PHARMACOLOGY

ANTI-MYCOBACTERIAL AGENTS
Maria Cristina Maranion, M.D.|| February 14, 2020
• Mycobacteria are notorious for their ability to develop
resistance.
OUTLINE
o Among anti-TB agents, less common to develop
resistance is ethambutol
I. Introduction
A. Properties o Most notorious is isoniazid
B. Goals of Treatment
C. Basic Principles in Treatment
• Some forms (caseation necrosis and fibrosis) block the
blood vessel supplying the necrotic area, thus making
II. First Line Anti-TB Drugs penetration by the anti-TB drug difficult
A. Main Properties
B. Site of Action
C. Bactericidal Activites
D. First Line Drugs
B. GOALS OF TREATMENT
1. Isoniazid 1. Cure of the patient and restore quality of life and
2. Rifampicin
3. Ethambutol productivity
4. Pyrazinamide 2. Prevent death from active TB or its late effects
E. Drug Dosage
F. Latent TB Infection 3. Prevent relapse
G. Mechanism of Drug Resistance
4. Minimize the transmission to others
III. Second Line Anti-TB Drugs 5. Prevent development of drug resistance
A. Indications
B. Principles in Treating MDR-TB/XDR-TB
C. Groups of Drugs to Treat MDR-TB
D. Group 1 C. BASIC PRINCIPLES IN THE TREATMENT OF TB
1. Rifapentine and Rifabutin a. Treatment regimen must contain multiple drugs to
E. Group 2
1. Streptomycin which the organisms are susceptible
2. Amikacin and Kanamycin
3. Capreomycin
b. Drug administration must continue for a sufficient
F. Group 3 period of time (6 mos.) to fully eradicate the tubercle
1. Quinolones
G. Group 4 bacilli to achieve lasting cure
1. Ethionamide
2. Aminosalicylic Acid (PAS) / Para-aminosalicylic Acid
c. The goal is to provide the most effective therapy at
3. Cycloserine the shortest period of time to prevent the emergence
H. Group 5
1. Linezolid of drug resistance
2. Bedaquiline
d. Give the safest, most effective therapy during the
IV. Prevention and Control of TB prescribed duration
V. Drugs for Atypical Mycobacteria e. Never add a single drug to a failing regimen
A. Macrolides
B. Minocycline/Doxycycline
f. Ensure complete adherence to treatment
C. Co-Trimoxazole/TMP-SMX

VI. Anti-Leprosy Drugs I. FIRST LINE ANTI-TB DRUGS

Mycobacterium spp.
A. MAIN PROPERTIES OF FIRST LINE ANTI-TB DRUGS
Mycobacterium tuberculosis pulmonary and extrapulmonary
infections – most pertinent 1. Relatively well absorbed and diffuses readily into body fluids and
tissues
- 1M cases yearly (underestimate) 2. Ability to prevent or delay emergence of resistance
3. Has low toxicity
- infects 7 out of 10 Filipinos
4. has dual activity against the organisms
• Bactericidal- rapid killing of actively multiplying organisms
WHY IS TB INFECTION DIFFICULT TO TREAT? thus decrease in bacterial load (H> R> E> Z)
• Mycobacteria grows slowly and may remain dormant for • Sterilizing- ability to kill all remaining microorganisms with
long periods slow metabolism or those residing in the macrophages (R>
o They are relatively resistant to antibiotics that are Z> H> E)
most active against growing cells
• The lipid-rich mycobacterial cell wall (mycolic acid &
arabinosyl layer) is impermeable to most agents.
• A substantial portion of mycobacteria reside inside
macrophages.
o Adds another permeability barrier that the anti-TB
agent must cross
 Anti-mycobacterials

B. SITE OF ACTION OF THE FIRST LINE ANTI-TB DRUGS ▪ Low INH resistance, (+) cross resistance with
ethionamide
o kasA mutation
DRUGS Rapidly Slowly Slowly
o ahpC overexpression occur in 1 in 106 tubercle bacilli
growing growing growing
• CORNERSTONE OF TREATMENT
extracellular extracellular intracellular
organisms organisms organisms • Preparation: Oral (tablet or suspension)
(neutral pH) (neutral pH) (acid pH) • Metabolism: liver-acetylation by N-acetyltransferase (NAT2) to form
AcINH, INA
H ++ +/- + Metabolite: monoacetyl hydrazine (associated with hepatotoxicity)
R ++ + + • Rapid acetylators: more rapid clearance, usually of no therapeutic
Z 0 0 +++ consequence when appropriate doses are administered
E +/- 0 +/- • Absorption: readily absorbed from the gastrointestinal tract, optimally
on an empty stomach, decreased by up to 50% when taken with a
fatty meal
C. ANTI-TB DRUGS BACTERICIDAL ACTIVITIES • Distribution: all body fluids and tissues
• Concentration in CNS/CSF: 20%-100% of serum concentrations
Period I Period II Period III • Excretion: Urine within 24 hours
(4-8 weeks) (4-6 months) • Renal Adjustment: None
(1-3 days) • Pregnancy Risk: Category C
Fast growing Slower growing Persistent
extracellular extracellular and extracellular bacilli • Drug Interactions: Inhibits CyP450 enzymes
bacilli (H, R, E) intracellular bacilli (R (R and H) o Increase levels of Phenytoin, Carbamazepine,
and Z) benzodiazepines, theophylline
Concentration of Concentration of Continued o Antacids decrease level of INH
viable bacilli Viable bacilli decrease o Vitamin C inactivates INH suspension
decreases by decreased by >99%
>90% INH
Intensive phase: 2 months HRZE MAINTENANCE Hypoglycemics Monitor glucose, may INCREASE BG
PHASE: APAP INCREASE Hepatotoxicity
4 months of HR Anticoagulants INCREASE anticoagulant effect
Benzodiazepines INCREASE toxicity

D. FIRST LINE ANTI-TB DRUGS Anti-epileptics INCREASE toxicity of carbamazepine and

phenytoin
Isoniazid Disulfiram Psychotic episodes
(Antabuse)
Haloperidol INCREASE toxicity antipsychotics
- most active drug for the treatment of tuberculosis caused by Ketoconazole DECREASE efficacy of ketoconazole
susceptible strains Dilantin INCREASE toxicity antiepileptic
- small molecule (MW 137) that is water-soluble Theophylline INCREASE toxicity theophylline: monitor levels
- similar structure to pyridoxine
- bactericidal for actively growing tubercle bacilli Valproate INCREASE Hepatic and CNS toxicity
- less effective against nontuberculous mycobacteria
- penetrates into macrophages • Dose: 5-15mg/kg/day
- active against both extracellular and intracellular
▪ Usual dose: 5mg/kg/day
• MOA: inhibit synthesis of mycolic acids, Isoniazid is a prodrug that is
activated by KatG, mycobacterial catalase-peroxidase. Activated form ▪ Malabsorption: 10mg/kg/day
forms covalent complex with acyl carrier protein (AcpM) and KasA, a ▪ If 2-3x weekly dosing: 15mg/kg/dose
beta-keto-acyl carrier proetin synthetase which blocks mycolic acid
synthesis • Adverse Effects
• Site of Action: extracellular > intracellular organisms ▪ CNS 2%
• Effect on MTb: bactericidal and sterilizing • Peripheral neuropathy (due to relative pyridoxine
• Mechanisms of resistance to Isoniazid deficiency; there is rapid excretion of pyridoxine in the
o katG gene mutation or deletion presence of INH)
▪ High INH resistance. No cross resistance with • Seizures
ethionamide
• Psychosis, Ataxia, Memory Loss
o inhA overexpression

2 ALEXANDER, M; BOBIER, L; AQUINO, M.; ALEA, E

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• Rx: Prophylactic Pyridoxine for patients at risk Oral hypoglycemic

