Nilsson Annika I, Berg Otto G, Aspevall Olle, Kahlmeter Gunnar, Andersson Dan I
Department of Bacteriology, Swedish Institute for Infectious Disease Control, S-171 82 Stockholm, Sweden.
Antimicrob Agents Chemother. 2003 Sep;47(9):2850-8. doi: 10.1128/AAC.47.9.2850-2858.2003.
Fosfomycin is a cell wall inhibitor used mainly for the treatment of uncomplicated lower urinary tract infections. As shown here, resistance to fosfomycin develops rapidly in Escherichia coli under experimental conditions, but in spite of the relatively high mutation rate in vitro, resistance in clinical isolates is rare. To examine this apparent contradiction, we mathematically modeled the probability of resistance development in the bladder during treatment. The modeling showed that during a typical episode of urinary tract infection, the probability of resistance development was high (>10(-2)). However, if resistance was associated with a reduction in growth rate, the probability of resistance development rapidly decreased. To examine if fosfomycin resistance causes a reduced growth rate, we isolated in vitro and in vivo a set of resistant strains. We determined their resistance mechanisms and examined the effect of the different resistance mutations on bacterial growth in the absence and presence of fosfomycin. The types of mutations found in vitro and in vivo were partly different. Resistance in the mutants isolated in vitro was caused by ptsI, cyaA, glpT, uhpA/T, and unknown mutations, whereas no cyaA or ptsI mutants could be found in vivo. All mutations caused a decreased growth rate both in laboratory medium and in urine, irrespective of the absence or presence of fosfomycin. According to the mathematical model, the reduced growth rate of the resistant strains will prevent them from establishing in the bladder, which could explain why fosfomycin resistance remains rare in clinical isolates.
磷霉素是一种细胞壁抑制剂，主要用于治疗单纯性下尿路感染。如下所示，在实验条件下，大肠杆菌对磷霉素的耐药性迅速产生，但尽管体外突变率相对较高，临床分离株中的耐药性却很罕见。为了研究这一明显的矛盾，我们对治疗期间膀胱中产生耐药性的概率进行了数学建模。建模显示，在典型的尿路感染发作期间，产生耐药性的概率很高（>10^(-2)）。然而，如果耐药性与生长速率降低相关，产生耐药性的概率会迅速下降。为了研究磷霉素耐药性是否会导致生长速率降低，我们在体外和体内分离了一组耐药菌株。我们确定了它们的耐药机制，并研究了不同耐药突变在有无磷霉素情况下对细菌生长的影响。在体外和体内发现的突变类型部分不同。体外分离的突变体中的耐药性是由ptsI、cyaA、glpT、uhpA/T和未知突变引起的，而在体内未发现cyaA或ptsI突变体。无论有无磷霉素，所有突变在实验室培养基和尿液中均导致生长速率降低。根据数学模型，耐药菌株生长速率的降低将阻止它们在膀胱中定植，这可以解释为什么临床分离株中磷霉素耐药性仍然罕见。
