Questions 19c, 22c, 24c, 26c, 40c, 41c, 42c, 49c, 48c, 47b, 47c

Microbial Pharmacology

Drugs used to combat malaria, amebiasis, toxoplasmosis and anthelmintic drugs (against nematodes,
trematodes and cestodes).

Mosquito borne infectious disease caused by parasitic protozoa, plasmodium. There are many types of
plasmodium, main 5 types and it is transmitted by infected female anopheles, where the bite introduces
parasites from the mosquito saliva into a person blood.
The parasites travel to the liver and mature and reproduce, causing hepatocytes destruction
Symptoms: yellow skin, tiredness, vomiting, headaches, seizures – worst case, death and coma
Pathogenesis
Malaria infection develops via 2 phases:
1. Exoerythrocytic phase – involves liver, a clinically silent phase
2. Erythrocytic phase - involves RBC – most symptoms
 Sporozoites in saliva enter bloodstream and migrate to the liver to infect hepatocytes
 Host remain asymptomatic for 8-30 days, sporozoites remaining dormant in liver
 After this dormant period, they differentiate into merozoites, rupturing host cells
 They escape into blood (protected by cell membrane of host hepatocyte – evade immune system) and
infect RBC starting phase 2 – the periodic release of merozoites cause chills, fever and sweats.
 Amplification of multiplying results in waves of fever
 P. falciparum – since infected RBC are destroyed by the spleen, these organisms display adhesive
proteins causing blood cells to stick to the walls.
 Macrophages become activated and produce cytokines and pro-inflammatory mediators, which are
responsible for all the systemic manifestation of malaria
 Sequestered RBC can breach BBB and cause cerebral malaria
Genetic factors that protect from malaria – SCA, thalassemia, G6PD deficiency – why? because Individuals
with sickle cell trait (heterozygotes) are protected against malaria because their red cells have too little
ATPase activity and cannot produce sufficient energy to support the growth of the parasite, and also the
parasite have hard time to invade the sickled cells due
to their shapes and increased rates of phagocytosis of • Plasmodium falciparum infection has the highest
infected sickled cells. mortality and causes cerebral malaria.
• P. malariae, P. ovale and P. vivax cause more benign
Treatment disease.
• The hepatic forms of P. ovale and P. vivax cause
The primary objective of treatment is to ensure
relapses.
complete cure, that is the rapid and full elimination of • Antimalarial drugs act at different stages of the malaria
the Plasmodium parasite from the patient’s blood, in parasite’s life cycle.
order to prevent progression of uncomplicated malaria • Resistance, especially of P. falciparum, to chloroquine,
to severe disease or death, and to prevent chronic sulfadoxine–pyrimethamine and mefloquine is an
infection that leads to malaria-related anaemia. increasing problem world-wide.
Malaria prophylaxis - These agents do not prevent the
acquisition of malaria but prevent severe
complications.
1. Disruptive prophylaxis – prevent parasite binding with RBC by blocking Ca signaling
2. Suppressive prophylaxis – Chloroquine, proguanil, mefloquine, doxycycline = effective at killing
malaria parasite once it entered into erythrocyte phase only which is why prophylactics must be
continuous 4 weeks after leaving risk area
o 3. Casual prophylaxis – target both stages e.g. malarone, primaquine
 Antimalarial medications – depends on type and severity of disease
o P. falciparum – artemisinin’s
o Amodiaquine
o Lumefantrine
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 Questions 19c, 22c, 24c, 26c, 40c, 41c, 42c, 49c, 48c, 47b, 47c

Prophylaxis include:
1. Doxycycline** 100 mg once daily (started one day before travel, and continued for four weeks after
returning);
2. Mefloquine (an arylaminoalcohols) 250 mg once weekly (started two-and-a-half weeks before
travel, and continued for four weeks after returning)
3. Atovaquone/proguanil** (Malarone) 1 tablet daily (started one day before travel and continued for
1 week after returning).
4. Chloroquine (4-aminoquinolines) weekly, plus proguanil (antifolate) daily
*chloroquine – used only as prophylactic where falciparum is not chloroquine
resistant
** for chloroquine resistant falciparum drugs

Chloroquine or mefloquine (in chloroquine-resistant areas) are believed to be

the most effective and safest antimalarial drugs for chemoprophylaxis in
pregnancy.

Doxycycline (broad spectrum antibiotic, part of tetracycline group)

Antibiotic that treats infections caused by bacteria and protozoa. It can be
used with quinine to treat malaria or alone, to prevent malaria.
MOA: bacteriostatic – inhibit protein production, also in protozoa – impair
progeny of apicoplast genes – abnormal cell division
PK – given orally or IV,
Adverse effects – diarrhea, nausea, vomiting, red rash

Indications – Lyme disease, sinusitis, rickettsial, chlamydia and malaria

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 Questions 19c, 22c, 24c, 26c, 40c, 41c, 42c, 49c, 48c, 47b, 47c

CI: pregnancy – disrupt bone and tooth development, childhood < 8 years

Tetracyclines – protein synthesis inhibitors – inhibit binding aminoacyl-tRNA to mRNA-ribosome complex

by binding to the 30S ribosome subunit in mRNA translation complex.
Tetracyclines can also inhibit matrix metalloproteinases
Resistance is built since the binding is reversible and by 3 ways – enzyme inactivation (by adding acetyl
group) of tetracycline, efflux pumps and ribosomal protection

2 groups of treatment of malaria:

