The CRE Path: Easily Resisted to Hard to Kill

20. March 2015

Carbapenem-resistance in Gram-negative bacilli limits antibiotic choice for lethal infections. With carbapenem-resistant Enterobacteriaceae (CRE) increasing globally, enhancements are desperately needed in understanding, prevention, and control.

Carbapenems: The last line of defense

As the world eagerly awaits the release of the two distinct volumes in the 19th edition of Harrison’s Principles of Internal Medicine, we pause to reflect on quite a different story from a time not too long ago, how carbapenems were characterized in the chapter on Infectious Diseases from Harrison’s 15th edition released in 2001. In the section titled “Approach to Therapy for Bacterial Diseases,” Gordon L. Archer, M.D., now Professor of Medicine at The University of Virginia and Ronald E. Polk, PharmD, FIDSA, FSHEA, now Emeritus Professor, School of Pharmacy and Affiliate Professor of Medicine at Virginia Commonwealth University, stated that:

“Resistance to imipenem and meropenem [Note: Carbapenems available in the U.S. at the time] is a problem only among nosocomial isolates of P. aeruginosa, approximately 20% of which are resistant. Because of their broad spectrum, carbapenems can be used as empirical therapy for serious nosocomial infections thought to be caused by multiple bacterial species or multiresistant organisms. Imipenem and meropenem are often used to treat hospital-acquired infections caused by Enterobacter spp. because these organisms produce inducible β-lactamases that inactivate third-generation cephalosporins but not the carbapenems. The latter antibiotics are often held in reserve as therapy for nosocomial infections due to gram-negative pathogens resistant to third-generation cephalosporins.”

At the time of their writing, Archer and Polk would have known that Robert P. Gaynes, M.D. and David H. Culver, M.D., using data from the National Nosocomial Infection Surveillance (NNIS) system from 1986 to 1990, found through their research that only 2.3% of 1825 Enterobacter isolates tested non-susceptible to imipenem. Archer and Polk wouldn’t have known that the first report of a carbapenem-resistant Klebsiella pneumonia was already well underway; it suggested that “the carbapenem resistance phenotype of the strain is mainly caused by the production of a novel class A β-lactamase, KPC-1.” The origins of the strain though dated from several years earlier; CRE had been isolated from a North Carolina intensive care unit as part of the Intensive Care Antimicrobial Resistance Epidemiology (ICARE) project and remained unnoticed until 1996.

The natural habitat of Enterobacter

The genus Enterobacter is described as any of a group of rod-shaped bacteria of the family Enterobacteriaceae. It is named for the organisms’ propensity to reside in the intestines of animals (from Greek enteron: intestine). Enterobacter are Gram-negative facultative anaerobes, meaning that they can thrive in aerobic and anaerobic conditions. Infectious disease expert, Dr. Bill Miller, author of The Microcosm Within: Evolution and Extinction in the Hologenome, shared that “Enterobacteriaceae are a large family of bacteria that are part of the human microbiome. Many reside harmlessly in our gut flora and even function as symbionts.”

Ground zero for CRE resistance

Carbapenem resistant Enterobacteriaceae (CRE) develop by several mechanisms, including resistance genes coding for carbapenemase enzymes that can be shared between different Gram-negative bacteria. Enterobacteriaceae that possess these genes are sometimes referred to as carbapenemase-producing CRE (CP-CRE), and are particularly worrisome due to their near complete resistance to antibiotics and continued global spread. According to the CDC and ECDC, CRE infections occur most frequently in healthcare settings, particularly long-term acute care hospitals (LTACHs). The ECDC recognizes that CRE (and carbapenem-resistant Acinetobacter baumannii) are a healthcare threat throughout Europe, although the exact prevalence remains unknown. “CRE is definitely found more commonly in hospital settings and in those who have had more frequent hospital contact or been treated with prolonged or multiple courses of antibiotics,” said Dr. Fink. CRE infections most commonly occur among patients with significant healthcare exposures, co-morbid conditions, invasive devices, and those who have received extended courses of antibiotics. In most countries, patients that have had prior use of any antimicrobials, including carbapenems and other antimicrobials are also considered at risk. Strong evidence also suggests patient transfers within the same hospital, patient travel from countries with high rates to healthcare facilities in other countries, and receiving medical care abroad in areas with high rates collectively increase transmission.

Breaking “this vicious circle”

Notwithstanding the need for research and development of new antimicrobial agents with a novel mechanism of action to aid in the prevention and control of antimicrobial resistance, several actions need to be considered. Dr. Miller suggests,

“Awareness of the infection status within the facility is key. The facility must be tracking their infections such as based on multiple factors, such as demographics, sites within the hospital where infections such as this or exposures have occurred. There are also critical procedures that can be followed to influence the likelihood of having infections with CRE. These concentrate on staff education in topics such as appropriate procedures for laboratory notification, understanding proper methods of contact precautions if a patient is infected or colonized, enforcing rigorous hand washing protocols and hand hygiene, and minimizing usage of medical devices that can spread CRE. Infected patients and people that have come in contact with CRE need to be epidemiologically screened with appropriate cultures.”

One necessary action is the prudent use of antimicrobial agents when needed, at the correct dose, duration, and intervals. Researchers recently conducted a systematic evaluation of all available evidence via PubMed and Scopus databases and concluded that combination antibiotic treatment (e.g. employing multiple antibiotics with different core structures and mechanisms of action) may be considered an optimal option for immunocompromised patients with severe infections.

“How can we stop the transmission? We need to raise awareness and be diligent in our continued antibiotic stewardship to break this vicious circle,” said Dr. Fink.

For more information on infection prevention and control, ECDC has developed a directory of guidance on prevention and control of CRE, published by ECDC, EU/EEA Member States, international and national agencies and professional societies. The CDC has also developed a CRE Toolkit – Guidance for Control of Carbapenem-resistant Enterobacteriaceae.

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