Basic and Clinical Pharmacology, 13th Ed.

Antimycobacterial Drugs

Daniel H. Deck, PharmD, & Lisa G. Winston, MD*

CASE STUDY

A 45-year-old homeless man presents to the emergency department complaining of a 2-month history of fatigue, weight loss (10 kg), fevers, night sweats, and a productive cough. He is currently living on the street and has spent time in homeless shelters and prison in the last several years. He reports drinking 2–3 pints of hard alcohol per day for the last 15 years and also reports a history of intravenous drug use. In the emergency department, a chest X-ray shows a right apical infiltrate. Given the high suspicion for pulmonary tuberculosis, the patient is placed in respiratory isolation. His first sputum smear shows many acid-fast bacilli, and a rapid HIV antibody test returns with a positive result. What drugs should be started for treatment of presumptive pulmonary tuberculosis? Does the patient have a heightened risk of developing medication toxicity? If so, which medication(s) would be likely to cause toxicity?

Mycobacteria are intrinsically resistant to most antibiotics. Because they grow more slowly than other bacteria, antibiotics that are most active against rapidly growing cells are relatively ineffective. Mycobacterial cells can also be dormant and thus completely resistant to many drugs or killed only very slowly. The lipid-rich mycobacterial cell wall is impermeable to many agents. Mycobacterial species are intracellular pathogens, and organisms residing within macrophages are inaccessible to drugs that penetrate these cells poorly. Finally, mycobacteria are notorious for their ability to develop resistance. Combinations of two or more drugs are required to overcome these obstacles and to prevent emergence of resistance during the course of therapy. The response of mycobacterial infections to chemotherapy is slow, and treatment must be administered for months to years, depending on which drugs are used. The drugs used to treat tuberculosis, atypical mycobacterial infections, and leprosy are described in this chapter.

image DRUGS USED IN TUBERCULOSIS

Isoniazid (INH), rifampin (or other rifamycin)pyrazinamideethambutol, and streptomycin are the traditional five first-line agents for treatment of tuberculosis (Table 47–1). Streptomycin is no longer recommended as first-line therapy in most settings. Isoniazid and rifampin are the most active drugs. An isoniazid-rifampin combination administered for 9 months will cure 95–98% of cases of tuberculosis caused by susceptible strains. The addition of pyrazinamide to an isoniazid-rifampin combination for the first 2 months allows the total duration of therapy to be reduced to 6 months without loss of efficacy (Table 47–2). In practice, therapy is usually initiated with a four-drug regimen of isoniazid, rifampin, pyrazinamide, and ethambutol until susceptibility of the clinical isolate has been determined. Neither ethambutol nor other drugs such as streptomycin adds substantially to the overall activity of the regimen (ie, the duration of treatment cannot be further reduced if another drug is used), but the fourth drug provides additional coverage if the isolate proves to be resistant to isoniazid, rifampin, or both. The prevalence of isoniazid resistance among clinical isolates in the United States is approximately 10%. Prevalence of resistance to both isoniazid and rifampin (which is termed multidrug resistance) is about 3%. Resistance to rifampin alone is rare.

TABLE 47–1 Antimicrobials used in the treatment of tuberculosis.

image

TABLE 47–2 Recommended duration of therapy for tuberculosis.

image

ISONIAZID

Isoniazid is the most active drug for the treatment of tuberculosis caused by susceptible strains. It is a small molecule (MW 137) that is freely soluble in water. The structural similarity to pyridoxine is shown below.

image

In vitro, isoniazid inhibits most tubercle bacilli at a concentration of 0.2 mcg/mL or less and is bactericidal for actively growing tubercle bacilli. It is less effective against atypical mycobacterial species. Isoniazid penetrates into macrophages and is active against both extracellular and intracellular organisms.

Mechanism of Action & Basis of Resistance

Isoniazid inhibits synthesis of mycolic acids, which are essential components of mycobacterial cell walls. Isoniazid is a prodrug that is activated by KatG, the mycobacterial catalase-peroxidase. The activated form of isoniazid forms a covalent complex with an acyl carrier protein (AcpM) and KasA, a beta-ketoacyl carrier protein synthetase, which blocks mycolic acid synthesis. Resistance to isoniazid is associated with mutations resulting in overexpression of inhA, which encodes an NADH-dependent acyl carrier protein reductase; mutation or deletion of the katG gene; promoter mutations resulting in overexpression of ahpC, a gene involved in protection of the cell from oxidative stress; and mutations in kasA. Overproducers of inhA express low-level isoniazid resistance and cross-resistance to ethionamide. KatG mutants express high-level isoniazid resistance and often are not cross-resistant to ethionamide.

