Johann D. D. Pitout

Extended-spectrum β-lactamase-producing Enterobacteriaceae: an emerging public-health concern

The medical community relies on clinical expertise and published guidelines to assist physicians with choices in empirical therapy for system-based infectious syndromes, such as community-acquired pneumonia and urinary-tract infections (UTIs). From the late 1990s, multidrug-resistant Enterobacteriaceae (mostly Escherichia coli) that produce extended-spectrum beta lactamases (ESBLs), such as the CTX-M enzymes, have emerged within the community setting as an important cause of UTIs. Recent reports have also described ESBL-producing E coli as a cause of bloodstream infections associated with these community-onset UTIs. The carbapenems are widely regarded as the drugs of choice for the treatment of severe infections caused by ESBL-producing Enterobacteriaceae, although comparative clinical trials are scarce. Thus, more rapid diagnostic testing of ESBL-producing bacteria and the possible modification of guidelines for community-onset bacteraemia associated with UTIs are required.

Clinical epidemiology of the global expansion of Klebsiella pneumoniae carbapenemases.

Klebsiella pneumoniae carbapenemases (KPCs) were originally identified in the USA in 1996. Since then, these versatile β-lactamases have spread internationally among Gram-negative bacteria, especially K pneumoniae, although their precise epidemiology is diverse across countries and regions. The mortality described among patients infected with organisms positive for KPC is high, perhaps as a result of the limited antibiotic options remaining (often colistin, tigecycline, or aminoglycosides). Triple drug combinations using colistin, tigecycline, and imipenem have recently been associated with improved survival among patients with bacteraemia. In this Review, we summarise the epidemiology of KPCs across continents, and discuss issues around detection, present antibiotic options and those in development, treatment outcome and mortality, and infection control. In view of the limitations of present treatments and the paucity of new drugs in the pipeline, infection control must be our primary defence for now.

Dissemination of Clonally Related Escherichia coli Strains Expressing Extended-Spectrum β-Lactamase CTX-M-15

E. coli ST131 and ST405 and multidrug-resistant IncFII plasmids may determine spread of this lactamase.

Molecular epidemiology of Escherichia coli producing CTX-M β-lactamases: the worldwide emergence of clone ST131 O25:H4

Since 2000, Escherichia coli producing CTX-M enzymes have emerged worldwide as important causes of community-onset urinary tract and bloodstream infections owing to extended-spectrum beta-lactamase (ESBL)-producing bacteria. Molecular epidemiological studies suggested that the sudden worldwide increase of CTX-M-15-producing E. coli was mainly due to a single clone (ST131) and that foreign travel to high-risk areas, such as the Indian subcontinent, might in part play a role in the spread of this clone across different continents. Empirical antibiotic coverage for these resistant organisms should be considered in community patients presenting with sepsis involving the urinary tract, especially if the patient recently travelled to a high-risk area. If this emerging public health threat is ignored, it is possible that the medical community may be forced, in the near future, to use carbapenems as the first choice for the empirical treatment of serious infections associated with urinary tract infections originating from the community.

A Multinational Survey of Risk Factors for Infection with Extended-Spectrum β-Lactamase-Producing Enterobacteriaceae in Nonhospitalized Patients

BACKGROUND Infections caused by extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae are increasing in frequency and are associated with high mortality rates. Circulation of CTX-M-type ESBLs in the community is of particular concern, because it may confound standard infection-control measures. METHODS We analyzed the results of epidemiologic studies of infection caused by ESBL-producing Enterobacteriaceae in nonhospitalized patients from 6 centers in Europe, Asia, and North America. Risk factors for infection with an ESBL-producing organism were identified by univariate and multivariate analyses. RESULTS A total of 983 patient-specific isolates were reviewed (890 [90.5%] of which were Escherichia coli, 68 [6.9%] of which were Klebsiella species, and 25 [2.5%] of which were Proteus mirabilis); 339 [34.5%] of the isolates produced ESBLs. CTX-M types were the most frequent ESBLs (accounting for 65%). Rates of co-resistance to ciprofloxacin among ESBL-producing isolates were high (>70%), but significant variation was seen among centers with respect to rates of resistance to gentamicin, amoxicillin-clavulanate, and trimethoprim-sulfamethoxazole. Similar risk factors for infection with an ESBL-producing organism were found in the different participating centers. Significant risk factors, identified by multivariate analysis, were recent antibiotic use, residence in a long-term care facility, recent hospitalization, age 65 years, and male sex (area under the receiver-operator characteristic [ROC] curve, 0.80). However, 34% of ESBL-producing isolates (115 of 336 isolates) were obtained from patients with no recent health care contact; the area under the ROC curve for the multivariate model for this group of patients was only 0.70, which indicated poorer predictive value. CONCLUSIONS Community-acquired ESBL-producing Enterobacteriaceae are now prevalent worldwide, necessitating international collaboration. Novel approaches are required to adequately address issues such as empirical treatment for severe community-acquired infection and infection control.

