In recent years, a shift of bacterial species from gram-positive to gram-negative bacteria as the causative agents of BSI was observed with a higher mortality in patients suffering from BSI[4, 15, 16, 17]. Neverthless, only few studies have focused on gram-negative bloodstream infections [18]. So our study examined the incidence and characteristics of gram-negative bloodstream infections in one of the largest tertiary-care hospitals in China and aimed to determine the antimicrobial susceptibility of the isolated pathogens against multiple antibiotics to achieve a clear outlook on the changing trend of their antibiotic susceptibility. According to our knowledge, thus far no such data about incidence rates of gram-negative BSIs based on large retrospective studies have been reported, most study have only reported on the distribution of the bacteria and the drug resistance.
In our 9-year study, the incidence of gram-negative BSIs switched order from 2.3 to 2.55 episodes per 10,00 admissions over 9 years. In the present study, there was no obvious change in overall incidence both in the ICU and on general ward per year. Nevertheless, many studies have reported a decrease in the incidence of gram-negative BSIs in general ward and ICU [19, 20, 21]. This might be explained with the incidence of gram-negative BSIs in our hospital was lower than other study[20] in china which has reported the incidence rate was 5.7/1000 admissions and our hospital is one of the largest general hospitals in China with more critically ill patients which means more invasive manipulation, more catheter indwelling, more comorbidity and other risk factors that lead to the occurrence of bloodstream infection.
BSIs are commonly associated with comorbidities, such as malignancies, diabetes mellitus and infections [22, 6]. In the present study, we found that malignancy was the most common comorbidity, and the major predisposing factor for BSIs was indwelling central intravenous catheters, this data was consistent with previous results [23, 24]. Several studies have reported that the second most common factors is abdominal and lower respiratory tract infections[25, 18]; while we found that chemoradiotherapy was the second most common predisposing factor for gram-negative BSIs. The observed differences might be due to the fact that the malignancy was the most common comorbidity with extensive use of central intravenous catheters for chemotherapy and the high rate of radiotherapy, which more commonly lead to BSIs.
The most common gram-negative bacterial species was Escherichia (34.3%), followed by Klebsiella pneumoniae (23.3%), these results was consistent with other studies[20, 26, 27]. In addition, 77% of infections were healthcare-associated while 23% were community-associated (77% VS 23%), but other studies have reported that gram-negative bacterial was more commonly the cause of community-associated[27]. We hypothesized that this occurred due to the following reasons: first, the study population was mainly focused on healthcare-associated infection and without outpatient, and blood collection and culturing was a routine examination for hospitalized patients with fever (T ≥ 38.5℃) in our hospital and the most blood was collected after admission with fever. Another reason was that the common predisposing factors of gram-negative BSIs such as central intravenous catheters, immunosuppression, and chemoradiotherapy were mainly found with hospitalized patients in our study. Furthermore, increasing use of medical technology in our hospital, the availability of life-saving treatments such as solid organ and hematopoietic stem cell transplantation, and improved intensive and supportive care have allowed for the survival of more severely ill patients, these patients who are extremely vulnerable to infection with healthcare-associated.
Escherichia coli showed a high level of resistance to penicillin, piperacillin/tazobactam, gentamicin, ciprofloxacin and Levofloxacin, the resistance of ESBLs-producing Escherichia coli to penicillin was 99.7% especially, these results were consistent with most studies[28, 29]. The reason might be ESBL was mainly transmitted between bacteria through plasmids, which can hydrolyze β-lactam antibiotics and carry resistance genes for aminoglycosides, quinolones and sulfonamides so that easily causing multiple drug resistance, and these plasmids frequently encode an inhibitor-resistant β-lactamase, namely OXA-1 which confers resistance to β-lactamase inhibitors including amoxicillin-clavulanate and piperacillintazobactam. Escherichia coli was susceptible to cephalosporin and carbapenems, but EARS-Net data indicated that in the EU mean resistance rate to the 3rd generation cephalosporins was 11.9%, ranging 4.4% in Sweden, 38.1% in Bulgaria, the ESBLs-producing Escherichia coli were reported between 71.5% and 100% in different European countries[30], the resistance rates were higher than our study especially for ESBLs-producing Escherichia coli. Carbapenem resistance in E. coli in Europe is rarely reported, the highest rates are found in Bulgaria (2.6%) and Turkey (4.0%) which was lower than our study, but our result was similar to a large multicenter surveillance study from China reported the prevalence of carbapenem resistant E. coli is 1.0%. In addition, the resistance of ESBLs-producing Escherichia coli to the most antibiotic was higher than non-ESBLs producing Escherichia coli but to carbapenems(0.7% VS 5.1%). Therefore, carbapenems may be considered as a first choice of treatment for BSI caused by E. coli and cephalosporin also as a good choice for BSI caused by non-ESBLs producing Escherichia coli especially the forth-generation cephalosporin.
