Antibiotic Cycling and Antibiotic Mixing: which one best mitigates antibiotic resistance?

Published onlineJournal ArticleThis is the final version of the article. Available from Oxford University Press via the DOI in this record.Can we exploit our burgeoning understanding of molecular evolution to slow the progress of drug resistance? One role of an infection clinician is exactly that: to foresee trajectories to resistance during antibiotic treatment and to hinder that evolutionary course. But can this be done at a hospital-wide scale? Clinicians and theoreticians tried to when they proposed two conicting behavioural strategies that are expected to curb resistance evolution in the clinic, these are known as 'antibiotic cycling' and 'antibiotic mixing'. However, the accumulated data from clinical trials, now approaching 4 million patient days of treatment, is too variable for cycling or mixing to be deemed successful. The former implements the restriction and prioritisation of di_erent antibiotics at di_erent times in hospitals in a manner said to 'cycle' between them. In antibiotic mixing, appropriate antibiotics are allocated to patients but randomly.Mixing results in no correlation, in time or across patients, in the drugs used for treatment which is why theorists saw this as an optimal behavioural strategy. So while cycling and mixing were proposed as ways of controlling evolution, we show there is good reason why clinical datasets cannot choose between them: by re-examining the theoretical literature we show prior support for the theoretical optimality of mixing was misplaced. Our analysis is consistent with a pattern emerging in data: neither cycling or mixing is a priori better than the other at mitigating selection for antibiotic resistance in the clinic.REB was funded during this work by an MRC Discipline Hopping Fellowship G0802611, RPM was funded by a Conacyt PhD award, all authors were supported by EPSRC grant EP/I00503X/1 (grant holder REB)

Assessing the public acceptability of proposed policy interventions to reduce the misuse of antibiotics in Australia: A report on two community juries

Objective To elicit the views of well-informed community members on the acceptability of proposed policy interventions designed to improve community use of antibiotics in Australia. Design Two community juries held in 2016. Setting and participants Western Sydney and Dubbo communities in NSW, Australia. Twenty-nine participants of diverse social and cultural backgrounds, mixed genders and ages recruited via public advertising: one jury was drawn from a large metropolitan setting; the other from a regional/rural setting. Main outcome measure Jury verdict and rationale in response to a prioritization task and structured questions. Results Both juries concluded that potential policy interventions to curb antibiotic misuse in the community should be directed towards: (i) ensuring that the public and prescribers were better educated about the dangers of antibiotic resistance; (ii) making community-based human and animal health-care practitioners accountable for their prescribing decisions. Patient-centred approaches such as delayed prescribing were seen as less acceptable than prescriber-centred approaches; both juries completely rejected any proposal to decrease consumer demand by increasing antibiotic prices. Conclusion These informed citizens acknowledged the importance of raising public awareness of the risks, impacts and costs of antibiotic resistance and placed a high priority on increasing social and professional accountability through restrictive measures. Their overarching aim was that policy interventions should be directed towards creating collective actions and broad social support for changing antibiotic use through establishing and explaining the need for mechanisms to control and support better prescribing by practitioners, while not transferring the burdens, costs and risks of interventions to consumers.This work was supported by a seed grant from the Marie Bashir Institute for Infectious Disease and Biosecurity and NHMRC CRE 1102962. CD, JJ and GLG received funding support from a NHMRC Project grant (#1083079). SMC is funded through NHMRC Career Development Fellowship (#1032963)

