ANTIMYCOBACTERIAL DRUGS

Dr. Ayan Ajuoi Magot

 CHEMOTHERAPY FOR TUBERCULOSIS

 M. tuberculosis is slow growing and requires treatment for

months to years.

 LTBI can be treated for 9 months with isoniazid (INH)

monotherapy or with 12 once-weekly doses of INH (900 mg) and
rifapentine (900 mg).

 In contrast, active TB disease must be treated with several

drugs.

 Treatment for drug-susceptible TB lasts for at least 6 months,

while treatment of MDR-TB typically lasts for about 2 years.
 A. STRATEGIES FOR ADDRESSING DRUG RESISTANCE

 Multidrug therapy is employed to suppress resistant

organisms.

 The first-line drugs isoniazid, rifampin, ethambutol, and

pyrazinamide are preferred because of their high efficacy and
acceptable incidence of toxicity.

 Rifabutin or rifapentine may replace rifampin under certain

circumstances.
 A. STRATEGIES FOR ADDRESSING DRUG RESISTANCE

 Active disease always requires treatment with multidrug

regimens, and preferably three or more drugs with proven in
vitro activity against the isolate.

 Although clinical improvement can occur in the first several

weeks of treatment, therapy is continued much longer to
eradicate persistent organisms and to prevent relapse.
 A. STRATEGIES FOR ADDRESSING DRUG RESISTANCE

 Standard short-course chemotherapy for tuberculosis

includes isoniazid, rifampin, ethambutol, and pyrazinamide
for 2 months, followed by isoniazid and rifampin for 4
months.

 Once susceptibility data are available, the drug regimen can

be individually tailored.

 Second line regimens for MDR-TB normally include an

aminoglycoside (streptomycin, kanamycin, or amikacin) or
capreomycin (all injectable agents).
 A. STRATEGIES FOR ADDRESSING DRUG RESISTANCE

 It also contains a fluoroquinolone (typically levofloxacin or

moxifloxacin), any first-line drugs that remain active, and one
or more of the following: cycloserine, ethionamide, or p-
aminosalicylic acid.

 For XDR-TB, clofazimine, linezolid, and other drugs may be

employed empirically.

 Patient adherence can be low when multidrug regimens last

for 6 months or longer.
 A. STRATEGIES FOR ADDRESSING DRUG
RESISTANCE
 One successful strategy for achieving better treatment
completion rates is directly observed therapy (DOT).

 Patients take their medications while being watched by a

member of the health care team.

 DOT has been shown to decrease drug resistance and to improve

cure rates.

 Most public health departments offer DOT services.

 B. ISONIAZID

1. Mechanism of action:
 Isoniazid is a prodrug activated by a mycobacterial catalase–

peroxidase (KatG).

 Isoniazid targets the enzymes acyl carrier protein reductase

(InhA) and β-ketoacyl-ACP synthase (KasA), which are
essential for the synthesis of mycolic acid.

 Inhibiting mycolic acid leads to a disruption in the bacterial

cell wall.
 B. ISONIAZID

2. Antibacterial spectrum:
 Isoniazid is specific for treatment of M. tuberculosis, although

M. kansasii may be susceptible at higher drug concentrations.

 Most NTM are resistant to INH.

 The drug is particularly effective against rapidly growing

bacilli and is also active against intracellular organisms.
 B. ISONIAZID

3. Resistance:
 Resistance follows chromosomal mutations, including

1. Mutation or deletion of KatG (producing mutants incapable

of prodrug activation),
2. Varying mutations of the acyl carrier proteins, or

3. Overexpression of the target enzyme InhA.

 Cross-resistance may occur between isoniazid and

ethionamide.
 B. ISONIAZID

4. Pharmacokinetics:
 Isoniazid is readily absorbed after oral administration.

 Absorption is impaired if isoniazid is taken with food,

particularly high-fat meals.

 The drug diffuses into all body fluids, cells, and caseous
material (necrotic tissue resembling cheese that is produced
in tuberculous lesions).
 B. ISONIAZID

 Drug concentrations in the CSF are similar to those in the

serum.

 Isoniazid undergoes N-acetylation and hydrolysis, resulting in

inactive products.

