trimethoprim--sulfamethoxazole-drug-combination and Extensively-Drug-Resistant-Tuberculosis

Topics: Adult; Antitubercular Agents; Colistin; Diarylquinolines; Drug Synergism; Extensively Drug-Resistant Tuberculosis; Humans; Isoniazid; Male; Medication Adherence; Mycobacterium tuberculosis; Netherlands; Nitroimidazoles; Oxazoles; Patient Isolation; Phenotype; Trimethoprim, Sulfamethoxazole Drug Combination; United Kingdom

Co-trimoxazole (SXT), a combination of sulfamethoxazole and trimethoprim, has shown in vitro activity against Mycobacterium tuberculosis. However, the pharmacokinetic and pharmacodynamic parameters of SXT in multidrug-resistant (MDR) tuberculosis (TB) are, thus far, lacking. Therefore, we evaluated its pharmacokinetics and drug susceptibility, along with its tolerability during treatment. Based on drug susceptibility testing, MDR-TB patients received SXT as a part of their MDR treatment. The pharmacokinetic parameters of sulfamethoxazole, the effective component of SXT against M. tuberculosis, were evaluated. The ratio of the area under the curve from 0 to 24 h (AUC0-24) to minimum inhibitory concentration (MIC) was used as the best pharmacokinetic/pharmacodynamic parameter to predict the efficacy of sulfamethoxazole. Adverse effects of SXT were also evaluated. 10 patients with MDR-TB (one of whom had extensively drug-resistant TB) received 480 mg of SXT with a median dosage of 6.5 mg·kg(-1) of SXT (range 6.1-6.8 mg·kg(-1)) once daily for a median treatment period of 381 days (range 129-465 days). In two patients, the dose was escalated to 960 mg. The free AUC0-24/MIC of sulfamethoxazole exceeded 25 in only one patient. SXT was safe and well-tolerated, except for one patient who had gastrointestinal side-effects after receiving 960 mg of SXT. Additional studies are needed to find the pharmacokinetic and pharmacodynamic targets, and consequently to set the optimal dose, of SXT for MDR-TB treatment.

Topics: Adult; Antitubercular Agents; Area Under Curve; Extensively Drug-Resistant Tuberculosis; Female; Humans; Male; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Treatment Outcome; Trimethoprim, Sulfamethoxazole Drug Combination; Tuberculosis, Multidrug-Resistant; Young Adult