Abstract：
Methicillin-resistant Staphylococcus aureus (MRSA) bacteremia is a serious clinical challenge with high mortality rates. Antibiotic combination therapy is currently used in cases of persistent infection; however, the limited development of new antibiotics will likely increase the need for combination therapy, and better methods are needed for identifying effective combinations for treating persistent bacteremia. To identify pairwise combinations with the most consistent potential for benefit compared to monotherapy with a primary anti-MRSA agent, we conducted a systematic study with an in vitro high-throughput methodology. We tested daptomycin and vancomycin each in combination with gentamicin, rifampicin, cefazolin, and oxacillin, and ceftaroline with daptomycin, gentamicin, and rifampicin. Combining cefazolin with daptomycin lowered the daptomycin concentration required to reach 95% growth inhibition (IC95) for all isolates tested and lowered daptomycin IC95 below the sensitivity breakpoint for five out of six isolates that had daptomycin minimum inhibitory concentrations at or above the sensitivity breakpoint. Similarly, vancomycin IC95s were decreased when vancomycin was combined with cefazolin for 86.7% of the isolates tested. This was a higher percentage than was achieved by adding any other secondary antibiotic to vancomycin. Adding rifampicin to daptomycin or vancomycin did not always reduce IC95s and failed to produce synergistic interaction in any of the isolates tested; the addition of rifampicin to ceftaroline was frequently synergistic and always lowered the amount of ceftaroline required to reach the IC95. These analyses rationalize further in vivo evaluation of three drug pairs for MRSA bacteremia: daptomycin+cefazolin, vancomycin+cefazolin, and ceftaroline+rifampicin.IMPORTANCEBloodstream infections caused by methicillin-resistant Staphylococcus aureus (MRSA) have a high mortality rate despite the availability of vancomycin, daptomycin, and newer antibiotics including ceftaroline. With the slow output of the antibiotic pipeline and the serious clinical challenge posed by persistent MRSA infections, better strategies for utilizing combination therapy are becoming increasingly necessary. We demonstrated the value of a systematic high-throughput approach, adapted from prior work testing antibiotic combinations against tuberculosis and other mycobacteria, by using this approach to test antibiotic pairs against a panel of MRSA isolates with diverse patterns of antibiotic susceptibility. We identified three antibiotic pairs-daptomycin+cefazolin, vancomycin+cefazolin, and ceftaroline+rifampicin-where the addition of the second antibiotic improved the potency of the first antibiotic across all or most isolates tested. Our results indicate that these pairs warrant further evaluation in the clinical setting.
摘要：
耐甲氧西林金黄色葡萄球菌（MRSA）菌血症是一个严重的临床挑战，死亡率高。抗生素联合治疗目前用于持续感染的病例；然而，新抗生素的有限开发可能会增加对联合治疗的需求，需要更好的方法来确定治疗持续性菌血症的有效组合。为了确定与使用主要抗MRSA药物的单一疗法相比具有最一致的潜在获益的成对组合，我们采用体外高通量方法进行了系统研究.我们测试了达托霉素和万古霉素与庆大霉素的组合，利福平,头孢唑啉,和苯唑西林,头孢洛林和达托霉素，庆大霉素,还有利福平.对于所有测试的分离株,头孢唑林与达托霉素的组合降低了达到95%生长抑制(IC95)所需的达托霉素浓度,并且对于具有处于或高于敏感性断点的达托霉素最小抑制浓度的6个分离株中的5个,达托霉素IC95降低到敏感性断点以下。同样，当万古霉素与头孢唑林组合时，万古霉素IC95降低了86.7％的测试分离株。这是比通过向万古霉素添加任何其他第二抗生素实现的更高的百分比。将利福平添加至达托霉素或万古霉素并不总是降低IC95,并且在任何测试的分离物中未能产生协同相互作用;将利福平添加至头孢洛林通常是协同的,并且总是降低达到IC95所需的头孢洛林的量。这些分析进一步合理地评估了MRSA菌血症的三种药物对：达托霉素+头孢唑林，万古霉素+头孢唑啉,还有头孢洛林+利福平.由耐甲氧西林金黄色葡萄球菌（MRSA）引起的血流感染尽管有万古霉素，但死亡率很高。达托霉素,和包括头孢洛林在内的新型抗生素。随着抗生素管道的缓慢输出和持续MRSA感染带来的严重临床挑战，更好的联合治疗策略变得越来越必要.我们证明了系统的高通量方法的价值，改编自以前的工作，测试抗生素组合对结核病和其他分枝杆菌，通过使用这种方法来测试针对一组具有不同抗生素敏感性模式的MRSA分离株的抗生素对。我们确定了三种抗生素对-达托霉素+头孢唑啉,万古霉素+头孢唑啉,和头孢洛林+利福平-其中第二种抗生素的添加提高了第一种抗生素在所有或大多数测试分离物中的效力。我们的结果表明，这些对值得在临床上进一步评估。
