3.1 Understanding the Epidemiology of KPC and the Apparent Inability of Standard Infection Control Practices To Contain and Control KPC
KPC was first reported in North Carolina in 2001, and to date it is the most common type of carbapenemase encountered in the United States. KPC is an enzyme that inactivates all β-lactam antibiotics, including penicillins, cephalosporins, monobactams, and carbapenems. Genes encoding for KPC enzymes are located on plasmids, and other resistance-factor genes are often linked on the same plasmid. There are 10 variants of KPC (KPC-2 to KPC-11). Klebsiella pneumoniae isolates positive for carbapenemases typically exhibit resistance to almost all available antimicrobial agents, and infection with a KPC-positive organism has been associated with high rates of morbidity and mortality, increased length of stay, and high costs. KPCs have also been found in many other gram-negative species including: Escherichia coli, Enterobacter species, Salmonella enterica, Proteus mirabilis, and Citrobacter freundii, Serratia species, Pseudomonas species, and Acinetobacter baumannii.
Since first described, KPC has spread rapidly in the United States as well as around the world. Endemic in areas such as the northeastern United States, Israel, Colombia, and Greece, KPC colonization is routinely found in patients in both acute- and long-term-care facilities, but reports of community-onset infections with KPC-producing organisms have been rare. Patient risk factors for KPC colonization include recent treatment with broad-spectrum antibiotics, advanced age, nursing home residence, or recent acute-care hospitalization. The rapid spread of KPC is thought to be related to the inter-institutional transfer of asymptomatic patients with rectal KPC colonization. The spread of KPC-producing organisms in health care settings represents a serious infection control issue.
Accurate detection of isolates harboring KPC remains challenging because automated susceptibility testing systems fail to detect low-level resistance. In addition, traditional infection control strategies that only target monitoring of clinical isolates as a trigger for initiating control interventions have not proved effective for KPC control, and are only addressing the "tip of the iceberg," since there are about 100 colonized patients for every infected patient.
Recently, the CDC has provided CRE prevention guidelines for health care professionals, acute- and long-term–care hospitals, and health departments. The recommendations emphasize the need to develop CRE prevention interventions on both a facility and regional basis. The new recommendations include enhancing compliance with hand hygiene, placing CRE-colonized or CRE-infected patients on contact isolation precautions, minimizing use of invasive medical devices, patient and staff cohorting (i.e. designated nursing staff working with colonized or infected patients), promoting antibiotic stewardship, and screening patients with risks for CRE. The CDC recommends that, in areas where CRE is endemic, health care facilities undertake two additional measures: active surveillance for CRE and use of chlorhexidine bath or wipes. Visit http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6209a3.htm?s_cid=mm6209a3_w and http://www.cdc.gov/hai/pdfs/cre/CRE-guidance-508.pdf (1.73 MB) for more information.
While active-surveillance-driven initiation of isolation precautions for MDRO control is a controversial topic in infection control circles, the literature suggests that active screening programs can effectively control MDRO prevalence when they rapidly identify colonized patients and place them into contact isolation precautions, such that a high percentage of total MDRO patient colonization days are spent as contact isolation days (see Burton, et al, below). Furthermore, numerous reports indicate that this strategy has reduced the prevalence of KPC colonization on a hospital unit, within an institution, and on a regional and national basis.
U.S. Centers for Disease Control and Prevention, National Center for Emerging and Zoonotic Infectious Diseases, Division of Healthcare Quality Promotion.Guidance for Control of Carbapenem-Resistant Enterobacteriaceae, 2012 CER Toolkit. Atlanta, GA: CDC. http://www.cdc.gov/hai/pdfs/cre/CRE-guidance-508.pdf (1.73 MB).
Siegel J, Rhinehart E, Jackson M, et al. Management of Multidrug-Resistant Organisms in Health Care Settings, 2006. Atlanta, GA: U.S. Centers for Disease Control and Prevention. http://www.cdc.gov/mmwr/preview/mmwrthml/mm5810a4.htm.
Peterson L, Diekma D. To screen or not to screen for methicillin-resistant Staphylococcus aureus. J Clin Microbiol 2010 March;48(3):683-689. PMCID: PMC2832433.
Currie B. Impact of molecular diagnostics on infection control. Inf Dis Special Edition 2011;14:11-15.
Kochar S, Sheard T, Sharma R, et al. Success of an infection control program to reduce the spread of carbapenem-resistant Klebsiella pneumoniae. Infect Control Hosp Epidemiol 2009 May;30(5):447-52. PMID: 19301985.
Burton N, Aguirre D, Leung S, et al. PCR based active surveillance for carbapenem-resistant Klebsiella pneumoniae (KPC) colonization with rapid initiation of contact isolation achieved significant reduction in KPC colonization prevalence in the ICUs of a NYC medical center. Presented as oral abstract at ID Week 2012, San Diego, CA.
Borer A, Eskira S, Nativ R, et al. A multifaceted intervention strategy for eradication of a hospital-wide outbreak caused by carbapenem-resistant Klebsiella pneumoniae in Southern Israel. Inf Control Hosp Epidemiol 2011 Dec;32(12):1158-65. Epub 2011 Oct 17. PMID: 22080653.
