Ellington Matthew J, Livermore David M, Pitt Tyrone L, Hall Lucinda M C, Woodford Neil
Antibiotic Resistance Monitoring and Reference Laboratory, Centre for Infections, Health Protection Agency 61 Colindale Avenue, London NW9 5EQ, UK.
J Antimicrob Chemother. 2006 Oct;58(4):848-52. doi: 10.1093/jac/dkl315. Epub 2006 Aug 5.
Fosfomycin is a possible oral treatment for lower urinary tract infections caused by Escherichia coli with CTX-M extended-spectrum beta-lactamases but is vulnerable to mutational resistance. Hypermutability among natural E. coli populations might facilitate the emergence of resistance to fosfomycin. We therefore examined the prevalence of mutators amongst urinary isolates of E. coli producing CTX-M beta-lactamases.
Urinary E. coli isolates with CTX-M beta-lactamases (n = 220) were screened for resistance to both rifampicin and fosfomycin, as well as a mutator phenotype, by rifampicin and fosfomycin disc assays. Mutation frequencies for 10 isolates, identified as mutators by the initial disc screen, were determined in triplicate on agar with rifampicin or fosfomycin at 4x MIC and with fosfomycin or nitrofurantoin at 256 mg/L.
The disc screen identified 10 likely mutators and quantitative tests indicated that 9 of these had mutation frequencies of 8.0 x 10(-6)-1.5 x 10(-4) for fosfomycin and 0.1-2.3 x 10(-6) for rifampicin. These mutators were diverse in terms of PFGE type and 4 of the 10 were confirmed as strong mutators with rifampicin and fosfomycin. Only the strongest mutator isolate and hypermutable MutS(-) control strain consistently gave single-step mutants resistant to 256 mg/L fosfomycin. No nitrofurantoin-resistant mutants were selected from any isolate, although they could be selected from the hypermutable MutS(-) control strain.
Mutator phenotypes were found among E. coli expressing CTX-M beta-lactamases and were independent of strain type. These had an increased propensity to fosfomycin resistance.
磷霉素是治疗由产CTX-M型超广谱β-内酰胺酶的大肠埃希菌引起的下尿路感染的一种可能的口服治疗药物，但易产生突变耐药性。自然大肠埃希菌群体中的高突变性可能促进对磷霉素耐药性的出现。因此，我们检测了产CTX-M型β-内酰胺酶的大肠埃希菌尿液分离株中突变体的流行情况。
通过利福平纸片扩散法和磷霉素纸片扩散法，对220株产CTX-M型β-内酰胺酶的大肠埃希菌尿液分离株进行利福平和磷霉素耐药性以及突变体表型的筛查。对最初纸片筛查鉴定为突变体的10株分离株，在含有4倍最低抑菌浓度（MIC）的利福平或磷霉素的琼脂平板上，以及含有256 mg/L磷霉素或呋喃妥因的琼脂平板上，一式三份测定其突变频率。
纸片筛查鉴定出10株可能的突变体，定量检测表明其中9株对磷霉素的突变频率为8.0×10⁻⁶ - 1.5×10⁻⁴，对利福平的突变频率为0.1 - 2.3×10⁻⁶。这些突变体在脉冲场凝胶电泳（PFGE）类型方面具有多样性，10株中有4株被确认为对利福平和磷霉素的强突变体。只有最强的突变体分离株和高突变性的MutS(-)对照菌株始终产生对256 mg/L磷霉素耐药的单步突变体。尽管可以从高突变性的MutS(-)对照菌株中筛选出呋喃妥因耐药突变体，但从任何分离株中均未筛选出呋喃妥因耐药突变体。
在表达CTX-M型β-内酰胺酶的大肠埃希菌中发现了突变体表型，且与菌株类型无关。这些突变体对磷霉素耐药的倾向增加。
