There has been an alarming increase in antibiotic-resistant infections, both in the United States and worldwide. The severity of the problem was recognized by the Obama Administration last fall, when the White House issued Executive Order 13676: Combating Antibiotic-Resistant Bacteria. This presidential directive created a task force to develop a five-year action to address the challenge.
Methicillin-resistant Staphylococcus aureus (MRSA) outbreaks have been reported by the media for more than a decade, and public awareness of the dangers they pose has been growing. According to the Centers for Disease Control and Prevention (CDC), the three most urgent antibiotic-resistant threats in the U.S. are the following:
On March 27, 2015, the presidential task force released the National Action Plan for Combating Antibiotic Resistant Bacteria. This document outlines goals and strategies to significantly reduce the incidence of urgent and serious threats, including CRE, MRSA, and C. diff., by 2020.
Among the strategies outlined in the Plan are the creation of a regional public health laboratory network to provide a standardized platform for resistance testing and advanced capacity for genetic characterization of bacteria (for example, through whole genome sequencing) and the promotion of laboratory capabilities, “to identify at least three of the seven World Health Organization (WHO) priority antimicrobial resistant (AMR) pathogens using standardized, reliable detection assays.”2
Preventing NDM outbreaks
What is a CRE? Carbapenems are advanced beta-lactam antibiotics. Enterobacteriaceae are a common group of clinically-significant bacteria that include, among many others, E. coli and Klebsiella pneumoniae. There are several molecular categories of CRE.
Just over a year ago, a hospital in Chicago discovered a CRE rarely found in the United States—a New Delhi Metallo-beta-lactamase (NDM)-producing E. coli.3-4 This organism had infected at least one of the hospital's endoscopic scopes. The scope spread the NDM to nearly 40 patients, some critically ill, despite the hospital following all proper sanitizing protocols between procedures.
What helped to prevent further spread of this highly transferrable CRE? First, the laboratory detected the NDM in a timely fashion. Second, the hospital's infection prevention team notified the Illinois Department of Public Health and the CDC that an NDM had been found in their institution. Third, the hospital contacted all 243 patients who had undergone an endoscopy there during the time of possible exposure and asked them to be tested for NDM colonization. Thirty-eight tested positive.
The hospital was widely praised for its surveillance and its entire approach to containing the spread of this dangerous CRE, which caused the death of two of the 38 patients who were NDM-positive. Notably, while only 10 of the infected individuals became ill, all 38 were capable of transmitting the infecting organism and could unknowingly spread the NDM despite being asymptomatic.
The role of the laboratory
Klebsiella pneumoniae carbapenemase (KPC) occurrence is endemic, and it has been particularly problematic in the area around New York City. Because of their prevalence, KPCs are on the antibiotic-resistant bacteria “hot list” for being the most prevalent form of CRE in the U.S. The first KPC-producing bacteria isolate to be identified was discovered in North Carolina in 1996. Since then, KPCs have spread to almost all states. KPCs are so widespread that the CDC released a CRE Toolkit in 2012 focused largely on the implementation of successful KPC prevention strategies.
Like most carbapenemases, KPCs are enzymes which inactivate all beta-lactam antibiotics, including carbapenems, penicillins, cephalosporins and monobactams. The gene for KPCs is located on a plasmid that may also contain other beta-lactamases such as extended spectrum beta-lactamases (ESBLs) and other resistance genes.
Within the laboratory, it is crucial to run antimicrobial susceptibility tests on any identified bacteria to determine if the bacterial strain is a CRE, and if so, whether the detected CRE resistance mechanism is plasmid-mediated, as is the case with KPCs, or non-plasmid mediated. Non-plasmid mediated carbapenem resistance, while serious, is not as easily transferrable, although treatment of the infected patient and infection control are important regardless of CRE mechanism. Although non-carbapenemase-producing CREs are an important infection control concern, plasmid-mediated CREs are easily transferable between strains, species, genera, patients, and facilities and pose serious endemic threats.
