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The emergence and spread of CTX-M-type ESBLs and KPC-type carbapenemases are the two major developments in β-lactam resistance that have taken place in the last decade. CTX-M-type ESBLs became the predominant ESBLs in E. coli in many parts of the world by the early 2000s . Although they were initially considered to be rare, recent reports indicate that CTX-M-type ESBLs are becoming more common in the USA as well, especially in E. coli . KPC-type carbapenemases rapidly spread among K. pneumoniae strains, which have caused nosocomial outbreaks in hospitals throughout the east coast of the USA . Studies from the USA that have addressed the clinical characteristics of bacteraemia caused by ESBL-producing Enterobacteriaceae were conducted either before the advent of these newer β-lactamases or without molecular characterization [2,11]. The present study was thus undertaken to identify the clinical features of bacteraemia caused by ESBL-producing and KPC-producing Enterobacteriaceae in a contemporary cohort of patients from tertiary hospitals in the northeastern USA.
Our results indicate that CTX-M-type ESBLs are now common among bacteraemic isolates of Enterobactericeae in this geographical area. Among E. coli, the majority had this group of ESBLs. About half of them had CTX-M-15, which is increasingly recognized as the most common CTX-M-type ESBL in many parts of the world , but the CTX-M-2 and CTX-M-9 groups, which are known to predominate in South America and Spain, respectively, were also present . SHV-type and TEM-type ESBLs constituted the rest, although they were much less common than CTX-M-type ESBLs. This trend was also reported in a recent study of ESBL-producing E. coli conducted in Philadelphia . Taking these findings together, we may assume that CTX-M-type ESBLs are now prevalent in this species in the northeastern USA. In Klebsiella spp. and Enterobacter spp., SHV was still the most common ESBL type, but CTX-M-type ESBLs were also present in both organisms. All 20 KPC-producing organisms were from the study site in New York City, where they are known to be endemic .
The 28-day mortality rate of patients with bacteraemia caused by organisms producing ESBL or KPC was significantly higher, at 29.1%, than in the control group, at 19.5%. This is in line with the results of a recent meta-analysis that pooled data from 16 studies and showed a significantly increased mortality rate for ESBL-associated bacteraemia . The subset of patients with KPC-producing K. pneumoniae in our study had an even higher mortality rate, at 47.4%, as opposed to 27.5% for those with ESBL-producing K. pneumoniae. Although the difference was not statistically significant, probably because of the relatively small number of patients, our data strengthen the previously reported association between KPC-producing K. pneumoniae bacteraemia and increased mortality .
The independent risk factors for ESBL-associated bacteraemia included recent antibiotic use, admission from a nursing home, length of hospital stay prior to infection, chronic renal failure, presence of a gastrostomy tube, and history of transplant. Recent antibiotic use has been pointed out as an independent risk factor in multiple studies that have investigated ESBL-associated bacteraemia [11,15–18]. Admission from a nursing home has also been identified as a risk factor for ESBL production in several studies investigating bacteraemia [19–21]. The presence of a gastrostomy tube has been associated with acquisition of ESBL-producing organisms among nursing home residents [22,23], whereas chronic renal failure has not been associated with acquisition of ESBL-producing organisms.
Independent risk factors for mortality in the ESBL group included higher Apache II score at the time of positive blood culture and inappropriate empirical therapy. The association of higher Apache II score with increased mortality is not surprising and this was an independent risk factor for mortality in control cases as well. Inappropriate empirical therapy, defined by the use of antibiotic(s) that lack in vitro activity against the causative organism, has been identified as independent risk factor for death in ESBL-associated bacteraemia in several studies [24,25]. We may therefore speculate that the significantly increased mortality with inappropriate empirical therapy, which occurred more frequently in the ESBL and KPC groups than in the control group, contributed to the excess mortality.
Our study has several limitations. First, we analysed ESBL-producing Enterobacteriaceae together, not by species. The selection of controls to be in the same proportions by species as the cases helped to address some of the potential bias arising from this. Second, our analysis of the KPC cases was limited, owing to the relatively small number of cases. Finally, we were not able to associate types of ESBL with clinical attributes, because of their heterogeneity.
In conclusion, mortality associated with bacteraemia caused by ESBL-producing or KPC-producing Enterobacteriaceae continues to be high, despite improved detection in the clinical laboratory. CTX-M-type ESBLs are now common in E. coli and are also present in other species in the northeastern USA. The frequent occurrence of delay in appropriate therapy probably contributes to the excess mortality. The use of antimicrobials with activity against ESBL-producing organisms, such as carbapenems, is generally accepted as appropriate in unwell patients with risk factors. However, the advent of K. pneumoniae producing KPC-type carbapenemase further complicates this issue.