Combating the spread of carbapenemases in Enterobacteriaceae: a battle that infection prevention should not lose

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1 REVIEW / Combating the spread of carbapenemases in Enterobacteriaceae: a battle that infection prevention should not lose P. Savard 1,2 and T. M. Perl 3,4 1) Department of Microbiology, Infectiology and Immunology, Universite de Montreal, 2) Medical Microbiology and Infectious Diseases Department, Centre Hospitalier Universitaire de Montreal, H^opital St-Luc, Montreal, QC, Canada, 3) Division of Infectious Diseases, Department of Medicine, Johns Hopkins University School of Medicine and 4) Epidemiology and Infection Prevention, The Johns Hopkins Health System and Johns Hopkins Medicine, Baltimore, MD, USA Abstract The emergence of carbapenemases in Enterobacteriaceae has raised global concern among the scientific, medical and public health communities. Both the CDC and the WHO consider carbapenem-resistant Enterobacteriaceae (CRE) to constitute a significant threat that necessitates immediate action. In this article, we review the challenges faced by laboratory workers, infection prevention specialists and clinicians who are confronted with this emerging infection control issue. Keywords: Carbapenemase, carbapenem-resistant, Enterobacteriaceae, infection prevention, review Article published online: 01 July 2014 Clin Microbiol Infect 2014; 20: Corresponding author: P. Savard, Department of Microbiology, CHUM St-Luc, 1058 rue St-Denis, Montreal, QC H2X 3J4, Canada patrice.savard.chum@ssss.gouv.qc.ca Introduction When Kumarasamy et al. [1] published the first epidemiological report on the emergence of Enterobacteriaceae producing a new carbapenemase (New Delhi metallo-b-lactamase-1 (NDM-1)) in India, Pakistan and the UK in 2010, the impact on the medical and public health authorities was probably underestimated. Previously, other carbapenemases had been described in Enterobacteriaceae, the most clinically important being KPC, VIM, and IMP. However, since 2010 and the description of NDM-1, >975 articles related to carbapenemases, their mechanisms of action, epidemiology and treatment have been indexed in PubMed. The emergence of carbapenemases in Enterobacteriaceae has caused global concern among the scientific, medical and public health communities [2 11]. Both the CDC and the WHO consider carbapenem-resistant Enterobacteriaceae (CRE) to constitute a significant threat that necessitates immediate action [12,13]. In this article, we review the challenges faced by laboratory workers, infection prevention specialists and clinicians who are confronted with this emerging infection control issue. CRE constitute a significant emerging threat to the public health and medical communities. Between 2001 and 2011, the National Nosocomial Infection Surveillance System/National Healthcare Safety Network data revealed that carbapenem resistance had increased ten-fold, from 1.6% to 10.4% in Klebsiella isolates, and four-fold, from 1.2% to 4.2%, in Enterobacter isolates. Even more concerning in the USA is that approximately 4% of acute-care hospitals but 18% of long-term acute-care hospitals (LTACHs) reported at least one CRE infection in the first half of 2012 (CDC website: Of particular note is that production of carbapenemases is one of the mechanisms conferring resistance to carbapenems among Enterobacteriaceae. Once the CLSI lowered the interpretive breakpoints for carbapenems in 2010, a concomitant and anticipated increase in the proportion of reported CRE (including expandedspectrum b-lactamase or AmpC hyperproducers combined with porin loss) that were not carbapenemase producers was seen. Furthermore, although antimicrobial testing is widely available in the usual clinical laboratory setting, phenotypic and genotypic testing to detect the presence of carbapenemases in Clinical Microbiology and Infection ª2014 European Society of Clinical Microbiology and Infectious Diseases

2 CMI Savard and Perl Combating the spread of carbapenemases in Enterobacteriaceae 855 CRE is often lacking. For infection prevention specialists, these organisms are associated with high rates of morbidity and mortality [5], and, because of carbapenem resistance, therapeutic choices are extremely limited. For this reason, stopping their transmission should be a common goal. Carbapenemases are most often located on genetic elements such as plasmids, which are mobile and can be easily shared among Enterobacteriaceae. Klebsiella pneumoniae carbapenemase (KPC) emerged in the USA in 2001, and is still the most common carbapenemase reported. Among the carbapenem-resistant K. pneumoniae strains recently reported from 14 hospitals in New York City, 29% were KPC producers [14]. Carbapenem resistance among invasive K. pneumoniae strains increased in many countries between 2005 and 2011, according to the European CDC report: five countries (Greece, Cyprus, Italy, Hungary, and Portugal) reported rates of CRE of >1%, as opposed to only two (Greece and Germany) in 2005 [15]. This interactive database provides up-to-date information on antimicrobial resistance in different European countries ( KPCs have also been described in Asia, initially in China in 2004 and then in South Korea, Taiwan, and Singapore, and community acquisition is suspected [16]. However, beginning in 2009, several isolates carrying metallo-b-lactamases such as NDM, VIM and IMP have been documented in the USA, and are often imported from other countries. Although KPCs are endemic in some hospitals in the Mid-Atlantic USA, many of the metallo-b-lactamases have been isolated from patients who have received healthcare in other countries. Endemicity of NDM-1 in India was supported by data demonstrating that bacteria harbouring this enzyme were present in seepage and drinking water in New Delhi [17]. Few data are available from clinical settings in many parts of the world, because there is no well-defined national surveillance programme. NDM-1 distribution in the community in Singapore was also recently suggested, as it was found in 23% of all CRE isolates that revealed wide genetic diversity and no epidemiological link to other known endemic areas [16]. Finally, the worldwide spread of NDM-1 was recently reviewed and effectively presented by the use of interactive mapping [18]. Why Infection Prevention Matters The plasmid carrying the gene encoding the carbapenemase enzyme also harbours other resistance genes, making Enterobacteriaceae potentially resistant to almost all of the antimicrobials included in our armamentarium [19]. Without existing appropriate treatment for patients, high rates of morbidity and mortality have been documented in different studies, reaching 70% in some of them, with an attributable mortality for bacteraemia of 50% [20]. Additionally, prolonged hospital stays and increased healthcare costs have been reported for CRE infections [19]. Moreover, Enterobacteriaceae (Escherichia coli in particular) cause most human infections, and the mortality rate is higher when resistance to multiple drugs is present [5]. Given the fact that limited therapeutic agents are available, good infection prevention practices (beginning with standard precautions that should always be emphasized as the cornerstone to prevent transmission) are the primary methods for stemming the spread of CRE in the healthcare setting (Table 1). Outbreaks involving these highly resistant microrganisms can result in several deaths and extensive disruption at a given institution until they can be contained. Risk factors for colonization and/or infection with CRE mirror those previously associated with other multidrug-resistant organisms (Fig. 1). The risks of colonization and infection have been associated with critical illness and surgery, comorbid conditions, including organ or stem cell transplantation, the presence of a wound, the use of invasive devices or mechanical ventilation, and previous use of antimicrobials (including cephalosporins, carbapenems, and fluoroquinolones). Additionally, the risk of CRE colonization increases with: (i) an intensive-care unit stay; (ii) sharing a room with a known carrier of a CRE strain; (iii) being transferred between facilities or units; or (iv) prolonged hospitalization [21 28]. Of those colonized with a CRE strain, almost one in ten will subsequently show growth of the organism in a clinical sample [24]. Some of the risks can be minimized by the use of appropriate infection prevention practices. TABLE 1. Infection prevention and antimicrobial stewardship recommendations published to prevent the spread of carbapenem-resistant Enterobacteriaceae Required infection prevention measures Implement a surveillance programme to identify potential carriers (screening) Use contact isolation precautions for colonized and infected patients Cohort colonized and infected patients Enhance hand hygiene and support with audits Increase the frequency of environmental cleaning Limit the use of devices and remove unnecessary devices Implement antimicrobial stewardship, including a programme Educate healthcare workers about critical prevention measures Suggested enhanced infection prevention measures Limit patient transfers One-to-one nursing Decolonize patients with chlorhexidine gluconate baths

