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.
Zarrouk
V
V
Institut National de la Santé et de la Recherche Médicale, EMI 9933, Hôpital Bichat-Claude Bernard, Paris, France.
Bozdogan
B
B
Leclercq
R
R
Garry
L
L
Feger
C
C
Carbon
C
C
Fantin
B
B
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