Background
The Study for Monitoring Antimicrobial Resistance Trends (SMART) is a global surveillance program, which monitors annually in vitro antimicrobial susceptibilities of hospital acquired (HA) and community acquired (CA) intra-abdominal and urinary tract infections due to aerobic and facultative Gram-negative bacilli (GNB). Intra-abdominal infections (IAIs) are the second most common cause of sepsis in intensive care units (ICU) [
1] where they are the second most common cause of infection-related mortality [
2]. IAIs are also the second most common cause of infection related to surgical interventions and according to a multicenter observational study in 68 medical institutions worldwide, [
3] the overall mortality rate of patients with complicated IAIs in 2012–2013 was 10.5%, [
4], with ESBL producing bacteria being a particular challenge for treatment [
5]. However, initiation of appropriate antimicrobial therapy can significantly reduce the mortality rate of IAI-induced septic shock [
6]. Since appropriate antibiotic therapy is essential for IAIs [
7,
8], institutional and nationwide surveillance of IAI-derived bacterial strain susceptibilities provides crucial information for the selection of the right choice of empirical antimicrobial treatment.
Although a significant increase of the proportion of ESBL-positive
Enterobacteriaceae hospital infections in Germany over the period 2007–2012 [
9] and in Japan from 2000 to 2010 have been reported [
10,
11] the situation in China is not clear. A limited number of ESBL-screen positive
Escherichia coli and
Klebsiella pneumoniae IAI isolates from 2012 and 2013 have been documented, but there is a wide diversity in ESBL-related molecular characteristics [
12].
The present study mainly focused on ESBL-screen positive rates of IAI isolates and concomitantly on resistance rates of IAIs, in particularly those caused by
Enterobacteriaceae against, 3rd and 4th generation cephalosporins, a cephamycin, 2nd generation fluoroquinolones, carbapenems, an aminoglycoside, as well as a combination of drugs containing
penicillins with
β-lactamase inhibitors. The data was collected from 21 centers in 16 Chinese cities between 2012 and 2014 in order to provide guidance for antimicrobial therapy of IAIs.
Discussion
The majority of IAI isolates collected in the participating centers consisted of
Escherichia coli and
Klebsiella pneumoniae which is similar with data from the 2002 to 2009 SMART study [
16]. However, in contrast to the 2002–2009 SMART study data, which revealed an increase particularly of ESBL-screen positive
Escherichia coli strains from 20.8% in 2002 up to 64.9% in 2009, in the present study ESBL+ rates in
Escherichia coli strains decreased from 67.5% in 2012 to 58.9% in 2014, which was reflected also in gall bladder, abscess, liver, peritoneal fluid, appendix and pancreas derived isolates sampled in 2014. In the present study the percentages of ESBL+
Klebsiella pneumoniae strains notably dropped from 40.4% in 2012 to 26.6% in 2014 (
P = 0.0215) (Table
2), which was also seen in the decreased ESBL+ percentages of isolates from the gall bladder, abscess, liver and appendix. However, the percentages of ESBL+
Escherichia coli (66.7%) and
Klebsiella pneumoniae (55.6%) strains isolated from pancreas remained high in 2014. Most of the infections occurred in the gall bladder and the peritoneum, which is in accordance with previous literature, but the number of isolates from the appendix was unusually low in our study [
4,
17]. In contrast to other organs, the number of
Klebsiella pneumoniae liver infections exceeded those caused by
Escherichia coli, which has also been reported in previous studies, and might be explained by cryptogenic infections with a new hypervirulent K1
Klebsiella pneumoniae ST23 strain, which developed in Asia and spread to Australia, European countries and the USA [
18‐
20], while a recent report by Qu et al. (2015) et al. noted that K1 ST23 were the predominant
Klebsiella pneumoniae liver abscess causing strains in east China [
21]. ESBL-producing
Escherichia coli and
Klebsiella pneumoniae are supposed to be susceptible to cefoxitin, but a high proportion of these isolates tested cefoxitin-resistant (Table
3) and a likely explanation is that they have acquired AmpC beta-lactamases and porin loss, which has been described in a previous study about cefoxitin resistant
Klebsiella pneumoniae strains in China, which expressed DHA-1 ß-lactamase combined with porin OmpK36 deficiency [
22].
The percentages of
Escherichia coli and
Klebsiella pneumoniae ESBL+ strains was higher in HA than in CA IAI isolates, which is in accordance with a previous Chinese SMART study by Yang et al. (2013). However, in the latter study
Escherichia coli ESBL+ rates in CA infections constantly rose from 19.1% in 2002–2003 to 61.6% in 2010–2011, whereas in our study the
Escherichia coli ESBL+ rates in CA IAIs were relative constant at around 60%, with a reduction to 51.6% only in 2013. In contrast, the
Escherichia coli ESBL+ rates in HA IAIs showed a decreasing trend from 70.6% in 2012 to 58.1% in 2014 in our study, but were relative stable in the years 2006–2011 (66.7%–70.0%) [
23].