(Malnutrition, Alcoholism, DM, AIDS, Uremia, • Chloramphenicol/ Clarithromycin
pregnant) • Protease inhibitors/ NNRTI
o Prophylaxis: 10-25mg/day or 25-50,g/day • Quinidine/ tocainide/ Digoxin/ Metoprolol/ Propanolol/ Ca-channel
o Treatment: 100mg/day blockers
• Liver • Anticonvulsants/ Theophylline
• Minor: Asymptomatic elevation of ALT (12-15%) • Cyclosporine
• Major: Hepatitis (1-2.7%) risk increases with age, • Ketoconazole, fluconazole, itraconazole
alcoholics and patients with coexisting liver disease
Rifampicin
• Immunologic Reactions (2%)
• Allergic rash DECREASE efficacy of antidiabetics, RIF also
Hypoglycemic
• ANA (+) on long term use (20% of patients) (sulfonylureas)
INCREASES intestinal glucose absorption and monitor
• Fever glucose
DECREASE
• Hemolysis in G6PD deficiency DECREASE
Anticoagulants Anticoagulant Diltiazem
Diltiazem effect
• Others effect
• Anemia, Tinnitus, GI discomfort DECREASE DECREASE
Antidepressants antidepressant Fluconazole fluconazole
effect effect
Rifampicin DECREASE
DECREASE
Beta-blockers Itraconazole itraconazole
beta blockade
effect
• semisynthetic derivative of rifamycin DECREASE
DECREASE
• most potent sterilizing drug available Contraceptives Haloperidol haloperidol
OCP effect
• active in vitro against Gram -positive organisms, Gram-negative effect
DECREASE
organisms (Neisseria, Haemophilus, Mycobacteria, Chlamydiae) DECREASE
Corticosteroids Methadone methadone
• No cross resistance to other classes of antimicrobial drugs, but steroid effect
effect
with cross -resistance to other rifamycin derivatives (e.g. rifabutin, DECREASE DECREASE
rifapentine) Cyclosporine CsA effect, Phenytoin phenytoin
• MOA: inhibits RNA polymerase binds to B subunit of bacterial INCREASE RIF effect
DNA-dependent RNA polymerase thus inhibiting RNA synthesis DECREASE Pi DECREASE
Protease
• Site of action: Extracellular > Intracellular effect, Verapamil verapamil
inhibitors
INCREASE RIF effect
• Effect on MTb: Bactericidal >> Sterilizing
DECREASE DECREASE
• Resistance: Delavirdine
effect DLV
Tetracyclines
TCNs effect
o Point mutations in rpoB gene for the B subunit of the Slightly
RNA polymerase DECREASE Possible RIF
o Occurs in 1 in 107 -108 tubercle bacilli Efavirenz TMP-SMX
effect EFV, toxicity
• Drug Interactions: Strong inducer of cytP450 DECREASE RIF
o DECREASE levels of methadone, anticoagulants, DECREASE DIG DECREASE
cyclosprone*, anticonvulsants, protease inhibitors*, Digoxin Chloramphenicol chloramphenicol
levels effect
NNRTI, contraceptives, CaCB, B blockers, ACEI,
paracetamol, diclofenac
• Dose: 10mg/kg/day
Adverse effects:
• Absorption: Complete oral absorption in fasting state; less with • Discoloration of body fluids (100%) due to its high
food and antacids; first pass metabolism lipophilicity which makes it bind to plasma proteins and
• Excretion: 30% excreted in urine and 60-65% in feces distributes to body tissues and fluids
• Other indications: • Rashes, pruritus, drug fever (6%)
o Prophylaxis for Meningococcal disease and H. • Flu like syndrome (6%)
Influenzae meningitis o (fever, chills, myalgias, anemia,
o Elimination of nasopharyngeal carrier state of N. thrombocytopenia) associated with intermittent
meningitidis and Staphylococcus
rather than daily therapy
o Treatment of serious staphylococcal infections
(osteomyelitis and prosthetic valve endocarditis) • Liver (1-2.7%)
o Cholestatic jaundice
DRUG-DRUG INTERACTIONS o Hepatitis
DME Inducer (decrease effects of the following): • Kidneys (1%)
• Anticoagulants/ Corticosteroids/Oral contraceptives/ Methadone/ o Light Chain proteinuria
3 ALEXANDER, M; BOBIER, L; AQUINO, M.; ALEA, E
 Anti-mycobacterials

o Nephritis • GIT Symptoms

o Acute tubular necrosis • Hyperuricemia due to decreased urate excretion
• Hypersensitivity: dermatitis, arthralgia, fever
Ethambutol o Contraindication: in children too young to permit
assessment of visual acuity and red-green color
• synthetic, water-soluble, heat stable compound discrimination
• dispensed as dihydrochloride salt
• used in combination with H, R, Z during initial intensive phase of Pyrazinamide
active tuberculosis treatment
• also used in combination with other agents for the treatment of • relative of nicotinamide, used ONLY for the treatment of
nontuberculous mycobacterial infections, such as MAC or M. tuberculosis
kansasii (15mg/kg once daily)
• stable and slightly soluble in water
• MOA: inhibits arabinosyl transferase which are encoded by
• inactive at neutral pH, at pH 5.5 it inhibits tubercle bacilli at
embCAB operon, inhibits polymerization reaction of
concentrations of approximately 20mcg/mL
arabinoglycan, an essential component of mycobacterial cell wall
• MOA: converted to pyrazinoic acid (active form of the drug) by
• Site of Action: extracellular (rapid growing only) and intracellular
mycobacterial pyrazinamidase which disrupts mycobacterial
• Effect on MTb: bactericidal and bacteriostatic cell membrane metabolism and transport functions
• Resistance: • MOA: disrupts cell membrane metabolism and transport functions
1. Overexpression of emb gene products
• Site of Action: intracellular only
2. embB structural gene mutation
• Effect on MTb: Sterilizing
• Preparation: oral (tablet, suspension)
• Resistance:
• Absorption: well absorbed from the gut
1. Mutation on pncA gene (impaired conversion to POA
• Distribution: crosses BBB only when inflamed, concentrations in which is the active form)
CSF are highly variable (4-64% of serum levels) - a higher dose 2. Impaired uptake of Z
can be used for treatment of tuberculous meningitis
• Preparation: Oral (tablet, suspension)
• Metabolism: liver SYP
• Metabolism: liver- hydrolyze into pyrazinoic acid then
• Excretion: Urine (unchanged) > Feces hydroxylated to 5-hydroxypyrazinoic acid by xanthine oxidase
• Renal dose adjustment: Yes (which explains the hyperuricemia)
• Pregnancy Risk category B • Excretion: urine (70%)
• Drug interactions: • Renal Adjustment: yes
o DECREASE absorption if taken with AlOH • Pregnancy Risk Category C
o ? Thiazide diuretics
• Drug interactions:
o DECREASE Immunologic response to vaccines: BCG,
o INCREASE levels of warfarin, abacavir
Cholera, Typhoid
o DECREASE levels of Z: acetazolamide
o DECREASE Theophylline
o INCREASE levels of Z: aceclofenac, acarbose,
• Dose: 15-25mg/kg/day acetaminophen
o Bacteriostatic: 15mg/kg/day
• Dose: 25mg/kg/day
o Bactericidal: 25mg/kg/day
• Adverse effects:
• Other indications:
o Hyperuricemia (40%)
o Atypical mycobacterial disease (MAC, M, Kansai)
o Hepatotoxic (10%)
▪ ***SHOULD NOT BE REINTRODUCED
o Nausea, vomiting, anorexia
• Adverse effects:
o Flushing; cutaneous hypersensitivity
• Retrobulbar neuritis (1-5%) dose related, duration related,
permanent and irreversible - resulting in loss of visual acuity
and red-green color blindness (25 mg/kg/d)
• ***REQUIRE VISUAL ACUITY, COLOR DISCRIMINATION
AND PERIMETRY STUDIES PRIOR TO INITIATION