Diversity of P1 phage-like elements in multidrug resistant Escherichia coli

© 2019, The Author(s). The spread of multidrug resistance via mobile genetic elements is a major clinical and veterinary concern. Pathogenic Escherichia coli harbour antibiotic resistance and virulence genes mainly on plasmids, but also bacteriophages and hybrid phage-like plasmids. In this study, the genomes of three E. coli phage-like plasmids, pJIE250-3 from a human E. coli clinical isolate, pSvP1 from a porcine ETEC O157 isolate, and pTZ20_1P from a porcine commensal E. coli, were sequenced (PacBio RSII), annotated and compared. All three elements are coliphage P1 variants, each with unique adaptations. pJIE250-3 is a P1-derivative that has lost lytic functions and contains no accessory genes. In pTZ20_1P and pSvP1, a core P1-like genome is associated with insertion sequence-mediated acquisition of plasmid modules encoding multidrug resistance and virulence, respectively. The transfer ability of pTZ20_1P, carrying antibiotic resistance markers, was also tested and, although this element was not able to transfer by conjugation, it was able to lysogenize a commensal E. coli strain with consequent transfer of resistance. The incidence of P1-like plasmids (~7%) in our E. coli collections correlated well with that in public databases. This study highlights the need to investigate the contribution of phage-like plasmids to the successful spread of antibiotic resistant pathotypes

Australian Group on Antimicrobial Resistance (AGAR) Australian Gram-negative Sepsis Outcome Programme (GnSOP) Annual Report 2020

The Australian Group on Antimicrobial Resistance (AGAR) performs regular period-prevalence studies to monitor changes in antimicrobial resistance in selected enteric gram-negative pathogens. The 2020 survey was the eighth year to focus on bloodstream infections caused by Enterobacterales, and the sixth year in which Pseudomonas aeruginosa and Acinetobacter species were included. Eight thousand seven hundred and fifty-two isolates, comprising Enterobacterales (7,871, 89.9%), P. aeruginosa (771, 8.8%) and Acinetobacter species (110, 1.3%), were tested using commercial automated methods. The results were analysed using Clinical and Laboratory Standards Institute (CLSI) and European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoints (January 2021). Of the key resistances, resistance to the third-generation cephalosporin ceftriaxone was found in 13.5%/13.5% (CLSI/EUCAST criteria) of Escherichia coli and 8.7%/8.7% of Klebsiella pneumoniae. Resistance rates to ciprofloxacin were 16.1%/16.1% for E. coli; 9.9%/9.9% for K. pneumoniae; 5.8%/5.8% for Enterobacter cloacae complex; and 4.5%/8.1% for P. aeruginosa. Resistance rates to piperacillin-tazobactam were 2.5%/6.6%; 3.9%/12.5%; 16.9%/26.3%; and 5.5%/14.4% for the same four species respectively. Thirty-two isolates from 32 patients were shown to harbour at least one carbapenemase gene: 19 blaIMP-4, three blaGES-5, two blaNDM-1, two blaNDM-5, two blaOXA-48, two blaOXA-181, one blaIMI-1, and one blaOXA-23+NDM-1

Whole-genome analysis of extraintestinal Escherichia coli sequence type 73 from a single hospital over a 2 year period identified different circulating clonal groups

© 2020 The Authors. Sequence type (ST)73 has emerged as one of the most frequently isolated extraintestinal pathogenic Escherichia coli. To examine the localized diversity of ST73 clonal groups, including their mobile genetic element profile, we sequenced the genomes of 16 multiple-drug resistant ST73 isolates from patients with urinary tract infection from a single hospital in Sydney, Australia, between 2009 and 2011. Genome sequences were used to generate a SNP-based phylogenetic tree to determine the relationship of these isolates in a global context with ST73 sequences (n=210) from public databases. There was no evidence of a dominant outbreak strain of ST73 in patients from this hospital, rather we identified at least eight separate groups, several of which reoccurred, over a 2 year period. The inferred phylogeny of all ST73 strains (n=226) including the ST73 clone D i2 reference genome shows high bootstrap support and clusters into four major groups that correlate with serotype. The Sydney ST73 strains carry a wide variety of virulence-associated genes, but the presence of iss, pic and several iron-acquisition operons was notable

Effect of selective decontamination of the digestive tract on hospital mortality in critically Ill patients receiving mechanical ventilation a randomized clinical trial

