Inhibition of Protein Synthesis

The rifamycins (rifampin, rifabutin, rifapentine) are bactericidal and inhibit deoxyribonucleic acid (DNA)-dependent ribonucleic acid (RNA) polymerase of mycobacteria (but not mammals). This enzyme is composed of four subunits; rifamycins bind to the β-subunit, which results in blocking the growing RNA chain (Fig. 49-2). Resistance is conferred by single mutations that tend to occur (>95%) in an 81-base pair region of the rpoB gene that codes for the β-subunit. The aminoglycosides streptomycin, kanamycin, and amikacin act by inhibiting protein synthesis and are described in Chapter 47. Capreomycin, a macrocyclic polypeptide antibiotic, has similar activity and toxicities as aminoglycosides.

FIGURE 49–2 Mechanism of rifampin action. The drug binds to the β-subunit of DNA-dependent RNA polymerase and inhibits RNA synthesis. A, Drug is absent. B, Drug is bound to the polymerase and distorts the conformation of the enzyme so that it cannot initiate a new chain.

Inhibition of Cell Wall Synthesis: Isoniazid (INH)

INH is a bactericidal agent that is thought to inhibit mycolic acid synthesis. Mycolic acids are a major constituent of mycobacterial cell walls (along with arabinogalactan and peptidoglycan). The mode of action of INH is complex, and a current model is shown in Figure 49-3. INH is a prodrug that has to be activated by the M. tuberculosis catalase-peroxidase enzyme encoded by the katG gene. Deletions or mutations in this gene may account for 40% to 50% of clinical INH-resistant isolates. Other mechanisms of resistance may include mutations in three other genes. inhA and kasA code for mycolic acid biosynthetic enzymes, and mutations are found in some INH-resistant isolates. ahpC has also been associated with some INH resistance strains, but its role is unclear.

FIGURE 49–3 Mechanism by which isoniazid kills tubercle bacilli. INH enters by passive diffusion and is activated by katG to a range of reactive species or radicals and isonicotinic acid. These attack multiple targets, including mycolic acid synthesis, lipid peroxidation, DNA, and NAD metabolism. Deficient efflux and insufficient antagonism of INH-derived radicals, such as defective antioxidative defense, may underlie the unique susceptibility of M. tuberculosis to INH.

Pyrazinamide (PZA) is active only against M. tuberculosis and M. africanum; it is inactive against M. bovis and nontuberculous mycobacteria. PZA is active at a low pH (e.g., pH 5), is bactericidal, and has excellent sterilizing activity against semidormant bacteria. PZA is thought to enter M. tuberculosis by passive diffusion and is then converted to the active metabolite pyrazinoic acid (POA) by nicotinamidase/pyrazinamidase (PZase). The target of POA may involve fatty acid synthase I and disruption of mycobacterial membranes by acid (Fig. 49-4). Selected mutations in the PZase gene (pncA) are associated with PZA resistance in M. tuberculosis.

FIGURE 49–4 Proposed mechanism of action of pyrazinamide (PZA). PZA is converted to pyrazinoic acid (POA) by the enzyme encoded by pncA. Its ability to kill M. tuberculosis and not other Mycobacteria species may be due to a selective defect in POA efflux in M. tuberculosis. Proposed targets include the mycobacterial fatty acid synthase 1 and disruption of mycobacterial membranes by acidic action.

Modified from Chan ED, Chatterjee D, Iseman MD, et al. Pyrazinamide, ethambutol, ethionamide, and aminoglycosides. In Rom WN, Garay SM, editors: Tuberculosis, 2nd ed, Philadelphia, Lippincott, Williams & Wilkins, 2004.

The mechanism of action of ethambutol is not well understood. It is thought to interfere with mycobacterial cell wall synthesis by inhibiting synthesis of polysaccharides and transfer of mycolic acids to the cell wall. The target is thought to be encoded by a three-gene operon (embC, embA, embB) that produces arabinosyl transferases that mediate polymerization of arabinose into arabinogalactan, particularly embB. Resistance to ethambutol is most common among M. tuberculosis isolates that are also resistant to INH and rifampin (i.e., MDR strains), probably because of mutations in embB. Ethambutol is effective only on actively dividing mycobacteria.

