The combination effect of meropenem/sulbactam/polymyxin-B on the pharmacodynamic parameters for mutant selection windows against carbapenem-resistant Acinetobacter baumannii

Abstract

The objective of this study was to evaluate whether combinations of sulbactam, meropenem, and polymyxin-B could reduce or close the gap of mutant selection window (MSW) of individual antibiotics against Acinetobacter baumannii harboring OXA-23. MICs of three antimicrobials used alone and in combination (meropenem/polymyxin-B or meropenem/polymyxin-B/sulbactam) were obtained in 11 clinical isolates and mutant prevention concentrations were determined in 4 of the 11 isolates. All isolates were resistant to meropenem or polymyxin-B. Combining meropenem and polymyxin-B with or without sulbactam resulted in synergistic bactericidal activities. Pharmacokinetic (PK) simulations of drug concentrations in the blood and epithelial lining fluid coupled with pharmacodynamic (PD) evaluations revealed that the fractions of time over the 24-h in terms of free drug concentration within the MSW (fT_MSW) and above the MPC (fT_>MPC) were optimized by combination therapy. The resultant clinical regimens of meropenem, polymyxin-B, and sulbactam evaluated in the PK-PD analysis were 2 g q8h, 2.5 mg/kg loading dose followed by 1.5 mg/kg q12h, and 3 g q8h, respectively, in patients with normal renal function. Subsequent corresponding equivalent exposure regimens would depend on the extent of renal failure. The overall results indicate that combination antibiotics consisting of sulbactam/meropenem/polymyxin-B can confer potential efficacy against A. baumannii harboring OXA-23, and reduce the opportunity for bacteria to develop further resistance. This study provides a framework for pharmacodynamic evaluation of drug-resistant mutant suppression in an antimicrobial co-administration setting. The results thereby lay the groundwork for additional studies and future clinical confirmation is warranted.

Keywords: Acinetobacter baumannii; OXA-23; meropenem; pharmacodynamics; polymyxin-B; sulbactam.

Figure 1

Static-concentration time-kill kinetics of meropenem and polymyxin-B alone and in combination at their respective MIC and 2 × MIC and also as triple combination with 4 mg/l sulbactam against two A. baumannii isolates. Monotherapy MICs for meropenem and polymyxin-B were 16 and 16 mg/l for isolate 2, and 128 and 16 mg/l for isolate E, respectively. MICs of meropenem and polymyxin-B were 4 and 4 mg/l for isolate 2, and 4 and < 1 mg/l for isolate E, respectively, in both the double and triple combinations.

Figure 2

Probability of target attainment of 50% fT_>MIC and 60% fT_>MIC for meropenem and sulbactam dosing regimens, respectively, by renal function category and PTA of fAUC/MIC of at least 8.2 for polymyxin-B dosing regimens. Probability of target attainment values were computed based on steady-state drug concentrations in the blood. LD, loading dose; CL_CR, creatinine clearance.

Figure 3

Sensitivity analysis to evaluate effect of variability in polymyxin plasma protein binding on the pharmacodynamic parameters fT_MSW and fT_>MPC after polymyxin dosing regimens in combination therapy consisting of 2.5 mg/kg loading dose followed by 1.5 mg/kg q12h at 12 h (top graph) and 2 mg/kg loading dose followed by 1.25 mg/kg q12h at 12 h (bottom graph) against A. baumannii E. The models assumed polymyxin MIC of 1 mg/l and MPC of 4 mg/l, whereas meropenem MIC and MPC were both 4 mg/l with or without 4 mg/l sulbactam. In this scenario, the proposed dosing regimens of both meropenem and sulbactam can achieve PTA ≥90%.

Figure 4

Probability of target attainment of 50% fT_>MIC and 60% fT_>MIC for meropenem and sulbactam dosing regimens, respectively, by renal function categoryand PTA of fAUC/MIC of at least 8.2 for polymyxin-B dosing regimens. Probability of target attainment values were computed based on steady-state drug concentrations in the epithelial lining fluid (ELF) and their respective ELF penetration. LD, loading dose; CL_CR, creatinine clearance.