Gavaldà J, Torres C, Tenorio C, López P, Zaragoza M, Capdevila J A, Almirante B, Ruiz F, Borrell N, Gomis X, Pigrau C, Baquero F, Pahissa A
Infectious Diseases Research Laboratory, Hospital General Vall d'Hebron, Universitat Autònoma de Barcelona, Spain.
Antimicrob Agents Chemother. 1999 Mar;43(3):639-46. doi: 10.1128/AAC.43.3.639.
The purpose of this work was to evaluate the in vitro possibilities of ampicillin-ceftriaxone combinations for 10 Enterococcus faecalis strains with high-level resistance to aminoglycosides (HLRAg) and to assess the efficacy of ampicillin plus ceftriaxone, both administered with humanlike pharmacokinetics, for the treatment of experimental endocarditis due to HLRAg E. faecalis. A reduction of 1 to 4 dilutions in MICs of ampicillin was obtained when ampicillin was combined with a fixed subinhibitory ceftriaxone concentration of 4 micrograms/ml. This potentiating effect was also observed by the double disk method with all 10 strains. Time-kill studies performed with 1 and 2 micrograms of ampicillin alone per ml or in combination with 5, 10, 20, 40, and 60 micrograms of ceftriaxone per ml showed a > or = 2 log10 reduction in CFU per milliliter with respect to ampicillin alone and to the initial inoculum for all 10 E. faecalis strains studied. This effect was obtained for seven strains with the combination of 2 micrograms of ampicillin per ml plus 10 micrograms of ceftriaxone per ml and for six strains with 5 micrograms of ceftriaxone per ml. Animals with catheter-induced endocarditis were infected intravenously with 10(8) CFU of E. faecalis V48 or 10(5) CFU of E. faecalis V45 and were treated for 3 days with humanlike pharmacokinetics of 2 g of ampicillin every 4 h, alone or combined with 2 g of ceftriaxone every 12 h. The levels in serum and the pharmacokinetic parameters of the humanlike pharmacokinetics of ampicillin or ceftriaxone in rabbits were similar to those found in humans treated with 2 g of ampicillin or ceftriaxone intravenously. Results of the therapy for experimental endocarditis caused by E. faecalis V48 or V45 showed that the residual bacterial titers in aortic valve vegetations were significantly lower in the animals treated with the combinations of ampicillin plus ceftriaxone than in those treated with ampicillin alone (P < 0.001). The combination of ampicillin and ceftriaxone showed in vitro and in vivo synergism against HLRAg E. faecalis.
本研究旨在评估氨苄西林 - 头孢曲松联合用药对10株对氨基糖苷类高水平耐药（HLRAg）粪肠球菌的体外抗菌活性，并评估以类人药代动力学给药的氨苄西林加头孢曲松治疗HLRAg粪肠球菌所致实验性心内膜炎的疗效。当氨苄西林与固定的亚抑菌浓度4微克/毫升的头孢曲松联合使用时，氨苄西林的最低抑菌浓度（MIC）降低了1至4倍稀释度。用双纸片法对所有10株菌进行检测时也观察到了这种增效作用。对每毫升单独含1微克和2微克氨苄西林或与每毫升含5、10、20、40和60微克头孢曲松联合使用进行的时间杀菌研究表明，相对于单独使用氨苄西林以及所有10株受试粪肠球菌的初始接种量，每毫升菌落形成单位（CFU）减少了≥2个对数10。对于每毫升含2微克氨苄西林加每毫升含10微克头孢曲松的联合用药，7株菌出现了这种效果；对于每毫升含5微克头孢曲松的联合用药，6株菌出现了这种效果。将导管诱导的心内膜炎动物静脉注射10⁸CFU的粪肠球菌V48或10⁵CFU的粪肠球菌V45，并以类人药代动力学每4小时给予2克氨苄西林单独治疗或联合每12小时给予2克头孢曲松治疗3天。兔体内氨苄西林或头孢曲松类人药代动力学的血清水平和药代动力学参数与静脉注射2克氨苄西林或头孢曲松的人类患者相似。由粪肠球菌V48或V45所致实验性心内膜炎的治疗结果表明，与单独使用氨苄西林治疗的动物相比，氨苄西林加头孢曲松联合治疗的动物主动脉瓣赘生物中的残留细菌滴度显著降低（P<0.001）。氨苄西林和头孢曲松联合用药对HLRAg粪肠球菌表现出体外和体内协同作用。