 Excretion is through glomerular filtration and secretion.

 Slow acetylators excrete more of the parent compound.

 B. ISONIAZID

5. Adverse effects:
 Hepatitis is the most serious adverse effect associated with

isoniazid.
 Peripheral neuropathy (This can be avoided by

supplementation of 25 to 50 mg per day of pyridoxine

(vitamin B6).
 Convulsions
 Hypersensitivity reactions (rashes and fever)

 Because isoniazid inhibits the metabolism of carbamazepine

and phenytoin, isoniazid can potentiate the adverse effects of

these drugs (for example, nystagmus and ataxia).
C. RIFAMYCINS: RIFAMPIN, RIFABUTIN, AND RIFAPENTINE

 Rifampin, rifabutin, and rifapentine are all considered rifamycins,

a group of structurally similar macrocyclic antibiotics, which are
first-line oral agents for tuberculosis.

1. Rifampin:
 Rifampin has broader antimicrobial activity than isoniazid and

can be used as part of treatment for several different bacterial

infections.

 Because resistant strains rapidly emerge during monotherapy, it

is never given as a single agent in the treatment of active
tuberculosis.
 C. RIFAMYCINS: RIFAMPIN, RIFABUTIN, AND RIFAPENTINE

a. Mechanism of action:
 Rifampin blocks RNA transcription by interacting with the β

subunit of mycobacterial DNA-dependent RNA polymerase.

b. Antimicrobial spectrum:
 Rifampin is bactericidal for both intracellular and

extracellular mycobacteria, including M. tuberculosis, and

NTM, such as M. kansasii and Mycobacterium avium complex
(MAC).
 C. RIFAMYCINS: RIFAMPIN, RIFABUTIN, AND RIFAPENTINE

 It is effective against many gram-positive gram-negative

organisms and is used prophylactically for and individuals
exposed to meningitis caused by meningococci or
Haemophilus influenzae.

 Rifampin also is highly active against M. leprae.

c. Resistance:
 Resistance to rifampin is caused by mutations in the affinity

of the bacterial DNA-dependent RNA polymerase gene for the

drug.
 C. RIFAMYCINS: RIFAMPIN, RIFABUTIN,
AND RIFAPENTINE
d. Pharmacokinetics:
 Absorption is adequate after oral administration.

 Distribution of rifampin occurs to all body fluids and organs.

 The drug is taken up by the liver and undergoes enterohepatic

recycling.

 Rifampin can induce hepatic cytochrome P450 enzymes and

transporters leading to numerous drug interactions.
 C. RIFAMYCINS: RIFAMPIN,
RIFABUTIN, AND RIFAPENTINE
 Unrelated to its effects on cytochrome P450 enzymes,
rifampin undergoes auto induction, leading to a shortened
elimination half-life over the first 1 to 2 weeks of dosing.

 Elimination of rifampin and its metabolites is primarily

through the bile and into the feces; a small percentage is
cleared in the urine
 C. RIFAMYCINS: RIFAMPIN, RIFABUTIN, AND
RIFAPENTINE
e. Adverse effects:
 Rifampin is generally well tolerated.

 Nausea, vomiting, and rash.

 Hepatitis and death due to liver failure are rare. or those with
chronic liver disease.

 There is a modest increase in the incidence of hepatic

dysfunction when rifampin is coadministered with isoniazid.
 C. RIFAMYCINS: RIFAMPIN,
RIFABUTIN, AND RIFAPENTINE
 When rifampin is dosed intermittently, especially with doses
of 1.2 g or greater, a flu-like syndrome can occur, with fever,
chills, and myalgia, sometimes extending to acute renal
failure, hemolytic anemia, and shock.

f. Drug interactions:
 Because rifampin induces a number of phase I cytochrome

P450 enzymes and phase II enzymes,it can decrease the half-

lives of coadministered drugs that are metabolized by these
enzymes.
 C. RIFAMYCINS: RIFAMPIN,
RIFABUTIN, AND RIFAPENTINE
 This may necessitate higher dosages for coadministered
drugs, a switch to drugs less affected by rifampin, or
replacement of rifampin with rifabutin.

