Marina Warner

Bio: Marina Warner is an academic researcher from Public Health England. The author has contributed to research in topics: Methicillin-resistant Staphylococcus aureus & Klebsiella pneumoniae. The author has an hindex of 47, co-authored 115 publications receiving 9784 citations. Previous affiliations of Marina Warner include Health Protection Agency & University of East Anglia.

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

Abstract: 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 UK's national reference laboratory. Antibiotic susceptibilities were assessed, and the presence of the carbapenem resistance gene bla NDM-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.

Community and hospital spread of Escherichia coli producing CTX-M extended-spectrum β-lactamases in the UK

Abstract: Objectives: During 2003, the Health Protection Agency’s Antibiotic Resistance Monitoring and Reference Laboratory began to receive isolates of Escherichia coli for confirmation of extended-spectrum b-lactamase production with a phenotype implying a CTX-M-type b-lactamase, i.e. MICs of cefotaxime > _8-fold higher than MICs of ceftazidime. Many were referred as being from community patients. We examined 291 CTX-M-producing isolates from the UK and investigated the genetic basis of their phenotype. Methods: PCR was used to detect alleles encoding CTX-M enzymes and to assign these to their blaCTX-M phylogenetic groups. Selected alleles were sequenced. Producers were compared by analysis of banding patterns generated by pulsed-field gel electrophoresis of Xba I-digested genomic DNA. MICs were determined by an agar dilution method or by Etest. Results: Of 291 CTX-M-producing E. coli isolates studied from 42 UK centres, 70 (24%) were reportedly from community patients, many of whom had only limited recent hospital contact. Community isolates were referred by 12 centres. Two hundred and seventy-nine (95.9%) producers contained genes encoding group 1 CTX-M enzymes and 12 contained blaCTX-M-9-like alleles. An epidemic CTX-M-15-producing strain was identified, with 110 community and inpatient isolates referred from six centres. Representatives of four other major strains also produced CTX-M-15, as did several sporadic isolates examined. Most producers were multi-resistant to fluoroquinolones, trimethoprim, tetracycline and aminoglycosides as well as to non-carbapenem b-lactams. Conclusions: CTX-M-producing E. coli are a rapidly developing problem in the UK, with CTX-M-15 particularly common. The diversity of producers and geographical scatter of referring laboratories indicates wide dissemination of blaCTX-M genes. Because of the public health implications, including for the treatment of community-acquired urinary tract infections, the spread of these strains—and CTX-M-15 b-lactamase in particular—merits close monitoring.

Dominance of EMRSA-15 and -16 among MRSA causing nosocomial bacteraemia in the UK: analysis of isolates from the European Antimicrobial Resistance Surveillance System (EARSS)

Abstract: Sir, The scale of the public health problem posed by methicillin-resistant Staphylococcus aureus (MRSA) in England and Wales increased significantly during the 1990s. Most dramatically, the proportion of cases of S. aureus bacteraemia due to MRSA increased from 1–2% in 1990–1992 to c. 40% in 2000. This increase coincided with the emergence of two particular epidemic MRSA (EMRSA) strains, EMRSA-15 and EMRSA-16, which now dominate MRSA submissions to the S. aureus Reference Service (SaRS) of the Laboratory of Hospital Infection. Nevertheless, EMRSA-15 and -16 have not formally been shown to be the principal agents of MRSA bacteraemia in the UK. Increasing MRSA prevalence rates have also been documented in many other countries. In response to widespread concern about resistance, the European Commission (Directorate General V) has funded pan-European surveillance of resistance. This programme, designated the European Antimicrobial Resistance Surveillance System (EARSS), currently has participants from all countries of the EU, plus Iceland, Norway and Switzerland. Since its commencement in late 1998, EARSS has focused on MRSA from nosocomial bacteraemia and penicillin-resistant pneumococci from community-acquired bacteraemia or meningitis. In the participating countries, data are collected from sentinel laboratories by national co-ordinators, then submitted to a central database maintained at the National Institute of Public Health and the Environment (RIVM), Bilthoven, The Netherlands. As methods of susceptibility testing vary between participating laboratories, the laboratories are encouraged, where possible, to obtain MIC data. In the UK, 26 geographically diverse hospitals are currently submitting data to EARSS. These hospitals record all their S. aureus bacteraemias and send all isolates identified as MRSA to the PHLS Antibiotic Resistance Monitoring and Reference Laboratory (ARMRL) for confirmation of resistance. This is undertaken by the agar incorporation method, and MICs are determined not only for methicillin, but for a range of other antibiotics including vancomycin, teicoplanin, erythromycin, ciprofloxacin, gentamicin, fusidic acid and rifampicin. Between late 1998 and the second quarter of 2000, 591 MRSA isolates were received by ARMRL under the aegis of EARSS, representing 37% of all S. aureus from bacteraemias reported by the participating laboratories. This prevalence rate is comparable to that among all S. aureus bacteraemias reported to the PHLS over approximately the same period. Comparative MRSA prevalence data for other countries participating in EARSS can be obtained from the EARSS website. All MRSA isolates submitted to ARMRL were additionally characterized by phage typing in the SaRS, which showed that 60.2% were EMRSA-15 and 35.4% were EMRSA-16. Isolates of EMRSA-15 were encountered in 25 of the 26 participating hospitals and EMRSA-16 occurred in 19. Although EMRSA-15 and -16 were already known to occur in many hospitals throughout the UK, our finding that they comprised 95.6% of MRSA from cases of bacteraemia is the first direct confirmation of their predominant role in bloodstream infections. This raises the intriguing question of whether the increase in the prevalence of MRSA bacteraemia reflects greater virulence of EMRSA-15 and -16, or simply that, by virtue of being among the most prevalent S. aureus strains in or on colonized patients, EMRSA-15 and -16 are among the strains most likely to cause endogenous bacteraemia. Further work on the epidemiology and pathogenicity of EMRSA-15 and -16 may give further insight into the success of EMRSA-15 and -16 in invasive disease.

