Short-course gentamicin in combination with daptomycin or vancomycin against Staphylococcus aureus in an in vitro pharmacodynamic model with simulated endocardial vegetations

Antimicrob Agents Chemother. 2005 Jul;49(7):2735-45. doi: 10.1128/AAC.49.7.2735-2745.2005.

Abstract

The ability to maximize bactericidal activity while minimizing toxicity is a therapeutic goal in the treatment of infective endocarditis. We evaluated the impact of administering short-course regimens of gentamicin in combination with daptomycin or vancomycin against one methicillin-susceptible (MSSA 1199) and one methicillin-resistant (MRSA 494) Staphylococcus aureus isolate using an in vitro pharmacodynamic model with simulated endocardial vegetations over 96 h. Human therapeutic dosing regimens for daptomycin (6 and 8 mg/kg of body weight), vancomycin, and gentamicin were simulated. Short-course combination regimens involving gentamicin were administered either as a single 5-mg/kg dose or three 1-mg/kg doses for only the first 24 h and compared to the regimens administered for the full 96-h duration. For all experiments, physiologic conditions of albumin, calcium, and pH were simulated. Both regimens of daptomycin achieved 99.9% kill by 32 h and maintained bactericidal activity against both isolates, which was significantly different from vancomycin, which displayed bacteriostatic activity (P < 0.05). The effects of all short-course regimens of gentamicin were equal to those of the full-duration regimens in combination with daptomycin. Adding three doses of gentamicin (1 mg/kg) to daptomycin resulted in enhancement and bactericidal activity at 24 h against both MRSA and MSSA. The addition of a single dose of gentamicin (5 mg/kg) enhanced or improved the activity of daptomycin and resulted in early bactericidal activity at 4 h against both isolates. The addition of three doses of gentamicin (1 mg/kg) did not improve the activity of vancomycin. However, the addition of a single 5-mg/kg dose of gentamicin to vancomycin resulted in early enhancement at 4 h and 99.9% kill at 32 h for MRSA. These results suggest that a single high dose of gentamicin in combination with daptomycin or vancomycin may be of utility to maximize synergistic and bactericidal activity and minimize toxicity. Further investigation is warranted.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Bacterial Agents / pharmacokinetics
  • Anti-Bacterial Agents / pharmacology*
  • Culture Media
  • Daptomycin / pharmacokinetics
  • Daptomycin / pharmacology*
  • Drug Therapy, Combination
  • Endocarditis, Bacterial / drug therapy*
  • Endocarditis, Bacterial / microbiology
  • Gentamicins / pharmacokinetics
  • Gentamicins / pharmacology*
  • Humans
  • Methicillin / pharmacokinetics
  • Methicillin / pharmacology
  • Methicillin Resistance
  • Microbial Sensitivity Tests
  • Models, Biological
  • Staphylococcus aureus / drug effects*
  • Staphylococcus aureus / growth & development
  • Vancomycin / pharmacokinetics
  • Vancomycin / pharmacology*

Substances

  • Anti-Bacterial Agents
  • Culture Media
  • Gentamicins
  • Vancomycin
  • Daptomycin
  • Methicillin