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Highly drug-resistant Klebsiella pneumoniae strain gains foothold, threatens to emerge nationwide
Infection control critical with high patient mortality, few antibiotic options
Trying to keep the genie in the bottle, the Centers for Disease Control and Prevention has issued new guidelines to halt the emergence of a highly drug-resistant, gram-negative pathogen that can cause a variety of infections with a strikingly high mortality rate.
Infection with carbapenem-resistant Enterobacteriaceae (CRE) or carbapenemase-producing Enterobacteriaceae threatens to become the next big prevention challenge in health care settings, the CDC reports.1 Currently, carbapenem-resistant Klebsiella pneumoniae (CRKP) is the species of CRE most commonly encountered in the United States. CRKP is resistant to almost all available antimicrobial agents, and infections with CRKP have been associated with high rates of morbidity and mortality.
A classic nosocomial pathogen, CRKP is striking very ill, hospitalized patients. "We [must] act against this very resistant pathogen before it gets a foothold in too many places," says Arjun Srinivasan, MD, a medical epidemiologist in the CDC's division of health care quality promotion. "That's why we are recommending such an aggressive approach while this pathogen really is not present endemically in most of the U.S. It is being sporadically recovered from lots of different places, but we think the time to act is now, rather than waiting for it to become more widespread."
Though primarily limited to the Northeast, CRKP has now been detected sporadically in 24 states. Once so rare it was thought to be a reporting error when discovered, 8% of all isolates of K. pneumoniae were resistant to carbapenems in 2007. Last year's data still are being analyzed, but the CDC is understandingly concerned that a major new drug-resistant pathogen may inexorably spread out through the health care system like so many of its predecessors. "That is certainly our concern," Srinivasan says. "It's impossible to know what the trajectory is going to be, but we don't want to find out. We want to control this before it becomes a major problem."
Mortality rates in the 40% range
All patients colonized or infected with CRE or carbapenemase-producing Enterobacteriaceae should be placed on contact precautions. Acute care facilities should establish a protocol, in conjunction with lab guidelines, to detect nonsusceptibility and carbapenemase production in Enterobacteriaceae, particularly Klebsiella spp. and Escherichia coli, and immediately alert epidemiology and infection control staff members if identified. As previously reported in Hospital Infection Control & Prevention, antibiotic resistance appears to be emerging through a distinct mechanism that can be transferred to other bacteria. A fully resistant E. coli 0157 strain is the worst-case scenario under current discussion. That raises the stakes of containment considerably, but CRKP is a significant threat in its own right due to mortality rates in the 40% range.
"The morbidity and mortality is one of the frightening aspects of these bacteria," says Srinivasan. "It has been reported as being very, very high. In [outbreaks] in Israel, they reported that overall mortality for these patients was about 40%."2
CRKP is a particular threat to patients with prolonged hospitalization and those who are critically ill and exposed to invasive devices (e.g., ventilators or central venous catheters). "The infections that have been reported run the gamut, but primarily they are urinary tract infections, bloodstream infections and ventilator-associated pneumonias," he says.
The combination of severity of illness and limited antimicrobial options can be fatal. "The drugs that we have available to treat these infections are not ones we use commonly or know a lot about," he says. "They are drugs that are definitely second- or third-line agents. They are sort of reserve agents. I think that there is a general sense that the limited efficacy of the drugs also contributes to the mortality."
With no miracle drugs in the pipeline, the CDC is recommending aggressive infection control actions in conjunction with implementing clinical and Laboratory Standards Institute (CLSI) guidelines for detection of carbapenemase production.3
"Labs are becoming increasingly aware of this issue," Srinivasan says. "CLSI put forward guidelines on exactly how to perform this type of testing in the micro lab in January of this year. So, the lab methods for detecting these organisms are now out there, and people are becoming more aware. What's critical is when they are detected making sure the information is properly communicated between the lab and the clinicians and the infection preventionist and health care epidemiology staff."
Look back six to 12 months
In areas where CRE are not endemic — which represents the vast majority of hospitals — acute care facilities should review microbiology records for the preceding six to 12 months to determine whether CRE have been recovered at the facility.
"It sounds labor-intensive, but in reality it is actually not that hard to do," Srinivasan says. "Most hospitals have some kind of electronic microbiology system that holds microbiology data. So, what we are looking for in that review is any report of a Klebsiella pneumoniae resistant to a carbapenem. We expect it to be a very rare occurrence, and in most places it might never have occurred. We are simply asking the lab to look for that single phenotype."
If the review finds previously unrecognized CRKP, 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, the CDC recommends. "The goal there is really to look for two things," Srinivasan says. "One is to look for unrecognized colonization that might be present in a facility, and the second is screening the 'epi' link to look for potential transmission."
Indeed, patients with unrecognized CRKP colonization have served as reservoirs for transmission during health care-associated outbreaks, the CDC warns. For example, during an outbreak of 39 cases of CRKP infection in a hospital in Puerto Rico in 2008, in addition to a review of infection control practices, active surveillance cultures were performed on patients in the same units as people with confirmed CRKP infection. Cultures performed on 30 patients in the intensive care unit revealed two colonized patients who were not previously known to harbor CRKP and were not placed in contact precautions (CDC, unpublished data; 2008). Control of the outbreak was hindered by lack of compliance with infection control practices. Health care personnel adherence to recommendations for gown and glove use was a low 62% at the hospital, and appropriate hand hygiene was observed in only 48% of patient encounters. The hospital eventually was able to control the outbreak through enhanced infection control compliance, patient cohorting, and weekly perirectal surveillance cultures of patients in the outbreak units until no new cases were identified, the CDC reports.