4 ALEXANDER, M; BOBIER, L; AQUINO, M.; ALEA, E

 Anti-mycobacterials

E. DRUG DOSAGE PER KG BODY WEIGHT II. SECOND LINE ANTI-TB DRUGS

Drug A. INDICATIONS FOR SECOND LINE ANTI-TB DRUGS

Katzung Guidelines
Adults Adults Children
4-6mg/kg 10-15mg/kg 1. Resistance to first-line anti-TB drugs is suspected or
Isoniazid (H) 5mg/kg Not toexceed Not toexceed confirmed
300,g/day 300mg/day 2. When severe adverse effects to first-line drugs develop
8-12mg/kg 10-20mg/kg 3. Failure of clinical response to first-line drugs
Rifampicin (R) 10mg/kg Not toexceed Not toexceed 4. Used when expert guidance is available to deal with the toxic
600mg/day 600mg/day effects
20-30mg/kg 20-40mg/kg
Pyrazinamide (Z) 25mg/kg Not toexceed Not toexceed
2g/day 2g/day B. PRINCIPLES IN TREATING MDR-TB/XDR-TB
15-20mg/kg 15-25mg/kg
15-
Ethambutol (E)
25mg/kg
Not toexceed Not toexceed MDR TB- Multidrug resistant TB: is a form of tuberculosis (TB) infection
1.6g/day 1.2g/day
caused by bacteria that are resistant to treatment with at least two of
the most powerful first-line anti-TB medications (drugs), isoniazid and
rifampin.
F. LATENT TB INFECTION XDR-TB- Extensively drug-resistant TB: is a rare type of multidrug-
resistant tuberculosis (MDR TB) that is resistant to isoniazid and
Screen: rifampin, plus any fluoroquinolone and at least one of three injectable
▪ HIV (pregnant or non-pregnant) second-line drugs (i.e., amikacin, kanamycin, or capreomycin). {CDC}
▪ Solid organ and hematopoietic stem cell transplant, RA
• Use first line agents showing susceptibility
patients on biological, CKD, pregnant with exposure , drug
• Include an injectable agent, fluoroquinolone
users, chronic steroids -Optional: 2nd line bacteriostatic agents
▪ DM poorly controlled, pregnant Group 5 agents
Prophylaxis • Treat for 2 years
-Intensive phase: 6 months
▪ HIV: patients and household contacts -Maintenance phase: 12-18 months
▪ Patients to start anti-TNF treatment
▪ CKD patients on HD or preparing for transplant C. GROUPS OF DRUGS TO TREAT MDR-TB
Regimen:
▪ Isoniazid monotherapy for 6 months – adults Group Example
▪ Isoniazid + Rifampicin for 3 months – age < 15 1 Rifapentine, Rifabutin
2 Streptomycin, Kanamycin or Amikacin, Capreomycin
G. MECHANISM OF DRUG RESISTANCE (Class of Aminoglycoside except Capreomycin)
(INJECTABLES)
Primary (initial) 3 Levofloxacin, Moxifloxacin, Ciprofloxacin
• The presence of resistant strains of MTb in a patient who, in (Class of Fluoroquinolones)
response to direct questioning denies having had anti-TB 4 Ethionamide, PAS, Terizidone, Cycloserine
treatment for more than a month 5 • Clofazimine, Linezolid, Bedaquiline
• Amoxicillin/clavulanate, Thioacetazone
• Spontaneous mutations in bacterial chromosomes • Imipenem/cilastatin, High dose isoniazid,
Clarithromycin
Secondary (acquired) Group 5 not 100% proven, not all are given
• Exists among patients diagnosed with TB and started on anti-TB
treatment whose bacilli then developed drug resistance to one or
more of the drugs used during the treatment.

*See appendix for complete adverse reactions, treatment

modification and recommended treatment regimen for adults and
children.

5 ALEXANDER, M; BOBIER, L; AQUINO, M.; ALEA, E

 Anti-mycobacterials

D. GROUP 1 o Loop diuretics will increase aminoglycoside

concentration within the nephron
Rifapentine and Rifabutin • Dose: 15 mg/kg/day (adults) 20-40 mg/kg/day (children)
• Therapeutic Uses:
• Profile is similar to rifampicin • used in conjunction with H, R, Z in life threatening forms of
• Cross-resistance to rifampicin TB o Replaces E in children <6 y/o (problems with cartilage
• CYP50 interaction formation) o TB meningitis since it crosses BBB & achieve
• Rifabutin: less potent inducer *Drug of choice for HIV therapeutic concentration in the CSF o Disseminated TB
patients on ART (Antiretroviral therapy)
• MDR-TB susceptible to streptomycin
• Rifapentine: more potent inducer
• Also has activity against MAC and also approved for Latent • Other indications: TB meningitis, replaces Ethambutol in
TB
children below 6 years old, enterococcal endocarditis
• Pregnancy risk category C (similar to Rifampicin) • Adverse effects:
• Dose o Ototoxicity: Vestibular dysfunction
o Rifabutin: 300 mg/day ***MANDATORY AUDIOGRAM
o Rifapentine: 600 mg once or twice weekly Manifestation of vestibular toxicity: tinnitus, loss of
• Rifapentine has longer half-life, permits weekly dosing balance, vertigo, dizziness
(good for compliance) o Nephrotoxicity
• Side effects: o Hypersensitivity: fever, skin rashes
o Leukopenia, Thrombocytopenia o Pain at injection site
o Rash and sin discoloration o Paresthesia, peripheral neuropathy
o Anterior uveitis
o Arthralgia
o Hepatotoxicity Kanamycin and Amikacin

E. GROUP 2 • Similar to Streptomycin (since they are also

aminoglycosides)
• NO CROSS RESISTANCE with Streptomycin
Streptomycin • Prevalence of Resistance
o Amikacin: LOW
o Kanamycin: HIGH
Thus Amikacin is preferred over Kanamycin when resistance to
Streptomycin occurs
• Excretion:
o Kanamycin: FECES
o Amikacin: URINE
• Dose: 10-15 mg/kg/day (Amikacin)
• MOA: Aminoglycoside: binds to 30S ribosomal subunit (16S 15 mg/kg/day (Kanamycin)
and S12) causing conformational change inhibiting protein • Ototoxic auditory dysfunction
synthesis Auditory manifestation: Mahina ang pagdinig, nabibingi
• Site of action: Extracellular
• Effect on M. TB: Bactericidal *Cavitary (also like Isoniazid) Capreomycin
• Resistance:
1. rpsL gene mutation (encodes for S12)
• MOA: Not an aminoglycoside, it is a peptide protein
2. rrs gene mutation (encodes for 16S)
synthesis inhibitor, binds to 70S ribosome(combination of
• Preparation: IM, IV
50S and 30S ribosomes)
• Absorption: Not absorbed from GIT (thus injectable) • Excretion: urine
• Metabolism: No metabolites
• Questionable cross-resistance to amikacin and kanamycin
• Excretion: Kidneys>milk (Unchanged): Do not Give
• Resistance to capreomycin: rrs, eis, tylA mutations
Streptomycin to Breastfeeding mothers (NICE TO KNOW)
• Renal adjustment: YES (due to nephrotoxicity; adjust based • Dose: 15 mg/kg/day IM
on GFR)
• Pregnancy category C
• Pregnancy risk category D
• Adverse effects:
• Drug interactions: o Nephrotoxic
o Synergistic with other ototoxic or nephrotoxic drugs
o Ototoxic: auditory and vestibular dysfunction
o Neuromuscular blocking agents
o Local pain, sterile abscess (on injection site)

6 ALEXANDER, M; BOBIER, L; AQUINO, M.; ALEA, E

 Anti-mycobacterials

F. GROUP 3 o QTc prolongation (Elderly)

G. GROUP 4
Quinolones

Ethionamide

• MOA: mycolic acid synthesis inhibitor (similar to isoniazid)