Drug-resistant mutants are normally present in susceptible mycobacterial populations at about 1 bacillus in 106. Since tuberculous lesions often contain more than 108 tubercle bacilli, resistant mutants are readily selected if isoniazid or any other drug is given as a single agent. The use of two independently acting drugs in combination is much more effective. The probability that a bacillus is initially resistant to both drugs is approximately 1 in 106 × 106, or 1 in 1012, several orders of magnitude greater than the number of infecting organisms. Thus, at least two (or more in certain cases) active agents should always be used to treat active tuberculosis to prevent emergence of resistance during therapy.

Pharmacokinetics

Isoniazid is readily absorbed from the gastrointestinal tract. A 300 mg oral dose (5 mg/kg in children) achieves peak plasma concentrations of 3–5 mcg/mL within 1–2 hours. Isoniazid diffuses readily into all body fluids and tissues. The concentration in the central nervous system and cerebrospinal fluid ranges between 20% and 100% of simultaneous serum concentrations.

Metabolism of isoniazid, especially acetylation by liver N-acetyltransferase, is genetically determined (see Chapter 4). The average plasma concentration of isoniazid in rapid acetylators is about one third to one half of that in slow acetylators, and average half-lives are less than 1 hour and 3 hours, respectively. More rapid clearance of isoniazid by rapid acetylators is usually of no therapeutic consequence when appropriate doses are administered daily, but subtherapeutic concentrations may occur if drug is administered as a once-weekly dose or if there is malabsorption.

Isoniazid metabolites and a small amount of unchanged drug are excreted mainly in the urine. The dosage need not be adjusted in renal failure. Dose adjustment is not well defined in patients with severe preexisting hepatic insufficiency and should be guided by serum concentrations if a reduction in dose is contemplated.

Clinical Uses

The typical dosage of isoniazid is 5 mg/kg/d; a typical adult dose is 300 mg given once daily. Up to 10 mg/kg/d may be used for serious infections or if malabsorption is a problem. A 15 mg/kg dose, or 900 mg, may be used in a twice-weekly dosing regimen in combination with a second antituberculous agent (eg, rifampin, 600 mg). Pyridoxine, 25–50 mg/d, is recommended for those with conditions predisposing to neuropathy, an adverse effect of isoniazid. Isoniazid is usually given by mouth but can be given parenterally in the same dosage.

Isoniazid as a single agent is also indicated for treatment of latent tuberculosis. The dosage is 300 mg/d (5 mg/kg/d) or 900 mg twice weekly, and the duration is usually 9 months.

Adverse Reactions

The incidence and severity of untoward reactions to isoniazid are related to dosage and duration of administration.

A. Immunologic Reactions

Fever and skin rashes are occasionally seen. Drug-induced systemic lupus erythematosus has been reported.

B. Direct Toxicity

Isoniazid-induced hepatitis is the most common major toxic effect. This is distinct from the minor increases in liver aminotransferases (up to three or four times normal), which do not require cessation of the drug and which are seen in 10–20% of patients, who usually are asymptomatic. Clinical hepatitis with loss of appetite, nausea, vomiting, jaundice, and right upper quadrant pain occurs in 1% of isoniazid recipients and can be fatal, particularly if the drug is not discontinued promptly. There is histologic evidence of hepatocellular damage and necrosis. The risk of hepatitis depends on age. It occurs rarely under age 20, in 0.3% of those aged 21–35, 1.2% of those aged 36–50, and 2.3% for those aged 50 and above. The risk of hepatitis is greater in individuals with alcohol dependence and possibly during pregnancy and the postpartum period. Development of isoniazid hepatitis contraindicates further use of the drug.

Peripheral neuropathy is observed in 10–20% of patients given dosages greater than 5 mg/kg/d, but it is infrequently seen with the standard 300 mg adult dose. Peripheral neuropathy is more likely to occur in slow acetylators and patients with predisposing conditions such as malnutrition, alcoholism, diabetes, AIDS, and uremia. Neuropathy is due to a relative pyridoxine deficiency. Isoniazid promotes excretion of pyridoxine, and this toxicity is readily reversed by administration of pyridoxine in a dosage as low as 10 mg/d. Central nervous system toxicity, which is less common, includes memory loss, psychosis, and seizures. These effects may also respond to pyridoxine.

Miscellaneous other reactions include hematologic abnormalities, provocation of pyridoxine deficiency anemia, tinnitus, and gastrointestinal discomfort. Isoniazid can reduce the metabolism of phenytoin, increasing its blood level and toxicity.

RIFAMPIN

Rifampin is a semisynthetic derivative of rifamycin, an antibiotic produced by Streptomyces mediterranei. It is active in vitro against gram-positive and gram-negative cocci, some enteric bacteria, mycobacteria, and chlamydiae. Susceptible organisms are inhibited by less than 1 mcg/mL. Resistant mutants are present in all microbial populations at approximately 1 in 106 organisms and are rapidly selected out if rifampin is used as a single drug, especially in a patient with active infection. There is no cross-resistance to other classes of antimicrobial drugs, but there is cross-resistance to other rifamycin derivatives, eg, rifabutin and rifapentine.

