Carbapenem is the most effective drugs for the treatment of severe infections with gram-negative bacteria due to its broad antimicrobial spectrum and high stability for hydrolysis of most β-lactamases, including extended-spectrum β-lactamases (ESBLs) and AmpC cephalosporinases [23]. But unreasonable use of antibiotics leads to the emergence of CR-GNB, which is becoming more and more serious, and the treatment of some drug-resistant infections is extremely limited [9, 24, 25]. Therefore, understanding the hazard factor for antibiotic-induced CR-GNB is very important in the early selection of empirical antibiotic program. We demonstrated that previous carbapenem exposure was the major risk factor for antibiotic-induced CR-GNB in our study population.
During the period, cephalosporins were the most commonly used antibiotics, followed by β-lactamase inhibitors and penicillins. Unlike this, physicians in Europe preferred to prescribe more penicillins than cephalosporins [26]. The difference might be explained by that most antibiotics were used for inpatient treatment in China while outpatient institutions accounted for the majority of antibiotic consumption in foreign countries [27–29]. The clinical application of carbapenem, as a special class antibiotic, is limited and requires pre-authorization during the using period in our country.
In this study, carbapenem, β-lactamase inhibitor, and cephalosporin had significantly higher hazards than other types of antimicrobial. Our finding that carbapenem was the most principal hazard factor associated with antibiotic-induced CR-GNB was in accordance with some previous study [6, 30–36]. The use of carbapenem may promote the production of carbapenemase, such as K pneumoniae carbapenemase and metallo-β-lactamases, which could increase carbapenem-resistant Escherichia coli (CRE) [37]. Other mechanisms of carbapenem resistance include outer membrane porin expression loss combined with extended-spectrum β-lactamase (ESBL) and AmpC enzyme, change of antimicrobial target and high expression of efflux pump [38–40]. This suggested that controlling the use of carbapenems could slow down the production of CR-GNB. However, unlike some studies, we did not find that previous use of quinolones was significantly correlated with antibiotic-induced CR-GNB [30, 35, 36, 41–46]. It was speculated that quinolones might induce the high expression of efflux pump and lead to the multidrug-resistant phenotype, probably CR-GNB [47–49]. The reason for this difference might be that our design or study population was different from previous studies. Another large-scale research in China showed that fluoroquinolone consumption was not associated with CR-GNB [6]. In one way, this may be a feature of our country, and could provide basis for our choice of anti-infective therapy. Although using antibiotic was an important risk factor for drug resistance, even without the use of any antimicrobials the hazard would increase with the length of hospital stay after cox model analysis. The result might be explained by that these patients with longer hospital stay had prolonged exposure to invasive devices or use of antibiotics.
ICU stay and tracheotomy were also an important hazard factors associated with antibiotic-induced CR-GNB. ICU is considered as the main source of multidrug-resistant bacteria creation and transmission due to the extremely critically ill patients, the use of invasive devices and higher intensity of selection pressure by broad-spectrum antibiotics. When patients receive tracheotomy and ventilator, the normal upper respiratory barrier will be destroyed and the pipe will be gradually polluted by bacteria which will increase chance of bacterial invasion. Our results showed that the risk of antibiotic-induced CR-GNB isolation was 1.563 times higher in patients receiving tracheotomy than in patients without tracheotomy. This indicated that some preventive and control measures related to the use of tracheotomy, such as understanding the indication of tracheotomy, operation procedure and hand hygiene, could effectively reduce the CR-GNB in our hospital.
In our hospital, infection control measures against resistant bacteria are relatively comprehensive, including training for prevention and control methods for bacteria, active surveillance of the most common multidrug resistant bacteria (MDRO), computer system alerts for MDRO species, active screening for high risk inpatients, supervision of adherence to precaution measures and so on, to reduce the spread of MDROs in hospital.
There are several potential limitations in our study. Firstly, this study was a retrospective design conducted in a large tertiary A-level hospital, not a multicenter research. Secondly, we did not take into account the dose of the antibiotic and antibiotic combinations. Thirdly, the generation of CR-GNB could be varied by the practice of infection control and other risk factors, but we did not take the former into account. Finally, the genotype test for resistance genes was not conducted in our study, because although the isolation of CR-GNB was not uncommon, the number of patients received resistance genes detection was relatively small. Despite these limitations, we believe that the main advantage of our research is its large cohort. Therefore, our research can at least provide reference value for the use of antibacterial drugs.