Other Mechanisms

p-Aminosalicylic acid (PAS) acts as a competitive inhibitor of p-aminobenzoic acid in folate synthesis. Because PAS inhibits only this step in M. tuberculosis, and sulfonamides do not generally inhibit mycobacteria, the enzyme in tubercle bacilli is thought to be distinct.

Other agents used in treatment of mycobacterial diseases include the fluoroquinolones (e.g., levofloxacin, moxifloxacin), which have emerged as important second-line drugs used in the treatment of XDR-TB. They are discussed in Chapter 48.

First Line

INH is well absorbed orally and is widely distributed, with peak concentrations achieved in pleural, peritoneal, and synovial fluids. Cerebrospinal fluid (CSF) concentrations are approximately 20% of plasma levels but can increase to 100% with meningeal inflammation. INH is metabolized by a liver N-acetyltransferase, and the rate of acetylation determines its concentration in plasma and its half-life. As discussed in Chapter 2, slow acetylation is inherited as an autosomal recessive trait. The average plasma concentration of drug in rapid acetylators is half of that in slow acetylators. However, there is no evidence that these differences are therapeutically important if INH is administered once daily, because plasma levels are well above inhibitory concentrations.

Rifampin is well absorbed orally and widely distributed, achieving therapeutic concentrations in lung, liver, bile, bone, and urine and entering pleural, peritoneal, and synovial fluids and CSF, tears, and saliva. Its high lipid solubility enhances its entrance into phagocytic cells, where it kills intracellular bacteria. Rifampin is metabolized in the liver to a desacetyl derivative that is biologically active. Unmetabolized drug is excreted in bile and reabsorbed from the gastrointestinal (GI) tract into the enterohepatic circulation; the deacetylated metabolite is poorly reabsorbed with eventual elimination in urine and from the GI tract. Rifampin induces its own metabolism by inducing the expression of cytochrome P450s, resulting in increased biliary excretion with continued therapy. Induction of metabolism results in reduction of the plasma life by 20% to 40% after 7 to 10 days of therapy. Patients with severe liver disease may require dose reduction, but dose adjustment is not necessary in renal failure. Oral bioavailability of rifabutin is less than that of rifampin, and the plasma half-life is approximately 10 times greater. Rifabutin is more lipid soluble than rifampin and is extensively distributed. Rifabutin also induces its own metabolism but has less of an effect on cytochrome P450s. Rifapentine is used once weekly in the continuation phase of highly selected patients with TB. It is metabolized in a similar manner but does not significantly induce its own metabolism.

Rifamycins are among the most-potent known inducers of hepatic cytochrome P450 oxidative enzymes and the P-glycoprotein transport system and have a large number of drug interactions. This greatly impacts clinical care as discussed in the following text.

PZA is well absorbed orally and widely distributed, readily penetrating cells and the walls of cavities. It enters the CSF if meninges are inflamed. PZA is metabolized by the liver, and its metabolic products are excreted mainly by the kidneys. Dose modifications are necessary in renal failure.

Approximately 75% to 80% of ethambutol is orally absorbed and widely distributed. Ethambutol crosses the placenta, and under normal circumstances, little penetrates into the CSF. However, with meningeal inflammation, CSF concentrations can reach 10% to 50% of plasma values. Ethambutol is mainly excreted unchanged by the kidneys, and dose adjustments are necessary in renal failure. It can be removed from the body by peritoneal dialysis or hemodialysis.

Second Line

The fluoroquinolones are discussed in Chapter 48 and the aminoglycosides in Chapter 47.

Capreomycin is administered by intramuscular (IM) or intravenous (IV) routes and is eliminated by the kidneys. It enters the CSF poorly and accumulates during renal dysfunction.

Ethionamide is well absorbed orally and widely distributed, entering the CSF and reaching concentrations equal to those in plasma. It is metabolized in the liver, with metabolites renally excreted. Ethionamide interferes with INH acetylation.

Cycloserine is rapidly absorbed orally and widely distributed, with CSF concentrations equal to those in plasma. Approximately 35% is metabolized; the remainder is excreted by glomerular filtration. It accumulates in renal failure but can be removed by hemodialysis.

PAS is available in the United States as granules in 4-g packets, and a solution for IV administration is available in Europe. PAS is well absorbed orally and enters lung tissue and pleural fluid. It is metabolized in the liver by an acetylase different from that acting on isoniazid. Most of the absorbed dose is excreted in the urine as metabolites.

