Mycobacterium tuberculosis and Sulfamethoxazole Susceptibility

We noted with interest the paper by Forgacs et al. (2) reporting on a case of tuberculosis with an apparent response to treatment with trimethoprim-sulfamethoxazole (TMP-SMX) and the subsequent in vitro studies indicating that the majority of Mycobacterium tuberculosis strains may be susceptible to TMP-SMX.

As the Forgacs paper implied that it is the sulfonamide component of TMP-SMX that has anti-M. tuberculosis activity, we sought to further test this hypothesis by testing 12 sequential patient M. tuberculosis isolates against SMX alone in a Mycobacterium Growth Indicator Tube (MGIT; Becton Dickinson [B-D]) broth dilution drug susceptibility test (DST) system.

SMX concentrations were chosen to match those used by Forgacs et al. and those found in commercially available broth microdilution systems for DSTs of nontuberculous mycobacteria. Briefly, suspensions of M. tuberculosis grown on solid media were prepared according to the B-D MGIT 960 SIRE antimicrobial susceptibility testing kit instructions, with the exception that the initial suspensions were made in Ringer's solution rather than Middlebrook 7H9 broth. A working solution of 60.8 mg of SMX (Fluka brand, supplied by Sigma-Aldrich Australia [batch number 048K1024]) dissolved in 10 ml distilled water was prepared and then diluted to give the final concentrations in MGIT tubes shown in Table 1. Growth of M. tuberculosis in both drug-containing and control tubes was automatically monitored in an MGIT 960 instrument.

TABLE 1.

Number of M. tuberculosis isolates^a inhibited by SMX at the indicated concentrations

SMX concn (μg/ml)	4.75	9.5	19	38	76	152
No. of isolates susceptible	1	5	5	1	0	0

^aA total of 12 isolates were tested.

Isolates used in the study were sourced from eight female and four male patients ranging in age from 1 to 86 years. Nine isolates were from respiratory specimens and three from extrapulmonary specimens. All isolates tested susceptible to first-line antituberculous drugs.

The MICs of the 12 isolates are shown in Table 1. All appear susceptible to SMX at a concentration ≤38 μg/ml in this system.

This brief study indicates that SMX alone does indeed appear to have at least bacteriostatic activity against M. tuberculosis in this DST system. The MICs are within readily achievable serum levels of SMX (3) and generally within the TMP-SMX breakpoints quoted for a wide range of vegetative bacteria (1). SMX and TMP-SMX are widely available and cheap, have favorable pharmacokinetic and tissue penetration properties (3), and are generally well tolerated. Their use as potential second-line antituberculous agents is an exciting prospect and deserves further in vitro and in vivo study.