Molecular Epidemiology of Third-Generation-Cephalosporin-Resistant Enterobacteriaceae in Southeast Queensland, Australia.

Third-generation cephalosporin-resistant (3GC-R) Enterobacteriaceae represent a major threat to human health. Here, we captured 288 3GC-R Enterobacteriaceae clinical isolates from 264 patients presenting at a regional Australian hospital over a 14-month period. In addition to routine mass spectrometry and antibiotic sensitivity testing, isolates were examined using rapid (∼40-min) real-time PCR assays targeting the most common extended-spectrum ß-lactamases (ESBLs; blaCTX-M-1 and blaCTX-M-9 groups, plus blaTEM, blaSHV, and an internal 16S rRNA gene control). AmpC CMY ß-lactamase (blaCMY) prevalence was also examined. Escherichia coli (80.2%) and Klebsiella pneumoniae (17.0%) were dominant, with Klebsiella oxytoca, Klebsiella aerogenes, and Enterobacter cloacae infrequently identified. Ceftriaxone and cefoxitin resistance were identified in 97.0% and 24.5% of E. coli and K. pneumoniae isolates, respectively. Consistent with global findings in Enterobacteriaceae, most (98.3%) isolates harbored at least one ß-lactamase gene, with 144 (50%) harboring blaCTX-M-1 group, 92 (31.9%) harboring blaCTX-M-9 group, 48 (16.7%) harboring blaSHV, 133 (46.2%) harboring blaTEM, and 34 (11.8%) harboring blaCMY genes. A subset of isolates (n = 98) were subjected to whole-genome sequencing (WGS) to identify the presence of cryptic resistance determinants and to verify genotyping accuracy. WGS of ß-lactamase-negative or carbapenem-resistant isolates identified uncommon ESBL and carbapenemase genes, including blaNDM and blaIMP, and confirmed all PCR-positive genotypes. We demonstrate that our PCR assays enable the rapid and cost-effective identification of ESBLs in the hospital setting, which has important infection control and therapeutic implications.

Association Between Minimum Inhibitory Concentration, Beta-lactamase Genes and Mortality for Patients Treated With Piperacillin/Tazobactam or Meropenem From the MERINO Study.

INTRODUCTION: This study aims to assess the association of piperacillin/tazobactam and meropenem minimum inhibitory concentration (MIC) and beta-lactam resistance genes with mortality in the MERINO trial. METHODS: Blood culture isolates from enrolled patients were tested by broth microdilution and whole genome sequencing at a central laboratory. Multivariate logistic regression was performed to account for confounders. Absolute risk increase for 30-day mortality between treatment groups was calculated for the primary analysis (PA) and the microbiologic assessable (MA) populations. RESULTS: In total, 320 isolates from 379 enrolled patients were available with susceptibility to piperacillin/tazobactam 94% and meropenem 100%. The piperacillin/tazobactam nonsusceptible breakpoint (MIC >16 mg/L) best predicted 30-day mortality after accounting for confounders (odds ratio 14.9, 95% confidence interval [CI] 2.8-87.2). The absolute risk increase for 30-day mortality for patients treated with piperacillin/tazobactam compared with meropenem was 9% (95% CI 3%-15%) and 8% (95% CI 2%-15%) for the original PA population and the post hoc MA populations, which reduced to 5% (95% CI -1% to 10%) after excluding strains with piperacillin/tazobactam MIC values >16 mg/L. Isolates coharboring extended spectrum ß-lactamase (ESBL) and OXA-1 genes were associated with elevated piperacillin/tazobactam MICs and the highest risk increase in 30-day mortality of 14% (95% CI 2%-28%). CONCLUSIONS: After excluding nonsusceptible strains, the 30-day mortality difference from the MERINO trial was less pronounced for piperacillin/tazobactam. Poor reliability in susceptibility testing performance for piperacillin/tazobactam and the high prevalence of OXA coharboring ESBLs suggests that meropenem remains the preferred choice for definitive treatment of ceftriaxone nonsusceptible Escherichia coli and Klebsiella.

When not to start antibiotics: avoiding antibiotic overuse in the intensive care unit.

BACKGROUND: Most intensive care unit (ICU) patients receive broad-spectrum antibiotics. While lifesaving in some, in others these treatments may be unnecessary and place patients at risk of antibiotic-associated harms. OBJECTIVES: To review the literature exploring how we diagnose infection in patients in the ICU and address the safety and utility of a 'watchful waiting' approach to antibiotic initiation with selected patients in the ICU. SOURCES: A semi-structured search of PubMed and Cochrane Library databases for articles published in English during the past 15 years was conducted. CONTENT: Distinguishing infection from non-infectious mimics in ICU patients is uniquely challenging. At present, we do not have access to a rapid point-of-care test that reliably differentiates between individuals who need antibiotics and those who do not. A small number of studies have attempted to compare early aggressive versus conservative antimicrobial strategies in the ICU. However, this body of literature is small and not robust enough to guide practice. IMPLICATIONS: This issue will not likely be resolved until there are diagnostic tests that rapidly and reliably identify the presence or absence of infection in the ICU population. In the meantime, prospective trials that identify clinical situations wherein it is safe to delay or withhold antibiotic initiation in the ICU until the presence of an infection is proven are warranted.

