First-Line Antituberculosis Drugs

FIRST-LINE ANTITUBERCULOSIS DRUGS

Isoniazid

Isoniazid (isonicotinic acid hydrazide, or INH) is the most active drug for the treatment of tuberculosis caused by susceptible strains. It is a synthetic agent with a structural similarity to that of pyridoxine.

Mechanism of Action

Isoniazid is active against susceptible bacteria only when they are undergoing cell division. Susceptible bacteria may continue to undergo one or two divisions before multiplication is arrested. Isoniazid can inhibit the syn-thesis of mycolic acids, which are essential components of mycobacterial cell walls. The mycobacterial enzyme cata-lase–peroxidase KatG activates the administered isoni-azid to its biologically active form. The target sites for the activated isoniazid action are acyl carrier protein AcpM and Kas A, a -ketoaceyl carrier protein synthetase that blocks mycolic acid synthesis. Isoniazid exerts its lethal effects at the target sites by forming covalent complexes.

Antimicrobial Activity

Isoniazid is bactericidal against actively growing M. tu-berculosis and bacteriostatic against nonreplicating or-ganisms. The minimal tuberculostatic inhibitory concen-tration (MIC) of isoniazid is 0.025 to 0.05  μg/mL.

Resistance

The most common mechanism of isoniazid resistance is the mycobacteria’s formation of mutations in cata-lase–peroxidase KatG, the enzyme that is responsible for activation of isoniazid. Another resistance mecha-nism is through a missense mutation related to the inhA gene involved in mycolic acid biosynthesis.

An active tuberculosis cavity may contain as many as 10⁷ to 10¹⁰ microorganisms. The frequency of isoni-azid-resistant mutants in a susceptible mycobacterial population is about 1 bacillus in 10⁶, and this organism is readily selected out if isoniazid is given as the sole agent. If a second drug having a similar drug resistance (1in 10⁶) is combined with isoniazid, the odds that a bacillus is resistant to both drugs become 1 in 10¹². Therefore, it is vital to combine at least two antitubercu-lar agents to which the organism is susceptible.

Pharmacokinetic Properties

Isoniazid is water soluble and is well absorbed when administered either orally or parenterally. Oral absorp-tion is decreased by concurrent administration of aluminum-containing antacids.

Isoniazid does not bind to serum proteins; it diffuses readily into all body fluids and cells, including the caseous tuberculous lesions. The drug is detectable in significant quantities in pleural and ascitic fluids, as well as in saliva and skin. The concentrations in the central nervous system (CNS) and cerebrospinal fluid are gen-erally about 20% of plasma levels but may reach close to 100% in the presence of meningeal inflammation.

Isoniazid is acetylated to acetyl isoniazid by N-acetyl-transferase, an enzyme in liver, bowel, and kidney. Individuals who are genetically rapid acetylators will have a higher ratio of acetyl isoniazid to isoniazid than will slow acetylators. Rapid acetylators were once thought to be more prone to hepatotoxicity, but this is not proved. The slow or rapid acetylation of isoniazid is rarely important clinically, although slow inactivators tend to develop pe-ripheral neuropathy more readily. Metabolites of isoni-azid and small amounts of unaltered drug are excreted in the urine within 24 hours of administration.

Clinical Uses

Isoniazid is among the safest and most active mycobac-tericidal agents. It is considered the primary drug for use in all therapeutic and prophylactic regimens for sus-ceptible tuberculosis infections. It is also included in the first-line drug combinations for use in all types of tu-berculous infections. Isoniazid is preferred as a single agent in the treatment of latent tuberculosis infections in high-risk persons having a positive tuberculin skin re-action with no radiological or other clinical evidence of tuberculosis. Mycobacterium kansasii is usually suscep-tible to isoniazid, and it is included in the standard mul-tidrug treatment regimen.

Adverse Effects

The incidence and severity of adverse reactions to iso-niazid are related to dosage and duration of therapy. Isoniazid-induced hepatitis and peripheral neuropathy are two major untoward effects.

A minor asymptomatic increase in liver aminotrans-ferase is seen in 10 to 20% of patients, whereas fatal hepatitis is seen in fewer than 1% of isoniazid recipi-ents. Risk factors for hepatitis include underlying liver disease, advanced age, pregnancy, and combination therapy with acetaminophen. Early recognition and prompt discontinuation of the drug is recommended to prevent further damage to the liver.

