Haaber Jakob, Friberg Cathrine, McCreary Mark, Lin Richard, Cohen Stanley N, Ingmer Hanne
Department of Veterinary Disease Biology, University of Copenhagen, Frederiksberg, Denmark.
Department of Genetics, Stanford University, Stanford, California, USA.
mBio. 2015 Jan 13;6(1):e02268-14. doi: 10.1128/mBio.02268-14.
Resistance of Staphylococcus aureus to beta-lactam antibiotics has led to increasing use of the glycopeptide antibiotic vancomycin as a life-saving treatment for major S. aureus infections. Coinfection by an unrelated bacterial species may necessitate concurrent treatment with a second antibiotic that targets the coinfecting pathogen. While investigating factors that affect bacterial antibiotic sensitivity, we discovered that susceptibility of S. aureus to vancomycin is reduced by concurrent exposure to colistin, a cationic peptide antimicrobial employed to treat infections by Gram-negative pathogens. We show that colistin-induced vancomycin tolerance persists only as long as the inducer is present and is accompanied by gene expression changes similar to those resulting from mutations that produce stably inherited reduction of vancomycin sensitivity (vancomycin-intermediate S. aureus [VISA] strains). As colistin-induced vancomycin tolerance is reversible, it may not be detected by routine sensitivity testing and may be responsible for treatment failure at vancomycin doses expected to be clinically effective based on such routine testing.
Commonly, antibiotic resistance is associated with permanent genetic changes, such as point mutations or acquisition of resistance genes. We show that phenotypic resistance can arise where changes in gene expression result in tolerance to an antibiotic without any accompanying genetic changes. Specifically, methicillin-resistant Staphylococcus aureus (MRSA) behaves like vancomycin-intermediate S. aureus (VISA) upon exposure to colistin, which is currently used against infections by Gram-negative bacteria. Vancomycin is a last-resort drug for treatment of serious S. aureus infections, and VISA is associated with poor clinical prognosis. Phenotypic and reversible resistance will not be revealed by standard susceptibility testing and may underlie treatment failure.
金黄色葡萄球菌对β-内酰胺类抗生素产生耐药性，导致糖肽类抗生素万古霉素越来越多地被用作治疗严重金黄色葡萄球菌感染的救命药物。由不相关细菌物种引起的合并感染可能需要同时使用针对合并感染病原体的第二种抗生素进行治疗。在研究影响细菌抗生素敏感性的因素时，我们发现，同时暴露于黏菌素（一种用于治疗革兰氏阴性病原体感染的阳离子肽抗菌剂）会降低金黄色葡萄球菌对万古霉素的敏感性。我们发现，黏菌素诱导的万古霉素耐受性仅在诱导剂存在时持续存在，并且伴随着与导致万古霉素敏感性稳定遗传降低的突变（万古霉素中介金黄色葡萄球菌[VISA]菌株）所产生的基因表达变化相似的变化。由于黏菌素诱导的万古霉素耐受性是可逆的，它可能无法通过常规敏感性测试检测到，并且可能是导致基于此类常规测试预期临床有效的万古霉素剂量治疗失败的原因。
通常，抗生素耐药性与永久性基因变化相关，例如点突变或耐药基因的获得。我们发现，在基因表达变化导致对抗生素产生耐受性而没有任何伴随基因变化的情况下，会出现表型耐药性。具体而言，耐甲氧西林金黄色葡萄球菌（MRSA）在暴露于目前用于治疗革兰氏阴性细菌感染的黏菌素时，表现得像万古霉素中介金黄色葡萄球菌（VISA）。万古霉素是治疗严重金黄色葡萄球菌感染的最后手段药物，而VISA与不良临床预后相关。表型和可逆性耐药性不会通过标准敏感性测试揭示，可能是治疗失败的原因。
