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 10000 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 log10 colony-forming units (CFU)/mL extracellular bacilli over 28 days. Efficacy was driven by the percentage of time concentration persisted above MIC (%TMIC), with 1.0 log10 CFU/mL kill achieved by %TMIC = 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.

Figure 1.

Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram. Abbreviations: EBA, early bactericidal activity; PD, pharmacodynamic; PK, pharmacokinetic.

Figure 2.

Sensititre d-cycloserine minimum inhibitory concentration (MIC) distribution for 415 clinical isolates. Using the MIC distribution of 415 clinical isolates from 4 countries, including rifampicin-susceptible and -resistant isolates, 64 mg/L was chosen as the tentative epidemiological cutoff for d-cycloserine using the Sensititre method based on visual inspection [49]. No (tentative) ECOFFs are available for other media [32]. Abbreviations: ECOFF, epidemiological cutoff; MIC, minimum inhibitory concentration; RIF-R, rifampicin resistant; RIF-S, rifampicin susceptible.

Figure 3.

d-cycloserine microbial kill in the hollow fiber system model of tuberculosis. A, Time to positivity (TTP) as a measure of bacterial burden when d-cycloserine doses were administered daily; the doses are shown as the 0- to 24-hour area under the concentration–time curve (AUC_0–24) values. TTP increases as bacterial burden decreases. The highest 2 doses with an area under the concentration–time curve (AUC) of 182 and 273 mg × h/L achieved TTP >56 days, and thus negative culture. The TTP >56 days is a more stringent cutoff point for negative cultures compared to the 42 days used in the clinic, though this varies between clinical laboratories. B, The once-weekly regimens did worse, with TTPs only increasing after 3 weeks; doses are shown as AUC_0–24 values. C, When microbial kill was measured using colony-forming units (CFU)/mL, the 2 highest doses achieved negative cultures by day 7, unlike what was seen with TTP. The CFU/mL assay is less sensitive at lower bacterial burdens. D, Based on CFU/mL, the once-weekly dosing schedules demonstrated microbial kill during the first 10 days, then failed, with regrowth after 21 days. The kill slopes were less steep compared to the daily dosing schedule. Doses are shown as AUC_0–24 values. AUC, area under the concentration–time curve; CFU, colony-forming units; MGIT, mycobacterial growth indicator tube; TTP, time to positivity.

Figure 4.

Performance of different d-cycloserine doses for pulmonary disease. d-cycloserine minimum inhibitory concentrations (MICs) based on the Sensititre assay were used. A, For the stasis target (ie, exposure at which there is no kill or growth compared to day 0), the target attainment probabilities (TAPs) are shown for doses of 250–750 mg at 2 dosing schedules. There is clear separation of performance by the 750-mg doses (shown in black) from the rest of the doses. At 750 mg daily, TAP falls at MICs of ≥32 mg/L. B, For cidal activity, the same pattern is shown, except that now there is also separation of TAPs between 750 mg once daily and 750 mg twice daily. At the latter dose and schedule, the MIC above which TAP falls below 90% is 32 mg/L. C, For the target of 80% of maximal kill (EC₈₀), even the dose if 750 mg twice a day would fall below 90% at around 32 mg/L. D, When an expectation was taken over the entire MIC range, the dose of 750 mg twice daily was able to achieve the exposure target of stasis, cidal effect, and EC_80, in 93%, 92%, and 81% of 10000 patients, respectively. Abbreviations: bid, twice daily; EC₈₀, 80% of maximal kill; MIC, minimum inhibitory concentration; OD, once daily.

Figure 5.

Target attainment probability (TAP) of various d-cycloserine doses in meningitis. Shown are TAP values for 10000 patients with tuberculous meningitis (TBM) and extracavitary compartments of tuberculosis. d-cycloserine has better penetration into cerebrospinal fluid (CSF) than lung cavities. A, The TAP for stasis target exposure demonstrated good performance for the dose of 500 mg twice daily, and only fell below 90% at a minimum inhibitory concentration (MIC) of 32 mg/L, and for the highest dose at an MIC of 64 mg/L. B, For the cidal exposure target, 500 mg twice daily and 750 mg twice daily achieved good TAP up to an MIC of 32 mg/L, such that the majority of patients with meningitis would be expected to achieve exposures that have cidal effect in CSF at these doses. This means that as long as MICs were <64 mg/L, cidal effect was achieved. Given the paucibacillary nature of TBM, this is thought to be the best pharmacokinetic/pharmacodynamic exposure target for meningitis. C, Even with good penetration into the subarachnoid space, the 80% of maximal kill was more difficult to achieve at all doses for MICs ≥16 mg/L. D, Cumulative fraction of patients who achieve responses for each dose. The dose of 500 mg twice daily falls just short of 90% for the cidal effect, but is proposed for use in TBM. Abbreviations: bid, twice daily; EC₈₀, 80% of maximal kill; MIC, minimum inhibitory concentration; OD, once daily.