ANTIMYCOBACTERIAL DRUGS

A. Q. Sangalang, MD, FPOGS

FACULTY OF PHARMACY
UNIVERSITY OF SANTO TOMAS

l Mycobacterium tuberculosis
l Mycobacterium leprae
l Mycobacterium avium

USE OF DRUG COMBINATIONS

l To delay emergence of resistance
l To enhance antimycobacterial efficacy
l
COMPLICATIONS OF CHEMOTHERAPY
l Limited information about the MOA
l Development of resistance
l Intracellular location of mycobacteria
l Chronic nature of the disease (protracted therapy and drug toxicities)
l Patient compliance

DRUGS FOR TUBERCULOSIS

l Bactericidal or bacteriostatic
o Drug concentration
o Strain susceptibility
l Initial treatment
o 3-or 4 drug combination regimens
o Known or anticipated rate of resistance to INH

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A. ISONIAZID
1. MOA
l Structural congener of pyridoxine
l Prodrug that is activated by KatG, the mycobacterial catalase-peroxidase
l Inhibition of enzymes required for the synthesis of mycolic acid and
mycobacterial cell walls
l Resistance can emerge rapidly if used alone

2. PHARMACOKINETICS
l Well absorbed orally
l Acts on intracellular mycobacteria
l Liver metabolism is by acetylation and is under genetic control
l Patients maybe fast (Asians) or slow inactivators of the drug
l Fast acetylators may require higher dosage

3. CLINICAL USE
l Single most important drug in TB
l Component of most drug regimen combinations
l Latent infection (prophylaxis)
l Sole drug treatment
l Latent infection (prophylaxis)
l Skin test converters
l Close contacts of patients with active disease

4. RESISTANCE
l Mutations resulting in overexpression of inhA, which encodes an NADH-
dependent acyl carrier protein reductase; mutation or deletion of the katG gene

5. TOXICITY AND DRUG INTERACTIONS

l Neurotoxic effects
o Peripheral neuritis, restlessness, muscle twitching, and insomnia
o Pyridoxine (25-50 mg/day)
l Hepatotoxic
o Abnormal liver function tests
o Jaundice, hepatitis
o Rare in children
l Inhibits the metabolism of other drugs (eg, phenytoin)
l Hemolysis in patients with G-6PD (Glucose 6-phosphate deficiency)
l Lupus-like syndrome

B. RIFAMPIN
1. MOA
l Derivative of rifamycin
l Bactericidal against M. tuberculosis
l Inhibits DNA-dependent RNA polymerase
l Resistance emerges rapidly if used alone

2. PHARMACOKINETICS
l Well absorbed orally
l Distributed to most body tissues, including CNS
l Enterohepatic cycling, partly metabolized by the liver

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l Free drug and metabolites (orange colored) are excreted in the feces

3. CLINICAL USES
l Used in combination with other drugs
l Leprosy
o Given monthly to delay the emergence of resistance to dapsone
l Sole drug therapy
o Latent TB in INH-intolerant patients
o Close contacts of patients with INH- resistant strains
l Meningococcal and staphylococcal carrier states

4. TOXICITY AND INTERACTIONS

l Imparts a harmless orange color to urine, sweat, and tears (soft contact lenses
may be permanently stained
l Light chain proteinuria
l May impair antibody immune responses
l Skin rashes, thrombocytopenia, nephritis, and liver dysfunction
l If given less often than twice weekly
l Flu-like syndrome and anemia
l Induces liver drug-metabolizing enzymes
l Enhances elimination
l Anticonvulsants Contraceptive steroids
l Cyclosporine Ketoconazole
l Methadone Terbinafine
l Warfarin
l Rifabutin
o Less likely to cause drug interaction than rifampin
o Equally as effective as antimycobacterial agent
o Another rifamycin
o Preferred for TB in HIV patients

C. ETHAMBUTOL
1. MOA
l Inhibits arabinoyl transferases
l Synthesis of arabinogalactan
l Component of mycobacterial cell walls
l Resistance emerges rapidly when used alone

2. PHARMACOKINETICS
l Well absorbed orally
l Distributed to most tissues, including CNS
l Large fraction is excreted unchanged in urine
l Dose reduction necessary in renal failure

