoites in feces
b. Based on history and clinical presentation
c. Microscopic analysis of blood sample
d. Identification of cysts in duodenal contents
Answer A is correct. Giardiasis, which is caused by the protozoan Giardia lamblia, is prevalent worldwide and is the most
common intestinal protozoal infection in the United States. Giardia is a zoonosis, and cysts shed in the feces of animals and
humans can contaminate recreational and drinking water supplies. Infection with Giardia results in an asymptomatic carrier
state, acute self-limited diarrhea, or chronic diarrhea. The diagnosis of giardiasis is made by identification of cysts or tropho-
zoites in fecal specimens or of trophozoites in duodenal contents.
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2. What is the most appropriate therapy to limit the acute diarrhea, prevent the development of
chronic diarrhea, and prevent the development of a “carrier state” in patients with giardiasis?
a. Nitazoxanide
b. Pentamidine
c. Metronidazole
d. Co-trimoxazole
Answer C is correct. Chemotherapy with a 5-day course of metronidazole or a single dose of tinidazole is usually successful in eradi-
cating giardiasis. Paromomycin has been used to treat pregnant women to avoid any possible mutagenic effects of the other drugs.
A 38-year-old male with no significant past medical history has returned from traveling to Nicaragua. He forgot to
take chemoprophylaxis for malaria and now presents with fever, chills, rigors, and diaphoresis.
QT therapy should be initiated in this patient?

1. Which
a. Chloroquine 600 mg
b. BL Quinine 648 mg
c. Mefloquine 250 mg
d. Quinidine 300 mg
PD
Answer A is correct. In an uncomplicated attack of malaria (for all plasmodia except CRPF), the recommended regimen is
chloroquine 600 mg (base) initially, followed by 300 mg (base) 6 hours later, and then 300 mg (base) daily for 2 days.
GD
Tips from the Field

Worms
1. Diagnosis of tape worms and pinworms is generally made by detection of eggs in stool. Stool should be
analyzed for the characteristic eggs, such as for the Ascaris lumbricoides-“round worm.” Because of a very
high egg burden, sample concentration techniques are generally not needed to make the diagnosis.
2. Patients may assist in diagnosis of pinworms with cellophane tape used to collect the eggs from the
perianal area and collected in the morning before bathing or using the toilet. The tape is removed and
brought in for examination under a microscope. The sensitivity of the tape test is about 50% for a one-
time collection and 90% for three collections.
Other Pearls
1. Remember:
• Systematic Approach for Selection of Antimicrobials (details provided earlier in this chapter).
• Refer to guidelines prior to ordering/administering subacute bacterial endocarditis (SBE) prophylaxis
to patients as the criteria for use have become more restrictive in order to reduce the overuse and
unnecessary use of antibiotics.
2. If a bacterial otitis media infection is established:

• Watchful waiting is encouraged for uncomplicated cases for which reliable follow-up is available.
• Amoxicillin or amoxicillin/clavulanate is the recommended first-line therapy.
• Macrolides, such as azithromycin, are not recommended due to high levels of Streptococcus pneumo-
niae antibiotic resistance (approximately 40%).
• For penicillin-allergic patients, doxycycline or a respiratory fluoroquinolone (levofloxacin or moxi-
floxacin) are recommended alternative agents.
3. Routine treatment of uncomplicated acute bronchitis with antibiotics is not recommended, regardless
of cough duration. Options for symptomatic therapy include:
• Cough suppressants (codeine, dextromethorphan)
• First-generation antihistamines (diphenhydramine)
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• Decongestants (phenylephrine)
• Beta agonists (i.e., albuterol).
• Decongestants (pseudoephedrine and phenylephrine) combined with a first-generation
antihistamine—may provide short-term symptom relief of nasal symptoms and cough
• Non-steroidal anti-inflammatory drugs—can be given to relieve symptoms
Evidence is lacking to support antihistamines (as monotherapy), opioids, intranasal corticosteroids,
and nasal saline irrigation as effective treatments for cold symptom relief.
4. Providers and patients must weigh the benefits and harms of symptomatic therapy.
• Antibiotic treatment for pharyngitis is NOT recommended unless the patient has a positive rapid an-
tigen detection test (RADT) or culture with group A streptococci (GAS).
• Amoxicillin and penicillin V remain first-line therapy due to their reliable antibiotic activity against GAS.
• For penicillin-allergic patients, cephalexin, cefadroxil, clindamycin, or macrolides are recommended.
• GAS antibiotic resistance to azithromycin and clindamycin are increasingly common.
• Recommended treatment course for all oral β-lactams is 10 days.
5. For acute uncomplicated cystitis in healthy adult non-pregnant, premenopausal women:
• Nitrofurantoin, trimethoprim/sulfamethoxazole (TMP-SMX)—where local resistance is <20%—and
fosfomycin are appropriate first-line agents.
• Fluoroquinolones (e.g., ciprofloxacin) should be reserved for situations in which other agents are not
appropriate.
6. For most agents that require nebulized inhalation administration (such as tobramycin):
• The solution for nebulization is administered by inhalation only. Do not administer subcutaneously,
intravenously, or intrathecally. Use care when ordering and administering.
• Do not dilute or mix with other medicines in the nebulizer (unless there are specific manufacturer’s
directions that offer these administration alternatives).
• Administer nebulized solution for inhalation while the patient is sitting or standing upright and
breathing normally through the mouthpiece of the nebulizer.
• Encourage gradual inhalation over approximately 15 minutes, using a hand-held nebulizer as recom-
mended by the specific product manufacturer. Full treatment dose has been administered when the
mouthpiece makes a spitting noise for at least 1 minute and the nebulizer cup is empty.
7. For most agents that require administration of the powder for inhalation:
• Capsules are for oral inhalation only; do not swallow the capsules.
• Devices to use for powder inhalation are specific to product used.
• Clean, store, and/or replace device according to manufacturer recommendations.
• Encourage your patients to have a spare device as a backup in case of loss, breakage, or dysfunction
of primary device currently in use. Do not remove capsules from original package until ready to use.
• Become familiar with stewardship programs and appropriate prescribing (refer to http://www.cdc
.gov/getsmart/community/improving-prescribing/outpatient-stewardship.html).
8. For most agents that require reconstitution prior to use:
• Many of these anti-infective agent injections are supplied as powder that must be reconstituted
prior to administration.
• It is important to read instructions on the specific diluent to use, and how long the product is good
for once reconstituted.
• Keep in mind that refrigerated storage of reconstituted injections often allows a longer beyond use date.
• Always label and indicate date of reconstitution.
References
Acosta EP, Flexner C. Antiviral agents (nonretroviral). In: Brunton LL, Chabner BA, Knollmann BC, eds. Goodman and Gilman’s The
Pharmacological Basis of Therapeutics. 12th ed. New York, NY: McGraw-Hill; 2011:1593-1622.
American Geriatrics Society. 2015 updated Beers criteria for potentially inappropriate medication use in older adults. J Am Geriatr Soc.
2015;63:2227-2246.
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American Thoracic Society, Centers for Disease Control and Prevention, Infectious Diseases Society of America. Treatment of tuberculo-
sis. MMWR. 2003;52(No. RR-11):1-88. http://www.cdc.gov/mmwr/pdf/rr/rr5211.pdf. Accessed June 14, 2016.
Anandan JV. Parasitic diseases. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, eds. DiPiro Pharmacotherapy: A
Pathophysiologic Approach. 9th ed. New York, NY: McGraw-Hill; 2014:1835-1848.
Anderson PL, Kakuda TN, Fletcher CV. Human immunodeficiency virus infection. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells
BG, Posey LM, eds. DiPiro Pharmacotherapy: A Pathophysiologic Approach. 9th ed. New York, NY: McGraw-Hill; 2014:2031-2054.
Arguin PM, Tan KR. Infectious diseases related to travel. Malaria. In: Centers for Disease Control and Prevention (Ed.), 2014 Yellow Book -
Traveler’s Health. Atlanta, GA: U.S. Department of Health and Human Services, Public Health Service. 2014. http://wwwnc.cdc.gov
/travel/yellowbook/2014/chapter-3-infectious-diseases-related-to-travel/malaria
Baden LR, Dolin R. Antiviral chemotherapy, excluding antiretroviral drugs. In: Kasper DL, Fauci AS, Hauser SL, Longo DL, Jameson JL,
Loscalzo J, eds. Harrison’s Principles of Internal Medicine. 19th ed. New York, NY: McGraw-Hill; 2016.
Bennett JE. Antifungal agents. In: Brunton LL, Chabner BA, Knollmann BC, eds. Goodman and Gilman’s The Pharmacological Basis of
Therapeutics. 12th ed. New York, NY: McGraw-Hill; 2011:1571-1592.
Bergman SJ, Ferguson MC, Santanello C. Interferons as therapeutic agents for infectious diseases. Infect Dis Clin North Am.
2011;25(4):819-834. doi: 10.1016/j.idc.2011.07.008.
Carver PL. Invasive fungal infections. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, eds. DiPiro Pharmacotherapy:
A Pathophysiologic Approach. 9th ed. New York, NY: McGraw-Hill; 2014:1931-1962.
Centers for Disease Control and Prevention. Deciding when to treat latent TB infection. http://www.cdc.gov/tb/topic/treatment
/decideltbi.htm. Accessed June 14, 2016.
Centers for Disease Control and Prevention. Treatment regimens for latent TB infection (LTBI). http://www.cdc.gov/tb/topic/treatment
/ltbi.htm. Accessed June 14, 2016.
Centers for Disease Control and Prevention. Treatment for TB disease. http://www.cdc.gov/tb/topic/treatment/tbdisease.htm. Accessed
June 14, 2016.
Dellinger RP, Levy MM, Rhodes A, et al. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic
shock: 2012. Crit Care Med. 2013;41(2):580-637.
Flexner C. Antiviral agents and treatment of HIV infection. In: Brunton LL, Chabner BA, Knollmann BC, eds. Goodman and Gilman’s
The Pharmacological Basis of Therapeutics. 12th ed. New York, NY: McGraw-Hill; 2011:1623-1664.
Food and Drug Administration. FDA drug safety communication: FDA to review study examining use of oral fluconazole (Diflucan) in
pregnancy. http://www.fda.gov/Drugs/DrugSafety/ucm497482.htm. Accessed September 18, 2016.
Gumbo T. Chemotherapy of tuberculosis, Mycobacterium avium complex disease, and leprosy. In: Brunton LL, Chabner BA, Knollmann
BC, eds. Goodman and Gilman’s The Pharmacological Basis of Therapeutics. 12th ed. New York, NY: McGraw-Hill; 2011:1549-1570.
Hey A. History and practice: antibodies in infectious diseases. Microbiol Spectr. 2015;3(2):AID-0026-2014. doi: 10.1128/microbiolspec.
AID-0026-2014
Lee GC, Burgess DS. Antimicrobial regimen selection. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, eds. DiPiro
Pharmacotherapy: A Pathophysiologic Approach. 9th ed. New York, NY: McGraw-Hill; 2014:1661-1674.
McCarthy J, Loukas A, Hoetz PJ, Chemotherapy of helminth infections. In: Brunton LL, Chabner BA, Knollmann BC, eds. Goodman and
Gilman’s The Pharmacological Basis of Therapeutics. 12th ed. New York, NY: McGraw-Hill; 2011:1443-1462.
McEvoy GK, ed. AHFS: Drug Information. Bethesda, MD: American Society of Health-System Pharmacists; 2016.
O’Donnell MR, Reddy D, Saukkonen JJ. Antimycobacterial agents. In: Kasper DL, Fauci AS, Hauser SL, Longo DL, Jameson JL, Loscalzo J,
eds. Harrison’s Principles of Internal Medicine. 19th ed. New York, NY: McGraw-Hill; 2016.
Phillips MA, Stanley SL Jr. Chemotherapy of protozoal infections: amebiasis, giardiasis, trichomoniasis, trypanosomiasis, leishmaniasis,
and other protozoal infections. In: Brunton LL, Chabner BA, Knollmann BC, eds. Goodman and Gilman’s The Pharmacological Basis of
Therapeutics. 12th ed. New York, NY: McGraw-Hill; 2011:1419-1442.
Weller PF, Nutman TB. Intestinal nematode infections. In: Kasper DL, Fauci AS, Hauser SL, Longo DL, Jameson JL, Loscalzo J, eds.
Harrison’s Principles of Internal Medicine. 19th ed. New York, NY: McGraw-Hill; 2016.
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Symbols QT
QT
QT
Renal impairment: Dose adjustment is recommended. BL Beers list criteria (avoid in elderly).
BL
BL
PD
Hepatic impairment: Dose adjustment is recommended. PD FDA-approved pediatric doses are available.
PD
GD
9781284110562_CH02_Pass01.indd 41
GD
Black box warning exists for this drug. GD FDA-approved geriatric doses are available.
QT
QT QTc prolongation effects have been reported. See primary body system.
QT
BL
QT
BL
BL
PD
BL
PD QT
PD
Anti-infective Agents
GD BL
PD
GD
GD
Universal prescribing alerts: PD
GD
• Known serious hypersensitivity to the specific drug or any other component of the
GD product/formulation selected warrants a contraindication for use.
• Adverse reactions associated with the use of some anti-infective agents include dizziness, drowsiness, vertigo, or fatigue; these agents may also impair the ability to
perform tasks requiring mental alertness. Caution should always be recommended when using any new drug for the first time, when there is a dose change, and for
continued use of known offending agents.
• Doses expressed are for usual adult dosage ranges only. “Geriatric doses” are assumed to be the same as adult doses unless otherwise noted with a symbol. Where FDA
approved geriatric or pediatric dosing is available, a symbol will guide the reader to additional prescribing references. Refer to real-time prescribing references for these age
specific doses.
• Use of anti-infective agents in pregnancy is based on clinical risk versus benefit; safety concerns are not represented in this grid. Refer to the package insert (PI) for
more information. Clinicians should continue to provide education about the reproductive risks of any medication and offer risk reduction strategies (which may
include contraceptive use) to women of childbearing age and understand that these reproductive risks may also extend to males. Anti-infective agents, as well as a
number of other medications, may decrease the effectiveness of oral contraceptives. Where necessary, an alternative means of birth control should be explored.
• Brand names are provided for those agents that are still available on the market. Due to the ever-changing product availability, refer to Food and Drug
Administration (FDA) resources to confirm the actual brands available. This drug summary is for educational purposes only. Prescribing decisions should be based on
real-time, comprehensive drug databases that are updated on a regular basis.
Anthelmintics
Drug Name FDA-Approved Indications Adult Dosage Range Precautions and Clinical Pearls
Generic Name Parenchymal Usual oral dose: • Can cause severe bone marrow suppression, especially in hepatic impairment;
Albendazole neurocysticercosis Patients weighing less than discontinue if clinically significant decreases in complete blood count (CBC) occur
Taenia solium 60 kg: • May elevate liver function tests (LFTs); discontinue if LFTs rise to more than 2
(pork tapeworm) 15 mg/kg per day in 2 divided times the upper limit of normal
Brand
QT
Name
doses (max 800 mg per day) • Take with high-fat meal for optimal bioavailability
Albenza
BL Cystic hydatid disease of the • When treating neurocysticercosis, use anticonvulsants and corticosteroids
PD liver, lung, or peritoneum Patients weighing 60 kg or during first week
Echinococcus granulosus more: • Monitor: fecal specimens for ova and parasites 3 weeks after treatment,
GD
(dog tapeworm) 800 mg per day in 2 divided LFTs, CBC with differential, and perform ophthalmic exam if treating
doses neurocysticercosis to determine eye involvement
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42
Generic Name Strongyloidiasis of intestinal Usual oral dose for • Systemic exposure can cause cutaneous and systemic reactions, especially in
Ivermectin tract onchocerciasis: hyper-reactive onchodermatitis
Strongyloides stercoralis 150 mcg/kg single dose • Assess for loiasis if has traveled to West and Central Africa, and pretreat
(nematode) before systemic exposure (serious/fatal encephalopathy has been reported in
Brand Name Usual oral dose for patients with Loa loa infection)
9781284110562_CH02_Pass01.indd 42
Stromectol Onchocerciasis strongyloidiasis: • Take oral on empty stomach with water for optimal bioavailability
Soolantra Onchocerca volvulus 200 mcg/kg single dose (bioavailability increased 2.5-fold when administered with a high-fat meal)
Sklice (immature nematode) (alternatively, once daily for • No activity against adult Onchocerca volvulus
2 days per CDC) • Monitor (systemic): skin and eye microfilarial counts, ophthalmologic exams,
Head lice stool exam post treatment
Pediculus capitis Topical lotion (head lice): • Leave lotion on for 10 minutes, then rinse out; recommend washing clothing,
apply enough to cover dry bedding, and hair accessories
scalp and hair for single use
Rosacea
Topical cream (rosacea):

apply to affected area daily
Generic Name Treatment of all species of Usual oral dose for • Use with caution in patients with cardiac abnormalities
Praziquantel Schistosoma (blood flukes) schistosomiasis: • Systemic exposure can increase in patients with moderate to severe hepatic
20 mg/kg per dose 3 times impairment
Brand Name Clonorchis sinensis per day separated by 4 to 6 • Not recommended for use if patient has a history of seizures or infection
(liver fluke) hours for 1 day
Pharmacotherapeutics for Advanced Nursing Practice
Biltricide involves the CNS

• Swallow tablets quickly with water to avoid potent bitter taste
Opisthorchis viverrini Usual oral dose
• Caution patients about driving and operating machinery (adverse effects may
(liver fluke) for clonorchiasis/
last for 2 days)
opisthorchiasis:
• Drug interactions may require dose adjustments
25 mg/kg per dose 3 times
• Patients with cerebral cysticercosis should be hospitalized during treatment
per day separated by 4 to
6 hours for 1 day • May not be effective in migrating schistosomiasis and can potentiate severe
reactions caused by a sudden inflammatory immune response
• Monitor: LFTs, seizures, patients with cardiac abnormalities, and a feces exam
for ova prior to use
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Generic Name Pinworms Usual oral dose: • Use with caution in patients with hepatic impairment owing to risk of
Pyrantel Enterobius vermicularis 11 mg/kg single dose increased exposure
(max 1 g per dose) • Alternative agent; not first-line therapy
Brand Name • Treat family members who were in close contact with the patient
9781284110562_CH02_Pass01.indd 43
Pamix • Monitor: feces for eggs, worms, and occult blood
Pin-X • Usual oral dose is based on pyrantel base
Reese’s
Pinworm
Medicine
Antibacterial
Aminoglycosides
Universal prescribing alerts:
• Can cause C. difficile–associated diarrhea and pseudomembranous colitis with extended use
Generic Name Treatment of serious gram- Usual parenteral dose: • Low therapeutic index: individualize dosing
Amikacin negative bacilli bacteria IM, IV: 5 to 7.5 mg/kg per • Use with caution if patient has low calcium
that cause bone infections, dose every 8 hours • Monitor: urinalysis, blood urea nitrogen (BUN), serum creatinine (SCr), peaks
respiratory tract infections,
Brand Name and troughs (usually after third dose), vital signs, temperature, weight, input
endocarditis, and septicemia
Amikin and output (I&O); audiograms at baseline, during, and after treatment if used
that is resistant to gentamicin
for an extended period of time
(See also and tobramycin (for example:
QT
Antituberculosis Associated with:
Pseudomonas, Proteus,
Agents) Serratia) • Nephrotoxicity; use caution when using with other nephrotoxic agents
BL
• Neuromuscular blockade and paralysis; do not give after using anesthesia or a
PD muscle relaxant
QT GD • Neurotoxicity; ototoxicity can occur with high doses at extended use and is
irreversible
BL
Generic
PDName Treatment of susceptible Usual parenteral dose: • May cause neuromuscular blockade and paralysis; do not give after using
Gentamicin bacteria that cause bone IM, IV: anesthesia or a muscle relaxant
QT GD infections, respiratory tract Conventional: 1 to 2.5 mg/kg • Low therapeutic index: individualize dosing
infections, skin and soft- per dose every 8 to 12 hours
BL
Brand NameQT • Decreased absorption in atrophic muscles
tissue infections, abdominal
Garamycin • Suitable solutions for administration are clear to slight yellow
PD BL
and urinary tract infections,
Extended dosing interval: 4 to
septicemia, and endocarditis • Use with caution if patient has low calcium
GD PD
7 mg/kg per dose once daily
(for example: Pseudomonas, • Monitor: urinalysis, urine output, BUN, SCr, troughs and peaks (usually after third
QT Proteus, Serratia, dose); audiograms at baseline, during, and after treatment if using for 2 weeks or more
GD Intrathecal: 4 to 8 mg per
Staphylococcus) • Inconclusive data show certain penicillins, when administered with
BL day
gentamicin, may result in loss of efficacy

PD
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QT GD
BL
44
Associated with:
• Nephrotoxicity; use caution when using with other nephrotoxic agents
• Neurotoxicity; ototoxicity can occur with high doses at extended use and is
irreversible
9781284110562_CH02_Pass01.indd 44
Generic Name Portal-systemic Usual oral dose • Doses greater than 12 g per day may cause malabsorption of certain nutrients,
Neomycin encephalopathy as adjunct for perioperative fats, and glucose
prophylaxis: 1 g at 1:00 • Do not administer parenterally or as surgical irrigation due to toxicity from
Perioperative prophylaxis as pm, 2:00 pm, and 11:00 pm increased systemic absorption
Brand Name
adjunct with erythromycin EC on the day before 8:00 am
Neo-Fradin • Monitor: SCr and BUN at baseline and throughout therapy; audiograms if
surgery as an adjunct
symptoms develop
• Contraindicated in intestinal obstruction, inflammatory or ulcerative bowel
Usual oral dose for
disease
QT hepatic encephalopathy:
Associated with:
BL
4 to 12 g daily in divided
dose every 4 to 6 hours for • Nephrotoxicity; use caution when using with other nephrotoxic agents
PD 5 to 6 days • Neuromuscular blockade and paralysis; do not give after using anesthesia or a
muscle relaxant
GD
Chronic hepatic • Neurotoxicity; ototoxicity can occur with high doses at extended use and is
insufficiency: 4 g daily irreversible
Generic
QTName Treatment of tuberculosis Usual parenteral dose: • Adjusted doses for renal impairment are suggested, although the
Streptomycin in combination with other IM: 15 to 30 mg/kg per day manufacturer does not provide specific dosing recommendations, refer to PI
BL
antibiotic agents in divided doses or 1 to 2 g • Specific dosing recommendations for patients undergoing intermittent
PD Treatment of numerous daily dialysis, refer to PI
infections involving the • Often used as second-line therapy due to the high risk of toxicities
QT GD
following susceptible
• Administer in mid lateral thigh muscle or upper gluteal muscle
BL bacteria: plague (Yersinia
• Exposure to light can darken the solution without loss of efficacy
pestis), tularemia (Francisella
PD
tularensis), Brucella, K. • Monitor: audiograms at baseline and periodically during treatment; BUN, SCr,
GD granulomatis, Haemophilus troughs and peaks after third dose
ducreyi, H. influenza, K. Associated with:
pneumoniae, E. coli, Proteus, • Nephrotoxicity; use caution when using with other nephrotoxic agents
E. aerogenes, E. faecalis, S.
viridans, E. faecalis
muscle relaxant
• Neurotoxicity; ototoxicity can occur with high doses at extended use and is
irreversible
• Parenteral infusions: need appropriate audiometric and laboratory testing
facility in place
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Generic Name Treatment of infections by Usual parenteral dose: • May cause neuromuscular blockade and paralysis; do not give after using
Tobramycin gram-negative bacilli IM, IV: anesthesia or a muscle relaxant
P. aeruginosa Conventional dosing: 1 to • Low therapeutic index: individualize dosing
Cystic fibrosis with 2.5 mg/kg per dose every 8 • Specific dosing recommendations for patients undergoing intermittent
9781284110562_CH02_Pass01.indd 45
Brand Name P. aeruginosa to 12 hours dialysis, refer to PI
Tobi Treatment of susceptible • Use caution if patient has low calcium
Tobi Podhaler bacteria that cause Extended interval dosing: • If patient uses a multiple dose inhaler for cystic fibrosis, use tobramycin last:
brucellosis, cholangitis, 4 to 7 mg/kg per dose daily 15 to 90 minutes after bronchodilator
Kitabis Pak QT
QT complicated diverticulitis,
Bethkis • Exposure of drug to light can darken the solution without loss of efficacy:
BL meningitis, pelvic
BL Usual nebulized dose for normal solution for inhalation is clear to pale yellow
inflammatory disease, plague
PD cystic fibrosis: • Monitor: urinalysis, urine output, BUN, SCr, peaks and troughs after third dose;
PD (Yersinia pestis), pneumonia,
300 mg of solution for audiograms at baseline and during treatment if used for extended period of
QT GD tularemia, urinary tract
GD inhalation nebulized every time
infections, ocular infections
BL 12 hours in 28-day cycles • Inconclusive data show certain penicillins, when administered with
Prophylaxis against
PD Usual oral inhalation dose tobramycin, may result in loss of efficacy
endocarditis
for cystic fibrosis • Injectable aminoglycoside dosing is highly variable and dependent on several
QT GD
(powder for inhalation): factors
BL 112 mg (four 28mg Associated with:
capsules) every 12 hours in • Nephrotoxicity; use caution when using with other nephrotoxic agents
PD
28-day cycles
GD Usual ophthalmic dose: muscle relaxant
Ointment: ½ inch, 2 to • Neurotoxicity; ototoxicity can occur with high doses at extended use and is
6 times per day irreversible
Solution: 1 to 2 drops every
2 to 4 hours
Paromomycin Refer to the Antiprotozoals section.
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46
Cephalosporins
• Known serious allergic reaction: use with caution if the patient is allergic to penicillin agents due to cross-reaction
• Cephalosporins have been associated with seizures, especially in patients with renal impairment given unadjusted doses. Dosage reductions are recommended in
these patients for certain cephalosporin agents.
• Can cause false-positive urinary glucose if the patient is using cupric sulfate (Benedict’s solution, Clinitest, Fehling’s solution)
9781284110562_CH02_Pass01.indd 46
First-Generation Cephalosporins
Generic Name Pharyngitis or tonsillitis Usual oral dose: • Use with caution in patients with colitis due to increased absorption
Cefadroxil Streptococcus pyogenes 1 to 2 g daily as single dose • Monitor: renal function
or 2 divided doses
Name
Brand QT Skin and skin structure
Duricef infections caused by
BL
staphylococci or streptococci
PD
Urinary tract infection (for
GD
example: E. coli, Proteus
mirabilis, Klebsiella)
Generic Name Treatment of susceptible Usual parenteral • May increase international normalized ration (INR)
Cefazolin bacteria that cause biliary dose for treatment of • High levels in patients with poor renal function can increase risk for seizures
QT
tract infections, bone and endocarditis:
• Reconstitution of powder formulation is required prior to administration

BL joint infections, endocarditis,
Name
Brand QT • Stability of reconstituted solution vary based on storage location (longer
genital infections, respiratory IM, IV:
PD
Ancef beyond use date when refrigerated; refer to PI
BL tract infections, septicemia, 1 to 1.5 g every 6 hours
GD skin and skin structure • Suitable solutions for administration range in color from light yellow to yellow
PD
(max of 12 g per day)
infections, and urinary tract • Monitor: renal function, LFTs, CBC
GD infections (for example: E. coli,
Perioperative
streptococci, P. mirabilis,
prophylaxis: 1 g, 30 to 60
Klebsiella, S. aureus, H.
minutes prior to surgery.
influenza)
Additional doses are often
QT required postoperatively
Perioperative prophylaxis
depending on type of
BL surgery (refer to PI for
PD specific details)
GD
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Generic Name Treatment of susceptible Usual oral dose: • May increase INR
Cephalexin gram-positive bacteria 250 to 1000 mg every • Store suspension in the refrigerator
that cause respiratory tract 6 hours (max 4 g per day) • Monitor: renal, hepatic, and hematologic function with extended use
infections, otitis media, skin
Name
Brand QT
and skin structure infections,
9781284110562_CH02_Pass01.indd 47
Keflex bone infections, and
BL
genitourinary tract infections
PD
GD Prophylaxis for acute

infective endocarditis
Second-Generation Cephalosporins
QT
• BLSome cephalosporins have been associated with seizures, especially in patients with renal impairment given unadjusted doses. Dosage reductions are
recommended in these patients for certain cephalosporin agents.
PD
• Can cause false-positive urinary glucose if the patient is using cupric sulfate (Benedict’s solution, Clinitest, Fehling’s solution)
GD
Generic Name Treatment of susceptible Usual oral dose: • Use with caution in patients with colitis due to increased absorption
Cefaclor bacteria that cause Immediate release (IR): 250 • Use with caution in patients with poor renal function
exacerbations of chronic to 500 mg every 8 hours • Beta-lactamase–negative, ampicillin-resistant (BLNAR) strains of H. influenza
bronchitis (ER only), lower
should be considered resistant to cefaclor
respiratory tract infections
Brand
QT Name Extended release (ER): • Administer ER tablets with food or within 1 hour of food
(capsules and suspension
Ceclor 500 mg every 12 hours
BL only), otitis media (capsules • Extended release (ER) 500 mg can be ordered 2 times per day as an alternative
and suspension only), to immediate release (IR) 250 mg 3 times per day
PD
pharyngitis and tonsillitis, • Monitor: renal function
GD secondary infection of acute
bronchitis (ER only), skin and
skin structure infections,
urinary tract infections (for
example: H. influenza,
M. catarrhalis, S. pneumoniae,
S. pyogenes, E. coli, P. mirabilis,
Klebsiella, coagulase-negative
staphylococci)
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48
Generic Name Treatment of susceptible Usual oral dose for • Use with caution in patients with colitis due to increased absorption
Cefprozil bacteria that cause uncomplicated skin • Store reconstituted suspension in a refrigerator
pharyngitis/tonsillitis, otitis infections:
• Monitor: renal function
media, acute bronchitis 250 to 500 mg every 12 to
secondary infection or 24 hours for 10 days
Name
Brand QT
exacerbation, skin and skin
9781284110562_CH02_Pass01.indd 48
Cefzil structure infections (for
BL
example: S. pyogenes, S.
PD
pneumoniae, H. influenza, M.
GD catarrhalis, S. aureus)
Generic Name Treatment of susceptible Usual oral dose for • May increase INR
Cefuroxime bacteria that cause bone uncomplicated skin • Use with caution in patients with colitis due to increased absorption
and joint infections, lower infections:
• High levels in patients with poor renal function can increase risk for seizures
QT respiratory infections, 250 to 500 mg every
• Swallow tablets whole due to potent bitter taste
septicemia, skin and skin 12 hours for 10 days
BL
Brand Name
structure infections, urinary • Administer suspension with food and store reconstituted suspension in a
Ceftin
PD QT refrigerator
tract infections, and early
Usual parenteral dose
Zinacef Lyme disease (for example: • Tablets and suspension are not bioequivalent and not equal on a milligram-to-
GD BL for uncomplicated skin
S. pneumoniae, H. influenza, milligram basis
PD
infections:
Klebsiella, S. aureus, • Transition patients to oral administration as soon as medically appropriate.
IM, IV: 750 mg every 8 hours
S. pyogenes, E. coli,
GD • Monitor: renal, hepatic, and hematologic function with extended use;
Enterobacter) Perioperative prothrombin time if extended use, poor renal or hepatic function, or
prophylaxis: IV: 1.5 g malnourished

