Carbapenem resistance: advice from the frontline

Ann Griswold

August 2015—The problem of carbapenem resistance first made its way to Detroit’s Henry Ford Hospital in 2007, when a multidrug-resistant organism appeared in a sputum sample from the intensive care unit. Within weeks, several other cases emerged.

“At that time, we had a brand-new physician in charge of infection control. So I contacted him and was sort of like, ‘Houston, I think we have a problem,’” recalls Eileen Burd, PhD, D(ABMM), Henry Ford’s clinical microbiology laboratory director at the time. “And he said, ‘Yes, I think we do.’”

“Just trying to get it contained was a major challenge,” says Dr. Burd, who soon after the outbreak left Detroit for Atlanta, where she is now director of clinical microbiology at Emory University Hospital and associate professor, Emory University School of Medicine.

Henry Ford wasn’t alone with its cluster of difficult cases. That year, the National Healthcare Safety Network reported new findings in a disturbing trend: Nearly four percent of Escherichia coli isolates and 10.8 percent of Klebsiella pneumoniae isolates from device-associated infections were carbapenem resistant.

Some warned it was only a matter of time before plasmid-borne carbapenemases would appear in other health-care–associated pathogens.

By many accounts, that time has come.

Carbapenem-resistant Enterobacteriaceae (CRE) now pose a serious threat to hospitalized patients in the United States and around the world, and the Centers for Disease Control and Prevention is monitoring the emergence of carbapenemases in superbugs such as Pseudomonas aeruginosa.

As of January of this year, all states except Idaho and Maine had reported to the CDC Klebsiella pneumoniae carbapenemase (KPC)-producing CRE. The New Delhi Metallo-beta-lactamase (NDM) has been reported in 22 states, while 13 states have reported the class D β-lactamase OXA-48. Five states have reported CRE harboring the Verona Integron-Mediated Metallo-β-lactamase, or VIM. Then there are noncarbapenemase-producing CREs, which rely on chromosomally encoded resistance mechanisms that are not readily spread.

“Carbapenem resistance is really of global concern. Not just in the United States, and not just in hospitals and health care facilities, but in communities as well,” says Dr. Burd, who convened a session on carbapenemases at the ASM annual meeting in May.

The question is: What should clinical laboratories do about it?

Answers to that question have evolved over time. In 2007, hospitals and clinical labs were coming to terms with the possibility that CRE might lurk on medical devices or linger in long-term care units. Some institutions took a more aggressive approach to dealing with the organisms than others.

Dr. Burd, for one, arrived in Atlanta still reeling from the outbreak at Henry Ford, only to find that Emory had a carbapenem resistance problem of its own. To her astonishment, no one appeared to be alarmed.

“But I was,” Dr. Burd says. “I asked about it and they said, ‘Yeah, we’ve had this problem for a while.’ They were simply flagging these organisms as multidrug resistant so that proper precautions could be put in place to prevent spread.”

Though molecular technologies have advanced considerably since those early years, clinical laboratories continue to question how best to formulate a plan for detecting CRE, and what to do when they find them.

The Association of Public Health Laboratories recently surveyed CRE capabilities and capacities in public health labs and found that about 50 percent of the respondents had an active CRE surveillance program in place.

Certain procedures should be in place in 100 percent of clinical labs, no matter their size, says Jean Patel, PhD, D(ABMM), deputy director of the Office of Antimicrobial Resistance for the CDC’s National Center for Emerging Zoonotic and Infectious Diseases. “The critical components for any laboratory include antimicrobial susceptibility testing methods that use the most up-to-date breakpoints, identification of a referral laboratory to which they can send problem isolates for further characterization if needed, a good relationship with the hospital infection control program, and a plan for responding to critical antimicrobial-resistant pathogens like CRE.”

That response plan, Dr. Patel says, should be consistent with the CDC’s CRE toolkit, which outlines how an institution should respond to a CRE infection (www.cdc.gov/hai/organisms/cre/cre-toolkit). The toolkit recommends that infection control programs and laboratories begin by identifying patients colonized with the organisms.