1. Acute malaria
2. Malaria relapsing

Acute Malaria – 2 drugs

1. 4-aminoquinolines (e.g. chloroquine) – terminate acute attack of vivax malaria but not latent
hepatic forms and therefore relapses occur.
 Combo: Primaquine given with chloroquine to prevent relapse and eliminate hepatic forms
 Indications: RA and SLE as well as malaria
 MOA: the erythrocyte stage of plasmodium is sensitive to chloroquine and this is where the
parasite digests the Hb in food vacuole to provide energy for the parasite – the food vacuole
is acidic, and chloroquine is a weak base therefore it is concentrated within it by ion trapping.
Chloroquine and others inhibit malarial haem polymerase within food vacuole of plasmodial
parasite inhibiting the conversion of toxic haemin to haemozoin. This leads to
ferriprotoporphyrin to accumulate in presence of chloroquine drug and this is toxic to parasite
which is killed by the waste product of its appetites.
 SE
o Short term therapy – mild headache, GIT, pruritus, IV chloroquine – associated with
encephalopathy
o Prolonged therapy – retinopathy (bulls eye macula), bleaching of hair, weight loss,
lichenoid skin eruption, weight loss and ototoxicity
 PK – rapidly and well adsorbed from intestine, 50% bound to proteins and 70% unchanged
and excreted via urine with metabolite. Half-life 120hrs. High concentrations in melanin
containing tissues thus retina is affected
 Drug interaction – chloroquine and quinine are antagonistic
2. Arylaminoalcohols (4-aminoquinolines derivatives) – e.g. quinine, quinidine and mefloquine
and halofantrine
 Quinine – alkaloid of cinchona bark
o Quinine sulphate – drug of choice in treating falciparum malaria which is resistant to
chloroquine
o Given IV and then orally (when improved) and reduce dosage in renal or hepatic
dysfunction patients
o Can give doxycycline or clindamycin as an adjunct
o SE – cause chinchonism (tinnitus, deafness, nausea, visual and headache), abdominal
pain, diarrhea, rash, fever, thrombocytopenia
o IV quinine – neurotoxicity, fits and coma
o PK – absorbed in upper part of SI and metabolised in liver

3. 8-aminoquinolines (Primaquine)
 Indication – eradicate hepatic forms of vivax malaria or malariae after chloroquine therapy or
as a prophylaxis with chloroquine
 MOA – affect mitochondrial ETC
 PK – GIT absorption is good and rapidly metabolised
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 Questions 19c, 22c, 24c, 26c, 40c, 41c, 42c, 49c, 48c, 47b, 47c

 SE – GIT upsets, methahemoglobemia and hemolytic anemia in G6PD

4. Artenusate and artemether

 Sesquiterpene lactone endoperoxide (semi synthetic of artemisinin)
 MOA: undergo haem-mediated decomposition of endoperoxide to yield free radicals with
carbon – thus selectively txic to malarial parasites due to the haem – rapid death occurs
 SE: nausea, vomiting, anorexia and dizziness
 CI – not used alone or as prophylaxis due to resistance risk
 PK – metabolised to active metabolites
5. Antifolates e.g. Dapsone, Proguanil, Pyrimethamine
 MAO: Inhibit folate biosynthesis at ALL stages of parasite life cycle.
o Acting as competitive inhibitors of malarial dihydropteroate synthases (dapsone)
o Inhibit malarial dihydrofolate reductase (proguanil or Pyrimethamine)
o SE – GIT upsets, rashes, myelosuppression

Amebiasis - an amoebicide is an agent used in the treatment of amoebozoa infections, called amoebiasis
The causative agent, Entamoeba histiolytica, lives and multiplies in the colon (symptom: diarrhea), its cyst
form residing also in the liver among other sites. In tropical regions, up to half the population can be
infested, transmission occurring by the faecal–oral route. The most effective treatment against both
intestinal infestation and systemic disease is administration of metronidazole. If monotherapy fails,
combination therapy with chloroquine, emetine or tetracyclines may be indicated.
Metronidazole
An antibiotic and antiprotozoal medication
 Indications: PID, endocarditis, bacterial vaginosis, giardiasis, trichomoniasis, amebiasis and
clostridium (pseudomembranous) colitis
 MOA: Metronidazole is of the nitroimidazole class. It inhibits nucleic acid synthesis by
disrupting the DNA of microbial cells. This function only occurs when metronidazole is partially
reduced, and because this reduction usually happens only in anaerobic cells, it has relatively little
effect upon human cells or aerobic bacteria.
 PK – available as oral, topical and IV, Metronidazole is bitter and so the liquid suspension
contains metronidazole benzoate. This requires hydrolysis in the stomach and so maybe
unsuitable in people with diarrhoea or feeding-tubes in the duodenum or jejunum.
 SE: nausea, metallic taste, loss of appetite and headaches. Also associated with thrombophlebitis.
It is carcinogenic
 Contraindication: not used during early pregnancy or breastfeeding, alcohol (disulfiram like
reaction)

Toxoplasmosis
A parasitic disease caused by toxoplasma gondii, which can appear asymptomatic or with flu-like
symptoms, muscle ache and tender LN.
Treatment only recommended in people that are immunocompromised
Trimethoprim/sulfamethoxazole is the drug of choice to prevent toxoplasmosis, but not for treating active
disease.
2 groups for treating the disease:
1. Acute
 Pyrimethamine — an antimalarial medication
 Sulfadiazine — an antibiotic used in combination with pyrimethamine to treat toxoplasmosis

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 Questions 19c, 22c, 24c, 26c, 40c, 41c, 42c, 49c, 48c, 47b, 47c

o Combination therapy is usually given with folic acid supplements to reduce incidence of
thrombocytopenia – most useful in HIV
 Clindamycin
 Spiramycin — an antibiotic used most often for pregnant women to prevent the infection of their
children.
 If infected during pregnancy, spiramycin is recommended in the first and early second trimesters
while pyrimethamine/sulfadiazine and leucovorin is recommended in the late second and third
trimesters

2. Latent
 In people with latent toxoplasmosis, the cysts are immune to these treatments, as the
antibiotics do not reach the bradyzoites in sufficient concentration.
 Atovaquone — an antibiotic that has been used to kill Toxoplasma cysts inside AIDS patients
 Clindamycin — an antibiotic that, in combination with atovaquone
3. Congenital
 When a pregnant woman develops acute toxoplasmosis, the tachyzoites have approx. 30%
chance of entering the placental tissue and infecting the fetus
 If the parasite has not yet reached the fetus, spiramycin can help to prevent placental
transmission.
 If the fetus has been infected, the pregnant woman can be treated with pyrimethamine and
sulfadiazine, with folic acid, after the first trimester.
o They are treated after the first trimester because pyrimethamine has an antifolate
effect, and lack of folic acid can interfere with fetal brain formation and cause
thrombocytopenia.
 Infection in earlier gestational stages correlates with poorer fetal and neonatal outcomes

Other anthelmintic

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 Questions 19c, 22c, 24c, 26c, 40c, 41c, 42c, 49c, 48c, 47b, 47c

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 Questions 19c, 22c, 24c, 26c, 40c, 41c, 42c, 49c, 48c, 47b, 47c

Antimicrobial combinations, advantages and disadvantages, example of synergism and antagonism of

individual combinations.

