Fluoroquinolones are an important addition to the drugs available for tuberculosis, especially for strains that are resistant to first-line agents. The World Health Organization recommends using a later generation fluoroquinolone such as moxifloxacin or levofloxacin. 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 additional active agents. Typically, resistance to one fluoroquinolone indicates class resistance. However, moxifloxacin may retain some activity in strains resistant to ofloxacin. The dosage of levofloxacin is 500–750 mg once a day, and some clinicians increase to 1000 mg daily if tolerated. The dosage of moxifloxacin is 400 mg once a day. Some experts recommend checking peak serum concentrations. Expected levels at about two hours post-dose are 8–12 mcg/mL for levofloxacin and 3–5 mcg/mL for moxifloxacin.
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. Experts recommend supplemental pyridoxine for patients treated with linezolid. Although linezolid may prove to be an important new agent for treatment of tuberculosis, at this point it should be used only for multidrug-resistant strains that also are resistant to several other firstand second-line agents. It is generally avoided in patients on concomitant serotonergic agents due to concern for serotonin syndrome.
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 often used in place of rifampin for treatment of tuberculosis in patients with HIV infection who are receiving antiretroviral therapy with a protease inhibitor, a nonnucleoside reverse transcriptase inhibitor (eg, efavirenz), or an integrase strand transfer inhibitor (eg dolutegravir), drugs that also are cytochrome P450 or UDP glucuronosyltransferase (UGT) substrates.