A CDC report published in March documented an increase in health care–associated infections related to carbapenem-resistant Enterobacteriaceae, raising concerns that the rates of the virtually untreatable infection could continue to increase if appropriate action is not taken.
According to the report, published in Morbidity and Mortality Weekly Report, 4.6% of acute-care hospitals reported at least one carbapenem-resistant Enterobacteriaceae (CRE)-related infection in 2012, including 3.9% of short-stay hospitals and 17.8% of long-term, acute-care hospitals. Although Enterobacteriaceae are a common cause of many infections, CRE were relatively uncommon before 2000. However, according to data from the National Nosocomial Infections Surveillance System Report and the National Healthcare Safety Network, the proportion of Enterobacteriaceae that were CRE increased from 1.2% in 2001 to 4.2% in 2011, nearly a fourfold increase.
“This is concerning for several reasons, the first being that there are limited treatment options for these CRE bacteria,” Arjun Srinivasan, MD, associate director for health care–associated infection prevention programs in the Division of Healthcare Quality Promotion at the CDC, told Infectious Disease News. “In some cases, there are absolutely no treatment options for these infections. As a result, we’ve seen mortality reports as high as 50% from bloodstream infections associated with CRE.”
CDC Director Thomas Frieden, MD, MPH, called CRE a “nightmare bacteria,” and urged everyone in the health care community to work together to implement strategies to stop these infections from spreading.
Infectious Disease News discussed CRE with several experts to determine the extent of the problem, who is most at risk, and what can be done to prevent the spread of this so-called superbug.
Reports of antibiotic resistance across all bacteria species are increasingly common. According to Brian Currie, MD, vice president for medical research and assistant dean for clinical research at Montefiore Medical Center in Bronx, N.Y., CRE were first reported in the United States in 2001.
“New York had several outbreaks from 2000 to 2005, but people perceived it to be a localized problem,” Currie said. “New York became the epicenter for further dissemination, both internationally and nationally. At this point in time, CRE have been reported in 42 states, whereas 2 years ago, it was only reported in 28 states. That’s a rapid dissemination.”
Arjun Srinivasan, MD, of the Division of
Healthcare Quality Promotion at the CDC,
said mortality reports are as high as 50%
from bloodstream infections associated with CRE.
Photo courtesy of Srinivasan A
Srinivasan said these numbers come from voluntary reporting, so it is possible that there have been isolated cases in other states that have not been reported.
CRE have become endemic in the Northeast, particularly in the New York and greater Philadelphia areas, Keith Kaye, MD, professor of medicine and corporate director of infection prevention, hospital epidemiology and antibiotic stewardship at Detroit Medical Center and Wayne State University, and a member of the Infectious Disease News Editorial Board, said in an interview. It has also established themselves in the Detroit and Chicago areas, Southern California and other large metropolitan areas in the United States. The bacteria are predominantly found among people in long-term acute-care facilities.
“The patients that develop these infections are typically chronically ill patients, representing the sickest surviving people from acute-care hospitals,” Kaye said. “These people have extensive health care exposure, extensive antibiotic exposure, and often have chronic indwelling catheters in place. This conglomerate of risk factors seems to be the formula for CRE carriage.”
Cause for concern
The most common CRE found in the United States thus far produce the Klebsiella pneumoniae carbapenemase (KPC), an enzyme that confers resistance to carbapenems. K. pneumoniae is responsible for the outbreak in New York and for a large outbreak in Israel. In the United States, K. pneumoniae has shown a sevenfold increase in the past decade, according to the MMWR report.
CRE typically become a regional challenge because patients are often transferred to and from hospitals and long-term care facilities. The nature of CRE allows the bacteria to spread quickly in health care facilities, as the organisms themselves can spread, and the mechanism that makes them resistant to carbapenems can be transferred to and shared with other organisms in the Enterobacteriaceae family.
