Trimethoprim/sulfamethoxazole pharmacodynamics against Stenotrophomonas maltophilia in the in vitro chemostat model

Abstract

Background Trimethoprim/sulfamethoxazole has historically been the treatment of choice for infection caused by Stenotrophomonas maltophilia. This study sought to define the pharmacodynamic indices and magnitude of exposure required for stasis and 1 log10 cfu reductions. Methods Pharmacodynamic studies were conducted using the in vitro chemostat model over 24 h against three trimethoprim/sulfamethoxazole-susceptible S. maltophilia isolates with MICs from 0.25/4.75 to 2/38 mg/L. The primary endpoint was the change in cfu at 24 h relative to baseline. The log ratio of the area under the cfu curve (LR AUcfu) was a secondary endpoint. Trimethoprim and sulfamethoxazole exposures required for stasis and 1 log10 cfu/mL reduction were determined. Results Trimethoprim/sulfamethoxazole exposures achieved stasis and 1 log10 cfu/mL reductions in 9/16 (56%) and 2/16 (13%) of experiments. Both the fAUC/MIC and fCmax/MIC were identified as equivalent pharmacodynamic drivers, with stasis achieved at an fAUC/MIC of 67.4 and 30.0 for trimethoprim and sulfamethoxazole, respectively. Clinically meaningful exposures required to achieve 1 log10 cfu/mL reductions were not quantifiable. The LR AUcfu analysis supported the lack of overall bacterial burden reduction against S. maltophilia. Conclusions In this in vitro chemostat model, trimethoprim/sulfamethoxazole monotherapy, even at higher doses, achieved limited activity against susceptible S. maltophilia.

Optimizing Antibiotic Therapy for Stenotrophomonas maltophilia Infections in Critically Ill Patients: A Pharmacokinetic/Pharmacodynamic Approach

“…According to the PK/PD breakpoint, cotrimoxazole should not be recommended to treat an infection due to isolates with MICs higher than 0.5 mg/L since drug exposure is insufficient. These results agree with Lasko et al [ 18 ], who demonstrated that cotrimoxazole in monotherapy even at a high dose displays limited activity against cotrimoxazole-susceptible S. maltophilia strains. In fact, several authors have pointed out the necessity of redefining the breakpoints of cotrimoxazole for S. maltophilia [ 8 , 19 , 20 ].…”

Steno‐sphere: Navigating the enigmatic world of emerging multidrug‐resistantStenotrophomonas maltophilia

“…A reduction in bacterial cell count was not observed for any S. maltophilia isolate while susceptible E. coli isolates experienced killing at all MIC values. The group also examined the same TMP‐SMX simulated dose in a chemostat model 49 . TMP‐SMX exhibited limited activity with only two experiments demonstrating a ≥ 1‐log 10 CFU/mL reduction.…”

“…The group also examined the same TMP-SMX simulated dose in a chemostat model. 49 TMP-SMX exhibited limited activity with only two experiments demonstrating a ≥ 1-log 10 CFU/mL reduction. These results corroborate previous evidence in which simulated doses up to 15 mg/kg (TMP component) q12h did not reduce bacterial cell counts of four susceptible S. maltophilia isolates in a one-compartment model.…”

Treatment approaches for severe Stenotrophomonas maltophilia infections

“…Time-kill analysis demonstrated that exposure of SXT-susceptible Sma isolates to 4/40 μg/ml for 24 h, which approximates the free steady-state concentration of a daily dose of 20 mg/kg of TMP, does not achieve colony forming unit (CFU) reduction [90 ▪▪ ]. Likewise, in an in vitro chemostat model, SXT stasis was achieved at a ratio of the area under the unbound drug time curve over 24 h to the MIC (fAUC/MIC) of 67.4 and 30 for TMP and sulfamethoxazole, respectively; however, clinically meaningful exposures required to achieve 1 log 10 CFU/ml reductions were not quantifiable [91 ▪▪ ]. The toxicity profile of high doses of SXT, which includes nausea/vomiting, hyperkalemia, fluid overload, and possible nephrotoxicity, is another issue that needs to be considered.…”

“…Average susceptibility rates for this agent varies among geographical regions, being the highest in Europe (>95%), followed by the Middle East (≈93%), USA (≈90%), Latin America (≈80%), and the lowest in Asia (<80% in China; 87% in Korea) [17,31 ▪ ,34 ▪ ,42,83 ▪▪ ,84 ▪ –88 ▪ ]. SXT lacks established PK/PD index or target threshold for efficacy or toxicity, which severely impairs the ability to optimize its clinical use [34 ▪ ,89 ▪ ,90 ▪▪ ,91 ▪▪ ,92]. In fact, data supporting guidance-recommended dosing of 8–12 mg/kg/day [trimethoprim (TMP) component] is sparse [93].…”