title: 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.affiliation: Division of Infectious Diseases, Department of Internal Medicine, Centre Hospitalier Universitaire Vaudois, 1011 Lausanne, Switzerland.
authors.forename: J
authors.initials: J
authors.lastname: Vouillamoz
authors.forename: J M
authors.initials: JM
authors.lastname: Entenza
authors.forename: C
authors.initials: C
authors.lastname: Féger
authors.forename: M P
authors.initials: MP
authors.lastname: Glauser
authors.forename: P
authors.initials: P
authors.lastname: Moreillon
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use*; D002435:Cefamandole / Q000097:blood / Q000627:therapeutic use; D000077723:Cefepime; D002511:Cephalosporins / Q000097:blood / Q000627:therapeutic use; D004195:Disease Models, Animal; D004352:Drug Resistance, Microbial; D018432:Drug Resistance, Multiple; D004359:Drug Therapy, Combination / Q000097:blood / Q000627:therapeutic use; D004697:Endocarditis, Bacterial / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality; D006801:Humans; D055231:Lincosamides; D018942:Macrolides; D008826:Microbial Sensitivity Tests; D051381:Rats; D013203:Staphylococcal Infections / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality; D013211:Staphylococcus aureus / Q000187:drug effects; D013997:Time Factors; D014769:Virginiamycin / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000900:Anti-Bacterial Agents; D002511:Cephalosporins; D055231:Lincosamides; D018942:Macrolides; D014769:Virginiamycin; C062940:quinupristin-dalfopristin; D002435:Cefamandole; D000077723:Cefepime