Antimycobacterial Drugs: Introduction
The chemotherapy of infections caused by Mycobacterium tuberculosis, M leprae, and M avium-intracellulare is complicated by numerous factors, including (1) limited information about the mechanisms of antimycobacterial drug actions; (2) the development of resistance; (3) the intracellular location of mycobacteria; (4) the chronic nature of mycobacterial disease, which requires protracted drug treatment and is associated with drug toxicities; and (5) patient compliance. Chemotherapy of mycobacterial infections almost always involves the use of drug combinations to delay the emergence of resistance and to enhance antimycobacterial efficacy.
Drugs for Tuberculosis
The major drugs used in tuberculosis are isoniazid (INH), rifampin, ethambutol, pyrazinamide, and streptomycin. Actions of these agents on M tuberculosis are bactericidal or bacteriostatic depending on drug concentration and strain susceptibility. Appropriate drug treatment involves antibiotic susceptibility testing of mycobacterial isolates. Initiation of treatment of pulmonary tuberculosis usually involves a 3- or 4-drug combination regimen depending on the known or anticipated rate of resistance to isoniazid (INH). Directly observed therapy (DOT) regimens are recommended in noncompliant patients and in drug-resistant tuberculosis.
Isoniazid
Mechanisms
Isoniazid (INH) is a structural congener of pyridoxine. Its mechanism of action involves inhibition of mycolic acids, characteristic components of mycobacterial cell walls. Resistance can emerge rapidly if the drug is used alone. High-level resistance is associated with deletion in the katG gene that codes for a catalase-peroxidase involved in the bioactivation of INH. Low-level resistance occurs via deletions in the inhA gene that encodes the "target enzyme,"an acyl carrier protein reductase. INH is bactericidal for actively growing tubercle bacilli, but is less effective against dormant organisms.
Pharmacokinetics
INH is well absorbed orally and penetrates cells to act on intracellular mycobacteria. The liver metabolism of INH is by acetylation and is under genetic control. Patients may be fast or slow inactivators of the drug. INH half-life in "fast acetylators" is 60-90 min; in "slow acetylators" it may be 3-4 h. The proportion of fast acetylators is higher among people of Asian origin (including Native Americans) than those of European or African origin. Fast acetylators may require higher dosage than slow acetylators for equivalent therapeutic effects.
Clinical Use
INH is the single most important drug used in tuberculosis and is a component of most drug combination regimens. In the treatment of latent infection (formerly known as "prophylaxis") including skin test converters and for close contacts of patients with active disease, INH is given as the sole drug.
Toxicity and Interactions
Neurotoxic effects are common and include peripheral neuritis, restlessness, muscle twitching, and insomnia. These effects can be alleviated by administration of pyridoxine (25-50 mg/d orally). INH is hepatotoxic and may cause abnormal liver function tests, jaundice, and hepatitis. Fortunately, hepatotoxicity is rare in children. INH may inhibit the hepatic metabolism of drugs (eg, carbamazepine, phenytoin, warfarin). Hemolysis has occurred in patients with glucose-6-phosphate dehydrogenase (G6PDH) deficiency. A lupus-like syndrome has been reported.
Rifampin
Mechanisms
Rifampin, a derivative of rifamycin, is bactericidal against M tuberculosis. The drug inhibits DNA-dependent RNA polymerase (encoded by the rpo gene) in M tuberculosis and many other microorganisms. Resistance via changes in drug sensitivity of the polymerase often emerges rapidly if the drug is used alone.
Pharmacokinetics
When given orally, rifampin is well absorbed and is distributed to most body tissues, including the central nervous system (CNS). The drug undergoes enterohepatic cycling and is partially metabolized in the liver. Both free drug and metabolites, which are orange-colored, are eliminated mainly in the feces.
