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Antimicrobial Agents and Chemotherapy, July 2000, p. 1789-1795, Vol. 44, No. 7
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.
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
Quinupristin-Dalfopristin Combined with
-Lactams for
Treatment of Experimental Endocarditis Due to Staphylococcus
aureus Constitutively Resistant to
Macrolide-Lincosamide-Streptogramin B Antibiotics
-Lactams consistently exhibited additive or synergistic activity with Q-D. Glycopeptides, quinolones, and aminoglycosides were indifferent. No
drugs were antagonistic. The positive Q-D--lactam interaction was
independent of MLSB or -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--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
-lactam-resistant MRSA in vivo. The mechanism of this beneficial
drug interaction is unknown. However, Q-D--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.
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