Infections with extended-spectrum beta-lactamase-producing enterobacteriaceae: changing epidemiology and drug treatment choices.

Since 2000, Escherichia coli producing CTX-M enzymes (especially CTX-M-15) have emerged worldwide as important causes of community-onset urinary tract infections (UTIs) and bloodstream infections due to extended-spectrum β-lactamase (ESBL)-producing bacteria. Molecular epidemiology studies suggested that the sudden worldwide increase of CTX-M-15-producing E. coli is mostly due to a single clone named ST131 and that foreign travel to high-risk areas such as the Indian subcontinent might in part play a role in the spread of this clone across different continents. Empirical antibacterial coverage for these resistant organisms should be considered in community patients presenting with sepsis involving the urinary tract especially if a patient recently travelled to a high-risk area. Infections due to ESBL-producing Enterobacteriaceae are associated with a delay in initiation of appropriate antibacterial therapy, which consequently prolongs hospital stays and increases hospital costs. Failure to initiate appropriate antibacterial therapy from the start appears to be responsible for higher patient mortality. The carbapenems are widely regarded as the drugs of choice for the treatment of severe infections due to ESBL-producing Enterobacteriaceae, although comparative clinical trials are lacking. Agents that may be useful for the treatment of ESBL-associated UTIs include fosfomycin, nitrofurantoin and temocillin. If this emerging public health threat is ignored, it is possible that clinicians may be forced in the near future to use the carbapenems as the first choice for empirical treatment of serious infections associated with UTIs originating from the community.Since 2000, Escherichia coli producing CTX-M enzymes (especially CTX-M-15) have emerged worldwide as important causes of community-onset urinary tract infections (UTIs) and bloodstream infections due to extended-spectrum beta-lactamase (ESBL)-producing bacteria. Molecular epidemiology studies suggested that the sudden worldwide increase of CTX-M-15-producing E. coli is mostly due to a single clone named ST131 and that foreign travel to high-risk areas such as the Indian subcontinent might in part play a role in the spread of this clone across different continents. Empirical antibacterial coverage for these resistant organisms should be considered in community patients presenting with sepsis involving the urinary tract especially if a patient recently travelled to a high-risk area. Infections due to ESBL-producing Enterobacteriaceae are associated with a delay in initiation of appropriate antibacterial therapy, which consequently prolongs hospital stays and increases hospital costs. Failure to initiate appropriate antibacterial therapy from the start appears to be responsible for higher patient mortality. The carbapenems are widely regarded as the drugs of choice for the treatment of severe infections due to ESBL-producing Enterobacteriaceae, although comparative clinical trials are lacking. Agents that may be useful for the treatment of ESBL-associated UTIs include fosfomycin, nitrofurantoin and temocillin. If this emerging public health threat is ignored, it is possible that clinicians may be forced in the near future to use the carbapenems as the first choice for empirical treatment of serious infections associated with UTIs originating from the community.

DETECTION OF PSEUDOMONAS AERUGINOSA PRODUCING METALLO-BETA-LACTAMASES IN A LARGE CENTRALIZED LABORATORY

ABSTRACT Metallo-β-lactamases (MBLs) have been increasingly recognized from clinical isolates worldwide, but the laboratory detection of these strains is not well defined. We report a study that developed an EDTA disk screen test and a molecular diagnostic assay for the detection of MBL-producing Pseudomonas aeruginosa. Using NCCLS disk methodology, inhibition zone diameters were determined in tests with imipenem (IPM) and meropenem (MEM) disks alone and in combination with 930 μg of EDTA. This test was compared with the MBL Etest. The duplex PCR assay showed 100% sensitivity and specificity for detecting MBL-producing control strains. Of the 241 clinical strains of IPM-nonsusceptible P. aeruginosa from the Calgary Health Region isolated from 2002 to 2004, 110/241 (46%) were MBL positive using phenotypic methods while 107/241 (45%) were PCR positive for MBL genes: 103/241 (43%) for blaVIM and 4/241 (2%) for blaIMP. The EDTA disk screen test using MEM showed 100% sensitivity and 97% specificity for detecting MBLs in control and clinical strains. The EDTA disk screen test is simple to perform and to interpret and can easily be introduced into the workflow of a clinical laboratory. We recommend that all IPM-nonsusceptible P. aeruginosa isolates be routinely screened for MBL production using the EDTA disk screen test and that PCR confirmation be performed at a regional laboratory.