2. Rifabutin:
 Rifabutin, a derivative of rifampin, is preferred for TB

patients coinfected with HIV who are receiving protease

inhibitors (PIs) or several of the non-nucleoside reverse
transcriptase inhibitors (NNRTIs).
 C. RIFAMYCINS: RIFAMPIN,
RIFABUTIN, AND RIFAPENTINE
 Rifabutin is a less potent inducer of cytochrome P450
enzymes, thus lessening certain drug interactions.

 Rifabutin has adverse effects similar to those of rifampin but

can also cause uveitis, skin hyperpigmentation, and
neutropenia.

3. Rifapentine:
 Rifapentine has activity greater than that of rifampin in

animal and in vitro studies, and it also has a longer half-life.

 C. RIFAMYCINS: RIFAMPIN,
RIFABUTIN, AND RIFAPENTINE
 In combination with isoniazid, rifapentine may be used once
weekly in patients with LTBI and in select HIV-negative
patients with minimal pulmonary TB.
 D. PYRAZINAMIDE

 Pyrazinamide is a synthetic, orally effective short- course

agent used in combination with isoniazid, rifampin, and
ethambutol.

 The precise mechanism of action is unclear.

 Pyrazinamide must be enzymatically hydrolyzed by

pyrazinamidase to pyrazinoic acid, which is the active form of
the drug.
 D. PYRAZINAMIDE

 Some resistant strains lack the pyrazinamidase enzyme.

 The drug distributes throughout the body, penetrating the CSF.

 Pyrazinamide may contribute to liver toxicity.

 Uric acid retention is common but rarely precipitates a gouty

attack.
 D. PYRAZINAMIDE

 Most of the clinical benefit from pyrazinamide occurs early in

treatment.

 Therefore, this drug is usually discontinued after 2 months of

a 6-month regimen.
 E. ETHAMBUTOL

 Ethambutol is bacteriostatic and specific for mycobacteria.

 Ethambutol inhibits arabinosyl transferase—an enzyme

important for the synthesis of the mycobacterial cell wall.

 Ethambutol is used in combination with pyrazinamide, isoniazid,

and rifampin pending culture and susceptibility data.

 [Note: Ethambutol may be discontinued if the isolate is

determined to be susceptible to isoniazid, rifampin, and
pyrazinamide.]
 E. ETHAMBUTOL

 Ethambutol is well distributed throughout the body.

 Penetration into the CNS is minimal, and it is questionably

adequate for tuberculous meningitis.

 Both the parent drug and metabolites are primarily excreted in

the urine.

 The most important adverse effect is optic neuritis, which results

in diminished visual acuity and loss of ability to discriminate
between red and green.
 E. ETHAMBUTOL

 The risk of optic neuritis increases with higher doses and in

patients with renal impairment.

 Visual acuity and color discrimination should be tested prior

to initiating therapy and periodically thereafter.

 Uric acid excretion is decreased by ethambutol, and caution

should be exercised in patients with gout.
 F. ALTERNATE SECOND-LINE DRUGS

 Streptomycin, para-aminosalicylic, capreomycin, cycloserine,

ethionamide, fluoroquinolones, and macrolides are second-
line TB drugs.

 In general, these agents are less effective and more toxic

than the first-line agents.
 F. ALTERNATE SECOND-LINE DRUGS

1. Streptomycin:
 Streptomycin, an aminoglycoside antibiotic, was one of the

first effective agents for TB.

 Its action appears to be greater against extracellular

organisms.

 Infections due to streptomycin-resistant organisms may be

treated with kanamycin or amikacin, to which these bacilli
usually remain susceptible.
 F. ALTERNATE SECOND-LINE DRUGS

2. Para-aminosalicylic acid:
 Para-aminosalicylic acid (PAS) was another one of the original

TB medications.

 From the early 1950s until well into the 1960s, isoniazid, PAS,
plus streptomycin was the standard 18-month treatment
regimen.

 While largely replaced by ethambutol for drug-susceptible TB,

PAS remains an important component of many regimens for
MDR-TB.
 F. ALTERNATE SECOND-LINE DRUGS
3. Capreomycin:
 This is a parenterally administered polypeptide that inhibits

protein synthesis.

