TABLE 75.5
Antituberculosis Drugs: Routes and Major Adverse Effects
| Drug | Route | Major Adverse Effects |
| FIRST-LINE DRUGS | ||
| Isoniazid | PO, IM | Hepatotoxicity, peripheral neuritis |
| Rifampin | PO, IV | Hepatotoxicity |
| Rifapentine | PO | Hepatotoxicity |
| Rifabutin | PO | Hepatotoxicity |
| Pyrazinamide | PO | Hepatotoxicity, polyarthritis |
| Ethambutol | PO | Optic neuritis |
| SECOND-LINE DRUGS | ||
| Fluoroquinolones | ||
| Levofloxacin | PO, IV | GI intolerance |
| Moxifloxacin | PO, IV | GI intolerance |
| Injectable Drugs | ||
| Capreomycin | IM | Eighth nerve damage, nephrotoxicity |
| Kanamycin | IM, IV | Eighth nerve damage, nephrotoxicity |
| Amikacin | IM, IV | Eighth nerve damage, nephrotoxicity |
| Streptomycin | IM | Eighth nerve damage, nephrotoxicity |
| Others | ||
| Para-aminosalicylic acid | PO | GI intolerance |
| Ethionamide | PO | GI intolerance, hepatotoxicity |
| Cycloserine | PO | Psychoses, seizure, rash |
Isoniazid
Isoniazid [generic in United States, Isotamine 
] is the primary agent for treatment and prophylaxis of TB. This drug has early bactericidal activity and is superior to alternative drugs with regard to efficacy, toxicity, ease of use, patient acceptance, and affordability. With the exception of patients who cannot tolerate the drug, isoniazid should be taken by all individuals infected with isoniazid-sensitive strains of M. tuberculosis.
Antimicrobial Spectrum and Mechanism of Action
Isoniazid is highly selective for M. tuberculosis. The drug can kill tubercle bacilli at concentrations 10,000 times lower than those needed to affect gram-positive and gram-negative bacteria. Isoniazid is bactericidal to mycobacteria that are actively dividing but is only bacteriostatic to “resting” organisms.
Although the mechanism by which isoniazid acts is not known with certainty, available data suggest the drug suppresses bacterial growth by inhibiting synthesis of mycolic acid, a component of the mycobacterial cell wall. Because mycolic acid is not produced by other bacteria or by cells of the host, this mechanism would explain why isoniazid is so selective for tubercle bacilli.
Resistance
Tubercle bacilli can develop resistance to isoniazid during treatment. Acquired resistance results from spontaneous mutation. The precise mechanism underlying resistance has not been established. Emergence of resistance can be decreased through multidrug therapy. Organisms resistant to isoniazid are cross-resistant to ethionamide, but not to other drugs used for TB.
Pharmacokinetics
Absorption and Distribution.
Isoniazid is administered orally and intramuscularly. Absorption is good with both routes. Following absorption, isoniazid is widely distributed to tissues and body fluids, including cerebrospinal fluid (CSF).
Metabolism.
Isoniazid is inactivated in the liver, primarily by acetylation. The ability to acetylate isoniazid is genetically determined: about 50% of people in the United States are rapid acetylators, and the other 50% are slow acetylators. The drug’s half-life is about 1 hour in rapid acetylators and 3 hours in slow acetylators. It is important to note that differences in rates of acetylation generally have little effect on the efficacy of isoniazid, provided patients are taking the drug daily. However, nonhepatic toxicities may be more likely in slow acetylators because drug accumulation is greater in these patients.
Excretion.
Isoniazid is excreted in the urine, primarily as inactive metabolites. In patients who are slow acetylators and who also have renal insufficiency, the drug may accumulate to toxic levels.
Therapeutic Use
Isoniazid is indicated only for treating active and LTBI. When used for LTBI, the drug is administered alone or combined with rifapentine. When used for active TB, it must be taken in combination with at least one other agent (e.g., rifampin). For patient convenience, isoniazid is available in two fixed-dose combinations: (1) capsules, sold as Rifamate, containing 150 mg of isoniazid and 300 mg of rifampin; and (2) tablets, sold as Rifater, containing 50 mg of isoniazid, 120 mg of rifampin, and 300 mg of pyrazinamide.
Adverse Effects
Hepatotoxicity.
