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Recent Insights in Understanding the Clinical Impact and Burden of Carbapenem-Resistant Enterobacteriaceae



A population-based study from seven US geographical areas found that urine (87%) was the predominant source of CRE, followed by blood (11.4%).10 Over half of hospitalized patients were discharged to a long-term care facility, and the incidence of CRE varied widely across regions. Similar to these findings, a prospective, multicenter observational study of carbapenem-resistant K. pneumoniae reported that urine culture (63%) was the predominant positive culture site, followed by respiratory culture (12%), wound culture (11%), and blood culture (10%).11
The majority of patients were admitted from a long-term care facility, and most (47%) were discharged to skilled nursing facilities. Gupta and colleagues reported similar findings from the BD database, as the top three sources of carbapenem-resistant E. coli, K. pneumoniae, and P. mirabilis were urine (64.2%), skin (16.7%), and respiratory cultures (9.4%), and 54% (n=3,100) of carbapenem-resistant isolates were recovered in the ambulatory setting.7


Antibiotic resistance in gram-negative infections is associated with an increased severity of illness, higher mortality, longer hospital and ICU length of stays, and increased costs.12,13 A review and meta-analysis of nine studies involving 985 patients (with most infections caused by K. pneumoniae) determined the rate of CRE-attributable deaths to range from 26% to 44%.14 More recent observational studies indicate mortality rates of 40% to 60% in patients with bacteremia due to carbapenemase-producing Enterobacteriaceae.15
In patients hospitalized with a urinary tract infection (UTI), pneumonia, or sepsis, inappropriate empiric therapy (IET) was significantly higher for patients with CRE compared with carbapenem-susceptible Enterobacteriaceae (CSE) (52.8% vs 11.1%; P <.001), with resistance being the strongest predictor IET. Hospital mortality was significantly higher for patients with CRE compared with CSE (14.5% vs 10.2%; P <.001), with UTIs encompassing the majority of infections.16
To identify patients at high risk of mortality, with the goal of optimizing early therapy, a predictive mortality model for patients with bloodstream infections due to CRE was constructed and validated. A classification of low (score, 0-8), intermediate (score, 9-13), and high (score, 14-17) mortality risks was developed, with corresponding mortality rates of approximately 18%, 50%, and 80%, respectively. Selected predictors included presence of severe sepsis or septic shock, Pitt score >6, Charlson comorbidity index >2, source of blood stream infection other than urinary or biliary tract, and inappropriate early targeted therapy.15


The impact of antimicrobial resistance on healthcare and societal costs is substantial. Bartsch and colleagues developed a clinical and economic model to determine the annual cost of CRE infection in the United States. Cost and health effects were determined from the hospital, third-party payer, and societal perspectives. The average cost of a single CRE infection from the hospital and thirdparty payer perspectives was $29,157 (95% Credibility Range (CR), $22,993-$35,503) and $15,647 (95% CR, $13,701-$18,286), respectively. Societal perspective cost varied with attributable mortality, ranging from $58,692 (95% CR, $32,155-$169,153) to $86,940 (95% CR, $43,961- $256,870).
Assuming 9,418 annual CRE infections in the United States (2.93/100,000 patients, similar to 2013 CDC data), an attributable mortality of 26% would result in a cost of $275 million (95% CR, $217-$334 million), $147 million (95% CR, $129-$172 million), and $553 million (95% CR, $303-$1,593 million) for hospitals, third-party payers, and society, respectively. Because the incidence of CRE infections in the United States is largely underestimated, the authors predicted annual costs for incidences 15 infections per 100,000 patients, with an estimated cost of up to $1.406 billion (95% CR, $1.109-$1.712 billion), $754 million (95% CR, $661-$882 million), and $2.830 billion (95% CR, $1.550-$8.155 billion) for hospitals, third-party payers, and society, respectively.17

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