Lange Pharm Ch 47

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The chemotherapy of infections caused by Mycobacterium tuberculosis, M Leprae and M avium-intracellulare is complicated by numerous factors, including

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1) limited info about mechanisms of antimycobacterial drug actions
2) development of resistance
3) INTRAcellular location of mycobacteria
4) chronic nature of mycobacterial disease which requires protracted drug treatment and is associated w drug toxicities
5) patient compliance

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chemotherapy of mycobacterial infections almost always involves the use of

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drug combinations to delay the emergence of resistance and to enhance antimycobacterial efficacy

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Per Krueger:
Treatment for TB patients (think RIPE)

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Rifampin, Isoniazid, Pyrazinamide, and Ethambutol

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Per Krueger:
Neurotoxicity with isoniazid (INH) prevented by

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Administration of Vit. B6 (pyridoxine)

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Per Krueger:
Inhibitors of CYP450

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Cimetidine, ketoconazole, erythromycin, isoniazid and grapefruit

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Per Krueger:
Common side effect of Rifampin

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Red urine discoloration

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Per Krueger:
Meningitis prophylaxis in exposed patients

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Rifampin

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Per Krueger:
Drug of choice for leprosy

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Dapsone, rifampin and clofazimine combination

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Per Krueger:
INDUCERS of Cytochrome P450 (CYP450)

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Barbiturates, phenytoin, carbamazepine, and rifampin

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Per Krueger:
Meningitis prophylaxis in exposed patients

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Rifampin

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The major drugs used in tuberculosis are

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isoniazid (INH), rifampin, ethambutol, pyrazinamide and streptomycin.

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isoniazid (INH), rifampin, ethambutol, pyrazinamide and streptomycin - actions of these agents on M tuberculosis

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are bactericidal or bacteriostatic depending on drug concentration and strain susceptibility. Appropriate drug treatment involves antibiotic susceptibility testing of mycobacterial isolates.

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Isoniazid (INH) MOA

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inhibition of mycolic acids, characteristic components of mycobacterial cells walls.

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Isoniazid (INH) resistance

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can emerge rapidly if the drug is used alone. INH is bactericidal for actively growing tubercle bacilli, but is less effective against dormant organisms

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Pharmacokinetics of INH (Isoniazid)

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well absorbed orally and penetrates cells to act on intracellular mycobacteria. Liver metabolism of INH is under genetic control. Patients may be fast or slow inactivators of the drug. 1/2 life can be 60-90 min or as long as 3-4 hours. Fast acetylators may require higher dosage for equivalent therapeutic effects

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INH (isoniazid)

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is the single most important drug used in TB. In the treatment of latent infection including skin test converters and for close contacts of patients with active disease, INH is given as the sole drug.

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Toxicity of INH (isoniazid)

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Neurotoxic effects are common and include peripheral neuritis, restlessness, muscle twitching and insomnia. Can be alleviated by administration of pyridoxine. INH is hepatotoxic and may cause abnormal liver function tests, jaundice and hepatitis. INH may inhibit the hepepatic metabolism of drugs.

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Rifampin mechanisms

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bactericidal against M tuberculosis. The drug inhibits DNA-dependent RNA polymerase in M tuberculosis and many other microorganisms. Resistance often emerges rapidly if the drug is used alone.

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Rifampin pharmacokinetics

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orally, rifampin is well absorbed and is distributed to most body tissues, including the CNS. Undergoes enterohepatic cycling and is partially metabolized in the liver.

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Rifampin clinical uses:

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In TB, Rifampin is almost always used in combo with other drugs. Rifampin can be used as the sole drug in treatment of latent TB in INH intolerant patients or in close contacts of patients with INH resistant strains or the organism. 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).

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Toxicity of Rifampin

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Rifampin commonly causes light-chain proteinuria and may impair antibody responses. Occasionally skin rashes, thrombocytopenia, nephritis and liver dysfunction. If given less often than twice weekly, may cause a flu-like syndrome and anemia. Rifampin STRONGLY induces liver drug-metabolizing enzymes and enhances the elimination rate of many drugs.