Mechanism of Action, Resistance, & Pharmacokinetics

Rifampin binds to the β subunit of bacterial DNA-dependent RNA polymerase and thereby inhibits RNA synthesis. Resistance results from any one of several possible point mutations in rpoB, the gene for the β subunit of RNA polymerase. These mutations result in reduced binding of rifampin to RNA polymerase. Human RNA polymerase does not bind rifampin and is not inhibited by it. Rifampin is bactericidal for mycobacteria. It readily penetrates most tissues and penetrates into phagocytic cells. It can kill organisms that are poorly accessible to many other drugs, such as intracellular organisms and those sequestered in abscesses and lung cavities.

Rifampin is well absorbed after oral administration and excreted mainly through the liver into bile. It then undergoes enterohepatic recirculation, with the bulk excreted as a deacylated metabolite in feces and a small amount excreted in the urine. Dosage adjustment for renal or hepatic insufficiency is not necessary. Usual doses result in serum levels of 5–7 mcg/mL. Rifampin is distributed widely in body fluids and tissues. The drug is relatively highly protein-bound, and adequate cerebrospinal fluid concentrations are achieved only in the presence of meningeal inflammation.

Clinical Uses

A. Mycobacterial Infections

Rifampin, usually 600 mg/d (10 mg/kg/d) orally, must be administered with isoniazid or other antituberculous drugs to patients with active tuberculosis to prevent emergence of drug-resistant mycobacteria. In some short-course therapies, 600 mg of rifampin is given twice weekly. Rifampin, 600 mg daily or twice weekly for 6 months, also is effective in combination with other agents in some atypical mycobacterial infections and in leprosy. Rifampin, 600 mg daily for 4 months as a single drug, is an alternative to isoniazid for patients with latent tuberculosis who are unable to take isoniazid or who have had exposure to a case of active tuberculosis caused by an isoniazid-resistant, rifampin-susceptible strain.

B. Other Indications

Rifampin has other uses in bacterial infections. An oral dosage of 600 mg twice daily for 2 days can eliminate meningococcal carriage. Rifampin, 20 mg/kg/d for 4 days, is used as prophylaxis in contacts of children with Haemophilus influenzae type b disease. Rifampin combined with a second agent is used to eradicate staphylococcal carriage. Rifampin combination therapy is also indicated for treatment of serious staphylococcal infections such as osteomyelitis and prosthetic valve endocarditis.

Adverse Reactions

Rifampin imparts a harmless orange color to urine, sweat, and tears (soft contact lenses may be permanently stained). Occasional adverse effects include rashes, thrombocytopenia, and nephritis. Rifampin may cause cholestatic jaundice and occasionally hepatitis, and it commonly causes light-chain proteinuria. If administered less often than twice weekly, rifampin may cause a flu-like syndrome characterized by fever, chills, myalgias, anemia, and thrombocytopenia. Its use has been associated with acute tubular necrosis. Rifampin strongly induces most cytochrome P450 isoforms (CYP1A2, 2C9, 2C19, 2D6, and 3A4), which increases the elimination of numerous other drugs including methadone, anticoagulants, cyclosporine, some anticonvulsants, protease inhibitors, some nonnucleoside reverse transcriptase inhibitors, contraceptives, and a host of others (see Chapters 4 and 66). Co-administration of rifampin results in significantly lower serum levels of these drugs.

ETHAMBUTOL

Ethambutol is a synthetic, water-soluble, heat-stable compound, the dextro-isomer of the structure shown below, dispensed as the dihydrochloride salt.

image

Mechanism of Action & Clinical Uses

Susceptible strains of Mycobacterium tuberculosis and other mycobacteria are inhibited in vitro by ethambutol, 1–5 mcg/mL. Ethambutol inhibits mycobacterial arabinosyl transferases, which are encoded by the embCAB operon. Arabinosyl transferases are involved in the polymerization reaction of arabinoglycan, an essential component of the mycobacterial cell wall. Resistance to ethambutol is due to mutations resulting in overexpression of emb gene products or within the embB structural gene.

Ethambutol is well absorbed from the gut. After ingestion of 25 mg/kg, a blood level peak of 2–5 mcg/mL is reached in 2–4 hours. About 20% of the drug is excreted in feces and 50% in urine in unchanged form. Ethambutol accumulates in renal failure, and the dose should be reduced by half if creatinine clearance is less than 10 mL/min. Ethambutol crosses the blood-brain barrier only when the meninges are inflamed. Concentrations in cerebrospinal fluid are highly variable, ranging from 4% to 64% of serum levels in the setting of meningeal inflammation.

As with all antituberculous drugs, resistance to ethambutol emerges rapidly when the drug is used alone. Therefore, ethambutol is always given in combination with other antituberculous drugs.

