Zapata Brianne, Alvarez Danya N, Farah Sabrina, Garcia-de-la-Maria Cristina, Miro Jose M, Sakoulas George, Bayer Arnold S, Mishra Nagendra N
Divison of Infectious Diseases, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA.
Center for Infectious Diseases, California State Department of Public Health, Richmond, CA, USA.
Curr Microbiol. 2018 Aug;75(8):1062-1067. doi: 10.1007/s00284-018-1491-3. Epub 2018 Apr 12.
Among the viridans group streptococci, S. mitis-oralis strains are frequently resistant to multiple β-lactams and tolerant to vancomycin (VAN). This scenario has led to the proposed clinical use of newer agents, like daptomycin (DAP) for such S. mitis-oralis strains. However, recent recognition of the rapid and durable emergence of high-level DAP-resistance (DAP-R; DAP MICs > 256 µg/ml) induced by DAP exposures in vitro and in vivo has dampened enthusiasm for such approaches. In this study, we evaluated a broad range of DAP combination regimens in vitro for their capacity to prevent emergence of high-level DAP-R in a prototype S. mitis-oralis strain (351) during serial passage experiments, including DAP + either gentamicin (GEN), rifampin (RIF), trimethoprim-sulfamethoxazole (TMP-SMX), imipenem (IMP), ceftaroline (CPT), tedizolid (TDZ), or linezolid (LDZ). In addition, we assessed selected DAP combination regimens for their ability to exert either an early bactericidal impact and/or synergistically kill the S. mitis-oralis study strain. During serial passage, three of the eight antibiotic combinations (DAP + GEN, CPT, or TMP- SMX) exhibited significantly reduced DAP MICs (≈ by 8-40 fold) vs serial exposure in DAP alone (DAP MICs > 256 µg/ml). In addition, combinations of DAP + GEN and DAP + CPT were both bactericidal and synergistic in early time-kill curve interactions.
在草绿色链球菌中，缓症链球菌-口腔链球菌菌株常常对多种β-内酰胺类药物耐药，并且对万古霉素（VAN）耐受。这种情况促使人们提议将新型药物，如达托霉素（DAP）用于此类缓症链球菌-口腔链球菌菌株的临床治疗。然而，最近人们认识到，在体外和体内达托霉素暴露诱导下，高水平达托霉素耐药（DAP-R；DAP MICs＞256 μg/ml）迅速且持久地出现，这削弱了人们对这种治疗方法的热情。在本研究中，我们在体外评估了多种达托霉素联合治疗方案，以观察其在连续传代实验中防止原型缓症链球菌-口腔链球菌菌株（351）出现高水平DAP-R的能力，这些联合方案包括DAP与庆大霉素（GEN）、利福平（RIF）、甲氧苄啶-磺胺甲恶唑（TMP-SMX）、亚胺培南（IMP）、头孢洛林（CPT）、特地唑胺（TDZ）或利奈唑胺（LDZ）联合。此外，我们评估了所选达托霉素联合治疗方案对缓症链球菌-口腔链球菌研究菌株发挥早期杀菌作用和/或协同杀菌的能力。在连续传代过程中，八种抗生素联合方案中的三种（DAP + GEN、CPT或TMP-SMX）与单独连续暴露于达托霉素（DAP MICs＞256 μg/ml）相比，DAP MICs显著降低（约降低8 - 40倍）。此外，DAP + GEN和DAP + CPT联合方案在早期杀菌曲线相互作用中均具有杀菌和协同作用。
