In the present study, we observed that cephalosporins (except for C/BLI combinations) had the largest consumption variety during the entire study period, despite showing a downward trend. In addition, the consumption of BL/BLI combinations showed an increasing trend, and piperacillin-tazobactam was the most frequently used antibiotic, which was consistent with a previous study conducted at a tertiary hospital in China [11]. Previous studies have shown that the history of using 3rd generation cephalosporins is an independent risk factor for extended-spectrum β-lactamase (ESBL)-producing K. pneumoniae or E. coli bacteremia [12]. Due to the high prevalence of ESBLs, the rational application of cephalosporins, especially 3rd generation of cephalosporins is extremely important. The replacement of 3rd generation cephalosporins by BL/BLI combinations was considered as a suitable strategy for reducing the incidence of ESBL-producing Enterobacteriaceae [13–15]. Additionally, our results revealed a significant increase in the consumption of carbapenems. Global antibiotic consumption of carbapenems has increased between 2000 and 2010 [16], which is consistent with the growth trend monitored from 2000 to 2015 [17]. Our results confirmed that the rise of carbapenems usage was consistent with an increase in the number of infections resistant to carbapenems during the entire study period. Yet, it is undeniable that the overuse of carbapenems presents an important problem and carbapenems should be used more rationally.
The isolation rate of the six bacterial isolates did not show an increasing trend in recent years. Instead, E. coli, E. cloacae, and B. cepacia showed a downward trend. As expected, E. coli was always shown as the most common isolate from 2012 to 2019 but was still highly sensitive to carbapenem antibiotics. Carbapenem resistance rates in K. pneumoniae at the hospital were significantly lower than the national level and relatively stable, ranging from 2% in 2012 to 3% in 2019. According to the reports from the bacterial resistance surveillance system in China [18, 19], the Incidence of CRKP showed a significant increase from 8.9% in 2005 to 26.3% in 2018. Surprisingly, the detection rate of CRKP declined for the first time in 2019 [18]. The rate of CRAB was the highest in all isolated species that were studied thus far, showing a rapidly rising trend between 2012 and 2019, which was valid for the whole country [18–20]. In China, the rate of CRAB was nearly 80% in 2019. Based on the fact that A. baumannii has a resistance rate of more than 50% to most antibacterial drugs, it is very important to select antibacterial agents based on the results of susceptibility testing [21].
Because of the urgent need to improve the rational use of antibiotics, a multidisciplinary antibiotic team (made up of infectious disease specialists, microbiologists, clinical pharmacists, and clinicians) was established in 2017 at the hospital. This team focused on appropriate administration of antibiotic therapy for inpatients, pointing out medication errors, and offering corrected suggestions. Coincidentally, carbapenem resistance rates in K. pneumoniae, P. aeruginosa, E. cloacae, and B. cepacia showed a downward trend from 2017 to 2019. Consequently, reducing the unreasonable use of antibacterial drugs may be an effective measure to reduce the spread of CRGN; however, further studies are needed to confirm these observations.
Our results showed a significant positive correlation between the resistance to carbapenems in A. baumannii and E. coli and the consumption of carbapenems, which was consistent with the study conducted across 153 tertiary hospitals in China [22]. Previous studies have indicated that the increasing rate of CRAB was related to carbapenem exposure [23, 24]. Carbapenems are the most powerful antibiotics for ESBL-producing Enterobacteriaceae. However, for CRGN infections, carbapenems need to be used with other antimicrobial agents for forming antimicrobial combinations and are recommended to be used in a high-dose with minimum inhibitory concentration (MIC) within a certain range [25], which can increase the use of carbapenem and other antibacterial drugs, further aggravate carbapenem resistance and produce new issues of drug resistance. Different from the results of Tan et al [26], which showed no significant association between the usage of BL/BLI combinations and the prevalence rates of CRAB, the resistance rate of A. baumannii to carbapenems was positively correlated with cefoperazone-sulbactam usage in the present study. We also observed a positive correlation between the consumption of tetracyclines and the resistance rate of A. baumannii to carbapenems.
Among the complicated mechanisms of CRAB, the most important one is the production of carbapenemases, which can be either inherent or obtained [27]. Similarly, combination treatments of two or more antibiotics were recommended for the treatment of severe infections with CRAB, aiming to achieve bactericidal effects through synergies at concentrations below the respective MIC of the relevant substances [28]. Among the many combination therapies, cefoperazone/sulbactam-based combination regimen, which is usually combined with tigecycline, minocycline, carbapenems or aminoglycosides, is most commonly used for the treatment of carbapenem-resistant and extensively drug-resistant A. baumannii infections [25]. Therefore, it is understandable that increased consumption of cefoperazone-sulbactam and tetracyclines is associated with carbapenem resistance of A.baumannii.
Contrary to what was expected, the increasing use of carbapenems and P/BLI combinations during the study period was significantly correlated with reduced resistance of E. cloacae to carbapenems. Nevertheless, the biochemical and molecular studies on E. cloacae have shown genomic heterogeneity, and the consumption of carbapenems has been indicated as an independent risk factor for the infection of imipenem-heteroresistant E. cloacae [29], which may be selected for highly resistant and pathogenic strains. Accordingly, this finding did not provide a strong basis for the selection of antimicrobials to E. cloacae infections. Given the lack of related research on the correlation between antibacterial consumption and carbapenem resistance of E. cloacae, further research is needed to verify this association. It is difficult to treat infections caused by B. cepacia, because of the high level of intrinsic and acquired resistance to many antimicrobial agents. Therefore, treatment is usually based on susceptibility testing. Carbapenems have proven to be one of the most reliable antibacterial drugs [30]. Yet, we found that the use of quinolones was positively correlated with the resistance rate of B.cepacia to carbapenems, which prompts us to pay more attention to the use of quinolones to slow down the resistance of B. cepacia to carbapenems.
There are some limitations in this study. Firstly, this study was conducted only at one tertiary hospital, while carbapenem resistance rates and antibacterial consumption may vary widely across hospitals; therefore, a multicentered study with more relevant data is needed to explore the correlation between antibacterial consumption and CRGN. Secondly, the development of carbapenem resistance in Gram-negative infection is associated with various factors, and the selective pressure of antibacterial drugs is only one of them. Multi-factor analysis needs to be further studied.