Influence of resistance to streptogramin A type antibiotics on the activity of quinupristin-dalfopristin in vitro and in experimental endocarditis due to Staphylococcus aureus.
We evaluated the activity of quinupristin-dalfopristin (Q-D) against three clinical strains of Staphylococcus aureus susceptible to Q (MIC, 8 microg/ml) and Q-D (MICs, 0.5 to 1 microg/ml) but displaying various levels of susceptibility to D. D was active against S. aureus HM 1054 (MIC, 4 microg/ml) and had reduced activity against S. aureus RP 13 and S. aureus N 95 (MICs, 32 and 64 microg/ml, respectively). In vitro, Q-D at a concentration two times the MIC (2xMIC) produced reductions of 4.3, 3.9, and 5.8 log(10) CFU/ml after 24 h of incubation for HM 1054, RP 13, and N 95, respectively. Comparable killing was obtained at 8xMIC. Q-D-resistant mutants were selected in vitro at a frequency of 2 x 10(-8) to 2 x 10(-7) for the three strains on agar containing 2xMIC of Q-D; no resistant bacteria were detected at 4xMIC. Rabbits with aortic endocarditis were treated for 4 days with Q-D at 30 mg/kg of body weight intramuscularly (i.m.) three times a day (t.i.d.) or vancomycin at 50 mg/kg i.m. t.i.d. In vivo, Q-D and vancomycin were similarly active and bactericidal against the three tested strains compared to the results for control animals (P < 0.01). Among animals infected with RP 13 and treated with Q-D, one rabbit retained Q-D-resistant mutants that were resistant to Q and to high levels of D (MICs, 64, >256, and 8 microg/ml for Q, D, and Q-D, respectively). We conclude that the bactericidal activity of Q-D against strains with reduced susceptibility to D and susceptible to Q-D is retained and is comparable to that of vancomycin. Acquisition of resistance to both Q and D is necessary to select resistance to Q-D.
Zarrouk
V
V
Institut National de la Santé et de la Recherche Médicale, EMI 9933, France.
Bozdogan
B
B
Leclercq
R
R
Garry
L
L
Carbon
C
C
Fantin
B
B
D000818:Animals; D004195:Disease Models, Animal; D004352:Drug Resistance, Microbial / Q000235:genetics / Q000502:physiology; D004359:Drug Therapy, Combination / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use*; D004697:Endocarditis, Bacterial / Q000188:drug therapy* / Q000378:metabolism; D008826:Microbial Sensitivity Tests; D009154:Mutation; D011817:Rabbits; D013203:Staphylococcal Infections / Q000188:drug therapy* / Q000378:metabolism; D013211:Staphylococcus aureus / Q000187:drug effects / Q000235:genetics; D014769:Virginiamycin / Q000031:analogs & derivatives* / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use
D014769:Virginiamycin; C113825:quinupristin; C113826:dalfopristin