Pharmacodynamic evaluation of suppression of in vitro resistance in Acinetobacter baumannii strains using polymyxin B-based combination therapy

Nayara Helisandra Fedrigo,Sheila Alexandra Belini Nishiyama,Peijuan Zhu,Josmar Mazucheli,Sherwin Kenneth B Sy,Mingming Yu,Danielle Rosani Shinohara,Floristher Elaine Carrara-Marroni,Frederico Severino Martins,Maria Cristina Bronharo Tognim

doi:10.1038/s41598-021-90709-2

Abstract

The emergence of polymyxin resistance in Gram-negative bacteria infections has motivated the use of combination therapy. This study determined the mutant selection window (MSW) of polymyxin B alone and in combination with meropenem and fosfomycin against A. baumannii strains belonging to clonal lineages I and III. To evaluate the inhibition of in vitro drug resistance, we investigate the MSW-derived pharmacodynamic indices associated with resistance to polymyxin B administrated regimens as monotherapy and combination therapy, such as the percentage of each dosage interval that free plasma concentration was within the MSW (%TMSW) and the percentage of each dosage interval that free plasma concentration exceeded the mutant prevention concentration (%T>MPC). The MSW of polymyxin B varied between 1 and 16 µg/mL for polymyxin B-susceptible strains. The triple combination of polymyxin B with meropenem and fosfomycin inhibited the polymyxin B-resistant subpopulation in meropenem-resistant isolates and polymyxin B plus meropenem as a double combination sufficiently inhibited meropenem-intermediate, and susceptible strains. T>MPC 90% was reached for polymyxin B in these combinations, while %TMSW was 0 against all strains. TMSW for meropenem and fosfomycin were also reduced. Effective antimicrobial combinations significantly reduced MSW. The MSW-derived pharmacodynamic indices can be used for the selection of effective combination regimen to combat the polymyxin B-resistant strain.

Highlights

The emergence of polymyxin resistance in Gram-negative bacteria infections has motivated the use of combination therapy
The population structure of the 1,557 sequence types available in the PubMLST A. baumannii database is shown in Fig. 1, based on the Pasteur scheme using the goeBURST algorithm implemented in Phyloviz Online[25]
Polymyxin B is one of the few remaining options for the treatment of CR-Ab, but its use in monotherapy has led to the emergence of resistant strains[9,10,11]

Summary

Introduction

The emergence of polymyxin resistance in Gram-negative bacteria infections has motivated the use of combination therapy. To evaluate the inhibition of in vitro drug resistance, we investigate the MSW-derived pharmacodynamic indices associated with resistance to polymyxin B administrated regimens as monotherapy and combination therapy, such as the percentage of each dosage interval that free plasma concentration was within the MSW (%TMSW) and the percentage of each dosage interval that free plasma concentration exceeded the mutant prevention concentration (%T>MPC). The upper limit of the window is the mutant prevention concentration (MPC) and the lower boundary is the minimum inhibitory concentration (MIC)[12] According to this hypothesis, keeping drug concentrations above MPC throughout therapy will restrict the emergence of resistance and achieve its therapeutic effect. Given that polymyxin B has a very narrow therapeutic window, administration of this drug as monotherapy failed to attain MPC safely, especially in patients with renal impairment[14]

Methods

Results

Conclusion