David L. Paterson

Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria: an international expert proposal for interim standard definitions for acquired resistance

Many different definitions for multidrug-resistant (MDR), extensively drug-resistant (XDR) and pandrug-resistant (PDR) bacteria are being used in the medical literature to characterize the different patterns of resistance found in healthcare-associated, antimicrobial-resistant bacteria. A group of international experts came together through a joint initiative by the European Centre for Disease Prevention and Control (ECDC) and the Centers for Disease Control and Prevention (CDC), to create a standardized international terminology with which to describe acquired resistance profiles in Staphylococcus aureus, Enterococcus spp., Enterobacteriaceae (other than Salmonella and Shigella), Pseudomonas aeruginosa and Acinetobacter spp., all bacteria often responsible for healthcare-associated infections and prone to multidrug resistance. Epidemiologically significant antimicrobial categories were constructed for each bacterium. Lists of antimicrobial categories proposed for antimicrobial susceptibility testing were created using documents and breakpoints from the Clinical Laboratory Standards Institute (CLSI), the European Committee on Antimicrobial Susceptibility Testing (EUCAST) and the United States Food and Drug Administration (FDA). MDR was defined as acquired non-susceptibility to at least one agent in three or more antimicrobial categories, XDR was defined as non-susceptibility to at least one agent in all but two or fewer antimicrobial categories (i.e. bacterial isolates remain susceptible to only one or two categories) and PDR was defined as non-susceptibility to all agents in all antimicrobial categories. To ensure correct application of these definitions, bacterial isolates should be tested against all or nearly all of the antimicrobial agents within the antimicrobial categories and selective reporting and suppression of results should be avoided.

EXTENDED-SPECTRUM BETA-LACTAMASES: A CLINICAL UPDATE

SUMMARY Extended-spectrum β-lactamases (ESBLs) are a rapidly evolving group of β-lactamases which share the ability to hydrolyze third-generation cephalosporins and aztreonam yet are inhibited by clavulanic acid. Typically, they derive from genes for TEM-1, TEM-2, or SHV-1 by mutations that alter the amino acid configuration around the active site of these β-lactamases. This extends the spectrum of β-lactam antibiotics susceptible to hydrolysis by these enzymes. An increasing number of ESBLs not of TEM or SHV lineage have recently been described. The presence of ESBLs carries tremendous clinical significance. The ESBLs are frequently plasmid encoded. Plasmids responsible for ESBL production frequently carry genes encoding resistance to other drug classes (for example, aminoglycosides). Therefore, antibiotic options in the treatment of ESBL-producing organisms are extremely limited. Carbapenems are the treatment of choice for serious infections due to ESBL-producing organisms, yet carbapenem-resistant isolates have recently been reported. ESBL-producing organisms may appear susceptible to some extended-spectrum cephalosporins. However, treatment with such antibiotics has been associated with high failure rates. There is substantial debate as to the optimal method to prevent this occurrence. It has been proposed that cephalosporin breakpoints for the Enterobacteriaceae should be altered so that the need for ESBL detection would be obviated. At present, however, organizations such as the Clinical and Laboratory Standards Institute (formerly the National Committee for Clinical Laboratory Standards) provide guidelines for the detection of ESBLs in klebsiellae and Escherichia coli. In common to all ESBL detection methods is the general principle that the activity of extended-spectrum cephalosporins against ESBL-producing organisms will be enhanced by the presence of clavulanic acid. ESBLs represent an impressive example of the ability of gram-negative bacteria to develop new antibiotic resistance mechanisms in the face of the introduction of new antimicrobial agents.

Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America Guidelines for Developing an Institutional Program to Enhance Antimicrobial Stewardship

Timothy H. Dellit, Robert C. Owens, John E. McGowan, Jr., Dale N. Gerding, Robert A. Weinstein, John P. Burke, W. Charles Huskins, David L. Paterson, Neil O. Fishman, Christopher F. Carpenter, P. J. Brennan, Marianne Billeter, and Thomas M. Hooton Harborview Medical Center and the University of Washington, Seattle; Maine Medical Center, Portland; Emory University, Atlanta, Georgia; Hines Veterans Affairs Hospital and Loyola University Stritch School of Medicine, Hines, and Stroger (Cook County) Hospital and Rush University Medical Center, Chicago, Illinois; University of Utah, Salt Lake City; Mayo Clinic College of Medicine, Rochester, Minnesota; University of Pittsburgh Medical Center, Pittsburgh, and University of Pennsylvania, Philadelphia, Pennsylvania; William Beaumont Hospital, Royal Oak, Michigan; Ochsner Health System, New Orleans, Louisiana; and University of Miami, Miami, Florida