An antimicrobial is a substance that kills or inhibits the growth of microorganisms such as bacteria, fungi,
protozoans as well as destroying viruses. Antimicrobial drugs either kill microbes (microbicidal) or prevent
the growth of microbes (microbistatic).

Antimicrobial combination is using two or more antimicrobial in treatment of microorganisms, however

mainly one drug targeting a specific organism is preferred because…
1. Reduce possibility of superinfection
2. Reduce emergence of resistant organisms
3. Minimise toxicity
Dosing schedules are based on pharmacological profiles of drugs used alone, therefore an estimation of the
dosage is important for combining medications.
Advantages of using combination therapy
1. Broad spectrum of anti-microbial – empirical therapy for polymicrobial infections
2. Minimise resistance to one drug
3. Reduce dosing by carrying out an additive inhibitory effect
Example: resistant coagulase negative staphylococci
 Oxacillin with Teicoplanin/vancomycin/linezolid
 Linezolid with teicoplanin
These drugs are used against methicillin and teicoplanin resistant coagulase negative staphylococci
Synergism
1. Co-trimoxazole is a sulfonamide antibiotic combination of trimethoprim and sulfamethoxazole used
in the treatment of bacterial infections
2. Penicillins and aminoglycosides
Cannot combine a bacteriostatic s vs bacteriocidal

Fluoroquinolones and quinolones and other drugs used for treatment of urinary tract infections.
A quinolone antibiotic is a broad-spectrum bactericide that has a bicyclic core similar to 4-quinolone. Most
quinolone antibiotics used are fluoroquinolones e.g. Ciprofloxacin (second generation fluoroquinolones),
which contain a fluorine atom and are effective against gram-negative and gram-positive bacteria.
Quinolones and fluoroquinolones are chemotherapeutic bactericidal drugs, eradicating bacteria by
interfering with DNA replication.

MOA: fluoroquinolones inhibit topoisomerase II, Quinolones inhibit the bacterial DNA gyrase or the
topoisomerase IV enzyme, thereby inhibiting DNA replication and transcription

First and second-generation fluoroquinolones selectively inhibit the topoisomerase II ligase domain, leaving
the two nuclease domains intact. This modification, coupled with the constant action of the topoisomerase II
in the bacterial cell, leads to DNA fragmentation via the nuclease activity of the intact enzyme domains.
Third and fourth generation fluoroquinolones are more selective for the topoisomerase IV ligase domain,
and thus have enhanced gram-positive coverage.

Pathology
Urinary tract infections are mainly caused by organisms:
 E. coli from the gut (80-85%)
 Staphylococcus saprophyticus (5-10%)
 Healthcare associated – E. coli, Klebsiella, pseudomonas, candida albicans and enterococcus
 Urinary tract infections due to Staphylococcus aureus typically occur secondary to blood-borne
infections.

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 Questions 19c, 22c, 24c, 26c, 40c, 41c, 42c, 49c, 48c, 47b, 47c

 Chlamydia trachomatis and Mycoplasma genitalium can infect the urethra but not the bladder
Quinolones can enter cells easily, which is why it is used to treat intracellular pathogens such as Legionella
pneumophila and Mycoplasma pneumoniae.
Fluoroquinolones can enter cells easily via porins and, therefore, are often used to treat intracellular
pathogens such as Legionella pneumophila and Mycoplasma pneumoniae.
For many gram-negative bacteria, DNA gyrase is the target, whereas topoisomerase IV is the target for
many gram-positive bacteria.
Some compounds in this class have been shown to inhibit the synthesis of mitochondrial DNA

1st generation – Oxolinic acid

2nd generation – Ciprofloxacin, norfloxacin, fleroxacin, rufloxacin
3rd generation – levofloxacin, balafloxacin, grepafloxacin
4th generation - act at DNA gyrase and topoisomerase IV. This dual action slows development of resistance -
Clinafloxacin, gatifloxacin

PK –

Indications – genitourinary infections and hospital acquired infections associated with urinary catheters
acute cases of pyelonephritis or bacterial prostatitis where the patient may need to be hospitalized,
fluoroquinolones are recommended as first-line therapy.

SE of fluoroquinolones: prolong AT interval by blocking VGK channels, which can lead to torsades des
pointes, clostridium difficile colitis, peripheral neuropathy, nervous system effects, GIT upset. The drugs
interact with different receptor e.g. blocking GABA causing excitotoxicity effects of the CNS.

CI – epilepsy, Ehlers-danlos syndrome, stroke or hypersensitivity

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 Questions 19c, 22c, 24c, 26c, 40c, 41c, 42c, 49c, 48c, 47b, 47c

Drugs used in the treatment of tuberculosis. Chemotherapy of mycobacterial.

TB is caused by the bacterium mycobacterium tuberculosis that occurs in the lungs but can affect any organ,
LN, gut, meninges, bone and urogenital tract.
Mycobacterium tuberculosis is an intracellular organism, an obligate aerobe
Treatment
Initial combination with 3-4 drugs (multidrug strategy)
1. Isoniazid
2. Rifampicin
3. Pyrazinamide
4. Ethambutol (streptomycin)
Administered for the 1st 2 months followed by rifampicin and isoniazid for 4 more months

First-line drugs in tuberculosis therapy e.g. Isoniazid (isonicotinic acid hydrazide)

