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Special Report: The Black-Box Bug: A strain of Klebsiella pneumoniae has researchers calling it ‘hypervirulent,’ and warning that it is not a potential threat but a real one

Scheck, Anne

doi: 10.1097/01.EEM.0000421861.27634.25
Special Report
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He was a nursing student in his mid-20s, and except for a history of asthma, he seemed healthy. Vomiting and fever took him to the emergency department one day, though, and he was diagnosed with viral enteritis. It was that simple.

Except that it wasn't.

The cause of his abdominal pain turned out to be a hepatic abscess, which was caused by a rampant infection from Klebsiella pneumoniae (KP), that had spread to his spleen. No one at the hospital had ever seen KP infect a liver this way. In fact, no one in upstate New York had even seen this particular strain of KP. It had been found in Asia but rarely in North America and never in Buffalo. (Eur J Clin Microbiol Infect Dis 2012;31[6]:981.)

“It's a black-box bug,” explained Thomas Russo, MD, a professor of medicine at the University at Buffalo-State University of New York. “It is still a mystery as to how this is acquired, how it gets into the critical site,” Dr. Russo said, explaining that he was immediately intrigued by this strain that researchers now call “hypervirulent” (hvKP). Having studied gram-negative bacteria for much of his career, Dr. Russo was fascinated that hvKP did not behave like most gram-negative bacteria. Instead, it had the ability to become quickly invasive. He and a team of researchers at UB are now investigating its genetic characteristics under a grant from the National Institutes of Health.

Emergency physicians are the health care professionals most likely to encounter it, he added. “What we are seeing … is this shows up in young, healthy people. And who is likely not to have insurance? They are. And who is likely to use emergency rooms? These people,” he said.

Only a handful of patients with hvKP have been identified in his area of the country, but the potential of this infective agent is worrisome. (Future Microbiol 2012;7[6]:669.) The young male student, for example, had a prolonged recovery, just as many hvKP patients do in Asian countries where it is more prevalent.

HvKP is still uncommon in the United States, but experts are concerned. The variant appears to be community-acquired, unlike its predecessor, carbapenemase-producing KP, more commonly known as Klebsiella pneumoniae carbapenemase (KPC), which is now believed to be responsible for carrying — and imparting to certain other bacteria — the most consistent cellular mechanism of antibiotic resistance.

KPC, however, has generally been limited to elderly or immunocompromised populations, often those confined to extended-care facilities. HvKP generally is adequately responsive to traditional antimicrobial therapy, but that could change. “If there is a confluence of these [two], we are now talking about what could be a severe health threat,” Dr. Russo said, stressing that his work is on hvKP, not KPC.

First found in the mid-1990s — a single case in North Carolina — KPC has become a serious threat to immunocompromised inpatients. Able to survive on environmental surfaces such as bed rails, it is now detected in as many as a third of K. pneumoniae isolates from patients in hospitals, said John Quale, MD, an associate professor of medicine at State University of New York (SUNY) Downstate Medical Center in Brooklyn. Dr. Quale has made KPC the focus of his research at SUNY Downstate, in much the same way hvKP has been the recent center of Dr. Russo's at SUNY in Buffalo.

KPC has the antibiotic-defeating property of beta-lactamase in the extreme, Dr. Quale stressed. The bacterium can resist antimicrobials from A (aztreonam) to Z (Zosyn). It easily hydrolyzes such standard therapies as penicillins and cephalosporins.

In fact, KPC is thwarting most antibiotic treatment so successfully that one Canadian multicenter study suggested a series of risk factors might help identify infected patients before lab results do. They include a previous nursing-home stay or admission to an acute-care facility and previous extensive antibiotic therapy. (Can J Infect Dis Med Microbiol 2009;20[3]:e43.)

One important potential indicator is past KPC infection. Now, because of “leisure tourism, the burgeoning industry of medical tourism, military conflict, natural disasters, and changing patterns of human migration,” country-to-country transfer of multiresistant bacterial infection is seen as a growing risk. (Clin Infect Dis 2011;53[1]:49.)