Ethambutol hydrochloride, 15–25 mg/kg, is usually given as a single daily dose in combination with isoniazid or rifampin for the treatment of active tuberculosis. The higher dose may be used for treatment of tuberculous meningitis. The dose of ethambutol is 50 mg/kg when a twice-weekly dosing schedule is used.

Adverse Reactions

Hypersensitivity to ethambutol is rare. The most common serious adverse event is retrobulbar neuritis, resulting in loss of visual acuity and red-green color blindness. This dose-related adverse effect is more likely to occur at dosages of 25 mg/kg/d continued for several months. At 15 mg/kg/d or less, visual disturbances are very rare. Periodic visual acuity testing is desirable if the 25 mg/kg/d dosage is used. Ethambutol is relatively contraindicated in children too young to permit assessment of visual acuity and red-green color discrimination.

PYRAZINAMIDE

Pyrazinamide (PZA) is a relative of nicotinamide, and it is used only for treatment of tuberculosis. It is stable and slightly soluble in water. It is inactive at neutral pH, but at pH 5.5 it inhibits tubercle bacilli at concentrations of approximately 20 mcg/mL. The drug is taken up by macrophages and exerts its activity against mycobacteria residing within the acidic environment of lysosomes.

image

Mechanism of Action & Clinical Uses

Pyrazinamide is converted to pyrazinoic acid—the active form of the drug—by mycobacterial pyrazinamidase, which is encoded by pncA. Pyrazinoic acid disrupts mycobacterial cell membrane metabolism and transport functions. Resistance may be due to impaired uptake of pyrazinamide or mutations in pncA that impair conversion of PZA to its active form.

Serum concentrations of 30–50 mcg/mL at 1–2 hours after oral administration are achieved with dosages of 25 mg/kg/d. Pyrazinamide is well absorbed from the gastrointestinal tract and widely distributed in body tissues, including inflamed meninges. The half-life is 8–11 hours. The parent compound is metabolized by the liver, but metabolites are renally cleared; therefore, PZA should be administered at 25–35 mg/kg three times weekly (not daily) in hemodialysis patients and those in whom the creatinine clearance is less than 30 mL/min. In patients with normal renal function, a dose of 40–50 mg/kg is used for thrice-weekly or twice-weekly treatment regimens.

Pyrazinamide is an important front-line drug used in conjunction with isoniazid and rifampin in short-course (ie, 6-month) regimens as a “sterilizing” agent active against residual intracellular organisms that may cause relapse. Tubercle bacilli develop resistance to pyrazinamide fairly readily, but there is no cross-resistance with isoniazid or other antimycobacterial drugs.

Adverse Reactions

Major adverse effects of PZA include hepatotoxicity (in 1–5% of patients), nausea, vomiting, drug fever, and hyperuricemia. The latter occurs uniformly and is not a reason to halt therapy. Hyperuricemia may provoke acute gouty arthritis.

STREPTOMYCIN

The mechanism of action and other pharmacologic features of streptomycin are discussed in Chapter 45. The typical adult dosage is 1 g/d (15 mg/kg/d). If the creatinine clearance is less than 30 mL/min or the patient is on hemodialysis, the dosage is 15 mg/kg two or three times per week. Most tubercle bacilli are inhibited by streptomycin, 1–10 mcg/mL, in vitro. Nontuberculosis species of mycobacteria other than Mycobacterium avium complex (MAC) and Mycobacterium kansasii are resistant. All large populations of tubercle bacilli contain some streptomycin-resistant mutants. On average, 1 in 108 tubercle bacilli can be expected to be resistant to streptomycin at levels of 10–100 mcg/mL. Resistance may be due to a point mutation in either the rpsL gene encoding the S12 ribosomal protein or the rrs gene encoding 16S ribosomal RNA, which alters the ribosomal binding site.

Streptomycin penetrates into cells poorly and is active mainly against extracellular tubercle bacilli. The drug crosses the blood-brain barrier and achieves therapeutic concentrations with inflamed meninges.

Clinical Use in Tuberculosis

Streptomycin sulfate is used when an injectable drug is needed or desirable and in the treatment of infections resistant to other drugs. The usual dosage is 15 mg/kg/d intramuscularly or intravenously daily for adults (20–40 mg/kg/d, not to exceed 1–1.5 g for children) for several weeks, followed by 1–1.5 g two or three times weekly for several months. Serum concentrations of approximately 40 mcg/mL are achieved 30–60 minutes after intramuscular injection of a 15 mg/kg dose. Other drugs are always given in combination to prevent emergence of resistance.

Adverse Reactions

Streptomycin is ototoxic and nephrotoxic. Vertigo and hearing loss are the most common adverse effects and may be permanent. Toxicity is dose-related, and the risk is increased in the elderly. As with all aminoglycosides, the dose must be adjusted according to renal function (see Chapter 45). Toxicity can be reduced by limiting therapy to no more than 6 months whenever possible.