Indications - Isoniazid is bactericidal only to Mycobacterium tuberculosis. It is used as a single agent for
chemoprophylaxis (a strategy used in some countries, including the USA, that do not use bacillus Calmette–
Guérin (BCG)) as a preventive measure). In countries such as the UK, isoniazid is used only in combination
with other drugs, usually rifampicin plus pyrazinamide and/or ethambutol. When using high-dose isoniazid
(e.g. treating tuberculous meningitis) or in patients with special risk factors (e.g. diabetes, alcoholism),
pyridoxine is given to prevent peripheral neuropathy
Mechanism of action - Isoniazid is a competitive inhibitor of bacterial fatty acid synthase II, an enzyme
involved in the synthesis of mycolic acid, a constituent of the M. tuberculosis cell wall. Isoniazid only acts
on growing bacteria.
Adverse effects
 restlessness, insomnia and muscle twitching;
 Sensory peripheral neuropathy, observed more commonly in slow acetylators, and prevented by
supplemental pyridoxine;
 Biochemical hepatitis, which is clinically significant in 1% of patients, and rarely progresses to
hepatic necrosis.
Acetylisoniazid may be responsible for this effect, since enzyme inducers, such as rifampicin, result in
higher production of this metabolite in the liver and are associated with increased toxicity;
 Bone marrow suppression, anaemia and agranulocytosis;
 Drug-induced systemic lupus erythematosus.
Pharmacokinetics
Isoniazid is readily absorbed from the gut and is widely distributed to tissues, including CSF, and into
macrophages where it kills intracellular tubercle bacilli. It undergoes acetylation in the liver. Abnormally
high and potentially toxic concentrations of isoniazid may occur in patients who are both slow acetylators
and have renal impairment.
Drug interactions - Isoniazid undergoes hepatic metabolism by CYP450s. It inhibits the metabolism of
several anticonvulsants, including phenytoin and carbamazepine, causing toxic concentrations of these drugs
in some patients.

Rifampicin
Indications - Rifampicin is a derivative of Rifamycine, which is produced by Amycolatopsis mediterranei
(Streptomyces mediterranei). Because of its high lipophilicity, it diffuses easily through cell membranes to
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 Questions 19c, 22c, 24c, 26c, 40c, 41c, 42c, 49c, 48c, 47b, 47c

kill intracellular organisms, such as Mycobacterium tuberculosis. It is also used to treat nasopharyngeal
meningococcal carriers (it enters well into saliva, tears and nasal secretions), Legionnaires’ disease and
refractory deep- sited staphylococcal infections (e.g. osteomyelitis).
Mechanism of action - Rifampicin acts by binding to the β-subunit of the DNA- directed bacterial RNA
polymerase, forming a stable drug– enzyme complex and suppressing initiation of chain formation in RNA
synthesis.
Adverse effects
Large doses of rifampicin produce toxic effects in about 1/3rd of patients:
 After a few hours influenza-like symptoms, flushing and rashes;
 Abdominal pain
 Hepatotoxicity – hepatitis and cholestatic jaundice
 Thrombocytopenia (rare)
 Urine and tears become orangey-pink.

Pharmacokinetics- Absorption from the gut is almost complete but delayed by food. Rifampicin penetrates
well into most tissues, cavities and exudates, but little enters the brain and CSF. The t1/2 is between one and
five hours. It is metabolized by deacetylation and both the metabolite and parent compound are excreted in
the bile and undergo enterohepatic circulation. Toxicity is increased by biliary obstruction or impaired liver
function. Less than 10% appears unchanged in the urine and thus standard dosing is unaffected by renal
failure.
Drug interactions - Rifampicin markedly induces a wide range of hepatic microsomal CYP450 enzymes,
thereby accelerating the metabolism of many commonly used drugs. Clinically important interactions
associated with reduced concentration and therapeutic failure are common, and include:
 corticosteroids;
 warfarin;
 sex steroids (rendering oral contraception unreliable);
 Immunosuppressants (including cyclosporine, tacrolimus, sirolimus leading to graft rejection);
 oral hypoglycaemic drugs (e.g. glibenclimide, gliburide);
 anticonvulsants (phenytoin, carbamazepine);
 HIV protease inhibitors.
Clinically important interactions may occur after rifampicin is discontinued. The dose of a second drug (e.g.
warfarin) may be increased during rifampicin therapy to compensate for the increased metabolism. If the
effect of such a drug is not closely monitored in the weeks following cessation of rifampicin treatment and
the dose reduced accordingly, serious complications (e.g. bleeding) may ensue.

Ethambutol
This is the D-isomer of ethylenediiminodibutanol. It inhibits some strains of Mycobacterium tuberculosis,
but other organ- isms are completely resistant. Resistance to ethambutol develops slowly and the drug often
inhibits strains that are resistant to isoniazid or streptomycin.
Mechanism of action - The mechanism of action of ethambutol is unclear. It inhibits bacterial cell wall
synthesis and is bacteriostatic.
Adverse effects
 Retrobulbar neuritis with scotomata and loss of visual acuity
o The 1st sign: loss of red–green perception.
 Rashes, pruritus and joint pains;
 Nausea and abdominal pain;
 Confusion and hallucinations
 Peripheral neuropathy
Pharmacokinetics - Ethambutol is well absorbed (75–80%) from the intestine. The plasma t1/2 is five to six
hours. Because ethambutol is 80% excreted unchanged in the urine, it is contraindicated in renal failure.

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 Questions 19c, 22c, 24c, 26c, 40c, 41c, 42c, 49c, 48c, 47b, 47c

Pyrazinamide
Indications: Pyrazinamide is a bactericidal drug which is well tolerated as oral therapy. Because of its ability
to kill bacteria in the acid intracellular environment of a macrophage, it exerts its main effects in the first
two to three months of therapy. Pyrazinamide is most active against slowly or intermittently metabolizing
organisms but is inactive against atypical mycobacteria. Resistance to pyrazinamide develops quickly if used
as monotherapy. Pyrazinamide should be avoided if there is a history of alcohol abuse, because of the
occurrence of hepatitis
Mechanism of action- The enzyme pyrazinamidase in mycobacteria cleaves off the amide portion of the
molecule, producing pyrazinoic acid which impairs mycolic acid synthesis by inhibiting the bacterial
enzyme fatty acid synthase I.
Adverse effects
 Flushing, rash and photosensitivity;
 Nausea, anorexia and vomiting;
 Hyperuricaemia and gout;
 Hepatitis
 Sideroblastic anaemia
 Hypoglycaemia
Pharmacokinetics
Pyrazinamide is converted by an amidase in the liver to pyrazinoic acid. This then undergoes further
metabolism by xanthine oxidase to hydroxypyrazinoic acid. Pyrazinamide is well absorbed and has a t1/2 of
11–24 hours. Pyrazinamide and its metabolites are excreted via the kidney, and renal failure necessitates
dose reduction. It crosses the BBB to achieve CSF concentrations almost equal to those in the plasma and is
a drug of first choice in tuberculous meningitis.