• MOA: DNA gyrase (topoisomerase II) and topoisomerase IV

inhibitor
• Structure: Quinolones vary according to what is on Carbon
6 (Fluorine), 7, 8; modified structures increase potency
Respiratory quinolones: Moxifloxacin, Gemifloxacin,
Levofloxacin
• Activity:
o Against MTb: • Resistance:
Moxifloxacin>Levofloxacin>Ofloxacin o Kat G mutation: remains active
o Against Atypcial Mycobacteria: Levofloxacin > o inhA mutation: becomes inactive
Moxifloxacin • Absorption: complete absorption, F 100%
o Against Gram positive: Moxifloxacin>Levofloxacin • Metabolism; liver metabolizes it to ethionamide sulfoxide
REMEMBER: • Excretion: Urine
Mycobacteria:Moxifloxacin • Drug interaction:
AtypicaL: Levofloxacin o Ethanol: psychoses
• Resistance: mutation in gyrase A subunit • Adverse effects:
• Resistance to one fluoroquinolone indicates class resistance o Gastric irritation
• Use have the potential to shorten treatment of Drug o Neurologic symptoms: Alleviated by
Resistant TB PYRIDOXINE
• DO NOT USE AS PROPHYLAXIS FOR OTHER o Hepatotoxicity
INFECTIONS IN PATIENTS WITH TB (it is a reserve drug)
• Well-absorbed except when in the presence of cationic Aminosalicylic Acid (PAS); Para-aminosalicylic acid
molecules e.g. calcium, magnesium, aluminum
• High volume of distribution: urine, kidney, lung, prostate,
stool, macrophages
• Other indications: UTI, prostatitis, STD, GIT infections,
bone/joint and soft tissue infections
o Prophylaxis for anthrax, tularemia
• Drug interactions: Form complexes with divalent and
trivalent cations
o Inhibits metabolism of theophylline
• Novel Quinolones: NICE TO KNOW • MOA: folate synthesis antagonist: Bacteriostatic
o Avarofloxacin • Structure: Similar to PABA (base of sulfonamides)
o Delafoxacin • Dosage:
o Finafloxacin 8-12 g/day for adults
o Zabofloxacin 300 mg/kg/day for children
o Nemonofloxacin • Widely distributed except in CSF (not for TB meningitis)
• Side effects: • Excretion: Urine
o Cartilage and joint toxicity (Pediatrics) • Side effects: GIT ulcers and hemorrhage
o Nausea
o Abdominal pain Cycloserine
o Restlessness, confusion, hallucinations, delirium
(Very Elderly)
o Headache, dizziness • MOA: inhibits cell wall synthesis
o Arthralgia, and joint pain • Structural analog of Alanine

7 ALEXANDER, M; BOBIER, L; AQUINO, M.; ALEA, E

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• Widely distributed including CSF o Headache

• Crosses placenta o Hepatotoxicity*
• Excretion: Renal o Cardiac toxicity*- QTc prolongation
• Dose: 0.5-1 g/day • Use in caution when co-administered with clofazimine and
• Drug interaction: ING and Thionamide fluoroquinolone
• Side effects: • Should not be used with rifampin and rifapentine (increases
o Seizure mortality)
o Peripheral neuropathy
o Depression
o Psychoses

REMEMBER: Drugs causing Peripheral Neuropathy include

Cycloserine, Isoniazid, Ethionamide

H. GROUP 5

Linezolid

• MOA: protein synthesis inhibitor

- Bacteriostatic agents Enterococci and Staphylococci
- Bactericidal against Streptococci
• Absorption: Well absorbed especially in bronchoalveolar
tissues
• Metabolism: Liver
• Excretion: Urine>feces (filtered in kidney, so in dialysis
patients it will be removed: SO give AFTER dialysis)
• Dosage: 600 mg OD or 400 mg BID
Ethionamide: affects mycolic acid
• Synergistic with Bedaquiline (latest drug)
Cyloserine, Linezolid: affects Peptidoglycan
• Adverse effects:
o Bone marrow suppression (Reversible: affects REVIEW!!
platelets the most causing thrombocytopenia) DOC for HIV: Rifabutin
o Irreversible peripheral and optic neuropathy Drug that causes vestibular ototoxicity: Streptomycin
Prophylactic drug used Pyridoxine Drug that cause auditory toxicity: Kanamycin, Amikacin
• Drug interactions: Serotonergic agents e.g Quinolone against Mycobacteria: Moxifloxacin
antipsychotics (MAO, SSRI, SNRI, etc.) causing Quinolone against Atypical: Levofloxacin
SEROTONIN SYNDROME (manifestation:
hyperreflexia, myoclonus, confusion, heavy sweating, III. PREVENTION AND CONTROL OF TB
more on CNS)
• Used in MDRTB and XDRTB • Prompt detection of cases and provision of short course
• Contact investigation and follow up (Also for the relatives,
close contacts)
Bedaquiline • Preventive therapy for LTBI (Latent TB Infection)
- HIV, receiving anti-TNF, CKD on hemodialysis
• NEW DRUG • Immunization (most benefited: pediatric population)
• MOA: inhibits ATP synthase in mycobacteria BCG (Bacille-Calmette-Guerin)
• Targets both actively replicating and nonreplicating bacilli o protects against severe forms of TB in
• Cross resistance with clofazimine (clofazimine used in children (TB meningitis and miliary TB)
leprosy) o variable efficacy in preventing PTB in adults
o Efflux pump: MmpL5 • Improvement of socio-economic condition
• Absorption: Increased with High-fat food o Ventilation and nutrition
• Metabolism: CYP450 (esp CYP3A4)
• Excretion: Feces IV. DRUGS FOR ATYPCIAL MYCOBACTERIA
• Dose: 400 mg OD for 2 weeks then tapered based on body
weight
• Adverse effects:
o Nausea
o Arthralgia
8 ALEXANDER, M; BOBIER, L; AQUINO, M.; ALEA, E
 Anti-mycobacterials

Clinical implication: When patient presents with skin and soft

tissue infection, penicillin and clindamycin resistant S.
aureus upon culture, DO NOT PRESCRIBE MACROLIDES
• Absorption: Clarithromycin>Azithromycin>Erythromycin
o Most potent: Clarithromycin
o Has high drug concentrations within cells:
Azithromycin
• Metabolism: Liver (Clarithromycin), Bile (azithromycin)
o Nonlinear pharmacokinetics thus longer half lives
in high doses
• Excretion: Urine
• Poor in vitro activity against M. tuberculosis but has better
activity against M. avium and M. kansasii (Two most
common atypical mycobacterial infection in
immunocompromised host)
• Synergistic effect with INH/RIF/ETH against M. tuberculosis
• Drug interaction:
o Inhibits CYP 3A4 and P-glycoprotein
o Contraindicated: cisapride, pimozide,
terfenadine RESULTS TO QTc prolongation,
ventricular tachycardia, ventricular fibrillation,
Torsades de pointes
o Increased toxic effects of carbamazepine,
corticosteroids, cyclosporine, digoxin, ergot
alkaloids, theophylline, warfarin (in general, most
likely affected are the drugs of the heart)
• Adverse effects:
o GI disturbances
o QTC prolongation with ventricular tachycardia
o Hepatotoxicity (cholestasis)
o Hypoglycemia

