Clinical and Molecular Epidemiology of Extended-Spectrum Beta-Lactamase-Producing Klebsiella spp.: A Systematic Review and Meta-Analyses

RESEARCH ARTICLE Clinical and Molecular Epidemiology of Extended-Spectrum Beta-LactamaseProducing Klebsiella spp.: A Systematic Review and Meta-Analyses Tirza C. Hendrik, Anne F. Voor in ‘t holt, Margreet C. Vos* Department of Medical Microbiology and Infectious Diseases, Erasmus MC University Medical Center, Rotterdam, The Netherlands * Abstract OPEN ACCESS Citation: Hendrik TC, Voor in ‘t holt AF, Vos MC (2015) Clinical and Molecular Epidemiology of Extended-Spectrum Beta-Lactamase-Producing Klebsiella spp.: A Systematic Review and MetaAnalyses. PLoS ONE 10(10): e0140754. doi:10.1371/ journal.pone.0140754 Editor: Vishnu Chaturvedi, California Department of Public Health, UNITED STATES Healthcare-related infections caused by extended-spectrum beta-lactamase (ESBL)-producing Klebsiella spp. are of major concern. To control transmission, deep understanding of the transmission mechanisms is needed. This systematic review aimed to identify risk factors and sources, clonal relatedness using molecular techniques, and the most effective control strategies for ESBL-producing Klebsiella spp. A systematic search of PubMed, Embase, and Outbreak Database was performed. We identified 2771 articles from November 25th, 1960 until April 7th, 2014 of which 148 were included in the systematic review and 23 in a random-effects meta-analysis study. The random-effects meta-analyses showed that underlying disease or condition (odds ratio [OR] = 6.25; 95% confidence interval [CI] = 2.85 to 13.66) generated the highest pooled estimate. ESBL-producing Klebsiella spp. were spread through person-to-person contact and via sources in the environment; we identified both monoclonal and polyclonal presence. Multi-faceted interventions are needed to prevent transmission of ESBL-producing Klebsiella spp. Received: July 2, 2015 Accepted: September 30, 2015 Published: October 20, 2015 Copyright: © 2015 Hendrik et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability Statement: All relevant data are within the paper and its Supporting Information files. Funding: The authors received no specific funding for this work. Competing Interests: The authors have declared that no competing interests exist. Introduction Healthcare-related infections (HRIs) are a major clinical problem worldwide. In 2011, the World Health Organization (WHO) reported that in a mixed patient population the pooled HRI-prevalence was 10.1% in low- and middle-income countries and 7.6% in high-income countries [1]. Prolonged hospital stay, higher costs, increased antimicrobial resistance, and risk of potentially life-threatening conditions indicate the enormous burden of HRIs [2]. Further, we are facing HRIs caused by multidrug-resistant gram-negative bacteria (MDR-GNB) without a parallel progression of the novel antibiotic classes [3]. Klebsiella spp. have been recognized as the most frequent cause of MDR-GNB outbreaks, particularly after the emergence of the extended-spectrum beta-lactamase (ESBL) enzymes [4, 5]. As a result, infections in hospitalized patients with this ESBL-producing Klebsiella spp. have PLOS ONE | DOI:10.1371/journal.pone.0140754 October 20, 2015 1 / 23 Epidemiology of ESBL-Producing Klebsiella spp. raised public concern due to the clinical outcomes and limited antibiotic options [6]. Patients whose care requires devices, and patients who are identified with multiple antibiotic-resistant strains in the intensive care unit (ICU) are at highest risk to acquire an infection with an ESBLproducing Klebsiella spp. [7, 8]. High discriminatory subtyping methods are beneficial to determine clonality of the outbreak strains with pulsed-field gel electrophoresis (PFGE) as the wellknown ‘gold standard’ for molecular epidemiological studies and for current clinical use [9]. It requires deep understanding of all outbreaks to optimally control transmission of ESBLproducing Klebsiella spp. [10]. Recent guidelines about the management of MDR-GNB underscore the need of well-managed and multi-faceted interventions [11]. Therefore, it is necessary to investigate the transmission dynamics and the risk factors for hospital outbreaks. This systematic review aimed to answer the following four questions. First, what are the risk factors for the presence of ESBL-producing Klebsiella spp.? Second, what are the main sources and reservoirs for this microorganism? Third, how can we identify the transmission patterns and the clonal relatedness among isolates from patients who acquired ESBL-producing Klebsiella spp.? Fourth, what are the most effective control strategies for ESBL-producing Klebsiella spp.? Materials and Methods This systematic review and meta-analysis followed the guidelines outlined in the PRISMA statement (S1 File)[12]. Search Strategy and Selection Criteria We searched PubMed, Embase, and the Outbreak Database (until April 7th, 2014) to identify studies which examined the transmission of multidrug-resistant (MDR) Klebsiella spp., identified potential risk factors, described modes of transmission, described laboratory methods used for the identification, and described the effective interventions to prevent transmission of MDR Klebsiella spp. with using the terms as applied in S2 File. The search strategy was not limited by language, date of publication, country, study design, enzyme type, or patient characteristics. We excluded studies about: 1) pathogenesis, validation of molecular techniques, drug options, cost, 2) non-human studies, 3) studies only about carriers, health-care workers (HCWs), or family members, 4) studies only about environmental contamination, 5) case report with no statement on transmission, 6) non-hospital studies, 7) letters, editorials, communications, weekly reports, and reviews. However, we also searched the eligible citations of all relevant reviews. TCH initiated full searches and AFV independently repeated the search for a 5 percent subset of articles. Data Extraction We first screened all articles based on titles and abstracts and then we subsequently assessed the articles in full text according to the inclusion and exclusion criteria. TCH initiated the screening and extracted the data with help of AFV and MCV. To retrieve articles that could not be found in full-text, we contacted first authors or corresponding authors of 80 publications. We also contacted the authors of 16 publications to obtain missing information about associated factors and cluster analyses. We defined the categories of MDR Klebsiella spp. as ESBL, possible ESBL and non-ESBL. We used the ESBL definition according to group 2b Bush criteria [13]. We found several articles that showed resistance to cephalosporins before the term ‘ESBL’ was established in 1989 [14]. These studies were included as being ‘ESBL’. Ultim (...truncated)