Infection preventionists must hold the line as pan-resistant gram negatives spread

With no new drugs, every patient encounter is critical

By Gary Evans, Senior Managing Editor

The continuing global emergence of multidrug resistant gram negative pathogens — bugs that are virtually impervious to all antibiotics and can transfer resistance mechanisms between species — means infection prevention is more critical than ever during every patient encounter.

Ruth Carrico"Every time we badge-in we need to be thinking, 'Are we doing the best we can for our patients at every encounter, at every touch, to protect their safety?" says Ruth Carrico, PhD, RN, CIC, an infection preventionist and assistant professor of health promotion and behavioral sciences at the University of Louisville, KY. "This has upped the ante on how we approach our jobs and the high consequence activities we are involved in with our patients. We really have to bring that message home."

The rising tide of gram negative resistance includes the widespread emergence of "KPC," — carbapenem-resistant Klebsiella pneumoniae— and the continuing global emergence of the New Delhi metallo-beta-lactamase (NDM-1) enzyme. While more specific strategies are being discussed and recommended, the problem in a nutshell is that there are no new drugs for gram negative infections in the foreseeable future. With treatment options severely limited, routine infection control measures like contact precautions for known infected patients suddenly take on critical importance with every patient encounter. As always, transmission from undiagnosed or merely colonized patients remains a threat. Lapses in hand hygiene, appropriate gloving and environmental cleaning with one patient could result in an untreatable infection in another. It's that simple and it's no exaggeration: mortality rates with some of the gram negative infections are being reported in the 40% range.1

"We are confronted with the reality that we may have patients that will not survive simply because we don't have anything to treat them with," she says. "But in the 35 years I have been in health care I have never encountered a health care worker that didn't want the best outcomes for their patients. We all want the best outcomes, but sometimes we have to have our frame of reference rattled a bit."

"A terrible choice"

This appears to be one of those times. Thus IPs are being asked to hold the line, emphasizing that infection control measures with all patients are critical to stop the emergence of gram negative bacteria resistant to the last-line carbapenem class of antibiotics. Colistin, a powerful antibiotic with intravenous dosing regimens that may be complicated to administer, is the single drug available for some of these patients.

Andrew Pavia"We are using colistin right now, which is a terrible choice," says Andrew Pavia, MD, chief of the division of pediatric infectious diseases at the University of Utah Health Sciences Center and Primary Children's Hospital in Salt Lake City. "In the area of surveillance and infection control, we have the tools, but they are not really adequately funded. And we have to be very cognizant of these highly drug resistant strains spreading their mechanisms of resistance beyond the individual organism. That can really act as a multiplier effect."

To exactly that point, it was recently reported that strains of multidrug-resistant Klebsiella pneumoniae and Escherichia coli exchanged the NDM-1 enzyme within a patient who died of sepsis in Canada.2 Though the "direction" of the plasmid transfer could not be determined, the case was a sobering reminder that the gram negatives can transfer resistance mechanisms between species.

"Right now we are primarily talking about Klebsiella pneumoniae, which is not a huge, predominant pathogen," Pavia says. "If this starts to appear in typical urinary tract isolates of E. coli, then it's going to start popping up in neonatal infections, and then start cropping up in community-acquired infections. Potentially, it could spread quite widely throughout other gram negatives."

The situation is somewhat analogous to the transfer of vancomycin resistance from enterococci to Staphylococcus aureus, which did eventually result in the sporadic appearance of vancomycin-resistant S. aureus (VRSA). However, the much feared "superbug" VRSA has not proven to transmit effectively and remains something of an anomaly. Whether the gram negative situation will result in a highly resistant strain with easier transmissibility and more epidemiological consequence remains an open question. There always is a concern that one of these genetic transfers may lead to broad proliferation of a highly resistant pathogen.

"It's jumping species," says Michael Mulvey, MD, chief of antimicrobial resistance and nosocomial Infections at the National Microbiology Laboratory of the Public Health Agency of Canada, and lead author in the aforementioned case.2 "It seems to be a highly mobile plasmid."

Putting it in perspective

While NDM — with its exotic origins in travelers from India and Pakistan — has captured press attention, KPC presents similar infection prevention challenges with a critical difference: it's already here.

"They are virtually in every hospital in this country, whereas there have been just a few reports of NDM-1 in the United States," says Robert Rapp, PharmD, professor of pharmacy at the University of Kentucky Chandler Medical Center. "At least, for now in the U.S., KPCs are a much more significant and immediate problem than NDM-1."