B. MINOCYCLINE/DOXYCLYCLINE

MOST COMMON THERAPY:
Clarithromycin + Ethambutol + Rifabutin/Rifampin or Minocycline
A. MACROLIDES
• Original: Erythromycin
- Clarithromycin: methylation of OH group at position 6
(broadest spectrum, most potent)
- Azithromycin: addition of a methyl-substituted Nitrogen
atom into the lactone ring
• MOA: 50S protein synthesis inhibitor
• Bacteriostatic agents
• Drug resistance: (NICE TO KNOW)
o Drug efflux by an active pump mechanism
o Production of methylase enzyme: Decrease drug
binding
o Macrolide hydrolysis by esterase produced by
Enterobacteriaceae
o Mutations in 50S ribosomal protein***
• Cross resistance among penicillin resistant S. pneumonia
and Clindamycin resistant S. aureus
• MOA: Tetracycline: Binds to 30S subunit resulting to protein
synthesis inhibitor
• Bacteriostatic
• Absorption: well absorbed (IV=oral)
o Decreased by cations, antacids
Immunocompromised give IV, then if stable oral
dosage form
• Metabolism: liver
• Excretion: Urine and bile
• Pregnancy Risk D
• Other indications: STDs, anthrax, respiratory tract infections
(just like quinolones)
• AE: GIT, Vestibular dysfunction
C. CO-TRIMOXAZOLE/TMP-SMX
• MOA: folic acid inhibitor
• Sulfonamide and trimethoprim are synergistic: Dual step
• Resistance: transfer of resistance by plasmids (point
mutation)
o Lower affinity of dihydropteroate synthase for
sulphonamides

9 ALEXANDER, M; BOBIER, L; AQUINO, M.; ALEA, E

 Anti-mycobacterials

o Decreased bacterial permeability or active efflux of Pregnancy C

the drug Risk
o Alternative metabolic pathway for synthesis of an Other MAC, multibacillary leprosy, erythema nodosum
essential metabolite indications leprosum due to dapsone
o Increased production of an essential metabolite or
drug antagonist DAPSONE
• Rapidly absorbed from GIT (intestine)
Mode of action Inhibits folate synthesis (bacteriostatic)
o Readily enters CSF, sputum, pleural fluid,
Competitive inhibitor of dihydropteroate
peritoneal fluid, synovial fluid, ocular area
synthesis inhibiting folate synthesis
o Pass readily the placenta
Absorption Slow but complete
• Metabolism: Liver (Metabolite: N4-acteylated sulphonamide:
*Retained in skin, muscles, liver and kidneys
causing the adverse reaction)
• Excretion: Urine (seen within 30 minutes) Metabolism Liver
• Dose: 400 mg sulphonamide/80 mg trimethoprim or 800 Excretion Bile (reabsorbed in the intestine) and urine
mg/1600 mg ratio
• Indications: UTI, Acute bronchitis, Traveller’s diarrhea Dose 100 mg/day adult
(alternative to quinolone), MRSA Adverse Effects Hemolysis (dose related),
o PCP pneumonia prophylaxis and treatment (give Methemoglobinemia, GI intolerance, fever,
highest dose), M. kansasii, M. marinum, M. pruritis, rash, erythema nodosum leprosum
fortuitum after initial dapsone therapy
• Adverse reactions: hypersensitivity in the form of rashes,
crystalluria, hemolytic anemia, GIT disturbances Contraindication Hypersensitivity to dapsone or any
• Drug interactions: warfarin, hypoglycemic agents, component
anticonvulsants Pregnancy Risk C
REMEMBER: Other indications Dermatitis herpetiformis, PCP pneumonia,
“If with Atypical Mycobacteria infections e.g. MAC, automatic there is all forms of leprosy
PCP”

IV. ANTI-LEPROSY DRUGS References: Lecture Notes 2020

Transcribed by: Alexander, Maureen Theresa S.
Bobier, Lourdes
• Combination Therapy: Dapsone+Rifampin+Clofazimine Edited by: Aquino, Michael.
Checked by: Alea, P
Paucibacillary Multibacillary
Rifampin 600 mg once a month 600 mg once a month
Dapsone 100 mg OD 100 mg OD
300 mg once a month
Clofazimine NONE
or 50 mg daily
Duration 6 months 12-24 months

CLOFAZIMINE
Mode of action Binds to mycobacterial DNA; exerts anti-
inflammatory effect
Absorption Variable, lipophilic
*stored in RET and skin
*Increased by food
Metabolism Liver
Excretion Feces
Dose 100-200 mg/day adult
Adverse Discoloration of skin (pink to brownish black) and
Effects conjunctivae (Just like rifampicin), GI symptoms,
infertility (questionable), crosses placenta and
excreted in breast milk

10 ALEXANDER, M; BOBIER, L; AQUINO, M.; ALEA, E

 PHARMACOLOGY
ANTI-FUNGAL AGENTS
Dr. Ma. Cristina A. Maranion || February 21, 2020

OUTLINE I. POLYENE ANTIBIOTICS

• MoA of Polyenes: binds to ergosterol creating pores causing
increased cell permeability and loss of cellular contents
– Low selectivity: cholesterol present in host cell membrane
resembles ergosterol and binds to it as well

A. AMPHOTERICIN B (AMB)
• Heptaene macrolide produced by Streptomyces nodosus
• Amphoteric: presence of carboxyl group on the main ring and a
primary amino group on mycosamine
• Effect: Fungicidal
• Limited by its toxicity
• Pharmacokinetics:
– primarily IV use
– poor meningeal penetration (CNS side effects due to
intrathecal injection)
– Excretion: urine (slow)>>>bile
– Route of elimination: Hepatic
– Renal dose adjustment: None
• Resistance: Ergosterol binding impairment; mutation at genes:
– ERG2 or ERG11 (most common)
– Others: ERG3, ERG5, ERG6
• DOC/Therapeutic use: Broadest spectrum of activity
– all life-threatening mycotic infections
– Invasive mucormycosis
– Cryptococcal meningitis (with Flucytosine)
– Specific for: Aspergillus fumigatus
• Adverse Effects:
– Infusion-Related (Acute) Toxicity
▪ Shake and Bake Syndrome- fever, chills, & muscle
spasms
▪ vomiting, headache, hypotension (rare), dyspnea
▪ Treatment: slow infusion or reduce daily dose
– Cumulative (Long-Term) toxicity
▪ Nephrotoxicity- severe K and Mg wasting due to
vasoconstrictive effects or renal and tubular injury
▪ Anemia- due to decreased erythropoietin production
▪ Azotemia- rising BUN and Creatinine
▪ CNS toxicity- occurs only on intrathecal injection
• Drug Interactions:
– Synergistic: Flucytosine
– Antagonistic: Triazoles
– Increase risk of nephrotoxicity: Vancomycin,
Aminoglycosides, Foscarnet, Pentamidine
– Potentiated by: Rifampicin and Minocycline
• New Formulations:
– produce milder acute reactions on IV infusion
– much lower nephrotoxicity and minimal anemia
– same efficacy as conventional AMB
– very expensive
▪ Lipid Complex (ABLC): 35% AMB + dimyristoyl
phospholipids
▪ Colloidal Dispersion (ABCD): 50% AMB + cholesteryl
sulfate
▪ Liposomal AMB: 10% AMB + lecithin and phospholipids
(stays in liver and spleen longer)
Fungal Cell Wall
• Contains Beta Glucans and Chitin
• Ergosterol- similar to cholesterol but contains double bond at
lactone ring and has a longer side chain.
 Anti-Fungal Agents
B. NYSTATIN – crosses the placenta
• polyene macrolide – teratogenic to rats
• isolated from Streptomyces noursei – Exception: Fluconazole, Ketoconazole, Voriconazole
• Effect: Fungistatic and Fungicidal (Category D)
• Pharmacokinetics: extremely toxic for systemic use (topical use
only- oral suspensions, creams, ointments, and suppositories) Imidazole Triazole
• Therapeutic use: Candida sp. Selectivity to ergosterol ↓ ↑
– oropharyngeal thrush, vaginal candidiasis, anal
candidiasis, cutaneous ans intestinal candidiasis Side effects ↑ ↓
– swish and spit AND swish and swallow Aspergillus ↓ ↑
• No adverse effects
• Drug interactions: decreases elimination of endothelin receptor
antagonists, statins, caspofungin, ACE/ARBS, and valsartan

II. AZOLES

Imidazoles Triazoles (“Tri” = 3 N atoms)