Activity of aminoglycosides, including ACHN-490, against carbapenem-resistant Enterobacteriaceae isolates

Abstract: Background The emergence of carbapenemases in Enterobacteriaceae is driving a search for therapeutic alternatives. We tested ACHN-490, a sisomicin derivative that evades all plasmid-mediated aminoglycoside-modifying enzymes, against 82 carbapenem-resistant Enterobacteriaceae isolates. Comparators included internationally and locally available aminoglycosides. Methods The isolates variously had KPC (n?=?12), SME-1 (n?=?1), IMP (n?=?13), VIM (n?=?5), NDM (n?=?17) or OXA-48 (n?=?19) carbapenemases, or had combinations of impermeability with AmpC (n?=?5) or extended-spectrum s-lactamases (n?=?10). They included 53 Klebsiella spp., 19 Enterobacter spp., 6 Escherichia coli and 4 others; most were multiresistant. Genes were identified by PCR and sequencing; MICs were measured by CLSI agar dilution. Results ACHN-490 was active at =2 mg/L against all 65 isolates with carbapenem resistance mechanisms other than NDM enzyme, mostly with MICs of 0.12–0.5 mg/L; isepamicin was active against 63/65 at =8 mg/L. In contrast, 35% were resistant to gentamicin at 4 mg/L, 61% to tobramycin at 4 mg/L and 20% to amikacin at 16 mg/L. However, 16 of the 17 isolates with NDM-1 enzyme were resistant to ACHN-490, with MICs =64 mg/L, and these were cross-resistant to all other human-use aminoglycosides tested. Their behaviour was associated with ArmA and RmtC 16S rRNA methylases. Apramycin (a veterinary aminoglycoside) retained its full activity, with MICs of 4–8 mg/L versus strains with armA or rmtC, though resistance was seen in one Klebsiella pneumoniae with AAC(3)-IV (MIC =256 mg/L). Conclusions ACHN-490 has potent activity versus carbapenem-resistant isolates, except those also harbouring 16S rRNA methylases; isepamicin is also widely active, though less potent than ACHN-490. Evasion of 16S rRNA methylases by apramycin is noteworthy and may provide a starting point for future aminoglycoside development.

Emergence of plasmid-mediated colistin resistance mechanism MCR-1 in animals and human beings in China: A microbiological and molecular biological study

Abstract: Summary Background Until now, polymyxin resistance has involved chromosomal mutations but has never been reported via horizontal gene transfer. During a routine surveillance project on antimicrobial resistance in commensal Escherichia coli from food animals in China, a major increase of colistin resistance was observed. When an E coli strain, SHP45, possessing colistin resistance that could be transferred to another strain, was isolated from a pig, we conducted further analysis of possible plasmid-mediated polymyxin resistance. Herein, we report the emergence of the first plasmid-mediated polymyxin resistance mechanism, MCR-1, in Enterobacteriaceae. Methods The mcr-1 gene in E coli strain SHP45 was identified by whole plasmid sequencing and subcloning. MCR-1 mechanistic studies were done with sequence comparisons, homology modelling, and electrospray ionisation mass spectrometry. The prevalence of mcr-1 was investigated in E coli and Klebsiella pneumoniae strains collected from five provinces between April, 2011, and November, 2014. The ability of MCR-1 to confer polymyxin resistance in vivo was examined in a murine thigh model. Findings Polymyxin resistance was shown to be singularly due to the plasmid-mediated mcr-1 gene. The plasmid carrying mcr-1 was mobilised to an E coli recipient at a frequency of 10 −1 to 10 −3 cells per recipient cell by conjugation, and maintained in K pneumoniae and Pseudomonas aeruginosa . In an in-vivo model, production of MCR-1 negated the efficacy of colistin. MCR-1 is a member of the phosphoethanolamine transferase enzyme family, with expression in E coli resulting in the addition of phosphoethanolamine to lipid A. We observed mcr-1 carriage in E coli isolates collected from 78 (15%) of 523 samples of raw meat and 166 (21%) of 804 animals during 2011–14, and 16 (1%) of 1322 samples from inpatients with infection. Interpretation The emergence of MCR-1 heralds the breach of the last group of antibiotics, polymyxins, by plasmid-mediated resistance. Although currently confined to China, MCR-1 is likely to emulate other global resistance mechanisms such as NDM-1. Our findings emphasise the urgent need for coordinated global action in the fight against pan-drug-resistant Gram-negative bacteria. Funding Ministry of Science and Technology of China, National Natural Science Foundation of China.