“The reason that CRE are the most urgent public health threat among resistant bacteria, particularly health care–associated bacteria, is that the enzyme that confers resistance can move readily from one organism to another,” Daniel Diekema, MD, professor of medicine and director of the division of infectious diseases at the Carver College of Medicine, University of Iowa, told Infectious Disease News. “These organisms have the propensity to cause devastating outbreaks within institutions, but more importantly, regional and national outbreaks.”
For example, one organism in the Enterobacteriaceae family is Escherichia coli, which is the most common cause of urinary tract infections in the community.
“There’s the potential that this resistance could spread to other infections, and then spread to infections that are not health care–related,” Srinivasan said.
Although KPC has not spread to the community, other enzymes that confer carbapenem resistance have. One of the most concerning enzymes that has seen a community presence is the New Delhi metallo-beta-lactamase (NDM), which has been found in the water supply or waste water in endemic areas, Diekema said. This enzyme is mostly seen in other parts of the world, but according to the CDC, it has been found in nine states: California, Colorado, Illinois, Maryland, Massachusetts, Minnesota, Rhode Island, Virginia and Washington.
Other enzymes that confer resistance include the Verona integron-encoded metallo-beta-lactamase (VIM) and the imipenemase (IMP) metallo-beta-lactamase. Both of these are more common in other parts of the world, but California has seen CRE with these enzymes, and Washington has had cases of CRE with VIM, according to the CDC.
“There is concern that those organisms, which have been sporadic in the United States so far, will become endemic here as well,” Diekema said. “With global travel and medical tourism, and all of the ways that organisms can move from one health care setting to another, the global spread of these organisms is a real possibility.”
One of the largest outbreaks of CRE was in Israel, when outbreaks of carbapenem-resistant K. pneumoniae were reported at several hospitals in 2006. By March 31, 2007, 1,275 patients in 27 hospitals were affected. Kaye said the KPCs identified during this outbreak, and in other outbreaks in other countries, were actually similar on a molecular level to the KPCs found in the early outbreak of K. pneumoniae in New York in the early 2000s.
It appears that the KPC enzyme responsible for this carbapenem-resistant K. pneumoniae originated in the United States, Srinivasan said, but because other varieties of CRE, particularly NDM, have garnered a lot of attention, this is a little-known fact.
“Many people were led to believe that because of the tremendous amount of attention that NDM was getting, CRE is something that had been imported from another country,” Srinivasan said. “In fact, the majority of CRE cases in the United States are due to KPC, which originated here.”
Few options left
Carbapenems are known as an antibiotic of last resort, according to Neil Fishman, MD, associate professor at Perelman School of Medicine at the University of Pennsylvania and director of the department of health care epidemiology and infection control at the University of Pennsylvania Health System. When organisms become resistant to carbapenems, there are limited options left for treatment.
“The option after carbapenems is polymyxins, which are old and toxic antibiotics,” Fishman said. “I distinctly remember learning in medical school that polymyxins act like detergent, in that they are toxic to normal cells, particularly kidney cells. They are not effective antibiotics. But at the current time, that’s what we’re left with. Some CRE are even becoming resistant to polymyxins, so we are seeing pandrug-resistant organisms.”
CRE also are associated with gram-negative sepsis, Kaye said, which means they can be virulent organisms compared with other carbapenem-resistant gram-negative organisms, such as Acinetobacter baumannii.
“Carbapenem resistance is usually associated with multidrug resistance or pandrug resistance,” Kaye said. “Gram-positive organisms are concerning pathogens, but there are several new drugs that are effective. But in the gram-negative world, you run out of treatment options quickly.”
Antibiotic development is a desperate need to combat the rising number of drug-resistant infections. Recently, two bills were introduced to Congress to help provide incentives for drug companies to develop new antibiotics: the Generating Antibiotic Incentives Now (GAIN) Act, sponsored by Rep. Phil Gingrey, R-Ga., and the Strategies to Address Antimicrobial Resistance (STAAR) Act, sponsored by Rep. Jim Matheson, D-Utah.
