Uppsala University, Dept. of Medical Biochemistry and Microbiology, Uppsala, Sweden.
Uppsala University, Dept. of Medical Biochemistry and Microbiology, Uppsala, Sweden.
EBioMedicine. 2022 Apr;78:103979. doi: 10.1016/j.ebiom.2022.103979. Epub 2022 Apr 1.
Treatment of Blood Stream Infections (BSIs) with a combination of a β-lactam and an aminoglycoside antibiotic is widely used in intensive care units (ICUs) around the world. However, no studies have systematically examined how these drugs interact and potentially influence the antimicrobial efficacy of the overall treatment.
We collected 500 E. coli isolates from the Uppsala University hospital that were isolated from blood of patients with suspicion of infection. Of those we tested the efficacy of combinations of 2 common β-lactam antibiotics (Ampicillin and Cefotaxime) combined with 2 common aminoglycosides (Gentamicin and Tobramycin) on 254 isolates. The efficacy of all 4 pairwise combinations in inhibiting bacterial growth was then examined on all susceptible strains. That was done by quantifying the Fractional Inhibitory index (FICi), a robust metric for antibiotic combinatorial behaviour, of all possible treatments on every strain. When non additive interactions were identified, results of the original screen were verified with time kill assays. Finally, combination behaviours were analysed for potential cross correlations.
Out of the 4 antibiotic combinations screened none exhibited synergistic effects on any of the 254 strains. On the contrary all 4 exhibited important antagonistic effects on several isolates. Specifically, the combinations of AMP-GEN and CTX-GEN were antagonistic in 1.97% and 1.18% of strains respectively. Similarly, the combinations of AMP-TOB were antagonistic on 0.78% of all strains. PCA analysis revealed that an important factor on the responses to the combination treatments was the choice of a specific aminoglycoside over another. Subsequent cross correlation analysis revealed that the interaction profiles of combinations including the same aminoglycoside are significantly correlated (Spearman's cross correlation test p<0.001).
The findings of this study elucidate potential risks of the common combination treatment for blood stream infections. They also demonstrate, previously unquantified metrics on how antibiotics in combination therapies are not interchangeable with others of the same class. Finally, they reiterate the need for case-by-case testing of antibiotic interactions in a clinical setting.
This work was funded by grants to DIA from the Swedish Research Council, the Wallenberg foundation and the Swedish Strategic Research Foundation.
在世界各地的重症监护病房（ICU）中，β-内酰胺类抗生素和氨基糖苷类抗生素联合治疗血流感染（BSI）被广泛应用。然而，尚无研究系统地检查这些药物如何相互作用，并可能影响整体治疗的抗菌疗效。
我们从乌普萨拉大学医院收集了 500 株来自疑似感染患者血液的大肠杆菌分离株。我们测试了 2 种常用的β-内酰胺类抗生素（氨苄西林和头孢噻肟）与 2 种常用的氨基糖苷类抗生素（庆大霉素和妥布霉素）组合对 254 株分离株的疗效。然后，我们使用量化的部分抑菌指数（FICi）检查所有 4 种组合在所有敏感菌株上抑制细菌生长的效果，FICi 是一种用于抗生素组合行为的稳健指标。对每个菌株的所有可能的治疗方法进行了分析。当发现非相加相互作用时，通过时间杀伤试验验证了原始筛选的结果。最后，对组合行为进行了潜在的交叉相关分析。
在所筛选的 4 种抗生素组合中，没有一种在 254 株菌株中的任何一株上表现出协同作用。相反，所有 4 种组合在几种分离株上都表现出重要的拮抗作用。具体来说，AMP-GEN 和 CTX-GEN 组合在分别有 1.97%和 1.18%的菌株中表现出拮抗作用。同样，AMP-TOB 组合在所有菌株中有 0.78%表现出拮抗作用。PCA 分析表明，对组合治疗反应的一个重要因素是选择特定的氨基糖苷类药物而不是另一种药物。随后的交叉相关分析表明，包括相同氨基糖苷类药物的组合的相互作用谱显著相关（Spearman 交叉相关检验，p<0.001）。
本研究的结果阐明了常见联合治疗血流感染的潜在风险。它们还表明，在组合治疗中，抗生素的相互作用不能与同类药物相互替代，这是以前未量化的指标。最后，它们再次强调了在临床环境中需要对抗生素相互作用进行个案测试的必要性。
本工作得到了瑞典研究理事会、瓦伦堡基金会和瑞典战略研究基金会授予 DIA 的资助。
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