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

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.

In Vitro Time-Kill Studies of Trimethoprim/Sulfamethoxazole against Stenotrophomonas maltophilia versus Escherichia coli Using Cation-Adjusted Mueller-Hinton Broth and ISO-Sensitest Broth.

Trimethoprim/sulfamethoxazole (TMP/SMZ) is considered the treatment of choice for infections caused by Stenotrophomonas maltophilia, but limited pharmacodynamic data are available to support current susceptibility breakpoints or guide optimal dosing. Time-kill studies using a TMP/SMZ concentration of 4/40 µg/mL were conducted to compare 4 S. maltophilia with 4 Escherichia coli isolates having the same MICs (0.25/4.75 to 4/76 µg/mL) in cation-adjusted Mueller-Hinton broth (CAMHB) and ISO-Sensitest broth (ISO broth). With the exception of the resistant isolates (4/76 µg/mL), which resulted in regrowth approaching the growth of the control, TMP/SMZ displayed significantly greater killing for E. coli than for S. maltophilia at each MIC. Against E. coli, the mean changes at 24 h were -4.49, -1.73, -1.59, and +1.83 log10 CFU for isolates with MICs of 0.25/4.75, 1/19, 2/39, and 4/74 µg/mL, respectively. The area under the concentration-time curve for the free, unbound fraction of the drug (fAUC)/MIC ratio required for stasis and 1-log10 and 2-log10 CFU reductions were 40.7, 59.5, and 86.3, respectively. In contrast, TMP/SMZ displayed no stasis or CFU reductions against any S. maltophilia isolate regardless of the MIC, and no pharmacodynamic thresholds were quantifiable. Observations were consistent in both CAMHB and ISO broth. These data add increasing evidence that current TMP/SMZ susceptibility breakpoints against S. maltophilia should be reassessed.

In Vivo Efficacy of WCK 5222 (Cefepime-Zidebactam) against Multidrug-Resistant Pseudomonas aeruginosa in the Neutropenic Murine Thigh Infection Model.

We describe the in vivo efficacy of human-simulated WCK 5222 (cefepime-zidebactam) exposure against multidrug-resistant Pseudomonas aeruginosa (meropenem MICs 8 to >256 µg/ml) in a neutropenic murine thigh infection model. WCK 5222 MICs ranged from 4 to 32 µg/ml. Substantial in vivo WCK 5222 activity was observed against all isolates, further enhancing the efficacy of zidebactam alone in 11/16 isolates (WCK 5222 mean reduction, -1.62 ± 0.58 log10 CFU/thigh), and a lack of activity was observed with cefepime monotherapy.