Benjamin A. Rogers

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.

Country-to-Country Transfer of Patients and the Risk of Multi-Resistant Bacterial Infection

Management of patients with a history of healthcare contact in multiple countries is now a reality for many clinicians. Leisure tourism, the burgeoning industry of medical tourism, military conflict, natural disasters, and changing patterns of human migration may all contribute to this emerging epidemiological trend. Such individuals may be both vectors and victims of healthcare-associated infection with multiresistant bacteria. Current literature describes intercountry transfer of multiresistant Acinetobacter spp and Klebsiella pneumoniae (including Klebsiella pneumoniae carbapenemase- and New Delhi metallo-β-lactamase-producing strains), methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, and hypervirulent Clostridium difficile. Introduction of such organisms to new locations has led to their dissemination within hospitals. Healthcare institutions should have sound infection prevention strategies to mitigate the risk of dissemination of multiresistant organisms from patients who have been admitted to hospitals in other countries. Clinicians may also need to individualize empiric prescribing patterns to reflect the risk of multiresistant organisms in these patients.

Current use of aminoglycosides: indications, pharmacokinetics and monitoring for toxicity

The new Australian Therapeutic Guidelines: Antibiotic, version 14 have revised the recommendations for the use and monitoring of aminoglycosides. The guidelines have clear distinctions between empirical and directed therapy as well as revised recommendations about the monitoring of aminoglycosides. This has led many clinicians to review their current practice with regard to the use of aminoglycosides. This review summarizes why aminoglycosides are still a valid treatment option and discusses the rationale for current dosing regimens in Gram‐negative infections. In particular it focuses on the various methods for monitoring aminoglycosides that are currently being used. The aminoglycoside monitoring methods can be categorized into three groups: linear regression analysis (one compartment model), population methods and Bayesian estimation procedures. Although the population methods are easy to use and require minimal resources they can recommend clinically inappropriate doses as they have constant pharmacokinetic parameters and are not valid in special population groups, that is, renal impairment. The linear regression and Bayesian methods recommend more accurate dosage regimens; however, they require additional resources, such as information technology and healthcare personnel with background training in pharmacokinetics. The Bayesian methods offer additional advantages, such as calculation of doses based on a single serum concentration and optimization of the patients previous pharmacokinetic data, in order to determine subsequent dosage regimens. We recommend the Bayesian estimation procedures be used, wherever feasible. However, they require the expertise of healthcare practitioners with a good understanding of pharmacokinetic principles, such as clinical pharmacists/clinical pharmacologists, in order to make appropriate recommendations.

Infectious Complications Following Transrectal Ultrasound–Guided Prostate Biopsy: New Challenges in the Era of Multidrug-Resistant Escherichia coli

Transrectal ultrasound (TRUS)-guided prostate biopsy is currently considered the standard technique for obtaining tissue to make a histological diagnosis of prostatic carcinoma. Infectious complications following TRUS-guided prostate biopsy are well described, and are reportedly increasing in incidence. The role of antibiotic prophylaxis in reducing post-TRUS biopsy infections is now established, and many guidelines suggest that fluoroquinolone antimicrobials are the prophylactic agents of choice. Of note, however, recent reports suggest an emerging association between TRUS biopsy and subsequent infection with fluoroquinolone-resistant Escherichia coli. Against this background, we provide an overview of the epidemiology, prevention, and treatment of infectious complications following TRUS biopsy, in the wider context of increasing global antimicrobial resistance.

Do Human Extraintestinal Escherichia coli Infections Resistant to Expanded-Spectrum Cephalosporins Originate From Food-Producing Animals? A Systematic Review

To find out whether food-producing animals (FPAs) are a source of extraintestinal expanded-spectrum cephalosporin-resistant Escherichia coli (ESCR-EC) infections in humans, Medline, Embase, and the Cochrane Database of Systematic Reviews were systematically reviewed. Thirty-four original, peer-reviewed publications were identified for inclusion. Six molecular epidemiology studies supported the transfer of resistance via whole bacterium transmission (WBT), which was best characterized among poultry in the Netherlands. Thirteen molecular epidemiology studies supported transmission of resistance via mobile genetic elements, which demonstrated greater diversity of geography and host FPA. Seventeen molecular epidemiology studies did not support WBT and two did not support mobile genetic element-mediated transmission. Four observational epidemiology studies were consistent with zoonotic transmission. Overall, there is evidence that a proportion of human extraintestinal ESCR-EC infections originate from FPAs. Poultry, in particular, is probably a source, but the quantitative and geographical extent of the problem is unclear and requires further investigation.

Uropathogenic Escherichia coli Mediated Urinary Tract Infection

Urinary tract infection (UTI) is among the most common infectious diseases of humans and is the most common nosocomial infection in the developed world. They cause significant morbidity and mortality, with approximately 150 million cases globally per year. It is estimated that 40-50% of women and 5% of men will develop a UTI in their lifetime, and UTI accounts for more than 1 million hospitalizations and

Treatment Options for New Delhi Metallo-Beta-Lactamase-Harboring Enterobacteriaceae

1.6 billion in medical expenses each year in the USA. Uropathogenic E. coli (UPEC) is the primary cause of UTI. This review presents an overview of the primary virulence factors of UPEC, the major host responses to infection of the urinary tract, the emergence of specific multidrug resistant clones of UPEC, antibiotic treatment options for UPEC-mediated UTI and the current state of vaccine strategies as well as other novel anti-adhesive and prophylactic approaches to prevent UTI. New and emerging themes in UPEC research are also discussed in the context of future outlooks.