SECOND-LINE DRUGS FOR TUBERCULOSIS

The alternative drugs listed below are usually considered only (1) in case of resistance to first-line agents; (2) in case of failure of clinical response to conventional therapy; and (3) in case of serious treatment-limiting adverse drug reactions. Expert guidance to deal with the toxic effects of these second-line drugs is desirable. For many drugs listed in the following text, the dosage, emergence of resistance, and long-term toxicity have not been fully established.

Ethionamide

Ethionamide is chemically related to isoniazid and similarly blocks the synthesis of mycolic acids. It is poorly water soluble and available only in oral form. It is metabolized by the liver.

image

Most tubercle bacilli are inhibited in vitro by ethionamide, 2.5 mcg/mL or less. Some other species of mycobacteria also are inhibited by ethionamide, 10 mcg/mL. Serum concentrations in plasma and tissues of approximately 20 mcg/mL are achieved by a dosage of 1 g/d. Cerebrospinal fluid concentrations are equal to those in serum.

Ethionamide is administered at an initial dose of 250 mg once daily, which is increased in 250-mg increments to the recommended dosage of 1 g/d (or 15 mg/kg/d), if possible. The 1 g/d dosage, though theoretically desirable, is poorly tolerated because of gastric irritation and neurologic symptoms, often limiting the tolerable daily dose to 500–750 mg. Ethionamide is also hepatotoxic. Neurologic symptoms may be alleviated by pyridoxine.

Resistance to ethionamide as a single agent develops rapidly in vitro and in vivo. There can be low-level cross-resistance between isoniazid and ethionamide.

Capreomycin

Capreomycin is a peptide protein synthesis inhibitor antibiotic obtained from Streptomyces capreolus. Daily injection of 1 g intramuscularly results in blood levels of 10 mcg/mL or more. Such concentrations in vitro are inhibitory for many mycobacteria, including multidrug-resistant strains of M tuberculosis.

Capreomycin (15 mg/kg/d) is an important injectable agent for treatment of drug-resistant tuberculosis. Strains of M tuberculosis that are resistant to streptomycin or amikacin usually are susceptible to capreomycin. Resistance to this drug, when it occurs, may be due to an rrs mutation.

Capreomycin is nephrotoxic and ototoxic. Tinnitus, deafness, and vestibular disturbances occur. The injection causes significant local pain, and sterile abscesses may develop.

Dosing of capreomycin is the same as that of streptomycin. Toxicity is reduced if 1 g is given two or three times weekly after an initial response has been achieved with a daily dosing schedule.

Cycloserine

Cycloserine is an inhibitor of cell wall synthesis and is discussed in Chapter 43. Concentrations of 15–20 mcg/mL inhibit many strains of M tuberculosis. The dosage of cycloserine in tuberculosis is 0.5–1 g/d in two divided oral doses. This drug is cleared renally, and the dose should be reduced by half if creatinine clearance is less than 50 mL/min.

The most serious toxic effects are peripheral neuropathy and central nervous system dysfunction, including depression and psychotic reactions. Pyridoxine, 150 mg/d, should be given with cycloserine because this ameliorates neurologic toxicity. Adverse effects, which are most common during the first 2 weeks of therapy, occur in 25% or more of patients, especially at higher doses. Adverse effects can be minimized by monitoring peak serum concentrations. The peak concentration is reached 2–4 hours after dosing. The recommended range of peak concentrations is 20–40 mcg/mL.

Aminosalicylic Acid (PAS)

Aminosalicylic acid is a folate synthesis antagonist that is active almost exclusively against M tuberculosis. It is structurally similar to p-amino-benzoic acid (PABA) and to the sulfonamides (see Chapter 46).

image

Tubercle bacilli are usually inhibited in vitro by aminosalicylic acid, 1–5 mcg/mL. Aminosalicylic acid is readily absorbed from the gastrointestinal tract. Serum levels are 50 mcg/mL or more after a 4 g oral dose. The dosage is 8–12 g/d orally for adults and 300 mg/kg/d for children. The drug is widely distributed in tissues and body fluids except the cerebrospinal fluid. Aminosalicylic acid is rapidly excreted in the urine, in part as active PAS and in part as the acetylated compound and other metabolic products. Very high concentrations of aminosalicylic acid are reached in the urine, which can result in crystalluria.

Aminosalicylic acid is used infrequently because other oral drugs are better tolerated. Gastrointestinal symptoms are common and may be diminished by giving the drug with meals and with antacids. Peptic ulceration and hemorrhage may occur. Hypersensitivity reactions manifested by fever, joint pains, skin rashes, hepatosplenomegaly, hepatitis, adenopathy, and granulocytopenia often occur after 3–8 weeks of PAS therapy, making it necessary to stop administration temporarily or permanently.