Clinical Uses
In the treatment of tuberculosis, rifampin is almost always used in combination with other drugs. However, rifampin can be used as the sole drug in treatment of latent tuberculosis in INH-intolerant patients or in close contacts of patients with INH-resistant strains of the organism. In leprosy, rifampin given monthly delays the emergence of resistance to dapsone. Rifampin may be used with vancomycin for infections due to resistant staphylococci (methicillin-resistant Staphylococcus aureus [MRSA] strains) or pneumococci (penicillin-resistant Streptococcus pneumoniae [PRSP] strains). Other uses of rifampin include the meningococcal and staphylococcal carrier states.
Toxicity and Interactions
Rifampin commonly causes light-chain proteinuria and may impair antibody responses. Occasional adverse effects include skin rashes, thrombocytopenia, nephritis, and liver dysfunction. If given less often than twice weekly, rifampin may cause a flu-like syndrome and anemia. Rifampin strongly induces liver drug-metabolizing enzymes and enhances the elimination rate of many drugs, including anticonvulsants, contraceptive steroids, cyclosporine, ketoconazole, methadone, terbinafine, and warfarin. Rifabutin , another rifamycin, is less likely to cause drug interactions than rifampin and is equally effective as an antimycobacterial agent. It is usually preferred over rifampin in the treatment of tuberculosis or other mycobacterial infections in AIDS patients.
Ethambutol
Mechanisms
Ethambutol inhibits arabinosyl transferases (encoded by the embCAB operon) involved in the synthesis of arabinogalactan, a component of mycobacterial cell walls. Resistance occurs rapidly via mutations in the emb gene if the drug is used alone.
Pharmacokinetics
The drug is well absorbed orally and distributed to most tissues, including the CNS. A large fraction is eliminated unchanged in the urine. Dose reduction is necessary in renal impairment.
Clinical Use
The main use of ethambutol is in tuberculosis, and it is always given in combination with other drugs.
Toxicity
The most common adverse effects are dose-dependent visual disturbances, including decreased visual acuity, red-green color blindness, optic neuritis, and possible retinal damage (from prolonged use at high doses). Most of these effects regress when the drug is stopped. Other adverse effects include headache, confusion, hyperuricemia and peripheral neuritis.
Pyrazinamide
Mechanisms
The mechanism of action of pyrazinamide is not known; however, its bacteriostatic action appears to require metabolic conversion via pyrazinamidases (encoded by the pncA gene) present in M tuberculosis.Resistance occurs via mutations in the gene that encodes enzymes involved in the bioactivation of pyrazinamide and by increased expression of drug efflux systems. This develops rapidly when the drug is used alone, but there is minimal cross-resistance with other antimycobacterial drugs.
Pharmacokinetics
Pyrazinamide is well absorbed orally and penetrates most body tissues, including the CNS. The drug is partly metabolized to pyrazinoic acid, and both parent molecule and metabolite are excreted in the urine. The plasma half-life of pyrazinamide is increased in hepatic or renal failure.
Clinical Use
The combined use of pyrazinamide with other antituberculous drugs is an important factor in the success of short-course treatment regimens.
Toxicity
Approximately 40% of patients develop nongouty polyarthralgia. Hyperuricemia occurs commonly but is usually asymptomatic. Other adverse effects are myalgia, gastrointestinal irritation, maculopapular rash, hepatic dysfunction, porphyria, and photosensitivity reactions.Pyrazinamide should be avoided in pregnancy.
Streptomycin
This aminoglycoside is now used more frequently than before because of the growing prevalence of drug-resistant strains of M tuberculosis. Streptomycin is used principally in drug combinations for the treatment of life-threatening tuberculous disease, including meningitis, miliary dissemination, and severe organ tuberculosis. The pharmacodynamic and pharmacokinetic properties of streptomycin are similar to those of other aminoglycosides (see Chapter 45).
Alternative Drugs
Several drugs with antimycobacterial activity are used in cases that are resistant to first-line agents; they are considered second-line drugs because they are no more effective, and their toxicities are often more serious than those of the major drugs.
Amikacin is indicated for the treatment of tuberculosis suspected to be caused by streptomycin-resistant or multidrug-resistant mycobacterial strains. To avoid emergence of resistance, amikacin should always be used in combination drug regimens.