“The antibiotic pipeline is dry,” Fishman said. “There are several drugs in development against CRE, but at this point, I suspect it will be at least 5 years before we have a new antibiotic that is available for clinical use.”
Detection and prevention
To prevent the dissemination of CRE, the first step is detection.
“We need to know when these organisms are present in our facilities, and we need to make sure that when they are present, infection control personnel and infectious disease clinicians are immediately notified so that they can take action,” Srinivasan said. “It’s important to work with microbiology labs to make sure that they are up to speed on the latest recommendations for detecting these organisms.”
However, one of the problems, according to Currie, is that the culture methods that are routinely used do not reliably detect all strains of CRE, and they have long turn-around times. There are no alternative, FDA-approved tests, but assays that can reliably and rapidly detect CRE are in development, he said.
“Having a rapid test that can identify patients is going to be important for both treatment and infection control purposes,” Currie said. “Some hospitals, particularly those in endemic areas, have developed their own polymerase chain reaction tests or have received prototype assays for use.”
Some of these facilities have also employed the use of active surveillance, screening patients for CRE colonization and isolating all those found to be positive, as part of their control strategy. Currie said that his institution in New York, considered a hyperendemic area, has adapted this strategy. Montefiore, Currie’s institution, use a targeted active surveillance program to reduce the prevalence of CRE colonization among ICU patients by 55%, he said.
“Among patients admitted to the ICU, 40% were positive for CRE when they are admitted,” Currie said. “The goal is to confine it to the patients who are already colonized, and not allow it to spread from patient to patient. We were able to virtually shut down horizontal transmission.”
Patients with CRE colonization or infection should be put into isolation, which is the standard procedure for any multidrug-resistant infection, Fishman said, adding that the value of antimicrobial stewardship should not be ignored.
“This plays a critical role in limiting the emergence of resistance and in improving patient care,” Fishman said. “This is an important point that sometimes gets lost because the goal of stewardship is not to restrict antibiotic use, but to make sure that patients receive the appropriate antimicrobial. When they do, it improves the quality of care, so it’s a win-win for everyone.”
Kaye agreed and said antibiotic stewardship is often underrated, despite many publications showing that antibiotic exposure is often the only unique risk factor among very sick patients.
“Extensive antibiotic exposure is an important risk factor for CRE,” Kaye said. “Having stewardship programs in hospitals and in long-term care facilities is important, so that we don’t overtreat people or keep them on unnecessary long durations of antibiotics.”
The backbone of any infection control policy in any health care facility, however, is hand hygiene.
“It is important to employ rigorous infection control intervention to prevent transmission with the health care setting and certainly from the health care setting to the community,” Fishman said. “That means flawless hand hygiene and rigorous adherence to contact precautions.”
If the patient is simply colonized with the bacteria, then they only need to be monitored closely, Kaye said. If it is a true infection, then treating at the site of the infection — such as removing catheters or surgically removing an abscess — may be warranted. Then microbiology tests need to be performed to see if the organism has any susceptibilities.
“If you have a true CRE, you may consider agents like aminoglycosides, polymyxins or tigecycline (Tygacil, Wyeth Pharmaceuticals), but they all have limitations as well,” Kaye said. “For serious infections, it’s sometimes warranted to use carbapenem therapy in combination with another second-line agent. There really are no formally-proven treatment strategies.”
The key message regarding CRE, however, is that it is a critical time of action, Srinivasan said.
“When it comes to resistance, as health care providers, we sometimes feel somewhat paralyzed to take action because we feel like there is nothing we can do,” he said. “If we continue to take steps in a concerted and aggressive manner, there is an opportunity to prevent CRE from becoming a bigger problem.” – by Emily Shafer
For more information:
Brian Currie, MD, MPH, can be reached at: Montefiore Medical Center, 111 East 210th Street, Bronx, NY 10467; email: email@example.com.
Daniel Diekma, MD, can be reached at Danielfirstname.lastname@example.org
Keith Kaye, MD, can be reached at: University Health Center; 4201 Saint Antoine, Suite 2B, Box 331, Detroit, MI 48201; email: email@example.com.