Importance Whether selective decontamination of the digestive tract (SDD) reduces mortality in critically ill patients remains uncertain. Objective To determine whether SDD reduces in-hospital mortality in critically ill adults. Design, Setting, and Participants A cluster, crossover, randomized clinical trial that recruited 5982 mechanically ventilated adults from 19 intensive care units (ICUs) in Australia between April 2018 and May 2021 (final follow-up, August 2021). A contemporaneous ecological assessment recruited 8599 patients from participating ICUs between May 2017 and August 2021. Interventions ICUs were randomly assigned to adopt or not adopt a SDD strategy for 2 alternating 12-month periods, separated by a 3-month interperiod gap. Patients in the SDD group (n = 2791) received a 6-hourly application of an oral paste and administration of a gastric suspension containing colistin, tobramycin, and nystatin for the duration of mechanical ventilation, plus a 4-day course of an intravenous antibiotic with a suitable antimicrobial spectrum. Patients in the control group (n = 3191) received standard care. Main Outcomes and Measures The primary outcome was in-hospital mortality within 90 days. There were 8 secondary outcomes, including the proportion of patients with new positive blood cultures, antibiotic-resistant organisms (AROs), and Clostridioides difficile infections. For the ecological assessment, a noninferiority margin of 2% was prespecified for 3 outcomes including new cultures of AROs. Results Of 5982 patients (mean age, 58.3 years; 36.8% women) enrolled from 19 ICUs, all patients completed the trial. There were 753/2791 (27.0%) and 928/3191 (29.1%) in-hospital deaths in the SDD and standard care groups, respectively (mean difference, −1.7% [95% CI, −4.8% to 1.3%]; odds ratio, 0.91 [95% CI, 0.82-1.02]; P = .12). Of 8 prespecified secondary outcomes, 6 showed no significant differences. In the SDD vs standard care groups, 23.1% vs 34.6% had new ARO cultures (absolute difference, −11.0%; 95% CI, −14.7% to −7.3%), 5.6% vs 8.1% had new positive blood cultures (absolute difference, −1.95%; 95% CI, −3.5% to −0.4%), and 0.5% vs 0.9% had new C difficile infections (absolute difference, −0.24%; 95% CI, −0.6% to 0.1%). In 8599 patients enrolled in the ecological assessment, use of SDD was not shown to be noninferior with regard to the change in the proportion of patients who developed new AROs (−3.3% vs −1.59%; mean difference, −1.71% [1-sided 97.5% CI, −∞ to 4.31%] and 0.88% vs 0.55%; mean difference, −0.32% [1-sided 97.5% CI, −∞ to 5.47%]) in the first and second periods, respectively. Conclusions and Relevance Among critically ill patients receiving mechanical ventilation, SDD, compared with standard care without SDD, did not significantly reduce in-hospital mortality. However, the confidence interval around the effect estimate includes a clinically important benefit. Trial Registration ClinicalTrials.gov Identifier: NCT0238903

The Earth System Prediction Suite: Toward a Coordinated U.S. Modeling Capability

The Earth System Prediction Suite (ESPS) is a collection of flagship U.S. weather and climate models and model components that are being instrumented to conform to interoperability conventions, documented to follow metadata standards, and made available either under open source terms or to credentialed users.The ESPS represents a culmination of efforts to create a common Earth system model architecture, and the advent of increasingly coordinated model development activities in the U.S. ESPS component interfaces are based on the Earth System Modeling Framework (ESMF), community-developed software for building and coupling models, and the National Unified Operational Prediction Capability (NUOPC) Layer, a set of ESMF-based component templates and interoperability conventions. This shared infrastructure simplifies the process of model coupling by guaranteeing that components conform to a set of technical and semantic behaviors. The ESPS encourages distributed, multi-agency development of coupled modeling systems, controlled experimentation and testing, and exploration of novel model configurations, such as those motivated by research involving managed and interactive ensembles. ESPS codes include the Navy Global Environmental Model (NavGEM), HYbrid Coordinate Ocean Model (HYCOM), and Coupled Ocean Atmosphere Mesoscale Prediction System (COAMPS); the NOAA Environmental Modeling System (NEMS) and the Modular Ocean Model (MOM); the Community Earth System Model (CESM); and the NASA ModelE climate model and GEOS-5 atmospheric general circulation model

Multi-Locus Sequence Analysis Reveals Profound Genetic Diversity among Isolates of the Human Pathogen Bartonella bacilliformis

