Antimicrobial susceptibilities of aerobic and facultative gram-negative bacilli isolated from Chinese patients with urinary tract infections between 2010 and 2014

Several national and international surveillance programs have been initiated for monitoring susceptibilities of clinically important pathogens in urinary tract infections (UTIs) [1‐3]. The Study for Monitoring Antimicrobial Resistance Trends (SMART) is a surveillance program designed to monitor globally susceptibilities of aerobic and facultative Gram-negative bacilli collected from intra-abdominal infections and UTIs (initiated in 2002) [4]. UTIs are frequently encountered in clinical practice and include uncomplicated and complicated pyelonephritis, ureteritis, cystitis and urethritis [5]. The etiologies of these infections arise from Gram-negative bacilli, especially Enterobacteriaceae, and some Gram-positive bacteria [6]. During the last decade, multidrug-resistant Gram-negative Enterobacteriaceae have become a challenge for physicians [7] and particularly E. coli and K. pneumonia strains isolated from UTIs have been reported to increasingly produce ESBLs in the recent years [8‐10]. The choice of an empiric UTI antimicrobial therapy should be based on knowledge of the pathogen distribution and the resistance extent of common microorganisms, in addition to hospital-specific resistance patterns particularly for HA infections. This study, as part of the global SMART project, focused on ESBL-producing rates of UTI isolates from 21 centers in 16 Chinese cities between 2010 and 2014 and on UTI derived sample resistance rates against carbapenems, a combination of drugs containing penicillins with β-lactamase inhibitors, a cephamycin, an aminoglycoside, 3rd and 4^thgeneration cephalosporins as well as 2nd generation fluoroquinolones, in order to provide guidance for antimicrobial therapies of IAIs.

Nitrofurantoin, trimethoprim-sulfamethoxazole, fosfomycin, fluoroquinolones and beta-lactams are commonly recommended antimicrobial agents for urinary tract infections [14]. However, fosfomycin and nitrofurantoin are not often used in China [2]. The usage of trimethoprim-sulfamethoxazole for the treatment of UTIs in China is also limited because of a high resistance rate to this agent among E.coli isolates [15]. In view of this finding, we focused on the activity of beta-lactams, fluoroquinolones and aminoglycoside against uropathogens in the present study. Since Enterobacteriaceae accounted for the majority of aerobic and facultative anaerobic pathogens causing UTIs (88.5% of all isolates) in our study, with E.coli, K. pneumonia, P. mirabilis and Enterobacter cloacae the most frequently isolated species, knowledge of their resistance pattern is beneficial.

Cephalosporins are commonly recommended as empirical choices for UTIs, but their efficacy is greatly reduced when the pathogens produce ESBL. Over the entire study period, susceptibility rates of Enterobacteriaceae to third-generation and fourth-generation cephalosporins were 51.4–66.0% for ceftazidime, 29.4–46.9% for cefotaxime, 29.9–41.2% for ceftriaxone and 35.1–47.1% for cefepime, indicating that these agents might not be the optimum medications for empirical UTI therapies. In the present study, the percentage of ESBL positive E. coli isolates decreased from 66.9% in 2010 to 59.1% in 2014, while for K. pneumonia it decreased from 59.7 to 48.8% and from 40.0 to 26.1% among P. mirabilis. The data were well matched with the non-susceptibility rates to cephalosporins against each species, which indicated that ESBL production might be a reason for cephalosporin resistance [16]. The decrease of ESBL rates in E. coli, K. pneumonia and P. mirabilis may have been a result of China’s antimicrobial stewardship policy on antimicrobial use, which has been promoted for a number of years [17‐19]. Our study also highlighted the variation in ESBL rates in different regions of China, with the Central-China region having a higher ESBL prevalence in E. coli and K. pneumonia. Researchers previously reported that the ESBL genotypes in China were mainly CTX-M types [20‐22], especially CTX-M-14, −15, and −55 for E. coli and K. pneumonia, and CTX-M-65 and −14 for P. mirabilis [22]. Plasmids encoding these CTX-M enzymes reached human opportunists, where they have proliferated in community E. coli and hospital K. species. CTX-M families are dominate in different regions: CTX-M-15 is predominant in most of Europe, North America, the Middle East, and India, but CTX-M-14 is most common in China, Southeast Asia and Spain, while CTX-M-2 is predominant in Argentina, Israel, and Japan [23, 24]. Increased numbers of enzyme types and prevalence made determination of resistance profiles more complicated.

