Quinupristin-dalfopristin combined with beta-lactams for treatment of experimental endocarditis due to Staphylococcus aureus constitutively resistant to macrolide-lincosamide-streptogramin B antibiotics.

Abstract

Quinupristin-dalfopristin (Q-D) is an injectable streptogramin active against most gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA). In experimental endocarditis, however, Q-D was less efficacious against MRSA isolates constitutively resistant to macrolide-lincosamide-streptogram B (C-MLS(B)) than against MLS(B)-susceptible isolates. To circumvent this problem, we used the checkerboard method to screen drug combinations that would increase the efficacy of Q-D against such bacteria. beta-Lactams consistently exhibited additive or synergistic activity with Q-D. Glycopeptides, quinolones, and aminoglycosides were indifferent. No drugs were antagonistic. The positive Q-D-beta-lactam interaction was independent of MLS(B) or beta-lactam resistance. Moreover, addition of Q-D at one-fourth the MIC to flucloxacillin-containing plates decreased the flucloxacillin MIC for MRSA from 500 to 1,000 mg/liter to 30 to 60 mg/liter. Yet, Q-D-beta-lactam combinations were not synergistic in bactericidal tests. Rats with aortic vegetations were infected with two C-MLS(B)-resistant MRSA isolates (isolates AW7 and P8) and were treated for 3 or 5 days with drug dosages simulating the following treatments in humans: (i) Q-D at 7 mg/kg two times a day (b.i.d.) (a relatively low dosage purposely used to help detect positive drug interactions), (ii) cefamandole at constant levels in serum of 30 mg/liter, (iii) cefepime at 2 g b.i.d., (iv) Q-D combined with either cefamandole or cefepime. Any of the drugs used alone resulted in treatment failure. In contrast, Q-D plus either cefamandole or cefepime significantly decreased valve infection compared to the levels of infection for both untreated controls and those that received monotherapy (P < 0.05). Importantly, Q-D prevented the growth of highly beta-lactam-resistant MRSA in vivo. The mechanism of this beneficial drug interaction is unknown. However, Q-D-beta-lactam combinations might be useful for the treatment of complicated infections caused by multiple organisms, including MRSA.

• Authors: J Vouillamoz, J M Entenza, C Féger, M P Glauser, P Moreillon
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 44 Issue 7 Pg. 1789-95 (Jul 2000) ISSN: 0066-4804 [Print] United States
• PMID: 10858332 (Publication Type: Journal Article)

Chemical References

• Anti-Bacterial Agents
• Cephalosporins
• Lincosamides
• Macrolides
• Virginiamycin
• quinupristin-dalfopristin
• Cefamandole
• Cefepime

Topics

• Animals
• Anti-Bacterial Agents (blood, pharmacology, therapeutic use)
• Cefamandole (blood, therapeutic use)
• Cefepime
• Cephalosporins (blood, therapeutic use)
• Disease Models, Animal
• Drug Resistance, Microbial
• Drug Resistance, Multiple
• Drug Therapy, Combination (blood, therapeutic use)
• Endocarditis, Bacterial (drug therapy, metabolism, mortality)
• Humans
• Lincosamides
• Macrolides
• Microbial Sensitivity Tests
• Rats
• Staphylococcal Infections (drug therapy, metabolism, mortality)
• Staphylococcus aureus (drug effects)
• Time Factors
• Virginiamycin (blood, pharmacology, therapeutic use)