Perioperative prophylaxis 30 to 60 minutes prior
to procedure. Additional
QT doses are often required
BL
postoperatively depending
on type of surgery (refer to
PD PI for specific details)
GD
Generic Name Refer to the Cephamycins section.
Cefoxitin
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Generic Name Refer to the Cephamycins section.
Cefotetan
Third-Generation Cephalosporins
9781284110562_CH02_Pass01.indd 49
• Can cause false-positive urinary glucose if patient is using cupric sulfate (Benedict’s solution, Clinitest, Fehling’s solution).
• Some cephalosporins have been associated with seizures, especially in patients with renal impairment given unadjusted doses. Dosage reductions are recommended in
Generic Name Treatment of susceptible Usual oral dose for acute • Use with caution in patients with colitis due to increased absorption
Cefdinir bacteria that cause acute otitis sinusitis: • Administer 2 hours before or after antacids or iron supplements
media, acute exacerbations 300 mg twice daily for 5 to • Monitor: renal function
of chronic bronchitis, sinusitis, 10 days or
• Specific recommendations provided for patients undergoing dialysis
community-acquired
600 mg once daily for
Name
Brand QT pneumonia, pharyngitis/
10 days
Omnicef tonsillitis, and skin and skin
BL
structure infections (for
PD example: H. influenza,
S. pneumoniae, M. catarrhalis,
GD
H. parainfluenzae, S. pyogenes,
S. aureus)
Generic Name Treatment of susceptible Usual oral dose for • Contraindicated if patient is carnitine deficient due to worsening of condition
Cefditoren bacteria that cause community acquired • May increase INR
QT
exacerbation of chronic pneumonia: 400 mg twice
• Use with caution in patients with hepatic impairment; cefditoren has not
BL bronchitis or community- daily for 14 days
been studied in patients with severe hepatic disease. No dose adjustment is
acquired pneumonia,
PD required with mild hepatic impairment (Child-Pugh Class A or B) per PI
Brand Name pharyngitis, tonsillitis, and skin
• High levels in patients with poor renal function can increase risk for seizures
Spectracef
GD and skin structure infections
(for example: H. influenzae, • Administer with food to increase absorption
H. parainfluenzae, • Monitor: renal function
S. pneumoniae, M. catarrhalis,
S. pyogenes, S. aureus)
QT
BL
PD
GD
30/11/16 6:38 PM
50
Generic Name Treatment of susceptible Usual oral dose for • Chewable tablets and suspensions achieve higher peak blood concentrations
Cefixime bacteria that cause uncomplicated UTI: compared with an equivalent dose of the capsule; otitis media should be
uncomplicated urinary 400 mg daily in divided treated with the chewable tablet or suspension
tract infections (UTI), otitis doses every 12 to 24 hours • No longer considered first-line therapy for uncomplicated gonorrhea in the
media, pharyngitis/tonsillitis, United States because of resistance; ceftriaxone is preferred
Name
Brand QT acute exacerbations of
9781284110562_CH02_Pass01.indd 50
• Monitor: renal and hepatic function with prolonged therapy
Suprax chronic bronchitis, and
BL • Specific recommendations for patients undergoing dialysis, refer to PI
uncomplicated cervical/
PD urethral gonorrhea (for
example: E. coli, P. mirabilis,
GD
H. influenzae, M. catarrhalis,
S. pyogenes, S. pneumoniae,
N. gonorrhoeae)
Generic Name Treatment of susceptible Usual parenteral dose for • Infuse bolus slowly; arrhythmias have been reported when infusing the bolus
QT
Cefotaxime bacteria that cause severe infection: in less than 1 minute
BL bacteremia/septicemia, bone IM, IV: 1 to 2 g every • May cause granulocytopenia with extended use greater than 10 days
and joint infections; CNS 8 hours
PD • Use with caution in patients with colitis due to increased absorption
infections, genitourinary
Brand Name • If administering 2 g, divide into 2 doses and give into different IM injection
GD QT infections, gynecologic
sites
Claforan infections, intra-abdominal
BL
infections, lower respiratory • To limit inflammation. change infusion sites when applicable
PD tract infections, and skin and • Monitor: CBC with differential and renal function
skin structure infections (for

GD
example: E. coli, Klebsiella,
S. marcescens, S. aureus,
Streptococcus, Pseudomonas,
P. mirabilis, N. meningitides,
QT
H. influenzae, S. pneumoniae,
Enterococcus, S. epidermidis,
BL Citrobacter, P. vulgaris, P.
PD
stuartii, M. morganii, P. rettgeri,
S. marcescens, N. gonorrhoeae,
GD Enterobacter, Bacteroides,
Clostridium, anaerobic cocci,
Fusobacterium, S. pyogenes,
H. parainfluenzae)
Surgical prophylaxis for

contaminated or potentially
contaminated procedure
30/11/16 6:38 PM

Generic Name Treatment of susceptible Usual oral dose for • Administer tablets with food to increase bioavailability
Cefpodoxime bacteria that cause chronic community acquired • Monitor: renal function
bronchitis exacerbations, pneumonia: 200 mg every
• Specific recommendations for patients undergoing dialysis, refer to PI
gonorrhea, otitis media, 12 hours for 14 days
pharyngitis/tonsillitis,
9781284110562_CH02_Pass01.indd 51
Name
Brand QT community-acquired
Vantin pneumonia, sinusitis, skin
BL
and skin structure infections,
PD and uncomplicated urinary
tract infections (for example:
GD
S. pneumoniae, H. influenzae,
M. catarrhalis, N. gonorrhoeae,
S. pyogenes, S. aureus, E. coli,
K. pneumoniae, P. mirabilis,
QT
S. saprophyticus)
Generic
BL Name Treatment of susceptible Usual parenteral dose • May increase INR
Ceftazidime bacteria that cause for uncomplicated • Neurotoxicity can develop in patients with poor renal function due to
PD
septicemia, bone and joint lower respiratory tract increased levels: decrease dose
GD infections, CNS infections, infections:
• Use with caution in patients with history of seizures; high levels can increase
gynecologic infections, IM/IV: 500mg to 1000mg risk for seizure
Brand Name intra-abdominal infections, every 8 hours
• With some organisms (such as Enterobacter and Serratia), resistance can
Fortaz QT lower respiratory infections,
develop during treatment; consider combination therapy or intermittent
Tazicef skin and skin structure
BL susceptibility testing for bacteria with inducible resistance
infections, and urinary tract
PD infections (complicated and • Monitor: renal function
uncomplicated) (for example: • Specific recommendations for patients undergoing dialysis, refer to PI
GD P. aeruginosa, Klebsiella, H.
influenzae, E. coli, Serratia,
S. pneumoniae, S. aureus,
Enterobacter, N. meningitides,
Bacteroides, P. mirabilis,
QT
Serratia, Citrobacter, S.
BL pyogenes, Proteus)
PD
Empiric treatment in
GD immunocompromised patients
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52
Generic Name Treatment of susceptible Usual parenteral dose for • May cause neurotoxicity, such as seizures and encephalopathy: may worsen in
Ceftazidime bacteria that cause complicated urinary tract renal impairment
with avibactam complicated intra-abdominal infections: • Infuse over 2 hours
infections (when used IV: 2.5 g every 8 hours for • Suitable solutions for administration range in color from clear to light yellow
with metronidazole) and 7 to 14 days
complicated urinary tract
9781284110562_CH02_Pass01.indd 52
Brand Name infections (for example: • Specific recommendations for patients undergoing dialysis, refer to PI
Avycaz C. freundii, C. koseri,
E. aerogenes, E. cloacae, E. coli,
K. pneumoniae, Proteus species,
P. aeruginosa, K. oxytoca,
P. mirabilis, P. stuartii)
Generic Name Treatment of susceptible Usual oral dose for otitis • Use with caution in patients with colitis due to increased absorption
Ceftibuten bacteria that cause media: 400 mg daily for • Administer suspension 2 hours before or 1 hour after meals (empty stomach)
exacerbations of chronic 10 days
QT • Refrigerate suspension
bronchitis, otitis media, and
• Monitor: renal, hepatic, and hematologic function with extended use
BL pharyngitis/tonsillitis
Name
Brand QT • Specific recommendations for patients undergoing dialysis, refer to PI
PD
Cedax
BL
GD
PD
GD
Generic Name Treatment of susceptible Usual parenteral dose • Administer suspension 2 hours before or 1 hour after meals
Ceftolozane and bacteria that cause for complicated UTI: • Suitable solutions for administration range in color from clear to slight yellow
tazobactam complicated intra-abdominal IV: 1.5 g every 8 hours for
infections (when used 7 days
QT with metronidazole) and
complicated UTI including
BL
Brand Name pyelonephritis (for example:
Zerbaxa
PD B. fragilis, S. anginosus, S
constellatus, S. salivarius, E.
GD cloacae, E. coli, K. pneumoniae,
P. aeruginosa, K. oxytoca, P.
mirabilis)
QT
BL
PD
GD
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Generic Name Treatment of susceptible Usual parenteral dose for • Contraindicated in IV solutions with lidocaine
Ceftriaxone bacteria that cause lower skin and skin structure • May increase INR
respiratory tract infections, infections:
• Rarely causes hemolytic anemia
otitis media, skin and skin IM, IV: 1 to 2 g every 12 to
• Use with caution if patient has biliary stasis or sludge; can cause pancreatitis
structure infections, bone
9781284110562_CH02_Pass01.indd 53
24 hours
Brand
QT Name and joint infections, intra- • Use with caution in patients with colitis due to increased absorption
Rocephin abdominal infections, • Do not administer concurrently with calcium due to precipitation; flush lines
BL
urinary tract infections, before and after infusion
PD pelvic inflammatory disease, • In patients with renal and hepatic impairment, do not use doses greater than
uncomplicated gonorrhea, 2 g daily
GD
septicemia, and meningitis
• Monitor: prothrombin time and INR
Fourth-Generation Cephalosporins
Generic Name Treatment of susceptible Usual parenteral dose • May increase INR
Cefepime bacteria that cause intra- for moderate to severe • Neurotoxicity can develop in patients with poor renal function due to
abdominal infections, pneumonia: increased levels: decrease dose
pneumonia, skin and IV: 1 to 2 g every 12 hours • Use with caution in patients with colitis due to increased absorption
skin structure infections, for 10 days
Name
Brand QT • Use with caution in patients with history of seizures; high levels can increase
and complicated and
risk for seizure
Maxipime uncomplicated urinary tract
BL
infections (for example: E. coli, • Decrease dose in elderly patients, who often have impaired renal function;
PD viridans group streptococci, increased risk of encephalopathy, myoclonus, and seizures
P. aeruginosa, K. pneumoniae, • The intramuscular (IM) administration is only indicated by the FDA for UTI
GD
Enterobacter, B. fragilis, due to E. coli when the IM route is considered a more appropriate route of
S. pneumoniae, S. aureus,
administration
S pyogenes, P. mirabilis) • Monitor: renal function
QT Empiric treatment of febrile
neutropenia
BL
PD
GD
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54
Fifth-Generation Cephalosporins
9781284110562_CH02_Pass01.indd 54
Generic Name Community-acquired Usual parenteral dose for • Rarely can cause hemolytic anemia
Ceftaroline pneumonia (for example those skin and skin structure • Administer by slow infusion over 5 to 60 minutes
caused by: S. pneumoniae, infections:
• Suitable solutions for administration range in color from clear to dark yellow
S. aureus, H. influenzae, IV: 600 mg every 12 hours
• Monitor: renal function and for allergic reaction
K. pneumoniae, K. oxytoca, for 5 to 14 days
Brand Name E. coli) • Specific recommendations for patients undergoing dialysis, refer to PI
Teflaro
Complicated skin and skin

structure infections (for
example those caused by:
S. aureus (MSSA and MRSA),
QT S. pyogenes, S. agalactiae, E. coli,
K. pneumoniae, K. oxytoca)
BL
Miscellaneous Beta-Lactams
PD
Carbapenems
GD
Universal prescribing alerts
• Contraindicated if patient has a known serious allergic reaction to carbapenems; use caution if patient is allergic to beta-lactams
Generic Name Treatment of susceptible Usual parenteral dose • Can cause confusion and seizures in high doses; use with caution in patients
Doripenem bacteria that cause for complicated intra- with poor renal function and CNS disorders
complicated intra-abdominal abdominal infections: • Monitor: renal function; hematologic function with extended use
infections, and complicated IV: 500 mg every 8 hours for • Switch to oral therapy when clinical improvement is appropriate for
urinary tract infections 5 to 14 days
Brand Name conversion.
Doribax
Aerobic gram-positive, aerobic
gram-negative (P. aeruginosa),
and anaerobic organisms
QT
30/11/16 6:38 PM
BL
PD

Generic Name Treatment of susceptible Usual parenteral dose for • Can cause confusion and seizures in high doses; use with caution in patients
Ertapenem bacteria that cause pelvic complicated UTI: with poor renal function and CNS disorders
infections, community- IV: 1 g daily for 10 to • IM is diluted with lidocaine
QT
acquired pneumonia, 14 days • Can increase risk of breakthrough seizures if used with valproic acid and
complicated intra-abdominal
9781284110562_CH02_Pass01.indd 55
IM administration may be derivatives: avoid combination use if possible
Brand Name
BL infections, complicated skin
used as an alternative to IV, • Monitor: renal, hepatic, and hematologic function with extended use; conduct
Invanz PD and skin structure infections,
however only administer neurologic assessment before use
and complicated UTI
IM injection for 7 days
GD Colorectal surgery prophylaxis
(for example: S. agalactiae, E, coli,
Usual dose for surgical
Bacteroides, P. asaccharolytica,
prophylaxis: IV: 1 g 1 hour
Peptostreptococcus, P. bivia,
before surgery
M. catarrhalis, C. clostridioforme,
QT E. lentim, S. aureus, S pyogenes,
K. pneumoniae, P. mirabilis
BL
sensitive to beta-lactamase–
PD producing bacteria)
GD
Generic Name Treatment of susceptible Usual parenteral dose for • Can cause confusion and seizures in high doses; use with caution in patients
Imipenem and bacteria that cause lower UTI: with poor renal function and CNS disorders
cilastatin respiratory tract infections, IV: 250 to 500 mg every • Do not administer IV push
sodium urinary tract infections, 6 hours. Duration of • If nausea/vomiting develops during administration, lower the infusion rate
intra-abdominal infections, treatment is based on
• May cause glucose monitoring by Clinitest to be inaccurate
gynecologic infections, severity of the infection
bone and joint infections, • Monitor: renal, hepatic, and hematologic function throughout therapy
Name
Brand QT skin and skin structure • Specific recommendations for patients undergoing dialysis, refer to PI
Primaxin infections, endocarditis, • Adults with lower body weight require dose adjustments (less than 70 kg)
BL
polymicrobic infections,
PD and septicemia (for example:
S. aureus, Streptococcus, E. coli,
GD
Klebsiella, Enterobacter,
P. aeruginosa, anaerobes
Sensitive to beta-lactamase–
producing bacteria)
QT
BL
PD
GD
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56
Generic Name Treatment of infections Usual parenteral dose for • Can cause confusion and seizures in high doses; use with caution in patients
Meropenem caused by susceptible complicated skin and skin with poor renal function and CNS disorders
bacteria such as: meningitis, structure infections: • Outpatients should not operate machinery or drive until it is determined that
complicated skin and skin IV: 500 to 1000mg daily the patient can tolerate the therapy
structure infections, and every 8 hours. Duration • Monitor: renal and liver function and CBC during extended use
Name
Brand QT intra-abdominal infections
9781284110562_CH02_Pass01.indd 56
of treatment is based on
• Specific recommendations for patients undergoing dialysis; refer to PI
Merrem (for example: S. pneumoniae, severity of infection
BL
H. influenzae, N. meningitides, • Age-specific dose/indications; refer to PI
PD S. aureus, S. pyogenes,
S. agalactiae, E. faecalis,
GD
viridans group streptococci,
P. aeruginosa, E. coli, P. mirabilis,
B. fragilis, Peptostreptococcus,
K. pneumoniae,
QT
B. thetaiotaomicron)
Cephamycins
BL
PD
• Known serious allergic reaction: contraindicated if patient has had an allergic reaction to a cephalosporin agent; use caution if patient has had an allergic reaction to
GD
a penicillin agent due to cross-reaction
• Can cause false-positive urinary glucose if patient is using cupric sulfate (Benedict’s solution, Clinitest, Fehling’s solution)
Generic Name Treats susceptible bacteria Usual parenteral dose for • Alcohol use may cause a disulfiram-like reaction
Cefotetan that cause respiratory tract complicated UTI: • Monitor: renal, hepatic, and hematologic function with extended use;
infections, skin and skin IM, IV: 1 to 2g every prothrombin time if poor renal/hepatic function, nutritionally deficient, or
structure infections, bone 12 hours extended use of treatment; for hemolytic anemia
and joint infections, UTI
Brand Name and gynecologic infections,
• Perioperative doses are given 30 to 60 minutes prior to surgery
Cefotan septicemia, intra-abdominal
infections, and mixed Contraindications:
infections
• Previous cephalosporin-associated hemolytic anemia (threefold increased risk
compared to other cephalosporins)
Active against gram-negative
bacilli: E. coli, Klebsiella,
Proteus; anaerobes
QT
Less active against
BL staphylococci and streptococci
PD
GD
30/11/16 6:38 PM

Generic Name Treatment of susceptible Usual parenteral dose • Use with caution in patients with colitis due to increased absorption
Cefoxitin bacteria that cause bone and for lower respiratory • Powder for solution requires reconstitution prior to use
joint infections, gynecologic infection:
• Cephalosporin agents, including cefoxitin, have been associated with seizures,
infections, intra-abdominal IV or IM: 1 to 2 g every 6 to especially in patients with renal impairment given unadjusted doses
infections, lower respiratory
9781284110562_CH02_Pass01.indd 57
8 hours (max 12 g per day)
Brand Name • High levels in patients with poor renal function can increase risk for seizures
tract infections, septicemia, skin
MefoxinQT and skin structure infections, • IV is preferred route since IM is painful
and urinary tract infections (for • Solution for injection can darken depending on storage conditions with no
BL example: S. aureus, E. coli, loss in efficacy
PD N. gonorrhoeae, B. fragilis, • Monitor: renal function and prothrombin time
Clostridium, P. niger,
GD Peptostreptococcus,
S. agalactiae, Klebsiella,
S. epidermidis, S. pyogenes, P.
mirabilis, Morganella morganii,
QT
P. vulgaris, Providencia)
BL
PD
Perioperative prophylaxis for
uncontaminated GI surgery,
GD hysterectomy, and cesarean
section
Monobactams
Generic Name Treatment of susceptible gram- Usual parenteral dose • Rarely can cause toxic epidermal necrolysis (TEN): use with caution in bone
Aztreonam negative bacilli bacteria that for lower respiratory marrow transplant patients who have risks for TEN
cause urinary tract infections, infections: • Suitable solutions for administration range in color from clear to light yellow
lower respiratory tract IM/IV: 1 to 2 g every 8 to to pink
infections, septicemia, skin 12 hours • Administer a bronchodilator before using the nebulizer to prevent
Brand Name and skin structure infections,
(max 8 g per day) bronchospasm
Azactam
QT intra-abdominal infections, and
• Special pharmacies distribute Cayston; contact Cayston Access Program
Cayston gynecologic infections
BL Usual nebulized dose • Monitor: liver function periodically
PD
for CF: • Specific recommendations for patients undergoing dialysis; refer to PI
Inhalation via nebulizer
75 mg 3 times per day for
improves respiratory
GD 28 days
symptoms in cystic fibrosis (CF).
P. aeruginosa
QT
BL
PD
30/11/16 6:38 PM
GD
58
Chloramphenicols
9781284110562_CH02_Pass01.indd 58
Generic Name Treatment of severe Usual parenteral dose for • Drug interactions may require dose adjustment
Chloramphenicol infections when other CNS infections: • May cause gray syndrome, which causes circulatory collapse: do not let blood
antibiotics are unable to IV: 50 to 100 mg/kg per day levels reach or exceed 50 mcg/mL; use with caution in patients with poor renal
eradicate the bacteria (for in divided doses every or hepatic function
example: Bacteroides, 6 hours • Use with caution in patients with glucose 6-phosphate dehydrogenase (G6PD)
Brand Name H. influenzae, N. meningitides,
deficiency: greater risk for hemolytic anemia
Chloromycetin Salmonella, Rickettsia)
• Can deplete vitamin B in patients: may need to supplement
• Use caution in preparing and disposing of infusion
Active against most
vancomycin-resistant • Aplastic anemia may develop weeks or months after use: caution patients on
QT
enterococci symptoms
BL • Monitor: CBC with differential at baseline and every 2 days during treatment;
PD renal and liver function periodically; chloramphenicol blood levels (greater
risk of high levels with poor renal or hepatic function)
GD
Contraindicated:
• In patients with viral infections or mild or moderate bacterial infections
• When used for bacterial prophylaxis and other minor infections due to
potential for toxicity

Associated with:
• Serious and fatal blood dyscrasia events when used on a short-term or long-
term basis
Macrolides
Erythromycins
Generic Name Treatment of infections Usual oral dose: 250 to • Rarely can cause QTc prolongation and ventricular arrhythmias: use with
Erythromycin caused by susceptible bacteria 500 mg every 6 to 12 hours caution in patients who already have prolongation, hypokalemia, or
(for example: S. pyogenes, S. (max 4 g per day) hypomagnesemia
pneumoniae, S. aureus, M. Delayed release tablet/ • Can cause hepatic impairment: use with caution in patients with existing poor
pneumoniae, L. pneumophila, capsule hepatic function
Brand Name diphtheria, pertussis,
Ery-Tab (delayed Chlamydia, erythrasma, N.
release) gonorrhoeae, E. histolytica,
30/11/16 6:38 PM

PCE Dispertab syphilis, Campylobacter) Ophthalmic: ½ inch, 2 to • High doses may cause ototoxicity
(delayed Nongonococcal urethritis 6 times per day on the • Do not administer with milk or acidic beverages
release, contains Colorectal preoperative underlid of the eye
• Administer with food if nausea/vomiting develops
polymer-coated prophylaxis in combination
• May worsen weakness caused by myasthenia gravis
particles) with neomycin
9781284110562_CH02_Pass01.indd 59
Gel (for acne): apply 1 to
• Elderly patients are at increased risk of adverse events
ERYC (delayed 2 times daily; response
release) • Alcohol may decrease absorption: avoid use
Conjunctivitis (ophthalmic only) should be seen in 6 to 8
Ilotycin weeks • Gel is flammable: do not put near heat source
(ophthalmic) • Monitor: for adverse events
Acne (topical only)
Romycin Ointment, solution, pads
(ophthalmic) (for acne):
Erygel Apply 2 times daily
Akne-Mycin
Ery
Generic Name See Erythromycin Usual oral dose: • See Erythromycin

Erythromycin 250 mg every 6 hours • More acid-stable compared to base
estolate 500 mg every 12 hours • Available as capsules, tablets and suspension
Name
Brand QT
Ilosone
BL
QT PD
BL GD
Generic Name See Erythromycin Usual oral dose for • See Erythromycin
PD
Erythromycin moderately severe • Refrigerate after reconstituting
ethylsuccinate
GD
lower respiratory tract
• More acid-stable compared to base
infections:
• 400mg EES is roughly equal to 250mg base/stearate
400 to 800 mg every
• Available as a tablet and suspension
6 to 12 hours (max 4 g
Brand Name erythromycin base per day)
E.E.S. granules
EryPed
E.E.S. Liquid
QT
E.E.S. Filmtab
BL
QT PD
BL GD
PD
GD
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60
Generic Name See Erythromycin Usual parenteral dose for • See Erythromycin
QT
Erythromycin lower respiratory tract • Administer IV slowly to minimize irritation to the vein
lactobionate infections:
BL
IV: 15 to 20 mg/kg per day in
QT PD divided doses every 6 hours
9781284110562_CH02_Pass01.indd 60
BL (max 4 g erythromycin base
GD
per day)
PD
Generic Name See Erythromycin Usual oral dose for • See Erythromycin
GD
Erythromycin lower respiratory tract • More acid-stable than base
stearate infections:
• Better bioavailability on empty stomach; however, most people take it with
250 to 500 mg every 6 to food to avoid nausea
12 hours
(max 4 g erythromycin base
Brand Name
per day)
QT
Erythrocin
Filmtab
BL
QT PD
BL GD
Ketolides
PD
• GDCan cause C. difficile–associated diarrhea and pseudomembranous colitis with extended use
Generic Name Treatment of infections Usual oral dose for • Rarely can cause QTc prolongation and ventricular arrhythmias: use
Telithromycin caused by susceptible community acquired with caution in patients with existing prolongation, hypokalemia, or
bacteria that cause pneumonia: hypomagnesemia
community-acquired 800 mg once daily for 7 to • Can cause hepatic impairment: use with caution in patients with existing
pneumonia (for example: 10 days poor hepatic function and discontinue therapy if signs and symptoms of liver
Brand Name S. pneumoniae, H. influenzae, damage occur
Ketek M. catarrhalis, Chlamydophila
• Can cause syncope, loss of consciousness, and visual disturbances: caution
pneumoniae, M. pneumoniae)
patients about operating machinery and driving until tolerance of the therapy
QT
is established
QT BL • Monitor: hepatic function including liver enzymes and signs and symptoms of
BL PD
liver failure, visual changes
PD GD
Contraindications:
QT GD • Myasthenia gravis
• History of hepatitis with macrolide use
BL
• Associated with life-threatening respiratory failure in myasthenia gravis; avoid
PD
use in patients with this condition
GD
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Other Macrolides
9781284110562_CH02_Pass01.indd 61
Generic Name Treatment of susceptible Usual oral dose for CAP: • Rarely can cause QTc prolongation and ventricular arrhythmias: use
Azithromycin bacteria that cause 500 mg day 1, then with caution in patients with existing prolongation, hypokalemia, or
infections such as: otitis 250 mg daily on days 2 hypomagnesemia
media, pharyngitis/ through 5. • Use with caution in patients with hepatic impairment: can cause cholestatic
tonsillitis, community- hepatitis and hepatic dysfunction
Alternatively may give ER:
Brand Name acquired pneumonia
2 g once as a single dose • Can delay or mask symptoms of gonorrhea or syphilis; assess for these
Zithromax (CAP), pelvic inflammatory
Alternatively may give diseases before initiating treatment
Tri-Pak disease, genital ulcer
Usual parenteral dose for • Use with caution if GFR less than 10 mL/min; increased gastrointestinal side
disease in males,
Zithromax Z-Pak CAP: effects are possible in such cases
exacerbations of chronic
Zmax QT obstructive pulmonary IV: 500 mg daily for at • Immediate-release forms are not interchangeable with the extended-release
AzaSite disease, sinusitis, least 2 days then convert suspension
BL
uncomplicated skin and to oral dose to complete 7 • Administer extended-release suspension on an empty stomach
QT PD skin structure infections, to 10 day course
• May cause worsening of existing myasthenia gravis symptoms or create new
BL
urethritis, and cervicitis (for symptoms
GD
example: H. influenzae, M. M. avium complex
PD
• Increased macrolide resistance is occurring in syphilis; macrolides are not
catarrhalis, S. pneumoniae, disease prophylaxis in recommended for early syphilis
Chlamydia pneumoniae, S. HIV patients:
GD • Monitor: hepatic function, CBC with differential; if used for gonorrhea, test
pyogenes, M. pneumoniae,
1200 mg once weekly for cure 7 days after treatment
C. trachomatis, N.
gonorrhoeae, M. hominis, 600 mg twice weekly
Contraindications:
H. ducreyl, S. aureus, S. 500 to 600 mg daily with
ethambutol • Prior azithromycin use was associated with cholestatic jaundice or hepatic
agalactiae)
dysfunction
Ophthalmic: 1 drop into
Prophylaxis against affected eye 2 times per
and treatment of day for 2 days, then once
Mycobacterium avium daily for 5 days
complex in HIV patients
Conjunctivitis
30/11/16 6:38 PM
62
Generic Name Treatment of susceptible Usual oral dose for CAP: • Rarely can cause QTc prolongation and ventricular arrhythmias: use
Clarithromycin bacteria that cause infections 250 every 12 hours for 7 to with caution in patients with existing prolongation, hypokalemia, or
such as: pharyngitis/ 14 days hypomagnesemia
tonsillitis, sinusitis, chronic • Can cause hepatic impairment: use with caution in patients with existing
Alternatively may give
bronchitis, community- poor hepatic function and discontinue therapy if signs and symptoms of liver
1000 mg ER once daily for
9781284110562_CH02_Pass01.indd 62
Brand NameQT acquired pneumonia (CAP), damage occur
7 days
Biaxin uncomplicated skin and skin
BL • Can cause TEN, Stevens–Johnson syndrome (SJS), and drug reaction with
structure infections, and
eosinophilia and systemic symptoms (DRESS): discontinue if patient develops
QT PD duodenal ulcer disease
rash or other symptoms
BL GD • Administer ER formulation with food
Prophylaxis against and
PD • ER tablets may appear in stools: consider alternative dosage form
treatment of Mycobacterium
• May cause worsening of existing myasthenia gravis symptoms or create new
GD avium complex in HIV
symptoms
patients (for example:
QT H. influenzae, S. pneumoniae, • Use with caution in patients with coronary artery disease: associated with an
M. catarrhalis, M. pneumoniae, increase in cardiovascular mortality
BL
Chlamydophila pneumoniae, • Do not use with ranitidine if patient has a history of porphyria or if CrCl less
PD S. pyogenes, H. parainfluenzae, than 25 mL/min
S. aureus, H. pylori) • Monitor: CBC with differential, BUN, SCr
GD
Contraindications:
• History of QTc prolongation or ventricular arrhythmias
• Prior clarithromycin use was associated with cholestatic jaundice or hepatic
dysfunction
Generic Name Treatment of C. difficile- Usual oral dose for CDAD: • Minimal absorption: not effective against systemic infections
Fidaxomicin associated diarrhea (CDAD) 200 mg 2 times per day for
10 days
Brand Name
Dificid
Penicillins
Natural Penicillins
• May cause false-positive or negative urinary glucose if patient is using Clinitest
30/11/16 6:38 PM
Generic Name Treatment of susceptible Usual parenteral dose for • Use with caution in patients with poor renal function
Penicillin G bacteria that cause upper respiratory tract • May increase risk of seizures in patients with history of seizure disorder
respiratory tract infections infections:
• To reduce the pain of injection, warm the medication to room temperature
9781284110562_CH02_Pass01.indd 63
caused by streptococci IM: 600,000 to 1.2 million
• Inject in the upper outer quadrant of the gluteal muscle; avoid injecting near
units once daily for at least
Brand Name an artery or nerve to prevent neurologic damage
10 days (duration is based
Treatment of syphilis, yaws,
QT
Benzathine on severity of infection) • Not recommended to treat congenital syphilis and neurosyphilis due to
bejel, and pinta
Bicillin L-A treatment failures
BL
• Assess the patient’s renal function and identify any history of seizures
PD Secondary prophylaxis
• Associated with cardiopulmonary arrest and death with IV use (never
against glomerulonephritis,
QT administer IV)
GD rheumatic fever, chorea, and
• May be give every 1 to 4 weeks for secondary prevention or latent syphilis
BL rheumatic heart disease
• Benzathine recommended for syphyllis
PD
Generic Name Treatment of susceptible Usual parenteral dose for • High levels may increase risk of seizures: use with caution in patients with
GD
Penicillin G bacteria that cause infections pneumonia: history of seizures
such as sepsis, pneumonia, IV: 5 to 24 million units per • Neurovascular damage may occur if administered via an artery or near
pericarditis, endocarditis, day in divided doses every peripheral nerves or blood vessels
meningitis, anthrax, botulism, 4 to 6 hours • May increase potassium in serum
Brand Name gas gangrene, and tetanus
QT
• 1 million units is approximately equal to 625 mg
Potassium
Pfizerpen-G • Monitor: electrolytes periodically; hepatic, renal, cardiac, and hematologic
BL
function if extended use or high doses
PD
Generic
GDName Treatment of susceptible Usual parenteral dose for • May cause fibrosis and atrophy with repeated injections in the anterolateral
Penicillin G bacteria that cause infections upper respiratory tract thigh
such as: anthrax, diphtheria, infections: • Transient neuropsychiatric reactions such as confusion and hallucinations
endocarditis, erysipeloid, IM: 600,000 to 1.2 million have occurred after receiving a large dose; they typically last for 15 to
fusospirochetosis, respiratory units once daily for at least 30 minutes
QT
Brand Name tract infections, rat-bite 10 days (duration is based • Use with caution in patients with poor renal function or history of seizures
QT
Procaine
BL fever, skin and soft-tissue on severity of infection)
• Neurovascular damage may occur if administered via the intra-arterial,
Wycillin infections, syphilis, yaws,
BL
PD intravascular, or IV route
bejel, and pinta
PD • If the patient has an allergy to procaine, test with 0.1 mL of procaine to
GD
determine if there is an allergic reaction; do not use if an allergic reaction
GD Prophylaxis against anthrax
occurs
• Monitor: injection-site reactions; mental status after injection; renal and
Treatment of susceptible hematologic function with extended use
streptococci and
staphylococci
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64
Generic Name Treatment of susceptible Usual oral dose for upper • Use with caution in patients with poor renal function or history of seizures
Penicillin V bacteria that cause tract infections: • Administer on an empty stomach to increase absorption
potassium respiratory tract infections, 250 to 500 mg every • Store reconstituted suspension in the refrigerator
otitis media, sinusitis, and 6 hours
• Monitor: renal and hematologic function periodically with extended use
skin and soft-tissue infections
• Treatment duration depends on severity of infection
Brand Name
Prophylaxis in rheumatic
9781284110562_CH02_Pass01.indd 64
Potassium fever
Pen-Vee
QT K
Veetids Strong activity in
BL
streptococcal species
PD
GD
Aminopenicillins
Generic Name Treatment of susceptible Usual oral dose for • Administer extended-release tablets within 1 hour after a meal
Amoxicillin bacteria that cause upper respiratory tract • Monitor: renal, hepatic, and hematologic function with extended use
genitourinary tract infections, infections:
H. pylori infections, lower 250 to 500 mg every
respiratory infections, 8 hours
QT
Brand Name pharyngitis/tonsillitis, otitis