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Rifabutin, another rifamycin, is less likely to cause

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drug interactions than rifampin and is preferred over rifampin in AIDS patients

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Ethambutol MOA

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inhibits arabinosyl transferases involved in the synthesis of arabinogalactan, a component of mycobacterial cell walls. Resistance occurs rapidly if the drug is used alone.

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Ethambutol pharmacokintics

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Well absorbed orally and distributed to most tissues, including the CNS. Large % is eliminated unchanged in the urine. Dose reduction is necessary in renal impairment

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Clinical use of ethambutol

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TB. Always in combo with other drugs

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Toxicity of ethambutol

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Dose-dependent visual disturbances, including decreased visual acuity, red-green color blindness, optic neuritis, and possible retinal damage (prolonged and at high doses). Most effects regress when drug is stopped.

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Pyrazinamide MOA

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mechanism is not known. Resistance develops rapidly when the drug is used alone.

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Pharmacokinetics of Pyrazinamide

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Well absorbed orally and penetrates most body tissues, including the CNS. Both parent molecules and metabolites are excreted in the urine. The plasma 1/2 life is increased in renal failure.

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Clinical use of Pyrazinamide

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Short-course treatment of TB in combo with other drugs

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Pyrazinamide toxicity

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40% of patients develop nongouty polyarthralgia. (polyarthralgia: joint pain) Commonly: hyperuricemia but usually is asymptomatic. (hyperuricemia is high uric acid in urine). Avoid Pyrazinamide in pregnancy.

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Streptomycin use

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This aminoglycoside is now used more frequently than before because of the growing prevalance of drug-resistant strains of M tuberculosis. Streptomycin is used principally in drug combos for the treatment of life-threatening TB disease, including meningitis, miliary dissemination and severe organ TB.

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2nd line drugs with antimycobacterial activity used in first-line resistance. They are no more effective and their toxicities are often more serious.

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Amikacin: TB caused by streptomycin-resistant or multidrug-resistant mycobacterial strains. use in combo to avoid developing resistance.
Ciprofloxacin and Ofloxacin: against strains of M tuberculosis resistant to 1st-line agents. Always used in combo with other drugs.
Ehionamide: congener of INH, but cross-resistance does not occur. Severe GI irritation & adverse neuro effects.
p-Aminosalicylic acid (PAS): rarely used 'cause resistance common. Toxicity: GI, peptic ulcers, hypersensitivy rxns, effects on kidney, liver and thyroid

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Antitubercular Drug Regimens
Standard:

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for empiric treatment of pulmonary TB, an initial 3-drug regiment of INH, rifampin and pyrazinamide. (Remember per Krueger RIPE - also throw in ethambutol).

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Antitubercular Drug regimens
Alternative to RIPE:

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In cases of fully susceptible organisms include INH+ rifampin for 9 mos, or INH + ETB for 18 mos.
Also, Intermittent (2 or 3 x weekly) high-dose RIPE is also effective.

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Antitubercular drug regimens
Resistance:

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If resistance to INH is higher than 4%, the initial drug regimen should include ethambutol or streptomycin. TB resistant only to INH (most common) can be treated for 6 mos with a regimen of RIF + pyrazinamide + ethambutol or streptomycin.
Multi-drug resistance (INH & rifampin) should be treated with 3 or more drugs to which the organism is susceptible for a period of more than 18 mos including 12 mos after sputum cultures become negative.

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Drugs for Leprosy

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sulfones like dapsone and acedapsone.

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Leprosy drugs (Dapsone)

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diaminodiphenylsulfone (Dapsone) remains the most active drug against M leprae.

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Leprosy drugs
Dapsone clinical use

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Because of increasing reports of resistance, it is recommended that the drug be used in combinations with rifampin and/or clofazimine. Dapsone can be given orally, penetrates tissues well, undergoes enterohepatic cycline and is eliminated in the urine, partly as acetylated metabs. Common SE include GI irritation, fever, skin rashes and methemeglobinemia.

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Leprosy drugs
Acedapsone

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is a repository form of dapsone that provides inhibitory plasma concentrations for several months.

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Drugs for atypical mycobacterial infections

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Mycobacterium avium complex (MAC) is a cause of disseminated infections in AIDS patients. Clarithromycin or azithromycin with or without rifabutin is recommended for primary prophylaxis in patients with CD4 counts less than 50/uL.