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The medications or medication classes listed alphabetically below are usually considered only in cases of drug resistance (clinical or laboratory) to first-line medications.

Bedaquiline, a mycobacterial ATP synthase inhibitor, is given as an oral tablet once daily for the treatment of multidrug-resistant tuberculosis. Bedaquiline has two black box warnings for QT prolongation and increased mortality compared with placebo. Subsequent post-marketing studies have not confirmed these high mortality rates and bedaquiline is now considered a first-line agent for the treatment of multidrug-resistant tuberculosis.

Capreomycin is an injectable agent given intramuscularly in doses of 15–20 mg/kg/day (maximal dose 1 g). Major toxicities include ototoxicity (both vestibular and cochlear) and nephrotoxicity. If the medication must be used in older patients, the dose should not exceed 750 mg.

Clofazimine is a phenazine dye used in the treatment of leprosy and is active in vitro against both nontuberculous Mycobacteria (eg, M avium complex, M kansasii, etc) and Mycobacterium tuberculosis. It is given orally as a single daily dose of 100 mg for treatment of M avium complex disease. With limited clinical efficacy data, its use for the therapy of tuberculosis is reserved for multidrug-resistant M tuberculosis. Adverse effects include nausea, vomiting, abdominal pain, and skin discoloration.

Cycloserine, a bacteriostatic agent, is given in doses of 10–15 mg/kg (not to exceed 1 g) orally and has been used in re-treatment regimens and for primary therapy of highly resistant M tuberculosis. It can induce a variety of central nervous system dysfunctions and psychotic reactions.

Ethionamide, like cycloserine, is bacteriostatic and is given orally in a dose of 15–20 mg/kg/day (maximal dose 1 g). It has been used in combination therapy but is poorly tolerated with marked gastric irritation.

The fluoroquinolones, particularly moxifloxacin, are active in vitro against M tuberculosis. These medications have been demonstrated to be efficacious in treating tuberculosis in patients unable to take isoniazid, rifampin, and pyrazinamide; however, rapid emergence of resistance has been described. The combination of 6 months of the long-acting rifamycin, rifapentine, in combination with moxifloxacin, is as effective as standard therapy in the treatment of tuberculosis. Levofloxacin can also be considered as a fluoroquinolone treatment option for multidrug-resistant tuberculosis.

Linezolid is effective in achieving culture conversion in patients with treatment-refractory, highly resistant pulmonary tuberculosis. However, the long-term use of this agent for tuberculosis is associated with bone marrow toxicity and neuropathy, particularly at doses of 600 mg daily.

Pretomanid targets both active and inactive M tuberculosis via inhibition of mycolic acid biosynthesis in actively dividing strains and generation of toxic nitric oxide in dormant strains under anaerobic conditions. Pretomanid was approved as a once daily oral tablet given in combination with bedaquiline and linezolid for the treatment of drug-resistant tuberculosis. Pretomanid carries several warnings for hepatotoxicity, lactic acidosis, myelosuppression, peripheral and optic neuropathy, reproductive toxicity, and QT ...

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