SECOND-LINE DRUGS FOR TUBERCULOSIS
The alternative drugs listed below are usually considered onlyin 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 is chemically related to isoniazid and similarly blocks the synthesis of mycolic acids. It is poorly water soluble and avail-able only in oral form. It is metabolized by the liver.
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 recom-mended 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 the intense gastric irritation and neurologic symptoms that commonly occur, and one often must settle for a total daily dose of 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 is a peptide protein synthesis inhibitor antibiotic obtained from Streptomyces capreolus. Daily injection of 1 g intra-muscularly 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 suscep-tible to capreomycin. Resistance to capreomycin, 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 occur.
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 is an inhibitor of cell wall synthesis. 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. Cycloserine is cleared renally, and the dose should be reduced by half if creatinine clear-ance is less than 50 mL/min.
The most serious toxic effects are peripheral neuropathy and central nervous system dysfunction, including depression and psy-chotic 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 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 .
Tubercle bacilli are usually inhibited in vitro by aminosalicylic acid, 1–5 mcg/mL. Aminosalicylic acid is readily absorbed fromthe 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 aminosalicylic acid and in part as the acetylated compound and other metabolic prod-ucts. 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, hepatosple-nomegaly, hepatitis, adenopathy, and granulocytopenia often occur after 3–8 weeks of aminosalicylic acid therapy, making it necessary to stop aminosalicylic acid administration temporarily or permanently.
Kanamycin has been used for treatment of tuberculosis caused by streptomycin-resistant strains, but the availability of less toxic alter-natives (eg, capreomycin and amikacin) has rendered it obsolete.
The role of amikacin in treatment of tuberculosis has increased with the increasing incidence and prevalence of multidrug-resistant tuberculosis. Prevalence of amikacin-resis-tant strains is low (< 5%), and most multidrug-resistant strains remain amikacin-susceptible. M tuberculosis is inhibited at con-centrations of 1 mcg/mL or less. Amikacin is also active against atypical mycobacteria. There is no cross-resistance between strep-tomycin 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 sus-pected or known to be caused by streptomycin-resistant or multi-drug-resistant strains. Amikacin 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.
In addition to their activity against many gram-positive and gram-negative bacteria, ciprofloxacin, levofloxa-cin, 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 Mtuberculosis by weight in vitro. Levofloxacin tends to be slightly moreactive than ciprofloxacin against M tuberculosis, whereas ciprofloxa-cin is slightly more active against atypical mycobacteria.
Fluoroquinolones are an important addition to the drugs avail-able for tuberculosis, especially for strains that are resistant to first-line agents. Resistance, which may result from any 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. Thestandard 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 inhibits strains of M tuberculosis in vitro at concentrations of 4–8 mcg/mL. It achieves good intra-cellular 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, and some may have been cured. Significant and at times treatment-limiting adverse effects, including bone marrow sup-pression 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 even-tually prove to be an important new agent for treatment of tuber-culosis, at this point it should be considered a drug of last resort for infection caused by multidrug-resistant strains that also are resistant to several other first- and second-line agents.
Rifabutin is derived from rifamycin and is related to rifampin. It has significant activity against M tuberculosis, MAC, and Mycobacterium fortuitum . Its activity is similar to thatof rifampin, and cross-resistance with rifampin is virtually com-plete. 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 infec-tion who are receiving antiretroviral therapy with a protease inhibitor or with 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 to 150 mg/d. If efavirenz (also a cytochrome P450 inducer) is used, the recommended dosage of rifabutin is 450 mg/d.
Rifabutin is effective in prevention and treatment of dissemi-nated atypical mycobacterial infection in AIDS patients with CD4 counts below 50/μL. It is also effective for preventive therapy of tuberculosis, either alone in a 3–4 month regimen or with pyrazi-namide in a 2-month regimen.
Rifapentine is an analog of rifampin. It is active against both M tuberculosis and MAC. As with all rifamycins, it is a bacterialRNA 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 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 infec-tion because of an unacceptably high relapse rate with rifampin-resistant organisms.