“That requires specialized testing that most laboratories don’t receive financial support for,” Dr. Patel acknowledges. “At the same time, that’s the kind of testing a hospital needs to do to control antimicrobial resistance in their institution. There needs to be an institutional decision to support that.”

Despite the toolkit’s recommendation, screening practices have been slow to catch on in some areas. Particularly for laboratories with limited resources, the decision to screen patients, and how extensively, is determined by the hospital’s location and the endemicity of CREs in that area. “Many hospitals don’t have much of a problem with CREs. Some hospitals have too much of a problem,” says Robert Bonomo, MD, chief of the medical service at the Louis Stokes Cleveland Department of Veterans Affairs Medical Center and vice chairman of the Department of Medicine at University Hospitals Case Medical Center, Case Western Reserve University School of Medicine.

Others argue that without screening data, endemicity can be tricky to measure. “If labs do not screen, of course there is no problem,” says Laurent Poirel, PhD, an associate professor in the medical and molecular microbiology unit at the University of Fribourg in Switzerland. “As long as there is not a big outbreak causing lots of deaths.”

“Clearly we need to screen patients to see if they are colonized, and not wait until we have infections caused by multidrug-resistant isolates,” Dr. Poirel says. “We must consider that for every patient infected, we may have something like 10 patients colonized. We should consider those colonized patients very seriously and implement contact precautions.”

Though universal screening is ideal, it may not be practical in the United States, Dr. Bonomo counters. “I’ve learned a couple things over the years, and usually Laurent [Poirel] is right. There are some places in the U.S. that aren’t aggressively screening and we’re probably not detecting as many CRE as we could. But here in the U.S., we have to balance the need for comprehensive screening with economics. Health care is really expensive.”

Valid points are made on both sides of the debate, Dr. Patel says: “I think the truth lies somewhere in between. There have been strenuous educational efforts on helping laboratories to detect CRE, and I think many laboratories have risen to the occasion and either implemented the revised Clinical and Laboratory Standards Institute breakpoints on their own, or implemented other kinds of testing that would help with CRE detection, like a carbapenemase test. But there are always going to be those hospitals that struggle with this. And we’re being naïve if we don’t think there are hospitals out there that are still using the old breakpoints and missing CRE.”

Targeting the screening efforts can stretch limited resources, Dr. Bonomo suggests. Those at highest risk of CRE infection—patients who have been infected or colonized with KPC in the past or treated with antibiotics, patients who have been treated with antibiotics at a long-term care facility, and some surgical patients—should be the highest priority for screening efforts, he says.

Soon after Dr. Burd arrived at Emory, her laboratory supported an effort to screen all new admissions to the hospital’s long-term care facilities and to follow them with weekly screening. “We screened for several months until we weren’t seeing any new cases and the screens were no longer cost-effective,” Dr. Burd says. Now, she estimates, the hospital sees two or three carbapenem-resistant Enterobacteriaceae infections each month.

When it comes to detecting CRE, deciding which antimicrobial susceptibility testing methods to use—molecular or microbiological—is as important as pinpointing which population to screen. Molecular methods are rapid but costly. Conventional AST can provide definitive data to inform treatment decisions but may take days to yield results.

“There are all these efforts to develop new tests that can get that answer to the clinician much faster,” Dr. Patel says. “And one of the debates is whether we need to focus on molecular methods or whether we should focus on phenotypic methods.” She herself thinks the focus should be phenotypic susceptibility methods “because that’s going to get you to the right answer and hopefully new technologies will make phenotypic testing as fast as molecular methods.”

“I worry that molecular methods are only going to give you part of the answer and we will still be waiting for the definitive information,” she says.

In the microbiology laboratory at Emory University Hospital, a standard identification susceptibility system (MicroScan Walkaway Plus) is used as a first step toward detecting CRE. “When there’s a carbapenem-resistant organism,” Dr. Burd says, “we use the Modified Hodge test to confirm.” Positive organisms are flagged in the computer to alert infection prevention staff and nurses on the floor to take proper precautions.