3. CLINICAL USE
l Main use in TB
l Used in combination with other drugs

4. TOXICITY
l Dose-dependent visual disturbances
o Increased visual acuity

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 o Red-green color blindness
o Optic neuritis
o Possible retinal damage (prolonged use at high doses)
l Neurotoxic
o Headache
o Confusion
o Peripheral neuropathy

D. PYRAZINAMIDE
1. MOA
l Specific drug target is unknown, but pyrazinoic acid disrupts mycobacterial cell
membrane metabolism and transport functions
l Taken up by macrophages and exerts its activity against mycobacteria residing
within the acidic environment of lysosomes
l Bacteriostatic
o Require metabolic conversion via pyrazinamidases present in M.
tuberculosis
l Resistance emerges rapidly when used alone
l Minimal cross-tolerance with other antimycobacterial drugs

2. PHARMACOKINETICS
l Well absorbed orally
l Distributed to most tissues, including CNS
l Partly metabolized to pyrazinoic acid
l Parent molecule and metabolite are excreted in urine
l Half-life is increased in hepatic or renal failure

3. CLINICAL USE
l Combined use with other drugs
o Short-course regimens
o Sterilizing agent active against residual intracellular organisms that may
cause relapse

4. TOXICITY
l 40% develop nongouty polyarthralgia
l Asymptomatic hypeuricemia
l Myalgia GI irritation
l Porphyria Hepatic dysfunction
l Maculopapular rash
l Photosensitivity reactions

E. STREPTOMYCIN
l Used more frequently than before
o Prevalence of drug-resistance strains of M. tuberculosis
l Administered intramuscularly
l Used in drug combinations for treatment of life-threatening TB disease
o Meningitis
o Miliary dissemination
o Severe organ TB
l Pharmacodynamics and kinetics similar to other aminoglycosides
l Kills mainly extracellular tubercle bacilli

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F. ALTERNATIVE DRUGS
l Considered only in
(1) Case of resistance to first-line agents;
(2) Case of failure of clinical response to conventional therapy; and
(3) Case of serious treatment-limiting adverse drug reactions
l Second-line drugs
l Not more effective than first-line drugs
l Toxicities are more serious

ETHIONAMIDE
l Congener of INH, blocks the synthesis of mycolic acid
l Cross-resistance does not occur
l Intense GI irritation and adverse neurologic effects (alleviated by B6) at doses
needed to achieve effective plasma levels

CAPREOMYCIN
l Peptide protein synthesis inhibitor
l Strains of M tuberculosis that are resistant to streptomycin or amikacin
l Limited use because of toxicity
l Ototoxicity and renal dysfunction

CYCLOSERINE
l Inhibitor of cell wall synthesis
l Limited use because of toxicity
l Peripheral neuropathy (alleviated by B6) and CNS dysfunction

p-AMINOSALICYLIC ACID (PAS)

l Folate synthesis antagonist
l Structurally similar to p -aminobenzoic acid (PABA) and to the sulfonamides
l Rarely used because of primary resistance
l Limited use because of toxicity
l GI irritation
l Peptic ulceration
l Hypersensitivity reactions
l Effects on kidney, liver and thyroid function

AMIKACIN
l Streptomycin-resistant or multi-drug resistant mycobacterial strains
l Used in combination with other drugs
l Kanamycin is rendered obsolete

FLUOROQUINOLONES
l Ciprofloxacin (more active for atypical tb), levofloxacin (more active than cipro for
M. tb), gatifloxacin, and moxifloxacin (most active for M. tb)
l Mycobacterial strains resistant to first-line drugs
l Used in combination with other drugs

LINEZOLID
l In combination with other second- and third-line drugs to treat MDR strains
l Drug of last resort to treat MDR strains that also are resistant to several other

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 first- and second-line agents

RIFABUTIN
l Derived from rifamycin and is related to rifampin
l Activity against M tuberculosis, MAC, and Mycobacterium fortuitum
l Cross-resistance with rifampin complete
l Less potent inducer, indicated in place of rifampin for treatment of TB with HIV
infection who are receiving antiretroviral therapy
o Protease inhibitor
o Nonnucleoside reverse transcriptase inhibitor

RIFAPENTINE
l Analog of rifampin
l Activity both M tuberculosis and MAC
l Bacterial RNA polymerase inhibitor
l Cross-resistance with rifampin complete
l Not used to treat patients with HIV infection because of high relapse rate