Alternatively may give:
BL
Moxatag media, rhinosinusitis, and
500 to 875 mg twice daily
skin and skin structure
PD
infections (for example: ER: 775 mg once daily
GD E. coli, P. mirabilis, E. faecalis,
Streptococcus, S. pneumoniae,
Staphylococcus, H. influenzae)
QT
ER: S. pyogenes
Generic Name Treatment of susceptible Usual oral dose for acute • More likely to cause diarrhea than amoxicillin due to the amounts of
BL
Amoxicillin and bacteria that cause otitis media: clavulanic acid used
PD
clavulanate community-acquired 500 mg every 8 to 12 hours • Can cause hepatic dysfunction (though rare)
pneumonia (XR only), otitis
GD
Alternatively may give • Dosed based on the amoxicillin component
media, lower respiratory
Brand Name 875 mg every 12 hours • Administer XR tablets with food; may administer other formulations with food
tract, sinusitis, skin and skin
Augmentin For sinusitis and other to decrease stomach upset
structure infections, and
Amoclan urinary tract infections • Refrigerate suspension after reconstitution
30/11/16 6:38 PM
QT
BL
PD
(for example: H. influenzae, M. infections may alternatively • Different formulations may contain different amounts of clavulanic acid and
catarrhalis, H. parainfluenzae, give: XR: 2000 mg every are not interchangeable
GD K. pneumoniae, S. aureus, S. 12 hours • Monitor: renal, hepatic, and hematologic function with extended use
pneumoniae, E. coli, Klebsiella,
Enterobacter)
Contraindications:
9781284110562_CH02_Pass01.indd 65
Sensitive to beta-lactamase– • Prior use caused hepatic dysfunction
QT
producing bacteria • XR tablets are contraindicated if CrCl less than 30 mL/min
BL
Generic Name Treatment of susceptible Usual oral dose for • May cause a rash that is not associated with hypersensitivity reaction; appears
Ampicillin
PD bacteria that cause the respiratory tract 3 to 14 days after first dose
following infections: infections: 250 to 500 mg • Rapid infusion may cause seizures: infuse slowly
GD every 6 hours
• Administer on an empty stomach to increase absorption
Oral: genitourinary tract
Name
Brand QT • Monitor: renal, hepatic, and hematologic function with extended use
infections, gastrointestinal Usual parenteral dose
Principen tract infections, respiratory • Specific recommendations for patients undergoing dialysis
BL for respiratory tract
tract infections Contraindications:
infections:
PD • Infection with penicillinase-producing bacteria
IM, IV: 250 to 500 mg every
Parenteral (IM, IV): meningitis,
GD 6 hours
gastrointestinal infections,
respiratory tract infections,
septicemia, endocarditis,
urinary tract infections (for
QT example: E. coli, P. mirabilis,
enterococci, Shigella,
BL Salmonella, N. gonorrhoeae,
PD H. influenzae, staphylococci,
streptococci, L. monocytogenes,
GD N. meningitides, S. pneumoniae,
S. aureus)
Generic Name Treatment of susceptible Usual parenteral dose for • May cause hepatic dysfunction: use with caution in patients with hepatic
Ampicillin and bacteria that cause skin and skin and skin structure impairment
sulbactam skin structure infections, infections: • May cause a rash that is not associated with hypersensitivity reaction; appears
intra-abdominal infections, IM, IV: 1.5 to 3 g every 6 3 to 14 days after first dose
and gynecologic infections hours (max 12 g per day) • Dose represents the combination of ampicillin and sulbactam
(for example: S. aureus,
Name
Brand QT • Monitor: renal, hepatic, and hematologic function with extended therapy; if
H. influenzae, E. coli, Klebsiella,
hepatic impairment exists, monitor LFTs periodically
Unasyn Acinetobacter, Enterobacter,
BL
anaerobes) Contraindications:
PD • Prior use caused hepatic dysfunction
Sensitive to beta-lactamase–
GD
producing bacteria
QT
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BL
PD
66
Penicillinase-Resistant Penicillins
Generic Name Treatment of susceptible Usual oral dose: • Administer on an empty stomach
9781284110562_CH02_Pass01.indd 66
Dicloxacillin bacteria that cause pneumonia, 125 to 500 mg every 6
skin and soft-tissue infections, hours for 7 to 14 days
and osteomyelitis
Brand
QT Name
Dynapen
BL Sensitive to penicillinase-
PD
producing staphylococci
GD
Generic Name Treatment of susceptible Usual parenteral dose for • Can cause neurotoxic effects: use caution when giving large doses or if patient
Nafcillin bacteria that cause osteomyelitis: has renal/hepatic impairment
osteomyelitis, bacteremia, IV: 1 to 2 g every 4 hours • Administer IM injections deep in the gluteal muscle
septicemia, endocarditis, and
Brand
QT Name Treatment duration based • IV formulation is a vesicant: avoid extravasation; if extravasation occurs, stop
CNS infections
on severity of infection the infusion immediately and give hyaluronidase
Nallpen
BL
• Monitor: CBC with differential at baseline and throughout treatment, urinalysis,
PD
Staphylococcus BUN, SCr, aspartate transaminase (AST), alanine aminotransferase (ALT)
• May administer for a longer period of time for more serious infections (6 weeks)
GD
Generic Name Treatment of infections Usual parenteral dose for • Can cause acute (but reversible) hepatitis 2 to 3 weeks after first dose
Oxacillin caused by penicillinase- mild to moderate severity • Use with caution in patients with poor renal function, although no specific
producing staphylococci skin infections: dosage reductions are recommended
Not for use if organism is IM, IV: 250 to 500 mg every • May contain a significant amount of sodium: use with caution in elderly
susceptible to penicillin G 4 to 6 hours patients and patients on salt-restricted diets
Brand
QT Name
• Can cause false-positive results for urinary and serum proteins
Bactocill
BL
• Monitor: CBC, urinalysis, BUN, renal and liver function
PD
GD
Extended-Spectrum Penicillins
• Can cause false-positive urinary glucose if patient is using copper reduction (Clinitest)
30/11/16 6:38 PM
Generic Name Treatment of susceptible Usual parenteral dose for • May cause severe skin reactions such as TEN, SJS, or DRESS; discontinue if rash
Piperacillin and bacteria that cause skin and skin structure progresses
tazobactam community-acquired infections: • Monitor electrolytes, especially if patient has low potassium
9781284110562_CH02_Pass01.indd 67
pneumonia, intra-abdominal IV: 3.375 g every 6 hours • Abnormal prothrombin time, platelet aggregation, and clotting times have
infections, nosocomial
occurred: use with caution in patients with renal impairment; discontinue if
QT pneumonia, pelvic infections,
Higher dose bleeding occurs
Brand Name and skin and skin structure
BL recommendations for more • Use with caution in patients with cystic fibrosis: increases the risk of fever and
Zosyn infections (for example:
severe infections rash
PD H. influenzae, P. aeruginosa,
E. coli, B. fragilis, B. ovatus, (max 18 g per day) • Use with caution in patients with renal impairment
GD B. thetaiotaomicron, • May increase risk of seizures: use with caution in patients with preexisting
B. vulgatus, S. aureus, seizure disorders or renal impairment
Acinetobacter baumanii, • Specific recommendations for patients undergoing dialysis
K. pneumoniae)
• Ratio of piperacillin to tazobactam is 8:1
QT • 1 g contains 2.79 mEq of sodium
Treatment of moderate to
BL • Can cause false-positive results with the Platelia Aspergillus enzyme
severe susceptible infections
immunoassay
PD
• Monitor: SCr, BUN, CBC with differential, prothrombin time (PT), partial
Sensitive to beta-lactamase– thromboplastin time (PTT), serum electrolytes, LFTs, urinalysis, signs of
GD
producing bacteria bleeding
Quinolones
• Can cause false-positive results with commercially available immunoassay kits for opioids
• May cause photosensitivity
• May cause QTc prolongation: use with caution in patients at high risk for arrhythmias
• May cause CNS effects such as tremor, restlessness, confusion, hallucinations, seizures, and pseudotumor cerebri: discontinue if severe adverse effects occur
• Because of the risk for serious and potentially permanent side effects associated with fluoroquinolone antibiotics, it is recommended that these agents be used only
when alternative treatment options cannot be used
• Pediatric dose symbols are not included for these agents. Specific cautions are noted in the PI for anyone under the age of 18. Refer to additional references when
treating this population
Associated with:
• Tendon inflammation or rupture: increased risk with concurrent corticosteroids, organ transplant, and age greater than 60 years
• Worsening weakness in myasthenia gravis: avoid use in patients with this condition
30/11/16 6:38 PM
68
Generic Name Treatment of susceptible Usual oral dose for • Rarely causes crystalluria: keep patient well hydrated
Ciprofloxacin bacteria that cause plague, complicated UTI: • May cause serious hypoglycemia: greater risk in diabetes and elderly
UTI, uncomplicated 250 to 500 mg every • Can cause hepatotoxicity: discontinue if signs of hepatitis occur
cystitis in females, chronic 12 hours
• Rarely can cause peripheral neuropathy: discontinue if symptoms occur
prostatitis, lower respiratory
Brand Name tract infections, sinusitis, • Use with caution in patients with rheumatoid arthritis or seizure disorder
9781284110562_CH02_Pass01.indd 68
Alternatively may give:
Cipro skin and skin structure • Hemolytic anemia is more likely to occur with G6PD deficiency
infections, bone and joint Usual ER dose: 1000 mg
Ciloxan • Immediate-release and extended-release tablets are not interchangeable
infections, complicated once daily
Cextraxal • Administer IV via slow infusion over 60 minutes and in a large vein to reduce
intra-abdominal infections, Alternatively may give:
venous irritation
infectious diarrhea, typhoid Usual IV dose:
QT • Administer at least 2 hours before or 6 hours after using antacids, calcium,
fever, uncomplicated cervical
200 to 400 mg every iron, zinc, and dairy products
QT BL and urethra gonorrhea, and
12 hours
nosocomial pneumonia • Do not administer suspension through feeding tubes to avoid adherence to
BL PD Duration 7 to 14 days the tube
PD depending on severity of
GD • Drug interactions may require doses adjustments or avoidance of certain drug
To prevent anthrax or prevent UTI infection
progression of disease combinations
QT GD
• May mask symptoms of syphilis: test patients for syphilis when treating them
BL Usual ophthalmic dose: for gonorrhea
Empiric treatment of febrile Solution: 1 to 2 drops every
PD neutropenic patients • Warm the otic solution to room temperature before use
15 minutes to 4 hours
• Monitor: CBC, renal and hepatic function with extended use
GD
Ophthalmic: bacterial Usual topical dose:
conjunctivitis and corneal Ointment: Apply ½ inch

ulcer under eye 2 to 3 times per day
Otic: otitis externa Usual otic dose: instill

contents of “single dose”
container twice per day for
7 days
Generic Name Treatment of susceptible Usual otic dose: 4 drops • Before instilling drops into affected ears, warm the bottle by holding it in the
Finafloxacin bacteria that cause acute twice daily for 7 days hand for 1 to 2 minutes
otitis externa May increase dose to • Shake well before administration
8 drops for first dose with
P. aeruginosa, S. aureus use of otowick
Brand Name
(including MRSA)
Xtoro
30/11/16 6:38 PM
Generic Name Treatment of susceptible Usual oral dose: • May cause serious hypoglycemia: greater risk in patients with diabetes and
Gemifloxacin bacteria that cause 320 mg once daily elderly patients
exacerbation of chronic • Rarely can cause peripheral neuropathy: discontinue if symptoms occur
bronchitis and community-
• Use with caution in patients with rheumatoid arthritis or seizure disorder
acquired pneumonia
9781284110562_CH02_Pass01.indd 69
Brand Name • Hemolytic anemia is more likely to occur in patients with G6PD deficiency
Factive • Administer 3 hours before or 2 hours after using iron, zinc, or magnesium
Treatment of multidrug-
supplements
resistant strains of
QT • May cause photosensitivity
S. pneumoniae
QT BL • Monitor: WBC, renal function
• Specific recommendations for patients undergoing dialysis
BL PD
Generic Name Treatment of susceptible Usual dose for sinusitis: • May cause serious hypoglycemia: greater risk in patients with diabetes and
PD GD
Levofloxacin bacteria that cause PO, IV: 500 mg every elderly patients
GD
community-acquired 24 hours for 10 to 14 days • Can cause hepatotoxicity: discontinue if signs of hepatitis occur
QT
pneumonia, nosocomial
Alternatively may give • Rarely can cause peripheral neuropathy: discontinue if symptoms occur
BL pneumonia, chronic
750 mg daily for 5 days • Use with caution in patients with rheumatoid arthritis or seizure disorder
Brand Name bronchitis exacerbation,
PD • Hemolytic anemia is more likely to occur in patients with G6PD deficiency
Levaquin rhinosinusitis, prostatitis,
urinary tract infections Usual ophthalmic dose: • Infuse slowly to prevent hypotension
GD
Quixin
(complicated and 1 to 2 drops 4 to 8 times
• Keep patients well hydrated to prevent crystalluria or cylindruria
uncomplicated), per day
(See also • Administer oral medication 1 hour before or 2 hours after meals
pyelonephritis, and
Antituberculosis skin and skin structure • Administer 2 hours before or after antacids, magnesium, aluminum, iron, and
Agents) infections (complicated and zinc supplements
uncomplicated) • Monitor: renal, hepatic, and hematopoietic function periodically during
QT therapy; WBC
QT BL • Specific recommendations for patients undergoing dialysis.
Reduce progression of
BL PD anthrax
PD GD
Treatment and prophylaxis of
QT GD plague
BL
Treatment of multidrug-
PD
resistant strains of
GD
S. pneumoniae
Ophthalmic: bacterial
conjunctivitis
30/11/16 6:38 PM
70
Generic Name Treatment of susceptible Usual dose for sinusitis: • May cause serious hypoglycemia: greater risk in patients with diabetes and
Moxifloxacin bacteria that cause PO, IV: 400 mg every elderly patients
community-acquired 24 hours for 10 days • Can cause hepatotoxicity: discontinue if signs of hepatitis occur
pneumonia, chronic
• Rarely can cause peripheral neuropathy: discontinue if symptoms occur
bronchitis exacerbation,
Brand Name Usual ophthalmic dose: • Use with caution in patients with rheumatoid arthritis or seizure disorder
sinusitis, complicated and
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1 drop 2 to 3 times per day • Hemolytic anemia is more likely to occur in patients with G6PD deficiency
Avelox uncomplicated skin and skin
for 7 days
Vigamox structure infections, and • Administer 4 hours before or 8 hours after antacids, magnesium, aluminum,
complicated intra-abdominal iron, and zinc supplements
Moxeza
infections • Infusion contains 34.2 mEq of sodium
• Monitor: WBC, ECG in patients with cirrhosis of the liver
QT Treatment of multidrug-
resistant S. pneumoniae
QT BL
BL PD Prophylaxis and treatment of

PD plague
GD
GD
Ophthalmic: conjunctivitis
Generic Name Treatment of susceptible Usual oral dose: 200 to • May cause serious hypoglycemia: greater risk in patients with diabetes and
Ofloxacin bacteria that cause chronic 400 mg every 12 to elderly patients
bronchitis exacerbation, 24 hours • Rarely can cause peripheral neuropathy: discontinue if symptoms occur
community-acquired
• Use with caution in patients with hepatic impairment

pneumonia, uncomplicated
Usual ophthalmic dose: • Use with caution in patients with rheumatoid arthritis or seizure disorder
Brand Name skin and skin structure
1 to 2 drops every 2 to 6
Oflox infections, gonorrhea, • Drug interactions may require dose adjustment or avoidance of certain drug
hours
urethritis and cervicitis, combinations
Ocuflox Usual otic dose: 10 drops
mixed infections of the • Hemolytic anemia is more likely to occur in patients with G6PD deficiency
Floxin 1 to 2 times per day
urethra and cervix, pelvic • Do not administer 2 hours before or after food, antacids, zinc, magnesium,
inflammatory disease, and aluminum supplements
uncomplicated cystitis,
• Can delay or mask symptoms of syphilis: assess for this infection before
QT complicated urinary tract
initiating treatment for gonorrhea
infections, and prostatitis
QT BL • Warm the otic solution to room temperature before administering it
BL PD • Monitor: CBC, renal and hepatic function with extended use
QT Ophthalmic: conjunctivitis
PD
QT
and corneal ulcer
GD
BL
BL
GD
PD Otic: otitis media, chronic
PD otitis media, and otitis
GD externa
GD
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Sulfonamides
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Generic
QTName Treatment of susceptible Usual oral dose for UTI: • May cause blood dyscrasias, including fatal agranulocytosis
Sulfadiazine bacteria that cause 2 to 4 g per day divided • Drug interactions may require dose adjustment or avoidance of certain drug
BL
chancroid, trachoma, into 3 to 6 doses combinations
PD inclusion conjunctivitis,
• Can cause SJS or TEN: discontinue if rash develops
nocardiosis, UTI,
GD • May cause hepatic necrosis: monitor and discontinue if adverse event
toxoplasmosis encephalitis,
becomes severe
malaria, meningococcal
meningitis, otitis medias, and • Use with caution in patients with asthma, hepatic impairment, or renal impairment
meningitis • Hemolytic anemia is more likely to occur in patients with G6PD deficiency
QT
• Administer with 8 ounces of water
Prophylaxis against • Avoid concomitant intake of vitamins or acidic foods due to increased risk
BL
rheumatic fever of crystalluria
PD • May give leucovorin to prevent adverse effects from folate deficiency
• Monitor: CBC, urinalysis, CD4+ count if treating for toxoplasmosis in HIV
GD
patients, sulfonamide blood levels if severe infection
Generic Name
Co-trixomazole
Generic Name Oral formulations treat Usual oral dose: 1 to 2 • May cause blood dyscrasias, including fatal agranulocytosis and thrombocytopenia
Sulfamthoxazole/ susceptible bacteria that double-strength (DS) every • Can cause SJS or TEN: discontinue if rash develops
Trimethoprim cause urinary tract infections, 12 to 24 hours
• May cause hepatic necrosis, hyperkalemia, hypoglycemia, hyponatremia:
otitis media, chronic
Brand Name monitor and discontinue if adverse event becomes severe
bronchitis exacerbations,
Bactrim Usual parenteral dose: • Use with caution in patients with asthma, thyroid dysfunction, folate
prophylaxis and treatment
IV: 8 to 20 mg/kg per day deficiency, porphyria, and slow acetylators
Septra QT of Pneumocystis pneumonia
divided into doses every 6 • Do not use with leucovorin when treating PCP in HIV patients: increases risk
Sulfatrim (PCP), traveler’s diarrhea, and
BL to 12 hours of failure and death
enteritis (for example:
PD E. coli, Klebsiella, Enterobacter, • Hemolytic anemia is more likely to occur in patients with G6PD deficiency
M. morganii, P. mirabilis, • Dosing is based on the trimethoprim component
GD
P. vulgaris, H. influenzae, • Double-strength: sulfamethoxazole 800 mg and trimethoprim 160 mg
S. pneumoniae, S. flexneri,
• Administer oral formulations with 8 ounces of water
S. sonnei)
• Some dosage forms contain propylene glycol; large amounts are toxic
• Monitor: CBC, potassium blood level, SCr, BUN
QT IV treats susceptible bacteria
that cause PCP, enteritis, and • May cause sun sensitivity
BL
complicated or severe urinary Contraindications:
PD tract infections • Megaloblastic anemia caused by folate deficiency
• Severe hepatic or renal impairment
GD
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72
Generic Name Treatment of susceptible Usual oral dose for • May cause blood dyscrasias, including fatal agranulocytosis
Sulfasalazine bacteria that cause juvenile ulcerative colitis: • Rarely can cause death from irreversible neuromuscular and central nervous
rheumatoid arthritis (EC), uncoated tablets: 1 g every system changes or from fibrosing alveolitis
rheumatoid arthritis (EC), and 6 to 8 hours • Can cause SJS or TEN: discontinue if rash develops
ulcerative colitis (IR and EC)
Brand Name • May decrease folate absorption
9781284110562_CH02_Pass01.indd 72
enteric coated tablets: • May cause hepatic necrosis: monitor and discontinue if adverse event
Azulfidine
QT
3 to 4 g per day divided becomes severe
Sulfazine
BL doses and given every • Reports of serious infections have occurred, including sepsis and pneumonia:
PD
8 hours. monitor CBC with differential and watch for signs and symptoms of infection
during and after treatment
GD
• Use with caution in patients with asthma, hepatic impairment, or renal
impairment, and slow acetylators
• Hemolytic anemia is more likely to occur in patients with G6PD deficiency
• Administer in evenly divided doses after meals
• Keep patients well hydrated to prevent crystalluria
• To prevent common gastrointestinal adverse effects, use EC or titrate dose to
goal
• If EC tablets are found in stool, discontinue and use IR formulation
• Monitor: CBC with differential and LFTs at baseline and throughout therapy,
urinalysis, renal function tests, stool frequency
Contraindications:
• Intestinal or urinary obstruction

• Porphyria
Tetracyclines
• Can cause permanently discolored teeth; refer to pediatric medication management guidelines
• May cause photosensitivity; protect skin from direct sunlight
• Some agents require administration 2 hours before or 4 hours after antacids, aluminum, and magnesium supplements to maintain absorption; refer to PI
Generic Name Treatment of susceptible Usual oral dose: • Can cause nephrogenic diabetes insipidus: dose dependent
Demeclocycline bacteria that cause acne, 150 mg 4 times per day • May increase BUN: use with caution in patients with renal impairment
urinary tract infections, and
300 mg twice daily • Rarely causes pseudotumor cerebri: resolves when discontinued
respiratory infections
Brand
QT Name • Use with caution in patients with hepatic and renal impairment: specific
Declomycin recommendations are not stated, but dose decrease or less frequent dosing
BL Covers gram-negative and interval is advised
PD
gram-positive organisms
GD
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• Administer 1 hour before or 2 hours after food or milk intake
• Administer with fluids to prevent esophageal irritation
• Monitor: CBC, renal and hepatic function
Generic Name Treatment of susceptible Usual oral dose for • Rarely can cause hepatotoxicity: discontinue if signs and symptoms occur
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Doxycycline bacteria that cause syphilis, lower respiratory tract • May cause hypersensitivity syndromes such as DRESS, angioneurotic edema,
gonorrhea, community- infections: and systemic lupus erythematosus exacerbation
acquired pneumonia, anthrax, 100 to 200 mg per day in
Brand Name • May increase BUN: use with caution in patients with renal impairment
plague, tularemia, Q fever, 1 to 2 divided doses
Adoxa • Rarely causes pseudotumor cerebri: do not use with isotretinoin; will resolve
intestinal amebiasis, severe acne,
when discontinued
Vibramycin and the following organisms:
IV dose is the same • Can cause hyperpigmentation in various body tissues, including nails and skin
Acticlate Rickettsia, Chlamydia,
Chlamydophila, Mycoplasma, • IV and oral formulations are bioequivalent except for Oracea
Avidoxy
Listeria, A. israelii, Clostridium, • Oral formulation is preferred; needs to be infused slowly, but prolonged
Doryx
B. recurrentis, U. urealyticum, administration can cause thrombophlebitis
Monodox H. decreyi, V. cholera, C. fetus, • Administer oral formulations with 8 ounces of water while sitting up for
Morgidox Brucella, B. bacilliformis, K. 30 minutes to decrease esophageal irritation
TargaDOX granulomatis
• Administer Oracea on an empty stomach
Oracea
QT • Can take with food to lessen stomach upset
Prophylaxis against malaria
Targadox • Drug interactions may require dose adjustment or avoidance of certain drug
BL
Oracea: inflammatory lesions combinations.
PD
due to rosacea • IV formulations with ascorbic acid may cause a false-negative urine glucose
GD when using glucose oxidase tests (Clinistix, Diastix, Tes-Tape)
Excels at treating uncommon • Monitor: CBC; hepatic and renal function with extended use; test of cure
gram-negative and gram- 7 days after treatment for gonorrhea
positive bacteria
Generic Name Treatment of susceptible Usual dose for lower • Can cause autoimmune syndromes such as lupus-like, hepatitis, and vasculitis
Minocycline bacteria that cause intestinal respiratory tract autoimmune syndromes: discontinue and monitor LFT, antinuclear antibodies
amebiasis, acne, actinomycosis, infections: (ANA), and CBC
anthrax, cholera, listeriosis, IV or oral : 200 mg, then • Rarely can cause hepatotoxicity when using for acne: discontinue if signs and
Brand Name
meningitis, ophthalmic 100 mg every 12 hours symptoms occur
Minocin
QT infections, relapsing fever,
• May cause severe skin reactions such as SJS and DRESS: discontinue if rash or
Solodyn respiratory tract infections,
BL other signs and symptoms appear
Rocky Mountain spotted
PD
• May increase BUN: use with caution in patients with renal impairment
fever, typhus fever, Q fever,
rickettsialpox, tick fevers, • Rarely causes pseudotumor cerebri: do not use with isotretinoin; will resolve
GD when discontinued
sexually transmitted infections,
skin and skin structure • Can cause hyperpigmentation in various body tissues, including nails and skin
infections, urinary tract • Oral formulation is preferred; needs to be infused slowly, but prolonged
infections, Vincent infection, administration can cause thrombophlebitis
QT
yaws, psittacosis, plague,
• Administer oral formulations with 8 ounces of water while sitting up for 30
tularemia, brucellosis, and
minutes to decrease esophageal irritation
BL
bartonellosis (for example:

PD
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GD
74
Campylobacter fetus, • Can take with food to lessen stomach upset
Clostridium, Acinetobacter, • Caution patients about operating machinery and driving until effects of the
E. coli, E. aerogenes, medication are known: may cause dizziness
Shigella, N. meningitides, C.
• IV formulation contains magnesium: use with caution in patients with renal
trachomatis, H. influenzae,
impairment
Klebsiella, M. pneumoniae, S.
9781284110562_CH02_Pass01.indd 74
• Monitor: liver and renal function tests and BUN with extended use;
pneumoniae, U. urealyticum,
magnesium in patients with renal impairment; if symptoms of an autoimmune
K. granulomatis, Treponema
disorder occur, ANA and CBC; visual exams, if visual disturbances occur; if
pallidum, S. aureus, Klebsiella)
treating for syphilis, follow up with a serologic test 3 months after treatment
Treatment of asymptomatic
carriers of N. meningitides
Generic Name Treats susceptible bacteria Usual oral dose for • Rarely can cause hepatotoxicity: use with caution in patients with renal and
Tetracycline that cause acne, chronic upper respiratory tract hepatic impairment
bronchitis exacerbations, infections: • May increase BUN: use with caution in patients with renal impairment
gonorrhea syphilis, tularemia 250 to 500 mg 2 to 4 times
Name
Brand QT • Drug interactions may require dose adjustment or avoidance of certain drug
per day combinations
Sumycin
BL Gram-positive organisms, • Expired medications can cause nephropathy
PD
gram-negative organisms,
• Rarely causes pseudotumor cerebri: do not use with isotretinoin; will resolve
Mycoplasma, Chlamydia,
when discontinued
GD Rickettsia
• Administer on an empty stomach to increase absorption
• Monitor: renal, hepatic, and hematologic function; temperature; WBC