"This is primarily transmitted by hands of health care workers and transient contamination of objects that might go from room to room," Srinivasan says. "There is also probably a component of environmental contamination as well, so it is probably those three mechanisms."
NYC 'dealing with endemic problem'
Experience from the outbreak in Puerto Rico and outbreaks in Israel suggests that early detection through use of targeted surveillance and introduction of strict infection control measures (including reinforcement of hand hygiene and contact precautions) can hinder the spread of CRKP. However, the CDC is not recommending active surveillance cultures for hospitals that have not seen the pathogen, which, again, should be most facilities in the United States. In areas where CRE are endemic, an increased likelihood exists for importation of cases, and facilities should consider additional strategies to reduce rates, the CDC recommends. Indeed, some hospitals in the Northeast have gone to active surveillance cultures to detect CRKP and CRE, with patients who are infected or asymptomatically colonized placed in contact isolation.4
"Most of the New York City area is dealing with an endemic problem," says David Calfee, MD, MS, an associate professor of medicine in the division of infectious diseases at Mount Sinai School of Medicine in New York City.
"[CRKP and CRE] are isolated on a relatively routine basis, but I still think that prevention measures and detection can make a difference," he adds. "We do active surveillance in our high-risk populations, including ICUs and in our transplant population. That's an area where we have seen the organism and a patient group that would be at high risk of bad outcomes if they were infected."
Calfee and colleagues conducted a case-control study of infected patients, comparing CRKP with drug-susceptible K. pneumoniae.5 They found that CRKP infection was independently associated with recent organ or stem cell transplant, receipt of mechanical ventilation, longer length of stay, and exposure to cephalosporins and carbapenems. Case patients were more likely than controls to die during hospitalization (48% vs. 20%) and to die from infection (38% vs. 12%).
"Most of these patients had long hospital stays, were in ICUs, and had received broad-spectrum antibiotic therapy prior to their infections," he says. "Fortunately — so far at least — these infections are not occurring in healthy people in the community."
Treatment failure probably contributes, but the cause of death is multifactorial, he adds. "We don't have clinical data to know how effective the antibiotics are that we have to treat these resistant infections," Calfee explains.
Even though the antibiotics may have in vitro activity that indicates susceptibility, other factors may undermine the drug's efficacy, he notes. "For example, one of the drugs — tigecycline — does not achieve very high levels in the blood, so treating a blood infection with that antibiotic may not be optimal," he says.
However, removal of the source of infection proved to be a particularly powerful intervention. "We know that is something that you should do with all infections when possible, but it really seems to be important in infections caused by these organisms that are almost untreatable with available antibiotics," Calfee says. "So, removing infected catheters, draining abscesses — things like that really seemed to make a difference."
No decolonization protocol
Another complicating factor is that there is no clear decolonization protocol for patients merely carrying the pathogen, meaning prolonged contact isolation may be necessary. "The strategy that has been effective is really to limit the transmission from colonized patients to other patients," Srinivasan says, "[but] we don't have any information on when it might be safe or prudent to discontinue isolation."
Investigators in Israel are looking at whether the colonization will naturally clear, looking at factors that may affect short- and long-term colonization, he adds.
"It is very difficult to decolonize patients because many of these organisms sort of live within the normal milieu and niche in humans," says Mark Rupp, MD, an infectious disease physician at the University of Nebraska Medical Center in Omaha. "They are going to be residing in our gastrointestinal tracts and mucosal membranes. That's where they naturally hang out, and it is really difficult to eradicate organisms from their normal habitat."
Thus contact isolation may need to be continued indefinitely, but if patients recover the colonization may end, he adds. "A lot of times when people are ill, they're homeostasis is altered, so these organisms will remain in them and on them for a prolonged period of time," he says. "It's only after health is restored, the antibiotic pressures are removed, the normal situation reverts, and patients can rid themselves of these organisms. But oftentimes, that is the period of time until health is restored and then a kind of a natural flora comes back and takes over."
Will IPs be proactive?
With CRKP rarely detected in the vast majority of hospitals, will infection preventionists and health care epidemiologists respond aggressively to a threat that is not yet present in much of the country? "I hope so," says Rupp. "The record seems to indicate that these organisms are spreading from east to west across the country, and we certainly are aware of them and are looking for them here."
Though none has been detected, the microbiology lab and infection prevention department have adopted the CDC guidelines, he adds. "It underscores how significant the CDC feels that these organisms are," he says. "It does take some effort to accomplish this look-back, but I think it is particularly important for laboratorians to be aware of this and certainly carry [the information] forward."
Gram-positive pathogens such as methicillin-resistant Staphylococcus aureus (MRSA) have dominated the public perception of infection prevention, in part because they also threaten healthy people in the community. "Most of the gram negatives are seen in patients who are at higher risk within our hospitalized population," he says.
Likewise, new antibiotic development has been more likely to focus pathogens such as MRSA.
"We don't have a lot of new classes for drugs for gram-negative organisms in the pipeline," says Rupp, the current president of the Society for Healthcare Epidemiology of America. "We are not likely to get any new antibiotics soon to treat these problematic organisms. We are being more proactive with this in trying to prevent the geographic distribution and spread of this particular type of resistance mechanism. It absolutely emphasizes the need for aggressive and comprehensive infection control programs."