Still, KPC is likeliest to be found in those with hospital- or hospital-like exposure, including nursing homes, said David Talan, MD, a professor of emergency medicine at the University of California, Los Angeles (UCLA) and the chair of emergency medicine at Olive View-UCLA Medical Center in Sylmar, CA. Elsewhere, KPC appears to be relatively rare — at present, that is, he observed.

But patients who do have the infection “may be even more difficult to treat, with susceptibilities that may be unique to the center,” he pointed out, “so help from the local infectious disease specialist may be particularly important if a case is suspected.”

KPC is “uniquely potent,” Dr. Quale said, and “entirely different” from other beta-lactamases because it confers resistance to all known beta-lactam antibiotics. The genetic machinery for KPC is carried in a plasmid, which can spread to other bacteria, rendering them just as resistant. Common bacterial pathogens of humans, such as Escherichia coli and Pseudomonas aeruginosa, have been found to harbor the plasmid as a result. Shortly after the beta-lactamase was identified, “the numbers kept increasing,” Dr. Quale noted.

Every patient admitted to the intensive care unit at Downstate Medical Center is now routinely screened for rectal colonization of carbapenem-resistant organisms. Patients confirmed to have it are immediately placed on contact precautions. The result: the incidence of patients at Downstate harboring KPC-producing organisms has fallen 90 percent.

Downstate's lab has developed a methodology for screening KPC, which is essentially an agar culture, not a rapid polymerase-chain assay (PCR). Dr. Quale said they “concocted” the protocol themselves, and based it on the experience of other institutions dealing with outbreaks of other resistant pathogens. No cost analysis of the program has been done, “but I cannot imagine that it isn't cost saving,” he said, adding that he is “cautiously optimistic” that the combination of heightened surveillance and new antimicrobial treatment will reduce the risk of KPC, despite the fact that the plasmid responsible for its impact is so transmissible to other bacteria.

“It is not a potential threat; it is a threat,” Dr. Quale said, and it is now being addressed that way — as a high-risk pathogen that needs aggressive infection control and new ways of fighting it, he said.

KPC alone is being hailed as an emerging superbug because of its multidrug resistance. As superbugs go, however, some experts are asking if hvKP is the higher risk variant. Liver abscess may be a presenting symptom, but the fast-moving systemic infection of hvKP is variable and can affect other organs, including the spinal cord. Moreover, complications, such as vision loss, may be permanent. “It is a serious disease,” Dr. Russo affirmed.

Unlike classic Klebsiella, hvKP seems to have a high affinity for acquiring iron, which may help in understanding it, Dr. Russo said. The UB team wants to identify the specific genes that make it different from its classic form, an intense focus of research because it could confer its virulence to antibiotic-resistant KPC if it spreads widely, and vice versa.

One problem is that KPC and the potential plasmid-carriers of similar antibiotic resistance such as E. coli fall under two broader categories, which seems to have the potential for making scientific comparisons confusing. These gram-negative bacteria are members of the family Enterobacteriaceae, giving rise to the term CRE for all the Enterobacteriaceae carbapenem-resistant genera, and CREs are frequently identified as producers of Extended Spectrum Beta-Lactamases, or ESBLs. Some French investigators — in an apparent attempt to refer to a strain identified in Europe that is both ESBL and CRE — call it NDM, for New Delhi metallo-beta-lactamase, in recognition of an Indian Hospital where a Swedish patient was thought to have been infected before returning to Europe. (J Antimicrob Chemother 2011;66[4]:689.) Acronyms aside, it is becoming clear that these bacterial infections are resisting all available antibiotics in more cases than ever, with some reports suggesting the situation is leaving patients across the globe medically defenseless. (Scientific American, April 2011).

“We are starting to see ESBLs in ED-presenting patients, even some from patients without hospital exposure,” said Dr. Talan.