Ciprofloxacin and ofloxacin are often active against strains of M tuberculosis resistant to first-line agents. The fluoroquinolones should always be used in combination regimens with two or more other active agents.
Ethionamide is a congener of INH, but cross-resistance does not occur. The major disadvantage of ethionamide is severe gastrointestinal irritation and adverse neurologic effects at doses needed to achieve effective plasma levels.
p-Aminosalicylic acid (PAS) is rarely used because primary resistance is common. In addition, its toxicity includes gastrointestinal irritation, peptic ulceration, hypersensitivity reactions, and effects on kidney, liver, and thyroid function.
Other drugs of limited use because of their toxicity include capreomycin (ototoxicity, renal dysfunction) and cycloserine (peripheral neuropathy, CNS dysfunction).
Antitubercular Drug Regimens
Standard Regimens
For empiric treatment of pulmonary TB (in most areas of <4% INH resistance), an initial 3-drug regimen of INH, rifampin, and pyrazinamide is recommended. If the organisms are fully susceptible (and the patient is HIV-negative), pyrazinamide can be discontinued after 2 mo and treatment continued for a further 4 mo with a 2-drug regimen.
Alternative Regimens
Alternative regimens in cases of fully susceptible organisms include INH + rifampin for 9 mo, or INH + ETB for 18 mo. Intermittent (2 or 3 x weekly) high-dose 4-drug regimens are also effective.
Resistance
If resistance to INH is higher than 4%, the initial drug regimen should include ethambutol or streptomycin. Tuberculosis resistant only to INH (the most common form of resistance) can be treated for 6 mo with a regimen of RIF + pyrazinamide + ethambutol or streptomycin. Multidrug-resistant organisms (resistant to both INH and rifampin) should be treated with 3 or more drugs to which the organism is susceptible for a period of more than 18 mo, including 12 mo after sputum cultures become negative.
Skill Keeper: Genotypic Variations in Drug Metabolism
(See Chapter 4)
Genotypic variants occur with regard to the metabolism of isoniazid. What other drugs exhibit such variation, and what enzymes are involved in their metabolism? What are the clinical consequences of genetic polymorphisms in drug metabolism? The Skill Keeper Answers appear at the end of the chapter.
Drugs for Leprosy
Sulfones
Dapsone (diaminodiphenylsulfone) remains the most active drug against M leprae. The mechanism of action of sulfones may involve inhibition of folic acid synthesis. Because of increasing reports of resistance, it is recommended that the drug be used in combinations with rifampin and/or clofazimine (see below). Dapsone can be given orally, penetrates tissues well, undergoes enterohepatic cycling, and is eliminated in the urine, partly as acetylated metabolites. Common adverse effects include gastrointestinal irritation, fever, skin rashes, and methemoglobinemia. Hemolysis may occur, especially in patients with G6PDH deficiency.
Acedapsone is a repository form of dapsone that provides inhibitory plasma concentrations for several months. In addition to its use in leprosy, dapsone is an alternative drug for the treatment of Pneumocystis jiroveci pneumonia in AIDS patients.
Other Agents
Drug regimens usually include combinations of dapsone with rifampin (or rifabutin, see prior discussion) plus or minus clofazimine. Clofazimine, a phenazine dye that may interact with DNA, causes gastrointestinal irritation and skin discoloration ranging from red-brown to nearly black.
Drugs for Atypical Mycobacterial Infections
Mycobacterium avium complex (MAC) is a cause of disseminated infections in AIDS patients. Currently, clarithromycin or azithromycin with or without rifabutin is recommended for primary prophylaxis in patients with CD4 counts less than 50/
L. Treatment of MAC infections requires a combination of drugs, one favored regimen consisting of azithromycin or clarithromycin with ethambutol and rifabutin. Infections resulting from other atypical mycobacteria (eg, M marinum, M ulcerans), though sometimes asymptomatic, may be treated with the described antimycobacterial drugs (eg, ethambutol, INH, rifampin) or other antibiotics (eg, amikacin, cephalosporins, fluoroquinolones, macrolides, or tetracyclines).
