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Time inside the mutant selection window as a predictor of staphylococcal resistance to linezolid

Kamilla N Alieva1, Elena N Strukova1, Maria V Golikova1

  • 1Gause Institute of New Antibiotics, Moscow, Russian Federation.

The Journal of Antibiotics
|January 20, 2018
PubMed

Insights

Time inside the mutant selection window (TMSW) predicts bacterial resistance to linezolid. This study found TMSW, time above mutant prevention concentration (T>MPC), and drug exposure metrics reliably predict Staphylococcus aureus resistance emergence.

Area of Science:

  • Pharmacology and Microbiology
  • Antimicrobial Resistance Research
  • Bacterial Pathogenesis

Background:

  • Bacterial resistance to antibiotics like linezolid is a growing public health concern.
  • Predicting the emergence of resistance is crucial for effective antimicrobial therapy.
  • The mutant selection window (TMSW) is a theoretical concept requiring validation as a resistance predictor.

Purpose of the Study:

  • To evaluate the time inside the mutant selection window (TMSW) as a predictor of bacterial resistance to linezolid.
  • To investigate the relationship between TMSW and the emergence of linezolid-resistant methicillin-resistant Staphylococcus aureus (MRSA).
  • To assess other pharmacokinetic/pharmacodynamic (PK/PD) parameters as predictors of resistance.

Main Methods:

  • Utilized an in vitro dynamic model simulating linezolid pharmacokinetics against MRSA.
  • Exposed mixed inocula of MRSA strains and their resistant mutants to simulated five-day treatments.
  • Analyzed the enrichment of resistant mutants in relation to TMSW, time above mutant prevention concentration (T>MPC), AUC24/MIC, and AUC24/MPC.

Main Results:

  • Resistant mutants were enriched in a TMSW-dependent manner across various simulated drug exposures.
  • Strain-independent sigmoid relationships were observed between normalized bacterial mutant concentration-time curve (AUBCM) and TMSW/T>MPC.
  • Bell-shaped relationships were found between normalized AUBCM and AUC24/MIC/AUC24/MPC, indicating their predictive value.

Conclusions:

  • TMSW, particularly when T>MPC > 0, is a reliable predictor of linezolid resistance emergence in S. aureus.
  • T>MPC, AUC24/MIC, and AUC24/MPC also serve as valuable, strain-independent predictors.
  • These findings support the use of these PK/PD indices for optimizing linezolid dosing strategies to mitigate resistance.

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