Entenza J M, Drugeon H, Glauser M P, Moreillon P
Department of Internal Medicine, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
Antimicrob Agents Chemother. 1995 Jul;39(7):1419-24. doi: 10.1128/AAC.39.7.1419.
RP 59500 is a new injectable streptogramin composed of two synergistic components (quinupristin and dalfopristin) which are active against erythromycin-susceptible and -resistant gram-positive pathogens. The present experiments compared the therapeutic efficacy of RP 59500 with that of vancomycin against experimental endocarditis due to either of two erythromycin-susceptible or two constitutively erythromycin-resistant isolates of methicillin-resistant Staphylococcus aureus. RP 59500 had low MICs for the four test organisms as well as for 24 additional isolates (the MIC at which 90% of the isolates were inhibited was < 1 mg/liter) which were mostly inducibly (47%) or constitutively (39%) erythromycin resistant. Aortic endocarditis in rats was produced with catheter-induced vegetations. Three-day therapy was initiated 12 h after infection, and the drugs were delivered via a computerized pump, which permitted the mimicking of the drug kinetics produced in human serum by twice-daily intravenous injections of 7 mg of RP 59500 per kg of body weight or 1 g of vancomycin. Both antibiotics reduced vegetation bacterial titers to below detection levels in ca. 70% of animals infected with the erythromycin-susceptible isolates (P < 0.05 compared with titers in controls). Vancomycin was also effective against the constitutively resistant strains, but RP 59500 failed against these isolates. Further experiments proved that RP 59500 failures were related to the very short life span of dalfopristin in serum (< or = 2 h, compared with > or = 6 h for quinupristin), since successful treatment was restored by artificially prolonging the dalfopristin levels for 6 h. Thus, RP 59500 is a promising alternative to vancomycin against methicillin-resistant S. aureus infections, provided that pharmacokinetic parameters are adjusted to afford prolonged levels of both of its constituents in serum. This observation is also relevant to humans, in whom the life span of dalfopristin in serum is also shorter than that of quinupristin.
RP 59500是一种新型注射用链阳菌素，由两种具有协同作用的成分（奎奴普汀和达福普汀）组成，对红霉素敏感和耐药的革兰氏阳性病原体均有活性。本实验比较了RP 59500与万古霉素对由两种红霉素敏感或两种组成型红霉素耐药的耐甲氧西林金黄色葡萄球菌分离株引起的实验性心内膜炎的治疗效果。RP 59500对四种测试菌株以及另外24株分离株（90%的分离株被抑制时的MIC<1mg/L）的MIC较低，这些分离株大多为诱导型（47%）或组成型（39%）红霉素耐药。通过导管诱导赘生物在大鼠中引发主动脉心内膜炎。感染后12小时开始为期三天的治疗，药物通过计算机控制的泵给药，这使得能够模拟每日两次静脉注射每千克体重7mg的RP 59500或1g万古霉素在人血清中产生的药代动力学。两种抗生素在约70%感染红霉素敏感分离株的动物中均将赘生物细菌滴度降低至检测水平以下（与对照组滴度相比，P<0.05）。万古霉素对组成型耐药菌株也有效，但RP 59500对这些分离株无效。进一步的实验证明，RP 59500治疗失败与达福普汀在血清中的极短半衰期（≤2小时，而奎奴普汀≥6小时）有关，因为通过人工延长达福普汀水平6小时可恢复成功治疗。因此，只要调整药代动力学参数以延长其两种成分在血清中的水平，RP 59500是治疗耐甲氧西林金黄色葡萄球菌感染的一种有前景的替代万古霉素的药物。这一观察结果对人类也有意义，在人类中达福普汀在血清中的半衰期也比奎奴普汀短。
