Antimicrobial treatment challenges in the era of carbapenem resistance

Infections due to carbapenem-resistant Gram-negative bacteria are burdened by high mortality and represent an urgent threat to address. Clinicians are currently at a dawn of a new era in which antibiotic resistance in Gram-negative bacilli is being dealt with by the availability of the first new antibiotics in this field for many years. Although new antibiotics have shown promising results in clinical trials, there is still uncertainty over whether their use will improve clinical outcomes in real world practice. Some observational studies have reported a survival benefit in carbapenem-resistant Enterobacteriaceae bloodstream infections using combination therapy, often including “old” antibiotics such as colistin, aminoglycosides, tigecycline, and carbapenems. These regimens, however, are linked to increased risk of antimicrobial resistance, and their efficacy has yet to be compared to new antimicrobial options. While awaiting more definitive evidence, antibiotic stewards need clear direction on how to optimize the use of old and novel antibiotic options. Furthermore, carbapenem-sparing regimens should be carefully considered as a potential tool to reduce selective antimicrobial pressure

Multiplex Microsphere PCR (mmPCR) Allows Simultaneous Gram Typing, Detection of Fungal DNA, and Antibiotic Resistance Genes

Objective: To show the high analytical specificity of our multiplex microsphere polymerase chain reaction (mmPCR) method, which offers the simultaneous detection of both general (eg, Gram type) and specific (eg, Pseudomonas species) clinically relevant genetic targets in a single modular multiplex reaction. Materials and Methods: Isolated gDNA of 16S/rRNA Sanger-sequenced and Basic Local Alignment Tool–identified bacterial and fungal isolates were selectively amplified in a custom 10-plex Luminex MagPlex-TAG microsphere-based mmPCR assay. The signal/noise ratio for each reaction was calculated from flow cytometry standard data collected on a BD LSR Fortessa II flow cytometer. Data were normalized to the no-template negative control and the signal maximum. The analytical specificity of the assay was compared to single-plex SYBR chemistry quantitative PCR. Results: Both general and specific primer sets were functional in the 10-plex mmPCR. The general Gram typing and pan-fungal primers correctly identified all bacterial and fungal isolates, respectively. The species-specific and antibiotic resistance–specific primers correctly identified the species- and resistance-carrying isolates, respectively. Low-level cross-reactive signals were present in some reactions with high signal/noise primer ratios. Conclusion: We found that mmPCR can simultaneously detect specific and general clinically relevant genetic targets in multiplex. These results serve as a proof-of-concept advance that highlights the potential of high multiplex mmPCR diagnostics in clinical practice. Further development of specimen-specific DNA extraction techniques is required for sensitivity testing

Multiorgan MRI findings after hospitalisation with COVID-19 in the UK (C-MORE): a prospective, multicentre, observational cohort study

