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Resistance studies with daptomycin.

J A Silverman1, N Oliver, T Andrew

  • 1Cubist Pharmaceuticals, Inc., Cambridge, Massachusetts 02139, USA. jsilverm@cubist.com

Antimicrobial Agents and Chemotherapy
|May 17, 2001
PubMed
Summary
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Emergence of daptomycin resistance in bacteria is rare and difficult to achieve in vitro. However, stable resistant mutants can arise, exhibiting altered membrane potential and reduced virulence, suggesting potential treatment efficacy in vivo.

Area of Science:

  • Microbiology
  • Infectious Diseases
  • Pharmacology

Background:

  • Daptomycin is a crucial antibiotic for treating Gram-positive bacterial infections.
  • Understanding the mechanisms and frequency of daptomycin resistance is vital for effective clinical use.

Purpose of the Study:

  • To investigate the in vitro emergence of daptomycin resistance in various bacterial species.
  • To characterize the phenotypes and potential virulence of daptomycin-resistant mutants.

Main Methods:

  • Assessing spontaneous resistance incidence.
  • Employing serial passage with increasing drug concentrations.
  • Utilizing chemical mutagenesis to induce resistance.
  • Analyzing bacterial membrane potential and in vivo virulence.

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Main Results:

  • No spontaneous daptomycin-resistant mutants were obtained across tested species.
  • Stable resistant Staphylococcus aureus mutants were generated via serial passage and mutagenesis, showing 8- to 32-fold higher MICs.
  • Resistant mutants displayed increased membrane potential (Delta psi) and some had reduced virulence in vivo.
  • Apparent resistance rates were influenced by calcium concentration and culture density.

Conclusions:

  • Daptomycin resistance emergence in vitro is infrequent.
  • Generated resistant mutants possess distinct characteristics, including altered membrane potential.
  • In vivo susceptibility may not always correlate with in vitro resistance levels, suggesting potential treatment success.
  • Further research is needed to fully elucidate the clinical implications of daptomycin resistance.