(“Imi” = 2 Nitrogen Rings)
Keto = used systemically
Mico & clotri = used locally
All are used systemically
• High H2O solubility = Fluconazole, Voriconazole, Isavuconazole
• Good Absorption = Fluconazole, Voriconazole, Isavuconazole,
Posaconazole
• CSF penetration = Fluconazole, Voriconazole
• Longest Half-life = Isavuconazole (newest drug)

A. IMIDAZOLES

1. KETOCONAZOLE
• Systemically given
• Pharmacokinetics
– Absorption: Good to variable
▪ requires an acidic environment therefore give during
• ALL azoles have the SAME MOA fasting state
– Inhibition of fungal CytP450 enzyme lanosterol 14- – High plasma protein binding (84%)
demethylase (aka 14-∝-sterol demethylase) thus leading ▪ DOES NOT CROSS CSF (whether inflamed or not)
to decreased ergosterol synthesis – Excretion: bile
▪ this enzyme converts lanosterol to ergosterol – Dosage: 400mg/day
▪ therefore if inhibited, ergosterol will not be incorporated • Indication:
to the cell membrane – Mucocutaneous infections (dermatophytes, yeast
• Selectivity to Ergosterol: Triazoles > Imidazoles infection)
– therefore there is less drug interactions because it would bind ▪ Dermatophytes are usually localized skin infections, if
more to fungal CYP450 and bind less to mammalian CYP450 hindi kaya ng ointment or cream d/t high body surface
– Ketoconazole = Mammalian > fungal area that needs to be covered, give Keto orally
• Effect: Fungistatic – Systemic mycoses (seborrheic dermatitis)
• Resistance: ERG11 mutation or overexpession • Drug interactions
• Broad spectrum of activity but no Aspergillus coverage – CYP 3A4 Inhibitor
– EXCEPT Itraconazole, Posaconazole, Voriconazole, – pinakamadami among azoles because it is not selective to
Isavuconazole (has Aspergillus coverage) ergosterol
• Has additional coverage against Leishmania – Decrease fungicidal effects of Amphotericin B
• Adverse Effects: Gastrointestinal – Torsades de Pointes: if given with terfenadine, astemizole,
– GI upset, Nausea, Vomiting cisapride*
– Elevations of transaminases – Adrenal Suppression: if given with steroids*
– Hepatits (rare) ▪ steroids alone cause adrenal insufficiency
• Metabolism: extensively metabolized in Liver ▪ Ketoconazole, since it is not selective, it will bind also
• CYP450 enzymes that they inhibit to cholesterol (w/c is a precursor of steroids and
– CYP 3A4 (most important) cortisol)
– CYP 2C9 ● inhibit cholesterol side chain cleavage
– CYP 2C19 ● inhibit 11β-hydroxylase
• Pregnancy Category: C

