Critical influence of resistance to streptogramin B-type antibiotics on activity of RP 59500 (quinupristin-dalfopristin) in experimental endocarditis due to Staphylococcus aureus

Abstract

In order to determine the microbiological and pharmacokinetic parameters that best predicted the in vivo antistaphylococcal activity of the streptogramin RP 59500 (quinupristin-dalfopristin), we evaluated the activity in rabbit aortic endocarditis of three regimens of quinupristin-dalfopristin against five strains of Staphylococcus aureus with various streptogramin B-type antibiotic resistance phenotypes and susceptible to streptogramin A-type antibiotics. Quinupristin-dalfopristin was as active as vancomycin against three strains that were susceptible to its streptogramin B component quinupristin, including one strain that was inducibly resistant to erythromycin, but had a significantly decreased activity against two strains that were resistant to quinupristin, for all quinupristin-dalfopristin regimens tested (P < 0.05). The area under the concentration-time curve for quinupristin-dalfopristin in plasma divided by the MIC of quinupristin was the only parameter retained by multilinear regression that predicted the in vivo activity of quinupristin-dalfopristin (P ‫؍‬ 0.0001), emphazing the importance of determining the susceptibility to quinupristin in order to predict the in vivo activity of quinupristin-dalfopristin against S. aureus.

Efficacies of Quinupristin-Dalfopristin Combined with Vancomycin In Vitro and in Experimental Endocarditis Due to Methicillin-Resistant Staphylococcus aureus in Relation to Cross-Resistance to Macrolides, Lincosamides, and Streptogramin B- Type Antibiotics

“…The Q-D dosing regimen provided areas under the curve for quinupristin and dalfopristin comparable to those achieved in humans after intravenous injection of 7.5 mg of Q-D/kg (6,8). The vancomycin regimen produced peak (40 Ϯ 8 g/ml) and trough (12 Ϯ 5 g/ml) levels in serum comparable to those recommended for humans with severe infections (18).…”

“…Therefore, in studies with this strain, the killing of control animals and the start of therapy were performed 36 h after inoculation of the bacteria. This resulted in comparable vegetation weights and bacterial concentrations in vegetations in the rabbits inoculated with the two strains (8).…”

“…The expression of MLS B resistance is more frequently constitutive than inducible in MRSA (13). When it is constitutive, strains are resistant to quinupristin but remain susceptible to Q-D, although the bactericidal activity of Q-D is reduced in vitro and in vivo (8).…”

“…Two MRSA strains were evaluated in this study: HM1054, a clinical strain that is susceptible to quinupristin, and HM1054R, a strain that is resistant to quinupristin and that was obtained by conjugative transfer to HM1054 of the ermC gene, which codes for MLS B resistance (8). The two strains remained susceptible to Q-D (MIC, 1 g/ml), whatever their profile of resistance to MLS B antibiotics (quinupristin MICs, 8 g/ml for HM1054 and 64 g/ml for HM1054R).…”

“…Antibiotics were used at concentrations achievable in human and rabbit sera (6,8,18). Q-D was used at concentrations of 1 and 4 g/ml, and vancomycin was used at concentrations of 1, 8, and 32 g/ml.…”