Isoniazid can cause hepatocellular injury and multilobular necrosis. Consequently, the FDA has issued a Black Box Warning. Deaths have occurred. Liver injury is thought to result from production of a toxic isoniazid metabolite. The greatest risk factor for liver damage is advancing age: the incidence is extremely low in patients younger than 20 years, 1.2% in those aged 35 to 49 years, 2.3% in those aged 50 to 64 years, and 8% in those older than 65 years. Patients should be informed about signs and symptoms of hepatitis and instructed to notify the provider immediately if these develop. Patients should also undergo monthly evaluation for these signs. Some clinicians perform monthly determinations of serum aspartate aminotransferase (AST) activity because elevation of AST activity is indicative of liver injury. However, because AST levels may rise and then return to normal, despite continued isoniazid use, increases in AST may not be predictive of clinical hepatitis. It is recommended that isoniazid be withdrawn if signs of hepatitis develop or if AST activity exceeds 3 to 5 times the pretreatment baseline. Caution should be exercised when giving isoniazid to alcoholics and individuals with preexisting disorders of the liver.
Black Box Warning: Isoniazid [Generic]
Isoniazid therapy may cause severe hepatitis. Fatalities have been reported.
Peripheral Neuropathy.
Dose-related peripheral neuropathy is the most common adverse event. Principal symptoms are symmetric paresthesias (tingling, numbness, burning, pain) of the hands and feet. Clumsiness, unsteadiness, and muscle ache may develop. Peripheral neuropathy results from isoniazid-induced deficiency in pyridoxine (vitamin B6). Prophylactic use of pyridoxine at 25-50 mg/day can decrease the risk of acquiring peripheral neuropathy. Preventive supplementation is especially important for at-risk people with diabetes or with high alcohol intake. If peripheral neuropathy develops, it can be reversed by administering pyridoxine, however, higher doses are required (typically 100 mg daily).
Other Adverse Effects.
Because isoniazid crosses the blood-brain barrier, a variety of central nervous system (CNS) effects can occur, including optic neuritis, seizures, dizziness, ataxia, and psychological disturbances (depression, agitation, impairment of memory, hallucinations, toxic psychosis). Gastrointestinal (GI) distress, dry mouth, and urinary retention occur on occasion. Allergy to isoniazid can produce fever and rashes. Antinuclear antibodies develop in 20% of patients taking this drug.
Drug Interactions
Interactions From Inhibiting Drug Metabolism.
Isoniazid is a strong inhibitor of three cytochrome P450 isoenzymes, namely CYP2C9, CYP2C19, and CYP2E1. By inhibiting these isoenzymes, isoniazid can raise levels of drugs that are metabolized by these isoenzymes, including phenytoin, carbamazepine, diazepam, and triazolam. Phenytoin is of particular concern. Plasma levels of phenytoin should be monitored, and phenytoin dosage should be reduced as appropriate. Dosage of isoniazid should not be changed.
Alcohol, Rifampin, Rifapentine, Rifabutin, and Pyrazinamide.
Daily ingestion of alcohol or concurrent therapy with rifampin, rifapentine, rifabutin, or pyrazinamide increases the risk for hepatotoxicity. Patients should be encouraged to reduce or eliminate alcohol intake.
Rifampin
Rifampin [Rifadin] equals isoniazid in importance as an anti-TB drug. Before the appearance of resistant tubercle bacilli, the combination of rifampin plus isoniazid was the most frequently prescribed regimen for uncomplicated pulmonary TB.
Antimicrobial Spectrum
Rifampin is a broad-spectrum antibiotic. The drug is active against most gram-positive bacteria as well as many gram-negative bacteria. The drug is bactericidal to M. tuberculosis and Mycobacterium leprae. Other bacteria that are highly sensitive include Neisseria meningitidis, Haemophilus influenzae, Staphylococcus aureus, and Legionella species.
Mechanism of Action and Bacterial Resistance
Rifampin inhibits bacterial DNA-dependent RNA polymerase and thereby suppresses RNA synthesis and, consequently, protein synthesis. The results are bactericidal. The drug is lipid soluble and hence has ready access to intracellular bacteria. Because mammalian RNA polymerases are not affected, rifampin is selectively toxic to microbes. Bacterial resistance to rifampin results from production of an altered form of RNA polymerase.
Pharmacokinetics
Absorption and Distribution.
Rifampin is well absorbed if taken on an empty stomach. However, if dosing is done with or shortly after a meal, both the rate and extent of absorption can be significantly lowered. Rifampin is distributed widely to tissues and body fluids; however, CSF distribution is only 10-20% of that in the systemic circulation.
Elimination.
Rifampin is eliminated primarily by hepatic metabolism. Only about 20% of the drug leaves in the urine. Rifampin induces hepatic drug-metabolizing enzymes, including those responsible for its own inactivation. As a result, the rate at which rifampin is metabolized increases over the first weeks of therapy, causing the half-life of the drug to decrease—from an initial value of about 4 hours down to 2 hours at the end of 2 weeks.
Therapeutic Use
Tuberculosis.
