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Healthcare-driven Antibiotic Resistance Evolution: CRE – An Example in Action

Antimicrobial stewardship programs (ASPs) focus on slowing the emergence of antibiotic resistant pathogens in healthcare environments. The rapid rise of many multidrug resistant organisms (MDROs) makes effective ASPs essential to the preservation of the efficacy of the antimicrobial agents we currently have, particularly in light of a diminished pipeline for new classes of antibiotics. But how do hospital environments drive the emergence of MDROs and how quickly does such resistance develop? Can hospital-based interventions reduce infections with MDROs?

The example of carbapenem-resistant Enterobacteriaceae (CRE) may provide a deeper understanding of the interaction between hospital environments, infection prevention, antimicrobial stewardship and MDROs. CRE has emerged as a rapidly spreading and deadly pathogen, killing up to 50% of those who develop severe infections.1

Hospitals and physicians reserved the most powerful antibiotics for the most serious cases, hoping that limited use would extend the efficacy of agents such as vancomycin and carbapenems. And, to some extent, this application of antimicrobial stewardship worked. Resistance to vancomycin took nearly 30 years to develop.2

From isolated case to urgent national threat

In 2000, researchers in the CDC’s Intensive Care Antimicrobial Resistance Epidemiology (ICARE) program found that a sample of Klebsiella pneumoniae had resistance to carbapenem.

In 2003, a surveillance program at The State University of New York (SUNY) Downstate Medical Center in Brooklyn identified several cases of carbapenem-resistant K. pneumoniae over the previous six years in data from its microbiology laboratory.

Shortly afterward, the number of cases detected in New York hospitals ballooned. Hospitals across the city saw patients with KPC infections in a matter of months and one case showed resistance to every known drug.

By 2007, carbapenem-resistance had spread to other bacteria as well. In a study that year, one-third of Acinetobacter baumannii isolates in the U.S. showed such resistance. Carbapenem-resistant K. oxytoca and Escherichia coli had also been reported in U.S. hospitals.3

By 2011, U.S. hospitals saw patients with Klebsiella and other common Enterobacteriaceae infections, including E. coli, that had carbapenem-resistance conferred by the NDM enzyme.

Within two years, the Centers for Disease Control and Prevention (CDC) classified CRE as an urgent threat, noting that more than 9,000 patients in the U.S. had contracted either carbapenem-resistant Klebsiella spp. or carbapenem-resistant E. coli.4 In the UK, the country’s top medical officer called CREs as serious a risk as terrorism.5

How CRE spreads

Why did CRE spread so quickly within healthcare settings? First, patients that develop diarrhea can easily contaminate equipment, the hospital room environment and the hands of healthcare workers. Second, the infection may go undetected, either because the patient is asymptomatic or because automated, rapid microbiology tests may give “misleading results and [cause] physicians to give patients doses or drugs that would not work,”2 allowing the strain to spread.

Detection is further complicated by the genomic variety of enzymes that confer carbapenem resistance. Nearly 1000 resistance-related beta-lactamases have been discovered so far, though, fortunately, most have not appeared in clinical settings.6

Halting the rise in CRE

It is possible to control outbreaks and reduce rates of CRE infection, but not currently through pharmacotherapy. Three drugs are used to treat CRE infections, often in combination: tigecycline, gentamicin and colistin (polymyxin E). Efficacy is low, whether the drugs are used as monotherapy or in combination, with mortality ranging from 57%-80%.7

Stringent infection prevention programs have produced the best results. Israel’s response to a CRE outbreak shows the potential effect of infection prevention efforts.

Israel saw its first case of KPC infection in 2005. In 15 months, the country had 1,275 cases and a monthly incidence of 55.5 cases per 100,000 patient days. National guidelines were introduced: isolation in self-contained nursing units of hospitalized CRE carriers and infected patients, dedicated staffing, mandated daily reporting of new laboratory-confirmed CRE infections and carriers, and oversight by a national task force. A year later, the monthly incidence rate had dropped by 80% to 11.7 cases per 100,000 patient days.

In the U.S., CRE has now been identified in every state except Idaho and Maine. There is no federal mandate to require reporting of CRE infections, but based on the available information, the CDC estimates that the prevalence of carbapenem-resistant K. pneumoniae rose 700% between 2003 and 2013.1

To prevent and control CRE, the CDC recommends all acute and long-term care facilities promote and monitor handwashing, implement contact precautions for infected and colonized patients and those transferred from high-risk settings, educate healthcare personnel about the importance of contact precautions with these patients, and develop protocols for alerts from labs when CRE infections are confirmed. In addition, hospitals are advised to isolate colonized or infected patients and dedicate staff to their care to minimize transmission, minimize the use of invasive devices, and promote antimicrobial stewardship.8

The CDC also recommends screening patients with epidemiologic links to unrecognized CRE colonized or infected patients and to conduct point prevalence surveys of units containing unrecognized CRE patients. As supplemental steps, facilities may screen high-risk patients and those transferred from facilities that have CRE at admissions and occasionally during their stay and bathe patients with a 2% chlorhexidine solution, particularly when CRE transmission persists. They should also notify local or regional health departments as CRE often spreads between facilities.

What are the most effective practices that your hospital has implemented to prevent CRE?

  1. Patients Face More Lethal Infections from CRE. CDC Features. Last updated: February 20, 2015. Accessed August 13, 2015.

  2. McKenna M. Antibiotic resistance: The last resort. Nature. 24 July 2013.

  3. Infection Control and Hospital Epidemiology. November 2008;29(11): -1011

  4. Antibiotic/Antimicrobial Resistance: Urgent Threats. Last updated September 16, 2013. Accessed August 13, 2015.

  5. Davies S. Annual report of the Chief Medical Officer 2011: volume two. Gov.UK Accessed August 13, 2015.

  6. Davies J, Davies D. Origins and Evolution of Antibiotic Resistance.Microbiology and Molecular Biology Reviews?: MMBR. 2010;74(3):417-433. doi:10.1128/MMBR.00016-10.

  7. Falagas ME, Lourida P, Poulikakos P, Rafailidis PI, Tansarli GS. Antibiotic
    treatment of infections due to carbapenem-resistant Enterobacteriaceae:
    systematic evaluation of the available evidence. Antimicrob Agents Chemother.
    2014;58(2):654-63. doi: 10.1128/AAC.01222-13. Epub 2013 Sep 30. Review. PubMed
    PMID: 24080646; PubMed Central PMCID: PMC3910850.

  8. 2012 CRE Toolkit–Guidance for Control of Carbapenem-resistant Enterobacteriaceae (CRE). Part 1: Facility-level CRE Prevention. Accessed August 12, 2015.

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