Treating pulmonary MDR-TB depends on whether the resistance is primary (infection with a drug-resistant strain prior to antibiotic therapy) or secondary (selective resistance by mutated strains acquired during therapy from inadequate dosage or discontinued drug regimen). In either case, administration of four or more second-line anti-TB drugs is usually necessary. Second-line drugs required for MDR-TB include high dosage isoniazid (INH), high dosage ethambutol (EMB), amikacin, capreomycin, ethionamide, kanamycin (the injectables), levofloxacin, ofloxacin (quinolones), para-aminosalicylic acid (PAS), rifabutin, and streptomycin (SM). A treatment regimen monitored by the directly observed treatment short course (DOTS) program has been shown to be the only effective method of monitoring patients whose treatment may extend from 12 to 18 months to control the selective resistance and reinfection known to develop.
There are fifteen genes, derived from the previously mentioned antibiotics, associated with MTB drug resistance that are grouped according to their mechanisms of resistance. The mechanisms, though not completely understood, include decreased drug uptake, drug inactivation by constitutive beta lactamases, increased efflux (eg, fluoroquinolone resistance) alteration of the target site (inhibits RNA synthesis in RMP and mycolic acid biosynthesis, etc. in INH), and reduced pro-drug-activating enzymes (pyrazinamide (PZA) resistance).
New anti-tuberculosis drugs
Despite the cost and complexity associated with side effects, newer drugs for both susceptible and resistant strains of MTB are expected to have greater bactericidal action and less cross-reaction with existing therapy (unlike the protease inhibitors for HIV therapy) than previous drugs. New classes of drugs include diarylquinoline, nitroimidazole, as well as oxazolidine (eg, linezolid). Of these, only linezolid is approved for therapeutic use or routine susceptibility testing. As of December 2016, 17 TB drugs were in clinical trials and being tested in new drug combination regimens.
Because second-line drugs are expensive, toxic, and less effective, the dosage and duration of regimen mandate the expertise of physician-specialists in tuberculosis. Questions of specific drugs to use, the number of drugs, the duration of therapy, and outcome were subjected to a meta-analysis with methods recommended by the Cochrane group. Their analysis, which included 9,153 MDR-TB patients, determined that four drugs should be used initially, with at least three continuing throughout treatment. Routine susceptibility testing was assumed part of the evaluation. Duration of therapy was seven to eight months initially, changing to 18-20 months in the succeeding phase, but information regarding individual drugs was not available. Clinical trials to answer questions and gain more information were highly recommended by the researchers to determine optimal treatment of MDR-TB patients.