Treats H. pylori when used
with additional medications
QT to reduce duodenal ulcer
recurrence
BL
Glycylcyclines
PD
• GDCan cause C. difficile–associated diarrhea and pseudomembranous colitis with extended use
Generic Name Treatment of susceptible Usual parenteral dose for • Can cause antianabolic effects (increase in BUN, azotemia, acidosis,
Tigecycline bacteria that cause skin and skin structure hyperphosphatemia)
community-acquired infections: 100 mg one- • Hepatotoxic
pneumonia, complicated skin time dose, then 50 mg
Brand Name • Can cause pancreatitis
and skin structure infections, every 12 hours for 7 to
Tygacil • Can cause pseudotumor cerebri
and complicated intra- 14 days
abdominal infections • Suitable solutions for administration are yellow-orange in color
(for example: S. pneumoniae, • Can cause significant nausea/vomiting; may need to premedicate patients
QT with antiemetics
BL
PD
QT
30/11/16 6:38 PM
GD
BL
PD
H. influenzae, L. pneumophila, • Can cause photosensitivity
Citrobacter, Enterobacter, • Monitor: CBC, allergic reactions
E. coli, Klebsiella, E.
• Associated with an increase in all-cause mortality (0.6%) compared to other
faecalis, S. aureus (MSSA/
antibiotics
MRSA), S. anginosus,
9781284110562_CH02_Pass01.indd 75
• Switch to appropriate oral therapy as soon as medically appropriate.
Bacteroides, Clostridium,
Peptostreptococcus
S. agalactiae, S. pyogenes,
E. cloacae)
Miscellaneous Antibacterials
Bacitracins
Generic Name Treatment of susceptible Usual ophthalmic dose: • Extended use may lead to overgrowth of nonsusceptible bacteria, such as
Bacitracin bacteria that cause superficial apply 1 to 3 times daily on fungi: treat if new infection develops
ocular infections the lower eyelid • Systemic formulation use is indicated only in specific age populations; refer to PI
Brand Name • Ointment: 1 unit = 0.026 mg
Topical ointment prgevents Topical: apply 1 to 3 times
Baciim
infection in minor cuts, daily on affected area
Ocu-Tracin scrapes, and burns: not
AK-Tracin
QT recommended to use for
Baciguent longer than 1 week
BL
PD
GD
Cyclic Lipopeptides
Generic Name Treatment of susceptible Usual parenteral dose for • May cause eosinophilic pneumonia, usually 2 to 4 weeks after initiating therapy
Daptomycin bacteria that cause skin and skin structure • May cause myopathy: discontinue if creatine phosphokinase (CPK) 10 times
complicated skin and skin infections: IV: 4 mg/kg upper normal limit (UNL) or higher or CPK more than 5 times ULN with signs
structure infections and once daily for 7 to 14 days and symptoms
Brand Name bloodstream infections
• May cause peripheral neuropathy
Cubicin (for example: S. aureus
Duration of treatment • Do not use with ReadyMED elastomeric infusion pumps due to leaching of an
including MRSA, S. pyogenes,
depends on severity of impurity into the solution
S. agalactiae, S. dysgalactiae
infection. Longer treatment
subspecies equismilis, • May falsely increase both PT and INR
may be warranted in
E. faecalis) • Monitor: CPK weekly or more often if using a statin, compromised renal
certain cases
function, or unexpected rise in CPK levels
QT
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BL
PD
76
Glycopeptides
Generic Name Treatment of susceptible Usual parenteral dose: • May cause reversible increase in transaminase levels
Dalbavancin bacteria that cause acute skin IV: 1500 mg single dose • May cause an infusion reaction resembling red man syndrome (hypotension,
and skin structure infections 1000 mg on day 1, then flushing, and/or maculopapular rash): slowing the infusion may alleviate
(for example: S. aureus 500 mg 1 week later symptoms
Brand Name
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• Suitable solutions for administration range in color from colorless to yellow
Dalvance S. agalactiae, S. dysgalactiae,
• Monitor: BUN, renal and liver function, infusion-related reaction symptoms
S. anginosus group, E. faecalis)
Generic Name Treatment of susceptible Usual parenteral dose: • May cause infusion reactions, which are resolved by slowing or discontinuing
Oritavancin bacteria that cause acute skin IV: 1200 mg single dose the infusion
and skin structure infections • May cause osteomyelitis
(for example: S. aureus
Brand Name • Infuse over 3 hours
QT
Orbactiv • Suitable solutions for administration range in color from colorless to pale
S. agalactiae, S. dysgalactiae,
yellow
BL S. anginosus group, E. faecalis)
• Monitor: serum urea nitrogen, renal and liver function
PD
Contraindication:
GD • If heparin is used 120 hours after oritavancin dose due to false elevation of
activated partial thromboplastin time (aPTT)
Generic Name Treatment of susceptible Usual parenteral dose for • May cause red man syndrome indicated by hypotension, flushing, and/or
Telavancin bacteria that cause HAP: maculopapular rash: slow or discontinue infusion
complicated skin and skin IV: 10 mg/kg every 24 hours • May cause QTc prolongation: use with caution in patients with preexisting
structure infections, hospital- for 1 to 3 weeks prolongation or heart conditions
Brand Name
acquired pneumonia (HAP),
• Handle as a hazardous agent
Vibativ and ventilator-associated
• May interfere with coagulation tests: perform levels as close to the next dose
pneumonia (VAP)
QT as possible (at least 18 hours after previous dose)
• Monitor: renal function at baseline, during therapy, and 48 to 72 hours after
QT BL S. aureus (including MRSA),
last dose
BL PD
E. faecalis, S. pyogenes,
• Infuse over 60 minutes
S. agalactiae, S. anginosus
PD Associated with nephrotoxicity:
GD
• Use with caution in patients with risk factors and monitor renal function
GD
throughout therapy and 48 to 72 hours after last dose
• Increased all-cause mortality compared to vancomycin when CrCl 50mL/min
or less when treating for HAP/VAP
30/11/16 6:38 PM
Generic Name IV treats infection caused by Usual parenteral dose • May cause nephrotoxicity: use with caution if patient has risk factors
Vancomycin staphylococci or streptococci, for lower respiratory • May cause neurotoxicity
including meningitis, infections:
• May cause neutropenia: higher risk if use is greater than 1 week and total dose
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pneumonia, and prophylaxis IV: 15 to 20 mg/kg per dose
Name
Brand QT exceeds 25 g
against endocarditis every 8 to 12 hours
Vancocin • May cause ototoxicity
BL Alternatively may give
• May cause red man syndrome indicated by hypotension, flushing, and/
PD
Oral dosing: C. difficile– 500 mg every 6 hours or maculopapular rash: slow infusion, dilute further, and treat with
associated diarrhea and
antihistamines and steroids
GD enterocolitis from S. aureus
Dose should be based on • Oral vancomycin use in inflammatory bowel disease may cause systemic
(including MRSA)
actual body weight absorption (IV product may be used orally)
• Vancomycin is an irritant: avoid extravasation; if extravasation does occur, stop
Usual oral dose: the infusion as soon as possible and aspirate the solution
QT
500 mg daily in divided • Monitor: IV: renal function tests, urinalysis, WBC, troughs if therapy extends for
BL doses every 6 hours more than 3 days with high-intensity dosing
Lincomycins
PD
Drug
GD
Name FDA-Approved Indications Adult Dosage Range Precautions and Clinical Pearls
Generic Name Treatment of susceptible Usual oral dose for • Use with caution in patients with severe allergy to tartrazine; reaction is more
Clindamycin bacteria that cause bone and skin and skin structure likely to occur if patients have allergy to aspirin
joint infections, gynecologic infections: • May cause severe skin reactions such as TEN: discontinue if severe rash occurs
infections, intra-abdominal 150 to 450 mg every
Brand Name • Use with caution in patients with hepatic impairment: less accumulation
infections, lower respiratory 6 hours occurs if dose is given every 8 hours
Cleocin tract infections, septicemia,
Usual parenteral dose: • Use with caution in patients with atopy
Clindacin and skin and skin structure
IM, IV: 600 to 2700 mg in 2
infections • Do not administer undiluted solution as a bolus
Clindagel to 4 divided doses daily
S. aureus (including • Do not administer more than 600 mg in a single IM dose
ClindaMax (IV max 4800 mg per day)
community-acquired MRSA), • Administer oral dosage forms with plenty of water to decrease the risk of
Clindesse
QT
anaerobes, S. pneumoniae, esophageal ulceration
Evoclin streptococci (not E. faecalis), Topical: apply 1 to 2 times
BL • Do not refrigerate oral solution: will thicken
S. pyogenes daily
PD • Not for meningitis: does not penetrate cerebrospinal fluid (CSF) adequately
• If bacteria are erythromycin resistant, perform D-zone test to ensure the
QT GD Vaginal cream: insert
Treatment of serious pathogen is not clindamycin-resistance inducible
BL infections caused by 1 applicatorful once daily
• Monitor: LFTs in patients with severe hepatic impairment; CBC, renal tests, and
streptococci, pneumococci, for 1 to 7 days (product
PD LFTs with extended use; signs and symptoms of colitis
and staphylococci specific durations)
• Associated with severe colitis that can be fatal: use only if necessary, and use
GD
with caution in patients with preexisting gastrointestinal disease
Topical agents: acne
• Vaginal creams are generally recommended for installation just prior to
bedtime (Clindesse brand is only 1 single dose at any time of the day)
Vaginal agents: bacterial
vaginosis
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78
Generic Name Treatment of severe Usual parenteral dose: • Extended use can cause overgrowth of bacteria or fungi
Lincomycin bacterial infections caused IM: 600 mg every 12 to • Use with caution in patients with asthma, gastrointestinal diseases (especially
by susceptible strains of 24 hours colitis), or poor hepatic or renal function
streptococci, pneumococci,
Brand NameQT • Do not give IV bolus of undiluted solution
and staphylococci
Lincocin IV: 600 to 1000 mg every • Infuse over 1 hour per gram to avoid cardiopulmonary arrest and hypotension
For patients who have severe
9781284110562_CH02_Pass01.indd 78
BL
8 to 12 hours • Not for meningitis: does not penetrate CSF adequately
allergy to penicillins
PD • Monitor: baseline SCr and LFTs; renal tests, LFTs, and CBC with differential with
QT (max 8 g IV per day) extended use; bowel changes throughout therapy
GD
Oxazolidinones
BL
PD
QT GD
Generic
BL Name Enterococcal vancomycin- Usual dose for CAP: • Can cause lactic acidosis
Linezolid resistant infections Oral, IV: 600 mg every • Myelosuppression may be dependent on length of use
PD
12 hours for 10 to 14 days
• Peripheral and optic neuropathy with extended use
GD Pneumonia: Longer treatment durations
Brand
QT Name • Rarely can cause serotonin syndrome
may be warranted based
Zyvox Community-acquired (CAP): • Monitor for hypoglycemia in patients with diabetes
BL on severity and extent of
S. pneumoniae, S. aureus
infection. • Use with caution in patients with history of seizures
PD
• Do not mix or infuse with other medications; flush line before and after use
Hospital-acquired: S. aureus
GD • Yellow color of the solution can intensify over time

(MSSA/MRSA), S. pneumoniae
• Avoid consumption of large amounts of tyramine-containing foods
• Protect tablets, suspensions, and infusions from light
Skin and skin structure
• Do not shake the suspension
infections
• Monitor: CBC weekly; visual function; hematopoietic/neuropathic adverse
Complicated: S. aureus
events in patients with poor renal function
(MSSA/MRSA), S. pyogenes,
S. agalactiae • Specific recommendations for patients undergoing dialysis
Uncomplicated: S. aureus,
S. pyogenes
Generic Name Treatment of susceptible Usual dose: • Do not use if neutrophil count is less than 1000 cells/mm3
Tedizolid bacteria that cause acute Oral, IV: 200 mg once daily • Suitable solutions for administration range in color from colorless to pale
skin and skin structure for 6 days yellow
infections (for example:
Brand Name • Inhibits monoamine oxidase, which can cause drug interactions
S. aureus [including MRSA],
Sivextro S. pyogenes, S. agalactiae, • Monitor: CBC with differential
S. anginosus group, E. faecalis)
30/11/16 6:38 PM
Polymyxins

Generic Name Sensitive to certain gram- Usual dose expressed as • Can cause transient CNS adverse effects such as dizziness, numbness, slurred
Colistimethate/ negative bacilli that are colistin base: IM, IV: 2.5 to speech, and tingling: reducing dose may alleviate symptoms
9781284110562_CH02_Pass01.indd 79
colistin typically resistant to other 5 mg/kg per day in 2 to 4 • Dose-dependent renal toxicity may develop: interrupt therapy if signs and
antibiotics divided doses (max 5 mg/ symptoms of renal impairment occur
Brand Name
P. aeruginosa kg per day) • Reports of respiratory arrest have occurred: use with caution in patients with
Coly-Mycin poor renal function
Used in meningitis if bacteria
• Colistimethate is the prodrug of colistin (equivalence data are available in the
are resistant and/or patient is
package insert)
allergic to first-line agents
• In obese patients, use ideal body weight to calculate the dose
• Caution patients about operating machinery and driving until tolerance of the
medication is established
• Monitor: renal function test at baseline; for nephrotoxicity, neurotoxicity, and
pulmonary toxicity throughout therapy
QT
Generic Name Treatment of susceptible Usual otic dose: 1 to 2 • IM formulation is not recommended due to the severe pain it causes
QT
Polymyxin
BL B strains of P. aeruginosa drops 3 to 4 times daily • IV formulation is reserved for patients in whom other antibiotics fail
BL
Usual ophthalmic dose: • Monitor: renal function tests, neurotoxicity signs/symptoms
PD 1 to 3 drops every 1 to 6 Associated with:
PD
hours daily • Nephrotoxicity: avoid use with other nephrotoxic agents
GD QT GD Usual parenteral dose: IM: • Neurotoxicity that can cause respiratory paralysis: use with caution in patients
BL 25,000 to 30,000 units/kg with renal impairment and high polymyxin serum levels
per day divided every 4 to • Need for giving only IM/intrathecal formulations in the hospital
PD
6 hours
GD IV: 15,000 to 25,000 units/
QT
kg per day divided every
BL 12 hours
Intrathecal: 50,000 units
PD
daily or every other day
GD Topical irrigation: 0.1
to 0.25% solution as part
of wet dressings or as a
wound irrigation
Rifamycins
Generic Name Hepatic encephalopathy Usual oral dose for • Use with caution in patients with severe hepatic impairment: efficacy may be
Rifaximin irritable bowel syndrome: diminished in preventing encephalopathy
Irritable bowel syndrome
550 mg 3 times daily for • Do not use for diarrhea if blood appears in the stool or the patient has a fever
Brand Name with diarrhea
14 days • Some dosage forms contain propylene glycol: large amounts are toxic
Xifaxan Traveler’s diarrhea caused by
• Not for systemic infections: not adequately absorbed
E. coli
• Monitor: body temperature and for presence of blood in the patient’s stool
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80
Generic Name Refer to the Antimycobacterials section.
Rifabutin

Rifampin
9781284110562_CH02_Pass01.indd 80
Rifapentine
Streptogramins
Generic Name Treatment of susceptible Usual parenteral dose for • Can cause arthralgia or myalgia: decrease dosing frequency in such cases
Quinupristin bacteria that cause skin and skin structure • May cause hyperbilirubinemia
and dalfopristin complicated skin and infections: IV: 7.5 mg/kg
• May cause phlebitis if used peripherally: hydrocortisone and
skin structure infections every 12 hours for at least
diphenhydramine do not relieve symptoms
(for example: S. aureus, S. 7 days.
Brand Name • Drug interactions may require dose adjustment or avoidance of certain drug
pyogenes)
Synercid combinations
• Infuse over 60 minutes to decrease toxicity: if venous irritation occurs, dilute

further
• Monitor: culture and sensitivity, periodically check infusion site
Miscellaneous Urinary Anti-infectives
Generic Name Treatment of susceptible Usual oral dose: • Always mix powder with water before administering
Fosfomycin bacteria that cause 3 g single dose in 3 to 4 • High concentrations persist for up to 48 hours in the urine
uncomplicated urinary tract ounces of water • Monitor: urine culture with sensitivity
infections in women (for
Brand Name example: E. coli, E. faecalis)
Monurol
30/11/16 6:38 PM
Generic Name Treatment of susceptible Usual oral dose: • Use with caution in patients with gout
Methenamine bacteria that cause recurrent Hippurate: 1 g twice daily • Use with caution in elderly patients
urinary tract infections
• Foods or dinks that may alkalinize the urine can decrease the activity of
9781284110562_CH02_Pass01.indd 81
Brand Name Mandelate: 1 g 4 times/day methenamine
Prophylaxis against urinary after meals and at bedtime • Monitor: urinalysis, hepatic function periodically
Hiprex
tract infections
Urex
QT
Contraindications:
Mandelamine • Severe renal or hepatic impairment
BL Decreases urinary tract
• Severe dehydration
PD
discomfort secondary to
hypermotility
GD
Generic Name Treatment of susceptible Usual oral dose for UTI: • Macrobid formulation and oral suspension are not interchangeable with other
Nitrofurantoin bacteria that cause urinary 50 to 100 mg every 6 hours nitrofurantoin products
tract infections (for example: Alternatively may give • May cause optic neuritis
E. coli, enterococci, S. aureus,
Brand Name Macrobid products: • May cause peripheral neuropathy: use with caution if patient has risk
Klebsiella, Enterobacter)
100 mg twice daily factors
Furadantin
Treatment usually for • Pulmonary toxicity has occurred: discontinue immediately if signs and
Macrobid
QT Macrobid: indicated only for 7 days or 3 days after symptoms occur
Macrodantin acute uncomplicated urinary
QT BL obtaining sterile urine • Administer with meals to increase absorption
tract infections (for example:
BL PD • Suspension may be mixed with water, milk, or fruit juice
E. coli, S. saprophyticus)
Prophylaxis (all products • Protect suspension from light to prevent darkening of nitrofurantoin
PD GD except Macrobid):
• Patients with G6PD deficiency are at higher risk of hemolytic anemia
GD 50 to 100 mg at bedtime
• Monitor: signs of pulmonary toxicity, signs of numbness or tingling of the
extremities, CBC, hepatic function periodically, renal function with extended
use
Contraindications:
• In patients with CrCl less than 60 mL/min
• Previous hepatic dysfunction associated with nitrofurantoin
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82
Generic Name Treatment of susceptible Usual oral dose for UTI: • May cause hyperkalemia: use with caution if administering high doses or in
Trimethoprim bacteria that cause UTI, 100 mg every 12 hours patients with renal impairment
(for example: E. coli, P. • Use with caution in patients with hepatic or renal impairment
Alternatively may give
mirabilis, K. pneumoniae,
Brand NameQT 200 mg every 24 hours • Administer with milk or food
Enterobacter, coagulase-
Primsol Treatment is generally • Drug interactions may require dose adjustment or avoidance of certain drug
negative Staphylococcus, S.
9781284110562_CH02_Pass01.indd 82
BL
recommended for 10 to combinations
saprophyticus)
QT PD 14 day duration • May need to supplement with folic acid
BL • Monitor: CBC and potassium with extended use
GD Treatment of otitis media
Contraindications:
PD S. pneumoniae, H. influenzae
• Megaloblastic anemia due to folate deficiency
GD
Antifungal Agents
QT
Allylamines
BL
PD
Generic Name Onychomycosis (tablets) Usual oral dose: • Not recommended for use in chronic or active hepatic disease or if CrCl 50 mL/
Terbinafine caused by dermatophytes 250 mg once daily for at minute or less
GD
least 6 weeks • May cause depression
Brand Name Tinea capitis (granules) • May cause taste and smell disturbances: discontinue if symptoms occur
Lamisil
QT
Topical: • Drug interactions may require dose adjustments or avoidance of certain drug
Topical formulations: tinea Cream: apply 2 times daily combinations
Terbinex
BL
pedis, tinea cruris, and tinea for 1 to 2 weeks • Can cause transient hematologic effects: monitor CBC in immunosuppressed
PD corporis patients if therapy lasts longer than 6 weeks
Gel or solution: apply once • Rare cases of hepatic failure have occurred: assess the patient for this
GD
daily for at least 1 week condition if signs and symptoms occur; discontinue if LFTs are significantly
elevated
• Serious skin reactions have been reported, such as SJS and DRESS: discontinue
if rash progresses
• Rarely can cause ocular changes in the lens and retina
• Can exacerbate or precipitate lupus: discontinue if signs and symptoms
develop
• Administer granules with food: sprinkle on soft food that is not acidic, such as
pudding or mashed potatoes, and swallow without chewing
• When administering topical solution, hold 4 to 6 inches away from skin
• Monitor: LFTs at baseline and again if duration of therapy exceeds 6 weeks;
changes in taste or smell
30/11/16 6:38 PM
Azoles
Generic Name Treatment of onychomycosis Usual topical dose: apply • May cause local irritation
Efinaconazole caused by T. rubrum or to affected toenails once • Toenails should be dry and clean before administration
T. mentagrophytes daily for 48 weeks
9781284110562_CH02_Pass01.indd 83
• Avoid nail products, such as nail polish, while using medication
Brand Name
Jublia
Generic Name Treatment of candidiasis Usual dose for • Can cause arrhythmias and QTc prolongation: use with caution in patients
Fluconazole infections: esophageal, oropharyngeal with preexisting arrhythmias and with concurrent use of agents that have a
oropharyngeal, peritoneal, candidiasis: similar effect
urinary tract, vaginal, Oral, IV: 200 mg once, then • Drug interactions may require dose adjustments
Brand Name
candidemia, pneumonia, and 100 daily for 2 weeks after • May cause hepatotoxicity that can be fatal: discontinue if signs and symptoms
Diflucan QT disseminated candidiasis the resolution of symptoms occur
BL • Rarely causes exfoliative skin disorders: discontinue if rash develops
Treatment of cryptococcal
QT PD • Do not use IV solution if cloudy or precipitated
meningitis
• Hazardous agent: use caution in preparing and disposing of medication
BL GD
PD Prophylaxis against
medication is established due to the potential for dizziness or seizures
candidiasis in allogenic bone
GD • Monitor: liver and renal function tests periodically, potassium
marrow transplant recipients
Generic
QT Name Invasive aspergillosis Usual dose for treatment: • Drug interactions may require dose adjustments
Isavuconazonium Oral, IV: 372 mg every • May cause hepatotoxicity that can be fatal: discontinue if signs and symptoms
BL
sulfate Invasive mucormycosis 8 hours for 6 doses then occur
PD once daily • Infusion-related reactions may occur such as hypotension, chills, and
Brand Name paresthesia: discontinue if they occur
GD
Cresemba • IV solution may contain clear to white particulates of isavuconazole: use 0.2-
to 1.2-micron in-line filter
QT
• Monitor: LFTs at baseline and during therapy, infusion-related reactions
BL during infusion
PD Contraindications:
• Familial short QT syndrome
GD
Generic Name Treatment of aspergillosis, Usual oral dose • Can cause transient or permanent hearing loss: usually resolves upon
Itraconazole blastomycosis, and for allergic discontinuation
histoplasmosis in bronchopulmonary • May cause hepatotoxicity that can be fatal: discontinue if signs and symptoms
immunocompromised and aspergillosis: occur
Brand Name
non-immunocompromised 600 mg in divided doses for • May cause neuropathy
Sporanox patients (capsule) 3 days, then 400 mg daily in
• Drug interactions may require dose adjustments or avoidance of certain drug
Onmel divided doses
combinations
QT
QT BL
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BL PD
PD GD
84
Onychomycosis caused by • Use with caution in patients with cystic fibrosis: displays erratic
dermatophytes (capsule), pharmacokinetics; use alternative therapy if infection does not improve
Trichophyton rubrum • Do not give more than 200 mg at one time
(tablet), or Trichophyton
• Do not administer with antacids: capsules and tablets need gastric acidity for
mentagrophytes (tablet)
proper absorption
9781284110562_CH02_Pass01.indd 84
• Capsules and oral solutions are not bioequivalent
Oral solution: oropharyngeal/
• Administer capsules and tablets with food; administer oral suspension on an
esophageal candidiasis
empty stomach
• Swish and swallow oral solution if treating for oropharyngeal and esophageal
candidiasis
medication is established due to the potential for CNS depression
• Monitor: LFTs if preexisting impairment and duration is greater than 1 month;
itraconazole blood levels, especially for oral therapy; renal function tests; signs
and symptoms of heart failure
Associated with:
• Heart failure: discontinue if signs and symptoms develop
• Ventricular dysfunction if treating patients for onychomycosis
Generic Name Treatment of systemic Usual oral dose: • Drug interactions may require dose adjustments
Ketoconazole fungal infections 200 to 400 mg once daily • May cause adrenocortical dysfunction that resolves upon discontinuation
including blastomycosis,
• Can cause increased long bone fragility
histoplasmosis,
Brand Name Usual topical dose: • Administer 2 hours before antacid use to maintain gastric acidity for
paracoccidoidomycosis,
Nizoral Cream: apply 1 to 2 times absorption
coccidoidomycosis, and
Extina chromomycosis when other daily (dose varies on • In patients with achlorhydria, administer with acidic liquids
therapies have failed affected area targeted for • Poorly penetrates the brain and should not be used for fungal meningitis
Ketodan
treatment)
Nizoral A-D • Gel and foam preparations are flammable
QT
Xolegel Cream: tinea corporis, tinea • Shampoo may remove curls, discolor hair, and change hair texture
BL cruris, tinea versicolor, OTC 1% shampoo: apply
• Monitor: LFTs at baseline and throughout therapy, calcium and phosphorus
QT PD cutaneous candidiasis, and and rinse once or twice
with extended use, adrenal function as needed
weekly
seborrheic dermatitis
QT BL Contraindications:
GD
• Acute or chronic liver disease
BL PD Foam/gel: seborrheic Foam: apply twice daily
Associated with:
PD dermatitis
GD • QTc prolongation: do not use with other medications that can cause QTc
Gel: apply once daily
GD prolongation
Shampoo: dandruff,
• Hepatotoxicity that can be fatal: discontinue if signs and symptoms occur
seborrheic dermatitis, and
tinea versicolor • Use only if other therapies have failed and the benefit outweighs the risk
30/11/16 6:38 PM
Generic Name Treatment of susceptible Usual topical dose: apply • Topical use only
Luliconazole fungi that cause tinea to affected area and 1 inch
pedis, tinea cruris, and tinea of surrounding area once
corporis daily for 1 to 2 weeks
Brand Name
9781284110562_CH02_Pass01.indd 85
Luzu
T. rubrum, E. floccosum
Generic Name Prophylaxis against invasive Usual dose for oral • Can cause QTc prolongation and arrhythmias: use with caution in patients at
Posaconazole Aspergillus and Candida candidiasis: high risk for arrhythmias
infections in severely Oral suspension: 100 to • Drug interactions may require dose adjustments
immunocompromised 400 mg 1 to 3 times daily
Brand Name • Can cause hepatotoxicity that can be fatal: discontinue if signs and symptoms
patients
occur; effects are usually reversible upon discontinuation
Noxafil
Usual dose for candiasis • DR tablets and oral suspensions are not interchangeable on a mg per mg basis
QT
Suspension: oropharyngeal prophylaxis: • If glomerular filtration rate (GFR) less than 50 mL/min, do not use IV due to
candidiasis
IV/Oral (DR tablets): 300 mg accumulation of cyclodextrin
BL
2 times per day on the • Limit peripheral IV infusion to one 30-minute infusion due to increased
PD first day, then once daily. chance of infusion-site reactions
Duration of therapy is
GD • Administer suspension and DR tablets with food
based on clinical progress
• Suitable IV solution color is clear to yellow
and recovery
• Monitor for breakthrough fungal infections in patients weighing more than
120 kg due to lower blood levels
• Monitor: LFTs at baseline ad throughout therapy, renal function tests,
electrolytes, CBC, breakthrough fungal infections
Generic Name Treatment of invasive Usual parenteral dose: • Can cause QTc prolongation and arrhythmias: caution in patients at high risk
Voriconazole aspergillosis; esophageal IV: 3 to 6 mg/kg every for arrhythmias, correct electrolytes prior to use
candidiasis; candidemia 12 hours • Drug interactions may require dose adjustments
(if non-neutropenic);
Brand Name • Can cause severe dermatologic reactions including melanoma and SJS: avoid
disseminated Candida
Usual oral dose: exposure to direct sunlight, perform skin examinations for lesions periodically,
Vfend infections of the skin and
Adjusted body weight and discontinue if signs and symptoms appear
abdomen, kidney, bladder
QT ABW 40 kg or greater: • Oral dosing based on adjusted body weight
wall, and wounds
200 mg every 12 hours • Can cause hepatotoxicity that can be fatal: discontinue if signs and symptoms
BL
occur; effects are usually reversible upon discontinuation
PD
Used in serious infections
• Can cause ocular adverse effects such as change in visual acuity, blurred
caused by Scedosporium
vision, and photophobia: reversible if duration of therapy is 28 days or less;
GD apiospermum and Fusarium if
QT long-term effects have not been studied
other treatments failed
• May cause renal toxicity in severely ill patients: use with caution if
BL
administering concurrently with other nephrotoxic agents
PD
GD
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86
• Can cause fluorosis or periostitis with extended use: discontinue if bone pain
develops and is supported by radiologic findings
• Can cause pancreatitis (rare)
• Infusion reactions presenting as anaphylactoid may occur: discontinue if
reaction occurs
9781284110562_CH02_Pass01.indd 86
• If CrCl is less than 50 mL/min, recommend using oral formulations due to
accumulation of cyclodextrin in the IV formulation
• Do not infuse IV in same line with other medications; do not infuse at the same
time (even when using separate lines) as concentrated electrolytes and blood
products
• Administer oral formulations 1 hour before or after meals to increase
absorption
medication is established due to the potential for visual changes
• A small increase in dose can cause toxicity leading to neurologic and
dermatologic effects
• Monitor: hepatic and renal function and electrolytes at baseline and throughout
therapy; eye exams if duration is greater than 28 days; voriconazole blood levels
on day 5, then weekly if treating severe infections, and otherwise as needed;
full-body skin examination yearly; phototoxic adverse events
Echinocandins
Generic Name Treatment of Candida Usual parenteral dose for • May cause hepatic impairment: discontinue if impairment progresses
Anidulafungin infections including intra- invasive candidiasis: • Infusion reactions such as bronchospasm, hypotension, and rash may occur if
abdominal, peritoneal, IV: 200 mg dose for day 1, the rate of infusion is too high
esophageal, and candidemia then 100mg once daily
Brand Name • Monitor: LFTs
Eraxis
Generic Name Treatment of invasive Usual parenteral dose for • May cause hepatic impairment: discontinue if impairment progresses
Caspofungin Aspergillus infections when invasive candidiasis: • Dose interactions may require dose adjustment or avoidance of certain drug
other agents fail IV: 70 mg dose for day 1, combinations
then 50mg once daily • Histamine-related reactions may occur, such as rash, flushing, and facial
Name
Brand QT
Treatment of candidemia and edema
Cancidas
BL Candida infections, including • Monitor: hepatic function, hypersensitivity reactions
PD
intra-abdominal abscesses,
peritonitis, and pleural space
GD infections
QT
BL
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PD
GD
Treatment of esophageal
candidiasis
Empiric treatment in patients
9781284110562_CH02_Pass01.indd 87
with febrile neutropenia
Generic Name Treatment of candidemia, Usual parenteral dose for • Hemolytic anemia and hemoglobinuria have been reported
Micafungin disseminated candidiasis, invasive candidiasis: • May cause hepatic and renal impairment: discontinue if impairment
Candida peritonitis and IV: 100 mg once daily progresses
abscesses, and esophageal
Brand
QT Name Treatment duration • Monitor: hepatic function
candidiasis
depends on severity of
Mycamine
BL infection and patient’s
PD
Prophylaxis against clinical progress
Candida infections during
GD hematopoietic stem cell
transplant
Oxaboroles
Generic Name Treatment of onychomycosis Usual topical dose: apply • May cause local irritation
Tavaborole due to T. rubrum or T. to affected toenails once • Before applying, make sure toenails are dry and clean
mentagrophytes daily for 48 weeks
• Discard 3 months after opening bottle
Brand Name
Kerydin
Polyenes
Generic Name Conventional: Treats life- Usual parenteral dose: • Use extra care when selecting amphotericin products. Liposomal product
Amphotericin B threatening fungal infections doses are generally HIGHER than conventional doses. Use extra care to check
including aspergillosis, if conventional product ordered exceeds 1.5 mg/kg (this may have been
cryptococcosis, North intended for liposomal administration).
Brand Name Conventional:
American blastomycosis, • Amphotericin B conventional is Amphocin
Amphocin systemic candidiasis, IV: 0.3 to 1.5 mg/kg/day
• Amphotericin B cholesterol sulfate complex (ABCD) is Amphotec
Conventional coccidioidomycosis, (max 1.5 mg/kg/day)
• Amphotericin B lipid complex (ABLC) is Abelcet
histoplasmosis, zygomycosis,
Conidiobolus, Basidiobolus, • Amphotericin B liposomal injection (LAmB) is AmBisome
Amphotec Amphotec:
and sporotrichosis • Administer the first dose with careful observation for respiratory distress
Cholesteryl IV: 3 to 4 mg/kg/day (max
• Can cause severe infusion reactions (fever, chills, shaking, hypotension,
sulfate complex 6 mg/kg/day)
nausea, vomiting, headache, tachypnea) 1 to 3 hours after initiating the
infusion: pretreat with medication or decrease the rate; with subsequent
doses, the reactions become more tolerable
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88
Abelcet Can be used in leishmaniasis, Abelcet: • Can cause nephrotoxicity: interrupt therapy, decrease the dose, or decrease
Lipid complex but is not first choice IV: 5 mg/kg once daily the frequency of dosing to help improve renal function; use with caution in
high-risk patients
Abelcet: invasive aspergillosis • If renal impairment is due to use of the conventional infusion, decrease the
AmBisome AmBisome:
after failure to respond to dose by 50%
Liposomal
QT IV: 3 to 6 mg/kg/day
amphotericin B deoxycholate
9781284110562_CH02_Pass01.indd 88
• Separate dosing from leukocyte transfusions to prevent pulmonary reactions
BL in neutropenic patients (conventional, lipid complex)
Amphotec: invasive • Rarely causes leukoencephalopathy (conventional)
PD
aspergillosis after failure to
• Conventional formulation is thought to have the highest rate of infusion-
QT GD respond to amphotericin B
related reactions and nephrotoxicity
deoxycholate and in patients
BL • If infusion-related reactions such as chills, fever, hypotension, and nausea
with poor renal function
occur, pretreat the patient 30 to 60 minutes before infusion with a nonsteroidal
PD
anti-inflammatory drug (NSAID) with or without diphenhydramine or
AmBisome: invasive
GD acetaminophen (APAP) with or without diphenhydramine or hydrocortisone
aspergillosis after failure to
50 to 100 mg with or without NSAID and diphenhydramine
respond to amphotericin B
• If the patient experiences rigors during the fusion, meperidine may be administered
deoxycholate and in patients
with poor renal function • To reduce nephrotoxicity, give a bolus of normal saline before the infusion or
before and after the infusion; doses greater than 1 mg/kg/day (conventional)
have a higher risk of nephrotoxicity
Treatment of Aspergillus,
Candida, and Cryptococcus • If therapy is interrupted for more than 7 days, restart at the lowest dose and
infections that are titrate up gradually
refractory to amphotericin B • Monitor: LFTs, electrolytes, renal function, BUN, SCr, CBC, PTT, temperature,
deoxycholate; cryptococcal I/O, signs and symptoms of hypokalemia

meningitis in HIV patients; Associated with:
visceral leishmaniasis
• Check product name and dose if conventional dose exceeds 1.5 mg/kg
• Use in progressive, life-threatening infections only
Empiric therapy in febrile,
neutropenic patients
Generic Name Treatment of susceptible Usual oral dose: 400,000 • Swish the suspension in the mouth as long as possible before swallowing
Nystatin fungus that cause cutaneous, to 600,000 units 3 to (a few minutes)
mucocutaneous, and oral 4 times per day • Refrigerate suspension
cavity infections
Brand Name • Apply powder in the shoes when treating tinea pedis
Usual topical dose:
Bio-Statin
Candida Cream/ointment: apply
Nyamyc
twice daily
Nystop
QT
Pediaderm AF
Powder: apply 2 to 3 times/
Complete
BL day
PD
GD
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Pyrimidines
Generic Name An adjunctive to treat Usual oral dose: • Use with caution in patients with preexisting bone marrow depression or
Flucytosine systemic fungal infections 50 to 150 mg/kg/day in hematologic disease: can cause irreversible bone toxicity
9781284110562_CH02_Pass01.indd 89
(septicemia, endocarditis, divided doses every • Can cause hepatotoxicity: use with caution in patients with preexisting
urinary tract infections, 6 hours hepatic dysfunction
Brand Name meningitis, pulmonary
• To diminish nausea and vomiting, administer a couple of capsules at once
Ancobon infections)
over 15 minutes
• Interferes with SCr measurements when using the Ektachem analyzer
Candida, Cryptococcus
• Monitor: perform baseline tests on electrolytes, CBC with differential, BUN,
QT
renal function, and blood culture; during treatment, monitor CBC with
BL differential and LFTs frequently, flucytosine blood levels, renal function
PD Associated with:
• Renal dysfunction
GD QT
• Need to monitor renal, hepatic, and hematologic function
BL
Miscellaneous Antifungals
PD
Generic
GDName Treatment of susceptible Usual oral dose for tinea • May cause granulocytopenia: discontinue if reaction occurs
Griseofulvin fungi that cause tinea corporis: • May cause hepatic dysfunction
infections of the skin, hair, Microsize: 500 mg once • Rarely causes SJS or TEN: discontinue if reaction occurs
and nails daily (or in divided doses)
Brand Name • Administer with a fatty meal to increase absorption
for 2 to 4 weeks
Grifulvin V • Causes increased photosensitivity: wear sunscreen and avoid direct sunlight
Microsporum, Epidermophyton,
(microsize) • Avoid ethanol use: will cause a disulfiram-like reaction
Trichophyton Ultramicrosize: 300 to 375
Gris-PEG
QT • Monitor: renal, hepatic, and hematopoietic function periodically
mg once daily (or to or in
(ultramicrosize) divided doses) for 2 to 4 Contraindications:
BL
weeks • Liver failure
PD
• Porphyria
GD
Potassium Refer to the Hormones and Synthetic Substitutes chapter.
iodide
Antimycobacterial
Antituberculosis Agents
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90
Generic Name Treatment of tuberculosis Usual oral dose: • Use with caution in patients with gastric ulcer or hepatic impairment
Aminosalicylic in combination with other 8 to 12 g per day in 2 to • Do not use granules if color is brown or purple or if packet is swollen
acid agents 3 divided doses • When dispensed, store in refrigerator or freezer
• Monitor: hepatic function at baseline, thyroid function at baseline and every
Brand
QT Name 3 months with extended use
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Paser Contraindications:
BL
• Severe renal impairment
PD
GD
Generic Name Treatment of susceptible Usual oral dose: 400 mg • May cause hepatic dysfunction and increase in hepatic enzymes
Bedaquiline strains of multidrug-resistant once daily for 2 weeks then • Use with caution in patients with poor renal function
pulmonary tuberculosis 200 mg 3 times per week
• Administer with food to increase absorption
when other agents cannot for weeks 3 to 24
Brand Name • For weeks 3 to 24 of regimen, doses should be administered at least 48 hours
be used
Sirturo apart from each other
Directly observe therapy
• Store in original container or discard within 3 months
QT
Use with 3 or more agents
• Monitor: ECG at baseline and weeks 2, 12, and 24 or weekly if patient has
active against the patient’s
QT BL risk factors; baseline potassium, calcium, and magnesium; hepatic function
tuberculosis strand
tests at baseline and monthly; weekly for arthralgia, chest pain, headache,
BL PD hemoptysis, nausea, and rash
PD GD • Drug interactions may require dose adjustments
Associated with:
GD
• Arrhythmias and QTc prolongation; discontinue if interval is greater than 500 ms

