Giuliano Simone, Angelini Jacopo, Campanile Floriana, Conti Paola, Flammini Sarah, Pagotto Alberto, Sbrana Francesco, Martini Luca, D'Elia Denise, Abdul-Aziz Mohd H, Cotta Menino O, Roberts Jason A, Bonomo Robert A, Tascini Carlo
Infectious Diseases Clinic, Azienda Sanitaria Universitaria Friuli Centrale, 33100, Udine, Italy.
Department of Medicine (DMED), University of Udine, Udine, Italy.
Sci Rep. 2025 Jan 28;15(1):3519. doi: 10.1038/s41598-025-87512-8.
Enterococcus faecalis is responsible for numerous serious infections, and treatment options often include ampicillin combined with an aminoglycoside or dual beta-lactam therapy with ampicillin and a third-generation cephalosporin. The mechanism of dual beta-lactam therapy relies on the saturation of penicillin-binding proteins (PBPs). Ceftobiprole exhibits high affinity binding to nearly all E. faecalis PBPs, thus suggesting its potential utility in the treatment of severe E. faecalis infections. The availability of therapeutic drug monitoring (TDM) for ampicillin and ceftobiprole has prompted the use of this drug combination in our hospital. Due to the time-dependent antimicrobial properties of these antibiotics, an infusion administration longer than indicated was chosen. From January to December 2020, twenty-one patients were admitted to our hospital for severe E. faecalis infections and were treated with this approach. We retrospectively analyzed their clinical characteristics and pharmacological data. Most patients achieved an aggressive PK/PD target (T > 4-8 minimum inhibitory concentration, MIC) when this alternative drug combination regimen was used. Our analysis included the study of E. faecalis biofilm production, as well as the kinetics of bacterial killing of ceftobiprole alone or in combination with ampicillin. Time-kill experiments revealed strong bactericidal activity of ceftobiprole alone at concentrations four times higher than the MIC for some enterococcal strains. In cases where a bactericidal effect of ceftobiprole alone was not evident, synergism with ampicillin and bactericidal activity were demonstrated instead. The prolonged infusion of ceftobiprole, either alone or with ampicillin, emerges as a valuable option for the treatment of severe invasive E. faecalis infections.
粪肠球菌可引发多种严重感染，治疗方案通常包括氨苄西林联合氨基糖苷类药物，或采用氨苄西林与第三代头孢菌素的双β-内酰胺疗法。双β-内酰胺疗法的机制依赖于青霉素结合蛋白（PBPs）的饱和。头孢比普对几乎所有粪肠球菌PBPs均表现出高亲和力结合，因此提示其在治疗严重粪肠球菌感染方面具有潜在效用。氨苄西林和头孢比普的治疗药物监测（TDM）的可用性促使我院使用这种药物组合。由于这些抗生素具有时间依赖性抗菌特性，因此选择了比规定时间更长的静脉输注给药方式。2020年1月至12月，21例因严重粪肠球菌感染入院的患者接受了这种治疗方法。我们回顾性分析了他们的临床特征和药理学数据。当使用这种替代药物组合方案时，大多数患者达到了积极的药代动力学/药效学目标（T＞4-8倍最低抑菌浓度，MIC）。我们的分析包括对粪肠球菌生物膜产生的研究，以及单独使用头孢比普或与氨苄西林联合使用时细菌杀灭动力学的研究。时间杀菌实验表明，对于某些肠球菌菌株，头孢比普在浓度高于MIC四倍时具有很强的杀菌活性。在单独使用头孢比普的杀菌效果不明显的情况下，反而证明了其与氨苄西林的协同作用和杀菌活性。延长头孢比普单独或与氨苄西林联合使用的输注时间，成为治疗严重侵袭性粪肠球菌感染的一种有价值的选择。
