Since 2000, there has been an increase in the rate of carbapenem- resistant Enterobacteriaceae (CRE) in the United States (US). CRE are resistant to a majority of first and second-line antibiotics, sometimes forcing healthcare providers to use last-line therapies that are often toxic, poorly efficacious, or both.
There has been a steady increase in CRE prevalence, with emergence due, in part, to increased use of carbapenems for the treatment of infections caused by extended spectrum ß-lactamase—producing Enterobacteriaceae.1,2 By 2011, the percentage of Enterobacteriaceae that was not susceptible to at least one carbapenem had risen to 4.2%, with the greatest increase observed among Klebsiella pneumoniae (1.6 to 10.4%).3 The most widely disseminated CRE in the United States are Klebsiella pneumoniae carbapenemase (KPC) producers whereas metallo-ß-lactamase producers remain localized and are often associated with outbreaks.4
In 2013, the Centers for Disease Control and Prevention (CDC) characterized CRE as an urgent threat to public health. Although the CDC cited 9000 infections caused by CRE in the United States annually, and 600 deaths, there was acknowledgement that this assessment is likely an underestimate. These estimates were derived from healthcare-associated infections (HAIs) reported as part of a 2011 Emerging Infections Program (EIP) survey of 11,282 patients in 10 states. Estimates of carbapenem resistance were derived from the National Healthcare Safety Network to predict the number of HAIs due to CRE. Infections occurring outside of acute care hospitals (ACHs) or diagnosed after discharge, as well as infections caused by Enterobacteriaceae other than Klebsiella spp. and Escherichia coli, were not included in this analysis.5
A report by Reuters indicated that due to the small sample size of the EIP survey and the methodology utilized for the 2013 report, the actual estimate of annual death from CRE could be up to twice the current estimate. Upon further collaboration and investigation with the CDC’s National Center for Health Statistics’ Division of Vital Statistics, Reuters predicted that more than 180,000 annual deaths are due to drug-resistant infections overall, compared with the original CDC estimate of 23,000. This new prediction may also be an underestimate due to lack of documentation on death certificates and lack of a unified surveillance system for drug-resistant infections.5,6
A recent estimate of the national prevalence of CRE infections in both the acute care and ambulatory settings was reported at IDWeek 2016 in New Orleans, using a Becton Dickinson & Company (BD) database. Susceptibility data from nonduplicate E. coli, K. pneumoniae, and Proteus mirabilis isolates were reported from 348 hospitals in the United States over one year (2015-2016) and statistical methods were applied to estimate national prevalence.
Although the rate of CRE in this report was 0.7%, the rate ranged from 0.5% in the ambulatory setting to 1.9% in the hospital-onset period. The estimated national prevalence of CRE infections was 53,724, almost 6 times greater than the CDC estimate, and 57% of cases occurred in the ambulatory setting.7 To add to the mounting evidence of CRE in the ambulatory setting, a regional antibiogram from Los Angeles County encompassing 61 acute-care hospitals (ACH) and 9 long-term acute care (LTAC) hospitals determined the incidences of carbapenem-resistant Klebsiella spp. to be approximately 21% and 71% in ACH and LTACs, respectively.8 Despite these reports, the true prevalence of CRE in the United States might be higher due to a lack of implementation of the 2010 revised Clinical Laboratory Standards Institute breakpoints for carbapenems and Enterobacteriaceae.9
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
New therapies with reliable activity against CRE are urgently needed, as clinicians have increasingly been forced to use such agents as polymyxins and tigecycline, which have efficacy and safety concerns. Increased use of both has, in turn, led to the emergence of resistance to these last-line agents. Colistin-resistant KPC-producing K. pneumoniae strains are now widely disseminated in some endemic countries.18,19,20,21 In a surveillance study of K. pneumoniae isolates collected in 18 US hospitals between 2011 and 2013, 46% of carbapenemresistant strains were not susceptible to tigecycline and receipt of tigecycline was an independent risk factor for nonsusceptibility to tigecycline.22 More recently, resistance to ceftazidime-avibactam, a newly approved agent with in vitro activity against CRE, was reported to emerge following ceftazidime-avibactam treatment in 30% (3/10) patients with CRE experiencing recurrent infections.23 The emergence of resistance to these antibiotics reinforces the need for additional agents and treatment strategies for CRE infection.
Although agents for CRE infection are urgently needed, the study of such patients under traditional antibacterial-development programs is challenging due to limited patient numbers, evolving epidemiology, competition for clinical trials, and the complex medical nature of patients with CRE. Many companies have shifted away from developing antimicrobials due to hurdles that render antibiotic development less attractive compared with more lucrative therapeutic areas. However, recently, certain incentives, like the Generating Antibiotic Incentives Now act have been put into place to attempt to reinvigorate the pipeline.