Performance standards for antimicrobial susceptibility testing

Abstract: The data in the interpretive tables in this supplement are valid only if the methodologies in the following Clinical and Laboratory Standards Institute (CLSI)–approved standards are followed: M02-A12—Performance Standards for Antimicrobial Disk Susceptibility Tests; Approved Standard—Twelfth Edition; M07-A10—Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard—Tenth Edition; and M11-A8—Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria; Approved Standard—Eighth Edition. The standards contain information about both disk (M02) and dilution (M07 and M11) test procedures for aerobic and anaerobic bacteria. Clinicians depend heavily on information from the microbiology laboratory for treatment of their seriously ill patients. The clinical importance of antimicrobial susceptibility test results demands that these tests be performed under optimal conditions and that laboratories have the capability to provide results for the newest antimicrobial agents. The tabular information presented here represents the most current information for drug selection, interpretation, and QC using the procedures standardized in the most current editions of M02, M07, and M11. Users should replace the tables published earlier with these new tables. (Changes in the tables since the previous edition appear in boldface type.) Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Susceptibility Testing. 27th ed. CLSI supplement M100 (ISBN 1-56238-804-5 [Print]; ISBN 1-56238-805-3 [Electronic]). Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087 USA, 2017. The Clinical and Laboratory Standards Institute consensus process, which is the mechanism for moving a document through two or more levels of review by the health care community, is an ongoing process. Users should expect revised editions of any given document. Because rapid changes in technology may affect the procedures, methods, and protocols in a standard or guideline, users should replace outdated editions with the current editions of CLSI documents. Current editions are listed in the CLSI catalog and posted on our website at www.clsi.org. If you or your organization is not a member and would like to become one, and to request a copy of the catalog, contact us at: Telephone: +1.610.688.0100; Fax: +1.610.688.0700; E-Mail: customerservice@clsi.org; Website: www.clsi.org. M100S, 26th ed. January 2016 Replaces M100-S25 Performance Standards for Antimicrobial Susceptibility Testing Jean B. Patel, PhD, D(ABMM) Franklin R. Cockerill III, MD George M. Eliopoulos, MD Stephen G. Jenkins, PhD, D(ABMM), F(AAM) James S. Lewis II, PharmD Brandi Limbago, PhD David P. Nicolau, PharmD, FCCP, FIDSA Robin Patel, MD M ir Pow ll, MD, FRCP, FRCPath Sandra S. Richter, MD, D(ABMM) Jana M. Swenson, MMSc Maria M. Traczewski, BS, MT(ASCP) John D. Turnidge, MD Melvi P. Weinstein, MD Barbara L. Zimmer, PhD

Extended-spectrum beta-lactamases: a clinical update.

Abstract: 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.

Antibiotic resistance—the need for global solutions

Abstract: The causes of antibiotic resistance are complex and include human behaviour at many levels of society; the consequences affect everybody in the world. Similarities with climate change are evident. Many efforts have been made to describe the many different facets of antibiotic resistance and the interventions needed to meet the challenge. However, coordinated action is largely absent, especially at the political level, both nationally and internationally. Antibiotics paved the way for unprecedented medical and societal developments, and are today indispensible in all health systems. Achievements in modern medicine, such as major surgery, organ transplantation, treatment of preterm babies, and cancer chemotherapy, which we today take for granted, would not be possible without access to effective treatment for bacterial infections. Within just a few years, we might be faced with dire setbacks, medically, socially, and economically, unless real and unprecedented global coordinated actions are immediately taken. Here, we describe the global situation of antibiotic resistance, its major causes and consequences, and identify key areas in which action is urgently needed.

Acinetobacter baumannii: Emergence of a Successful Pathogen

Abstract: 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.