2 AGUILA, J., ALENTON, R., AZURIN, M., BAUTISTA, E., BELASA, E., BIAG, I., CO, P., CONCEPCION, C., DE GUZMAN, A.
 Anti-Fungal Agents
▪ therefore keto alone can cause adrenal insufficiency • Metabolism:
and problems with steroid synthesis – Hepatic
▪ Manifestations: muscle wasting, hypotensive, – Least effect on hepatic microsomal enzymes → less drug
hypoglycemia, bradycardia interactions
• Adverse Effects • Excretion:
– since it inhibits steroid pathway, – Urine
▪ decrease in androgen effects (↓ testosterone synthesis) Preparation
▪ increase in aldosterone effects (fluid retention and • Oral (tablet, suspension)
hypertension) • Parenteral
• Contraindication – Only given when patient is unable to tolerate oral medications
– in pregnancy, lactation, & hepatic dysfunction Dose
▪ if you have hepatic dysfunction, it will contribute to • 100 - 800 mg/day
problems in steroid synthesis and metabolism Therapeutic Uses
• Drug of Choice: Mucocutaneous candidiasis and Cryptococcosis
2. MICONAZOLE • AZOLE of Choice: Treatment and secondary prophylaxis of
• Topical imidazole cryptococcal meningitis
• Readily penetrates stratum corneum and persists more than 4 days – D/t good CSF penetration → can be used as an alternative
– lipophilic = therefore it binds to lipid bilayer of keratins in to Amphotericin B AFTER it decreases fungal burden load
stratum corneum (discontinue Amp B then give Fluconazole)
• Preparation: Creams or shampoo • System candidiasis (refractory thrush)
• Indication: – Used when Nystatin is unable to cure oral thrush
– Tinea corporis, pedis, cruris • Prophylaxis for bone marrow transplant patients and AIDS patients
– vulvovaginal candidiasis • IV Fluconazole: Candidemia in ICU patients with normal WBC
• Adverse Effects (localized) counts (Katzung)
– itching, pelvic cramps (if given as cream sa vaginal area), • Only triazole with NO activity against Aspergillus sp.
rash Drug Interactions
• Inhibitor of CYP3A4 and CYP2C9
3. CLOTRIMAZOLE • Causes QTc prolongation if used with Azithromycin, Granisteron,
• Topical imidazole Arsenic Trioxide
• Low bioavailability (therefore oral is not used unless needed to – Note: If taken ALONE, does NOT cause QTc prolongation
cover a wide surface area) • Increased concentration: Benzodiazepines, TMP-SMX,
• Preparation: shampoo, cream, oral solution (200mg/day), vaginal Cyclosporine, Statin
suppositories (100, 200, 500 mg/day) • Decreased concentration: Phenytoin
– vaginal suppositories are given if candidiasis is found inside • DO NOT use with Clopidogrel, Warfarin, Conivaptan, Lopinavir
• persists for 3 days and Quinine
• Indication: – Fluconazole decreases their efficacy
– oral candidiasis Adverse Effects
– vulvovaginal candidiasis = activity in vagina remains for 3 • Teratogenic: Abortion, cranio-facial abnormalities
days • Nausea, vomiting, diarrhea
– tinea corporis, pedis, cruris • Reversible alopecia
• Adverse Effects: • Rash
– Burning sensation • Rhabdomyolysis
▪ felt by the sexual partner not the one taking it
▪ stinging sensation sa penile urethra 2. ITRACONAZOLE
– erythema Pharmacokinetics
– vesication – Absorption
▪ Good absorption
B. TRIAZOLES ▪ Increased by food intake and acidic gastric pH → variable
bioavailability
1. FLUCONAZOLE ▪ Highly bound to plasma proteins
Has widest therapeutic index of the azoles d/t less drug interactions and ▪ Most potent among the triazoles
better GI tolerance → allows for more aggressive dosing in a variety of
fungal infections (Katzung) – Distribution
Pharmacokinetics ▪ Lipid soluble: Well distributed to bone, sputum and adipose
• Absorption tissue
– High oral bioavailability (oral = IV) ▪ No CSF penetration
– Not affected by food or gastric acidity – Metabolism:
• Distribution ▪ Active metabolite: Hydroxy-itraconazole → responsible for
– Diffuses readily into body fluids adverse effects
– Good CSF penetration (50-90%) – Excretion:
– Highly water soluble ▪ Urine (40% unchanged) & Feces
3 AGUILA, J., ALENTON, R., AZURIN, M., BAUTISTA, E., BELASA, E., BIAG, I., CO, P., CONCEPCION, C., DE GUZMAN, A.
 Anti-Fungal Agents
Preparation – Especially with neutropenic patients (cancer patients)
• Oral (tablet, capsule, suspension) • Esophageal candidiasis
• Parenteral Drug Interactions
Dose • Potent inhibitor of CYP2C19 > CYP2C9 > CYP3A4
• 200 mg TID for first 3 days then 100 mg BID or 200 mg OD • Dose reduction of Cyclosporine, Tacrolimus, HMG-CoA reductase
• 100-400 mg/day (Katzung) inhibitors
Therapeutic Uses • Decreased serum concentration if given with Rifabutin and
• Good coverage against Aspergillus sp. Phenytoin
– (According to Doc Maranion) AZOLE of choice for • QTc prolongation with Methadone, Haloperidol, Quinidine,
Aspergillosis but cannot be drug of choice d/t its variable Risperidone
bioavailability • Contraindicated with Sirolimus
• DRUG of Choice: Indolent invasive aspergillosis outside the CNS – Sirolimus - immunosuppressant given to post-kidney
(extracranial) transplant patients; increases in concentration by 11-fold if
• AZOLE of Choice: Infections from Histoplasma, Blastomyces and given with Voriconazole → causing hypercholesterolemia,
Sporothrix (Katzung) rash, leukopenia, anemia, thrombocytopenia and interstitial
• Non-meningeal infections from Histoplasma, Blastomycoses, pneumonitis.
Sporothrix, Coccidioides immites, P. brasillensis Adverse Effects
• Used extensively for dermatophytes and onychomycosis (Katzung) • Visual disturbances: blurring of vision, changes in color vision or
• Prophylaxis for bone marrow transplant patients brightness
Drug Interactions – Occur in 30% of patients receiving IV Voriconazole
• Substrate and potent inhibitor of CYP3A4 and CYP2C9 – Resolve within 30 minutes (Katzung)
• Decreased bioavailability if taken with Rifamycins (Rifampin, • Rash/Photosensitivity dermatitis
Rifabutin, Rifapentine) – In patients receiving chronic oral therapy (Katzung)
• Causes cardiac arrhythmia if given with Quinidine, Halofantrine, • Elevated hepatic enzymes
Levomethadyl, Cisapride • Teratogenic
• Does NOT affect mammalian steroid synthesis (Katzung)
Adverse Effects 4. POSACONAZOLE
• Hypertriglyceridemia (11%) Pharmacokinetics
– Itraconazole increases apo-B concentrations (apo-B is a – Absorption
precursor of triglycerides) ▪ Good absorption
• Hypokalemia ▪ Increased with high fat meals
• Rash ▪ 90% bioavailability with less protein binding (Katzung)
• Chemical phlebitis
• Rhabdomyolysis – Distribution
• Cramps ▪ Poor tissue distribution
• Diarrhea – Metabolism
▪ Glucoronidation
3. VORICONAZOLE – Excretion:
Pharmacokinetics ▪ Feces
• Absorption ▪ Measure trough levels
– Good absorption ▪ Monitored in patients with serious invasive fungal infections:
– Decreased with high fat meal 0.5 - 1.5 mg/mL (Katzung)
– Less protein binding compared to Itraconazole Preparation
– 90% bioavailability (Katzung) • Oral (tablet, suspension)
• Metabolism: Dose
– Non-linear metabolism: increase in dose will result in an • 600-800 mg/day loading dose followed by 300 mg/day maintenance
even higher increase in body concentration dose
– Hepatic (CYP2C19 and CYP2C9) → Voriconazole N-oxide Therapeutic Uses
• Excretion: • Azole with broadest spectrum of activity against Candida and
– Renal Aspergillus sp. (Katzung)
– Trough levels must be monitored to achieve a therapeutic • Azole with greatest activity against Mucormycosis
dose: target of 1 - 5 mg/L • Salvage therapy in invasive aspergillosis
• Preparation • Prophylaxis during induction chemotherapy for leukemia and
– Oral (tablet, suspension) allogeneic bone marrow transplant patients with graft-versus-host
– Parenteral disease (Katzung)
• Dose Drug Interactions
– IV: 6 mg/kg q12 (12 mg/day) loading dose followed by 3 • Same as Voriconazole
mg/kg q12 (6 mg/day) • Increased concentration of CYP3A4 substrates (Tacrolimus,
– Oral: 400 mg/day Cyclosporine) (Katzung)
Therapeutic Uses Adverse Effects
• Drug of Choice: Invasive aspergillosis • Headache
4 AGUILA, J., ALENTON, R., AZURIN, M., BAUTISTA, E., BELASA, E., BIAG, I., CO, P., CONCEPCION, C., DE GUZMAN, A.
 Anti-Fungal Agents
Adverse effects:
5. ISAVUCONAZOLE (ISAVUCONAZONIUM SULFATE) – Bone marrow toxicity (Aplastic anemia, leukopenia,
• New drug (Phase III clinical trial) thrombocytopenia
Pharmacokinetics – Elevated transaminases
• Absorption – Alopecia
– Good absorption and bioavailability – Rash, nausea, vomiting
– Decreased with food intake – Diarrhea and severe enterocolitis
– Highly protein bound (99%)
• Metabolism: IV. HETEROCYCLIC BENZOFURAN
– Hepatic (CYP3A4 and CYP3A5)
• Excretion: A. GRISEOFULVIN
– Urine • MoA: Binds to microtubules and Newly formed Keratin →
Preparation
Inhibit fungal mitosis
• Oral
• Effect on Fungi: Fungistatic
• Parenteral
Dose • Absorption: Increased if taken with Fatty meals
• Metabolism: none
• 2 day loading dose of 372 mg every 8 hours followed by a single
372 mg daily dose • Excretion: Urine and Feces
Therapeutic Uses • Pregnancy Category: D
• Invasive aspergillosis • Preparation: Microcrystalline Oral form (Katsung)
• Dose: 5-15mg/kg(Children), 0.5-1g -4divided doses(Adults), 1.5-2
• Mucormycosis
• Candidiemia and invasive candidiasis g daily (severe infection)
Drug Interactions • Indication:
• Substrate and potent inhibitor of CYP3A4 – Skin and Nail infection only (Tinea, Microsporum,
Adverse Effects Trichophyton, Epidermophyton)
– Systemic Treatment of Dermatophytosis (Katsung)
• Only azole that does NOT cause QTc prolongation
– Not effective against Candida or Malassezeria
• Pyrexia
• Drug Interaction: CYP Inducer
• Hypokalemia
– Decrease conc. of Warfarin, OCP,salicylates, phenobarbital
• Headache
– Disulfiram like reaction with Alcohol
• Constipation
• Cough

III. PYRIMIDINE ANALOG

A. FLUCYTOSINE
• Novel Antineoplastic / Antimetabolite agents
• Poorly CHON-bound
• Penetrates well into all body fluids + CSF (65-90%)
• Pregnancy Category:C
• Metabolism: Liver → 5FU(most important metabolite), 5FdUMP,
FUTP
• Eliminated via Renal (Glomerular filtration)
MoA: Inhibit fungal DNA and RNA synthesis by Inhibiting Thymidylate
synthase.(Insert Figure from lect.)
• Effect on Fungi: Fungistatic
Indications:
– C. neoformans meningitis(+AMB) in HIV patients
– Dematiaceous molds=Chromoblastomycosis (+Itraconazole)
– Some Candida sp.
– Combination therapy with Amphotericin B for Cryptococcal
meningitis (Katsung)
Preparation: • Adverse Effect: Do U Have Griseofulvin Pills Mammy? (Fig.)
• Dose: 50-150mg/kg/day (4 divided doses) – Allergic syndrome
Drug Interactions: ▪ Serum sickness
– Delay absorption: Aluminum or Magnesium hydroxide ▪ Serious skin rxn
– Azotemia: Amphotericin B, Aminoglycosides, Cyclosporine, ▪ Lupus like syndrome
Pentamidine ▪ Hepatotoxic
– Seen in Px with AIDS or Azotemia – CNS symptoms: Headache (15%)
• Contraindication: Porphyria, Liver failure, Pregnancy