Introduction: The multiorgan impact of moderate to severe coronavirus infections in the post-acute phase is still poorly understood. We aimed to evaluate the excess burden of multiorgan abnormalities after hospitalisation with COVID-19, evaluate their determinants, and explore associations with patient-related outcome measures. Methods: In a prospective, UK-wide, multicentre MRI follow-up study (C-MORE), adults (aged ≥18 years) discharged from hospital following COVID-19 who were included in Tier 2 of the Post-hospitalisation COVID-19 study (PHOSP-COVID) and contemporary controls with no evidence of previous COVID-19 (SARS-CoV-2 nucleocapsid antibody negative) underwent multiorgan MRI (lungs, heart, brain, liver, and kidneys) with quantitative and qualitative assessment of images and clinical adjudication when relevant. Individuals with end-stage renal failure or contraindications to MRI were excluded. Participants also underwent detailed recording of symptoms, and physiological and biochemical tests. The primary outcome was the excess burden of multiorgan abnormalities (two or more organs) relative to controls, with further adjustments for potential confounders. The C-MORE study is ongoing and is registered with ClinicalTrials.gov, NCT04510025. Findings: Of 2710 participants in Tier 2 of PHOSP-COVID, 531 were recruited across 13 UK-wide C-MORE sites. After exclusions, 259 C-MORE patients (mean age 57 years [SD 12]; 158 [61%] male and 101 [39%] female) who were discharged from hospital with PCR-confirmed or clinically diagnosed COVID-19 between March 1, 2020, and Nov 1, 2021, and 52 non-COVID-19 controls from the community (mean age 49 years [SD 14]; 30 [58%] male and 22 [42%] female) were included in the analysis. Patients were assessed at a median of 5·0 months (IQR 4·2–6·3) after hospital discharge. Compared with non-COVID-19 controls, patients were older, living with more obesity, and had more comorbidities. Multiorgan abnormalities on MRI were more frequent in patients than in controls (157 [61%] of 259 vs 14 [27%] of 52; p<0·0001) and independently associated with COVID-19 status (odds ratio [OR] 2·9 [95% CI 1·5–5·8]; padjusted=0·0023) after adjusting for relevant confounders. Compared with controls, patients were more likely to have MRI evidence of lung abnormalities (p=0·0001; parenchymal abnormalities), brain abnormalities (p<0·0001; more white matter hyperintensities and regional brain volume reduction), and kidney abnormalities (p=0·014; lower medullary T1 and loss of corticomedullary differentiation), whereas cardiac and liver MRI abnormalities were similar between patients and controls. Patients with multiorgan abnormalities were older (difference in mean age 7 years [95% CI 4–10]; mean age of 59·8 years [SD 11·7] with multiorgan abnormalities vs mean age of 52·8 years [11·9] without multiorgan abnormalities; p<0·0001), more likely to have three or more comorbidities (OR 2·47 [1·32–4·82]; padjusted=0·0059), and more likely to have a more severe acute infection (acute CRP >5mg/L, OR 3·55 [1·23–11·88]; padjusted=0·025) than those without multiorgan abnormalities. Presence of lung MRI abnormalities was associated with a two-fold higher risk of chest tightness, and multiorgan MRI abnormalities were associated with severe and very severe persistent physical and mental health impairment (PHOSP-COVID symptom clusters) after hospitalisation. Interpretation: After hospitalisation for COVID-19, people are at risk of multiorgan abnormalities in the medium term. Our findings emphasise the need for proactive multidisciplinary care pathways, with the potential for imaging to guide surveillance frequency and therapeutic stratification

Risk factors for relapse or persistence of bacteraemia caused by Enterobacter spp.: a case-control study

Results of case-control design study for risk factors associated with relapse or persistence of bacteraemia caused by Enterobacter spp. We determined clinical risk factors for persistence or relapse defined as repeated positive blood cultures collected between 72 hours and up to 28 days post initial positive blood culture

Clinical meta-data from patients with bloodstream infections caused by 3GC-resistant E. coli

This dataset includes the clinical and genomic data associated with 3rd generation cephalosporin-resistant E. coli strains cultured from patients enrolled in an international randomised controlled trial (the MERINO Trial).&nbsp

Health risks of flood disasters

Floods are the most common natural disaster occurring worldwide, with their impact expected to grow in the future due to the effects of climate change and population shift. Floodwaters pose immediate dangers to human health, but also long-term effects resulting from displacement and worsened living conditions. This review examines the health impact of flood disasters, including skin and soft-tissue infections, gastroenteritis, and zoonotic infections such as leptospirosis, and the impact on noncommunicable diseases and health infrastructure. Further work in the development of cost-efficient preparedness strategies may mitigate the morbidity and mortality associated with such natural disasters

Mortality, hospital length of stay, and recurrent bloodstream infections associated with extended-spectrum beta-lactamase-producing Escherichia coli in a low prevalence region: A 20-year population-based large cohort study

Objectives: This population-based study aimed to investigate the risk factors and effect of extended-spectrum beta-lactamase (ESBL) production on clinical outcomes in Escherichia coli bloodstream infection (BSI) patients. Methods: The study population was defined as patients aged ≥15 years with E. coli BSI in Queensland, Australia, from 2000 to 2019. Outcomes were defined as 30-day case fatality, hospital length of stay (LOS), and recurrent E. coli BSI. Results: A total of 27,796 E. coli BSIs were identified, of which 1112 (4.0%) were ESBL-producers. Patients with ESBL-Ec BSI were more frequently older, male, with comorbidity, recurrent E. coli BSI, and less likely with community-associated community-onset infections as compared to non-ESBL-Ec BSI patients. The standardized mortality rate of ESBL-Ec BSI increased 8-fold from 2000 to 2019 (1 to 8 per million residents) and case fatality was 12.8% (n = 142) at 30 days from positive blood culture. Patients with ESBL-Ec BSI were not at higher risk of 30-day case fatality (adjusted hazard ratio [HR] = 0.98, 95% CI: 0.83-1.17), but had higher risk of recurring episodes (adjusted subdistribution HR = 1.58, 95% CI: 1.29-1.92) and observed 14% longer LOS (adjusted incidence rate ratio = 1.14, 95% CI: 1.10-1.18) than non-ESBL-Ec BSI patients. Conclusion: In this large patient cohort, ESBL-Ec BSI did not increase case fatality risk but observed higher hospital LOS and recurrent E. coli BSI than non-ESBL-Ec BSI. Clinical resources are warranted to account for the higher morbidity risk associated with ESBL production and incidence.</p