Streptomycin
Indications - Streptomycin is an aminoglycoside antibiotic. It has a wide spectrum of antibacterial activity
but is primarily used to treat mycobacterial infections. It is only administered parenterally (intramuscularly).
Therapeutic drug monitoring of trough plasma concentrations allows dosage optimization.
Mechanism of action - Like other aminoglycosides, it is actively transported across the bacterial cell wall,
and its antibacterial activity is due to specific binding to the P12 protein on the 30S subunit of the bacterial
ribosome, inhibiting protein synthesis.
Adverse effects - The major side effects are eighth nerve toxicity (vestibulotoxicity more than deafness),
nephrotoxicity and, less commonly, allergic reactions.
Contraindications - Streptomycin is contraindicated in patients with eighth nerve dysfunction, in those who
are pregnant and in those with myasthenia gravis, as it has weak neuromuscular blocking activity.
Pharmacokinetics - Oral absorption is minimal and it is given intramuscularly. Streptomycin is mainly
excreted via the kidney and renal impairment requires dose adjustment. The t1/2 of streptomycin is in the
range of two to nine hours. It crosses the BBB when the meninges are inflamed.

PREPARATIONS CONTAINING COMBINED ANTI-TUBERCULOUS DRUGS

Several combination preparations of the first-line drugs are available. They are helpful when patients are
established on therapy, and the reduced number of tablets should aid compliance and avoid monotherapy.
Combined preparations avail- able include Mynah (ethambutol and INH, in varying dosages), Rifinah and
Rimactazid (containing rifampicin and INH) and Rifater (containing INH, rifampicin and pyrazinamide).

Second-line drugs and treatment of refractory tuberculosis

The commonest cause of M. tuberculosis treatment failure or relapse is non-compliance with therapy.
 The previous drug regimen used should be known and the current bacterial sensitivity defined.
 If the organisms are still sensitive to the original drugs, then better supervised and
prolonged therapy with these drugs should be prescribed.
o Alternative drugs are needed if bacterial resistance has arisen.
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 Questions 19c, 22c, 24c, 26c, 40c, 41c, 42c, 49c, 48c, 47b, 47c

 Organisms that are resistant to INH, rifampicin, pyrazinamide and ethambutol ICTION

Leprosy manifests in 2 forms

1. Lepromatoid (the organism being localized to skin or nerve)

2. Lepromatous (a generalized bacteraemic disease that effects many organs, analogous to
miliary tuberculosis).

The main drugs used to treat leprosy are dapsone, rifampicin and clofazimine.

The WHO regimen for multibacillary leprosy is:

 rifampicin, once a month;

 dapsone, daily unsupervised given for 24 months;
 clofazimine, daily unsupervised, plus a larger dose under supervision every four weeks.
Other anti-lepromatous drugs include ofloxacin, minocycline, clarithromycin and
thalidomide.

Dapsone

Dapsone (4,4-diaminodiphenyl sulphone) is a bacteriostatic sulphone. It has been the standard

drug for treating all forms of leprosy, but irregular and inadequate duration of treatment as a
single agent has produced resistance.

Indications - Dapsone is used to treat dermatitis herpetiformis, as well as leprosy, pneumocystis

and, combined with pyrimethamine, for malaria prophylaxis.

Mechanism of action - Dapsone is a competitive inhibitor of dihydropteroate (folate) synthase,

thereby impairing production of dihydrofolic acid.

Adverse effects

 anaemia and agranulocytosis;

 gastro-intestinal disturbances and (rarely) hepatitis;
 allergy and rashes, including Stevens–Johnson syndrome;
 peripheral neuropathy;
 methaemoglobinaemia;
 haemolytic anaemia, especially in glucose-6-phosphate dehydrogenase (G6PDH)-deficient
patients.

PK- Dapsone is well absorbed (90%) from the gastro-intestinal tract. The t1/2 is on average 27
hours. It is extensively metabolized in the liver, partly by N-acetylation, with only 10–20% of the
parent drug being excreted in the urine. There is some enterohepatic circulation. Drug interactions
The metabolism of dapsone is increased by hepatic enzyme inducers (e.g. rifampicin) such that its
t1/2 is reduced to 12–15 hours.

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 Questions 19c, 22c, 24c, 26c, 40c, 41c, 42c, 49c, 48c, 47b, 47c

Classify beta-lactam antibiotics and other cell wall synthesis inhibitors: mode of actions and adverse
effects.

Beta lactam antibiotics are bactericidal drugs interfere bacterial cell wall synthesis, peptidoglycan, which is
the main component of thick, gram positive organisms and thin component in gram negative organisms. Due
to this, beta lactams are not effective against microbes with no peptidoglycan in the cell wall for example,
mycobacterium species has mycolic acids in the cell wall or fungal cell wall consisting chitin.

Beta lactam antibiotics ae non-toxic, acid-labile and decompose with gastric juice, and they affect bacterial
enzymes called penicillin-binding proteins (PBP) – also DD-transpeptidase – that terminate on
peptidoglycan fibres. Absorption of beta lactams from GIT is limited, and therefore most forms are
parenteral forms or esterification of the drug facilitate absorption but must be administered with food as
digestive juices increases the absorption rate.

Beta lactams spread mostly in extracellular space, and penetration

across biological barriers is limited but can be overcome with higher
dosing. Intracellular penetration of beta lactams is poor.
Most beta lactams are excreted through kidneys, but exceptions include:
 Oxacillin
 Cefoperazone
 Ceftriaxone
 Some partly metabolised by liver enzymes
The half life is short (30m to 2.5 hours), except Ceftriaxone with a
long half-life of 8 hours.