A more dramatic change was visible for
Klebsiella pneumoniae ESBL+ rates in HA IAIs dropping from 43.6% in 2012 and 42.0% in 2013, which is similar to the Chinese HA values (39.4%) reported for
Klebsiella pneumoniae IAIs in 2010–2011 [
23], to 24.4% in 2014
(P = 0.006), but in CA IAIs the
Klebsiella pneumoniae ESBL+ rates were relatively constant (between 24.7% and 31.0%), which is somewhat higher than the 22.2% reported for CA
Klebsiella pneumoniae IAIs in 2010–2011 [
23]. Taken together, the total ESBL+ rates in
Klebsiella pneumoniae and
Escherichia coli isolates from IAIs in our study dropped between 2012 and 2014, which was due to less ESBL+ rates in HA IAIs and rather constant percentages of CA ESBL+
Klebsiella pneumoniae and
Escherichia coli IAI isolates (Table
2). The decrease of ESBL+ GNBs might be explained by new restrictions for the clinical application of antimicrobial agents, which has been introduced by the Chinese ministry of health in 2012 [
24]. The overall susceptibilities of ESBL positive
Escherichia coli strains was 96.77%–98.8% to IPM, 91.26%–93.16% to ETP, 89.48%–92.75% to AMK and 84.86%–89.34% to TZP, while ESBL-screen positive
Klebsiella pneumoniae strains were 70.56% -80.15% susceptible to ETP, 80.0%–87.5% to IPM, 83.82%–87.06% to AMK and 63.53%–68.38% to TZP within the three year study. However, it is noteworthy that reduced susceptibilities of
Klebsiella pneumonia strains to the carbapenems IPM and ETP derived from centers located in east China indicated a local carbapenem-resistance, which has also been described in other countries [
25,
26]. Because the eastern part of China is the most developed region with the highest incomes, antimicrobial overuse [
27,
28] might be an explanation for the carbapenem susceptibility difference in this area, which has been described also for the eastern Zhejiang Province before [
29]. In general a previous study noted that Chinese individuals were harboring the highest number and abundance of antibiotic resistance genes in their gut microbiota compared to Danish and Spanish individuals [
30], but we did not include investigations of molecular mechanisms of resistances.
All tested cephalosporins and fluoroquinolones were <70% effective for
Escherichia coli and <60% for
Klebsiella pneumoniae isolates that produced ESBLs. This finding is in agreement with previous literature that suggested that carbapenems are the best choice as empirical mono therapies, especially for complicated IAIs [
31], but that cephalosporins, fluoroquinolones and SAM are not ideal choices for empirical treatment of IAIs in China [
16]. For non-ESBL-screen positive
Escherichia coli strains, cefoxitin, levofloxacin, ciprofloxacin and ampicillin-sulbactam, and for non-ESBL-screen positive
Klebsiella pneumoniae strains, cefoxitin and ampicillin-sulbactam were the least effective antibiotics (Fig.
1).
Taken together, the relatively high susceptibility percentages seen for imipenem and, to a slightly lesser degree, ertapenem, against
Escherichia coli —whether ESBL-positive or -negative—are important considerations in China, where ESBL+ rates around 60% are seen, and many other drugs from the beta-lactam class and fluoroquinolones are no longer viable options for therapy and should be avoided unless susceptibilities to this antimicrobial agents have been confirmed. Against
Klebsiella pneumoniae, the carbapenem activity is somewhat lower, presumably because of presence of more carbapenemases (such as KPC-2-type) in
Klebsiella pneumoniae [
32,
33], as well as other mechanisms that include porin loss combined with AmpC or ESBL enzymes; however, even the reduced activity of carbapenems to
Klebsiella pneumoniae is dramatically higher than all other drugs evaluated in SMART except for amikacin and piperacillin-tazobactam. Considering the relatively high ESBL rates in China, and the low susceptibility to fluoroquinolones that are usually seen in conjunction with ESBL-positive isolates, carbapenems are among the few antimicrobial agents in China retaining sufficient in vitro activity to be considered for empiric therapy. On the other hand, it is very important to retain the activity of carbapenems, so step-down therapy to other agents should always be considered once the susceptibility of a specific pathogen is known.
A limitation of the study was that genotypic or molecular data of the strains were not included, since the SMART project does not involve these kind of analyzes.
Conclusions
From 2012 to 2014, a total of 5160 IAI isolates were obtained, of which 81.1% were caused by Enterobacteriaceae and 18.9% by non-Enterobacteriaceae, with Escherichia coli (45.4%) being the most common followed by Klebsiella pneumoniae (20.1%). The most common non-Enterobacteriaceae were Pseudomonas aeruginosa (9.8%) and Acinetobacter baumannii (6.7%). The percentages of ESBL-screen positive Escherichia coli and Klebsiella pneumoniae strains in IAI GNB isolates showed a decreasing trend from 2012 to 2014, which can be explained by less ESBL+ percentages in strains from HA IAIs.
Susceptibility of ESBL-screen positive Escherichia coli strains was >80% to imipenem, ertapenem, amikacin and piperacillin-tazobactam, while ESBL-screen positive Klebsiella pneumoniae strains were >70% susceptible only to imipenem, ertapenem and amikacin.
In contrast to gall bladder, abscess, peritoneal fluid, appendix and pancreas, the percentage of Klebsiella pneumoniae causing liver infections was higher than that caused by Escherichia coli. It is noteworthy that Klebsiella pneumoniae and Escherichia coli isolates from pancreatic infections exhibited consistently high ESBL+ rates.
The apparent trend of declining percentages of ESBL-screen positive Escherichia coli and Klebsiella pneumoniae strains needs to be closely monitored.