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, bacteriostatic effect was determined and patient validations were performed prospectively. The activity of Cs against 104 wild-type 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 () 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 /MIC ratio of ≥1 was statistically significantly higher than that among the group with a/MIC ratio of <1 ( = 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 /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.

<p>Cycloserine for treatment of multidrug-resistant tuberculosis: a retrospective cohort study in China</p>

“…A possible explanation for this finding is that treatment of MDR-TB includes multiple drugs, and an observational study without strict placebo controls hardly assesses the efficacy of a single agent. Furthermore, a recent study has shown that more than half of patients with the recommended dosage of 10 mg/kg of cycloserine prescription had peak serum concentrations lower than the minimum inhibitory concentrations of the strains isolated from the corresponding patients, suggesting the need for adjusting each patient’s dosages depending on the clinical pharmacokinetic and pharmacodynamic assessments 24,25…”

<p>Efficacy and safety of cycloserine-containing regimens in the treatment of multidrug-resistant tuberculosis: a nationwide retrospective cohort study in China</p>

“…Despite exhibiting promising safety, we found that the administration of CS produces a higher proportion of serious ADRs resulting in discontinuation of CS. In addition, low plasma concentration is another important concern for the clinical application of CS 24,25. Although the increased dosage of CS could overcome this obstacle, it may also pose a higher safety risk.…”

An inexpensive, efficient and safe regimen containing Pasiniazid for MDR-TB in high Tuberculosis epidemic areas – A prospective study in China

“…PZA was always controversial in the treatment of MDR-TB and XDR-TB, some studies showed that PZA resistant or not did not impact its anti-microbial activity (21,26,27), however, the high resistant rate of PZA had been considered its application in the future (28). In the present study, we tested PZA resistance by MIC value, the resistance rate was 50.9%.…”

“…The other drugs made up the regimen, Cs had low resistant rate and Cs containing regimen can achieve a highly successful outcome (66% of cure rate) in China reported by one study (19) and 69.4% of treatment success rate in another study (20). MIC for 90% of the recruited stains were below 32 µg/ml (21). Above studies demonstrated the slight side effects of Cs in the treatment of MDR-TB,the present study also veri ed its safety and e cacy.…”