• Increased risk of death: use as last-line therapy
Generic Name Treatment of pulmonary Usual parenteral dose: • Can cause electrolyte imbalances: monitor calcium, potassium, and magnesium
Capreomycin tuberculosis with concurrent IM, IV: 1 g once daily for 5 • May cause nephrotoxicity: if BUN greater than 30 mg/dL or renal function is
QT use of other agents when to 7 days a week, reduced falling, adjust dosing or discontinue
primary agents are ineffective to 2 to 3 times a week after
Brand NameBL • Can cause permanent hearing impairment: monitor using audiometric
the first 2 to 4 months
assessment
Capastat Sulfate
PD Total duration of treatment
• Dosing per weight is based on ideal body weight
often requires culture
GD • Specific doses for those 60 years and older
conversion
QT • Monitor: audiometric assessment and vestibular function at baseline and
throughout therapy, renal function at baseline and weekly during treatment,
BL electrolytes at baseline and throughout therapy, hepatic function tests
PD Associated with:
• Hearing impairment and/or renal impairment
QT GD
• Increased risk with concurrent use of other ototoxic or nephrotoxic agents
BL • Increased risk with concurrent use with other IV antituberculous agents due to
PD high risk of toxic effects
GD
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Generic Name Treatment of pulmonary or Usual oral dose: 250 mg • Dose-related CNS effects, such as seizures, psychosis, depression, and
Cycloserine extrapulmonary tuberculosis every 12 hours for 14 days, confusion have occurred: pyridoxine can help prevent/treat CNS adverse
with concurrent use of other then 500 to 1000 mg/day in effects
agents when primary agents 2 divided doses • Can cause allergic dermatitis: decrease dose or discontinue if rash develops
Brand Name are inadequate
9781284110562_CH02_Pass01.indd 91
• May need to supplement with folic acid and vitamin B12
Seromycin
• Monitor: hepatic, renal, and hematologic function; cycloserine blood levels;
Treatment-susceptible neuropsychiatric status at least every month
bacteria causing urinary tract
Contraindications:
infections when organism is
resistant • Severe renal function
• Epilepsy
Enterobacter, E. coli • Depression

• Severe anxiety
• Psychosis
• Excessive use of alcohol
Generic Name Treatment of pulmonary Usual oral dose: • May cause hepatotoxicity: monitor LFTs
Ethambutol tuberculosis with concurrent 15 to 25 mg/kg once daily • Dosing strategy is based on whether patient is treatment naïve or if they have
use of other agents already received therapy
Name
Brand QT • Can cause optic neuritis: discontinue immediately if changes in vision occur;
usually reversible over a period of time
Myambutol
BL
• Use with caution in patients with ocular disease: determine if visual changes
PD are due to ocular disease or ethambutol use
• Can administer with food to decrease stomach irritation
GD
• Monitor: visual examination at baseline and monthly if receiving more than
15 mg/kg/day (test in both eyes separately and together); hepatic, renal, and
hematopoietic function at baseline and throughout therapy
Contraindications:
QT
• Optic neuritis
BL • Unconscious patients
PD • Patients who cannot communicate visual changes due to ethambutol
Generic Name Treatment of tuberculosis Usual oral dose: • Can cause hypoglycemia: use with caution in patients with diabetes
GD
Ethionamide along with other 15 to 30 mg/kg/day (max • Can cause porphyria and hypothyroidism
mycobacterial diseases with 1 g per day in divided • Use with cycloserine has resulted in seizures
concurrent use of other doses)
Brand
QT Name • Can increase isoniazid blood levels if used concurrently and cross-resistance
agents when primary agents
Trecator may develop if inhA mutation is present
BL
fail
• Administering with food, at bedtime, or with an antiemetic may alleviate
PD gastrointestinal adverse events
GD
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92
• Concurrent use of pyridoxine can prevent or treat the neurotoxic effects
• Do not drink alcohol: can cause psychotic adverse events
• Monitor: LFTs at baseline and throughout therapy, blood glucose, thyroid-
stimulating hormone (TSH) every 6 months, ophthalmic exams at baseline
and throughout therapy
Contraindications:
9781284110562_CH02_Pass01.indd 92
• Severe hepatic impairment due to risk of hepatotoxicity
Generic Name Treatment of tuberculosis Usual dose: • If ALT or AST is more than 3 times the UNL, then temporarily hold isoniazid
Isoniazid and latent tuberculosis with PO, IM: 5 mg/kg per dose • Use with caution in patients with severe renal impairment
concurrent use of other once daily or 5 times per • Drug interactions may require dose adjustments
agents week • May need to supplement folic acid, niacin, and magnesium
Name
Brand QT
(maximum 300 mg per day) • If IV vials crystalize, warm the vial to room temperature to dissolve the
Nydrazid
BL precipitates
PD Dosing recommendations • Pyridoxine use can help prevent peripheral neuropathies in high-risk groups
by the CDC may change such as patients with HIV, malnourished patients, and patients with diabetes
QT GD
with changes in resistance • Isoniazid is a weak monoamine oxidase (MAO) inhibitor and may cause
BL patterns adverse effects with tyramine-containing food
PD
• Avoid histamine-containing foods (tuna, tropical fish) due to potential
adverse effects of headache, sweating, palpitations, flushing, diarrhea,
Oral is preferred route of
GD wheezing, itching, dyspnea, and hypotension: treat with corticosteroids and
administration
antihistamines
• May cause a false-positive urinary glucose result with Clinitest
• Monitor: LFTs at baseline and throughout therapy, sputum cultures monthly

until 2 consecutive cultures are negative, signs and symptoms of hepatitis,
regular ophthalmic exams
Contraindications:
• Acute liver disease
• History of drug-induced hepatitis
• History of hepatic injury due to isoniazid
• Previous severe reaction to isoniazid
Associated with:
• Hepatitis, which can be fatal: monitor for signs and symptoms and liver
function regularly
Generic
QTName Treatment of tuberculosis Usual oral dose: • Hepatotoxicity is dose dependent and rarely can cause liver atrophy
Pyrazinamide with concurrent use of other 15 to 30 mg/kg per dose • Use with caution in patients with history of alcoholism, concurrent use of
BL
agents once daily (max 3g per day) hepatotoxic medications, porphyria, and renal impairment
PD or 50 to 70 mg/kg per dose • May inhibit secretion of uric acid, leading to gout attacks
2 times per week
GD
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QT
BL
• Can cause a pink-brown color when used with Acetest and Ketostix
• Monitor: LFTs, uric acid blood levels, sputum culture, chest x-ray 2 to 3 months
after first dose and upon completion of therapy
Contraindications:
9781284110562_CH02_Pass01.indd 93
• Severe hepatic impairment
• Active gout flare
Generic Name Prevents Mycobacterium Usual oral dose: • Can cause hematologic toxicity: discontinue if signs of thrombocytopenia occur
Rifabutin avium complex (MAC) in 300 mg once daily • May cause uveitis: increased risk with concurrent macrolide or azole use; refer
patients with HIV the patient to an ophthalmologist if signs and symptoms of uveitis occur
150 mg twice daily
• Drug interactions may require dose adjustment or avoidance of certain drug
Brand Name
combinations
Mycobutin
• Use with caution in patients with hepatic impairment: discontinue if
significant elevation in LFTs occurs
• Do not administer if patient has active TB: may cause resistance to rifampin
• Can be administered with meals to reduce nausea
• A brown/orange discoloration of bodily fluids and the skin may occur: remove
contact lenses to prevent staining
• Monitor: LFTs, CBC with differential, platelet count
Generic
QT Name Treatment of active Usual dose: Oral, IV: 10 • May cause flu-like symptoms: more likely if patient takes more than 600 mg
Rifampin tuberculosis in combination mg/kg per dose given once 1 to 2 times/week
BL with other agents daily or 2, 3 or 5 times per • Can cause hematologic adverse events including thrombocytopenia: more
PD week likely if patient takes more than 600 mg 1 to 2 times/week
Brand Name
Eradicates meningococci (max 600 mg per day) • Drug interactions may require dose adjustment or avoidance of certain drug
Rifadin
GD
from asymptomatic carriers combinations
• May cause hyperbilirubinemia: discontinue if signs and symptoms develop
• Use with caution in patients with hepatic impairment and alcoholism: dose
adjustments may be necessary
• Use with caution in patients with porphyria: exacerbations can occur
• Administer oral formulations on an empty stomach with 8 ounces of water to
increase absorption
• Separate administration time of oral formulations from antacids
• A brown/orange discoloration of bodily fluids may occur: remove contact
lenses to prevent staining
• Can cause false-positive detection of opioids in the urine
• Interferes with standard microbiological assays for measuring folate and
vitamin B12 blood levels
Monitor: LFTs at baseline and every 2 to 4 weeks during therapy; CBC; CNS
effects; sputum culture; chest x-ray 2 to 3 months after first dose
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94
Generic Name Treatment of active Usual oral dose for • Use with caution in patients with hepatic impairment: use only when
Rifapentine tuberculosis in combination treatment of TB: necessary and monitor LFTs
with other agents 600 mg 2 times per week • Use with caution in patients with porphyria: exacerbations can occur; use in
for 2 months with interval this population is not recommended
Brand
QT Name
Not recommended in of no less than 3 days • Administer with food to increase absorption
Priftin (72 hours) between doses
BL HIV patients during the • Ensure compliance before starting therapy or resistance may develop
9781284110562_CH02_Pass01.indd 94
PD
continuation phase due to Must be administered • A brown/orange discoloration of bodily fluids, skin, and teeth may occur:
increased failure rate with at least one other remove contact lenses to prevent staining
GD antituberculosis agent • Drug interactions may require dose adjustment or avoidance of certain drug
Treatment of latent combinations
tuberculosis in combination • Interferes with standard microbiological assays for measuring folate and
with other agents vitamin B12 blood levels
• Monitor: LFTs at baseline and every 2 to 4 weeks if preexisting hepatic
impairment exists; LFTs at baseline and as needed if treating latent disease in
HIV patients, patients with hepatic impairment, and patients with constant
alcohol consumption
Amikacin Refer to the Antibacterials section.
Ciprofloxacin
Clarithromycin
Levofloxacin
Moxifloxacin
Streptomycin
Miscellaneous Antimycobacterials
Generic Name Leprosy Usual oral dose for • May cause severe blood dyscrasias: monitor
Dapsone dermatitis herpetiformis: • Rarely serious skin reactions can occur, such as TEN
Dermatitis herpetiformis 50 once daily. Maintenance • May cause peripheral neuropathy
doses may range 25 to • Use with caution in patients with G6PD deficiency: higher risk for anemia
Brand Name
300 mg daily • Use lowest effective dose possible
Avlosulfon
QT Acne vulgaris
Aczone
BL Usual topical dose: apply combinations
PD
once daily • Use with caution in patients with hemoglobin M or methemoglobin reductase
deficiency: higher risk of methemoglobinemia
GD • Can cause C. difficile–associated diarrhea and pseudomembranous colitis with
extended use
• Separate the time it is given from intake of antacids, alkaline foods, or alkaline
medications
• If using with benzoyl peroxide, may cause reversible yellow/orange color to the skin
• Monitor: G6PD levels baseline; CBC weekly for first month, monthly for 6
months, then semiannually; reticulocyte counts; LFTs
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Antiviral Agents
Adamantanes
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Generic Name Prophylaxis and treatment of Usual oral dose for • May cause compulsive behavior such as gambling, hypersexuality, and binge
Amantadine influenza A treatment of influenza A eating if used for Parkinson’s disease: reduce dose or discontinue
virus infection: • Increased risk of developing melanoma in patients with Parkinson’s disease:
Drug-induced extrapyramidal 200 mg daily monitor for new/changed skin lesions
Brand
QT Name
QT
symptoms 100 mg 2 times per day • May cause neuroleptic malignant syndrome if dose is decreased or
Symmetrel
BL BL discontinued
PD QT PD Parkinson’s disease • May worsen psychiatric illness: monitor for suicidal ideation
• Use with caution in patients with the following conditions: cardiovascular
GD BL GD
disease, eczema, glaucoma, poor hepatic or renal function, seizure history
PD • Influenza A is highly resistant to therapy, and resistance can develop during
therapy
GD
• Administer within 48 hours of flu symptoms’ appearance
QT
BL medication is established
• May cause withdrawal syndrome: taper slowly, especially in patients with
PD
Parkinson’s disease
GD • Tolerance can develop over time
• Elderly patients are at an increased risk of experiencing CNS adverse effects
such as dizziness and weakness
• May lead to false-positive results for amphetamines
• Monitor: renal function, mental status, blood pressure, and symptoms of
Parkinson’s disease or influenza
• Special recommendations for patients undergoing dialysis
• Additional reference to drug use in Central Nervous System
Generic Name Prophylaxis and treatment of Usual oral dose: 100 mg • Use with caution in patients with hepatic and/or renal impairment
Rimantadine influenza A 2 times per day • Avoid use in patients with psychosis
• Use with caution in patients with history of seizures: increased risk of seizures
Brand Name
QT • Influenza A is highly resistant to therapy, and resistance can develop during
QT
Flumadine therapy
BL BL
• Administer within 48 hours of flu symptoms’ appearance
PD PD • Elderly patients are at an increased risk of experiencing CNS adverse effects
such as dizziness and weakness
GD GD
• Monitor for CNS and gastrointestinal symptoms in elderly patients, patients
with impaired renal function, and patients with impaired hepatic function
QT
QT
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BL
BL
PD
PD
96
Antiretrovirals
HIV Entry and Fusion Inhibitors
Generic Name Treatment of HIV-1 infection Usual parenteral dose: • May cause immune reconstitution syndrome, in which an inflammatory
Enfuvirtide when used with other SubQ: 90 mg 2 times a day reaction develops due to a residual opportunistic infection or activation of an
antiretroviral agents in autoimmune disorder
9781284110562_CH02_Pass01.indd 96
treatment-experienced • Commonly causes injection-site reactions
Brand
QT Name patients
• Patients are more likely to develop pneumonia: use with caution in patients
Fuzeon
BL with a high viral load
PD • Increased risk of bleeding in patients with preexisting coagulation disorders
• Rotate injection sites
GD
• Powder for injection may take up to 45 minutes to completely dissolve
• Do not inject near a nerve to avoid nerve pain
• Monitor: viral load, CD4 count
Generic Name Treatment of CCR5-tropic Usual oral dose: 300 mg • May cause immune reconstitution syndrome, in which an inflammatory
Maraviroc HIV-1 infection when used twice daily reaction develops due to a residual opportunistic infection or activation of an
with other antiretroviral autoimmune disorder
agents • Can cause postural hypotension: use with caution in patients with poor renal
Brand Name
function and cardiovascular disease
Selzentry
• Hypersensitivity reactions such as SJS and DRESS have occurred: discontinue
use
QT
medication is established due to the potential for dizziness
BL • Monitor: viral load, CD4 count, LFTs, and bilirubin before treatment and during
therapy; tropism testing before initiation
PD
• Contraindicated in patients with CrCl less than 30 mL/min with other factors
QT GD that add risk, such as drug interactions that may require dose adjustments
• Dose recommendations are specific for CYP inhibitors and inducers; refer to PI
BL
Associated with:
PD
• Drug-induced hepatotoxicity with allergic-type features: use with caution in
GD patients with hepatic impairment; discontinue if signs and symptoms occur
HIV Protease Inhibitors
• Can cause fat redistribution, elevated bilirubin, prolonged PR interval, diabetes, hepatic impairment, nephrolithiasis, hemolytic anemia, elevated triglycerides, and
elevated cholesterol
• Contraindicated in patients who experience specific drug-induced hypersensitivity reactions (including SJS and DRESS) and drug interactions that may require dose
adjustments
30/11/16 6:38 PM
Generic Name Treatment of HIV infection Usual oral dose: • May cause immune reconstitution syndrome, in which an inflammatory
Atazanavir when used with other 300 mg once daily with reaction develops due to a residual opportunistic infection or activation of an
antiretroviral agents ritonavir 100 mg or autoimmune disorder
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cobicistat 150 mg • Not recommended for use in antiretroviral-experienced patients with end-
Brand Name
QT
stage renal disease (ESRD)
Reyataz
BL • Administer with food, and separate administration from that of antacids and
Additional adjustments
QT PD when used with H2 buffered medications
antagonist or proton pump • Limit dose of H2 blocker (see PI) AND when using H2 blockers, administer at
BL GD inhibitor (i.e., increase to the same time as atazanavir or at least 10 hours after the atazanavir dose.
PD 400 mg once daily) • Patients with hemophilia A or B are at an increased risk of bleeding
GD
QT • Confirm that baseline/pretreatment HIV RNA greater than 100,000 copies/mL
BL • Monitor: viral load, CD4 count, blood glucose, LFTs, bilirubin, atazanavir
levels if used with interacting medications, ECG in patients with preexisting
PD prolonged PR interval or concurrent use of atrioventricular (AV) nodal-
blocking medications
GD
Generic Name Treatment of HIV infection Usual oral dose: • Can cause fat redistribution, diabetes, hepatic impairment, pancreatitis, and
Darunavir when used with other 800 mg once daily with elevated cholesterol
antiretroviral agents ritonavir 100 mg or • Drug interactions may require dose adjustments
cobicistat 150 mg • May cause hypersensitivity reactions such as SJS or DRESS: discontinue if rash
Brand
QT Name
appears
Prezista
BL
Suspected resistance: • May cause immune reconstitution syndrome, in which an inflammatory
PD 600 mg twice daily reaction develops due to a residual opportunistic infection or activation of an
Treatment experienced autoimmune disorder
GD
patients may require higher • Not recommended in patients with severe hepatic impairment: discontinue if
doses hepatic function worsens during therapy
• Administer with food
• Patients with hemophilia A or B are at an increased risk of bleeding
• Do not use darunavir/ritonavir if CD4 count is less than 200 cells/mm3 and/or
HIV RNA greater than 100,000 copies/mL
• Monitor: viral load, CD4 count, baseline genotyping in treatment-experienced
patients, blood glucose, LFTs at baseline and throughout therapy, cholesterol,
triglycerides
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98
Fosamprenavir when used with other 1400 mg with ritonavir reaction develops due to a residual opportunistic infection or activation of an
antiretroviral agents 100 to 200 mg once daily autoimmune disorder
Alternatively may give: • Drug interactions may require dose adjustments
Name
Brand QT
700 mg with ritonavir • Administer suspension without food in adults; if vomiting occurs within
Lexiva
9781284110562_CH02_Pass01.indd 98
BL 30 minutes, readminister
100 mg twice daily
PD • Administer tablet with food if taken with ritonavir
• Twice-daily dosing is recommended in protease inhibitor–experienced adults
GD
• Monitor: viral load, CD4 count, blood glucose, LFTs in patients with hepatitis
B or C, cholesterol, triglycerides
QT
• Regimens without ritonavir are available, but not recommended by guidelines
BL
Generic Name Treatment of HIV infection Usual oral dose: • May cause tubulointerstitial nephritis: monitor for leukocytopenia (rare)
Indinavir when used with other 800 mg with ritonavir 100 • May cause immune reconstitution syndrome, in which an inflammatory
PD
antiretroviral agents to 200 mg 2 times per daily reaction develops due to a residual opportunistic infection or activation of an
GD autoimmune disorder
Brand Name
Alternative dose schedules • Use with caution in patients with preexisting hepatic disease: can exacerbate
Crixivan
using other antiretrovirals symptoms
are available, refer to PI • Drug interactions may require dose adjustments
• Administer with water on an empty stomach when unboosted
• Keep patients well hydrated: drink 48 ounces of water daily to help prevent
nephrolithiasis
• Dispense in original container
QT
BL • Monitor: viral load, CD4 count, blood glucose, LFTs, cholesterol, triglycerides,
CBC, urinalysis (especially monitor for leukocyturia)
PD
• Regimens without ritonavir are available, but not recommended by guidelines
GD
Generic Name Treatment of HIV infection Usual oral dose: • May cause QTc prolongation and other conduction abnormalities, and
Lopinavir and when used with other lopinavir 400 mg with patients may have a higher risk of myocardial infarction (MI): use with caution
ritonavir antiretroviral agents ritonavir 100 mg twice daily in patients with preexisting cardiac disease
Alternatively may give: • May cause immune reconstitution syndrome, in which an inflammatory
reaction develops due to a residual opportunistic infection or activation of an
Name
Brand QT Lopinavir 800 mg with
autoimmune disorder
Kaletra ritonavir 200 mg once daily
BL • Administer solution with food
QT PD • Drug interactions may require dose adjustments
BL GD
• Use with caution in patients with poor renal function to ensure accumulation
PD and toxicity do not occur
GD
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• Monitor: viral load, CD4 count, baseline genotyping or phenotypic testing before
starting therapy, blood glucose, LFTs, electrolytes, cholesterol, triglycerides
9781284110562_CH02_Pass01.indd 99
Nelfinavir when used with other 750 mg 3 times per day reaction develops due to a residual opportunistic infection or activation of an
antiretroviral agents autoimmune disorder
• Not recommended in patients with moderate to severe hepatic impairment:
Name
Brand QT 1250 mg 2 times per day
discontinue if hepatic function worsens during therapy
Viracept
BL • Administer with food; mixing a crushed tablet with acidic foods or juices will
QT PD
cause a bitter taste
BL GD
• Monitor: viral load, CD4 count, blood glucose, LFTs, cholesterol, triglycerides,
PD CBC with differential
Generic
GD Name Treatment of HIV infection Usual oral dose: • Use dose escalation strategy to reduce nausea
Ritonavir when used with other 600 mg 2 times per day • Can cause fat redistribution, QT interval prolongation, diabetes, hepatic
antiretroviral agents (titrate up from 300 mg 2 impairment, pancreatitis, and elevated cholesterol
times per day and increase • Drug interactions may require dose adjustments
by 100 mg 2 times per day
Brand Name
QT
• Use with caution in patients with preexisting cardiovascular disease
every 2 to 3 days)
Norvir • May cause immune reconstitution syndrome, in which an inflammatory
BL
QT PD autoimmune disorder
• Not recommended in patients with severe hepatic impairment: discontinue if
QT BL GD
hepatic function worsens during therapy
BL PD • Tablets are not bioequivalent to capsules
PD GD • Administer with food and advise patients to stay well hydrated
• Mix solution with chocolate to mask bad taste
GD
• Contains 43% ethanol and 26.57% propylene glycol: monitor for toxicity
• Monitor: viral load, CD4 count, blood glucose, LFTs, cholesterol, triglycerides,
CBC, CPK, uric acid, amylase and lipase serum levels
• Lower doses of ritonavir are used to enhance or “boost” the serum
concentrations of other antiretroviral agents (purposeful drug interaction)
30/11/16 6:38 PM
100
Generic Name Treatment of HIV infection Usual oral dose: • Can cause QTc prolongation, fat redistribution, photosensitivity, diabetes,
Saquinavir when used with other 1000 mg with ritonavir hepatic impairment, electrolyte imbalances, and elevated cholesterol
antiretroviral agents 100 mg 2 times per day • May cause immune reconstitution syndrome, in which an inflammatory
autoimmune disorder
Brand Name
• Administer within 2 hours after a meal; do not take with grapefruit juice
9781284110562_CH02_Pass01.indd 100
Invirase
QT • Monitor: viral load, CD4 count, blood glucose, cholesterol and triglycerides
at baseline and throughout treatment; ECG at baseline and 3-4 days after
BL
starting therapy; potassium and magnesium blood levels
PD • Contraindicated for use in patients with severe hepatic impairment
Generic
GD Name Treatment of HIV infection Usual oral dose: • Can cause fat redistribution, skin reactions such as rash and photosensitivity,
Tipranavir when used with other 500 mg with ritonavir impaired platelet aggregation, diabetes, hepatic impairment, and elevated
antiretroviral agents in 200 mg 2 times per day for cholesterol
treatment-experienced or 7 days, then may increase • May cause immune reconstitution syndrome, in which an inflammatory
multiple protease inhibitor– to standard dose of 1000 reaction develops due to a residual opportunistic infection or activation of an
Name
Brand QT resistant patients autoimmune disorder
mg with ritonavir 100 mg 2
Aptivus times per day • Not recommended in patients with severe hepatic impairment: discontinue if
BL
hepatic function worsens during therapy
PD
• Administer with food when administering with ritonavir tablets
QT GD • Solution contains vitamin E; capsules contain dehydrated ethanol
BL • Patients with hemophilia A or B are at an increased risk of bleeding