3 856 Clinical Microbiology and Infection, Volume 20 Number 9, September 2014 CMI Colonization COPD Malignancy Diaper Use Postsurgical conditions Transfers between units Sharing a room with carrier ICU stay Wounds Critical illness Invasive device use use of carbapenems/ cephalosporins/ fluoroquinolones Longer hospitalization Organ transplant Infection Advanced age Diabetes Previous use of metronidazole Previous use of glycopeptides FIG. 1. A schematic of risk factors associated with carbapenem-resistant Enterobacteriaceae colonization, infection, or both. Those in italics are potentially preventable with appropriate infection control or antimicrobial stewardship. COPD, chronic obstructive pulmonary disease; ICU, intensive-care unit. Worldwide, authorities have published guidance for laboratories and infection prevention specialists to better manage CRE (including NDM, VIM, IMP and KPC producers) [19,25]. Schwaber and Carmeli also reported the Israeli experience and the strategies implemented when the government had to contain a decade-long but rapid spread of KPC-producing Enterobacteriaceae [20]. Bundled interventions are required to control CRE transmission. Hand hygiene and standard precautions remain the cornerstone of the prevention strategies. The use of surveillance cultures to identify unrecognized carriers, contact precautions and isolation with or without cohorting of patients and staff, enhanced antimicrobial stewardship to prevent the emergence of resistance and enhanced environmental cleaning are all viewed as important and are reviewed here. All of these interventions require educated healthcare workers, and have been recommended to control the spread of other multidrug-resistant organisms. The recommended practices are extrapolated from information about other Gram-negative bacteria, past experience, and the magnitude of resistance. These recommendations have been effective in outbreak settings, although additional supporting evidence is needed in endemic situations. Additional infection prevention practices that seem to be relevant to carbapenemase producers merit our attention, and include the screening of travellers, because of the risk of colonization or infection associated with global travel, immigration, and medical tourism, and high-risk healthcare facilities such as long-term-care facilities. Identifying Carriers: Epidemiological Surveys and Screening Cultures Expert panels have identified key elements to prevent the spread of CRE. One of the primary mechanisms is to act pro-actively and survey for those at risk of being colonized or infected, and some recommend that we should pre-emptively isolate high-risk individuals with contact precautions [9]. Studies have found that patients asymptomatically colonized with CRE constitute a reservoir for transmission of the pathogen to others, highlighting the importance of timely detection [29]. Screening activities can be developed that reflect the epidemiology of the setting, depending on whether the institution has a low prevalence or no known cases of CRE, or whether it is located in an endemic area [13]. In institutions with a low prevalence, public health authorities worldwide have recommended the initial use of epidemiological surveys (screening with rectal swabs sent for culture) to identify high-risk patients, including those returning from endemic areas who were hospitalized while abroad or who have been transferred from a healthcare facility where the prevalence is high [13,30,31]. For example, nurses screen patients in the emergency department or at admission by asking about travel or hospitalization abroad or in endemic institutions during the last year. This early initial evaluation may be essential in low-prevalence areas, given that there are insufficient data at this point to recommend active surveillance cultures for all admitted patients in that setting [30]. On the other hand, based on recent findings, institutions with a high prevalence, located in endemic areas or facing an outbreak situation should strongly consider active screening of all patients deemed to be at risk, including those previously colonized or infected, and pre-emptively isolating them with contact precautions. The Israeli Ministry of Health implemented this strategy to control the spread of CRE among all: (i) ward contacts of patients growing CRE; (ii) patients transferred from another hospital; and (iii) patients housed in wards with a high prevalence in the previous months [20]. Various reports support several practices when a hospital identifies an outbreak. The first is to identify whether there has been spread by culturing contacts of cases and to maintain surveillance cultures for at least 2 weeks after the last carrier has been discharged from the hospital [32]. Second, random point-prevalence surveys on previously affected units are also