13
 Questions 19c, 22c, 24c, 26c, 40c, 41c, 42c, 49c, 48c, 47b, 47c

PD – effect of beta lactams depends on time > MIC – the target of dosing is to keep the level of antibiotic >
MIC at the site of infection as long as possible

SE – not toxic and low minimum concentration-dependent adverse effects which can be used in gravid or
breast-feeding women and in newborns.
Allergic reactions
Cross allergy between penicillin and cephalosporins (5%-10%) – therefore cephalosporins is given to
patients with a history of mild penicillin allergy (exanthema)
Allergy to cephalosporins implies high probability of cross allergy to penicillins
Phlebitis – which occurs with IV (hyperosmolar solutions), local pain and infiltrates during intramuscular
administration and dyspepsia during oral admin
Broad spectrum antibiotics – lead to dysmicrobia and post antibiotic colitis
Indications – beta lactams are for acute infections in tissue or for treatment for sepsis, surgical prophylaxis –
frequent dosing needed to reach a strong affect

Properties
1. Time dependent = > MIC
2. Concentration dependent = > MIC

Penicillin – 4 groups:
1. Natural penicillin e.g. Penicillin G or benzylpenicillin (unstable in gastric juice, therefore IV admin
only), Penicillin IV (acid stable form – orally given), procaine (IM admin, daily)
 Low dose penicillin against tonsillitis, streptococcal skin infections (impetigo)
 High dose – infective endocarditis (viridans, streptococci, enterococci), pneumococcal
or meningococcal sepsis
2. Antistaphylococcal penicillins e.g. oxacillin (standard in CZ), methicillin (not used anymore)
 Resistant to staphylococcal beta-lactamase but not those produced by gram negative
microbes
 Drugs have a very narrow spectrum
3. Aminopenicillin e.g. amoxicillin (better absorption after oral
admin), ampicillin (parenteral admin)
 Aminopenicillin should not be prescribed for
tonsillitis until infectious mononucleosis is
excluded as they would develop severe
maculopapular exanthema caused by heterophile
antibodies
 Usually given with a beta lactamase inhibitor e.g.
amoxicillin-clavulanic acid
 Not effective against nosocomial pathogens e.g. pseudomonas aeruginosa,
acinetobacter or MRSA
4. Anti-pseudomonal penicillin e.g. piperacillin (or co-piperacillin + tazobactam)
 Parenteral forms only
 For severe mixed infections only
Some penicillin is combined with a beta-lactamase inhibitor
MRSA or MRSE – changed PBP receptor and are resistant to all beta-lactam antibiotics

Cephalosporins
4 groups “generations” which are broader spectrum antibiotics compared to penicillins, with a enhanced
effect against gram negative bacteria. Cephalosporins are not effective against enterococci and listeria
monocytogenes.
1. First generation

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 Questions 19c, 22c, 24c, 26c, 40c, 41c, 42c, 49c, 48c, 47b, 47c

 Against gram positive cocci (streptococci, staphylococci), Corynebacterium, meningococci,

E. coli or proteus mirabilis
o Cefalotin – Parenteral admin or Cefalexin – oral admin
 Treat – skin and soft tissues infections but not effective against MRSA
2. Second generation
 Against community acquired gram negative bacteria e.g. hemophilus influenza, Moraxella
o Cefuroxim or Cefoxitin
 Intraabdominal, pelvic and gynecological infections, foot infections in diabetics and mixed
aerobic-anaerobic infections
 Resistance develops quickly
3. Third generation
 2 subgroups:
o Subgroup A e.g Cefotaxim. – enhanced effect against gram negative (weaker against
staphylococci)
 Treat severe and life-threatening infections such as purulent meningitis,
epiglottis, sepsis or hepatobiliary tract origin
o Subgroup B e.g. Ceftazidim – activity against pseudomonas aeruginosa with a strong
anti-pseudomonal effect
 This drug is excreted by bile – hence affective against hepatobiliary tract
infections and renal insufficiency patients
4. Fourth generation e.g. Cefepim
 Resist beta lactamases
 Used to treat nosocomial infections and febrile neutropenia
5. FIFTH Generation - effective against MRSA
“LAME”
L – Listeria
A - Atypical (including Mycoplasma and Chlamydia)
M – MRSA
E - Enterococci
Mechanism of action
1. Cephalosporins are bactericidal and have the same mode of action as other β-lactam antibiotics (such
as penicillins) but are less susceptible to β-lactamases.
2. Cephalosporins disrupt the synthesis of the peptidoglycan layer forming the bacterial cell wall. The
peptidoglycan layer is important for cell wall structural integrity.
3. The final transpeptidation step in the synthesis of the peptidoglycan is facilitated by penicillin-
binding proteins (PBPs).
4. PBPs bind to the D-Ala-D-Ala at the end of muropeptides (peptidoglycan precursors) to crosslink the
peptidoglycan.
5. Beta-lactam antibiotics mimic the D-Ala-D-Ala site, thereby irreversibly inhibiting PBP crosslinking
of peptidoglycan.
Compared to penicillin, cephalosporins are broader-spectrum antibiotics against gram negative bacteria but
not effective against enterococci and listeria monocytogenes

Adverse effects
1. Common adverse drug reactions diarrhea, nausea, rash, electrolyte disturbances, and pain and
inflammation at injection site.
2. Allergic hypersensitivity
3. Infrequent include vomiting, headache, dizziness, oral and vaginal candidiasis, pseudomembranous
colitis, superinfection, eosinophilia, nephrotoxicity, neutropenia, thrombocytopenia, and fever.

Monobactams e.g. aztreonam, nocardicin A

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 Questions 19c, 22c, 24c, 26c, 40c, 41c, 42c, 49c, 48c, 47b, 47c

 β-lactam compounds wherein the β-lactam ring is alone and not fused to another ring, in contrast to
most other β-lactams.
 They are effective only against aerobic Gram-negative bacteria (e.g., Neisseria, Pseudomonas).
 Adverse effects: skin rash and occasional abnormal liver functions.
 They have no cross-hypersensitivity reactions with penicillin but like penicillins can trigger seizures
in patients with history of seizures.