PD • Monitor: viral load, CD4 count, blood glucose, LFTs (including bilirubin) at
baseline and frequently throughout therapy, cholesterol and triglycerides
GD at baseline and throughout treatment; monitor patients coinfected with
hepatitis B or C carefully
Associated with:
• Hepatotoxicity when used with certain other drugs, which can be fatal
• Use with caution in patients with preexisting hepatic impairment
• Rare cases of intracranial hemorrhage when used with certain other drugs
HIV Integrase Inhibitors
Generic Name Treatment of HIV infection Usual oral dose: • Risk of lactic acidosis when used in combination with higher doses of
Dolutegravir when used with other 50 mg once a day, may metformin
antiretroviral agents increase to 50 mg 2 times • Avoid co-administration with multivitamins or supplements containing
daily when coadministered calcium, magnesium, or iron
with specific antiretrovirals;
Brand Name refer to PI
Tivicay
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Generic Name Treatment of HIV infection Usual oral dose: • Higher dose options are available in combination with other agents
Elvitegravir and when used with other 85 mg (with ritonavir • May cause elevations in serum creatinine
cobicistat antiretroviral agents in 100 mg and atazanavir • Avoid in renal dysfunction
adults who are antiretroviral 300 mg) once a day
experienced
9781284110562_CH02_Pass01.indd 101
Brand Name
Vitekta
Generic Name Treatment of HIV infection Usual oral dose: • Can cause myopathy: use with caution in patients who are at risk for
Raltegravir when used with other 400 mg twice daily elevated CK
antiretroviral agents • Severe skin and hypersensitivity reactions have occurred, including SJS and
TEN: discontinue if rash occurs
• May cause immune reconstitution syndrome, in which an inflammatory
Brand
QT Name
Isentress
BL autoimmune disorder
PD
• Store chewable tablets and oral suspensions in their original containers
• Chewable tablets, oral suspensions, and film-coated tablets are not
GD bioequivalent
• Do not use darunavir/ritonavir and raltegravir if the patient’s pre-antiretroviral
therapy (ART) CD4 count less than 200 cells/mm3 and/or HIV RNA greater than
100,000 copies/mL
• Monitor: viral load, CD4 count, complete lipid profile
combinations
HIV Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
Generic Name Treatment of HIV-1 infection Usual oral dose: • May cause fat redistribution or a rash that requires interruption of therapy
Delavirdine when used with other 400 mg 3 times per day • Use with caution in patients with hepatic and renal impairment
antiretroviral agents
autoimmune disorder
Brand Name
• Do not administer with antacids to ensure gastric acidity for absorption
Rescriptor
combinations
• Monitor: viral load, CD4 count, LFTs if used with saquinavir
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102
Generic Name Treatment of HIV infection Usual oral dose: • Not recommended in patients with moderate to severe hepatic impairment;
Efavirenz when used with other 600 mg once per day avoid use in patients with HIV-associated dementia
antiretroviral agents • May cause immune reconstitution syndrome, in which an inflammatory
autoimmune disorder
Brand
QT Name
• Administer on an empty stomach; recommended to take at bedtime due to
9781284110562_CH02_Pass01.indd 102
Sustiva increased tolerability of CNS effects
BL
PD
combinations
GD • Oral solution is available only through an expanded access program
• Do not use efavirenz with abacavir and lamivudine if the patient’s pre-ART HIV
RNA greater than 100,000 copies/mL
• Can cause false-positive tests for cannabinoids if using the CEDIA DAU
Multilevel THC assay
• Can cause false-positive tests for benzodiazepines
• Monitor: LFTs, cholesterol and triglycerides, psychiatric adverse effects
Generic Name Treatment of HIV infection Usual oral dose: • May cause fat redistribution or a rash (SJS, TEN, DRESS): discontinue if rash
Etravirine when used with other 200 mg 2 times per day becomes severe
antiretroviral agents in • May cause immune reconstitution syndrome, in which an inflammatory
treatment-experienced reaction develops due to a residual opportunistic infection or activation of an
patients with NNRTI autoimmune disorder
Brand Name
QT resistance
• Administer after meals
Intelence
BL • Can disperse in water; do not use grapefruit juice, carbonated drinks, or warm
PD
water when taking etravirine
GD combinations
• Monitor: cholesterol and triglycerides, blood glucose, LFTs if signs and
symptoms of hypersensitivity occur
Generic Name Treatment of HIV infection Usual oral dose: • May cause fat redistribution or rhabdomyolysis
Nevirapine when used with other IR: 200 mg once daily for • Not recommended in combination with nevirapine due to increased adverse
antiretroviral agents 14 days, then increase to effects
twice daily • May cause immune reconstitution syndrome, in which an inflammatory
Brand Name
XR: 400 mg once daily autoimmune disorder
Viramune
QT
for maintenance (must • Drug interactions may require dose adjustments or avoidance of certain drug
Viramune XR
BL have received 200 mg IR combinations
formulation before XR; refer • Do not administer in antiretroviral-naïve patients if CD4+ cell counts greater than
PD
to PI for details) 250 cells/mm3 in females or CD4+ cell counts greater than 400 cells/mm3 in males
QT GD • If rash appears during first 14 days of use, do not increase dose until it
BL disappears; use alternative therapy if rash duration exceeds 28 days
PD
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GD
• Monitor: viral load; CD4 count; CBC; baseline LFTs, then every 2 weeks for the
first 4 weeks and monthly for the first 18 weeks, then every 3 to 4 months;
signs of rash
Contraindications:
• Moderate to severe hepatic impairment
9781284110562_CH02_Pass01.indd 103
• Use in postexposure prophylaxis
Associated with:
• Severe hepatotoxicity: risk is greatest in the first 6 weeks; monitor intensely for
the first 18 weeks
• Life-threatening skin reactions such as SJS and TEN: risk is greatest in the first
6 weeks; monitor intensely for the first 18 weeks
Generic Name Treatment of HIV infection Usual oral dose: • May cause depressive disorders, fat redistribution, hepatotoxicity, or
Rilpivirine when used with other 25 mg once daily hypersensitivity reaction such as DRESS: discontinue if severe or rash develops
antiretroviral agents in • Drug interactions may require dose adjustments
treatment-naïve patients if
• Use with caution in patients with severe renal impairment
HIV RNA 100,000 copies/ml
Brand Name • Doses greater than 25 mg/day can cause QTc prolongation
or less and/or pre-ART CD4
Edurant count greater than • May cause immune reconstitution syndrome, in which an inflammatory
200 cells/mm3 reaction develops due to a residual opportunistic infection or activation of an
QT autoimmune disorder
• Administer with a meal—not just a protein shake
BL
• Keep in original container
PD
• Monitor: viral load, CD4, cholesterol and triglycerides, LFTs
GD
Nucleoside and Nucleotide Reverse Transcriptase Inhibitors
Associated with
• Lactic acidosis and severe hepatomegaly with steatosis: use with caution in patients at risk for liver disease
• Pancreatitis: discontinue upon diagnosis
Generic Name Treatment of HIV infection Usual oral dose: • Use with caution in patients with coronary heart disease
Abacavir when used with other 300 mg twice daily • May cause fat redistribution
600 mg once daily reaction develops due to a residual opportunistic infection or activation of an
autoimmune disorder
Brand Name
QT
• Ethanol can increase the risk of toxicity; avoid use
Ziagen
BL
• Monitor: CBC with differential, CK, CD4 count, HIV RNA levels, LFTs,
PD triglycerides, amylase, HLA-B*5701 genotype testing before starting therapy,
signs and symptoms of hypersensitivity reactions
QT GD
BL
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PD
QT
GD
BL
104
Associated with:
• Serious hypersensitivity reactions; testing for HLA-B*5701 allele is
recommended before treatment as these patients are at an increased risk
• Severe hepatotoxicity and/or lactic acidosis
Generic Name Treatment of HIV infection Usual oral dose: • May cause noncirrhotic portal hypertension: discontinue if signs and
9781284110562_CH02_Pass01.indd 104
Didanosine when used with other For patients weighing 60 kg symptoms occur
antiretroviral agents or more: • May cause retinal changes and optic neuritis, peripheral neuropathy, and fat
Oral solution: 200 mg twice redistribution
daily (preferred) or 400 mg • Use with caution in patients with hepatic and renal impairment
Brand Name
once daily • Specific recommendations for patients undergoing dialysis
Videx QT
Videx EC
BL Capsule: 400 mg once daily combinations
PD • Dosing for patients weighing less than 60 kg is available; refer to PI
QT GD
BL autoimmune disorder
PD • Administer on an empty stomach
• Oral suspension needs to be mixed with antacid solution before dispensing
QT GD
• Monitor: viral load, CD4 count, potassium, uric acid, SCr, hemoglobin, CBC
BL with neutrophil and platelet count, LFTs, bilirubin, albumin, INR, amylase,
retinal exam every 6 months, ultrasonography if portal hypertension is
PD
suspected
GD Associated with:
• Hepatotoxicity and/or lactic acidosis
• Pancreatitis
Generic Name Treatment of HIV infection Usual oral dose: • May cause fat redistribution
Emtricitabine when used with other Capsule: • Use with caution in patients with renal impairment
200 mg once daily • Avoid use with lamivudine due to potential for cross-resistance
• Capsules and solution are not interchangeable on a mg per mg basis
Recommended as initial
Brand Name
QT Solution: • May cause immune reconstitution syndrome, in which an inflammatory
therapy with other agents
Emtriva 240 mg once daily reaction develops due to a residual opportunistic infection or activation of an
BL
autoimmune disorder
PD • Monitor: viral load, CD4 count, LFTs, hepatitis B screening before initiating
therapy
QT GD
BL
Associated with:
PD • Coinfection with hepatitis B: severe exacerbations of HBV have occurred when
discontinuing HIV therapy
QT GD
BL
PD
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GD
Generic Name Treatment of HIV-1 infection Usual oral dose: • May cause fat redistribution and pancreatitis
Lamivudine when used with other 150 mg twice per day or • Use with caution in patients with renal impairment, not recommended in
antiretroviral agents 300 mg once per day patients with impaired renal function.
• Use caution when lamivudine is used in patients on interferon alfa (i.e.,
Recommended for initial HIV/HBV-coinfected patients) due to increased risk of hepatotoxicity. Not
9781284110562_CH02_Pass01.indd 105
Brand Name
therapy (including in patients recommended for use in patients with impaired hepatic function
Epivir QT coinfected with HBV) when • Avoid use with emtricitabine due to potential for cross-resistance
Epivir HBV used with other agents
BL • May cause immune reconstitution syndrome, in which an inflammatory
PD
Treatment of chronic autoimmune disorder
QT GD hepatitis B (has not been • Monitor: viral load; CD4 count; amylase; bilirubin; LFTs every 3 months;
BL
studied in coinfected hematologic parameters; HBV DNA if treating for HBV; HBeAg and anti-HBe 1
patients with HIV and is not year after starting HBV therapy, then every 3 to 6 months; signs/symptoms of
PD recommended as first-line relapse after stopping HBV treatment for several months
therapy)
QT GD Associated with:
• Need to monitor patients after discontinuing therapy for hepatitis B:
BL
exacerbations may develop that require retreatment
PD • HIV-1 resistance development if treating for chronic hepatitis B: if patients are
unaware they have HIV-1, resistance can develop
GD
• Need to use Epivir HBV tablets or solution only for hepatitis B and not HIV
infection
Generic Name Treatment of HIV infection Usual oral dose: • May cause fat redistribution and peripheral neuropathy
Stavudine when used with other For patients weighing 60 kg • May cause motor weakness: discontinue if it develops
antiretroviral agents or more: • Use with caution in patients with renal and hepatic impairment or preexisting
40 mg every 12 hours bone marrow suppression
Brand Name
QT
• Avoid use with didanosine, hydroxyurea, and zidovudine due to increased risk
of adverse events; use with caution when patients are also receiving interferon
Zerit
BL alfa
PD • May cause immune reconstitution syndrome, in which an inflammatory
QT GD autoimmune disorder
BL • Doses for those weighing less than 60 kg are available; refer to PI
PD Associated with:
• Pancreatitis when used with certain other drugs upon diagnosis
QT GD
BL
PD
GD
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106
Generic Name Treatment of HIV infection Usual oral dose: • May cause fat redistribution, decrease in bone mineral density, osteomalacia,
Tenofovir when used with other 300 mg once daily pancreatitis, or renal toxicity: avoid use in high-risk patients
antiretroviral agents • Use with caution in patients with hepatic and renal impairment
• If treating the patient for HBV, screen for HIV to ensure resistance will not
Recommended in initial develop to HIV
Brand Name
QT
regimen when used with
9781284110562_CH02_Pass01.indd 106
Viread other agents
BL reaction develops due to a residual opportunistic infection or activation of an
PD
autoimmune disorder
Treatment of chronic • Mix powder with 2 to 4 ounces of soft food to avoid bitter taste
QT GD hepatitis B infection • May need to supplement with calcium and vitamin D due to decrease in bone
BL mineral density
PD • Monitor:
• HIV: viral load, CD4 count, CBC with differential, reticulocyte count, CK, HIV
QT GD
RNA levels, phosphorus, SCr at baseline and throughout therapy, urine
glucose and protein if at risk for renal impairment, LFTs, bone density if at
BL
risk, screen for HBV before use
PD
• HBV: phosphorus, SCr, urine glucose and protein, bone density, HBV DNA
GD
every 3 to 6 months, HBeAg and anti-HBe, LFTs every 3 months and several
months after therapy
Associated with:
• Severe exacerbations of HBV upon discontinuation
• Monitor for relapse for several months

Generic Name Treatment of HIV infection Usual parenteral dose: • May cause fat redistribution
Zidovudine when used with other 1 mg/kg per dose every • Use with caution in patients with hepatic and renal impairment
antiretroviral agents 4 hours around the clock
Usual oral dose: reaction develops due to a residual opportunistic infection or activation of an
Brand Name
QT
300 mg twice per day autoimmune disorder
Retrovir
BL
• If assay is negative for HIV in an infant who received preventive therapy, retest
PD Oral therapy is preferred in 2 to 4 weeks to confirm diagnosis
• The injection vial’s stopper contains latex
QT GD
• Monitor: viral load, CD4 count, CBC with differential every 3 to 6 months, LFTs
BL every 6 to 12 months, lipid profile, blood glucose levels
PD Associated with:
• Hematologic toxicity, including neutropenia and anemia; may need to
QT GD
interrupt therapy
BL • Myopathy over prolonged use
PD • Hepatotoxicity and/or lactic acidosis
GD
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Interferons
Generic Name Alfa-2b: AIDS-related Usual parenteral dose • Causes bone marrow suppression, which can lead to anemia, neutropenia,
Interferon alfa Kaposi sarcoma, chronic for AID’s related Kaposi’s and thrombocytopenia
9781284110562_CH02_Pass01.indd 107
hepatitis B, chronic hepatitis sarcoma: • In combination with ribavirin can cause dental and periodontal disorders,
C with other agents, IM, SubQ: 30 million including dry mouth
condylomata acuminata, units/m2 3 times/week • Can cause hypertriglyceridemia, changes in vision and other eye disorders,
Brand Name follicular lymphoma with until disease progression is pulmonary infections and other disorders, arrhythmias, thyroid disorders,
Intron QT other agents, and hairy cell confirmed or achievement strokes, and diabetes
Alferon N leukemia; adjunct therapy for of maximum response after
BL • Use with caution in patients with coagulation and pulmonary disorders
malignant melanoma 16 weeks of treatment
PD
• Recommended to administer acetaminophen before injection to reduce
adverse effects
QT Alferon N: condylomata
GD • If dose is 10 million units/m2 or greater, recommend using an antiemetic
acuminata
BL concurrently
• Administration in the evening results in increased tolerability
PD
• Inject IM into the anterior thigh, deltoid, and superlateral buttock
QT GD
• IM injection is preferred; use SubQ administration if concerned about
bleeding or thrombocytopenia
BL
• Continue to use the same brand for in the patient due to differences in dosages
PD
• Monitor:
GD • Baseline and as needed: chest x-ray, SCr, albumin, PTT
• Baseline and during therapy: CBC with differential; platelets (PLT);
hemoglobin; LFTs; electrolytes; TSH; ophthalmic exams; ECG if preexisting
cardiac conditions or advanced cancer; bilirubin; lactate dehydrogenase
(LDH) at 2, 8, and 12 weeks, then every 6 months
• During therapy: weight, neuropsychiatric changes
Contraindications:
• Autoimmune hepatitis
• Severe liver disease
Associated with:
• Causing or exacerbating neuropsychiatric disorders, including depression,
psychosis, mania, suicidal ideation, and homicidal ideation: discontinue if
symptoms worsen; usually is reversible upon discontinuation
• Causing or exacerbating autoimmune diseases infectious disorders, and
ischemic disorders: discontinue if symptoms worsen
• Fever and flu-like symptoms associated with interferon administration
requires extra caution in patients with cardiac disease
• Hepatotoxicity, which can be fatal: discontinue if severe injury develops
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108
Generic Name Alfa-2a: chronic hepatitis B Usual parenteral dose: • Causes bone marrow suppression, which can lead to anemia, neutropenia,
Peginterferon and chronic hepatitis C Alfa-2a (Pegasys): and thrombocytopenia
alfa SubQ: 180 mg once weekly • Can cause hepatotoxicity, which can be fatal: discontinue if severe injury
Hepatitis C should also be develops
treated concurrently with • In patients with hepatitis B, flares may occur for ALT levels: reduce the dose
Alfa-2b PegIntron:
antiviral medications and discontinue if ALT does not drop
9781284110562_CH02_Pass01.indd 108
Brand Name max doses SubQ 1 mcg/
kg/week for monotherapy • Can cause serious skin reactions such as SJS and exfoliative dermatitis, flu-
Pegasys (2a)
Alfa-2b: chronic hepatitis or 1.5 mcg/kg/week for like symptoms, gastrointestinal ulcerative colitis and other serious disorders,
Peg-Intron (2b) hypertriglyceridemia, changes in vision and other eye disorders, pancreatitis,
C; adjunct therapy for combination therapy
Sylatron (2b) melanoma pulmonary infections and other disorders, arrhythmias, thyroid disorders,
QT
dental/periodontal disorders in combination therapy, and diabetes
Alfa-2b Sylatron:
BL • Do not drink alcohol
max doses: SubQ 6 mcg/
PD QT • Do not shake vial, syringe, or autoinjector
kg/week
BL • Warm by rolling between the palms of the hands for a vial and syringe; let the
GD
autoinjector warm by setting it outside the refrigerator
PD
QT • Caution patients about operating machinery and driving due to the potential
QT GD for CNS depression
BL
• Continue to use the same brand for the patient due to differences in dosages
BL
PD • Monitor: CBC, hemoglobin, PLT, LFTs, and uric acid at weeks 1, 2, 4, 6, and 8,
PD and every 4 to 6 weeks after; TSH every 12 weeks; ECG if preexisting cardiac
GD disease; neuropsychiatric symptoms
GD
Contraindications:
• Autoimmune hepatitis
• Severe liver disease
Associated with:
• Causing or exacerbating neuropsychiatric disorders, including depression,
psychosis, mania, suicidal ideation, and homicidal ideation: discontinue if
symptoms worsen; usually is reversible upon discontinuation
• Causing or exacerbating autoimmune diseases infectious disorders, and
ischemic disorders: discontinue if symptoms worsen
• Drug interactions that require dose adjustments or avoidance of certain drug
combinations
• Myocardial infarction and stroke
30/11/16 6:39 PM
Neuraminidase Inhibitors
Generic Name Prophylaxis against and Usual oral dose: • Rarely causes neuropsychiatric adverse events, including confusion and
Oseltamivir treatment of influenza A 75 mg 1 to 2 times daily for hallucinations
9781284110562_CH02_Pass01.indd 109
and B 5 to 10 days • Use with caution in patients with cardiovascular disease, severe hepatic
impairment, renal impairment, and respiratory disease
Recommended to be used in Start within 48 hours of • Safety and efficacy have not been proved in immunocompromised patients
Name
BrandQT
patients at a higher risk for symptoms or contact with • Monitor: signs and symptoms of neuropsychiatric changes
Tamiflu complications from influenza
BL an infected individual
PD
Generic
GD Name Treatment of acute influenza Usual parenteral dose: • May cause severe skin reactions, such as SJS
Peramivir when patient has been IV: 600 mg single dose • Infuse over 15 to 30 minutes
symptomatic for 2 or fewer
• Administer within 48 hours of onset of flu symptoms
days
• May cause neuropsychiatric events, such as delirium and hallucination: usually
QT
Brand Name symptoms appear soon after use and in pediatric patients
Rapivab
BL • Hypersensitivity reactions have been reported when peramivir is used with
other neuraminidase inhibitors: caution is advised
PD
• Monitor: BUN and SCr, rash after administration
GD
Generic Name Prophylaxis against and Usual oral inhaled dose: • May cause neuropsychiatric adverse events, including confusion, seizures, and
Zanamivir treatment of influenza A 2 inhalations 1 to 2 times hallucinations
and B daily for 5 days • May cause bronchospasm: not recommended for use in patients with
respiratory disease; discontinue if lung function decreases
QT Recommended to be used in Treatment: begin within 2 • Efficacy has not been established for use as prophylaxis in nursing homes
Brand Name
patients at a higher risk for days of symptoms • If patient needs a bronchodilator, use it before administering zanamivir
Relenza
BL
complications from influenza
Diskhaler • Monitor: signs and symptoms of neuropsychiatric changes and bronchospasm
PD Prophylaxis: begin within
36 hours to 5 days after
GD
contact with an infected
person
Nucleosides and Nucleotides
Generic Name Oral therapy: herpes zoster Usual oral dose for • Can cause renal impairment: use with caution in patients at high risk
Acyclovir (shingles), genital herpes herpes zoster in • May cause thrombocytopenic purpura/hemolytic uremic syndrome in
simplex virus, varicella immunocompetent immunocompromised patients
(chickenpox) patients:
• Treatment for chickenpox should start within 24 hours of rash appearance if
800 mg every 4 hours (5 patient is at an increased risk of complications
times per day) for 7 to 10
• Treatment for shingles should start within 72 hours of rash appearance
days
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110
Brand Name Parenteral (IV) therapy: Usual parenteral dose for • Use IV acyclovir with caution in patients with neurologic abnormalities, severe
ZoviraxQT herpes simplex virus in immunocompromised hepatic dysfunction, serious electrolyte imbalances, or significant hypoxia
immunocompromised patients: • If patient is obese, dose based on ideal body weight (IBW)
Sitavig
BL patients, severe genital IV: 10 mg/kg per dose every • Keep well hydrated to help protect the kidneys
PD
herpes simplex virus, 8 hours for 7 days
• Infuse IV formulation over 1 hour to avoid kidney damage
herpes simplex encephalitis,
9781284110562_CH02_Pass01.indd 110
GD herpes zoster (shingles) • Available also as a buccal tablet
Topical:
in immunocompromised • If buccal tablet falls out within 6 hours of placement, replace the tablet
patients Ointment: apply ½-inch or apply a new tablet: for maximum effect, apply 1 hour after prodromal
ribbon per 4-inch square symptoms are noted
surface every 3 hours for
Buccal tablet/cream: • Apply ointment while wearing a glove to prevent transmission of virus to
QT 7 days
recurrent herpes labialis (cold other parts of the body
BL sores) • Monitor: urinalysis, BUN, SCr, LFTs, CBC
Cream/ointment:
PD
apply 5 times/day for
Ointment: genital herpes
GD 4 days to lesions
simplex virus and mild
mucocutaneous herpes
simplex virus infections
in immunocompromised
patients
Generic Name Treatment of chronic Usual oral dose: • Do not use with tenofovir, as it decreases the efficacy of tenofovir
Adefovir hepatitis B if there is evidence 10 mg once daily • Not a first-line treatment
of active viral replication

• Monitor: HIV status before starting therapy, SCr at baseline and throughout
therapy, LFTs for several months after stopping therapy, HBV DNA every 3 to 6
months while using adefovir, HBeAg and anti-HBe
Brand Name
Associated with:
Hepsera
• Severe lactic acidosis and hepatomegaly with steatosis when using nucleoside
analogues: use with caution in patients with risk factors for liver dysfunction;
interrupt therapy if signs and symptoms occur
QT
• Severe exacerbation of hepatitis B upon discontinuation: usually occurs within
BL the first 12 weeks and may dissipate or resolve with initiating treatment
PD • Risk of developing HIV resistance in patients who do not realize they are HIV
infected: determine status before treatment
QT GD
• Nephrotoxicity: use with caution in patients at high risk for toxicity or with
preexisting renal impairment
BL
PD
GD
30/11/16 6:39 PM
Generic Name Treatment of Usual parenteral dose: • Reports of metabolic acidosis have been reported: monitor for signs and
Cidofovir cytomegalovirus (CMV) IV: 5 mg/kg per dose every symptoms including low bicarbonate and renal wasting syndrome
retinitis in patients infected other week while receiving • Ensure proper hydration throughout
with AIDS maintenance therapy
• Can cause ocular dysfunction: monitor intraocular pressure; treat the patient
with a topical steroid if uveitis or iritis occurs
9781284110562_CH02_Pass01.indd 111
Brand Name
• Monitor: SCr and urine protein at baseline and within 48 hours prior to
Vistide
administering a dose, WBC with differential before each dose, intraocular
pressure and visual acuity, signs and symptoms of uveitis/iritis and metabolic
acidosis
QT
Contraindications:
BL • Use of nephrotoxic agents with the last 7 days
PD • Direct intraocular injection
• SCr greater than 1.5 mg/dL, CrCl 55 mL/min or less, or 2+ proteinuria
QT GD
Associated with:
BL • Categorized as a possible carcinogen and teratogen based on animal data; can
cause hypospermia
PD
• Renal failure and death when administering 1 to 2 doses: monitor renal
GD function within 48 hours before administering a dose; must administer with
probenecid and saline
• Neutropenia
Generic Name Treatment of chronic Usual oral dose: • Use with caution in patients with hepatic impairment
Entecavir hepatitis B with evidence 0.5 to 1 mg once daily • Administer on an empty stomach: food delays absorption
of active viral replication
• Available as tablet and solution
in patients with elevated
• Cross-resistance may develop in patients who have failed lamivudine therapy:
transaminase or histologically
Brand Name
QT
resistance can develop quickly
active disease
Baraclude • Monitor: HIV status before starting therapy; hepatic and renal function tests; if
BL
coinfected with HIV, monitor HIV viral load and CD4 count; HBV DNA every 3
PD months; HBeAg
Associated with:
QT GD
BL analogues: use with caution in patients with risk factors for liver dysfunction;
PD interrupt therapy if signs and symptoms occur
• Severe exacerbation of hepatitis B upon discontinuation: may dissipate or
QT GD
resolve with initiating treatment
BL • Risk of developing HIV resistance in patients who do not realize they are HIV
infected: determine status before treatment
PD
GD
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112
Generic Name Treatment of herpes zoster Usual oral dose for • Use with caution in patients with renal impairment: dose appropriately
Famciclovir (shingles), herpes labialis treatment of herpes zoster: • Treatment for shingles should start within 72 hours of rash’s appearance
(cold sores), and recurrent 500 mg every 8 hours for • Monitor: CBC with extended use
orolabial/genital herpes 7 days
simplex in HIV-infected
Brand Name patients
9781284110562_CH02_Pass01.indd 112
Cold sores: 1500 mg once
Famvir
as single dose
Treatment and suppression
of recurrent genital herpes
Generic Name Treatment of susceptible Usual parenteral dose for • When handling, use hazardous precautions due to its extreme basic nature
Ganciclovir viruses that cause CMV retinitis: • Administer via slow IV infusion over 1 hour
CMV retinitis in IV: 5 mg/kg per dose every • Monitor: CBC with differential, platelet count, SCr
immunocompromised 12 hours for a minimum of
Associated with:
patients 14 days
QT
Brand Name • Blood dyscrasias: may need to adjust or interrupt therapy until white blood
Cytovene
BL cell levels increase
Prophylaxis against CMV
Zirgan • Carcinogenic and potential teratogenic effects
PD infection in transplant
patients
GD
QT
Generic Name Chronic hepatitis C infection: Usual oral dose (tablets) • Use with caution in patients with hepatic and renal impairment
Ribavirin
BL for chronic hepatitis C • Risk of autoimmune/infectious disorders, bone marrow suppression, dental
with concurrent use of
and periodontal disorders, dermatologic reactions such as SJS, diabetes,

PD
other recommended serious ophthalmic disorders, pancreatitis, psychiatric disorders, and
GD
medications: pulmonary adverse events
QT
Brand Name
1000 to 1200 mg per day in • Administer with food to increase absorption
Copegus
BL 2 divided doses daily
• Inhalation monitoring: respiratory function, hemoglobin, reticulocyte count,
Moderiba
PD CBC with differential, ins and outs (I&O)
Rebetol Treatment duration and • Oral monitoring: hematologic and biochemical tests before administration
GD
Ribasphere QT formulation selected is and during therapy, dental exam, ECG if preexisting cardiac disease exists,
Virazole individualized based on ophthalmic exam, TSH at week 12, pregnancy screening and tests monthly,
BL patient’s clinical status HCV RNA before administration and at 12, 24, and 24 weeks after completion
PD and dose is based on
• Formulations have different indications for use; refer to PI prior to prescribing.
weight (patients weighing
QT GD Contraindications:
less than 75 kg are
BL recommended to get lower • Hemoglobinopathy and concurrent use of didanosine
dose) • CrCl less than 50 mL/min
PD
• Hepatic decompensation in cirrhosis (when used with other specific agents)
QT GD • Autoimmune hepatitis
BL
PD
GD
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Associated with:
• Hemolytic anemia: can worsen cardiac diseases; use with caution in patients at
risk for anemia
• Should not be used as monotherapy in patients with chronic hepatitis C
9781284110562_CH02_Pass01.indd 113
• Sudden respiratory deterioration when initiating via inhalation in infants
• Interference with effective ventilation; use of inhalation formulation in
patients with assisted ventilation may increase risk
Generic Name Treatment of chronic Usual oral dose: • May cause myopathy and peripheral neuropathy: discontinue if either
Telbivudine hepatitis B with evidence 600 mg once daily condition is diagnosed
of active viral replication • Safety and efficacy have not been studied in African American and Hispanic
in patients with elevated subpopulations; in patients coinfected with HIV, hepatitis C, or hepatitis D; or
transaminase or histologically in liver transplant patients
Brand Name active disease
• Cross-resistance may develop in patients who failed to respond to lamivudine
Tyzeka
• Not considered first-line therapy due to the high rate of resistance
• Monitor: LFTs during therapy and post therapy, renal function tests before
initiating and during use, CK, HBV DNA every 3 to 6 months, HBeAg and
QT
anti-Hbe
BL • Specific recommendations for patients undergoing dialysis.
PD Associated with:
QT GD
analogues: use with caution in patients with risk factors for liver dysfunction;
interrupt therapy if signs and symptoms occur
BL
• Severe exacerbation of hepatitis B upon discontinuation: may dissipate or
PD
resolve with initiating treatment
Generic
GD Name Treatment of susceptible Usual oral dose: 1 to 2 g • May cause CNS effects such as hallucinations, delirium, seizures, and
Valacyclovir viruses that cause shingles, 2 times per day for 1 to encephalopathy
genital herpes, suppression 7 days • Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome has
of genital herpes in Dose and duration are occurred in immunocompromised patients: use caution with doses of
immunocompetent and HIV- individualized based 8 g per day
Name
BrandQT infected patients, cold sores, on type of episode and • Has not been studied in severely immunocompromised patients: use with
Valtrex and chickenpox severity of infection
BL caution when CD4 < 100 cells/mm3
PD
• Start treatment as soon as symptoms arise: treatment for shingles and genital
herpes should begin within 72 hours (24 hours if recurrent genital herpes)
GD • Monitor: urinalysis, BUN, SCr, LFTs, CBC
QT
BL
PD
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GD
114
Generic Name Treatment of Usual oral dose: • Can cause renal failure: keep patient well hydrated and use with caution with
Valganciclovir cytomegalovirus (CMV) 900 mg once or twice other nephrotoxic agents
retinitis in patients with AIDS per day depending on • Manufacturer recommends tablets over solution in adults
indication for use and • Administer with meals to increase absorption
Prevention of CMV disease severity of infection
Brand Name
QT
• Use gloves to avoid contact with crushed tablets, powder from solution, and
in high-risk patients who are
9781284110562_CH02_Pass01.indd 114
oral solution due to their carcinogenic and mutagenic potential
Valcyte getting a kidney, heart, or
BL
• Monitor: ophthalmic exam every 4 to 6 weeks when treating CMV retinitis,
pancreas transplant
PD CBC, platelet count, SCr at baseline and throughout therapy
Associated with:
QT GD
• Blood dyscrasias: may need to adjust or interrupt therapy until white blood
BL cell levels increase
PD • Carcinogenic and potential teratogenic effects
HCV Antiviral
GD Agents NS5B Polymerase Inhibitors
QT
BL
Generic Name Treatment of chronic Usual oral dose: • May cause hepatic decompensation, and ALT elevation
PD hepatitis C with or without
Dasabuvir 250 mg 2 times per day • Drug interactions may require dose adjustments
coinfection of HCV/HIV-1
GD • Viekira Pak and Viekira SR are not interchangeable on a mg per mg basis
when used with other
• Take with food for optimal absorption
medication
Brand Name • Dispense in original container
Viekira Pak • Monitor: hepatic function tests, serum HCV RNA, hepatic decomposition if
For genotypes 1b and 1a
(in combination patient has cirrhosis

without cirrhosis or with
with ombitasvir, compensated cirrhosis
paritaprevir, and
ritonavir)
Generic Name Treatment of chronic Usual oral dose: • Can cause bradycardia when used with amiodarone
Sofosbuvir hepatitis C with or without 400 mg daily with ribavirin • Dispense in original container
infection of HCV/HIV-1 with and with or without • Monitor: bilirubin, LFTs, SCr, inpatient EKG monitoring for 48 hours when on
other medications peginterferon alfa for 12 amiodarone and self-monitoring for 2 weeks of heart rate, serum HCV RNA
to 24 weeks or until liver
• Can be used for treatment naïve patients and those with prior relapse able to
Brand Name transplant for patients with
Genotypes 1, 2, 3, and 4 receive interferon products
Sovaldi hepatocellular carcinoma
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NS3/4A Protease Inhibitors
Generic Name Treatment of chronic Usual oral dose: • Keep in original container until use
Grazoprevir hepatitis C infection with or 100 mg once per day for • Drug interactions may require dose adjustments
9781284110562_CH02_Pass01.indd 115
without cirrhosis and with 12 to 16 weeks • May cause elevated ALT: discontinue if ALT remains higher than 10 times the
or without infection of HCV/
upper limit of normal
HIV-1
Brand Name • Monitor: hepatic function tests at baseline, week 8, and week 12; testing for
NS5A resistance for genotype 1a; serum HCV RNA at baseline, weeks 4, 8, and
Zepatier (in Genotypes 1a, 1b, and 4 12, and during follow-up
combination
with elbasvir)
Generic Name Treatment of chronic Usual oral dose: • May cause hepatic decompensation, and ALT elevation
Paritaprevir hepatitis C with or without Technivie: 2 tablets every • Drug interactions may require dose adjustments
coinfection of HCV/HIV-1 morning for 12 weeks • Take with food for optimal absorption
when used with other
medication
Brand Name Viekira Pak: 2 tablets every • Monitor: hepatic function tests, serum HCV RNA, hepatic decomposition if
morning for 12 to 24 weeks patient has cirrhosis
Technivie
Genotypes 1b and 1a
(in combination • Discontinue Technivie if ALT is continuously greater than 10 times ULN
without cirrhosis or with
with ombitasvir compensated cirrhosis
and ritonavir) (Viekira)
Viekira Pak Genotype 4 without cirrhosis