Rapp is an outspoken advocate of antibiotic stewardship, calling for physician leaders to step up in hospitals while infection control departments try to prevent emergence from becoming endemicity. Indeed, in some areas like New York City, KPC infections are already establishing an endemic hospital presence, leading to stepped-up strategies like screening of high-risk patients. A classic nosocomial pathogen, KPC strikes severely ill patients such as those in ICUs or transplant units. After originating in the Northeast, KPC has now been detected in most states throughout the country, Rapp says.

"They began in Manhattan and the NYC area," he says. "They spread to Pennsylvania, New Jersey and on up the NY Thruway to Albany. Now they are sweeping across the entire country. Our health care personnel and our patients are so mobile — these things get colonized in the gut flora of patients and then get transferred to other hospitals. There are very few hospitals in the U.S. that have not seen at least some KPCs at this point."

Contact isolation for known cases is a given, but what about decolonizing carriers? Don't ask.

"That's tough — we have not been very successful," Rapp says. "That would require multiple antibiotics long term. Decolonization, particularly with gram negative bacteria has not been that successful. Many hospitals now, particularly for patients coming in from other institutions — will automatically put them in isolation under barrier precautions while they do surveillance cultures."

With decolonization unlikely, IPs face the same "isolation for life" scenario seen with multidrug-resistant Acinetobacter baumannii patients. For it's part, the Centers for Disease Control and Prevention currently advises that it has insufficient information to determine when lifting isolation measures for KPC or NDM-1 could be considered safe. In addition, the CDC has had the difficult task of raising awareness while refining its message as it tries to reinforce its previously issued infection control guidelines on KPC while urging people not to get too star-struck with the gradual emergence of novel NDM-1.

Arjun Srinivasan"I don't think the specific mechanism of carbapenem resistance is all that important, but that is getting a little bit lost in the shuffle," says Arjun Srinivasan, MD, a medical epidemiologist in the CDC's division of health care quality promotion. "There are these [KPC] carbapenem resistant Enterobacteriaceae present in the United States — by a different enzyme — but they present the same challenge. They are not treatable by most of the antibiotics we have. They [cause] infections associated with very high rates of morbidity and mortality."

The price of 'bug du jour'

The New Delhi metallo-beta-lactamase is an enzyme that "chews up antibiotics," Srinivasan explains. KPC has a more common enzyme that essentially does the same thing, with the upshot being that whole classes of antibiotics have been rendered useless against either mechanism.

"The awareness of these [NDM-1] organisms is important, but the real message for hospitals right now is to be aware of the whole issue," Srinivasan says. "Look specifically to see if you are seeing cases of these [KPCs] in your hospital. If you are, the CDC has guidelines to investigate. We are encouraging every hospital to do an assessment to know if you have these organisms in your facility. If you do, take the recommended steps to prevent them from being spread from person to person. If you don't have any cases, make sure that your clinicians and labs are on the lookout so if you do see a case you can jump on it."

In areas where KPC is not endemic the CDC has recommended that acute care facilities review microbiology records for the preceding six to 12 months to determine whether the pathogens have been recovered at the facility. If the review finds previously unrecognized cases, the CDC advises IPs to perform a point-prevalence culture survey in high-risk units to look for other cases, and perform active surveillance cultures of patients with epidemiologic links to people from whom the pathogen has been recovered. "This is primarily transmitted by hands of health care workers and transient contamination of objects that might go from room to room," he says. "There is also probably a component of environmental contamination as well, so it is probably those three mechanisms."

The active screening approach for MRSA have been much debated, and to some the emergence of the resistant gram negatives underscores the high price of focusing on single types of pathogens.

"This is another example that should make us question our approach to active surveillance culturing," Carrico says. "From my perspective, this is another new organism — another 'bug du jour.' The only way we are going to be able address it is to implement best practices among our health care personnel and make sure that our programs are dictating basic infection prevention. There are so many factors involved in an emerging infection, but the one thing we can do is to ensure that our basic practices are at the level that they need to be."


  1. Samra Z, Ofir O, Lishtzinsky Y, et al. Outbreak of carbapenem-resistant Klebsiella pneumoniae producing KPC-3 in a tertiary medical centre in Israel. Int J Antimicrob Agents 2007;30:525-529.
  2. Mulvey MR, Grant JM, Plewes K, Roscoe D, Boyd DA. New Delhi metallo-β-lactamase in Klebsiella pnemoniae and Escherichia coli, Canada. Emerg Infect Dis. 2011 Jan; [Epub ahead of print].