Département de Médecine Aiguë Spécialisée, Hôpital Universitaire Raymond Poincaré, Assistance Publique-Hôpitaux de Paris, France.
Antimicrob Agents Chemother. 2012 Dec;56(12):6291-7. doi: 10.1128/AAC.00926-12. Epub 2012 Oct 1.
Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) can cause osteomyelitis with severe sepsis and/or local complications in which a Panton-Valentine leukocidin (PVL) role is suspected. In vitro sub-MIC antibiotic effects on growth and PVL production by 11 PVL(+) MRSA strains, including the major CA-MRSA clones (USA300, including the LAC strain; USA400; and USA1000), and 11 PVL(+) methicillin-susceptible S. aureus (MSSA) strains were tested in microplate culture. Time-kill analyses with ceftobiprole at its MIC were also run with LAC. Efficacies of ceftobiprole (40 mg/kg of body weight subcutaneously [s.c.] four times a day [q.i.d.]) or vancomycin (60 mg/kg intramuscularly [i.m.] twice a day [b.i.d.]) alone or combined with rifampin (10 mg/kg b.i.d.) against rabbit CA-MRSA osteomyelitis, induced by tibial injection of 3.4 × 10(7) CFU of LAC, were compared. Treatment, started 14 days postinoculation, lasted 14 days. In vitro, 6/11 strains cultured with sub-MICs of ceftobiprole produced 1.6- to 4.8-fold more PVL than did the controls, with no link to specific clones. Rifampin decreased PVL production by all tested strains. In time-kill analyses at the LAC MIC (0.75 mg/liter), PVL production rose transiently at 6 and 8 h and then declined 2-fold at 16 h, concomitant with a 2-log(10)-CFU-count decrease. In vivo, the mean log(10) CFU/g of bone for ceftobiprole (1.44 ± 0.40) was significantly lower than that for vancomycin (2.37 ± 1.22) (P = 0.034), with 7/10 versus 5/11 bones sterilized, respectively. Combination with rifampin enhanced ceftobiprole (1.16 ± 0.04 CFU/g of bone [P = 0.056], 11/11 sterile bones) and vancomycin (1.23 ± 0.06 CFU/g [P = 0.011], 11/11 sterile bones) efficacies. Ceftobiprole bactericidal activity and the rifampin anti-PVL effect could play a role in these findings, which should be of interest for treating CA-MRSA osteomyelitis.
社区相关性耐甲氧西林金黄色葡萄球菌（CA-MRSA）可引起骨髓炎，并伴有严重败血症和/或局部并发症，怀疑其与杀白细胞素（PVL）有关。在微孔板培养中，检测了 11 株 PVL（+）MRSA 株（包括主要 CA-MRSA 克隆 USA300，包括 LAC 株；USA400；和 USA1000）和 11 株 PVL（+）甲氧西林敏感金黄色葡萄球菌（MSSA）株对生长和 PVL 产生的亚 MIC 抗生素作用。还使用 LAC 对头孢洛林的 MIC 进行了时间杀伤分析。比较了兔 CA-MRSA 骨髓炎的疗效，该骨髓炎由胫骨注射 3.4×10（7）CFU 的 LAC 诱导，单独使用头孢洛林（40mg/kg 体重皮下注射，每天 4 次[q.i.d.]）或万古霉素（60mg/kg 肌肉注射，每天 2 次[b.i.d.]），或联合使用利福平（10mg/kg，每天 2 次[b.i.d.]）。治疗从接种后 14 天开始，持续 14 天。在体外，用头孢洛林的亚 MIC 培养 6/11 株产生的 PVL 比对照增加了 1.6 至 4.8 倍，与特定克隆无关。利福平降低了所有测试菌株的 PVL 产量。在 LAC MIC（0.75mg/l）的时间杀伤分析中，PVL 产量在 6 和 8 小时短暂增加，然后在 16 小时下降 2 倍，同时细菌计数减少 2 个对数（10）。在体内，头孢洛林（1.44±0.40）的平均骨 CFU/g 对数显著低于万古霉素（2.37±1.22）（P=0.034），分别有 7/10 和 5/11 根骨头被灭菌。与利福平联合使用可增强头孢洛林（1.16±0.04 CFU/g 骨[P=0.056]，11/11 根无菌骨）和万古霉素（1.23±0.06 CFU/g [P=0.011]，11/11 根无菌骨）的疗效。头孢洛林的杀菌活性和利福平的抗 PVL 作用可能在这些发现中发挥作用，这对治疗 CA-MRSA 骨髓炎具有重要意义。