First Line

Although adverse reactions to INH are not common, a few are serious. Hepatotoxicity is the most potentially serious side effect, although recent data suggest the incidence is lower than previously thought (0.1% to 0.15%). The risk of hepatotoxicity is age related and is rare in persons less than 20 years old; however, the incidence is approximately 2% in people aged 50 to 64 years old. The risk of hepatitis is higher when INH is administered with other potentially hepatotoxic drugs such as PZA or rifampin. The risk may also increase with underlying liver disease, a history of heavy alcohol consumption, or in the postpartum period (especially among Hispanics). Asymptomatic elevation of aminotransferases, which are generally transient, can occur in 10% to 20% of those taking INH for LTBI. Although the incidence of clinical hepatitis is low (approximately 1% of recipients), it can be fatal when it occurs. The drug should be discontinued when aminotransferases are increased by more than fivefold normal in asymptomatic patients or more than threefold in symptomatic patients. Patients should be advised to discontinue INH at the onset of symptoms consistent with hepatitis such as nausea, loss of appetite, and dull mid-abdominal pain. Routine laboratory monitoring is recommended for persons at increased risk of toxicity. Liver function tests should be obtained on any patient who develops symptoms that could suggest hepatitis.

Other side effects of INH include peripheral neuropathy, which occurs more commonly in slow acetylators, those with a nutritional deficiency, diabetes, HIV infection, renal failure, and alcoholism, and in pregnant and breast-feeding women. The neuropathy is due to a relative pyridoxine deficiency, because INH increases the excretion of pyridoxine. Thus pyridoxine is recommended for all patients with these risk factors to help prevent neuropathy and may be administered to reverse the neuropathy, should it occur. INH-induced central nervous system (CNS) toxicity is less common than peripheral neuropathy and includes dysarthria, irritability, psychosis, seizures, dysphoria, and inability to concentrate, but the prevalence is not well quantified. Other side effects include rare hypersensitivity reactions such as fever, rash, hemolytic anemia, and vasculitis. CNS toxicity can also be treated with pyridoxine. A lupus-like syndrome is rare (<1%), although approximately 20% of patients develop anti-nuclear antibodies.

Rifampin is generally well tolerated. Patients should be advised that it will result in an orange discoloration of sputum, urine, sweat, and tears, and soft contact lenses may become stained. Rifampin causes nausea and vomiting in 1% to 2% of patients, but they are rarely severe enough to warrant discontinuation. The major toxicity of rifampin is hepatitis. Transient, asymptomatic hyperbilirubinemia may occur in up to 0.6% of patients. More severe hepatitis that has a cholestatic pattern may also occur. It is more common when the drug is given in combination with INH (2.7%) than when given alone or in combination with other drugs (1.1%). Severe hepatic toxicity has been reported when rifampin is used in combination with PZA for short-course (2-month) therapy for treatment of LTBI, and the risk of death has been estimated to be as high as 0.09%. This combination is no longer recommended for LTBI, but both drugs remain important components of multidrug regimens described previously.

Hypersensitivity reactions are uncommon but include thrombocytopenia, hemolysis, transient leukopenia, and renal failure caused by interstitial nephritis. A flu-like syndrome with fever, chills, muscle aches, headache, and dizziness may occur when patients take the drug on a biweekly regimen, but it does not occur with a daily regimen.

Rifampin interacts with many other drugs, usually resulting in increased metabolism and enhanced clearance. It is a potent inducer of cytochrome P450 enzymes, resulting in a number of clinically significant drug-drug interactions (Box 49-1). The concomitant use of anti-TB drugs, including rifampin, and antiretroviral drugs is complex. Rifampin cannot be used with protease inhibitors, although it can be used with nucleoside and some non-nucleoside reverse transcriptase inhibitors. Rifabutin has less of an effect on cytochrome P450s than rifampin and can be used with several protease inhibitors. It is substituted for rifampin when treating HIV-infected patients taking protease inhibitors. The Centers for Disease Control and Prevention has established a website that provides updated information on TB/HIV drug interactions at http://www.cdc.gov/nchstp/tb/tb_hiv_drugs/toc.htm.

Women of child-bearing age should be advised to use alternative contraceptive methods while on rifampin, because oral contraceptives will not be effective.

