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Testing the mutant selection window hypothesis in vitro and in vivo with Staphylococcus aureus exposed to fosfomycin
1Department of Infectious Diseases, First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui, China.
Abstract:
The purpose of this study was to test the mutant selection window (MSW) hypothesis in vitro and in vivo with Staphylococcus aureus exposed to fosfomycin. With the in vitro time-kill studies, S. aureus ATCC 29213 [with a minimal concentration that inhibits colony formation by 99% (MIC99) of 2.2 μg/mL and a mutant prevention concentration (MPC) of 57.6 μg/mL] lost fosfomycin susceptibility at antibiotic concentrations (2×, 4×, and 8× MIC) that are between the lower and upper boundaries of the MSW. In the tissue-cage model, S. aureus was exposed to fosfomycin pharmacokinetics at concentrations below the MIC99, between the MIC99 and the MPC, and above the MPC, respectively. Changes in susceptibility and counts of total and resistant viable bacteria were monitored in tissue-cage fluid obtained daily. However, the selection of resistant mutants was not observed during antibacterial treatment and 48 h after the termination of fosfomycin treatment, regardless of the fosfomycin dosage. Besides, we found no differences between the in vitro-isolated mutant and its sensitive parental strain, which indicates the absence of fitness cost of fosfomycin resistance in S. aureus ATCC 29213. These findings demonstrate that agar plate determinations do not fit the MSW for fosfomycin treatment of rabbits infected with S. aureus ATCC 29213; therefore, the existence of the window must be demonstrated not only in vitro but also in vivo. Further research is needed on the exact mechanism of resistance.
Insights
This study investigated the mutant selection window (MSW) for fosfomycin against Staphylococcus aureus. In vivo, resistant mutants were not selected, challenging the MSW hypothesis in clinical settings.
Area of Science:
- Microbiology
- Pharmacology
- Infectious Diseases
Background:
- The mutant selection window (MSW) hypothesis suggests a specific antibiotic concentration range selects for resistant bacterial mutants.
- Understanding MSW is crucial for optimizing antibiotic therapy and preventing resistance development.
Purpose of the Study:
- To evaluate the in vitro and in vivo validity of the MSW hypothesis for fosfomycin against Staphylococcus aureus.
- To determine if fosfomycin resistance emerges within the predicted MSW in a rabbit infection model.
Main Methods:
- In vitro time-kill studies were performed using Staphylococcus aureus ATCC 29213 exposed to varying fosfomycin concentrations.
- An in vivo rabbit tissue-cage model assessed bacterial response to fosfomycin pharmacokinetics at concentrations below, within, and above the MSW.
- Bacterial susceptibility, total viable counts, and resistant counts were monitored daily in tissue-cage fluid.
Main Results:
- In vitro, Staphylococcus aureus lost susceptibility to fosfomycin at concentrations within the predicted MSW.
- In vivo, no resistant mutants were selected during or after fosfomycin treatment, irrespective of dosage.
- No fitness cost associated with fosfomycin resistance was observed in vitro-isolated mutants.
Conclusions:
- Agar plate-based MSW determinations may not accurately predict in vivo resistance selection for fosfomycin in Staphylococcus aureus infections.
- The existence and relevance of the MSW require validation in relevant in vivo models.
- Further research is needed to elucidate the precise mechanisms of fosfomycin resistance in Staphylococcus aureus.
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