Skill Keeper Answer: Genotypic Variations in Drug Metabolism
(See Chapter 4)
Examples of genotypic variations in drug metabolism include succinylcholine (pseudocholinesterase) and isoniazid (N-acetytransferase). Genetic polymorphisms also occur in isoforms of cytochrome P450 and contribute to variability in the rates of metabolism of phenformin, dextromethorphan, and metoprolol. Variants in the CYP2D6 isoform have been implicated in excessive responses to codeine and nortriptyline, and variants in CYP2C9 may be responsible for unusual sensitivity to the anticoagulant effects of warfarin.
Enzyme Drugs Clinical Consequences Aldehyde dehydrogenase Ethanol Facial flushing, emesis, and cardiovascular symptoms in Asians with low enzyme activity N-acetyltransferase Isoniazid Increased dose requirement in fast acetylators Hydralazine Increased risk of lupus-like syndrome in slow acetylators Procainamide Increased cardiotoxicity in fast acetylators Pseudocholin-esterase SuccinylcholineDeficiences may lead to prolonged apnea
Checklist
When you complete this chapter, you should be able to:
List 5 special problems associated with chemotherapy of mycobacterial infections.
Identify the characteristic pharmacodynamic and pharmacokinetic properties of isoniazid and rifampin.
List the typical adverse effects of ethambutol, pyrazinamide, and streptomycin.
Describe the standard protocols for drug management of latent tuberculosis, pulmonary tuberculosis, and multidrug-resistant tuberculosis.
Identify the drugs used in leprosy and in the prophylaxis and treatment of M avium-intracellulare complex disease.
Drug Summary Table: First-Line Antimycobacterial Drugsa
Drugs Mechanism of Action Activity & Clinical Uses Pharmacokinetics & Interactions Toxicities Isoniazid (INH) Requires bioactivation; inhibits mycolic acid synthesis; resistance via expression of katG and inhA genes Bactericidal; primary drug for LTBI and a primary drug for use in combinations Oral and IV forms; hepatic clearance (fast and slow acetylators); inhibits metabolism of carbamazepine, pheytoin and warfarin Hepatotoxicity, peripheral neuropathy (use pyridoxine); hemolysis in G6PDH deficiency Rifamycins Rifampin (RIF)b Rifabutin Rifapentine Inhibit DNA-dependent RNA polymerase; bactericidal; resistance emerges rapidly when drug is used alone Bactericidal; RIF is an optional drug for LTBI, a primary drug used in combinations for active TB Rifampin (oral, IV); others oral; enterohepatic cycling with some metabolism; induced formation of CYP450 by RIF leads to decreased efficacy of many drugs (rifabutin less) Rash, nephritis, cholestasis, thrombocytopenia; flu-like syndrome with intermittent dosing Ethambutol (ETB) Inhibits formation of arabinoglycan, a component of mycobacterial cell wall; resistance emerges rapidly if drug is used alone Bacteriostatic; component of many drug combination regimens for active TB Oral; renal elimination with large fraction unchanged; reduce dose in renal dysfunction Dose-dependent visual disturbances, reversible on discontinuance; headache, confusion, hyperuricemia & peripheral neuritis Pyrazinamide (PYR) Uncertain, but requires bioactivation via hydrolytic enzymes to form pyrazoic acid (active) Bacteriostatic; component of many drug combination regimens for active TB Oral; both hepatic and renal elimination (reduce dose in dysfunction) Polyarthralgia (40% incidence), hyperuricemia, myalgia, maculopapular rash, porphyria, and photosensitivity; avoid in pregnancy Streptomycin (SM) Binds to S12 ribosomal subunit inhibiting protein synthesis Bactericidal; used in TB when injectable drug needed, or in treatment of drug-resistant strains Parenteral; renal elimination Ototoxicity, nephrotoxicity
aBackup drugs include amikacin, aminosalicylic acid, ciprofloxacin, cycloserine, ethionamide, and levofloxacin.
bRifampin is also used for eradication of staphylococci and meningococci in carriers.
G6PDH, glucose-6-phosphate dehydrogenase; LTBI, latent tuberculosis infection.