Challenges to effective testing and identification
Today's automated antimicrobial susceptibility testing systems are programmed to flag bacteria which show antibiotic resistance to the carbapenems, and these tests are run daily in hospital laboratories nationwide. But, as the CDC reports, KPC detection poses unique and significant challenges: “KPC-positive bacterial isolates exhibit high variability regarding which carbapenems they hydrolyze, as well as exhibiting day-to-day variation in their ability to hydrolyze any given carbapenem drug.”5
Susceptibility testing is usually performed with several carbapenems. In the U.S., ertapenem is the most common due to its sensitivity for KPC resistance, but it is not highly specific and additional testing must be done to verify KPC isolates. In addition, because KPCs are found in many gram-negative species—including E. coli, Enterobacter species, and very occasionally Salmonella and other species—it might be important to determine if the organism is carbapenemase-producing, and thus highly transferrable.
Laboratories leaders must be sure to stay abreast of the newest science and adjust testing best practices in their laboratory accordingly. The Clinical and Laboratory Standards Institute (CLSI), in its annual susceptibility test guidelines M100-S25, included an easy-to-follow chart listing several CRE confirmatory tests. These include the Modified Hodge Test, a newly added test called the Carba NP test, and molecular tests. A positive result indicates that additional infection control precautions may need to be put into place to prevent a potential endemic.
Laboratories on the front line
From the National Action Plan for Combating Antibiotic Resistant Bacteria to the CDC CRE Control and Prevention Toolkit to global CRE research and prevention initiatives, all experts agree that the role of the laboratory has never been more important to helping curb the threats of “superbug” endemics and epidemics worldwide. KPCs, especially, are spreading and they are deadly. As noted by the CDC, one 2010 study indicated that “overall mortality for patients infected with KPC was 23 percent in 7 days, 42 percent in 30 days, and 60 percent by the end of their hospitalization.”5
- Today's recommended best practices for laboratories include:
- Incorporating current CLSI standards;
- Educating teams on new and emerging CREs and the importance of detection and containment;
- Establishing a baseline measurement of the presence of CREs and, specifically, KPCs within the institution to identify normal patterns and report any increase in KPC prevalence;
- Creating system rules (along with pre-defined software rules) to ensure all needed testing takes place immediately when CREs are identified;
- Periodic testing of a sample subset of patients from areas most likely to have a prevalence of CREs, including geriatric patients, patients from the ICU, and emergency department patients who were recently discharged from acute care or nursing home facilities;
- Testing of all new ICUR patients and all patients transferred from another acute care, nursing or other long-term care facility (important in areas where CREs are not routinely isolated);
- Ensuring that laboratory staff remain aware of infection control reports impacting the region and share information regionally, so that testing practices can be adjusted to meet changing needs.
Information is as important as isolation and containment. By monitoring KPC levels and sharing information on any increased prevalence in the region, all laboratories, hospitals, and care facilities can institute proper measures to curb the spread of KPCs when they occur. The CDC recommends escalating KPC control efforts any time prevalence rates increase to more than two percent to avoid reaching endemic (five percent) or epidemic (seven percent) rates in a region. By working together and leading the way in testing and reporting, laboratories can hold the line on the spread of these deadly bacteria.
References
- U.S. Health and Human Services, Centers for Disease Control, “Antibiotic Resistance Threats in the United States, 2013,” http://www.cdc.gov/drugresistance/pdf/ar-threats-2013-508.pdf
- U.S. White House, “National Action Plan for Combating Antibiotic-Resistant Bacteria,” March 2015, https://www.whitehouse.gov/sites/default/files/docs/national_action_plan_for_combating_antibotic-resistant_bacteria.pdf
- McCoppin, Robert and Cynthia Dizikes, Chicago Tribune, “Superbug found at suburban hospital,” January 10, 2014, http://articles.chicagotribune.com/2014-01-10/health/ct-hospital-bacteria-exposure-met-20140110_1_bacteria-superbug-cre
- MMWR Morb Mortal Wkly Rep. 2014 Jan 3;62(51-52):1051. “Notes from the Field: New Delhi metallo-β-lactamase-producing Escherichia coli associated with endoscopic retrograde cholangiopancreatography – Illinois, 2013,” U.S. National Library of Medicine, National Institutes of Health, http://www.ncbi.nlm.nih.gov/pubmed/24381080
- Agency for Healthcare Research and Quality, U.S. Department of Health and Human Services, “Carbapenem-Resistant Enterobacteriaceae (CRE) Control and Prevention Toolkit,” AHRQ Publication No. 14-0028-EF April 2014, http://www.ahrq.gov/professionals/quality-patient-safety/patient-safety-resources/resources/cretoolkit/