Kanamycin & Amikacin

The aminoglycoside antibiotics are discussed in Chapter 45. Kanamycin had been used for treatment of tuberculosis caused by streptomycin-resistant strains, but the availability of less toxic alternatives (eg, capreomycin and amikacin) has rendered it obsolete.

Amikacin is playing a greater role in the treatment of tuberculosis due to the prevalence of multidrug-resistant strains. Prevalence of amikacin-resistant strains is low (< 5%), and most multidrug-resistant strains remain amikacin-susceptible. M tuberculosis is inhibited at concentrations of 1 mcg/mL or less. Amikacin is also active against atypical mycobacteria. There is no cross-resistance between streptomycin and amikacin, but kanamycin resistance often indicates resistance to amikacin as well. Serum concentrations of 30–50 mcg/mL are achieved 30–60 minutes after a 15 mg/kg intravenous infusion. Amikacin is indicated for treatment of tuberculosis suspected or known to be caused by streptomycin-resistant or multidrug-resistant strains. This drug must be used in combination with at least one and preferably two or three other drugs to which the isolate is susceptible for treatment of drug-resistant cases. The recommended dosages are the same as those for streptomycin.

Fluoroquinolones

In addition to their activity against many gram-positive and gram-negative bacteria (discussed in Chapter 46), ciprofloxacin, levofloxacin, gatifloxacin, and moxifloxacin inhibit strains of M tuberculosis at concentrations less than 2 mcg/mL. They are also active against atypical mycobacteria. Moxifloxacin is the most active against M tuberculosis in vitro. Levofloxacin tends to be slightly more active than ciprofloxacin against M tuberculosis, whereas ciprofloxacin is slightly more active against atypical mycobacteria.

Fluoroquinolones are an important addition to the drugs available for tuberculosis, especially for strains that are resistant to first-line agents. Resistance, which may result from one of several single point mutations in the gyrase A subunit, develops rapidly if a fluoroquinolone is used as a single agent; thus, the drug must be used in combination with two or more other active agents. The standard dosage of ciprofloxacin is 750 mg orally twice a day. The dosage of levofloxacin is 500–750 mg once a day. The dosage of moxifloxacin is 400 mg once a day.

Linezolid

Linezolid (discussed in Chapter 44) inhibits strains of M tuberculosis in vitro at concentrations of 4–8 mcg/mL. It achieves good intracellular concentrations, and it is active in murine models of tuberculosis. Linezolid has been used in combination with other second- and third-line drugs to treat patients with tuberculosis caused by multidrug-resistant strains. Conversion of sputum cultures to negative was associated with linezolid use in these cases. Significant adverse effects, including bone marrow suppression and irreversible peripheral and optic neuropathy, have been reported with the prolonged courses of therapy that are necessary for treatment of tuberculosis. A 600 mg (adult) dose administered once a day (half of that used for treatment of other bacterial infections) seems to be sufficient and may limit the occurrence of these adverse effects. Although linezolid may prove to be an important new agent for treatment of tuberculosis, at this point it should only be used for multidrug-resistant strains that also are resistant to several other first- and second-line agents.

Rifabutin

Rifabutin is derived from rifamycin and is related to rifampin. It has significant activity against M tuberculosis, MAC, and Mycobacterium fortuitum (see below). Its activity is similar to that of rifampin, and cross-resistance with rifampin is virtually complete. Some rifampin-resistant strains may appear susceptible to rifabutin in vitro, but a clinical response is unlikely because the molecular basis of resistance, rpoB mutation, is the same. Rifabutin is both substrate and inducer of cytochrome P450 enzymes. Because it is a less potent inducer, rifabutin is indicated in place of rifampin for treatment of tuberculosis in patients with HIV infection who are receiving antiretroviral therapy with a protease inhibitor or a nonnucleoside reverse transcriptase inhibitor (eg, efavirenz), drugs that also are cytochrome P450 substrates.

The typical dosage of rifabutin is 300 mg/d unless the patient is receiving a protease inhibitor, in which case the dosage should be reduced. If efavirenz (also a cytochrome P450 inducer) is used, the recommended dosage of rifabutin is 450 mg/d.

Rifapentine

Rifapentine is an analog of rifampin. It is active against both M tuberculosis and MAC. As with all rifamycins, it is a bacterial RNA polymerase inhibitor, and cross-resistance between rifampin and rifapentine is complete. Like rifampin, rifapentine is a potent inducer of cytochrome P450 enzymes, and it has the same drug interaction profile. Toxicity is similar to that of rifampin. Rifapentine and its microbiologically active metabolite, 25-desacetylrifapentine, have an elimination half-life of 13 hours. Rifapentine, 600 mg (10 mg/kg) once or twice weekly, is indicated for treatment of tuberculosis caused by rifampin-susceptible strains during the continuation phase only (ie, after the first 2 months of therapy and ideally after conversion of sputum cultures to negative). Rifapentine should not be used to treat patients with HIV infection because of an unacceptably high relapse rate with rifampin-resistant organisms. Rifapentine, given once weekly for 3 months in combination with isoniazid, is an effective short course treatment for latent tuberculosis infection.