RIFAXIMIN
l Rifampin derivative that is not absorbed from the GI tract
l Prevention of hepatic encephalopathy
l Treatment of travelers diarrhea caused by noninvasive strains of Escherichia coli
l For patients 12 years of age and older

DRUGS FOR LEPROSY

Mycobacterium leprae

A. SULFONES
DAPSONE
1. MOA
l Diaminodiphenylsulfone
l Inhibition of folic acid synthesis
l Resistance can develop if low doses are given
l Combination with rifampin, and clofazimine is recommended for initial therapy

2. PHARMACOKINETICS
l Well absorbed orally
l Penetrates tissues well
l Enterohepatic cycling
l Eliminated in the urine,
l Partly as acetylated metabolites

3. CLINICAL USES
l Most active drug against M. leprae
l Rarely used alone

4. TOXICITY
l GI irritation Fever
l Skin rashes Methemoglobinemia
l Hemolysis in patients with G-6PD

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 B. RIFAMPICIN
l Drug is given in combination with dapsone or another antileprosy drug
l Single monthly dose of 600 mg may be beneficial in combination therapy

ACEDAPSONE
l Repository form of dapsone
l Provides inhibitory plasma concentrations for several months
l Alternative drug for P. jiroveci pneumonia in HIV patients

C. OTHER AGENTS
l Combination of dapsone with rifampin (or rifabutin) plus or minus clofazimine
l Clofazimine
l Phenazine dye
l Alternative to dapsone
l MOA is unknown but may involve DNA binding
l Toxicity
o Skin discoloration ranging from red-brown to nearly black
o GI irritation

DRUGS FOR ATYPICAL MYCOBACTERIAL INFECTIONS

l M. marinum
l M. avium-intracellulare
l M. unlearns
l M. kansasii

l Sometimes asymptomatic
l Generally not communicable from person to person.
l Less susceptible than M tuberculosis to anti- TB drugs
l Antimycobacterial drugs
l Ethambutol Rifampin
l Other antibiotics
l Erythromycin Tetracycline
l Sulfonamides

M. avium complex (MAC)

l Disseminated infection in HIV patients
l Combination of drugs
l Clarithromycin (drug of choice) or azithromycin
l With ethambutol and rifabutin
l Recommend use of a third agent, such as ciprofloxacin

DIRECTLY OBSERVED TREATMENT SHORT COURSE (DOTS)

l Noncompliant patients
l Drug-resistant tuberculosis
l Direct sputum smear microscopy
l Primary diagnostic tool
l Definitive diagnosis of active TB
l Simple and economical
l Microscopy center would be organized even in remote areas

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 l All tb symptomatics must undergo sputum examination prior to initiation of
treatment, with or without x-ray results
l Contraindication to examination is massive hemoptysis
l No diagnosis of TB shall be made based on the result of x-ray examinations
alone

TYPES OF TB CASES
l Based on history of antimycobacterial treatment
l Important in determining treatment regimen
1. NEW
No treatment or < 1month treatment
2. RELAPSE
Not cured & smear (+) again
3. TRANSFER-IN
Change treatment facility
4. RETURN AFTER DEFAULT (RAD)
Interrupted treatment, smear (+)
5. TREATMENT FAILURE
Still (+) on 5th month of treatment
6. OTHERS
Became (+) on 2nd month
Interrupted treatment, smear (-)

DIRECTLY OBSERVED TREATMENT (DOT)

H = ISONIAZID
R = RIFAMPICIN
Z = PYRAZINAMIDE
E = ETHAMBUTOL
S = STREPTOMYCIN

REGIMEN TB PATIENT TO BE GIVEN TREATMENT

Regimen I l New pulmonary smear (+) cases
2HRZE/4HR l New seriously ill pulmonary smear (-) with
extensive parenchymal involvement
l New severely ill extrapulmonary TB cases

Regimen II l Failure cases

2HRZES/1HREZ/ 5HRE l Relapse cases
l RAD (smear +)
l Others (smear +)

Regimen III l New smear (-) but with minimal

2HRZE/4HR pulmonary TB on radiography as
confirmed by a medical officer
l New extra-pulmonary TB (not serious)

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