CARB-X (Xccelerating global antibacterial innovation), the world’s largest global antibacterial public—private partnership to combat antibioticresistant bacteria, was formed in July 2016 in response to the 2015 US National Action Plan on Combating Antibiotic-Resistant Bacteria (CARB). In its first year, the CARB-X portfolio will largely focus on therapeutics to treat gram-negative bacteria, including CRE.24 The Figure25,26 lists antibiotics currently in phase 2 or 3 development that have activity against CRE.
Figure. Antibiotics Currently in Clinical Development 25,26
PIPELINE AGENT (COMPANY)
Aztreonam + avibactam (AstraZeneca PLC/Allergan PLC [formerly Actavis])
Monobactam + novel beta-lactamase inhibitor
Complicated intra-abdominal infections
Fosfomycin (IV) (Zavante Therapeutics)
Complicated urinary tract infections, including acute pyelonephritis
Health care-associated pneumonia, bloodstream infections, hospital- acquired bacterial pneumonia/ventilator-associated bacterial pneumonia, complicated urinary tract infections
Imipenem/cilastatin + relebactam
(Merck & Co, Inc)
Carbapenem + novel beta-lactamase inhibitor
Complicated urinary tract infections, including acute pyelonephritis; complicated intra-abdominal infections; hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia
Carbapenem + novel
Complicated urinary tract infections, complicated intra-abdominal
Vaborbactam (Rempex Pharmaceuticals,
Inc, a wholly owned subsidiary of The Medicines Company)
boronic beta-lactamase inhibitor
infections, hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia, febrile neutropenia, bacteremia, acute carbapenem-resistant Enterobacteriaceae)
pyelonephritis (some indications specifically target infections caused by
Eravacycline (Tetraphase Pharmaceuticals, Inc)
Complicated intra-abdominal infections, complicated urinary tract infections
Plazomicin (Achaogen, Inc)
Complicated urinary tract infections, including acute pyelonephritis; bloodstream infections; hospital-acquired bacterial pneumonia/ventilator- associated bacterial pneumonia, in patients with limited treatment options (some indications specifically target infections caused by carbapenem- resistant Enterobacteriaceae)
The authors acknowledge John Mohr, PharmD, and Katie Luepke, PharmD, BCPS, for their contributions in developing this manuscript.
Keith Kaye, MD, MPH, is an infectious diseases physician and professor of internal medicine at the University of Michigan Medical School, where he is the director of clinical research in the Division of Infectious Diseases. He is the current vice president for the Society for Healthcare Epidemiology of America.
Lynn Connolly, MD, PhD, is an infectious diseases physician and assistant clinical professor of Medicine at the University of California in San Francisco. She is the senior medical director and head of late development at Achaogen.
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17. Bartsch SM, McKinnell JA, Mueller LE, et al. Potential economic burden of carbapenem-resistant Enterobacteriaceae (CRE) in the United States. Clin Microbiol Infect. 2016. pii: S1198-743X(16)30389-5.
18. Monaco M, Giani T, Raffone M, et al. Colistin resistance superimposed to endemic carbapenem-resistant Klebsiella pneumoniae: a rapidly evolving problem in Italy, November 2013 to April 2014. Euro Surveill. 2014;19(42):pii:20939.
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20. Tumbarello M, Viale P, Bassetti M, De Rosa FG, Spanu T, Viscoli C. Infections caused by KPC-producing Klebsiella pneumoniae: differences in therapy and mortality in a multicentre study--authors’ response. J Antimicrob Chemother. 2015;70(10):2922.
21. Meletis G, Oustas E, Botziori C, Kakasi E, Koteli A. Containment of carbapenem resistance rates of Klebsiella pneumoniae and Acinetobacter baumannii in a Greek hospital with a concomitant increase in colistin, gentamicin and tigecycline resistance. New Microbiol. 2015;38(3):417-421.
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23. Shields RK, Potoski BA, Haidar G, et al. Clinical outcomes, drug toxicity and emergence of ceftazidime-avibactam resistance among patients treated for carbapenem-resistant Enterobacteriaceae infections. Clin Infect Dis. 2016. pii:ciw636.
24. CARB-X Xccelerating global antibacterial innovation website. www.carb-x.org. Accessed November 2, 2016.
25. Antibiotics currently in clinical development. The Pew Charitable Trusts website. www.pewtrusts.org/~/media/assets/2016/05/ antibiotics-currently-in-clinical-development.pdf. Updated May 2016. Accessed November 4, 2016.
26. Zavante Therapeutics. Safety and efficacy of ZTI-01 (IV fosfomycin) vs piperacillin/tazobactam for treatment cUTI/AP infections (ZEUS). Clinicaltrials.gov website. https://clinicaltrials.gov/ct2/show/ NCT02753946. Verified October 2016. Accessed November 1, 2016.