Validation of Cycloserine Efficacy in Treatment of Multidrug-Resistant and Extensively Drug-Resistant Tuberculosis in Beijing, China

Abstract

Cycloserine (Cs) is recommended by the World Health Organization as a second-line drug to treat multidrug-resistant tuberculosis (MDR-TB); however, its efficacy has never been sufficiently evaluated. To gain some insights into the value of cycloserine for MDR-TB treatment, in vitro bacteriostatic effect was determined and patient validations were performed prospectively. The in vitro activity of Cs against 104 wild-type Mycobacterium tuberculosis strains was determined, and serum Cs concentrations were measured for 73 MDR TB patients 2 h after administration. The treatment outcomes for 27 MDR-TB patients who had baseline isolates and were treated with Cs-containing regimens were followed up. The MICs for 90% of the recruited 104 wild-type strains were below 32 μg/ml. Eighteen out of 52 patients had peak serum concentrations (C_max) below 20 μg/ml at the dosage of 500 mg daily, while 13 out of 21 patients had peak serum concentrations higher than 35 μg/ml at the dosage of 750 mg daily. The percentage of favorable treatment outcomes among patients with a C_max/MIC ratio of ≥1 was statistically significantly higher than that among the group with a C_max/MIC ratio of <1 (P = 0.022). The epidemiological cutoff value for Cs susceptibility testing was 32 μg/ml. A high percentage of patients receiving the recommended dosage of 10 mg/kg for Cs administration could not acquire desirable blood concentrations; therefore, adjusting the dosage according to drug concentration monitoring is necessary. The C_max/MIC ratio might be a good indicator for predicting the treatment outcome for patients with MDR-TB or extensively drug-resistant TB (XDR-TB) who are being administered Cs-containing regimens.

Keywords: cycloserine; efficacy; extensive drug resistance; multiple drug resistance; therapeutic drug monitoring; tuberculosis.

FIG 1

Cycloserine MIC distribution for 104 M. tuberculosis clinical isolates.

FIG 2

Two-hour postdose peak Cs serum concentrations for the enrolled patients. (A) Serum concentration distribution of 80 tests for 73 patients. ***, P < 0.001. (B) Serum concentration changes for the 7 patients with dosage adjustment. Two patients had their dosage increased from 500 mg/day to 750 mg/day, and five patients had their dosage decreased from 750 mg/day to 500 mg/day.