(in combination (Technivie)
with ombitasvir,
ritonavir, and
dasabuvir)
Generic Name Treatment of chronic Usual oral dose: • May cause hepatic decomposition; photosensitivity when used with
Simeprevir hepatitis C for 12 to 24 weeks 150 mg once daily peginterferon alfa and ribavirin, which has led to hospitalization; and rash,
in combination with other which usually appears within 4 weeks of therapy initiation
medications • Drug interactions may require dose adjustments
QT
Brand
BL Name
Genotypes 1 and 4 • Dispense in original container
Olysio
PD • Monitor: bilirubin and liver enzymes; serum HCV RNA at baseline and weeks 4,
12, and 24; screen for NS3 Q80K polymorphism for genotype 1a; inpatient EKG
GD
monitoring for 48 hours when on amiodarone and self-monitoring for 2 weeks
of heart rate
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116
NS5A Replication Complex Inhibitors
Generic Name Treatment of chronic Usual oral dose: 60 mg • May cause bradycardia when used with amiodarone; use with caution in
Daclatasvir hepatitis C with or without once daily with sofosbuvir patients with cardiovascular diseases and hepatic disease
compensated cirrhosis for 12 to 24 weeks and with • Drug interactions may require dose adjustments
9781284110562_CH02_Pass01.indd 116
or without ribavirin
• Monitor: screen for NS5A polymorphisms for genotype 1a in patients
Genotypes 1 and 3 with cirrhosis; LFTs; SCr; inpatient EKG monitoring for 48 hours when on
Brand Name
amiodarone and self-monitoring for 2 weeks of heart rate
Daklinza
Generic Name Treatment of chronic Usual oral dose: 50 mg • Keep in original container until use
Elbasvir hepatitis C infection with or once daily for 12 to 16 • Drug interactions may require dose adjustments
without cirrhosis and with weeks
• May cause elevated ALT: discontinue if ALT remains higher than 10 times the
or without infection of HCV/
upper limit of normal (moderate to severe hepatic impairment)
HIV-1
Brand Name • Monitor: hepatic function tests at baseline and weeks 8 and 12; testing for
NS5A resistance for genotype 1a; serum HCV RNA at baseline, weeks 4, 8, and
Zepatier (in Genotypes 1a, 1b, and 4 12, and during follow-up
combination
with
grazoprevir)
Generic Name Treatment of chronic Usual oral dose: 90 mg • Can cause bradycardia when used with amiodarone
Ledipasvir hepatitis C with or without once daily for 12 to 24 • Dispense in original container
infection of HCV/HIV with or weeks
• Monitor: bilirubin, LFTs, SCr, inpatient EKG monitoring for 48 hours when on
without ribavirin
amiodarone and self-monitoring for 2 weeks of heart rate, serum HCV RNA
Brand Name
Genotypes 1, 4, 5, and 6
Harvoni (in
combination
with sofosbuvir)
Generic Name Treatment of chronic Usual oral dose: • Contraindicated in patients with moderate to severe hepatic impairment and
Ombitasvir hepatitis C with or without Technivie: 2 tablets every ribavirin use
coinfection of HCV/HIV when morning for 12 weeks • May cause QTc prolongation that is concentration dependent (Viekira only),
used with other medication hepatic decompensation, and ALT elevation
Viekira Pak: 2 tablets every • Drug interactions may require dose adjustments
Brand Name
Genotypes 1b and 1a morning for 12 to 24 weeks • Take with food for optimal absorption
Technivie without cirrhosis or with
(in combination compensated cirrhosis
with paritaprevir • Monitor: hepatic function tests, serum HCV RNA, hepatic decomposition if
(Viekira)
and ritonavir) patient has cirrhosis
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Viekira Pak Genotype 4 without cirrhosis • Discontinue Technivie if ALT is continuously greater than 10 times ULN
(in combination (Technivie) • Viekira Pak and Viekira XR are not interchangeable on a mg per mg basis
with
paritaprevir,
ritonavir, and
9781284110562_CH02_Pass01.indd 117
dasabuvir)
QT
BL
Miscellaneous Antivirals
PD
Generic
GD Name Treatment of acyclovir- Usual parenteral dose • May cause anemia, and granulocytopenia
QT resistant mucocutaneous for herpes simplex
Foscarnet • May cause electrolyte imbalances: correct before initiating treatment
BL
herpes simplex indication: IV: 40 mg/
• Some products contain sodium: use with caution in patients with heart failure
virus infections in kg per dose every 8 to 12
PD • Foscarnet is a vascular irritant; administer into a vein with adequate blood
immunocompromised hours for 2 to 3 weeks or
Brand Name flow
patients until lesions are healed
GD • Monitor: 24-hour CrCl at baseline and throughout therapy; during induction,
Foscavir
monitor CBC and electrolytes twice weekly, then weekly during maintenance
Treatment of CMV retinitis in
QT therapy; hydration status
patients with AIDS
Associated with:
QT BL
• Renal impairment: most patients will experience some degree of renal
BL PD impairment; reduce dose if needed and monitor carefully
PD GD • Seizures associated with electrolyte imbalance
GD
Antiprotozoals
QT
Amebicides
BL
PD
Generic Name Treatment of intestinal Usual oral dose: 650 mg • May cause optic atrophy/neuritis: avoid extended use at high doses and use
GD amebiasis 3 times/day for 20 days with caution in elderly patients
Iodoquinol
(max 1.95 g/day) • May cause peripheral neuropathy: avoid extended use at high doses
Trophozoite and cyst forms of • Use with caution in patients with thyroid abnormalities
Entamoeba histolytica • Administer after meals
Brand
QT Name
Yodoxin • Monitor: ophthalmologic exam with extended use
BL
Contraindications:
PD • Hepatic impairment
GD
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118
Generic Name Intestinal amebiasis Usual oral dose for hepatic • Patients with ulcerative bowel lesions may experience renal toxicity due to
Paromomycin coma: 4 g daily in divided increased absorption
Hepatic coma adjunct or doses for 5 to 10 days • Administer with food
encephalopathy • Alternative agent; not first-line therapy
Intestinal amebiasis: 25 to • Not effective for extra-intestinal amebiasis
Brand Name
35 mg/kg/day in 3 divided
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Humatin • Contraindicated in: intestinal obstruction
doses for 7 to 10 days
Generic Name Refer to the Miscellaneous Antiprotozoals section.
Metronidazole
Antimalarials
Generic Name Treatment of uncomplicated Usual oral dose: • May cause QTc prolongation
Artemether and malaria due to Plasmodium 4 tablets per dose • Drug interactions may require dose adjustment: avoid use of grapefruit juice
lumefantrine falciparum (20 mg artemether/120 mg because it increases the concentration of the medication
lumefantrine per tablet); • Use with caution in patients with hepatic and renal impairment
Sensitive to regions with treat with a 3-day oral • Administer with a full meal to increase absorption: if vomiting occurs within
chloroquine resistance regimen with a total of 2 hours of swallowing tablets, readminister
Name
Brand QT
6 doses including the initial
Coartem • If malaria returns, treat with a different medication
BL dose, then a second dose
• Monitor: adequate food intake with medication, ECG if patients is concurrently
8 hours later, then 1 dose
QT PD taking other medications that can cause QTc prolongation

PO twice daily (morning
BL GD and evening) for the next
2 days for a total course of
PD
24 tablets.
GD
Generic Name Treatment of uncomplicated Usual oral dose: • Can cause hepatic impairment and rarely hepatic failure: use with caution in
Atovaquone malaria due to Plasmodium Prevention: 250 mg/ patients with preexisting renal function impairment
and proguanil falciparum 100 mg once daily starting • Diarrhea/vomiting can decrease the absorption of the medication: use an
1 to 2 days before entering antiemetic or alternative therapy
Sensitive to regions with malaria region, throughout • Administer with food or milk: if patient vomits within 1 hour after taking dose,
BrandQT
Name chloroquine resistance stay, and 7 days after readminister
leaving • In patients who weigh more than 100 kg, treatment failure has been reported:
Malarone
BL
Malaria prophylaxis due to follow up after completion of therapy to ensure cure
PD Plasmodium falciparum Treatment: 1000 mg/ • Monitor: hepatic and renal function, cure in patients weighing more than 100 kg
400 mg once daily for 3 Contraindications:
GD
days • Use as prophylaxis if CrCl less than 30 mL/min
QT
BL
PD
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GD
Generic Name Suppressive treatment and Usual oral dose • Can cause ECG changes along with QTc prolongation: use with caution in
Chloroquine acute treatment of malaria (phosphate): patients with preexisting QTc prolongation
Chemoprophylaxis: 500 mg • Can cause extrapyramidal effects that resolve after finishing therapy or
P. vivax, P. malariae, P. ovale, weekly 1 to 2 weeks before treating the symptoms
P. falciparum exposure, during travel, • May can cause hematologic effects, including agranulocytosis: discontinue if
9781284110562_CH02_Pass01.indd 119
Name
BrandQT and 4 weeks after severe
Aralen
BL • May can cause myopathy or neuromyopathy: discontinue if weakness occurs
Several regions have highly
QT PD resistant strands of Treatment: 1 g on day 1, • Can cause severe ophthalmic damage, including macular degeneration:
P. falciparum then 500 mg 6 hours, monitor closely and discontinue if signs and symptoms occur
BL GD 24 hours, and 48 hours
• Patients with G6PD deficiency are at higher risk of hemolytic anemia
PD
after first dose
Treatment of extraintestinal • Use with caution in patients with hepatic impairment, porphyria, psoriasis,
amebiasis and seizures due to exacerbations
GD
Amebiasis: 1 g daily for
• Chloroquine phosphate to base equivalence data are available in the package
2 days, then 500 mg daily
insert
for 2 to 3 weeks
• Monitor: ophthalmic exams at baseline and with extended use, CBC with
extended use
Contraindications:
• History of retinal or visual changes due to 4-aminoquinoline compounds or
due to other etiology
Generic Name Suppressive treatment and Usual oral dose: • May cause cardiomyopathy with extended use
Hydroxychloroquine acute treatment of malaria Chemoprophylaxis: • May cause hematologic effects, including agranulocytosis: discontinue if
400 mg once weekly severe
Treatment of systemic lupus starting 2 weeks before • May cause myopathy or neuromyopathy: discontinue if weakness occurs
erythematosus and continuing for 8 weeks
Name
BrandQT • May cause severe ophthalmic damage, including loss of visual acuity: monitor
after exposure
closely and discontinue if signs and symptoms occur
Plaquenil
BL
Treatment of rheumatoid • Patients with G6PD deficiency are at higher risk of hemolytic anemia
PD arthritis (RA) Treatment: 800 mg, then
• Use with caution in patients with hepatic impairment, porphyria, and
400 mg at 6, 24, and
psoriasis, due to exacerbations
QT GD 48 hours after first dose
Not effective against • Hydroxychloroquine sulfate to base (and chloroquine phosphate) equivalence
BL chloroquine-resistant data are available in the package insert
PD P. falciparum • Chloroquine is preferred to hydroxychloroquine
• Refer to CDC guidelines for alternative schedules and dosing based on
GD
infection surveillance
• Administer with food or milk
• Monitor: CBC at baseline and throughout therapy, LFTs, ophthalmic exam
at baseline and every 3 months with extended use, muscle strength with
extended use
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120
Contraindications:
• History of retinal or visual changes due to 4-aminoquinoline compounds
Associated with:
• Should be prescribed only by clinicians familiar with the medication (requires
experienced clinician)
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Generic Name Treatment of mild to Usual oral dose: • Reports of agranulocytosis and anemia have occurred
Mefloquine moderate malaria infections Chemoprophylaxis: • Can cause ECG changes and QTc prolongation: use with caution in patients
due to P. falciparum and 250 mg once weekly with preexisting QTc prolongation
P. vivax beginning 1 or 2 weeks • Drug interactions may require dose adjustments
prior to exposure,
Name
Brand QT • Use with caution in patients with cardiovascular disease, impaired hepatic
Sensitive to chloroquine- continuing weekly during
function, and seizures
Lariam resistant P. falciparum exposure and 4 weeks after
BL
• Administer with food and at least 8 ounces of water: if vomiting occurs 30
exposure
PD QT minutes after dose, readminister; if vomiting occurs 30 to 60 minutes after
Prophylaxis against malaria dose, administer half the dose
QT GD BL Treatment:
• If treating for P. vivax, also give an 8-aminoquinoline derivative to prevent
BL PD 1250 mg once relapse
PD • Resistance has developed in Southeast Asia: do not use mefloquine in this
GD
region
GD
• Monitor: LFTs, ophthalmic exams, and for neuropsychiatric adverse events
with extended use
Contraindications:
• Use as prophylaxis in patients with a history of seizure or major psychiatric
disorder
Associated with:
• Neuropsychiatric adverse events that can outlast therapy (including but not
limited to seizures and psychosis): discontinue if they occur during use
Generic Name Used to prevent relapse of Usual oral dose: 15 mg • Can cause ECG changes and QTc prolongation: use with caution in patients
P. vivax malaria once daily with chloroquine with preexisting QTc prolongation
Primaquine
for 14 days • Can cause hematologic effects, including anemia, methemoglobinemia, and
leukopenia: discontinue if signs and symptoms occur
Primaquine
phosphate • Patients with G6PD deficiency are at higher risk of hemolytic anemia
• Use with caution in patients with hepatic impairment, porphyria, psoriasis,
QT and seizures due to exacerbations
BL • Primaquine base to phosphate equivalence data are available in the package
insert
PD
• Administer with meals to lessen gastrointestinal upset: if patient vomits within
GD 30 minutes of taking dose, readminister
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• May have cross-resistance with other aminoquinolines
• Use with caution in patients with NADH methemoglobin reductase deficiency:
methemoglobinemia is more likely to occur
• Monitor: screen for G6PD deficiency before initiating therapy, CBC, check
urine for darkening color (hematologic symptom), glucose, electrolytes, ECG
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in patients at high risk for QTc prolongation
• If hemolysis is suspected during treatment, monitor CBC, haptoglobin,
peripheral smear, and urinalysis dipstick for occult blood
Contraindications:
• Acutely ill patients who may develop granulocytopenia (systemic lupus
erythematosus, rheumatoid arthritis)
• Concurrent use of medications that can cause hemolytic anemia or bone
marrow suppression
• Concurrent or recent use of quinacrine
Generic Name Chemoprophylaxis of malaria Usual oral dose for • Can cause hematologic effects, including megaloblastic anemia,
Pyrimethamine toxoplasmosis: thrombocytopenia, and leukopenia: monitor CBC and PLT twice weekly when
50 to 75 mg once per treating for toxoplasmosis; discontinue if signs and symptoms occur
Resistance to pyrimethamine
has developed worldwide day, in combination with • Patients with G6PD deficiency are at higher risk of hemolytic anemia
QT sulfonamide for 1to 3 • Use with caution in patients with folate deficiency, hepatic impairment, renal
Brand Name weeks impairment, and seizures
BL
Daraprim Treatment of malaria
and toxoplasmosis in • Administer with meals to decrease gastrointestinal upset
PD
combination with a • Pyrimethamine can cause folic acid deficiency: supplement with leucovorin
GD sulfonamide • Monitor: CBC; CBC and platelet count twice weekly when treating for
toxoplasmosis; liver and renal function tests
Contraindications:
• Megaloblastic anemia due to folate deficiency
Generic Name Treatment of uncomplicated Usual oral dose: • Drug interactions may require dose adjustments
chloroquine-resistant P.
Quinine 648 mg every 8 hours for • Can cause severe hypersensitivity reactions such as SJS: discontinue if signs
falciparum malaria with the 7 days; administer with and symptoms occur
use of other agents tetracycline, doxycycline, or • Can cause hypoglycemia
clindamycin
Brand Name • Immune-related thrombocytopenia, including hemolytic uremic syndrome/
thrombotic thrombocytopenic purpura, has been reported: usually resolves
Qualaquin
within 1 week of discontinuation
QT • Can cause QTc prolongation: use with caution in patients with preexisting
arrhythmias
QT BL
• Do not use in patients with severe hepatic or renal impairment
BL PD
PD
GD
GD
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QT
BL
PD
122
• Do not take with antacids containing aluminum or magnesium due to
decreased absorption
• Swallow tablet whole to avoid bitter taste
• Can cause false-positive results for opioids in the urine
• Can cause false-positive results for steroids in the urine when using
9781284110562_CH02_Pass01.indd 122
Zimmerman assay
• Monitor: CBC, platelet count, LFTs, blood glucose, ECG, ophthalmic exam
Contraindications:
• Prolonged QTc interval
• Myasthenia gravis
• Optic neuritis
• G6PD deficiency
Associated with:
• Serious and life-threatening hematologic reactions
• Benefit does not outweigh risk for the treatment of nocturnal leg cramps
Quinidine Refer to the Cardiovascular Agents chapter.
Miscellaneous Antiprotozoals
QT
Drug
BL
Name FDA-Approved Indications Adult Dosage Range Precautions and Clinical Pearls
Generic
PD
Name Treatment of mild to Usual oral dose: 1500 mg • Use with caution in patients with gastrointestinal disorders: may impair
Atovaquone moderate Pneumocystis once daily or 750 mg twice absorption
GD
jirovecii pneumonia (PCP) daily • Use with caution in patients with hepatic impairment
in patients who cannot
• Must be administered with food, preferably high fat
take trimethoprim–
Brand Name • Absorption may be inadequate if patient has diarrhea/vomiting: give with an
sulfamethoxazole (TMP-SMZ)
antiemetic
Mepron
• Monitor: hepatic function tests at baseline and as needed, CD4 count for
Prophylaxis against PCP in
maintenance treatment in toxoplasmosis, patient’s tolerability to ingest
patients who cannot use
atovaquone
TMP-SMZ
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Generic Name Treatment of susceptible Usual oral dose for • May cause CNS effects including aseptic meningitis, encephalopathy, seizures,
Metronidazole organisms that cause trichomoniasis peripheral neuropathy, and optic neuropathy: avoid chronic therapy with high
intestinal amebiasis, amebic 500 mg twice daily, or may doses
liver abscess, anaerobic alternatively use 250 mg • May cause leukopenia: use with caution in patients with history of blood
bacterial infections, bacterial 3 times daily for 7 days dyscrasias
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Brand Name septicemia, bone and joint (max oral or IV 4 g/day) • Use with caution in patients with ESRD: accumulation may occur
Flagyl infections, CNS infections,
• Can cause C. difficile–associated diarrhea and pseudomembranous colitis with
Metro endocarditis, gynecologic
extended use
infections, intra-abdominal
MetroCream • IV solution should not come in contact with aluminum equipment
infections, lower respiratory
Metrogel infections, skin and skin • Administer ER formulation on an empty stomach
MetroLotion structure infections, bacterial Usual vaginal dose for • Avoid use of ER tablets in patients with severe hepatic impairment if possible
Noritate vaginosis, and trichomoniasis bacterial vaginosis • Injection contains 28 mEq sodium/g: use with caution in patients with
Nuvessa (for example: Bacteroides, (product dependent): One sodium-retaining states (e.g., heart failure, edema)
Clostridium, Peptococcus, applicatorful 1 to 2 times
Rosadan QT • May disrupt AST, ALT, TAG, glucose, and LDH results
Peptostreptococcus, per day for 5 days day for
Vandazole Fusobacterium, Eubacterium, • Monitor: CBC with differential at baseline and with extended use
BL 1 to 5 days
Trichomonas vaginalis) • IV formulations are available for specific FDA approved indications including
PD
surgical prophylaxis
Usual topical dose: apply
QT GD Contraindications:
Perioperative colorectal 1 to 2 times per day
BL surgery prophylaxis • Use of disulfiram in the previous 2 weeks
• Ethanol use during therapy and 3 days after the last dose
PD
QT Topical: bacterial vaginosis Associated with:
GD and rosacea • Carcinogenicity in animal data: use only if needed
BL
PD
Generic Name Treatment of diarrhea caused Usual oral dose: 500 mg • Use with caution in patients with hepatic and renal impairment
Nitazoxanide
GD by Cryptosporidium parvum every 12 hours for 3 days • Safety and efficacy have not been established in HIV-infected and
or Giardia lamblia immunocompromised patients
Brand
QT Name
Alinia
BL
PD
GD
Generic Name Treatment of pneumonia Usual parenteral dose: IM, • May cause hypotension: monitor after infusion
Pentamidine caused by Pneumocystis IV: 4 mg/kg once daily for • May cause QTc prolongation: use with caution in patients with preexisting
jirovecii (IM, IV) 14 to 21 days cardiovascular disease
• May cause anemia, leukopenia, thrombocytopenia, pancreatitis, and SJS
• Use with caution in patients with diabetes: can cause abnormal glucose levels
• Use with caution in patients with hepatic and renal impairment,
30/11/16 6:39 PM
124
Brand Name Prophylaxis against PCP Usual inhalation dose: hypocalcemia, and asthma (when using the nebulizer)
Nebupent in high-risk, HIV-infected 300 mg nebulized once • Do not dilute with normal saline
patients with a history of PCP every 4 weeks
Pentam • Refer to PI for specific nebulizing equipment (Respirgard II nebulizer)
or with a CD4+ count ≤ 200/
• Pentamidine is vesicant-like: avoid extravasation
QT
mm3 (inhalation)
9781284110562_CH02_Pass01.indd 124
BL • Monitor: liver and renal function tests, blood glucose, potassium and calcium,
PD
CBC and platelets, ECG, blood pressure
Generic Name Treatment of trichomoniasis Usual oral dose: • May cause seizures or peripheral neuropathy
GD
Tinidazole caused by T. vaginalis, 2 g per day for 1 to 5 days • Use with caution in patients with hepatic impairment or history of blood
giardiasis caused by dyscrasia
Duration is dependent
G. duodenalis, intestinal
on type and severity of • Can cause C. difficile–associated diarrhea and pseudomembranous colitis with
amebiasis and amebic liver
infection extended use
Name
BrandQT abscess caused by
Tindamax E. histolytica, bacterial
BL
vaginosis caused by • Avoid ethanol during treatment and 3 days after to prevent a disulfiram-like
PD Bacteroides, Gardnerella reaction
vaginalis, and Prevotella in • May interfere with AST, ALT, triglycerides, glucose, and LDH testing
QT GD
nonpregnant women Associated with:
BL
• Carcinogenic properties; avoid unnecessary use
PD
Co-trimoxazole Refer to the Antibacterials section.
GD
Dapsone Refer to the Antimycobacterials section.
30/11/16 6:39 PM
Page 1
VI. Antifungal Agents

Fungal Infections
Fungal infections are caused by microscopic organisms that can invade the epithelial tissue. The
fungal kingdom includes yeasts, molds, rusts and mushrooms. Fungi, like animals, are
hetrotrophic, that is, they obtain nutrients from the environment, not from endogenous sources
(like plants with photosynthesis). Most fungi are beneficial and are involved in biodegradation,
however, a few can cause opportunistic infections if they are introduced into the skin through
wounds, or into the lungs and nasal passages if inhaled.
Diseases caused by fungi include superficial infections of the skin by dermatophytes in the
Microsporum, Trichophyton or Epidermophyton genera. These dermophytic infections are named
for the site of infection rather than the causative organism.
Dermophytic Infection Causative Organism
Tinea corporis (ringworm) Microsporum canis, Trichophyton mentagrophytes
Tinea pedis (athlete’s foot) T. rubrum, T. mentagrophytes, Epidermophyton floccosum
Tinea cruis (jock itch) T. rubrum, T. mentagrophytes, E. floccosum
Tinea capis (scalp) M. canis T. tonsurans
Tinea barbae (beard/hair) T. rubrum, T. mentagrophytes
Tinea unguium (nails) T. rubrum, T. mentagrophytes, E. floccosum
Systemic infections are caused by the inhalation of spores and cause fungal pneumonia. This
pneumonia cannot be transmitted from human to human. These infections can occur in otherwise
healthy individuals. Many of the organisms that cause systemic fungal infections are confined to
specific geographic locations due to favorable climates for their proliferation.
Systemic Infections Causative Organism Geographic Location
Coccidioidomycosis Cocidioides immitis Southwestern U.S. and parts of Latin America
Histoplasmosis Histoplasma capsulatum Central and Eastern U.S.
Brazilian Blastomycosis Paracoccidioides brasiliensis South America
Blastomycosis Blastomyces dermatitidis Southeastern U.S. and Mississippi River valley
Organisms that cause opportunistic infections will not gain a foothold in healthy individuals, but
in the immunocompromised they can cause serious, sometimes life-threatening infections.
Patients especially susceptible to these infections include individuals with leukemia and other
blood diseases, cancer, HIV and other immunodeficiencies, and diabetes. These organisms can be
found throughout the U.S.
Opportunistic Infections Causative Organism Target Organs
Candidaisis, Thrush,
Vulvovaginitis Candida albicans GI tract and vagina
Cryptococcal meningitis Cryptococcus neoformans Through inhalation, may cause mild lung
infection. Mainly affects CNS
Aspergillosis Aspergillus sp. Lung, brain, sinuses and other organs
Mucormycosis Murcor sp. Sinuses, eyes, blood and brain
Pneumocystis carinii pneumonia Pneumocystis carinii Lungs (especially prevalent in HIV patients)
MEDCH 401 Immunizing and Antimicrobial Agents Spring 2006

R.S. Myers
Page 2
Biochemical Targets for Antifungal Chemotherapy

Fungal cells are complex organisms that share many biochemical targets with other eukaryotic
cells. Therefore, agents that interact with fungal targets not found in eukaryotic cells are needed.
The fungal cell wall is a unique organelle that fulfills the criteria for selective toxicity.
The fungal cell wall differs greatly from the bacterial cell wall and is not affected by antibacterial
cell wall inhibitors such as the β-lactams or vancomycin.
Mannoprotein
-Glucan/Chitin
-Glucan
Plasma Membrane
Arrangement of the biomolecular components of the cell wall accounts for the individual identity
of the organism. Although, each organism has a different biochemical composition, their gross
cell wall structure is similar. There are three general mechanisms of action for the antifungal
agents: cell membrane disruption, inhibition of cell division and inhibition of cell wall formation.
Inhibition of Cell Wall Formation
Interference with fungal cell wall biosynthesis has not been as successful and effective as
penicilins and cephalosporins against bacteria. Many chemicals have been discovered that
interfere with various steps in fungal cell wall synthesis with excellent antifungal activity in vitro.
Unfortunately, development of these agents into useful drugs has proven very difficult. Many of
these agents are developed to target β-glucan synthesis.
Cell Membrane Disruption
Antifungal agents that disrupt the cell membrane do so by targeting ergosterol, either by binding
to the sterol, forming pores and causing the membrane to become leaky (as with polyene
antifungals), or inhibiting ergosterol biosynthesis (as seen with azole antifungal agents).
Ergosterol is similar to mammalian cholesterol, thus agents binding ergosterol may have a
cytotoxic effect in the host tissue. Ergosterol has two conjugated double bonds that are lacking in
mammalian sterols.
H 3C CH 3 CH 3
CH 3 H H 3C CH 3
CH 3
CH 3 H
CH 3 H CH 3
CH 3
H H
HO H H
HO
Cholesterol Ergosterol

R.S. Myers
Page 3
Inhibition of Cell Division

Nucleoside antifungal agents affect cell division by targeting the microtubule effects in forming
the mitotic spindle:
or by inhibiting DNA transcription:

R.S. Myers
Page 4
Polyene Antifungal Agents (Cell Membrane Disruption)

Amphotericin B
Ergosterol PORE
Phospholipid HO H2 O H2
H O N N H
O O H
Water C OH HO C O
Lipid
OH HO
OH
HO
OH
HO
OH
HO
OH
HO
OH HO
Lipid
Water O O
O C OH HO C
H H N N O H
H2 O H 2 OH
Fig. 1: Mechanism of Action of Polyenes

(Amphotericin B as example)
AMPHOTERICIN B
Class of Antifungal: Polyene
Mechanism of Action: Binds to ergosterol in fungal membrane causing membrane to become
leaky (see Fig. 1)
Indications: Amp. B is indicated for treatment of severe, potentially life threatening fungal
infections. Unfortunately, it must be given IV and is toxic (due to nonselective action on
cholesterol in mammalian cell membranes). Serious fungal infections involve long therapy.
Resistance is due to lower production of membrane sterols or altered sterols, but is relatively rare
at present. Target modification and reduced access to target. Antifungal resistance to date
generally involves emergence of naturally resistant species. No data to suggest that antibiotic
modification in an important antifungal resistance mechanism.
Disposition: Amp. B is not absorbed orally. It is given as a colloidal dispersion by slow IV
infusion. It is highly bound to cholesterol-lipoprotein and has a plasma T1/2 of about 1 day and
1-2 weeks from tissues. It is excreted in urine over a long time. Penetration into the CNS is poor.
However, for fungal infections of the CNS, amphotericin B is mized with cerebrospinal fluid

R.S. Myers
Page 5
(CSF) that is obtained from a spinal tap. The solution of amphotericin is then reinjected through
the tap.
Adverse Effects
Headache, fever, chills, anorexia, vomiting, muscle and joint pain.
Pain at site of injection and thrombophlebitis (Drug must never be given intramuscular)
Can give aspirin, meperidine, steroids, antiemetics etc.
Nephrotoxicity - chronic renal tox in up to 80% of patients taking the drug for prolonged periods.
It is reversible but can be irreversible in high doses. Test for kidney function regularly. This is
the most common limiting toxicity of the drug.
Hematologic - hemolytic anemia due to effects on rbc membrane.
Other less common reactions - cardiac, convulsions, neuropathy, hearing loss, allergic, etc.
The use of liposomal preparations will decrease some adverse effects particularly nephrotoxicity.
It is believed the lipid preps decrease nonspecific binding to mammalian membranes.
Products
Fungizone (Bristol Myers Squibb) 50 mg/vial with 41mg of sodium deoxycholate. Reconstitute
with water. Give a test dose and gradually increase dose. Don't exceed 1.5mg/kg/d. Alternate
day therapy is sometimes used. Several months of therapy is usually needed.
Abelcet (Liposome Co.) 1:1 mixture of amphotericin and lipid complex, 100 mg/20 ml.
Rationale for this lipid preparation is that amphotericin B should have a greater affinity for the
lipid vehicle than for cholesterol in cell membranes, thus lower toxicity. Lipid associated
amphotericin B is drawn into the reticuloendothelial system, concentrating in lymphatic tissues,
spleen, liver and lungs where infectious fungi concentrate. Lipases excreted from fungi release
drug from lipid carrier allowing to bind to ergosterol in fungal cell membranes to exert fungistatic
and fungicidal activities.
Aphotec (Sequus Pharmaceuticals) cholesterol colloidal dispersion, 50 or 100 mg/20 ml (not on
UW formulary) Supplied in variety of topical forms including a 3% cream, lotion or ointment
and 100mg/mL oral suspension to treat cutaneous and mucocutaneous mycoses caused by
Candida albicans
AmBiosome (Fujisawa) liposomal, 50mg/vial.
NYSTATIN
leaky (see Fig. 1)

R.S. Myers
Page 6
Indications: Nystatin was originally isolated from Streptomyces noursei in 1951. A conjugated
tetraene, it was the first clinically useful polyene antifungal antibiotic.
Disposition: Available in oral tablets, powder for suspension, vaginal tablets, pastilles, for local
therapy only (not absorbed). Nystatin will treat gut candidiasis, and is used in a "swish and
swallow" routine for oral candidiasis.
Adverse Effects: No significant adverse effects with these uses, however itching, irritation and
burning may occur. Rarely nystatin can cause diarrhea and nausea Nystatin can be combined with
tetracycline to prevent monilial overgrowth caused by the destruction of bacterial microflora of
the intestine during tetracycline therapy.
Product: Mycostatin ® and other generic products.
natamycin
NATAMYCIN (Pimaricin, Natacyn)

leaky (see Fig. 1)
Indications: Natamycin was first isolated from cultures of Streptomyces natalensis. suspension
intended for the treatment of fungal conjunctivitis, blepharitis and keratitis. Structures consists of
26-membered lactone instead of the 38 for Nystatin and Amphotericin B. The 26-membered
polyenes cause both K leakage and cell lysis at same concentration.
Disposition: Natamycin is supplied as a 5% ophthalmic suspension intended for the treatment of
fungal conjunctivitis, blepharitis and keratitis.
Adverse Effects: Eye irritation, redness and swelling not present prior to use.
Product: Natacyn

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Azoles and Triazole Antifungal Agents:

Ergosterol Biosynthesis Inhibitors
Fig. 2: Ergosterol biosynthesis from squalene.