Vancomycin therapeutics and monitoring: a contemporary approach

The New Delhi metallo-β-lactamase gene (bla(NDM-1)) has emerged as a worldwide concern among isolates of Enterobacteriaceae. Its epidemiology is been strongly associated with travel and healthcare on the Indian Subcontinent. We report two cases of urinary tract infection with Enterobacteriaceae harboring a bla(NDM-1). Both cases presented as infection in community-dwelling individuals in Australia and were associated with travel to the Indian Subcontinent. One isolate of Escherichia coli harbored the previously undescribed enzyme variant bla(NDM-3), differing from bla(NDM-1) by a single nonsynonymous SNP conferring a putative peptide sequence change at the 95th position (ASP→ASN). The second was an Enterobacter cloacae harboring bla(NDM-1). Further genetic characterization included identification of additional β-lactamase and aminoglycoside resistance genes. Legacy antimicrobials were used for treatment. Oral therapy with nitrofurantoin was successful in one case, while combination of colistin and rifampicin was required in the second patient. Such infection, due to extensively drug-resistant pathogens, poses significant challenges in balancing the efficacy and toxicity of potential antimicrobial therapies.

Meropenem versus piperacillin-tazobactam for definitive treatment of bloodstream infections due to ceftriaxone non-susceptible Escherichia coli and Klebsiella spp (the MERINO trial): study protocol for a randomised controlled trial

Vancomycin remains a clinically useful antibiotic despite the advent of several alternative drugs. Optimising vancomycin therapy with therapeutic drug monitoring is widely recommended. The aim of therapeutic drug monitoring is to help the clinician to achieve target pharmacodynamic parameters in the case of vancomycin, an area under the concentration time curve/minimum inhibitory concentration ratio of ≥400. Vancomycin monitoring methods can be categorised into four categories: empiric trough concentrations; linear regression analysis (one‐compartment model), population methods and Bayesian estimation procedures. Although the empiric trough concentrations and population methods are easy to use and require minimal resources, there are large differences in the published vancomycin model parameters. This demonstrates that there is great variance in pharmacokinetic parameters between the models and a single vancomycin model cannot be applied to all patient populations. The linear regression and Bayesian methods recommended more accurate dosage regimens; however, they require additional resources such as information technology and healthcare personnel with background training in pharmacokinetics. The Bayesian methods offered additional advantages such as calculation of doses based on a single‐serum concentration and optimisation of the patients previous pharmacokinetic data to determine subsequent dosage regimens. Computerised programs, utilising the Bayesian estimation procedures, are able to achieve target concentrations in a greater percentage of patients earlier in the course of therapy than the empiric trough concentrations and population methods. We recommend the use of these programs providing there is appropriate expertise available to make appropriate recommendations.

How Soon Is Now? The Urgent Need for Randomized, Controlled Trials Evaluating Treatment of Multidrug-Resistant Bacterial Infection

BackgroundGram-negative bacteria such as Escherichia coli or Klebsiella spp. frequently cause bloodstream infections. There has been a worldwide increase in resistance in these species to antibiotics such as third generation cephalosporins, largely driven by the acquisition of extended-spectrum beta-lactamase or plasmid-mediated AmpC enzymes. Carbapenems have been considered the most effective therapy for serious infections caused by such resistant bacteria; however, increased use creates selection pressure for carbapenem resistance, an emerging threat arising predominantly from the dissemination of genes encoding carbapenemases. Recent retrospective data suggest that beta-lactam/beta-lactamase inhibitor combinations, such as piperacillin-tazobactam, may be non-inferior to carbapenems for the treatment of bloodstream infection caused by extended-spectrum beta-lactamase-producers, if susceptible in vitro. This study aims to test this hypothesis in an effort to define carbapenem-sparing alternatives for these infections.Methods/DesignThe study will use a multicentre randomised controlled open-label non-inferiority trial design comparing two treatments, meropenem (standard arm) and piperacillin-tazobactam (carbapenem-sparing arm) in adult patients with bacteraemia caused by E. coli or Klebsiella spp. demonstrating non-susceptibility to third generation cephalosporins. Recruitment is planned to occur in sites across three countries (Australia, New Zealand and Singapore). A total sample size of 454 patients will be required to achieve 80% power to determine non-inferiority with a margin of 5%. Once randomised, definitive treatment will be for a minimum of 4 days, but up to 14 days with total duration determined by treating clinicians. Data describing demographic information, antibiotic use, co-morbid conditions, illness severity, source of infection and other risk factors will be collected. Vital signs, white cell count, use of vasopressors and days to bacteraemia clearance will be recorded up to day 7. The primary outcome measure will be mortality at 30 days, with secondary outcomes including days to clinical and microbiological resolution, microbiological failure or relapse, isolation of a multi-resistant organism or Clostridium difficile infection.Trial registrationThe MERINO trial is registered under the Australian New Zealand Clinical Trials Register (ANZCTR), reference number: ACTRN12613000532707 (registered 13 May 2013) and the US National Institute of Health ClinicalTrials.gov register, reference number: NCT02176122 (registered 24 June 2014).