Xiong Y Q, Kupferwasser L I, Zack P M, Bayer A S
St. John's Cardiovascular Research Center, LAC-UCLA Medical Center, Torrance, California 90509, USA.
Antimicrob Agents Chemother. 1999 Jul;43(7):1737-42. doi: 10.1128/AAC.43.7.1737.
Optimal treatment strategies for serious infections caused by Staphylococcus aureus have not been fully characterized. The combination of a beta-lactam plus an aminoglycoside can act synergistically against S. aureus in vitro and in vivo. MiKasome, a new liposome-encapsulated formulation of conventional amikacin, significantly prolongs serum half-life (t1/2) and increases the area under the concentration-time curve (AUC) compared to free amikacin. Microbiologic efficacy and left ventricular function, as assessed by echocardiography, were compared in animals administered either oxacillin alone or oxacillin in combination with conventional amikacin or MiKasome in a rabbit model of experimental endocarditis due to S. aureus. In vitro, oxacillin, combined with either free amikacin or MiKasome, prevented the bacterial regrowth observed with aminoglycosides alone at 24 h of incubation. Rabbits with S. aureus endocarditis were treated with either oxacillin alone (50 mg/kg, given intramuscularly three times daily), oxacillin plus daily amikacin (27 mg/kg, given intravenously twice daily), or oxacillin plus intermittent MiKasome (160 mg/kg, given intravenously, a single dose on days 1 and 4). The oxacillin-alone dosage represents a subtherapeutic regimen against the infecting strain in the endocarditis model (L. Hirano and A. S. Bayer, Antimicrob. Agents Chemother. 35:685-690, 1991), thus allowing recognition of any enhanced bactericidal effects between oxacillin and either aminoglycoside formulation. Treatment was administered for either 3 or 6 days, and animals were sacrificed after each of these time points or at 5 days after a 6-day treatment course (to evaluate for posttherapy relapse). Left ventricular function was analyzed by utilizing serial transthoracic echocardiography during treatment and posttherapy by measurement of left ventricular fractional shortening. At all sacrifice times, both combination regimens significantly reduced S. aureus vegetation counts versus control counts (P < 0.05). In contrast, oxacillin alone did not significantly reduce S. aureus vegetation counts after 3 days of therapy. Furthermore, at this time point, the two combinations were significantly more effective than oxacillin alone (P < 0.05). All three regimens were effective in significantly decreasing bacterial counts in the myocardium during and after therapy compared to controls (P < 0.05). In kidney and spleen abscesses, all regimens significantly reduced bacterial counts during therapy (P < 0.0001); however, only the combination regimens prevented bacteriologic relapse in these organs posttherapy. By echocardiographic analysis, both combination regimens yielded a significant physiological benefit by maintaining normal left ventricular function during treatment and posttherapy compared with oxacillin alone (P < 0.001). These results suggest that the use of intermittent MiKasome (similar to daily conventional amikacin) enhances the in vivo bactericidal effects of oxacillin in a severe S. aureus infection model and preserves selected physiological functions in target end organs.
金黄色葡萄球菌引起的严重感染的最佳治疗策略尚未完全明确。β-内酰胺类药物与氨基糖苷类药物联合使用在体外和体内均可对金黄色葡萄球菌发挥协同作用。米卡索姆（MiKasome）是一种新型的常规阿米卡星脂质体包封制剂，与游离阿米卡星相比，它能显著延长血清半衰期（t1/2）并增加浓度-时间曲线下面积（AUC）。在金黄色葡萄球菌所致实验性心内膜炎的兔模型中，比较了单独给予苯唑西林或苯唑西林与常规阿米卡星或米卡索姆联合给药的动物的微生物学疗效及通过超声心动图评估的左心室功能。在体外，苯唑西林与游离阿米卡星或米卡索姆联合使用，可防止单独使用氨基糖苷类药物在孵育24小时时观察到的细菌再生长。患有金黄色葡萄球菌心内膜炎的兔子分别接受以下治疗：单独苯唑西林（50mg/kg，每日肌肉注射3次）、苯唑西林加每日阿米卡星（27mg/kg，每日静脉注射2次）或苯唑西林加间歇性米卡索姆（160mg/kg，静脉注射，第1天和第4天各1剂）。单独使用苯唑西林的剂量在该心内膜炎模型中对感染菌株而言是亚治疗方案（L. Hirano和A. S. Bayer，《抗菌药物与化疗》，35:685 - 690，1991），这样就能识别苯唑西林与任何一种氨基糖苷类制剂联合使用时增强的杀菌效果。治疗持续3天或6天，在这些时间点之后或6天治疗疗程后的第5天处死动物（以评估治疗后复发情况）。在治疗期间和治疗后，通过连续经胸超声心动图测量左心室缩短分数来分析左心室功能。在所有处死时间点，与对照计数相比，两种联合治疗方案均显著降低了金黄色葡萄球菌赘生物计数（P < 0.05）。相比之下，单独使用苯唑西林在治疗3天后并未显著降低金黄色葡萄球菌赘生物计数。此外，在这个时间点，两种联合治疗方案比单独使用苯唑西林显著更有效（P < 0.05）。与对照组相比，所有三种治疗方案在治疗期间和治疗后均能有效显著降低心肌中的细菌计数（P < 0.05）。在肾和脾脓肿中，所有治疗方案在治疗期间均显著降低了细菌计数（P < 0.0001）；然而，只有联合治疗方案在治疗后防止了这些器官中的细菌学复发。通过超声心动图分析，与单独使用苯唑西林相比，两种联合治疗方案在治疗期间和治疗后通过维持正常左心室功能产生了显著的生理益处（P < 0.001）。这些结果表明，在严重金黄色葡萄球菌感染模型中，间歇性使用米卡索姆（类似于每日使用常规阿米卡星）可增强苯唑西林的体内杀菌效果，并保留靶心器官中特定的生理功能。