The resistant rate of Klebsiella pneumoniae to penicillin was more than 90% and Klebsiella pneumoniae showed a moderate level of resistance to piperacillin/tazobactam, gentamicin, ciprofloxacin and Levofloxacin, to our knowledge, this is the first study which has reported such detailed results of resistance and be able to help guide the choice of antibiotics in clinical. The cephalosporin resistance rate of Klebsiella pneumoniae was similar to other Asia country[31] but be consistent with the studies done by Europe[32, 33] which have reported the resistance rate ranged between 2.7–88%, especially the ESBL positivity in these isolates were 65–100%. This may be explained with the species distribution and antimicrobial resistance that varies geographically. In addition, the carbapenems resistance rate of Klebsiella pneumoniae in our study was much higher than the most countries in the EU(༜2%)[32], this may be related to the unreasonable use of carbapenems in our hospital, which should arouse a great attention and vigilance the medical staff.
Enterobacter cloacae showed a high level of resistance to β-lactams such as penicillin(71.3%), but the resistance rate of the compound preparation is relatively good such as Piperacillin/tazobactam(11.8%). This difference may be due to the low expression of the AmpC enzyme gene through ECL with the high spontaneous mutagenicity leading to the emergence of drug-resistant strains. In addition, Enterobacter cloacae showed a good susceptibility to Gentamicin, Levofloxacin, the forth generation cephalosporin and Carbapenems but the three generation cephalosporin(31.6%), especially the resistant rate of Carbapenems was 1.4%. Therefore, it may be relatively easy to choose antibiotics in clinical. But it worth remembering that, although carbapenems and other antibiotics still maintain their high antibacterial activity, but carbapenem resistant strains have been reported to be on the rise[34] and rational use of antimicrobial agents to prevent the emergence of drug-resistant strains is still imminent.
Acinetobacter baumannii showed a high level of resistance to almost all antibiotics include carbapenems(73.3%), which was similarity to the results of the most studies from EU[35], while the resistant rate of carbapenems in Switzerland was 11%. Therefore, the treatment of acinetobacter baumannii resistant strains is still facing great difficulties, patients with acinetobacter baumannii bloodstream infections has accepted more invasive operation, mechanical ventilation, and a variety of history of antibiotic treatment after admission which has caused MDR bacterial infection with high mortality, clinician should pay more attention to identification the high-risk patients and began to activity treatment in time in order to reduce the risk of death. In addition, tigecycline and colistin maybe as a good choice for BSI caused by Acinetobacter baumannii, especially the resistance to colistin was rarely reported[36].
There was a good drug susceptibility to most antibiotics for Pseudomonas aeruginosa include Piperacillin/tazobactam, ciprofloxacin, levofloxacin, cephalosporin and carbapenems, almost all resistant rates was about 20% except the carbapenems(27.8%), the increasing resistant rate of carbapenems may be related to the wide application of carbapenems in clinic in recent years which has caused the metalloenzyme. Therefore, although the drug resistance of pseudomonas aeruginosa is optimistic at present, but attention still should be paid to the rational use of antibiotics and avoid exacerbating the resistance situation.
The crude mortality of gram-negative BSIs and the mortality of Escherichia coli, Acinetobacter baumannii, and Pseudomonas aeruginosa have shown a significant downward trend from 2010 to 2018. One possible reason might be that the number, correct timing and accuracy of blood cultures were all greater in a tertiary-care hospital thus medical workers could more correctly choose antibiotics in a timely manner and even choose a combination of cephalosporins and carbapenems to treatment infection in appropriately, and also as a reason to explain why acinetobacter baumannii bloodstream infection have a serious resistance situation but the mortality rate was reducing. Further, the use of high grade antibiotics such as carbapenems was restricted in non-tertiary hospitals. Another reason might be that tertiary-care hospitals have more complete strategy for strict control of infection that can reduce the mortality factors in BSIs. The mortality in the ICU has shown a decreased trend, while the general ward without obvious change, and the mortality was lower than other studies[37, 38, 39]. This could be explained by combinations regimens including at least 2 antibiotics have been associated with reduced mortality in comparison with the use of only one antibiotic, especially when the combination includes the carbapenems, which was used as a common treatment regimen in our ICU. Another important reason was the management of critically ill patients in the ICU that We optimize the antimicrobial doses and ways of administration according to the antibiotic instructions in order to achieve and maintain optimal plasmatic concentrations. besides, the diagnosis and treatment technologies of ICU such as ventilator and ECMO have been rapidly developing rapidly in our hospital over recent five years, and a variety of positive treatment measures have shown effective to improve cure rate and reduce mortality. Some other reasons that highlighted the importance of infection control measures among the medical staff of ICU are strict aseptic operations, good hand hygiene and similar. On the contrary, the mortality in the general ward without obvious change, the possible reason might be that the reason of bloodstream infection for the general ward was the use of indwelling central intravenous catheter because of chemotherapy and venous nutrition employed, while the main bacterial of these patients were gram-positive bacterial, and the incidence of gram-negative bacterial bloodstream infection was relatively low. In addition, the patients in general ward with lightly ill and the most of these patients were cured even if with the bloodstream infection thus maintain the mortality without obvious change.
There are several limitations in the present study that should be considered. First, the collection of clinical data depended on medical records rather than interviews and the comprehensive assessment of clinical symptoms. Second, there was an inevitable bias this was a single-centre study, and some of the results might have been affected by the small sample size. Finally, many drug susceptibility results could not be evaluated because of a lack of unified standards also and not all isolates underwent the same antimicrobial agent sensitivity tests, so many isolates lacked resistance comparisons with other isolates in the present study.