Measuring patient-centred long-term outcome following a bloodstream infection: a pilot study.

OBJECTIVES: To evaluate the sequential organ failure assessment (SOFA) and modified SOFA (mSOFA) scoring and a novel performance score based on the Karnofsky score for measuring outcome following a bloodstream infection (BSI). METHOD: This prospective observational cohort study assessed patients with BSI for mortality and functional outcomes with a novel performance score: the functional bloodstream infection score (FBIS). We also tested the SOFA and, given the difficulties with measuring SOFA on ward-based patients, the mSOFA over the first 7 days following a BSI for their association with outcomes. RESULTS: One hundred participants were prospectively recruited. Mortality at 52 weeks following BSI was 21% (21/100). Only 57% of survivors (39/69) were at their baseline functional status at 52 weeks. Stable or improved SOFA/mSOFA over the first 7 days was associated with survival and return to premorbid performance score (risk ratio 3.2, 95%CI 1.3-9.4, p < 0.01). CONCLUSIONS: The acute change in SOFA/mSOFA was associated with 52-week survival and return to premorbid functional performance. The FBIS measurement represents a simple and easy-to-apply measure of functional performance for patients with BSI and was associated with a high response rate (89%) from participants.

Proposed primary endpoints for use in clinical trials that compare treatment options for bloodstream infection in adults: a consensus definition.

OBJECTIVES: To define standardized endpoints to aid the design of trials that compare antibiotic therapies for bloodstream infections (BSI). METHODS: Prospective studies, randomized trials or registered protocols comparing antibiotic therapies for BSI, published from 2005 to 2016, were reviewed. Consensus endpoints for BSI studies were defined using a modified Delphi process. RESULTS: Different primary and secondary endpoints were defined for pilot (small-scale studies designed to evaluate protocol design, feasibility and implementation) and definitive trials (larger-scale studies designed to test hypotheses and influence clinical practice), as well as for Staphylococcus aureus and Gram-negative BSI. For pilot studies of S. aureus BSI, a primary outcome of success at day 7 was defined by: survival, resolution of fever, stable/improved Sequential Organ Failure Assessment (SOFA) score and clearance of blood cultures, with no microbiologically confirmed failure up to 90 days. For definitive S. aureus BSI studies, a primary outcome of success at 90 days was defined by survival and no microbiologically confirmed failure. For pilot studies of Gram-negative BSI, a primary outcome of success at day 7 was defined by: survival, resolution of fever and symptoms related to BSI source, stable or improved SOFA score and negative blood cultures. For definitive Gram-negative BSI studies, a primary outcome of survival at 90 days supported by a secondary outcome of success at day 7 (as previously defined) was agreed. CONCLUSIONS: These endpoints provide a framework to aid future trial design. Further work will be required to validate these endpoints with respect to patient-centred clinical outcomes.

Antibiotic therapy for inducible AmpC ß-lactamase-producing Gram-negative bacilli: what are the alternatives to carbapenems, quinolones and aminoglycosides?

Some bacteria that possess chromosomally determined AmpC ß-lactamases may express these enzymes at a high level following exposure to ß-lactams, either by induction or selection for derepressed mutants. This may lead to clinical failure even if an isolate initially tests susceptible in vitro, a phenomenon best characterised by third-generation cephalosporin therapy for Enterobacter bacteraemia or meningitis. Several other Enterobacteriaceae, such as Serratia marcescens, Citrobacter freundii, Providencia spp. and Morganella morganii (often termed the 'ESCPM' group), may also express high levels of AmpC. However, the risk of clinical failure with ß-lactams that test susceptible in vitro is less clear in these species than for Enterobacter. Laboratories frequently do not report ß-lactam or ß-lactamase inhibitor combination drug susceptibilities for ESCPM organisms, encouraging alternative therapy with quinolones, aminoglycosides or carbapenems. However, quinolones and carbapenems present problems with selective pressure for multiresistant organisms, and aminoglycosides with potential toxicity. The risk of emergent AmpC-mediated resistance for non-Enterobacter spp. appears rare in clinical studies. Piperacillin/tazobactam may remain effective and may be less selective for AmpC derepressed mutants than cephalosporins. The potential roles for agents such as cefepime or trimethoprim/sulfamethoxazole are also discussed. Clinical studies that better define optimal treatment for this group of bacteria are required.