Evaluation Of Combination Of Sulbactam And Meropenem Regimens Suppressing Emergence Of Spontaneous Resistance In Acinetobacter Baumannii

Objective:To explore suppressing drug-resistance of combination of sulbactam and meropenem regimens in Pharmacoknetics/Pharmacodynamics (PK/PD) model of Acinetobacter baumannii in vitro.Method:MIC of antimicrobial monotherapy of Acinetobacter baumannii was measured by disc diffusion method. MIC and MPC of monotherapy and combination therapy of meropenem and sulbactam were measured by broth microdilution method and solid agar method. PK/PD model in vitro was established to simulate two kinds of meropenem monotherapy regimen (1.030min Q8h,1.03h Q8h) and6kinds of sulbactam monotherapy regimen (1.030min Q8h,2.030min Q8h,3.030min Q8h,1.03h Q8h,2.03h Q8h,3.03h Q8h);6kinds of combination therapy of meropenem (1.030min Q8h combined with sulbactam1.030min Q8h,2.030min Q8h,3.030min Q8h respectively). Meropenem1.03h Q8h combined with Sulbactam1.03h Q8h,2.03h Q8h,3.03h Q8h respectively. Every regimem was continuous administrated for7days.The amount of total bacteria and drug-resistance bacteria was measured in setting time, and drug concentration of meropenem and sulbactam were measured by HPLC (high performance liquid chromatography) and HPLC-MS/MS (high performance liquid chromatography-Mass Spectrum/Mass Spectrum) method respectively.Results:The MIC of meropenem and sulbactam was2μg·mL-1and128μg·mL-1for Acinetobacter baumannii45791strain respectively,while the MPC was28.8μg·mL-1and128μg·mL-1respectively. This srain was resistant to penicillins, quinolone,aminoglycoside, cephalosporins and compounds containing beta-lactamase. Checkerboard method showed an synergistic effect from the combined MIC. The combined MPC values of meropenem and sulbactam for Acinetobacter baumannii45791declined to8gμ/mL and32μg/mL respectively. The total amount of bacteria showed no decrease in168hours for six kinds of sulbactam monotherapy regimen. In both meropenem1.0g q8h30min infusion and1.0g q8h3h infusion regimen, the total amount of bacteria continued to decline in72h and24h respectively, with a decrease of approximately103cfu/mL, after basically unchanged at144h and96h, the bacteria grew stablely.The final concentration exceeds to106cfu/mL.Then the resistant mutant bacteria grew for its enrichment in72hours. Six kinds of combination regimen couldn’t prevent resistant mutation of bacteria. There was no significant difference for meropenem1.0Q8h30min infusion and sulbactam1.0Q8h30min infusion,2.0Q8h30min infusion combined regimen, the total amount of bacterial continued to decline,with a decrease of approximately105cfu/mL, the resistant mutant bacteria grew for its enrichment in144h hours. Meanwhile, there was no significant difference for meropenem1.0Q8h3h infusion combined with sulbactam1.0Q8h3h infusion, sulbactam2.0Q8h3h infusion,and sulbactam3.0Q8h3h infusion respectively.Total bacterial count continued to decline, down about106cfu/mL, The resistant bacteria did not grow abundantly In all of administration regimens,all bacteria became resistant mutants strains at168h.Conclusion:For Acinetobacter baumannii45791, combination of sulbactam and meropenem could significantly reduce MSW(mutant selection window) of meropenem. The combination of sulbactam and meropenem therapy could slow down the speed of the enrichment of resistant mutants of bacteria. especially in3h infusion regimens. For combination of sulbactam and meropenem therapy, increasing the dose of sulbactam could not improve the bactericidal effect and suppress drug-resistant mutations.