d-Cycloserine Pharmacokinetics/Pharmacodynamics, Susceptibility, and Dosing Implications in Multidrug-resistant Tuberculosis: A Faustian Deal

Abstract

Background. d-cycloserine is used to treat multidrug-resistant tuberculosis. Its efficacy, contribution in combination therapy, and best clinical dose are unclear, also data on the d-cycloserine minimum inhibitory concentration (MIC) distributions is scant. Methods. We performed a systematic search to identify pharmacokinetic and pharmacodynamic studies performed with d-cycloserine. We then performed a combined exposure-effect and dose fractionation study of d-cycloserine in the hollow fiber system model of tuberculosis (HFS-TB). In parallel, we identified d-cycloserine MICs in 415 clinical Mycobacterium tuberculosis (Mtb) isolates from patients. We utilized these results, including intracavitary concentrations, to identify the clinical dose that would be able to achieve or exceed target exposures in 10 000 patients using Monte Carlo experiments (MCEs). Results. There were no published d-cycloserine pharmacokinetics/pharmacodynamics studies identified. Therefore, we performed new HFS-TB experiments. Cyloserine killed 6.3 log 10 colony-forming units (CFU)/mL extracellular bacilli over 28 days. Efficacy was driven by the percentage of time concentration persisted above MIC (%T MIC), with 1.0 log 10 CFU/mL kill achieved by %T MIC = 30% (target exposure). The tentative epidemiological cutoff value with the Sensititre MYCOTB assay was 64 mg/L. In MCEs, 750 mg twice daily achieved target exposure in lung cavities of 92% of patients whereas 500 mg twice daily achieved target exposure in 85% of patients with meningitis. The proposed MCE-derived clinical susceptibility breakpoint at the proposed doses was 64 mg/L. Conclusions. Cycloserine is cidal against Mtb. The susceptibility breakpoint is 64 mg/L. However, the doses likely to achieve the cidality in patients are high, and could be neurotoxic.

Ethionamide Pharmacokinetics/Pharmacodynamics-derived Dose, the Role of MICs in Clinical Outcome, and the Resistance Arrow of Time in Multidrug-resistant Tuberculosis

“…A final important implication is the following corollary: increases in MIC are a sine qua non of increasing resistance and the resistance breakpoints represent a concentration above which there is uniform failure at that dose of drug used [43,44]. Conversely, cycloserine MICs were not important predictors of outcome consistent with HFS-TB and MCEs elsewhere [45].…”

Phylogenetically informative mutations in genes implicated in antibiotic resistance in Mycobacterium tuberculosis complex

“…The possibility that the entire M. africanum/ animal branch likely has intrinsically elevated MICs to DCS is particularly concerning in light of the severe toxicity of DCS and terizidone [5,29]. More MIC data are urgently needed to inform pharmacokinetic/pharmacodynamic (PK/PD) modelling to set a clinical breakpoint for DCS and to assess whether this increase is clinically relevant [49].…”

Pharmacokinetic/Pharmacodynamic Background and Methods and Scientific Evidence Base for Dosing of Second-line Tuberculosis Drugs

“…Next, because a major focus of discussion at the WHO PK/PD session was the role of group B or injectable agents in Table 1, and their high rates of toxicity, a systematic analysis addressing amikacin efficacy versus toxicity was performed [47][48][49][50]. Group C agents have had no formal PK/PD studies, so the next grouping includes articles on cycloserine, ethionamide, and both old and new oxazolidinones [51,52]. With regard to group D drugs, would high-dose moxifloxacin plus high-dose group D drugs such as isoniazid and pyrazinamide be able to shorten therapy?…”