Acinetobacter baumannii: Emergence of a Successful Pathogen

SUMMARY Acinetobacter baumannii has emerged as a highly troublesome pathogen for many institutions globally. As a consequence of its immense ability to acquire or upregulate antibiotic drug resistance determinants, it has justifiably been propelled to the forefront of scientific attention. Apart from its predilection for the seriously ill within intensive care units, A. baumannii has more recently caused a range of infectious syndromes in military personnel injured in the Iraq and Afghanistan conflicts. This review details the significant advances that have been made in our understanding of this remarkable organism over the last 10 years, including current taxonomy and species identification, issues with susceptibility testing, mechanisms of antibiotic resistance, global epidemiology, clinical impact of infection, host-pathogen interactions, and infection control and therapeutic considerations.

Emergence of a new antibiotic resistance mechanism in India, Pakistan, and the UK: a molecular, biological, and epidemiological study.

Summary Background Gram-negative Enterobacteriaceae with resistance to carbapenem conferred by New Delhi metallo-β-lactamase 1 (NDM-1) are potentially a major global health problem. We investigated the prevalence of NDM-1, in multidrug-resistant Enterobacteriaceae in India, Pakistan, and the UK. Methods Enterobacteriaceae isolates were studied from two major centres in India—Chennai (south India), Haryana (north India)—and those referred to the UKs national reference laboratory. Antibiotic susceptibilities were assessed, and the presence of the carbapenem resistance gene blaNDM-1 was established by PCR. Isolates were typed by pulsed-field gel electrophoresis of XbaI-restricted genomic DNA. Plasmids were analysed by S1 nuclease digestion and PCR typing. Case data for UK patients were reviewed for evidence of travel and recent admission to hospitals in India or Pakistan. Findings We identified 44 isolates with NDM-1 in Chennai, 26 in Haryana, 37 in the UK, and 73 in other sites in India and Pakistan. NDM-1 was mostly found among Escherichia coli (36) and Klebsiella pneumoniae (111), which were highly resistant to all antibiotics except to tigecycline and colistin. K pneumoniae isolates from Haryana were clonal but NDM-1 producers from the UK and Chennai were clonally diverse. Most isolates carried the NDM-1 gene on plasmids: those from UK and Chennai were readily transferable whereas those from Haryana were not conjugative. Many of the UK NDM-1 positive patients had travelled to India or Pakistan within the past year, or had links with these countries. Interpretation The potential of NDM-1 to be a worldwide public health problem is great, and co-ordinated international surveillance is needed. Funding European Union, Wellcome Trust, and Wyeth.

Critical care services and 2009 H1N1 influenza in Australia and New Zealand

BACKGROUND Planning for the treatment of infection with the 2009 pandemic influenza A (H1N1) virus through health care systems in developed countries during winter in the Northern Hemisphere is hampered by a lack of information from similar health care systems. METHODS We conducted an inception-cohort study in all Australian and New Zealand intensive care units (ICUs) during the winter of 2009 in the Southern Hemisphere. We calculated, per million inhabitants, the numbers of ICU admissions, bed-days, and days of mechanical ventilation due to infection with the 2009 H1N1 virus. We collected data on demographic and clinical characteristics of the patients and on treatments and outcomes. RESULTS From June 1 through August 31, 2009, a total of 722 patients with confirmed infection with the 2009 H1N1 virus (28.7 cases per million inhabitants; 95% confidence interval [CI], 26.5 to 30.8) were admitted to an ICU in Australia or New Zealand. Of the 722 patients, 669 (92.7%) were under 65 years of age and 66 (9.1%) were pregnant women; of the 601 adults for whom data were available, 172 (28.6%) had a body-mass index (the weight in kilograms divided by the square of the height in meters) greater than 35. Patients infected with the 2009 H1N1 virus were in the ICU for a total of 8815 bed-days (350 per million inhabitants). The median duration of treatment in the ICU was 7.0 days (interquartile range, 2.7 to 13.4); 456 of 706 patients (64.6%) with available data underwent mechanical ventilation for a median of 8 days (interquartile range, 4 to 16). The maximum daily occupancy of the ICU was 7.4 beds (95% CI, 6.3 to 8.5) per million inhabitants. As of September 7, 2009, a total of 103 of the 722 patients (14.3%; 95% CI, 11.7 to 16.9) had died, and 114 (15.8%) remained in the hospital. CONCLUSIONS The 2009 H1N1 virus had a substantial effect on ICUs during the winter in Australia and New Zealand. Our data can assist planning for the treatment of patients during the winter in the Northern Hemisphere.

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.