Carbapenem
Carbapenems are beta lactam antibiotic used for the treatment of infections known or suspected to be caused
by multidrug-resistant (MDR) bacteria.
They are very potent antibiotics for extremely broad spectrum and can resist many bata lactamases
Their use is primarily in people who are hospitalized.

What are MDR bacteria? Examples:

1. Vancomycin-Resistant Enterococci (VRE)

2. Methicillin-Resistant Staphylococcus aureus (MRSA) – but carbapenem does NOT have affect on
this organism
3. Extended-spectrum β-lactamase (ESBLs) producing Gram-negative bacteria
4. ESKAPE group (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae,
Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter species).

MOA: carbapenems kill bacteria by binding to penicillin-binding proteins and inhibiting cell wall synthesis
but they exhibit a broader spectrum of activity compared to cephalosporins and penicillins – they are less
likely to be affected by resistance.
Indications: abdominal infections, complicated UTI, pneumonia, bloodstream infections – for extremely
resistant nosocomial infections and sepsis
CI: allergic reactions
SE: anaphylaxis, seizures, clostridium difficille-related diarrhea
Drugs:
1. Imipenem – first clinically used, seizures in phase 2 trials and hydrolysed by kidney to a nephrotoxic
metabolite so a dehydropeptidase inhibitor is given with this IV - effective
2. Meropenem – stable, do not require inhibitor, but less potent than imipenem, effective for bacterial
meningitis, lower SE, more potent against gram –ve
3. Ertapenem – admin 1xday, but not effective against p. aeruginosa and acinetobacter
4. Doripenem – less likely to produce seizures

16
 Questions 19c, 22c, 24c, 26c, 40c, 41c, 42c, 49c, 48c, 47b, 47c

Antifungal drugs and local and systemic antifungal agents in clinical applications
Antifungal or anti-mycotic drugs are antimicrobials agents fungal organisms which prevent mycoses such as
athlete foot, ringworm or candidiasis
Can be used for local or systemic therapy
Topical or local antifungal drugs are used for superficial fungal infections on skin and mucous membranes
and if they are not cleared up by the topical drugs, systemic drugs are used
Systemic fungal drugs (oral or IV) are mainly used for invasive fungal infections such as:
 Invasive candidiasis
 Aspergillosis
 Cryptococcosis
Recent years have seen an increase in resistance

Classes:
1. Polyene antifungals e.g. amphotericin B, liposomal
amphotericin B
 Binding to ergosterol in fungal membrane
 This results in increased membrane permeability, leakage of cellular
components and cell death
 Amphotericin B is poorly absorbed when given orally therefore IV is
used

 Amphotericin B
A deoxycholate that is toxic but highly effective and broad
activity against fungal organism.
Indications; progressive, life threatening fungal infections
such as cryptococcosis, aspergillosis, histoplasmosis,
systemic candidiasis, blastomycosis and coccidioidomycosis
PK – administrated by slow IV over 2-6 hours and about 0.7mg/kg/day, can be combined with
fluorocytosine
SE – severe, kidney toxicity and anemia. Other include fever, chills, shakes, altered BP, irregular
HR, shock thrombophlebitis, nausea/vomiting

 Lipid-based amphotericin B – used to reduce the toxicity of amphotericin B which improves its
clinical effects.
This form is better tolerated and allow administration of higher dose of drug
SE is more milder and includes low blood potassium, elevated Cr, fever, vomiting, rash, headache
Disadvantage – higher priced.
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 Questions 19c, 22c, 24c, 26c, 40c, 41c, 42c, 49c, 48c, 47b, 47c

2. Azoles
 MOA: inhibit enzyme lanosterol 14 alpha demethylase which is needed to convert lanosterol to
ergosterol
 Depletion of ergosterol in fungal membrane disrupts structure and function of fungal membrane
leading to inhibition of fungal growth
 Less toxic than other fungal drugs and inhibits CY3PA4 – may lead to drug-drug interactions with
digoxin, statins, oral contraceptives and some antivirals
 3 groups:
 Imidazoles e.g. Ketoconazole
 Treat superficial fungal infections
 Metabolised by the liver and requires an acidic environment for good absorption
 Penetration into CSF is very low, and drug is not useful for treatment of fungal infections
of CNS
 Indicated for superficial candidiasis, tinea vesicolur, mycetoma
 SE – most frequent is nausea, vomiting, abdominal pain
 Triazoles e.g. Fluconazole, Itraconazole, Voriconazole
 Fluconazole is used to treat and prevent superficial and systemic fungal infections and
penetrates well into CSF
 Itraconazole – broader spectrum but require acidic gastric environment for good
absorption and penetration into CSF is poor and SE is well tolerated with common side
effects such as nausea, rash, drug-drug interactions
 Voriconazole – treat serious, highly invasive fungal infections
 Thiazoles e.g. Meloxicam

3. Allylamines e.g. Naftifine which acts to fight common fungus causing infections such as athletes foot,
jock itch, ringworm
It is a topical agent for treating tinea pedis, cruris, corporis
Naftifine has triple action: antifungal, antibacterial and anti-inflammatory.
Its precise mechanism of action is unknown, but may involve selectively blocking sterol biosynthesis via
inhibition of the squalene 2,3-epoxidase enzyme
The half-life is approximately 2–3 days. The metabolites are excreted in the urine and feces.

4. Echinocandins – new class of lipopetides with fungicidal activity against most species of candida spp.
And aspergillus spp.
MOA – block synthesis of glucan in fungal cell wall by inhibiting of enzyme 1, 3-beta glucan
synthase
Cryptococcus is resistant
These drugs are degraded in the liver and metabolites (without fungicidal activity) excreted in bile
and faeces
SE – dose adjustment needed in liver diseases, nausea, vomiting, diarrhea, fever and headache
Example of drugs – Caspofungin, Micafungin, Anidulafungin
Caspofungin – first one approved from practice, administered by IV and treats empirical therapy in
febrile neutropenia, candidiasis and aspergillosis (invasive) – the only one approved for children
Micafungin – used for treatment of invasive and esophageal candidiasis and as prophylaxis in those
undergoing HSC transplant

5. Fluorocytosine
Antimetabolic pyrimidine derivative
inhibits DNA synthesis in fungal cells
Administered oral, drug absorbed completely from GIT and penetrates readily into CSF

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 Questions 19c, 22c, 24c, 26c, 40c, 41c, 42c, 49c, 48c, 47b, 47c

Used as an adjunct to amphotericin B in therapy of serious cryptococcal infections in AIDS patients

SE – bone marrow suppression, rash, nausea, diarrhea, vomiting and liver damage

Antiviral drugs.
Antiviral drugs are used specifically for treatment of viral infections by inhibiting the viral replication at a
cellular level.