Bedaquiline

Bedaquiline, a diarylquinoline, is the first drug with a novel mechanism of action against M tuberculosis to be approved since 1971. Bedaquiline inhibits adenosine 5′-triphosphate (ATP) synthase in mycobacteria, has in vitro activity against both replicating and nonreplicating bacilli, and has bactericidal and sterilizing activity in the murine model of tuberculosis. No cross-resistance has been found between bedaquiline and other medications used to treat tuberculosis.

Peak plasma concentration and plasma exposure of bedaquiline increase approximately twofold when administered with high-fat food. Bedaquiline is highly protein-bound (> 99%), is metabolized chiefly through the cytochrome P450 system, and is excreted primarily via the feces. The mean terminal half-life of bedaquiline and its major metabolite (M2), which is four to six times less active in terms of antimycobacterial potency, is approximately 5.5 months. This long elimination phase probably reflects slow release of bedaquiline and M2 from peripheral tissues. CYP3A4 is the major isoenzyme involved in the metabolism of bedaquiline and potent inhibitors or inducers of this enzyme cause clinically significant drug interactions.

Current recommendations state that bedaquiline, in combination with at least three other active medications, may be used for 24 weeks of treatment in adults with laboratory-confirmed pulmonary tuberculosis if the isolate is resistant to both isoniazid and rifampin. The recommended dosage for bedaquiline is 400 mg once daily orally for 2 weeks, followed by 200 mg three times a week for 22 weeks taken orally with food in order to maximize absorption. Bedaquiline has been associated with both hepatotoxicity and cardiac toxicity (prolongation of the QTc interval), so patients must be closely monitored during treatment.

image DRUGS ACTIVE AGAINST ATYPICAL MYCOBACTERIA

Many mycobacterial infections seen in clinical practice in the United States are caused by nontuberculous or “atypical” mycobacteria. These organisms have distinctive laboratory characteristics, are present in the environment, and are generally not communicable from person to person. As a rule, these mycobacterial species are less susceptible than M tuberculosis to antituberculous drugs. On the other hand, agents such as macrolides, sulfonamides, and tetracyclines, which are not active against M tuberculosis, may be effective for infections caused by atypical mycobacteria. Emergence of resistance during therapy is also a problem with these mycobacterial species, and active infection should be treated with combinations of drugs. M kansasii is susceptible to rifampin and ethambutol, partially susceptible to isoniazid, and completely resistant to pyrazinamide. A three-drug combination of isoniazid, rifampin, and ethambutol is the conventional treatment for M kansasii infection. A few representative pathogens, with the clinical presentation and the drugs to which they are often susceptible, are given in Table 47–3.

TABLE 47–3 Clinical Features and treatment options for infections with atypical mycobacteria.

image

M avium complex (MAC), which includes both M avium and M intracellulare, is an important and common cause of disseminated disease in late stages of AIDS (CD4 counts < 50/μL). MAC is much less susceptible than M tuberculosis to most antituberculous drugs. Combinations of agents are required to suppress the infection. Azithromycin, 500 mg once daily, or clarithromycin, 500 mg twice daily, plus ethambutol, 15–25 mg/kg/d, is an effective and well-tolerated regimen for treatment of disseminated disease. Some authorities recommend use of a third agent, especially rifabutin, 300 mg once daily. Other agents that may be useful are listed in Table 47–3. Azithromycin and clarithromycin are the prophylactic drugs of choice for preventing disseminated MAC in AIDS patients with CD4 cell counts less than 50/μL. Rifabutin in a single daily dose of 300 mg has been shown to reduce the incidence of MAC bacteremia but is less effective than macrolides.

image DRUGS USED IN LEPROSY

Mycobacterium leprae has never been grown in vitro, but animal models, such as growth in injected mouse footpads, have permitted laboratory evaluation of drugs. Only those drugs with the widest clinical use are presented here. Because of increasing reports of dapsone resistance, treatment of leprosy with combinations of the drugs listed below is recommended.

DAPSONE & OTHER SULFONES

Several drugs closely related to the sulfonamides have been used effectively in the long-term treatment of leprosy. The most widely used is dapsone (diaminodiphenylsulfone). Like the sulfonamides, it inhibits folate synthesis. Resistance can emerge in large populations of M leprae, eg, in lepromatous leprosy, particularly if low doses are given. Therefore, the combination of dapsone, rifampin, and clofazimine is recommended for initial therapy of lepromatous leprosy. A combination of dapsone plus rifampin is commonly used for leprosy with a lower organism burden. Dapsone may also be used to prevent and treat Pneumocystis jiroveci pneumonia in AIDS patients.

image

Sulfones are well absorbed from the gut and widely distributed throughout body fluids and tissues. Dapsone’s half-life is 1–2 days, and drug tends to be retained in skin, muscle, liver, and kidney. Skin heavily infected with M leprae may contain several times more drug than normal skin. Sulfones are excreted into bile and reabsorbed in the intestine. Excretion into urine is variable, and most excreted drug is acetylated. In renal failure, the dose may have to be adjusted. The usual adult dosage in leprosy is 100 mg daily. For children, the dose is proportionately less, depending on weight.