Site of action of azole antifungals (Flu, Itra, Vor) and Terbinafine (Terb) indicated.
Azole antifungal agents are the largest class of synthetic antimycotics. About 20 agents on the
market today. Some used topically to treat superficial dermatophytic and yeast infections. Others
used systemically to treat severe fungal infections. Antifungal activity stems from the presence
of an aromatic five member heterocyclic, either an imidazole or a triazole.
The first members of the class were highly substituted imidazoles (clotrimazole, miconazole)
were not absorbed orally. Ketoconazole introduced in 1984 was the first effective oral therapy for
Candida. Structure activity studies revealed that the imidazole ring can be replaced by a
bioisosteric triazole ring without affecting the antifungal activity but achieving higher selectivity
of the fungal targets vs. host. Itraconazole and Fluconazole are more potent, less toxic and
provide effective oral therapy for many systemic fungal infections. These two are triazoles.
Another triazole has been recently introduced (voriconazole). That said, amphotericin B is
usually the preferred drug for life threatening systemic fungal infections. It is still the “gold
standard”.
Mechanism of Action: These imidazoles and triazoles inhibit CYP P450 14 α- demethylase in
fungi. This enzyme is involved in the conversion of lanosterol to ergosterol. Other P450s in
sterol biosynthesis may be affected. The basic nitrogen of the azole ring forms a tight bond with

R.S. Myers
Page 8
the heme iron of the fungal P450 preventing substrate and oxygen binding. Inhibition of the
C14α-demethylase results in accumulation of sterols still bearing a C14 methyl group changing
the exact shape and physical properties of the membrane causing permeability changes and
malfunction of membrane imbedded proteins. They have a lower affinity for mammalian P450's.
The effect is fungistatic, but may be fungicidal at higher concentrations.
P450
CH 3
HO HO
lanosterol ergosterol
Spectrum and Uses of Azole and Triazole Antifungals

N Cl
O
N H2C Cl Miconazole
R CH2
CH O
Cl H 2C Cl Econazole
R=
Cl
N O
Cl H2C Cl Oxiconazole
S
H2C Cl Sulconazole
O
H2C Tioconazole
S
Cl
Five azole antifungals, miconazole, econazole, oxiconazole, sulconazole and tioconazole share a
common general structure but differ by the additional structural elements attached to the central
methylene carbon. All five antifungals are used in topical application only.
MICONAZOLE (developed by Janssen Pharmaceutica) is used for skin infections such as tinea
pedis, tinea cruris and vulvovaginitis. It comes in cream, lotion, powder, spray liquid and spray
powder, and also in suppository form for vaginal use. Miconazole is used once or twice a day for
one month for tinea pedis or two weeks for other skin infections. For vaginal infections it is used
once a day at bedtime for three or seven days.
Adverse effects include: increased burning, itching or irritation of the skin or vagina, stomach
pain, fever or foul-smelling vaginal discharge.
Products: Micatin, Monistat-3, Monistat-7, Monistat-Derm, Monistat Dual-Pak
ECONAZOLE (developed by Janssen Pharmaceutica) is a topical cream applied to the skin to
treat fungal infections including: tinea corporis, tinea pedis, tinea cruris, and superficial
candidiasis.
Adverse effects include: Burning, itching, stinging, redness and skin rash.

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Products: Spectrazole, Ecostatin

OXICONAZOLE (developed by F. Hoffmann-LaRoche and Siegfried AG) is a cream or lotion
applied to the skin in the treatment of tinea corporis, tinea pedis and tinea cruris.
Adverse effects include: Burning, itching, blistering, crusting, dryness or flaking of the skin,
scaling, severe redness, soreness, swelling and pain in hairy areas with pus at the root of hair.
Products: Oxistat, Oxizole
SULCONAZOLE (developed by Syntex Research) is a topical cream or solution to treat tinea
corporis, tinea pedis and tinea cruris.
Adverse effects include: Burning, stinging, itching and redness of the skin.
Products: Exelderm
TIOCONAZOLE (developed by Pfizer U.K.) is a cream to treat tinea corporis, tinea pedis, tinea
cruris and cutaneous candidiasis.
Adverse effects include: Burning, itching, redness, skin rash and swelling.
Products: Trosyd AF, Trosyd J
N
O N
O
N N O O
H 3C Cl
Ketoconazole
Cl
KETOCONAZOLE is supplied as a cream or in shampoos at one- or two-percent, for the

treatment of tinea pedis, tinea corporis, tinea cruris and cutaneous candidiasis.
Adverse effects include: itching, stinging, skin rash, dry skin, and dry or oily scalp.
Products: Nizoral Cream, Nizoral A-D Shampoo (1%), Nizoral Shampoo (2%)
N N
O O
Cl
Cl
N
N N N O
N
Itraconazole
ITRACONAZOLE is taken orally in capsule form to treat fungal infections that start in the
lungs and spread throughout the body. Itraconazole can also be used to treat fungal infections of
the nails, although it is important to point out that treatment of nail fungal infections does not
result in healthier looking nails. Normal nail appearance will occur only with new growth, which
can take up to six months for full nail growth. Oral solutions of this antifungal agent can be used
to treat oral candidiasis.

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Drug Interactions: Patients on proton pump inhibitors should take itraconazole with a cola soft
drink to aid in bioavailability.
Adverse effects include: diarrhea, constipation, gas, stomach pain, heartburn, sore or bleeding
gums, sores in and around the mouth, headache, dizziness, sweating, muscle pain, decreased
sexual desire or ability, nervousness, depression and runny nose. More severe side effects can
include: excessive tiredness, loss of appetite, upset stomach, vomiting, tingling or numbness in
the extremities, fever, chills, rash, hives and difficulty breathing or swallowing.
HEPATOXICITY: yellowing of the eyes or skin, dark urine or pale stools.
Product: Sporanox
N
N
N
F
N HO
N N F
Fluconazole
FLUCONAZOLE is a one-a-day tablet or suspension to treat yeast infections of the vagina,

mouth, throat, esophagus, abdomen, lungs, blood and other organs. Fluconazole is also used to
treat meningitis and can prevent yeast infections in patients who are likely to become infected due
to chemotherapy or radiation therapy before a bone marrow transplant.
Adverse effects include: headache, dizziness, diarrhea, stomach pain, heartburn and changes in
the ability to taste food. More severe side effects can include: excessive tiredness, loss of appetite,
upset stomach, vomiting, tingling or numbness in the extremities, fever, chills, rash, hives and
difficulty breathing or swallowing. HEPATOXICITY: yellowing of the eyes or skin, dark urine
or pale stools.
Product: Diflucan
N
N
N
F
N N HO
Voriconazole F
F
VORICONAZOLE is formulated in an oral suspension, tablets or parenteral injection. It is used

to treat different kinds of serious fungal infections and may be used in patients who have not
responded to other antifungal agents.
Drug interactions: Xanax, Versed, Halcion, Agenernase, Viracept, Invirase, Hismanal,
barbiturates, cyclosporine, ergot alkaloids, HMG CoA reductase inhibitors and warfarin.
Adverse effects include: rash, bloating or swelling of face, arms, hands, lower legs or feet,
stomach pain, blurred vision, chills, convulsions, dizziness, dry mouth, headache and muscle
pain. HEPATOXICITY: dark urine or pale stools.
Product: VFEND

R.S. Myers
Page 11
Cl
Cl
Cl N
Butoconazole N
BUTOCONAZOLE is a cream suppository used to treat vulvovaginitis. It is used either once or

in a seven-day regimen at bedtime.
Adverse effects include: burning or irritation in the vagina when cream is inserted, stomach pain,
fever or foul-smelling vaginal discharge.
Product: Gynazole-1
O Cl
N N Cl
O
Terconazole O
N
N
N
TERCONAZOLE is supplied as a cream or suppository to treat vulvovaginitis. It is usually used

daily at bedtime for either three or seven days.
Adverse effects include: headache, missed menstrual periods, burning or irritation in vagina when
cream or suppository is inserted, stomach pain, fever, or foul-smelling vaginal discharge.
Product: Terazol 3, Terazol 7.
N
O
N N O OH
N
O N N N
N
F
Posaconazole
POSACONAZOLE (Schering-Plough) is a novel triazole in Phase II clinical trials to be used as

an oral suspension to treat invasive fungal infections caused by Candida and aspergillus. The
current clinical trial will conclude in October 2006.

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Antifungal Agents Targeting Squalene Epoxidase:

Ergosterol Biosynthesis Inhibitors
The allylamines have a more limited spectrum of activity than the azoles and triazoles and are
only effective against dermatophytes. They are employed in the treatment of fungal infections of
the skin and nails.
Mechanism of Action: These antifungal agents are reversible, noncompetitive inhibitors of the
first step in ergosterol biosynthesis (see fig. 2), the conversion of squalene to squalene-2,3-
epoxide by squalene epoxidase. The buildup of squalene in the cell membrane is toxic to the cell,
causing pH imbalances and malfunction of membrane bound proteins.
Terbinafine
TERBINAFINE comes as a tablet to take orally or as a topical cream It is used to treat fungal
infections of the nails.
Drug interactions: warfarin, antidepressant drugs, beta-blockers, proton pump inhibitors and
drugs to suppress the immune system.
Adverse effects include: headache, dizziness, diarrhea, stomach pain, heartburn and changes in
the ability to taste food. More severe side effects can include: excessive tiredness, loss of appetite,
upset stomach, vomiting, tingling or numbness in the extremities, fever, chills, rash, hives and
difficulty breathing or swallowing. HEPATOXICITY: yellowing of the eyes or skin, dark urine
or pale stools.
Product: Lamisil,
O N
Tolnatate
TOLNAFTATE is is a topical cream to treat tinea infections of the skin.

Mechanism of Action: The exact mechanism unknown; however, it has been reported to distort
the hyphae and to stunt mycelial growth in susceptible organisms. Inhibition of squalene
epoxidation has also been reported.
Adverse effects are rare. Skin irritation has been reported.
Products:Aftate, Tinactin, Ting, Breezee

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Page 13
Other Antifungals Affecting Cell Membrane Stability

O-
O N
Ciclopirox
CICLOPIROX is a topical solution used to treat fungal infections of the nails and hair.It is a
broad-spectrum antifungal medication that also has antibacterial and anti-inflammatory
properties.
Mechanism of Action: Its main mode of action is thought to be its high affinity for trivalent
cations, which inhibit essential co-factors in enzymes. Ciclopirox exhibits either fungistatic or
fungicidal activity in vitro against a broad spectrum of fungal organisms, such as dermatophytes,
yeasts, dimorphic fungi, eumycetes, and actinomycetes. In addition to its broad spectrum of
action, ciclopirox also exerts antibacterial activity against many Gram-positive and Gram-
negative bacteria. Furthermore, the anti-inflammatory effects of ciclopirox have been
demonstrated in human polymorphonuclear cells, where ciclopirox has inhibited the synthesis of
prostaglandin and leukotriene. Ciclopirox can also exhibit its anti-inflammatory effects by
inhibiting the formation of 5-lipoxygenase and cyclooxygenase.
Ciclopirox is thought to act through the chelation of polyvalent metal cations, such as Fe3+ and
Al3+. These cations inhibit many enzymes, including cytochromes, possibly disrupting the
biosynthesis of ergosterol. Ciclopirox also appears to modify the plasma membrane of fungi,
resulting in the disorganization of internal structures.
Adverse effects: redness, irritation, burning, blistering or swelling at the site of application and
discoloration of the nails or surrounding area. Treated nails may become ingrown.
Product: Loprox, Penlac nail lacquer
Inhibitors of Cell Division
NH2 OH
Cytosine
F Deaminase F
N
O N O N
H H
FLUCYTOSINE was synthesized in 1957 as an antitumor agent. It was inactive but it was
found to have antifungal activity.
Mechanism of Action: The drug enters the fungal cell through active transport on ATPases that
normally transport pyrimidines. Once inside cells, fungal cytosine deaminase convert the drug to
active 5-fluorouracil (5FU, a very effective antitumor agent, by the way!) which is incorporated
into RNA causing faulty RNA synthesis and also is a strong, non competitive inhibitor of
thymidylate synthesis interrupting the one carbon pool substrate. Mammalian cells do not contain
cytosine deaminase.
Resistance develops rapidly and occurs on many levels e.g. transport into the cell and cytosine
deaminase steps. After a few dosing intervals the drug is essentially useless. To avoid rapid
resistance, combination with Amphotericin B, and the combination is synergistic. It is also
synergistic with itraconazole and fluconazole, and interest in these combinations for treatment of

R.S. Myers
Page 14
systemic Candida infections is increasing. Amphotericin B damaged membranes are thought to

allow better entry of flucytosine. Used (with Amp. B) for Cryptococcal meningitis, systemic
Candida infections, and some other systemic fungal infections. This is an oral drug. Good also
for fungal UTI.
Disposition: The drug is well absorbed and well distributed. CSF levels are 65-90% of plasma
levels. Is eliminated unchanged largely in the urine.
Adverse Effects: GI upset, hepatic involvement seen in the increase in transaminases,
Hematologic involvement include anemia, leucopenia. Thrombocytopenia is the major
complication of therapy and may be due to low levels of 5-FU circulating.
Product: Ancobon (Roche)
O O O
O O
Cl
Griseofulvin
GRISEOFULVIN is an antifungal produced from Penicillium griseofulvin. Therapy must

continue until new tissue replaces old diseased tissue. When given orally, plasma-borne
griseofulvin becomes incorporated into keratin precursor cells and ultimately into
kearatin that cannot support fungal growth.
Mechanism of Action: Griseofulvin inhibits microtubule polymerization thus inhibiting the
formation of the mitotic spindle.
Adverse effects: Headache is a common adverse effect. May cause aplastic anemia. Being
gradually replaced by newer agents.
Products: Fulvicin-U/F, Grifulvin V, Gris-PEG
Cell Wall Inhibitors

H 2N
NH OH
O O
HO H
N
H N
H 2N N O H 3C
O HN OH
CH 3 CH 3
HO NH O CH 3
O H N
N
HO
OH
O
OH
HO
CASPOFUNGIN acetate is an parenteral injection used in the treatment of invasive aspergillosis

in patients refractory to or intolerant of other antifungal therapies. Studies have shown
caspofungin to be effective against invasive candidaisis. It is a semisynthetic lipopeptide
(echinocandin) derived from a fermentation product of Glarea lozoyensis.

R.S. Myers
Page 15
Mechanism of Action: Caspofungin is a (1,3)-D-glucan synthesis inhibitor, thus disrupting

the formation of β-glucan in the cell walls. β-glucan is essential to the structural integrity
of the cell wall.
Drug interactions: Reduces AUC, Cmax and concentration of tacrolimus. Cyclosporine increases
AUC of caspofungin.
Adverse effects: thrombophlebitis, vein irritation, histamine-related symptoms, anaphylaxis has
been reported.
Product: Cancidas
ANIDULAFUNGIN (Pfizer) has recently been approved to treat infections by Candida.

Mechanism of Action: It inhibits glucan synthase, disrupting the formation of b-glucan. It is
especially effective against fluconazole-resistant Candida.
Adverse Effects: Diarrhea, elevation of liver enzymes.
Product: Eraxis
O
Undecylenic Acid OH
UNDECYLENIC ACID is widely used topically as the zinc salt in OTC preparations for topical
treatment of infections by dermatophytes.
Mechanism of Action: This organic acid will interact non-specifically with components in the cell
membrane. It can be used in concentrations up to 10% in solution, powder and emulsions.
Traditionally used for athlete’s foot (tinea pedis) although cure rates are low.
Adverse effects are rare. Skin irritation has been reported.
Products: Desenex, Cruex, Decylenes Powder, Caldesene, Gordochom Solution

R.S. Myers
Page 16
Other Inhibitors of Fungal Cell Wall Synthesis: Under Development
Mannoprotein
-Glucan/Chitin
-Glucan
Plasma Membrane
Other β-1,3 glucan synthetase inhibitors: Papulacandins – glycolipid antifungal produced by

Papularia sp. Loss of b-glucan results in weakening of the cell wall, thus internal pressures can
cause the cells to lyse
Chitin Synthase inhibitors: Polyoxins and Nikkomycins– nucleoside peptides. Chitin is also a
major component to the cell wall and its loss will also weaken the cell walls.
C Mannan binding antifungals: Pradimicins and benanomicins. C-mannan is a cell wall
glycoprotein that combats the host immune response through disruption of cytokine response and
possibly T-lymphocyte action.

R.S. Myers
Anti-fungal Drugs
PREPARED BY:
Assistant Professor
Lovely Professional University Phagwara Punjab
Introduction
❑ The chemical compounds used in the treatment of fungal infection
called anti fungal agents.
❑ There are two types of fungal infection:
A. Superficial infection: Affect skin – mucous membrane
Dermatophytes : Fungi that affect keratin layer of skin, hair, nail.

e.g. tinea pedis, ring worm infection
Candidiasis : Candidia (Yeast) infection like, oral thrush,

vulvovaginitis, nail infections.
B. Deep infections : Affect internal organs as : lung ,heart , brain

leading to pneumonia, endocarditis, meningitis.
Targets of antifungal drugs
CLASSIFICATION OF ANTIFUNGAL DRUGS
AMPHOTERICIN B
Chemistry
-Amphotericin B is a polyene antibiotic (polyene: containing
many double bonds)
Mechanism of action
-Binding to ergosterol present in the membranes of fungal cells

Formation of “pores” in the membrane

Leaking of small molecules (mainly K+) from the cells
-The ultimate effect may be fungicidal or fungistatic

depending on the organism and on drug concentration.
Model for Amphotericin B induced
Pore in Cell Membrane
PHARMACOLOGY OF FLUCYTOSINE
Chemistry
-Flucytosine is a fluorinated pyrimidine
Mechanism of action
-The drug is accumulated in fungal cells by the action of a membrane
permease and is converted by a cytosine deaminase to 5-fluorouracil
(selectivity occurs because mammalian cells do not accumulate and
do not deaminate flucytosine)

5-fluorouracil is metabolized to 5-fluorouridylic acid
which can be
a) incorporated into the RNA (this leads to a misreading of the fungal
genetic code)
b) further metabolized to 5-deoxyfluorouridylic acid, a potent inhibitor
of thymidylate synthase (this leads to a blockade of fungal DNA
synthesis)
-The ultimate effect may be fungicidal or fungistatic depending on the
organism and on drug concentration.
Flucytosine (5-flucytosine, 5-FC) is an analogue of cytosine that was
originally synthesized for possible use as an antineoplastic agent. 5-
FC is converted to 5-fluorouracil inside the cell by the fungal enzyme
cytosine deaminase. The active metabolite 5-fluorouracil interferes
with fungal DNA synthesis by inhibiting thymidylate synthetase.
Incorporation of these metabolites into fungal RNA inhibits protein
synthesis.
AZOLES ANTIFUNGAL AGENTS
Chemistry
-Imidazole derivatives: ketoconazole, miconazole, econazole,
clotrimazole
-Triazole derivatives: itraconazole, fluconazole.
Mechanism of action
-Inhibition of sterol 14-alpha-demethylase, a cytochrome
P450-dependent enzyme (relative selectivity occurs because
the affinity for mammalian P450 isozymes is less than that
for the fungal isozyme)

blockade of the synthesis of ergosterol in fungal cell
membranes
-The ultimate effect may be fungicidal or fungistatic
depending on the organism and on drug concentration.
Isoconazole
Econazole
Ticoconazole
Flutrimazole
Sertconazole
Bifonazole
Pharmacologic properties of five systemic azole drugs
Water Absorption CSF: Serum t 1/2 Elimination Formulations

Solubility Concentration (Hours)
Ratio
Ketoconazole Low Variable < 0.1 7–10 Hepatic Oral
Itraconazole Low Variable < 0.01 24–42 Hepatic Oral, IV
Fluconazole High High > 0.7 22–31 Renal Oral, IV
Voriconazole High High ... 6 Hepatic Oral, IV
Posaconazole Low High ... 25 Hepatic Oral
PHARMACOLOGY OF GRISEOFULVIN
Chemistry
-Griseofulvin is a benzofuran derivative
-The drug is practically insoluble in water
Mechanism of action
-An active transport accumulates the drug in sensitive fungal cells where

griseofulvin causes disruption of the mitotic spindle by interacting with
polymerized mycrotubules
-The ultimate effect is fungistatic
Undecylenic Acid
Ciclopirox olamine
Synthesis of Clotrimazole
Antiviral
Drugs
Medicinal Chemistry
Presented by:
Dr. Sanjeev Kumar Sahu
Lovely Professional University Phagwara
Jalandhar Punjab.
Structure Of Viruses
• Nucleic acid (single-or
double-stranded RNA or DNA)
never both.
• Surrounded by a Protein
Coat: “Capsid” and sometimes
an outer lipid “envelope”
• A fully assembled infectious

virus: “virion”
• Often contain crucial virus-
specific enzymes
• Often visible by electron
microscopy
•DNA viruses
✓ Adenoviruses (upper respiratory infections)
✓ Hepadnaviruses
✓ Herpes virus(HSV-1,HSV-2,VZV,CMV)
✓ Poxvirus ( small pox)
✓ Papilloma viruses (warts) Retro viruses
•
• A retrovirus is a type of RNA virus that inserts a
•RNA viruses copy of its genome into the DNA of a host cell. It
✓ Arborvirus-yellow fever invades host cell and thus changing the genome
✓ Arenaviruses- meningitis of that cell.
✓ Bunya viruses- encephalitis
✓ Coronaviruses- URI • Any of a group of viruses that belong to the family
✓ Influenza A and B Retroviridae are known as Retrovirus and
✓ Paramyxoviruses – Measles, mumps
✓ Rhabdoviruses- Rabbies characteristically carry their genetic blueprint in
✓ Human immunodeficiency virus (HIV) the form of ribonucleic acid (RNA). e.g HIV
Viral Diseases Routes of viral transfer
• Skin contact
• Respiratory
• Common Cold • Mumps, measles and rubella
• Faecal
• Chickenpox • Shingles
• Oral
• Flu (influenza) • Viral gastroenteritis (stomach
flu) • Milk
• Herpes
• Viral hepatitis • Transplacental
• HIV/AIDS
• Viral meningitis • Sexual
• Human papillomavirus (HPV)
• Viral pneumonia • Insect vector
• Infectious mononucleosis
• Animal bite
Stages of Viral 7 Steps of viral replication
Replication 1. Adsorption: Attachment of virus to the host cell

2. Penetration: Penetration of virus into the cell
3. Uncoating: Cell enzymes (lysosomes) strip off the
protein coat of virus and expose the genome
4. Transcription: Production of viral mRNA from the
viral genome
5. Translation: Viral genome enters the nucleoplasm
and utilises the host nucleic acid machinery for
synthesis of new viral protein. It also modifies the cell
irreversibly to produce more viral genomes.
6. Assembly: New viral protein coat assembles into
capsid and viral genomes
7. Release of new virus: Release of mature virus after
budding and rupture of the host cell
7 Steps of viral replication
1. Adsorption
2. Penetration
3. Uncoating
4. Transcription
5. Translation
6. Assembly
7. Release of new
virus
Purine, Pyrimidine analogues, Amantadine derivatives
Reverse transcriptase inhibitors (block penetration)
(block nucleic acid synthesis)
Methimazole;
Protease inhibitors
(block protein
processing)
Drugs’
Target Sites
Classification
ANTI-HERPES VIRUS (DNA VIRUS)
Nucleoside analogues (Nucleoside DNA polymerase inhibitors )
Pyrimidine Nucleosides: Idoxuridine, Trifluridine
Purine Nucleosides: Vidarabine,
Acyclic Purine Nucleosides: Acyclovir, Penciclovir, Famciclovir , Ganciclovir,
Acyclic Pyrimidine Nucleosides: Cidofovir
Non-nucleoside analogues (Non -nucleoside DNA polymerase inhibitors ): Foscarnet*
ANTI-RETRO VIRUS (HIV)
Nucleoside analogues (Nucleoside reverse transcriptase inhibitors or NRTI)
Pyrimidine Nucleosides: Zidovudine, Stavudine, Zalcitabine, Lamivudine
Purine Nucleosides: Didanosine, Abacavir
Acyclic Purine Nucleosides: Adefovir*
Non-nucleoside analogues (Non-nucleoside reverse transcriptase inhibitors or NNRTI): Nevirapine, Efavirenz
Protease inhibitors: Nelfinavir, Saquinavir,
Classification
ANTI-INFLUENZA VIRUS (RNA VIRUS)

Amantadine, Rimantadine (Inhibitors of Viral penetration & uncoating)
NONSELECTIVE ANTIVIRAL DRUGS:

Ribavirin (m-RNA Synthesis Inhibitors) , Interferons (Immunomodulators)
Nucleoside analogues (Nucleoside DNA polymerase inhibitors )
Idoxuridine Trifluridine Vidarabine,

Acyclovir Ganciclovir
Cidofovir
Oxidation &
Deacetylatio
n
Famciclovir Penciclovir
(Prodrug of Pencyclovir)
(Nucleoside Analogues like Acyclovir)
Mechanism of Action
Acyclovir
Viral specific thymidine kinase
Acyclovir monophosphate
Host cell kinases

Acyclovir triphosphate
Competitively inhibits and inactivates HSV-specified

DNA polymerase enzyme
Further preventing viral DNA synthesis without affecting

the normal cellular processes.
ANTI-RETRO VIRUS (HIV)
Nucleoside analogues (Nucleoside reverse transcriptase inhibitors or NRTI)
Pyrimidine Nucleosides
Zidovudine, Stavudine, Zalcitabine Lamivudine

Purine Nucleosides
Abacavir
Didanosine
(Nucleoside Analogues like Zidovudine)
Mechanism of Action
Zidovudine
Viral specific kinases

Zidovudine monophosphate
Host cell kinases

Zidovudine triphosphate
Competitively inhibits and inactivates viral RNA reverse transcriptase enzyme (RNA-
dependent DNA polymerase) in preference to cellular DNA polymerase
Further preventing viral DNA synthesis from RNA without

affecting the normal cellular processes.
Non-nucleoside analogues (Non-nucleoside reverse transcriptase inhibitors or NNRTI):
NNRTI directly inhibit HIV reverse

transcriptase without
the need for intracellular phosphorylation.
Nevirapine Efavirenz
Protease inhibitors
Nelfinavir Saquinavir
(Protease inhibitors) Mechanism of Action
Large Viral Polyprotein
Protease Enzyme Saquinavir and Nelfinavir inhibits protease enzyme

Various functional components
Provides required core proteins and enzymes to RNA genome
Maturation of the new virus particles

ANTI-INFLUENZA VIRUS (RNA VIRUS) (Inhibitors of Viral penetration & uncoating)
Amantadine Rimantadine
NONSELECTIVE ANTIVIRAL DRUGS:
Ribavirin (m-RNA Synthesis Inhibitors) Interferons (Immunomodulators)

Interferons
(Non-selective antivirals/Immunomodulators)
Interferons (IFNs) are a group of signaling proteins made

and released by host cells in response to the presence of
several pathogens, such as viruses, bacteria, parasites, and
also tumor cells. In a typical scenario, a virus-infected cell will
release interferons causing nearby cells to heighten their
anti-viral defenses.
Interferons Healthy
(Non-selective antivirals/Immunomodulators) Human
Cell
Mechanism IFNA1
of Action Infected
IFNA1
Healthy
Human Human
Cell Cell
Viral RNA/DNA
IFNA1
Healthy
Human
Cell
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BP601T Unit 1-3

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BP601T Medicinal Chemistry III (Theory)

Mrs. Sneha Kushwaha

Historical background, Nomenclature, Stereochemistry, Structure activity relationship

Macrolide: Erythromycin, Clarithromycin, Azithromycin.

Miscellaneous: Chloramphenicol*, Clindamycin.

Prodrugs: Basic concepts and application of prodrug design.

Antimalarials: Etiology of malaria.

Quinolines: SAR, Quinine sulphate, Chloroquine*, Amodiaquine, Primaquine phosphate,

Biguanides and dihydro triazines: Cycloguanil pamoate, Proguanil.

Miscellaneous: Pyrimethamine, Artesunete, Artemether, Atovoquone.

 Macrolides are protein synthesis inhibitors.

(1) N-demethylation imparts activity against gram-negative bacteria.

(3) The thiomethyl ether of a-thiolincosamide moiety is essential for activity

 Chloramphenicol is an antibiotic useful for the treatment of a number of bacterial infections.

 Chloramphenicol is a bacteriostatic by inhibiting protein synthesis.

Life cycle of malaria

Quinine & Related Compounds

Other Quinine Analogues

 Fluorine is commonly used in drug design.

Medicinal Chemistry of Other Antimalarial Drugs

a. Activate AMP activated protein kinase (AMPA-PK)

Applications of Prodrug design

2. Reduction of gastric irritation

Eg: Aspirin is a prodrug of salicylic acid designed to reduce gastric irritation

3. Reduction in Pain at Site of Injection

4. Enhancement of drug solubility and dissolution rate

5. Enhancement of chemical stability

 Chemical stability is an utmost necessary parameter for every therapeutic agent.

 Improvement of Bioavailablity and Enhancement of Oral Bioavailablity

8. Prevention of Presystemic metabolism

9. Prodrugs may protect a drug from presystemic metabolism

10. Prolongation of duration of action

 Drug Prodrug Testosterone Testosterone propionate Estradiol Estradiol propionate Fluphenazine

• Antibiotics that contains the β-lactam (a four membered cyclic

• β-lactam are the most widely used group of antibiotics available.

(inhibitors of cell wall synthesis)

• Their structure contains a beta-lactam ring.

The major subdivisions are:

(a)penicillins whose official names usually include or end in “cillin”

“ceph” in their official names.

(c) carbapenems (e.g. meropenem, imipenem)

(d) monobactams (e.g. aztreonam)

(e) beta-lactamase inhibitors (e.g. clavulanic acid, sulbactam).

• It was isolated from fungus Penicillium notatum.

• Beta lactam ring (Ring B) – (Broken by Beta-lactamase)

Side chain is attached at position – 6- (NHCOR)

• Side chains attached through amide linkage. (Broken by

• Beta Lactam ring is broken by –

• Penicillinase (Beta Lactamase), and by gastric acid.

Basic chemistry:Beta lactum ring+Thiazolidine ring

Site of Penicillinase action

PENICILLIN G (BENZYL PENICILLIN)

• More acid stable than Penicillin G.

• Administered by oral route.

• Electron withdrawing group is present in acyl side chain.

• Has no electron withdrawing group on the side chain.

• Acid sensitive and has to be injected.

• Steric shields can be added to penicillins to protect from

• If hydrophilic groups like (NH2, OH , COOH ) are attached to the

carbon that is α to the carbonyl group on the side chain then α

hydrophilic group aids the passage of penicillins through porins of

gram –ve bacteria.

• Same spectrum of activity as that of penicillin G but more active

against gram–ve bacteria.