Budget impact analysis of routinely using whole-genomic sequencing of six multidrug-resistant bacterial pathogens in Queensland, Australia

Objective To predict the cost and health effects of routine use of whole-genome sequencing (WGS) of bacterial pathogens compared with those of standard of care.Design Budget impact analysis was performed over the following 5 years. Data were primarily from sequencing results on clusters of multidrug-resistant organisms across 27 hospitals. Model inputs were derived from hospitalisation and sequencing data, and epidemiological and costing reports, and included multidrug resistance rates and their trends.Setting Queensland, Australia.Participants Hospitalised patients.Interventions WGS surveillance of six common multidrug-resistant organisms (Staphylococcus aureus, Escherichia coli, Enterococcus faecium, Klebsiella pneumoniae, Enterobacter sp and Acinetobacter baumannii) compared with standard of care or routine microbiology testing.Primary and secondary outcomes Expected hospital costs, counts of patient infections and colonisations, and deaths from bloodstream infections.Results In 2021, 97 539 patients in Queensland are expected to be infected or colonised with one of six multidrug-resistant organisms with standard of care testing. WGS surveillance strategy and earlier infection control measures could avoid 36 726 infected or colonised patients and avoid 650 deaths. The total cost under standard of care was $A170.8 million in 2021. WGS surveillance costs an additional$A26.8 million but was offset by fewer costs for cleaning, nursing, personal protective equipment, shorter hospital stays and antimicrobials to produce an overall cost savings of $30.9 million in 2021. Sensitivity analyses showed cost savings remained when input values were varied at 95% confidence limits.Conclusions Compared with standard of care, WGS surveillance at a state-wide level could prevent a substantial number of hospital patients infected with multidrug-resistant organisms and related deaths and save healthcare costs. Primary prevention through routine use of WGS is an investment priority for the control of serious hospital-associated infections

HAIviz: an interactive dashboard for visualising and integrating healthcare-associated genomic epidemiological data

Existing tools for phylogeographic and epidemiological visualisation primarily provide a macro-geographic view of epidemic and pandemic transmission events but offer little support for detailed investigation of outbreaks in healthcare settings. Here, we present HAIviz, an interactive web-based application designed for integrating and visualising genomic epidemiological information to improve the tracking of healthcare-associated infections (HAIs). HAIviz displays and links the outbreak timeline, building map, phylogenetic tree, patient bed movements, and transmission network on a single interactive dashboard. HAIviz has been developed for bacterial outbreak investigations but can be utilised for general epidemiological investigations focused on built environments for which visualisation to customised maps is required. This paper describes and demonstrates the application of HAIviz for HAI outbreak investigations.</p

Evolving insights into the epidemiology of Moraxella species bloodstream infection from two decades of surveillance in Queensland, Australia

The epidemiology of Moraxella species bloodstream infection (BSI) is poorly defined due to their rarity. We sought to determine the incidence, risk factors, and outcomes of Moraxella species BSI in a large Australian population. All Moraxella species BSIs in patients admitted to Queensland (population estimate 5 million) public health facilities between 2000 and 2019 and submitted to Queensland pathology laboratory-based surveillance were included. Clinical and hospitalisation data were matched with laboratory-based surveillance data. Incidence rate ratios (IRR) with 95% confidence intervals (CI) were calculated. In total, 375 incident Moraxella species BSI occurred during 86 million person-years of surveillance, with an annualised age and sex standardised incidence of 4.3 per million residents. Isolates were most commonly identified as M. catarrhalis (n = 128; 34%) and community-associated (n = 225; 60%). Incidence was highest in infants, with increasing age associated with lower incidence rate. Males were at higher risk (incidence 2.9 vs. 2.0 per million, IRR1.4; 95% CI, 1.2–1.8), this was most pronounced at age extremes. Two-thirds of adults and 43% of children with Moraxella BSI had at least one comorbid illness. When compared to infections in adults, children were more likely to have community-associated disease, and a head and neck source focus of infection. The all-cause 30-day case-fatality rate was 4% (15/375) and this was significantly higher among adults (14/191; 7% vs 1/183; 1%; p < 0.001). Our findings demonstrate the low burden of Moraxella species BSI in a state-wide cohort, for which young children have the highest risk.</p