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Pharmacodynamics to combat resistance.

G Woodnutt1

  • 1SmithKline Beecham Pharmaceuticals, Collegeville, PA 19426-0989, USA. Gary_Woodnutt@sbphrd.com

The Journal of Antimicrobial Chemotherapy
|September 21, 2000
PubMed
Summary

Gemifloxacin

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Area of Science:

  • Pharmacology
  • Microbiology
  • Infectious Diseases

Background:

  • Optimizing antimicrobial agents requires balancing potency, pharmacokinetics, and pharmacodynamics.
  • Understanding these relationships is crucial for maximizing bacteriological cure and minimizing antimicrobial resistance.
  • Gemifloxacin's efficacy correlates with the AUC0-24h/MIC ratio, indicating drug exposure, not dosing frequency, is key.

Purpose of the Study:

  • To evaluate the pharmacokinetic/pharmacodynamic (PK/PD) drivers of gemifloxacin efficacy.
  • To compare gemifloxacin's in vivo activity against resistant bacterial strains.
  • To assess gemifloxacin's efficacy relative to other oral agents for respiratory infections.

Main Methods:

  • Murine thigh infection models (neutropenic and immunocompetent) were used to determine the required AUC0-24h/MIC ratios for efficacy.
  • In vitro and in vivo studies assessed gemifloxacin activity against Gram-negative bacilli and Streptococcus pneumoniae, including resistant strains.
  • Rat models were employed to compare gemifloxacin's efficacy with other oral agents at human-equivalent doses.

Main Results:

  • Gemifloxacin efficacy correlated strongly with the AUC0-24h/MIC ratio, with minimal correlation to time above MIC.
  • A higher AUC0-24h/MIC ratio was needed for Gram-negative bacilli (approx. 100) compared to S. pneumoniae (approx. 25).
  • Gemifloxacin maintained efficacy against S. pneumoniae with penicillin, macrolide, and ciprofloxacin resistance, including efflux mutants, suggesting minimal impact of efflux in vivo.

Conclusions:

  • Gemifloxacin's antibacterial effect is driven by the total drug exposure (AUC0-24h/MIC ratio), consistent with other quinolones.
  • The drug demonstrates potent in vivo activity against S. pneumoniae, even with resistance mechanisms like efflux.
  • Gemifloxacin shows excellent efficacy against key respiratory pathogens, including resistant strains, supporting its use for respiratory infections.

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