1. Antiviral agents for respiratory tract infections

 Prophylaxis and treatment for influenza type A – amantadine, rimantadine, zanamivir and
oseltamivir (latter two drugs for influenza type B)
− Neuraminidase inhibitor prevent release of virus from cells: oseltamivir and
zanamivir
− M2 protein inhibitors (adamantine) – inhibit a viral ion channel, which regulates
the pH, so the virus can enter the cell, inhibiting replication of influenza A
 Drugs are used to reduce the duration of fever systemic symptoms and to be effective it
must be given within 48 hours of symptoms onset.
 Adverse effects
− Amantadine - CNS difficulties, anti-cholinergic effect (dry mouth and urinary
retention)
− Zanamivir inhaled – bronchospasm
− Oseltamivir – produce GIT side effects
2. Antiviral agents for HSV
 Acyclovir – used for HSV and VZV for 5-7 days (IV or oral)
o MOA: acyclovir is activated by viral thymidinkinase to become an inhibitor of
viral DNA polymerase and blocks viral DNA synthesis
 CMV – does not produce thymidinkinase and it is resistant
o Side effects – infrequent and rarely severe (renal dysfunction, neurotoxicity)
o Can be given to pregnant woman and if patient has renal failure, dosage must be
adjusted
 Famciclovir and Valaciclovir (rapid absorption from GIT) or topical agents such as
idoxuridine for keratoconjunctivitis
3. Antiviral agents for CMV e.g. Ganciclovir and Foscarnet
 MOA: ganciclovir must be phosphorylated intracellularly to its active triphosphate form
to become an inhibitor of viral DNA polymerase
 Foscarnet – blocks viral DNA polymerase and stops DNA chain elongation (does not
require phosphorylation by viral or cellular enzymes to be active)
 Indications – infections by CMV especially if immunocompromised (e.g. HIV)
 SE: myelosuppression (neutropenia) – foscarnet is less well tolerated than ganciclovir.
Nephrotoxicity is most common with foscarnet, and Hematotoxicity
4. Antiviral agents for HBV and C
 Lamivudine – deoxycytidine analogue which is active against both HBV and HIV
because it inhibits both viral dNA polymerase and reverse transcriptase
o Toxicity is mild development of resistance
 Adefovir dipivoxil – is a nucleotide analogue
 Entecavir is a nucleoside analogue
5. Antiviral agents for HIV

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 Questions 19c, 22c, 24c, 26c, 40c, 41c, 42c, 49c, 48c, 47b, 47c

HIV is the human immunodeficiency virus.

It is the virus that can lead to acquired immune deficiency syndrome, or AIDS
There are 2 types of HIV:
HIV-1 and HIV-2.

20
 Questions 19c, 22c, 24c, 26c, 40c, 41c, 42c, 49c, 48c, 47b, 47c

Both types of HIV damage a person’s body by destroying specific blood cells, called CD4+ T cells, which
are crucial to helping the body fight diseases.

Within a few weeks of being infected with HIV, some people develop flu-like symptoms that last for a week
or two, but others have no symptoms at all. People living with HIV may appear and feel healthy for several
years.
HIV infection has four basic stages:
1. incubation period - The initial incubation period upon infection is asymptomatic and usually lasts
between two and four weeks.

2. The second stage, acute infection, lasts an average of 28 days and can include symptoms such as
fever, lymphadenopathy (swollen lymph nodes), pharyngitis (sore throat), rash, myalgia (muscle
pain), malaise, and mouth and esophageal sores.

3. The latency stage, which occurs third, shows few or no symptoms and can last anywhere from two
weeks to twenty years and beyond.

4. AIDS, the fourth and final stage of HIV infection shows as symptoms of various opportunistic
infections.

Main forms of transmission – sexual, blood and

mother-to-child

Treatment
3 classes of therapeutic agents are available:
1. Fusion inhibitors
2. Reverse transcriptase inhibitors (RTI), 3
subcategories:
 Nucleoside analogue (NRTI)
 Nucleotide analogue (NtRTI)
 Non-nucleoside inhibitors
(NNRTI)
3. Protease inhibitors (PI)

Goal of treatment of HIV

1. To achieve viral suppression and to maintain
it.
2. To restore and preserve immune functions
3. Improve a person´s quality of life

Baseline assessment- test the CD4+ count at

baseline
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 Questions 19c, 22c, 24c, 26c, 40c, 41c, 42c, 49c, 48c, 47b, 47c

Choice of initial treatment:

o First-line combination treatment for naive patient:
 2 NRTI + (NNRTI or PI od InSTI)
 NRTI and NtRTI
Special considerations:
1. Combinations to be avoided
2. Management of side effects and drug interactions
3. Treatment of specific patient populations: TB, VHB, VHC, pregnant women

ART (Anti-Retroviral therapy)

Combination of ART (cART) – require a minimum of 3 antiretroviral drugs
Involves:
 Maximal and durable suppression of viral load
 Restoring immunological function
 Improve quality of life
 Restore HIV-related morbidity and mortality
Note – drug cannot completely eradicate the virus from the body

Classes
ART inhibit one of the key viral enzymes required for HIV replication or block entry of HIV into target
cells.
1. Reverse transcriptase inhibitors
 NRTI – Lamivudin, Zidovudin, Azidothymidine – Inhibit replication of mitochondrial DNA
which cause a defect in respiratory chain function
 NtRTI – Tenofovir
 NNRTI – Nevirapin, Efavirenz, Etravirin
2. Protease Inhibitors – Saquinavir
3. Integrase inhibitor - Raltegravir
4. Fusion Inhibitor – Enfuvitide
5. CCR5 antagonist – Maraviroc

22