4 CMI Savard and Perl Combating the spread of carbapenemases in Enterobacteriaceae 857 advised [32]. On the basis of several guidelines, the rectal site (reflecting the colonic content) is most commonly screened for CRE [13,30,31,33]. Other frequently colonized sites that can be cultured include urine, wounds, throat or nares, groin, and catheters. As yet, there has been no systematic comparative study performed to identify the most efficacious site to screen for carbapenemase-producing organisms. One recent study determined that the rectum was the single most sensitive site for detection of KPC producers (sensitivity of 88%), and adding an inguinal skin swab increased the sensitivity to 100% [34]. Detecting gastrointestinal carriers is challenging, and several different screening protocols and types of medium are employed in clinical laboratories. The choice of method should be dictated by the associated costs and the technical skills required. Recommendations vary, and examples include plating the screening specimen on a selective medium (including MacConkey) with previous overnight incubation in selective enrichment broth containing a carbapenem disk (usually meropenem) [35]; the sensitivity and specificity range from 47% to 99% and from 10% to 86%, respectively [36,37]. A new medium, SUPERCARBA, was specifically developed to detect carbapenemase producers among Enterobacteriaceae with a sensitivity and specificity of 96% and 82%, respectively; also, it seems to be easier to use in the clinical laboratory [38,39]. Colorimetric agars have also been used for screening carbapenemase producers, with varying sensitivity and specificity, depending on the medium used and the carbapenemase enzyme involved (range: 40 97% for sensitivity and 6 100% for specificity) [36,37,39,40]. A new chromogenic medium, chromid Carba (biomerieux, Lyon, France), designed specifically for the screening of carbapenemase producers, has a sensitivity of % and a specificity of 76 97% [36,37,41]. Finally, molecular testing is emerging as a powerful technology, and was used in the Israeli national screening programme as the reference standard for CRE detection. It is noteworthy that, according to the Israeli experience, 15% of patients with a CRE identified by PCR had negative cultures with traditional techniques [20]. The higher sensitivity of PCR is notable, but it comes with higher costs and requires technical skills that are not available in every clinical laboratory. If it is performed in a reference laboratory, the delays make it impractical for infection control purposes. Furthermore, PCR may suffer from a lower specificity, which can be seen with the detection of carbapenemase genes in bacteria other than Enterobacteriaceae (NDM-1 can be recovered from Acinetobacter species or Pseudomonas species, for example). On the other hand, PCR is considered to be the preferred method for confirming the CRE resistance mechanism in Enterobacteriaceae [42]. Recently published data have shown that matrix-assisted laser desorption ionization time-of-flight mass spectrometry is also a powerful, rapid and cost-effective way of confirming the presence of most carbapenemases in Enterobacteriaceae [43,44]. Preventing Transmission: Contact Isolation and Cohorting For these highly resistant organisms, the use of contact precautions and single rooms is recommended. With multiple cases or an outbreak setting, physical separation of non-carriers, those at high risk of colonization/infection until the results of rectal screening at admission are known (pre-emptive contact isolation) and those found to be colonized or infected with CRE is commonly used, and contributes to controlling the outbreak situations [13,19,20,25,30,31,45]. Both contact isolation and this cohorting have been shown to limit the number of secondary cases and control outbreaks in different settings [9,46]. Furthermore, several studies have reported an additional measure that includes cohorting the nursing staff to prevent cross-transmission [8,25]. In 2007, several hospitals in Israel implemented this measure to stem the spread of CRE in acute-care hospitals [20]. The duration of isolation for those colonized or infected by CRE is unknown. The mean duration of excretion of CRE associated with gastrointestinal colonization varies significantly between 9.8 days and 19 days, and depends on the carbapenemase enzyme isolated in Enterobacteriaceae. One study found a median carriage time of 3 months [25], but prolonged excretion for up to 1 year has been documented [24,47 50]. Schechner et al. [24] documented three factors associated with persistent carriage: fluoroquinolone use, intra-facility transfer, and re-admission within 3 months of a culture growing CRE. Feldman et al. conducted a prospective cohort study of 125 patients with positive KPC screening test results. Three-quarters remained positive when tested within 30 days of the first positive test result, but <30% were still positive after 6 months. The persistence of positive screening cultures was associated with the presence of any catheter, low functional status, recent acquisition (<4 months), and stay in a long-term-care facility. Recent antimicrobial use was not associated with persistent carriage in this study, but a high proportion of patients in both groups had been recently exposed to antimicrobials [51]. For all of these reasons, and because good data on the number of tests required to confirm clearance are still lacking, many recommend that isolation be maintained until hospital discharge [19].