Dapsone is usually well tolerated. Many patients develop some hemolysis, particularly if they have glucose-6-phosphate dehydrogenase deficiency. Methemoglobinemia is common but usually is not a problem clinically. Gastrointestinal intolerance, fever, pruritus, and various rashes occur. During dapsone therapy of lepromatous leprosy, erythema nodosum leprosum often develops. It is sometimes difficult to distinguish reactions to dapsone from manifestations of the underlying illness. Erythema nodosum leprosum may be suppressed by thalidomide (see Chapter 55).

RIFAMPIN

Rifampin (see earlier discussion) in a dosage of 600 mg daily is highly effective in leprosy and is given with at least one other drug to prevent emergence of resistance. Even a dose of 600 mg per month may be beneficial in combination therapy.

CLOFAZIMINE

Clofazimine is a phenazine dye used in the treatment of multibacillary leprosy, which is defined as having a positive smear from any site of infection. Its mechanism of action has not been clearly established. Absorption of clofazimine from the gut is variable, and a major portion of the drug is excreted in feces. Clofazimine is stored widely in reticuloendothelial tissues and skin, and its crystals can be seen inside phagocytic reticuloendothelial cells. It is slowly released from these deposits, so the serum half-life may be 2 months. A common dosage of clofazimine is 100 mg/d orally. The most prominent untoward effect is discoloration of the skin and conjunctivae. Gastrointestinal side effects are also common.

SUMMARY First-Line Antimycobacterial Drugs

image

PREPARATIONS AVAILABLE

image

image

REFERENCES

Gillespie SH et al: Early bactericidal activity of a moxifloxacin and isoniazid combination in smear-positive pulmonary tuberculosis. J Antimicrob Chemother 2005;56:1169.

Griffith DE et al: An official ATS/IDSA statement: Diagnosis, treatment, and prevention of nontuberculous mycobacterial disease. Am J Respir Crit Care Med 2007;175:367.

Hugonnet J-E et al: Meropenem-clavulanate is effective against extensively drug-resistant Mycobacterium tuberculosis. Science 2009;323:1215.

Jasmer RM, Nahid P, Hopewell PC: Latent tuberculosis infection. N Engl J Med 2002;347:1860.

Kinzig-Schippers M et al: Should we use N-acetyltransferase type 2 genotyping to personalize isoniazid doses? Antimicrob Agents Chemother 2005;49:1733.

Lee M et al: Linezolid for treatment of chronic extensively drug-resistant tuberculosis. N Engl J Med 2012;367:1508.

Mitnick CD et al: Comprehensive treatment of extensively drug-resistant tuberculosis. N Engl J Med 2008;359:563.

Provisional CDC Guidelines for the use and safety monitoring of bedaquiline fumarate (Sirturo) for the treatment of multidrug-resistant tuberculosis. MMWR Morb Mortal Wkly Rep 2013;62:1.

Recommendations for use of an isoniazid-rifapentine regimen with direct observation to treat latent Mycobacterium tuberculosis infection. MMWR Morb Mortal Wkly Rep 2011;60:1650.

Sulochana S, Rahman F, Paramasivan CN: In vitro activity of fluoroquinolones against Mycobacterium tuberculosis. J Chemother 2005;17:169.

Targeted tuberculin testing and treatment of latent tuberculosis infection. Am J Respir Crit Care Med 2000;161(4 Part 2):S221.

Update: Adverse event data and revised American Thoracic Society/CDC recommendations against the use of rifampin and pyrazinamide for treatment of latent tuberculosis infection—United States, 2003. MMWR Morb Mortal Wkly Rep 2003;52:735.

Zhang Y, Yew WW: Mechanisms of drug resistance in Mycobacterium tuberculosis. Int J Tuberc Lung Dis 2009;13:1320.

Zumla A et al: Current concepts—Tuberculosis. N Engl J Med 2013;368:745.

CASE STUDY ANSWER

The patient should be started on four-drug therapy with rifampin, isoniazid, pyrazinamide, and ethambutol. If a protease-inhibitor-based antiretroviral regimen is used to treat his HIV, rifabutin should replace rifampin because of the serious drug-drug interactions between rifampin and protease inhibitors. The patient is at increased risk of developing hepatotoxicity from both isoniazid and pyrazinamide given his history of chronic alcohol dependence.

_______________

*The authors thank Henry F. Chambers, MD, for his contributions to previous editions.