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 (fTMSW) 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.

Testing the mutant selection window hypothesis with meropenem: In vitro model study with OXA-48-producing Klebsiella pneumoniae

“…The Figs show that accurate bell-shaped relationships fitted with Gaussian function were observed. Similar bell-shaped "PK/PD index-resistance" relationships were previously reported in several studies with non-beta-lactam antibiotics with an account of the mutant selection window (MSW) hypothesis [10][11][12][13][14][15][16][17]; in this regard, beta-lactam antibiotics were not well described. Interestingly, despite meropenem degradation throughout time-kill experiments and the resultant pharmacokinetic profiles that differed significantly from targets, T MSW values, calculated with desired meropenem concentrations, were consistent with the enrichment of the bacterial population with resistant cells.…”

“…To address these issues we tested the well-known mutant selection window hypothesis with meropenem. The mutant selection window (MSW) hypothesis is applicable [10] to explain resistance patterns of several classes of antibiotics [11][12][13][14][15][16][17]; however, only a few such studies have been reported with beta-lactams [12,17].…”

Metabolomics revealed mechanism for the synergistic effect of sulbactam, polymyxin-B and amikacin combination against Acinetobacter baumannii

“…Our previous study demonstrated the synergistic effect of another triple-combination therapy consisting of polymyxin-B/ meropenm/sulbactam (Menegucci et al, 2019;Fedrigo et al, 2021;Zhang et al, 2022;Zhu et al, 2022b) and demonstrated disruption of the metabolomic profile of a clinical A. baumannii isolate (Zhu et al, 2022c). The metabolites involved in the cell wall synthesis, outer membrane integrity and central carbon metabolism were primarily affected by polymyxin-B/meropenem or polymyxin-B/ meropenem/sulbactam combinations.…”

“…In contrast, the present study replaced meropenem with amikacin; this triple-antibiotic combination with amikacin also disrupted metabolisms of the nucleotides, amino acids and peptides. There is a stark difference in treatment effects for the two triple-antibiotic combinations that may explain why the combination with amikacin resulted in a better bactericidal effect and inhibition of mutant selection for their clinical regimens based on model-simulated parameters ( Zhang et al, 2022 ; Zhu et al, 2022a ).…”

Physiologically based pharmacokinetic modelling to inform combination dosing regimens of ceftaroline and daptomycin in special populations

“…Coadministration of 2 or more antibiotics is a potential solution to the global problem of limited antibiotic monotherapy options against these multidrug-resistant bacteria. [7][8][9][10][11] Ceftaroline is a fifth-generation cephalosporin with in vitro and in vivo MRSA activities for the treatment of bacterial skin and skin structure infections. 12,13 There are clinical and experimental evidences showing that β-lactams and cationic antimicrobial peptides have synergistic activities and can sensitize innate host defence to decrease the virulence of the pathogen.…”