5 858 Clinical Microbiology and Infection, Volume 20 Number 9, September 2014 CMI Protecting Patients: Hand Hygiene Hand hygiene remains the key intervention to prevent transmission. Guidelines on CRE prevention from the CDC, Health Protection Agency, Health Canada and others all recommend strict hand hygiene for all staff and visitors entering and leaving the patient s room. Compliance with hand hygiene practices is of paramount importance to prevent CRE transmission. Furthermore, with a mathematical model, the transmission dynamics of carbapenemase-producing K. pneumoniae in a surgical unit in Greece showed that the minimum hand hygiene compliance rate needed to control the transmission of these bacteria was 50% [46]. According to these data, hand hygiene seems to be the single most important measure to control transmission. Other sources of indirect transmission of CRE have been reported, including contaminated endoscopes or ventilators [27]. In most of the outbreaks reported that were related to endoscopy, insufficient reprocessing was the main reason for nosocomial transmission [52]. Preventing CRE Emergence: Antimicrobial Stewardship The causal relationship between antimicrobial misuse and the emergence of antimicrobial-resistant pathogens is well documented, and supports the need for antimicrobial stewardship programmes to limit the development of resistance among bacteria (including Enterobacteriaceae) [53]. Good data on the real impact of antimicrobial stewardship programmes on the development or persistence of CRE colonization or infection are still lacking and, at times, the data are controversial. Different antimicrobial agents have been associated with an increased risk of CRE colonization in past studies, so many experts advocate decreasing antimicrobial consumption in general instead of targeting specific agents on the basis of these data [24,25,54,55]. As previously mentioned, not all studies have shown a link between antimicrobial exposure and an increased risk of colonization [51]. However, more data on the benefits of antimicrobial stewardship programmes for CRE development are needed. Environment Cleaning Although several studies have found low rates of recovery of CRE in the environment [34,49,56], contamination of the environment has been suspected in some outbreaks, and this has led to the recommendation of frequent cleaning of environmental surfaces (especially high-touch surfaces). The use of dedicated material to avoid indirect transmission via fomites to non-carriers is prudent, and extensive, enhanced cleaning has been used in different outbreaks [19,32,45]. The efficacy of new and adjuvant environment cleaning technologies is yet to be studied for multidrug-resistant Gram-negative bacteria, including CRE; however, Passaretti et al. [57] demonstrated a reduction (although not statistically significant) in the acquisition of multidrug-resistant Gram negative bacteria with vaporized hydrogen peroxide disinfection of the environment. This technology was used for additional disinfection after terminal cleaning in other settings where CRE were reported [32,45]. Infection Control in Hospitals with Limited Resources Most of the infection control strategies presented in this review were studied and implemented in hospitals located in high-income or medium-income countries, and might not be possible or sustainable in hospitals with limited resources. For these institutions, standard precautions with strict hand hygiene and auditing of compliance should be taken at all times. Epidemiological questionnaires to identify those at risk of being colonized (e.g. transferred from an endemic institution, area, or country) might be implemented to enhance case-finding. Targeting the most at-risk patients in the hospital (in intensive-care or oncology units, or those exposed to wide-spectrum antimicrobials and invasive devices) can also enhance resource utilization. The use of contact precautions (gown and gloves) when caring for a known carrier will also decrease transmission, and, in some settings, cohorting may be a practical solution. Other (enhanced) Infection Control Measures Other infection prevention strategies have also been used in different outbreaks to control the spread of CRE, but their effectiveness is still unclear. Education of healthcare personnel is part of outbreak management [25]. In 2011, in a KPC-producing K. pneumoniae outbreak that involved 18 patients (11 of whom died), universal gowns and gloves were utilized by all staff members and visitors on the affected intensive-care unit. Also, visiting was restricted [32]. Decolonization of patients by the use of daily chlorhexidine bathing was reported by Munoz-Price et al. [58] as part of a bundled intervention plan