Adverse effects of rifabutin are similar to those of rifampin. In addition, neutropenia has been described, especially among persons with advanced HIV/AIDS. Rifabutin can also cause uveitis, and the risk is increased with higher doses or when used in combination with macrolide antibiotics that reduce its clearance. It may also occur with other drugs that reduce clearance, such as protease inhibitors and azole antifungal drugs. Although drug interactions are less problematic with rifabutin than with rifampin, they still occur, and close monitoring is required.

Adverse effects of rifapentine are similar to those of rifampin. Monitoring is also similar.

Hepatotoxicity is the most serious adverse effect of PZA, and elevation of liver aminotransferase concentration is the first sign. The effect is less frequent in patients who receive the more current lower doses as compared with the higher doses used in earlier trials. Mild anorexia and nausea are common, but severe nausea and vomiting are rare. PZA causes hyperuricemia by inhibiting renal excretion of urate. Clinical gout caused by PZA is rare, although non-gouty polyarthralgia can occur in up to 40% of patients. As mentioned earlier, severe hepatotoxicity has been reported among patients taking rifampin and PZA for short-course therapy for LTBI, and liver function should be carefully monitored.

The most important toxicity of ethambutol is a dose-related retrobulbar (optic) neuritis. This is manifest as decreased visual acuity or decreased red-green color discrimination. Patients should have baseline visual acuity and color discrimination monitored and be questioned about possible visual disturbances. Monthly testing is recommended for patients taking doses greater than 15 mg/kg/day, receiving the drug for longer than 2 months, or with renal insufficiency.

Second Line

Most second-line drugs are less active against M. tuberculosis and have significantly greater toxicity. They are generally used in treatment of drug-resistant TB (including MDR-TB) and should be used only in consultation with an expert.

Adverse effects of the aminoglycosides and fluoroquinolones are discussed in Chapters 47 and 48. Adverse effects of capreomycin are similar to those of aminoglycosides and include nephrotoxicity and ototoxicity. Close monitoring of renal function is required.

CNS effects are most important for cycloserine and are not uncommon. They range from mild reactions, such as headache or restlessness, to severe reactions including depression, psychosis, and seizures. Cycloserine may exacerbate underlying seizure disorders or mental illness. Pyridoxine may help prevent and treat these side effects. Rarely cycloserine can cause peripheral neuropathy.

Ethionamide frequently causes significant GI reactions, and many patients cannot tolerate elevated doses. Nausea, vomiting, abdominal pain, diarrhea, a metallic taste in the mouth, and many CNS complaints including depression, headache, and feelings of restlessness are typical. Endocrine disturbances including gynecomastia, alopecia, hypothyroidism, and impotence have been described. Diabetes may be more difficult to manage. Ethionamide is similar in structure to INH and may cause similar side effects, including hepatitis (approximately 2%). Liver function tests should be monitored if there is underlying liver disease and if symptoms develop. Thyroid hormone levels should also be monitored.

The most common side effects of PAS include nausea, vomiting, abdominal pain, and diarrhea. The incidence of GI side effects is lower with the granular formulation, which is the only formulation available in the United States. A malabsorption syndrome has been described, and hypothyroidism is not uncommon, especially among those taking PAS and ethionamide. Hepatitis is uncommon. With prolonged therapy, thyroid function should be monitored.

Chemotherapy-Associated Reactions in Leprosy

Patients with leprosy can experience episodic immunologically mediated acute inflammatory responses termed “reactions,” which can cause nerve damage (see Clinical Problems Box). These reactions can be characterized by swelling and edema in preexisting skin lesions, or peripheral neuropathy/neuritis, which can cause pain, tenderness, and loss of function. They occur in up to one third of patients with leprosy and, if not recognized and treated aggressively, can lead to irreversible nerve damage and limb deformity. There are two common types: type I, or reversal, reactions characterized by cellular hypersensitivity; and type 2, or erythema nodosum leprosum, characterized by a systemic inflammatory response to immune complex deposition. In-depth characterization and treatment of these two types of reactions are beyond the scope of this chapter. However, the reversal reactions typically occur after initiation of treatment (especially with dapsone and rifampin) but can occur spontaneously before therapy or after multidrug therapy. A decline in type 2 reactions has been observed since introduction of multidrug therapy and is thought to be due in part to the antiinflammatory effects of daily clofazimine treatment. Recurrences of both types of reactions are common and can result in prolonged use of steroids for suppression.