Ben-David D, Maor Y, Keller N, et al. Potential role of active surveillance in the control of a hospital-wide outbreak of carbapenem-resistant Klebsiella pneumoniae infection. Infect Control Hosp Epidemiol 2010 Jun;31(6):620-6. PMID: 20370465.
Munoz-Price L, Hayden MK, Lolans K, et al. Successful control of an outbreak of acute Klebsiella pneumoniae carbapenemase-producing K. pneumonia at a long-term acute care hospital. Infect Control Hosp Epidemiol 2010 Apr;31(4):341-7. PMID: 20175685.
Schwaber M. Lev B, Israel A, et al. Containment of a country-wide outbreak of carbapenem-resistant Klebsiella pneumoniae in Israeli hospitals via a nationally implemented intervention. Clin Infect Dis 2011 Apr 1;52(7):848-55. PMID: 21317398.
Detection of KPC has already proven itself to be a diagnostic problem for the clinical laboratory. 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. Particular issues with phenotypic or culture identification arise when measured minimum inhibitory concentrations are low, as phenotypic testing may misidentify some isolates as carbapenem susceptible when they are in fact KPC positive.
A variety of phenotypic (culture-based) approaches for the detection of KPC colonization have been reported in the literature. They rely on the use of selective screening plates to identify carbapenemase production, followed by speciation of the isolate using standard automated clinical microbiological systems routinely used. Selective screening plates have included:
- MacConkey agar plates supplemented with 1.0 µg/ml of meropenem.
- Selective and Disclosing Media (select for carbapenem resistant-colonies which are color tinged depending on species). These products are commercially available and are marketed as CHROM agar KPC, Brilliance CRE, Hardy CHROM carbapenemase, and Chrom ID.
Similar to routine diagnostic testing in the clinical lab, these screening plates will have issues with sensitivity and specificity, especially when carbapenem MICs are low. They are also associated with fairly long turnaround times to get results, and they require a trained microbiologist to pick appropriate colonies from the plates. They are labor intensive to perform and do not easily fit into clinical laboratory workflow patterns. On the other hand, they are relatively inexpensive and will work well in surveillance situations where rapid turnaround is not necessary. Typical turnaround times for phenotypic detection of KPC are 3–5 days.
A variety of molecular diagnostic approaches for KPC detection have been described in the literature. These approaches primarily consist of "homegrown" real-time multiplex polymerase chain reaction (PCR) assays. PCR primers have been designed to detect all known variants of the KPC gene (KP2 to KPC 12) and their sequences have been published. A single commercial product, Hy-KPC PCR (Hy Laboratories, Ltd.), is available. None of the assays are FDA approved. These assays have been proven to be highly sensitive and specific, with turnaround times of several hours, and have been optimized for use with direct swab samples. However, PCR testing will require purchase of specialized equipment and trained technicians. Successful KPC control interventions using PCR-driven active surveillance coupled with timely initiation of contact isolation have been previously reported. Rapid turnaround time may be critical to intervention success.
In summary, both traditional culture-based methodologies and PCR detection have been used successfully as part of KPC control efforts. While molecular detection methods appear to offer many advantages as a screening tool (rapid turnaround time and improved sensitivity and specificity), they are not FDA approved and are only commercially available on a limited basis.
Each institution will need to carefully choose among the available screening methodologies to support their active surveillance program, and lack of ability to implement molecular testing should not otherwise prevent pursuit of aggressive CRE control efforts using existing culture techniques.
Birgy A, Bidet P, Genel N, et al. Phenotypic screening of carbapenemases and associated β-lactamases in carbapenem-resistant Enterobateriaceae. J Clin Microbiol 2012 Apr;50(4):1295-1302. Epub 2012 Jan 18. PMID: 22259214.
Wilkinson KM, Winstanley TG, Lanyon C, et al. Comparison of four chromogenic culture media for carbapenemase-producing Enterobateriaceae. J Clin Microbiol 2012 Sep;50(9):3102-4. Epub 2012 Jul 3. PMID: 22760041.
Singh K, Managold KA, Wyant K, et al. Rectal screening for Klebsiella pneumoniae carbapenemases: comparison of real-time PCR and culture using two selective screening agar plates. J Clin Microbiol 2012 Aug;50(8):2596-2600. Epub 2012 May 23. PMID: 22622443.
Richter SN, Frasson I, Biasolo MA, et al. Ultrarapid detection of bla KPC ½-12 from perirectal and nasal swabs by use of real time PCR. J Clin Microbiol 2012 May;50 (5):1718-1720. Epub 2012 Feb 29. PMID: 22378915.
Chen L, Mediavilla JR, Endimiani A, et al. Mulitplex real-time PCR assay for detection and classification of Klebsiella pneumoniae carbapenemase gene (blaKPC) variants. J Clin Microbiol 2011 Feb;49(2):579-585. Epub 2010 Dec 1. PMID: 21123529.