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Time Kill Curve PD Modelling Experiments Are Affected by Trailing MIC Endpoints: Refinement of MIC Determination for

Andrew Mead1, Ludovic Pelligand1,2

  • 1Comparative Biomedical Sciences, The Royal Veterinary College, London, UK.

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|October 28, 2025
PubMed
Summary

Refining minimum inhibitory concentration (MIC) testing for trimethoprim-sulphonamide combinations against Staphylococcus pseudintermedius improves pharmacodynamic (PD) study design. This method enhances accuracy for bacteriostatic agents, aiding dose prediction and reducing misclassification in clinical settings.

Keywords:
PK/PD modellingpharmacodynamicspharmacokineticssulphonamidetrimethoprim

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Area of Science:

  • Microbiology
  • Pharmacology
  • Veterinary Medicine

Background:

  • Trailing endpoints pose challenges in broth microdilution MIC testing, especially for bacteriostatic agents like trimethoprim (TMP) and sulphonamides.
  • Accurate MIC determination is crucial for reliable pharmacodynamic (PD) study design and translational applications.

Purpose of the Study:

  • To apply a pharmacodynamically guided refinement for MIC determination of TMP-sulphonamide combinations against Staphylococcus pseudintermedius.
  • To improve MIC determination for better pharmacodynamic (PD) study design, not to redefine clinical susceptibility.
  • To support optimization of PD modeling and inform dose prediction and reduce misclassification in PD contexts.

Main Methods:

  • Comparison of visual MICs with MICs derived from log10 changes in CFU/mL over 24 hours.
  • Utilized pharmacodynamic thresholds of +2.3 log10 (visible growth) and 0 log10 change (stationary concentration).
  • Time-kill curve experiments were anchored on count-based MICs.

Main Results:

  • Visual MICs often underestimated the concentration required to suppress growth by 2-4 fold, particularly for sulphonamides.
  • TMP-sulphonamide combinations (1:19 ratio) demonstrated reduced trailing and closer agreement between visual and count-based MICs.
  • Count-based MICs provided more accurate PD responses in time-kill curves compared to visual MICs.

Conclusions:

  • Pharmacodynamically guided MIC refinement improves accuracy for bacteriostatic agents and combinations.
  • This method supports rational selection of concentrations for PD studies, especially for slow-acting or ratio-sensitive combinations.
  • The approach has translational value for sulphonamides used in human and veterinary medicine.