A large outbreak of Clostridium difficile‐associated disease with an unexpected proportion of deaths and colectomies at a teaching hospital following increased Fluoroquinolone use

BACKGROUND AND OBJECTIVE Fluoroquinolones have not been frequently implicated as a cause of Clostridium difficile outbreaks. Nosocomial C. difficile infections increased from 2.7 to 6.8 cases per 1000 discharges (P < .001). During the first 2 years of the outbreak, there were 253 nosocomial C. difficile infections; of these, 26 resulted in colectomy and 18 resulted in death. We conducted an investigation of a large C. difficile outbreak in our hospital to identify risk factors and characterize the outbreak. METHODS A retrospective case-control study of case-patients with C. difficile infection from January 2000 through April 2001 and control-patients matched by date of hospital admission, type of medical service, and length of stay; an analysis of inpatient antibiotic use; and antibiotic susceptibility testing and molecular subtyping of isolates were performed. RESULTS On logistic regression analysis, clindamycin (odds ratio [OR], 4.8; 95% confidence interval [CI95], 1.9-12.0), ceftriaxone (OR, 5.4; CI95, 1.8-15.8), and levofloxacin (OR, 2.0; CI95, 1.2-3.3) were independently associated with infection. The etiologic fractions for these three agents were 10.0%, 6.7%, and 30.8%, respectively. Fluoroquinolone use increased before the onset of the outbreak (P < .001); 59% of case-patients and 41% of control-patients had received this antibiotic class. The outbreak was polyclonal, although 52% of isolates belonged to two highly related molecular subtypes. CONCLUSIONS Exposure to levofloxacin was an independent risk factor for C. difficile-associated diarrhea and appeared to contribute substantially to the outbreak. Restricted use of levofloxacin and the other implicated antibiotics may be required to control the outbreak

Escherichia coli O25b-ST131: a pandemic, multiresistant, community-associated strain

Escherichia coli sequence type 131 (ST131) is a worldwide pandemic clone, causing predominantly community-onset antimicrobial-resistant infection. Its pandemic spread was identified in 2008 by utilizing multilocus sequence typing (MLST) of CTX-M-15 extended-spectrum β-lactamase-producing E. coli from three continents. Subsequent research has confirmed the worldwide prevalence of ST131 harbouring a broad range of virulence and resistance genes on a transferable plasmid. A high prevalence of the clone (∼30%-60%) has been identified amongst fluoroquinolone-resistant E. coli. In addition, it potentially harbours a variety of β-lactamase genes; most often, these include CTX-M family β-lactamases, and, less frequently, TEM, SHV and CMY β-lactamases. Our knowledge of ST131s geographical distribution is incomplete. A broad distribution has been demonstrated amongst antimicrobial-resistant E. coli from human infection in Europe (particularly the UK), North America, Canada, Japan and Korea. High rates are suggested from limited data in Asia, the Middle East and Africa. The clone has also been detected in companion animals, non-companion animals and foods. The clinical spectrum of disease described is similar to that for other E. coli, with urinary tract infection predominant. This can range from cystitis to life-threatening sepsis. Infection occurs in humans of all ages. Therapy must be tailored to the antimicrobial resistance phenotype of the infecting isolate and the site of infection. Phenotypic detection of the ST131 clone is not possible and DNA-based techniques, including MLST and PCR, are described.

Outcome of Cephalosporin Treatment for Serious Infections Due to Apparently Susceptible Organisms Producing Extended-Spectrum β-Lactamases: Implications for the Clinical Microbiology Laboratory

ABSTRACT Although extended-spectrum beta-lactamases (ESBLs) hydrolyze cephalosporin antibiotics, some ESBL-producing organisms are not resistant to all cephalosporins when tested in vitro. Some authors have suggested that screening klebsiellae or Escherichia colifor ESBL production is not clinically necessary, and when most recently surveyed the majority of American clinical microbiology laboratories did not make efforts to detect ESBLs. We performed a prospective, multinational study of Klebsiella pneumoniae bacteremia and identified 10 patients who were treated for ESBL-producingK. pneumoniae bacteremia with cephalosporins and whose infecting organisms were not resistant in vitro to the utilized cephalosporin. In addition, we reviewed 26 similar cases of severe infections which had previously been reported. Of these 36 patients, 4 had to be excluded from analysis. Of the remaining 32 patients, 100% (4 of 4) patients experienced clinical failure when MICs of the cephalosporin used for treatment were in the intermediate range and 54% (15 of 28) experienced failure when MICs of the cephalosporin used for treatment were in the susceptible range. Thus, it is clinically important to detect ESBL production by klebsiellae or E. coli even when cephalosporin MICs are in the susceptible range (≤ 8 μg/ml) and to report ESBL-producing organisms as resistant to aztreonam and all cephalosporins (with the exception of cephamycins).