Activities of the combination of quinupristin-dalfopristin with rifampin in vitro and in experimental endocarditis due to Staphylococcus aureus strains with various phenotypes of resistance to macrolide-lincosamide-streptogramin antibiotics.
We evaluated the activities of quinupristin-dalfopristin (Q-D), alone or in combination with rifampin, against three strains of Staphylococcus aureus susceptible to rifampin (MIC, 0.06 microg/ml) and to Q-D (MICs, 0.5 to 1 microg/ml) but displaying various phenotypes of resistance to macrolide-lincosamide-streptogramin antibiotics: S. aureus HM1054 was susceptible to quinupristin and dalfopristin (MICs of 8 and 4 microg/ml, respectively); for S. aureus RP13, the MIC of dalfopristin was high (MICs of quinupristin and dalfopristin for strain RP13, 8 and 32 microg/ml, respectively); and S. aureus HM1054R was obtained after conjugative transfer of macrolide-lincosamide-streptogramin B constitutive resistance to HM1054, and the MIC of quinupristin for this strain was high (MICs of quinupristin and dalfopristin, 64 and 4 microg/ml, respectively). In vitro time-kill curve studies showed an additive effect [corrected] between Q-D and rifampin, at a concentration of four times the MIC, against the three strains. Rabbits with aortic endocarditis were treated 4 days with Q-D, rifampin, or their combination. In vivo, the combination was highly bactericidal and synergistic against strains susceptible to quinupristin (HM1054 and RP13) and sterilized 94% of the animals. In contrast, the combination was neither synergistic nor bactericidal against the quinupristin-resistant strain (HM1054R) and did not prevent the emergence of mutants resistant to rifampin. We conclude that the in vivo synergistic and bactericidal activity of the combination of Q-D and rifampin against S. aureus is predicted by the absence of resistance to quinupristin but not by in vitro combination studies.
Institut National de la Santé et de la Recherche Médicale, EMI 9933, Hôpital Bichat-Claude Bernard, Paris, France.
V
V
Zarrouk
B
B
Bozdogan
R
R
Leclercq
L
L
Garry
C
C
Feger
C
C
Carbon
B
B
Fantin
D000818:Animals; D000900:Anti-Bacterial Agents / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use*; D004352:Drug Resistance, Microbial; D004357:Drug Synergism; D004359:Drug Therapy, Combination / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use*; D004697:Endocarditis, Bacterial / Q000097:blood / Q000188:drug therapy*; D005260:Female; D007700:Kinetics; D055231:Lincosamides; D018942:Macrolides; D008826:Microbial Sensitivity Tests; D009154:Mutation; D010641:Phenotype; D011817:Rabbits; D012293:Rifampin / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use*; D013203:Staphylococcal Infections / Q000097:blood / Q000188:drug therapy*; D013211:Staphylococcus aureus / Q000187:drug effects / Q000235:genetics; D014769:Virginiamycin / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use*
D000900:Anti-Bacterial Agents; D055231:Lincosamides; D018942:Macrolides; D014769:Virginiamycin; C062940:quinupristin-dalfopristin; D012293:Rifampin