Bartonella bacilliformis is the aetiological agent of human bartonellosis, a potentially life threatening infection of significant public health concern in the Andean region of South America. Human bartonellosis has long been recognised in the region but a recent upsurge in the number of cases of the disease and an apparent expansion of its geographical distribution have re-emphasized its contemporary medical importance. Here, we describe the development of a multi-locus sequence typing (MLST) scheme for B. bacilliformis and its application to an archive of 43 isolates collected from patients across Peru. MLST identified eight sequence types among these isolates and the delineation of these was generally congruent with those of the previously described typing scheme. Phylogenetic analysis based on concatenated sequence data derived from MLST loci revealed that seven of the eight sequence types were closely related to one another; however, one sequence type, ST8, exhibited profound evolutionary divergence from the others. The extent of this divergence was akin to that observed between other members of the Bartonella genus, suggesting that ST8 strains may be better considered as members of a novel Bartonella genospecies

A randomised controlled trial of a physical activity and nutrition program targeting middle-aged adults at risk of metabolic syndrome in a disadvantaged rural community

Background: Approximately 70% of Australian adults aged over 50 are overweight or obese, with the prevalence significantly higher in regional/remote areas compared to cities. This study aims to determine if a low-cost, accessible lifestyle program targeting insufficiently active adults aged 50-69 y can be successfully implemented in a rural location, and whether its implementation will contribute to the reduction/prevention of metabolic syndrome, or other risk factors for type 2 diabetes, and cardiovascular disease.Methods/Design: This 6-month randomised controlled trial will consist of a nutrition, physical activity, and healthy weight intervention for 50–69 year-olds from a disadvantaged rural community. Five hundred participants with central obesity and at risk of metabolic syndrome will be recruited from Albany and surrounding areas in Western Australia (within a 50 kilometre radius of the town). They will be randomly assigned to either the intervention (n = 250) or wait-listed control group (n = 250). The theoretical concepts in the study utilise the Self-Determination Theory, complemented by Motivational Interviewing. The intervention will include a custom-designed booklet and interactive website that provides information, and encourages physical activity and nutrition goal setting, and healthy weight management. The booklet and website will be supplemented by an exercise chart, calendar, newsletters, resistance bands, accelerometers, and phone and email contact from program staff. Data will be collected at baseline and post-intervention.Discussion: This study aims to contribute to the prevention of metabolic syndrome and inter- related chronic illnesses: type 2 diabetes mellitus, cardiovascular disease, and some cancers; which are associated with overweight/obesity, physical inactivity, and poor diet. This large rural community-based trial will provide guidelines for recruitment, program development, implementation, and evaluation, and has the potential to translate findings into practice by expanding the program to other regional areas in Australia. Trial registration: Australian and New Zealand Clinical Trials Registry [ACTRN12614000512628, registration date 14th May 2014]

Multi-Locus Sequence Typing of Bartonella henselae Isolates from Three Continents Reveals Hypervirulent and Feline-Associated Clones

Bartonella henselae is a zoonotic pathogen and the causative agent of cat scratch disease and a variety of other disease manifestations in humans. Previous investigations have suggested that a limited subset of B. henselae isolates may be associated with human disease. In the present study, 182 human and feline B. henselae isolates from Europe, North America and Australia were analysed by multi-locus sequence typing (MLST) to detect any associations between sequence type (ST), host species and geographical distribution of the isolates. A total of 14 sequence types were detected, but over 66% (16/24) of the isolates recovered from human disease corresponded to a single genotype, ST1, and this type was detected in all three continents. In contrast, 27.2% (43/158) of the feline isolates corresponded to ST7, but this ST was not recovered from humans and was restricted to Europe. The difference in host association of STs 1 (human) and 7 (feline) was statistically significant (P≤0.001). eBURST analysis assigned the 14 STs to three clonal lineages, which contained two or more STs, and a singleton comprising ST7. These groups were broadly consistent with a neighbour-joining tree, although splits decomposition analysis was indicative of a history of recombination. These data indicate that B. henselae lineages differ in their virulence properties for humans and contribute to a better understanding of the population structure of B. henselae