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 is a peptide protein synthesis inhibitor antibiotic obtained from Streptomyces capreolus. Daily injection of 15 mg/kg intramuscularly results in peak serum levels of 35–45 mcg/mL 2 hours after a dose. 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 usually are susceptible to capreomycin, though some data suggest cross-resistance with strains resistant to amikacin and kanamycin. Resistance to capreomycin, when it occurs, has been associated with rrs, eis, or tlyA gene mutations.
Capreomycin is nephrotoxic and ototoxic. Tinnitus, deafness, and vestibular disturbances occur. The injection causes significant local pain, and sterile abscesses may develop.
Typical dosing of capreomycin is 15 mg/kg/day initially, which is then reduced to two or three times weekly after an initial response has been achieved with a daily dosing schedule. The intermittent dosing regimen may minimize risk of toxicity.
Cycloserine—a structural analog of d-alanine—inhibits cell wall synthesis, as discussed in Chapter 43. Concentrations of 15–20 mcg/mL inhibit many strains of M tuberculosis. The usual dosage of cycloserine in tuberculosis is 0.5–1 g/d in two divided oral doses. The drug is widely distributed to tissues, including the central nervous system. This drug is cleared renally, and the dose should be reduced by half if creatinine clearance is less than 50 mL/min. Alternatively, it may be reduced to 500 mg three times weekly.
The most serious toxic effects are peripheral neuropathy and central nervous system dysfunction, including depression and psychoses. Pyridoxine, 100 mg or more per day, 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 leading to peak concentrations greater than 35 mcg/mL. 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 20–35 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 is thought to have a similar mechanism of action to the sulfonamides (see Chapter 46). In the USA, PAS is commercially available as a 4-g packet of delayed-release granules. In order to protect the integrity of the delayed-release coating, the granules must be administered sprinkled over applesauce or yogurt, or swirled in fruit juice and swallowed whole.