Arjun Srinivasan, MD, can be reached at: CDC, 1600 Clifton Rd, MS A07, Atlanta, GA, 30333; email: firstname.lastname@example.org.
Disclosure: Currie, Diekema, Fishman, Kaye and Srinivasan report no relevant financial disclosures.
Is active surveillance for CRE a good idea at this time?
I can’t get excited about telling people to do active surveillance for CRE.
In general, active surveillance is labor-intensive, resource-intensive and it has a lot of opportunity costs. A great deal of energy is spent with active surveillance and isolating patients. But often, hospitals get tied up in active surveillance, and lose sight of all the other things that we do to reduce infections due to all organisms. For several years, I have argued for not focusing on any particular organism, but rather focusing on activities that reduce infections due to all pathogens. Hand washing would be the cornerstone of that. All organisms that are transmitted via hand contact are reduced when you drive hand hygiene compliance to very high levels. There are other examples, but the concept is the same. Focus on activities that reduce all infections, don’t try to target specific organisms. Today it’s CRE, but who knows what the next organism is? At my hospital, we don’t see much CRE, and I would argue it’s because we continue to focus on the same behavioral things with health care workers, in terms of getting them to be compliant with good practices.
There are certain times when active surveillance may be useful, such as if there is an outbreak, or if you’re trying to determine the prevalence of CRE in a hospital. But in terms of controlling these organisms in the long run, active surveillance is not a useful way to do it. For methicillin-resistant Staphylococcus aureus, active surveillance have been shown to be ineffective — there was no reduction in the MRSA rates with active surveillance in the recent study by Huang et al (N Engl J Med. 2013;368;2255-2265). It was only when that was combined with decolonization that they saw a reduction in infection rates, and universal decolonization without active surveillance was even more effective. There was a big lesson in that paper. People have debated for years about whether active surveillance was beneficial for MRSA, and that paper finally answered the question. We don’t know if it applies exactly to CRE, but in principle, for any organism that is transmitted in the same fashion, the same control mechanisms apply. There are many other things that need to be done also, including antibiotic stewardship and environmental cleaning, all horizontal infection control strategies.
Michael Edmond, MD, is the Richard P. Wenzel professor of Internal Medicine in the Division of Infectious Diseases at Virginia Commonwealth University. Disclosure: Edmond reports no relevant financial disclosures.
It is a different situation; one which may benefit significantly with active surveillance.
We don’t have answers to all of the questions, but we can’t wait to act until it is too late. What we’re talking about are gram-negative organisms of public health importance, particularly those with multidrug resistance that leave us more vulnerable to having untreatable infections. This includes CRE. Active surveillance may be burdensome and costly, and it has also been shown recently to be clearly superseded by other, broader approaches, when it pertains to methicillin-resistant Staphylococcus aureus. The recent NEJM paper showed that greater reductions in MRSA could be afforded by decolonizing everyone. But to put that in context, MRSA is very prevalent in ICUs. In general, S. aureus is the most common cause of device- and procedure-related infections, and more than half of all S. aureus are MRSA. MRSA is found in nearly every ICU in the country. In contrast, CRE is found in less than 10% of hospitals in the United States. We should also consider the history in the Netherlands, where MRSA was held at bay for years through active surveillance of high-risk patients, including those who had transferred from another country, like the United States where MRSA is so common. They continued to see a low rate of MRSA with that process.
With that said, there is no one-size-fits-all approach to preventing every infection. It may be costly, but right now active surveillance is the way to go to contain CRE while it’s still early in the game. Nonetheless, there are limited ways to test for CRE, and many institutions are left developing their own methods for detection. CDC has recommended a method culturing rectal or perirectal swabs. It’s not the easiest method to perform, but we are working to improve this.
Cliff McDonald, MD, is chief of the prevention and response branch in the division of Healthcare Quality Promotion at the CDC. Disclosure: McDonald reports no relevant financial disclosures.