e1-11: Alternative Medications in Tuberculosis Treatment

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 to 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 prolongation.

Artesunate is administered an intravenous infusion for the treatment of severe malaria in children and adults. Once patients can take oral therapy, a full treatment course of oral antimalarials is required. Concomitant therapy (eg, primaquine) is also needed for patients who acquired malaria in P vivax or P ovale endemic areas since artesunate is inactive against the liver stage form of Plasmodium. Patients should be monitoring for post-treatment hemolytic anemia for 4 weeks after receiving artesunate and, because artesunate is a substrate of uridine 5′-diphosphate glucuronosyltransferases (UGT), patients taking strong UGT inducers or inhibitors (eg ritonavir or diclofenac, respectively) need to be monitored for reduced efficacy and increased toxicity, respectively.