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Antimicrobial Agents and Chemotherapy, July 2000, p. 1789-1795, Vol. 44, No. 7
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Quinupristin-Dalfopristin Combined with beta -Lactams for Treatment of Experimental Endocarditis Due to Staphylococcus aureus Constitutively Resistant to Macrolide-Lincosamide-Streptogramin B Antibiotics

J. Vouillamoz,1 J. M. Entenza,1 C. Féger,2 M. P. Glauser,1 and P. Moreillon1,*

Division of Infectious Diseases, Department of Internal Medicine, Centre Hospitalier Universitaire Vaudois, 1011 Lausanne, Switzerland,1 and Rhône-Poulenc Rorer, F-92165 Antony Cedex, France2

Received 2 August 1999/Returned for modification 23 September 1999/Accepted 29 March 2000

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-MLSB) than against MLSB-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 MLSB 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-MLSB-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.

* Corresponding author. Mailing address: Division of Infectious Diseases, Department of Internal Medicine, Centre Hospitalier Universitaire Vaudois, 1011 Lausanne, Switzerland. Phone: 41-21-314.10.26. Fax: 41-21-314.10.36. E-mail: pmoreill{at}chuv.hospvd.ch.

Antimicrobial Agents and Chemotherapy, July 2000, p. 1789-1795, Vol. 44, No. 7
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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