In vitro susceptibility of Escherichia coli strains isolated from urine samples obtained in mainland China to fosfomycin trometamol and other antibiotics: a 9-year surveillance study (2004–2012)

Background As a result of extensive use of fluroquinlones and cephalosporins, urinary tract pathogens producing extended-spectrum beta-lactamase (ESBL) pose a considerable clinical challenge in the treatment of UTIs. In the present study we retrospectively assessed the susceptibility of E. coli strains to fosfomycin trometamol and other antibiotics commonly used for the treatment of such infections. Methods A total of 908 nonreplicate clinical E. coli urinary isolates were collected from 20 Chinese hospitals over four consecutive 1-year periods between October 2004 and June 2012. Susceptibility to antimicrobial agents fosfomycin trometamol, piperacillin-tazobactam, cefuroxime, cefotaxime, cefepime, imipenem, amikacin, levofloxacin, and nitrofurantoin was determined using the agar dilution method. A reference strain E. coli (ATCC 25922) was used as a positive control. Results were analyzed using Chi-square test or Fisher’s exact tests. Results Fosfomycin trometamol, piperacillin-tazobactam, amikacin, and imipenem were consistently the most active agents against most of the isolates. There was a decline in susceptibility to cefuroxime, cefotaxime, and cefepime between 2004 and 2010. We showed that 528 of the 908 E. coli isolates (58.1%) produced ESBLs. The ESBL-positive rates increased from 41.7% in 2004−2005 to 60.9% in 2011−2012. ESBL-producing E. coli isolates showed significantly higher resistance rates to levofloxacin than the ESBL-negative isolates. Fosfomycin trometamol, piperacillin-tazobactam, amikacin, and imipenem had good activity against both levofloxacin-susceptible and levofloxacin- nonsusceptible isolates (sensitivity rate > 90%). However susceptibility of levofloxacin-resistant isolates to cefuroxime, cefotaxime, cefepime, amikacin, and nitrofurantoin was significantly lower than that of levofloxacin-susceptible isolates. Conclusions Owing to the increase in the bacterial resistance across the world, the European Urology Association has recommended fosfomycin trometamol as the drug of choice in its Guidelines on Urological Infections released in 2013. Our results confirm this recommendation for use in China and continued monitoring of the susceptibility of E. coli to fosfomycin trometamol is need with the widely use of the drug in China.


Background
Urinary tract infections (UTIs) are among the most common conditions, which require diagnostic and therapeutic intervention. Escherichia coli is to date the most frequent uropathogen, which accounted for 30.7% and 51.5% of all UTIs in men and women, respectively, during 2010 in China [1]. Fluoroquinolones and cephalosporins were the most commonly used antibiotics for the treatment of UTIs in China. However, in the recent years, many resistant strains have emerged because of the use of broadspectrum cephalosporins. In particular, strains producing extended-spectrum beta-lactamase (ESBL) pose a considerable clinical challenge in the treatment of UTIs.
Fosfomycin has been extensively used in several European countries for the treatment of uncomplicated UTIs since 1988, but it was not available in China until recently. This study aimed to reassess the susceptibility of E. coli strains isolated from patients with UTIs between October 2004 and June 2012 to fosfomycin trometamol and other antibiotics commonly used for the treatment of such infections.

Bacterial isolates
A total of 908 nonreplicate clinical E. coli urinary isolates were collected from 20 widely dispersed tertiary Chinese hospitals over four 1-year periods

Antimicrobial susceptibility testing
Susceptibility to antimicrobial agents was determined using the agar dilution method according to the Clinical and Laboratory Standards Institute [2]. The following antimicrobial agents were tested: fosfomycin trometamol, piperacillin-tazobactam, cefuroxime, cefotaxime, cefepime, imipenem, amikacin, levofloxacin, and nitrofurantoin. ESBL)-producing isolates were detected according to previously described methods [2]. The reference strain E. coli ATCC 25922 was used as the positive control.

Statistical analyses
Statistical tests were performed using Social Sciences software for Windows Version 14.0 (SPSS, Inc., Chicago, IL, USA). Enumeration data were expressed as percentage values. The differences in susceptibility between the groups were compared using the Chi-square test or Fisher's exact test. The differences between the groups were considered significant if the p-values were smaller than 0.05(two-sided test). The Bonferroni method was used to adjust the significant levels (0.05/6 = 0.0083) in multiple comparisons between any two levels of the susceptibility outcome.

Comparison of antimicrobial susceptibilities between 2004 and 2012
Fosfomycin trometamol, piperacillin-tazobactam, amikacin, and imipenem were consistently the most active agents against most of the isolates. We observed a decline in the susceptibility to cefuroxime, cefotaxime, and cefepime from 2004 to 2010. In particular, the susceptibility to cefepime decreased significantly from 88.    periods from 2004 to 2012, respectively. ESBL-producing E. coli isolates showed significantly higher resistance rates to cefepime and levofloxacin than the ESBL-negative isolates. Fosfomycin trometamol, piperacillin-tazobactam, imipenem, amikacin, and nitrofurantoin showed good activity against both ESBL-producing and ESB-negative isolates; the sensitivity rates were greater than 85% ( Table 2).

Comparison of susceptibility of levofloxacin-resistant and levofloxacin-susceptible strains of E. coli to various antimicrobial agents
Fosfomycin trometamol, piperacillin-tazobactam, amikacin, and imipenem had good activity against both levofloxacinsusceptible and levofloxacin-nonsusceptible isolates (sensitivity rate > 90%). The rate of susceptibility to cefuroxime, cefotaxime, cefepime, amikacin, and nitrofurantoin was significantly lower in the levofloxacin-resistant isolates than in the levofloxacin-susceptible isolates (p < 0.001) ( Table 3).

Discussion and conclusion
E. coli plays an important role in UTI; UTI is one of the most frequently encountered infectious diseases. Cephalosporins and levofloxacin are the widely used agents for the treatment of UTI. The production of ESBLs by E. coli is associated with the reduced susceptibility to fluoroquinolones and other antimicrobial agents. The resistance rates of ESBL-producing E. coli to levofloxacin in this study were higher than those reported in other studies performed in different countries [3,4]. Nitrofurantoin were seldom used in China, it is maybe the reason that the susceptibility of nitrofurantoin increased over time.
Our data confirm that E. coli isolated from Chinese UTI patients remain exclusively susceptible to fosfomycin trometamol. In addition, the ESBL-producing and levofloxacin-resistant strains of E. coli were susceptible to fosfomycin trometamol. Our results are similar to those reported in recent studies on the same pathogens isolated from other areas of the world [5,6].
Fosfomycin trometamol was excreted renally within 48 hours and urinary titres showed that concentrations > 128 mg/L, sufficient to inhibit most urinary pathogens, were maintained for 24 to 48 hours after a single oral dose (≅3g fosfomycin), but the mean peak plasma concentrations were only 22 to 32 mg/L [7] The European Urology Association has recommended fosfomycin trometamol, nitrofurantoin and pivmecillinam as the drug of choice in its Guidelines on Urological Infections released in 2013 [8]. An uncontrolled and multicentre study showed clinical efficacy rates for acute uncomplicated cystitis, recurrent lower urinary tract infection and complicated lower urinary tract infection were 94.71, 77.22% and 62.69% [9]. Continued monitoring of the susceptibility of E.coli to fosfomycin trometamol is needed with the widely use of the drug in China.