Bulman Zackery P, Cirz Ryan, Hildebrandt Darin, Kane Tim, Rosario Zuelay, Wlasichuk Ken, Park Minjong, Andrews Logan D
Department of Pharmacy Practice, University of Illinois at Chicago College of Pharmacy, Chicago, Illinois, USA.
Achaogen Inc., South San Francisco, California, USA.
Antimicrob Agents Chemother. 2020 Aug 20;64(9). doi: 10.1128/AAC.00533-20.
The gentamicin drug product is a complex mixture of numerous components, many of which have not individually undergone safety and efficacy assessments. This is in contrast to the majority of medicines that require rigorous characterizations of trace impurities and are dosed as single components. In gentamicin, four components, known as gentamicin congeners C1, C1a, C2, and C2a, comprise the majority of the mixture. A liquid chromatography-mass spectroscopy analysis revealed that the relative abundances of each gentamicin congener in commercial formulations can vary up to 1.9-fold depending on the commercial source of the gentamicin. To determine if the gentamicin used for antibiotic susceptibility testing (AST) would be predictive of the microbiological activity of the product used to dose patients, the relative abundances of the four congeners contained on commercial AST disks were measured. It was found that the congener abundances on the commercial AST disks varied up to 4.1-fold. After purification of the four gentamicin congeners, similar potencies against bacterial strains lacking aminoglycoside-modifying enzymes (AMEs) were observed. However, the potency of the congeners against strains harboring a common AME differed up to 128-fold. Nephrotoxicity of the individual gentamicin congeners also differed significantly in cell-based and repeat-dose rat nephrotoxicity studies. Variations in the composition of commercial gentamicin products combined with toxicity differences between gentamicin congeners suggest that some gentamicin formulations may be more nephrotoxic. Our results also raise the concern that gentamicin susceptibility test results may not be predictive of patient outcomes and could lead to unexpected clinical treatment failures.
庆大霉素药品是多种成分的复杂混合物，其中许多成分尚未单独进行安全性和有效性评估。这与大多数需要对痕量杂质进行严格表征并以单一成分给药的药物形成对比。在庆大霉素中，四种成分，即庆大霉素同系物C1、C1a、C2和C2a，构成了混合物的大部分。液相色谱-质谱分析表明，根据庆大霉素的商业来源，市售制剂中每种庆大霉素同系物的相对丰度可相差高达1.9倍。为了确定用于抗生素敏感性测试（AST）的庆大霉素是否能预测用于给患者给药的产品的微生物活性，测量了市售AST药敏纸片上所含四种同系物的相对丰度。结果发现，市售AST药敏纸片上同系物的丰度相差高达4.1倍。纯化四种庆大霉素同系物后，观察到它们对缺乏氨基糖苷修饰酶（AMEs）的细菌菌株具有相似的效力。然而，这些同系物对携带常见AME的菌株的效力相差高达128倍。在基于细胞的和重复给药的大鼠肾毒性研究中，各庆大霉素同系物的肾毒性也有显著差异。市售庆大霉素产品成分的差异以及庆大霉素同系物之间的毒性差异表明，某些庆大霉素制剂可能具有更高的肾毒性。我们的结果还引发了人们的担忧，即庆大霉素敏感性测试结果可能无法预测患者的治疗结果，并可能导致意外的临床治疗失败。