A few years ago, Canadian physicians began picking up KP the same way; it was being acquired in the community and the hospital. Like the team at UB, they speculated that the virulent organisms could harbor ESBLs, too. Some of the ESBL-producing KP had moved into the community even at that time, and were “creating therapeutic problems in a setting where empiric, oral antimicrobial therapy is a common practice,” they warned. (Int J Antimicrob Agents 2007;30[5]:385.) “These multidrug-resistant organisms are affecting the choice of antimicrobial therapy, [and] are a major cause for increasing hospital costs and duration of hospitalizations,” according to the two authors, researchers at the University of Manitoba in Winnipeg.

Isolation should be immediate, said Dr. Talan. “Your best bet is to call the infectious disease specialist” of the hospital, he reiterated. Confirmation by culture takes time, he cautioned. Writing in EMN earlier this year, Dr. Talan described the demographics as relatively far-ranging in terms of ED presentation. (EMN 2012;34[7]:10; see FastLinks.) “Some places see none, some places see them rarely and only in at-risk groups, and some see them more generally,” he said.

The search is on for more-rapid testing for KPC, which is generally taking a PCR-based form. (See sidebar.) Some newer PCR testing has taken place in Europe (J Clin Microbiol 2011;49[6]:2252), and other systems employ mass spectrometry that uses matrix-assisted light desorption to identify pathogenicity. (Clin Microbiol Infect 2010;16[1]:1620.)

Combating CREs will require a coordinated effort across health care, public health, and industry,” according to Alexander J. Kallen, MD, MPH, an epidemiologist at the Centers for Disease Control and Prevention in Atlanta. The CDC recently released its Guidance for Control of Carbapenem-Resistant Enterobacteriaceae, to tackle this threat, and the new resource toolkit expands on the 2009 recommendations and will continue to evolve as new information becomes available. (See FastLinks.)

Click and Connect!Access the links in EMN by reading this issue on our website or in our iPad app, both available onwww.EM-News.com.

Gram stain of Klebsiella pneumoniae in sputum. Clinical Laboratory Medicine, 2nd Edition. Philadelphia: Lippincott Williams & Wilkins, 2002.

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FastLinks

  • Read the CDC's Guidance for Control of Carbapenem-Resistant Enterobacteriaceae at http://1.usa.gov/NXCuRm.
  • Read Dr. James Roberts' column, “Extended Spectrum Beta-Lactamases: Far Worse than MRSA?” and Dr. David Talan's article, “Infectious Disease Advice on ESBLs” in the July issue of EMN at http://bit.ly/OsgWc1.
  • Comments about this article? Write to EMN at emn@lww.com.

Read Dr. James Roberts' InFocus column this month, “Neisseria Gonorrhoeae: The New Superbug,” about how the wily gonococcus has slowly developed antibiotic resistance and morphed from an easy-to-treat organism into a potential superbug. See p. 10.

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The Pre-Med Student and the Rapid KPC Test

Who would have guessed that a rapid test for KPC-producing bacteria would come, at least in part, from the work of a pre-med student? Meet Kristin Wiggins, a junior at Northern Arizona University in Flagstaff. She is heading into a medical career that combines hospital-based patient care with research on disease processes, and she's gotten an early start, thanks to a nonprofit research facility near the university, which is part of the Phoenix-based Translational Genomics Research Institute (TGen).

Most standard testing for detecting carbapenemases is limited to time-consuming culture techniques, so Ms. Wiggins jumped at the chance to find something that would improve on the streak-plate method. She had lots of help, of course.

Ms. Wiggins got the opportunity as an intern at TGen North in Flagstaff to help create a polymerase-chain reaction (PCR) assay for KPC, explained David Engelthaler, the former state epidemiologist for Arizona and now the director of programs and operations for TGen North. TGen has government contracts and federal grants for researching potential solutions to infectious disease, he said.

The experimental PCR assay takes from 90 minutes to two hours to confirm KPC, compared with current method that can take two to three days, he said. The assay was aimed at KPC, but “our goal is not just to use it for Klebsiella,” he noted.

TGen North investigators are already expanding this PCR testing to include other multidrug resistant organisms. “I go into work every day with a lot of passion and pride in what I am doing,” said Ms. Wiggins.— AS

© 2012 by Lippincott Williams & Wilkins