Fluoroquinolones, especially ciprofloxacin and levofloxacin, were considered to be effective antimicrobial agents against uropathogens because of high drug concentrations are reached in the urine. However, fluoroquinolone-resistant E. coli is also problematic in China. The susceptibility of E. coli to fluoroquinolones (ciprofloxacin and levofloxacin) was 26.9–28.9%, with rates of 30.2–32.1% against CA isolates and 25.7–27.8% against HA isolates. Wang et al. also previously reported about ciprofloxacin-resistant E. coli strains with multiple gyrA and parC gene substitutions [25]. Regarding the low effectiveness of fluoroquinolones against Enterobacteriaceae, ciprofloxacin and levofloxacin should not be considered as first line agents for empirical therapies of complicated UTIs. Our data also showed that susceptibilities of ESBL-producing E. coli and K. pneumonia strains to fluoroquinolones were significantly lower than that of ESBL-non-producing strains, which is in agreement with previous findings [26].

Carbapenems can still be considered to be suitable for severe infections and as alternative empiric treatment for UTIs caused by bacterial strains highly suspicious of being ESBL-producing or AmpC-derepressed Enterobacteriaceae [27‐29]. Although carbapenems were not the first line choices for uncomplicated cystitis and pyelonephritis in women according to the IDSA guideline, they were good alternatives against multidrug resistant Gram-negative bacilli that caused UTIs. Our study showed that ertapenem and imipenem were the most effective agents against Enterobacteriaceae causing UTIs, with susceptibility rates of 92.5–96.5% and 89.9–95.2%, respectively (2010–2014). On the other hand, carbapenem-resistant Enterobacteriaceae have emerged, which has also been noted in other reports [30‐33], especially KPC-producing K. pneumonia in the north-eastern area of the United States of America [31], KPC/VIM-producing Enterobacteriaceae in Greece [32, 33] and KPC-producing isolates in eastern China. In our study, very few E. coli isolates (<4%) were non-susceptible to carbapenems, while there was a certain proportion of carbapenem-non-susceptible K. pneumonia isolates (13.8% to ertapenem), P. mirabilis (85% to imipenem) and E. cloacae (21.3% to ertapenem and 14.9% to imipenem), which should be noted by clinicians. Especially for E. cloacae the susceptibility of HA samples to ertapenem has dropped to 53.9%, while for CA UTIs its susceptibility rate is 100%. Hospital infections caused by E. cloacae, which is a typical commensal under normal conditions, have been suggested to be mainly caused by endogenous translocation from the digestive tract in debilitated patients and that under antibiotic therapy, E. cloacae strains may selectively reproduce excessively in the gastrointestinal tract [34]. This might be the reason for the high ertapenem resistance in UTIs mainly caused by HA E. cloacae. The main resistance mechanism to carbapenem in Enterobacteriaceae was reported to be carbapenemase production and porin loss in China [35]. However, the resistance of P. mirabilis to imipenem was caused by a mechanism other than carbapenemase [13].

Among the tested antimicrobial agents, amikacin exhibited good activity against most of the uropathogens (80.0–96.2% susceptibility rate against Enterobacteriaceae and 83.6% against P. aeruginosa). Although the use of this aminoglycoside is limited because of its toxicity, it has also been recommended as an alternative to carbapenems against ESBL-producing isolates that cause UTIs [36].