6 CMI Savard and Perl Combating the spread of carbapenemases in Enterobacteriaceae 859 to control an outbreak of KPC-producing Klebsiella species in a long-term-care facility, and was found to be successful. people travelling around the world yearly who could be potential carriers. The Importance of Long-term-care Facilities and Travel for CRE Acquisition Two specific situations have been associated with an increased risk of CRE colonization, and differentiate our approach to CRE prevention and control from the practices related to other multidrug-resistant bacteria, especially Gram-negative bacteria. In the USA, several reports have associated LTACHs with high rates of CRE colonization and a high risk of transmission within the facility. This dynamic creates a continuous influx of colonized patients into acute-care hospitals [58 63]. Although the prevalence varies according to the geographical area surveyed, it can reach up to 54% [61]. The extensive network of exposure and the relationships between LTACHs, nursing homes and acute-care hospitals were nicely shown by Won et al. [64], using molecular epidemiological methods following an outbreak of KPC-producing Enterobacteriaceae. These studies support the need for integrated regional, if not national, approaches to CRE prevention, open channels of communication between institutions, and enhanced infection control policies in long-term-care facilities. Travel to endemic countries is associated with the importation of carbapenemase-producing Enterobacteriaceae into non-endemic settings, and was demonstrated vividly with one of these enzymes (NDM-1) following its description in India a few years ago. The introduction of NDM-1 to the UK was described in the first epidemiological study published on the then new resistance mechanism. The authors reported that 60% of the affected patients had travelled to India or Pakistan within 1 year, and many had been hospitalized abroad for medical emergencies or elective cosmetic surgery [1]. Since then, many reports have highlighted the importance of international travel (including tourism, medical tourism, and hospitalization abroad) as a potential source of carbapenemase-producing Enterobacteriaceae cases and outbreaks [9,42,65,66]. Furthermore, not all single cases reported can be epidemiologically linked to endemic regions, and a group of researchers from France hypothesized potential cross-transmission from healthcare workers, who can also become colonized when travelling abroad [67]; however, this merits further assessment. It is important for those who have been hospitalized in a foreign country with a high prevalence to be targeted first for screening and pre-emptive isolation. Again, this challenges the infection prevention specialist, as targeting those at risk is made even more difficult by the number of Conclusion CRE constitute an emerging threat and a worldwide concern. Given the limited antimicrobial therapy available at this point, infection prevention remains the primary opportunity that we have to stem the spread of these worrying organisms. Prevention strategies for these organisms are similar to those for other resistant microorganisms, and include hand hygiene, surveillance cultures, the use of barrier precautions and isolation, aggressive environmental cleaning, and, sometimes, enhanced measures. Most importantly, infection control practices are usually bundled, and should be tailored to the situation and available resources. Laboratory procedures have been refined recently, and require specific methods to identify organisms. Finally, it is paramount to act pro-actively and develop regional or national approaches to prevent transmission. 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