 Capreomycin is primarily reserved for the treatment of MDR-

TB.

 Careful monitoring is necessary to minimize nephrotoxicity

and ototoxicity.
 F. ALTERNATE SECOND-LINE DRUGS
4. Cycloserine:
 This is an orally effective, tuberculostatic drug that disrupts

d-alanine incorporation into the bacterial cell wall.

 It distributes well throughout body fluids, including the CSF.

 Cycloserine is primarily excreted unchanged in urine.

 Accumulation occurs with renal insufficiency.

 F. ALTERNATE SECOND-LINE DRUGS

 Adverse effects involve CNS disturbances (for example, lethargy,

difficulty concentrating, anxiety, and suicidal tendency), and
seizures may occur.

5. Ethionamide:
 This is a structural analog of isoniazid that also disrupts mycolic

acid synthesis.

 The mechanism of action is not identical to isoniazid, but there is

some overlap in the resistance patterns.
 F. ALTERNATE SECOND-LINE DRUGS
 Ethionamide is widely distributed throughout the body, including
the CSF.

 Metabolism is extensive, most likely in the liver, to active and

inactive metabolites.

 Adverse effects that limit its use include nausea, vomiting, and
hepatotoxicity.

 Hypothyroidism, gynecomastia, alopecia, impotence, and CNS

effects.
 F. ALTERNATE SECOND-LINE DRUGS
6. Fluoroquinolones:
 The fluoroquinolones, specifically moxifloxacin and levofloxacin,

have an important place in the treatment of multidrug-resistant

tuberculosis.

 Some NTM also are susceptible.

7. Macrolides:
 The macrolides azithromycin and clarithromycin are included in

regimens for several NTM infections, including MAC.

 F. ALTERNATE SECOND-LINE DRUGS
 Azithromycin may be preferred for patients at greater risk for
drug interactions

8. Bedaquiline:
 Bedaquiline, an ATP synthase inhibitor, is the first in a new

class of drugs approved for the treatment of MDR-TB.

 Bedaquiline is administered orally, and it is active against

many types of mycobacteria.
 F. ALTERNATE SECOND-LINE DRUGS
 Bedaquiline may cause QT prolongation, and monitoring of
the electrocardiogram is recommended.

 This agent is a CYP3A4 substrate, and administration with

strong CYP3A4 inducers (for example, rifampin) should be
avoided.
 DRUGS FOR LEPROSY
 Leprosy can be treated effectively with dapsone and rifampin,
adding clofazimine in multibacillary cases.

A. Dapsone
 Dapsone is structurally related to the sulfonamides and

similarly inhibits dihydropteroate synthetase in the folate

synthesis pathway.

 It is bacteriostatic for M. leprae, and resistant strains may be

encountered.
 DRUGS FOR LEPROSY
 Dapsone also is used in the treatment of pneumonia caused
by Pneumocystis jirovecii in immunosuppressed patients.

 The drug is well absorbed from the gastrointestinal tract and

is distributed throughout the body, with high concentrations
in the skin.

 The parent drug undergoes hepatic acetylation.

 Both parent drug and metabolites are eliminated in the urine.

 DRUGS FOR LEPROSY
 Adverse reactions include hemolysis (especially in patients
with glucose-6-phosphate dehydrogenase deficiency),
methemoglobinemia, and peripheral neuropathy.

 B. Clofazimine
 Clofazimine is a phenazine dye.

 Its mechanism of action may involve binding to DNA,

although alternative mechanisms have been proposed.
 DRUGS FOR LEPROSY
 Its redox properties may lead to the generation of cytotoxic
oxygen radicals that are toxic to the bacteria.

 Clofazimine is bactericidal to M. leprae, and it has potentially

useful activity against M. tuberculosis and NTM.

 Following oral absorption, the drug accumulates in tissues,

allowing intermittent therapy but does not enter the CNS.
 DRUGS FOR LEPROSY
 Patients typically develop a pink to brownish-black
discoloration of the skin.

 Eosinophilic and other forms of enteritis.

 Clofazimine has some anti-inflammatory and anti-immune

activities.


 Thus, erythema nodosum leprosum may not develop in

patients treated with this drug.