Carbapenemases: molecular diversity and clinical consequences

Carbapenemases are beta-lactamases that hydrolyze most beta-lactams including carbapenems. Carbapenemases are classified in four molecular classes; those belonging to class A are the chromosomally-encoded and clavulanic acid-inhibited IMI, NMC-A and SME, identified in Enterobacter cloacae and Serratia marcescens; the plasmid-encoded KPC enzymes identified in Enterobacteriaceae (and rarely in Pseudomonas aeruginosa); and the GES-type enzymes identified in Enterobacteriaceae and P. aeruginosa. The class B enzymes are the most clinically-significant carbapenemases; they are metallo-beta-lactamases, mostly of the IMP and the VIM series. They have been reported worldwide and their genes are plasmid- and integron-located, hydrolyzing all beta-lactams with the exception of aztreonam. One single plasmid-mediated AmpC beta-lactamase, CMY-10, identified in an Enterobacter aerogenes isolate, has been shown to be a cephaslosporinase with some carbapenemase properties. Finally, the class D carbapenemases are being increasingly reported, mostly in Acinetobacter baumannii, and they compromise the efficacy of imipenem and meropenem significantly.

Phenotypic and Molecular Detection of CTX-M-β-Lactamases Produced by Escherichia coli and Klebsiella spp.

ABSTRACT Organisms producing CTX-M-β-lactamases are emerging around the world as a source of resistance to oxyiminocephalosporins such as cefotaxime (CTX). However, the laboratory detection of these strains is not well defined. In this study, a molecular detection assay for the identification of CTX-M-β-lactamase genes was developed and used to investigate the prevalence of these enzymes among clinical isolates of Escherichia coli and Klebsiella species in the Calgary Health Region during 2000 to 2002. In addition, National Committee for Clinical Laboratory Standards (NCCLS) recommendations were evaluated for the ability to detect isolates with CTX-M extended-spectrum β-lactamases (ESBLs). The PCR assay consisted of four primer sets and demonstrated 100% specificity and sensitivity for detecting different groups of CTX-M-β-lactamases in control strains producing well-characterized ESBLs. Using these primer sets, 175 clinical strains producing ESBLs were examined for the presence of CTX-M enzymes; 24 (14%) were positive for blaCTX-M-1-like genes, 95 (54%) were positive for blaCTX-M-14-like genes, and the remaining 56 (32%) were negative for blaCTX-M genes. Following the NCCLS recommendations for ESBL testing, all of the control and clinical strains were detected when screened with cefpodoxime and when both cefotaxime and ceftazidime with clavulanate were used as confirmation tests.

The Role of Epidemic Resistance Plasmids and International High-Risk Clones in the Spread of Multidrug-Resistant Enterobacteriaceae

SUMMARY Escherichia coli sequence type 131 (ST131) and Klebsiella pneumoniae ST258 emerged in the 2000s as important human pathogens, have spread extensively throughout the world, and are responsible for the rapid increase in antimicrobial resistance among E. coli and K. pneumoniae strains, respectively. E. coli ST131 causes extraintestinal infections and is often fluoroquinolone resistant and associated with extended-spectrum β-lactamase production, especially CTX-M-15. K. pneumoniae ST258 causes urinary and respiratory tract infections and is associated with carbapenemases, most often KPC-2 and KPC-3. The most prevalent lineage within ST131 is named fimH30 because it contains the H30 variant of the type 1 fimbrial adhesin gene, and recent molecular studies have demonstrated that this lineage emerged in the early 2000s and was then followed by the rapid expansion of its sublineages H30-R and H30-Rx. K. pneumoniae ST258 comprises 2 distinct lineages, namely clade I and clade II. Moreover, it seems that ST258 is a hybrid clone that was created by a large recombination event between ST11 and ST442. Epidemic plasmids with bla CTX-M and bla KPC belonging to incompatibility group F have contributed significantly to the success of these clones. E. coli ST131 and K. pneumoniae ST258 are the quintessential examples of international multidrug-resistant high-risk clones.