Drug Tolerance in Mycobacterium tuberculosis

Abstract

Although Mycobacterium tuberculosis is eradicated rapidly during therapy in some patients with pulmonary tuberculosis, it can persist for many months in others. This study examined the relationship between mycobacterial drug tolerance (delayed killing in vitro), persistence, and relapse. It was performed with 39 fully drug-susceptible isolates from a prospective trial of standard short-course antituberculous therapy with sputum smear-positive, human immunodeficiency virus-uninfected subjects with pulmonary tuberculosis in Brazil and Uganda. The rate of killing in vitro was determined by monitoring the growth index (GI) in BACTEC 12B medium after addition of drug to established cultures and was measured as the number of days required for 99% sterilization. Drugs differed significantly in bactericidal activity, in the following order from greatest to least, rifampin > isoniazid-ethambutol > ethambutol (P < 0.001). Isolates from subjects who had relapses (n = 2) or in whom persistence was prolonged (n = 1) were significantly more tolerant of isoniazid-ethambutol and rifampin than isolates from other subjects (P < 0.01). More generally, the duration of persistence during therapy was predicted by strain tolerance to isoniazid and rifampin (P = 0.012 and 0.026, respectively). Tolerance to isoniazid-ethambutol and tolerance to rifampin were highly correlated (P < 0.001). Tolerant isolates did not differ from others with respect to the MIC of isoniazid; the rate of killing of a tolerant isolate by isoniazid-ethambutol was not increased at higher drug concentrations. These observations suggest that tolerance may not be due to drug-specific mechanisms. Tolerance was of the phenotypic type, although increased tolerance appeared to emerge after prolonged drug exposure in vivo. This study suggests that drug tolerance may be an important determinant of the outcome of therapy for tuberculosis.

Whole Blood Bactericidal Activity during Treatment of Pulmonary Tuberculosis

“…Some of these models appear to show clinical relevance. We found, for example, that phenotypic tolerance in a model of prolonged drug exposure was associated with increased risk of relapse [42]. Tolerance was not drug specific and was unrelated to drug concentration and MIC.…”

“…One possible explanation lies in the ability of M. tuberculosis to adapt to hostile environmental conditions by entering a nonreplicating state. Researchers have used several in vitro models of nonreplicating persistence to examine its biologic basis, including hypoxia, nutrient deprivation, and prolonged drug exposure [38][39][40][41][42]. Some of these models appear to show clinical relevance.…”

In vitro and ex vivo activity of peptide deformylase inhibitors against Mycobacterium tuberculosis H37Rv

“…The inevitable emergence of multidrug-resistant Mycobacterium tuberculosis strains has made many of the currently available antitubercular drugs (ATDs) ineffective [2]. Therefore, new drugs with novel targets are required to prevent the global spread of M. tuberculosis.…”

Persistence, Not Resistance, Is the Cause of Loss of Isoniazid Effect

“…However, their conclusion that the rapid emergence of isoniazid-resistant mutants is responsible for the cessation of its action in early bactericidal activity (EBA) studies is not supported by clinical data. Drug resistance occurred in only 1 of 12 patients in the original 14-day EBA study [2] and took up to 12 months to appear in early trials of isoniazid monotherapy in India, with half taking 12 months [3]. Numerous subsequent EBA studies used isoniazid as a positive control, and drug resistance was never encountered in tests routinely set up after the period of monotherapy.…”

“…In 1999, we described a model to study phenotypic drug tolerance in M. tuberculosis by adding drugs to Bactec radiometric cultures and monitoring the rate of decline of growth indices [2]. Resistance emerged in M. tuberculosis H37Ra after 1 week of exposure to isoniazid.…”