Rifampin is one of our most effective anti-TB drugs. This agent is bactericidal to tubercle bacilli at extracellular and intracellular sites. Rifampin is a drug of choice for treating pulmonary TB and disseminated disease. Because resistance can develop rapidly when rifampin is employed alone, the drug is always given in combination with at least one other anti-TB agent. Despite the capacity of rifampin to produce a variety of adverse effects, toxicity rarely requires discontinuing treatment.
Leprosy.
Rifampin is bactericidal to M. leprae and has become an important agent for treating leprosy. (In 2015, the CDC reported 100 people in the United States had leprosy.)
Meningococcus Carriers.
Rifampin is highly active against N. meningitidis and is indicated for short-term therapy to eliminate this bacterium from the nasopharynx of asymptomatic carriers. Because resistant organisms emerge rapidly, rifampin should not be used against active meningococcal disease.
Adverse Effects
Rifampin is generally well tolerated. When employed at recommended dosages, the drug rarely causes significant toxicity.
Hepatotoxicity.
Rifampin can cause hepatotoxicity, posing a risk for jaundice and even hepatitis. Asymptomatic elevation of liver enzymes occurs in about 14% of patients; however, the incidence of overt hepatitis is less than 1%. Hepatotoxicity is most likely in people who abuse alcohol and patients with preexisting liver disease. These individuals should be monitored closely for signs of liver dysfunction. Tests of liver function (serum aminotransferase levels) should be made before treatment and every 2 to 4 weeks thereafter. Patients should be informed about signs of hepatitis (jaundice, anorexia, malaise, fatigue, nausea) and instructed to notify the prescriber if they develop.
Discoloration of Body Fluids.
Rifampin frequently imparts a red-orange color to urine, sweat, saliva, and tears. Patients should be informed of this harmless effect. Permanent staining of soft contact lenses has occurred on occasion, and hence the patient should consult an ophthalmologist regarding contact lens use.
Other Adverse Effects.
Gastrointestinal disturbances (anorexia, nausea, abdominal discomfort) and cutaneous reactions (flushing, itching, rash) occur occasionally. Rarely, intermittent high-dose therapy has produced a flu-like syndrome, characterized by fever, chills, muscle aches, headache, and dizziness. This reaction appears to have an immunologic basis. In some patients, high-dose therapy has been associated with shortness of breath, hemolytic anemia, shock, and acute renal failure.
Drug Interactions
Accelerated Metabolism of Other Drugs.
Rifampin is a powerful inducer of CYP1A2, CYP2A6, CYP2B6, CYP2C19, CYP2C8, CYP2C9, and CYP3A4 cytochrome P450 isoenzymes. It can hasten the metabolism of many drugs, thereby reducing their effects. This interaction is of special concern with oral contraceptives, warfarin (an anticoagulant), and certain protease inhibitors and NNRTIs used for HIV infection. Women taking oral contraceptives should consider a nonhormonal form of birth control. The dosage of warfarin may need to be increased.
Isoniazid and Pyrazinamide.
Rifampin, isoniazid, and pyrazinamide are all hepatotoxic. Hence, when these drugs are used in combination, as they often are, the risk for liver injury is greater than when they are used alone.
Rifapentine
Rifapentine [Priftin] is a long-acting analog of rifampin. Both drugs have the same mechanism of action, adverse effects, and drug interactions. When rifapentine was approved in 1998, it was the first new drug for TB in more than 25 years.
Actions and Uses
Rifapentine is indicated only for pulmonary TB. At therapeutic doses, the drug is lethal to M. tuberculosis. The mechanism underlying cell kill is inhibition of DNA-dependent RNA polymerase. To minimize emergence of resistance, rifapentine must always be combined with at least one other anti-TB drug.
Pharmacokinetics
Rifapentine is well absorbed from the GI tract, especially in the presence of food. Plasma levels peak 5 to 6 hours after dosing. In the liver, rifapentine undergoes conversion to 25-desacetyl rifapentine, an active metabolite. Excretion is primarily (70%) fecal. Rifapentine and its metabolite have the same half-life—about 13 hours.
Adverse Effects
Rifapentine is well tolerated at recommended doses. Like rifampin, the drug imparts a red-orange color to urine, sweat, saliva, and tears. Permanent staining of contact lenses can occur.
Hepatotoxicity is the principal concern. In clinical trials, serum transaminase levels increased in 5% of patients. However, overt hepatitis occurred in only one patient. Because of the risk for hepatotoxicity, liver function tests (bilirubin, serum transaminases) should be performed at baseline and monthly thereafter. Patients should be informed about signs of hepatitis (jaundice, anorexia, malaise, fatigue, nausea) and instructed to notify the prescriber if these develop.
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