Peripheral neuropathy is observed in 10 to 20% of patients taking more than 5 mg/kg/day of isoniazid. Patients with underlying chronic disorders such as alco-holism, malnutrition, diabetes, and AIDS are at particu-lar risk for neurotoxicity; compared with fast acetyla-tors, neurotoxicity is more frequent in slow acetylators because slow acetylators achieve higher drug plasma levels. Isoniazid promotes renal excretion of pyridoxine, resulting in a relative deficiency and neuropathy. CNS toxicity may range from excitability and seizures to psy-chosis. The neurotoxic effects are reversed without al-tering the antimycobacterial action by the administra-tion of 10 to 50 mg/day of pyridoxine. Other adverse reactions include gastrointestinal (GI) intolerance, ane-mia, rash, tinnitus, and urinary retention.

Drug Interactions

High isoniazid plasma levels inhibit phenytoin metabo-lism and potentiate phenytoin toxicity when the two drugs are coadministered. The serum concentrations of phenytoin should be monitored, and the dose should be adjusted if necessary.

Rifampin

Mechanism of Action

Rifampin is a semisynthetic macrocyclic antibiotic pro-duced from Streptomyces mediterranei. It is a large lipid-soluble molecule that is bactericidal for both intracellu-lar and extracellular microorganisms. Rifampin binds strongly to the -subunit of bacterial DNA-dependent RNA polymerase and thereby inhibits RNA synthesis. Rifampin does not affect mammalian polymerases.

Antibacterial Activity and Resistance

In addition to M. tuberculosis, rifampin is active against Staphylococcus aureus, Neisseria meningitidis, Haemo-philus influenzae, Chlamydiae, and certain viruses. Rifampin resistance results from a point mutation or deletion in rpoB, the gene for the -subunit of RNA polymerase, thereby preventing the binding of RNA polymerase.

Pharmacokinetic Properties

Rifampin is well absorbed orally, and a peak serum con-centration is usually seen within 2 to 4 hours. Drug ab- sorption is impaired if rifampin is given concurrently with aminosalicylic acid or is taken immediately after a meal. It is widely distributed throughout the body, and therapeutic levels are achieved in all body fluids, in-cluding cerebrospinal fluid. Rifampin is capable of in-ducing its own metabolism, so its half-life can be re-duced to 2 hours within a week of continued therapy. The deacetylated form of rifampin is active and under-goes biliary excretion and enterohepatic recirculation. Most of the drug is excreted into the GI tract and a small amount in the urine. Moderate dose adjustment is required in patients with underlying liver disease.

Clinical Uses

Rifampin is a first-line antitubercular drug used in the treatment of all forms of pulmonary and extrapul-monary tuberculosis. Rifampin is an alternative to iso-niazid in the treatment of latent tuberculosis infection. Rifampin also may be combined with an antileprosy agent for the treatment of leprosy and to protect those in close contact with patients having H. influenza type b and N. meningitidis infection; rifampin is also used in methicillin-resistant staphylococcal infections, such as osteomyelitis and prosthetic valve endocarditis.

Adverse Reactions

The most commonly observed side effects are GI dis-turbances and nervous system symptoms, such as nau-sea, vomiting, headache, dizziness, and fatigue. Hepatitis is a major adverse effect, and the risk is highest in pa-tients with underlying liver diseases and in slow isoni-azid acetylators; the rate of hepatotoxicity is increased if isoniazid and rifampin are combined.

Other major untoward reactions are the result of ri-fampin’s ability to induce hepatic cytochrome P-450 en-zymes, leading to an increased metabolism of many drugs; this action has especially complicated the treat-ment of tuberculosis in HIV-infected patients whose reg-imen includes protease inhibitors and nonnucleoside re-verse transcriptase. Since rifabutin has relatively little of these effects, it is commonly substituted for rifampin in the treatment of tuberculosis in HIV-infected patients.

Hypersensitivity reactions, such as pruritus, cuta-neous vasculitis, and thrombocytopenia, are seen in some patients, and an immune-mediated systemic flulike syn-drome with thrombocytopenia also has been described. Rifampin imparts a harmless red-orange color to urine, feces, saliva, sweat, tears, and contact lenses. Patients should be advised of such discoloration of body fluids.