5 AGUILA, J., ALENTON, R., AZURIN, M., BAUTISTA, E., BELASA, E., BIAG, I., CO, P., CONCEPCION, C., DE GUZMAN, A.
 Anti-Fungal Agents
V. ALLYLAMINE – Single loading dose (70mg) followed by daily dose (50mg)
• Drug interaction:
A. TERBINAFINE – Increases level of tacrolimus by 16%
• Synthetic allylamine – Cyclosporine increases caspofungin levels
• Ketophilic
• MoA: reversible noncompetitive inhibition of squalene epoxidase B. MICAFUNGIN
or monooxygenase • Origin: Coleophoma empedri
– Ergosterol biosynthesis Inhibitor → Inhibition of • Water soluble and highly protein bound
• Half-life: 13 hours
Squalene Epoxidase would result to accumulation • Vd: 14 L
of Sterol Squalene (Toxic to the Fungi) - Katsung • Metabolism:
• Effect on Fungi: Fungicidal – Hydroxylation
• Absorption:Good(70%) but bioavailability (40%) due to first-pass – Metabolized by: arylsulfatase and catechol-O-
effect methyltransferase
• Metabolism: Does not Inhibit CYP450 • Excretion: Urine
• Excretion: Urine(80%)> Feces (20%) • Indication:
• Dose::250mg/day – Invasive candidiasis
• Indication: – Mucocutaneous candidemia
– Skin Dermatophytes and Nail Infection (Onychomycosis) – Prophylaxis of esophageal candidiasis in bone marrow
• Drug Interaction: Minimal transplant patients
– Rifampicin- dec conc. of Terbinafine • Dose: Maintenance dose of 50-150 mg
– Cimetidine- inc. conc. of Terbinafine • Drug interaction:
• Adverse effect: GI distress, headache, rash – Increases level of nifedipine (18%), cyclosporine, sirolimus
• Rare: hepatotoxicity, neutropenia,SJS (21%)

C. ANIDULAFUNGIN
• Origin: A. nidulans
VI. ECHINOCANDINS • Half-life: 25.6 hours
• Newest class • Vd: 33.4 L
• Mode of action: Inhibits synthesis of 1,3 glucan • No metabolite
• Effect on fungi: • Excretion: Urine
– Fungicidal - Candida • Indication:
– Fungistatic - Aspergillosis – Esophageal candidiasis
• Extensive protein binding – Invasive candidiasis (intra-abdominal abscess, peritonitis)
– Inability to penetrate CSF • Dose:
• Metabolism: Liver – Loading dose of 100 mg
• Excretion: Renal – Maintenance dose of 50 mg
• Preparation: Parenteral • Drug interaction:
• Adverse effects: – No significant drug interaction; histamine release during
– Phlebitis at infusion site infusion
– Flushing
– GIT disturbance
– Elevated liver enzymes References:
• Pregnancy category: D Katzung 12th Ed., Dr. Maranion’s Lecture and powerpoint
Transcribed by: Alenton ,R., Aguila, J., Biag, I., Concepcion, C.,
A. CASPOFUNGIN De Guzman, A., Bautista, E.
• Origin: Glarea lozoyensis
Edited by: Azurin, M., Belasa, E., Co, P.
• Water soluble and highly protein bound
• Half-life: 10 hours Checked and edited by: Alea, EP
• Vd: 9.5 L
• Metabolism:
– Hydrolysis
– N-acetylation
• The only drug that needs hepatic dose adjustment
• Excretion: Urine
• Indication:
– Disseminated and mucocutaneous candidiasis
– Salvage therapy for invasive aspergillosis
– Empiric antifungal for febrile neutropenia
• Dose:
6 AGUILA, J., ALENTON, R., AZURIN, M., BAUTISTA, E., BELASA, E., BIAG, I., CO, P., CONCEPCION, C., DE GUZMAN, A.
 Anti-Fungal Agents

SUMMARY TABLES

Ketoconazole Fluconazole Itraconazole Voriconazole Posaconazole Isavuconazole

Selectivity to Decreased Increased Increased Increased Increased Increased
ergosterol
Aspergillus coverage None None Strong Strong Good Good

Water solubility Low High Low High Low High

Absorption Variable High Variable High High High

CSF penetration None Good (50-90%) None Yes No data No data

Excretion Urine Urine Urine, Feces Urine Feces Urine

*trough level

Contraindicated in Yes Yes No Yes No No

pregnancy
CYP3A4 inhibitor Yes + Substrate Yes Yes + Substrate Yes + Substrate Yes (Potent Yes + Substrate
inhibitor)
CYP2C19 inhibitor No Yes No Yes + Substrate No No

CYP2C9 inhibitor No Yes (Strong) No Yes + Substrate No No

Others P-GP Substrate + None P-GP inhibitor None P-GP Substrate + CYP2B6 inhibitor
inhibitor inhibitor

CYP1A2, 2A6, 2E1

inhibitor
Drug interaction Torsades de pointe, QTc prolongation Cardiac Dose reduction w/ Like Voriconazole Like Voriconazole BUT
Adrenal suppression arrhythmia certain drugs DOES NOT PROLONG
QTc
DO NOT USE WITH Amphotericin B, Clopidogrel, Cisapride, Sirolimus Sirolimus Sirolimus
Cisapride, Steroids Warfarin, Quinine Quinidine
Dose 400mg/day 100-800mg/day 200mg TID → IV 6mg/kg q12 → 600-800mg → 372mg q8 x 6 doses →
200mg OD 3mg k12 300mg/day 372mg OD

Oral 400mg OD
Drug of choice Dermatophyte infection Mucocutaneous Indolent CNS Aspergillosis Prophylaxis for Invasive aspergillosis and
candidiasis, invasive Candidiasis and mucormycosis
aspergillosis Invasive Aspergillus during
Cryptococcosis, outside CNS aspergillosis in induction chemo
Refractory thrush neutropenic for leukemia,
Non meningeal patients allogenic BMT
Prophylaxis for infections
BMT and AIDS Mucormycosis
Prophylaxis for
BMT
Adverse Effect Dec. testosterone Reversible HyperTGL, Visual disturbances, Headache, fever Pyrexia, hypokalemia,
synthesis, fluid alopecia, abortion, hypoK, rash, QTc prolongation headache, constipation,
retention, and cranio-facial chemical cough
hypertension abnormalities phlebitis,
cramps

7 AGUILA, J., ALENTON, R., AZURIN, M., BAUTISTA, E., BELASA, E., BIAG, I., CO, P., CONCEPCION, C., DE GUZMAN, A.
 Anti-Fungal Agents

Amphotericin B Azoles Flucytosine Griseofulvin Terbinafine Echinocandins

Squalene
Mode of Binds to ergosterol Inhibits lanosterol Thymidylate synthase Inhibits 1,3
Inhibits fungal mitosis epoxidase
action *pores 14-demethylase inhibitor glucan synthase
inhibitor
Fungistatic
Effect on Fungicidal and
Fungicidal *except Fungistatic Fungistatic Fungicidal
Fungi Fungistatic
itraconazole
Water
Insoluble Varied Soluble Insoluble Slightly soluble Soluble
solubility

Excretion Urine > Bile Urine, Feces Urine Urine, Feces Urine, Feces Renal, GIT

Invasive
C. Neoformans Tinea, Trichophyton,
Drug of mucormycosis, Refer to previous Skin and nail
meningitis with AMB Epidermophyton,
choice Cryptococcal table infections
in HIV patients Microsporum
meningitis

Drug Synergistic with Azotemia with AMB Disulfiram-like

Minimal
interaction Flucytosine aminoglycosides reaction with OH

0.5-0.6mg/kg or 1- 0.5-1g adults

Dose 50-150mg/kg/day 250mg/day
5mg/kg 5-15mg/kg child

GIT, QTc GIT, headache,

Bone marrow toxicity, Phlebitis at
Adverse prolongation, Porphyria, headache, rash,
Nephrotoxicity elevated infusion rate,
Reaction cranio-facial albuminuria hepatotoxicity,
transaminases flushing
abnormalities SJS

8 AGUILA, J., ALENTON, R., AZURIN, M., BAUTISTA, E., BELASA, E., BIAG, I., CO, P., CONCEPCION, C., DE GUZMAN, A.