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Infection and drug resistance
2022;15 4995-5010.

Assessing the Emergence of Resistance in vitro and Invivo: Linezolid Combined with Fosfomycin Against Fosfomycin-Sensitive and Resistant .

Yaowen Li, Yu Peng, Na Zhang, Huiping Liu, Jun Mao, Yisong Yan, Shuaishuai Wang, Guang Yang, Yanyan Liu, Jiabin Li, Xiaohui Huang
Author Information
  1. Yaowen Li: Department of Basic and Clinical Pharmacology, School of Pharmacy, Anhui Medical University, Hefei, People's Republic of China. ORCID
  2. Yu Peng: Department of Basic and Clinical Pharmacology, School of Pharmacy, Anhui Medical University, Hefei, People's Republic of China.
  3. Na Zhang: Department of Basic and Clinical Pharmacology, School of Pharmacy, Anhui Medical University, Hefei, People's Republic of China.
  4. Huiping Liu: Department of Basic and Clinical Pharmacology, School of Pharmacy, Anhui Medical University, Hefei, People's Republic of China.
  5. Jun Mao: Department of Basic and Clinical Pharmacology, School of Pharmacy, Anhui Medical University, Hefei, People's Republic of China.
  6. Yisong Yan: Department of Pharmacy, Anhui College of Traditional Chinese Medicine, Wuhu, Anhui, People's Republic of China.
  7. Shuaishuai Wang: Department of Basic and Clinical Pharmacology, School of Pharmacy, Anhui Medical University, Hefei, People's Republic of China.
  8. Guang Yang: Department of Pharmacy, The Third People's Hospital of Tongling, Tongling, Anhui, People's Republic of China. ORCID
  9. Yanyan Liu: Department of Infectious Diseases, The First Affiliated Hospital of Anhui Medical University, Hefei, People's Republic of China.
  10. Jiabin Li: Department of Infectious Diseases, The First Affiliated Hospital of Anhui Medical University, Hefei, People's Republic of China.
  11. Xiaohui Huang: Department of Basic and Clinical Pharmacology, School of Pharmacy, Anhui Medical University, Hefei, People's Republic of China.
PMID: 36065277 DOI: 10.2147/IDR.S377848

Abstract

Purpose: We aimed to evaluate the synergistic effect of linezolid and fosfomycin on fosfomycin-sensitive and -resistant clinical isolates in vitro and in vivo and whether the emergence of fosfomycin resistance in is associated with changes in strain virulence, from the perspective of fitness cost.
Methods: The synergistic effect of linezolid and fosfomycin was studied via in vitro checkerboard and static time-kill assays, as well as based on the in vivo survival rate and hemolymph load of a infection model. Fosfomycin resistance was induced via a stepwise increase in concentration. Changes in the virulence of the strains after drug resistance were investigated using the infection model and reverse transcription quantitative polymerase chain reaction (RT-qPCR). In vitro and in vivo growth curves and competitive experiments were used to study the fitness cost of the strain. Finally, a static time-kill assay was performed to explore the effect of the combined medication.
Results: In vitro and in vivo data showed that linezolid combined with fosfomycin had a good synergistic effect on treatment. The infection model and RT-qPCR data showed that the virulence of the resistant strains was weakened to varying degrees. A survival curve and competition experimental data showed that this was related to the fitness cost of strains while acquiring resistance and negatively impacted linezolid treatment; however, the combination still showed a good synergistic effect in drug-resistant strains.
Conclusion: Linezolid combined with fosfomycin had a synergistic effect on both fosfomycin-sensitive and -resistant strains. Strains incur fitness costs as they develop drug resistance, which leads to a decrease in virulence. There is an interaction between fitness cost, virulence, and drug resistance, which indirectly affects drug treatment.

Keywords

fitness cost fosfomycin linezolid resistance virulence

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Journal Article

Word Cloud

Created with Highcharts 10.0.0resistanceeffectfosfomycinvirulencefitnesssynergisticlinezolidvitrocoststrainsvivodrugshowedinfectionmodelcombineddatatreatmentfosfomycin-sensitive-resistantstrainviastatictime-killsurvivalFosfomycinRT-qPCRgoodLinezolidPurpose:aimedevaluateclinicalisolateswhetheremergenceassociatedchangesperspectiveMethods:studiedcheckerboardassayswellbasedratehemolymphloadinducedstepwiseincreaseconcentrationChangesinvestigatedusingreversetranscriptionquantitativepolymerasechainreactiongrowthcurvescompetitiveexperimentsusedstudyFinallyassayperformedexploremedicationResults:resistantweakenedvaryingdegreescurvecompetitionexperimentalrelatedacquiringnegativelyimpactedhowevercombinationstilldrug-resistantConclusion:StrainsincurcostsdevelopleadsdecreaseinteractionindirectlyaffectsAssessingEmergenceResistanceInvivo:CombinedFosfomycin-SensitiveResistant

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