Pyrazinamide

Pyrazinamide is a synthetic analogue of nicotinamide. Its exact mechanism of action is not known, although its target appears to be the mycobacterial fatty acid synthetase involved in mycolic acid biosynthesis. Pyrazinamide requires an acidic environment, such as that found in the phagolysosomes, to express its tuber-culocidal activity. Thus, pyrazinamide is highly effective on intracellular mycobacteria. The mycobacterial en-zyme pyrazinamidase converts pyrazinamide to pyrazi-noic acid, the active form of the drug. A mutation in the gene (pncA) that encodes pyrazinamidase is responsi-ble for drug resistance; resistance can be delayed through the use of drug combination therapy.

Pyrazinamide is well absorbed from the GI tract and is widely distributed throughout the body. It penetrates tissues, macrophages, and tuberculous cavities and has excellent activity on the intracellular organisms; its plasma half-life is 9 to 10 hours in patients with normal renal function. The drug and its metabolites are ex-creted primarily by renal glomerular filtration.

Clinical Uses

Pyrazinamide is an essential component of the mul-tidrug short-term therapy of tuberculosis. In combina-tion with isoniazid and rifampin, it is active against the intracellular organisms that may cause relapse.

Adverse Reactions

Hepatotoxicity is the major concern in 15% of pyrazi-namide recipients. It also can inhibit excretion of urates, resulting in hyperuricemia. Nearly all patients taking pyrazinamide develop hyperuricemia and possibly acute gouty arthritis. Other adverse effects include nausea, vomiting, anorexia, drug fever, and malaise. Pyrazinamide is not recommended for use during pregnancy.

Ethambutol

Ethambutol is a water-soluble, heat-stable compound that acts by inhibition of arabinosyl transferase en-zymes that are involved in cell wall biosynthesis. Nearly all strains of M. tuberculosis and M. kansasii and most strains of Mycobacterium avium-intracellulare are sensi-tive to ethambutol. Drug resistance relates to point mu-tations in the gene (EmbB) that encodes the arabinosyl transferases that are involved in mycobacterial cell wall synthesis.

Orally administered ethambutol is well absorbed (70–80%) from the gut, and peak serum concentrations are obtained within 2 to 4 hours of drug administration; it has a half-life of 3 to 4 hours. Ethambutol is widely distributed in all body fluids, including the cere-brospinal fluid, even in the absence of inflammation. A majority of the unchanged drug is excreted in the urine within 24 hours of ingestion. Up to 15% is excreted in the urine as an aldehyde and a dicarboxylic acid metabolite. Ethambutol doses may have to be modified in patients with renal failure.

Ethambutol has replaced aminosalicylic acid as a first-line antitubercular drug. It is commonly included as a fourth drug, along with isoniazid, pyrazinamide, and rifampin, in patients infected with MDR strains. It also is used in combination in the treatment of M. avium-intracellulare infection in AIDS patients.

The major toxicity associated with ethambutol use is retrobulbar neuritis impairing visual acuity and red-green color discrimination; this side effect is dose re-lated and reverses slowly once the drug is discontinued. Mild GI intolerance, allergic reaction, fever, dizziness, and mental confusion are also possible. Hyperuricemia is associated with ethambutol use due to a decreased re-nal excretion of urates; gouty arthritis may result.

Streptomycin

Streptomycin, an aminoglycoside antibiotic, was the first drug shown to reduce tuberculosis mortality. Streptomycin is bactericidal against M. tuber-culosis in vitro but is inactive against intracellular organisms. Most M. tuberculosis strains and nontuber-culosis species, such as M. kansasii and M. avium-intracellulare, are sensitive. Spontaneous resistance to streptomycin, seen in approximately 1 in 10⁶ tubercle bacilli, is related to a point mutation that involves the gene (rpsl or rrs) that encodes for ribosomal proteins and binding sites. About 80% of strains that are resist-ant to isoniazid and rifampin are also resistant to strep-tomycin.

Streptomycin is indicated as a fourth drug in combi-nation with isoniazid, rifampin, and pyrazinamide in pa-tients at high risk for drug resistance. It is also used in the treatment of streptomycin-susceptible MDR tuber-culosis.

Ototoxicity and nephrotoxicity are the major con-cerns during administration of streptomycin and other aminoglycosides. The toxic effects are dose related and increase with age and underlying renal insufficiency. All aminoglycosides require dose adjustment in renal fail-ure patients. Ototoxicity is severe when aminoglyco-sides are combined with other potentially ototoxic agents.