Biology subjects

MacFadden, D. R.

Publications and source records attributed to MacFadden, D. R..

8 recordsLinked to original sources

bioRxiv2025

Neighbour Typing Using Long Read Sequencing Provides Rapid Prediction of Sequence Type and Antimicrobial Susceptibility of Klebsiella pneumoniae

The rapid genome-based diagnostic approach of long read sequencing coupled with neighbor typing offers the potential to improve empiric treatment of infection. However, this approach is still in development, and clinical validation is needed to support its use. In this study, we present an assessment of a neighbour typing method (RASE - resistance associated sequence elements) to predict lineage or sequence type (ST) and antimicrobial susceptibility in real time for Klebsiella pneumoniae sensu lato. We analysed the initial reads generated during the early phase of long read sequencing from pure culture (n=99), mock communities (n=20) and metagenomic samples (n=20). RASE accurately identified 69.7% and 70% of STs in pure culture and metagenomes, respectively, and identified the STs of the isolates representing the highest proportion in mock communities. Regarding antimicrobial susceptibility prediction, the probability of susceptibility increased to 72% (95% CI 63%-80%) across all tested antibiotics, when RASE predicted susceptibility, and decreased probability of susceptibility to 8.9% (95% CI 6.4%-9.6%) when was indicative of a resistant phenotype. Our study confirmed that genomic neighbor typing in K. pneumoniae sensu lato is capable of providing informative predictions of ST and antibiotic susceptibility in less than ten minutes (after the start of sequencing) with 200-500 reads. IMPORTANCEThe growing burden of antimicrobial resistance is leading to high rates of mortality and morbidity worldwide. This situation has made the selection of empirical antibiotic therapy challenging, due to the risk of treatment failure and the overuse of last-resort antibiotics. The development of new sequencing technologies is helping to reduce the waiting time for a microbiological diagnosis, providing information in the early phase of bacterial infections, which could help improve clinical outcomes in a time of rising antimicrobial resistance. In this context, we assessed the performance of RASE (resistance associated sequence elements) in Klebsiella pneumoniae, an opportunistic pathogen frequently associated with nosocomial infections, which can rapidly acquire antibiotic resistance genes. Thus, in our study we provide insights that may aid in the validation of RASE for clinical use.

genomics↗

bioRxiv2021

Performance characteristics of next-generation sequencing for antimicrobial resistance gene detection in genomes and metagenomes

Short-read sequencing provides a culture-independent method for the detection of antimicrobial resistance (AMR) genes from single bacterial genomes and metagenomic samples. However, the performance characteristics of these approaches have not been systematically characterized. We compared assembly- and read-based approaches to determine sensitivity, positive predictive value, and sequencing limits of detection required for AMR gene detection in an Escherichia coli ST38 isolate spiked into a synthetic microbial community at varying abundances. Using an assembly-based method the limit of detection was 15X genome coverage. We are confident in AMR gene detection at target relative abundances of 100% to 1%, where a target abundance of 1% would require assembly of approximately 30 million reads to achieve 15X target coverage. Recent studies assessing AMR gene content in metagenomic samples may be inadequately sequenced to achieve high sensitivity. Our study informs future sequencing projects and analytical strategies for genomic and metagenomic AMR gene detection.

bioinformatics↗

bioRxiv2018

The distribution of antibiotic use and its association with antibiotic resistance

Antibiotic use is a primary driver of antibiotic resistance. However, antibiotic use can be distributed in different ways in a population, and the association between the distribution of use and antibiotic resistance has not been explored. Here we tested the hypothesis that repeated use of antibiotics has a stronger association with population-wide antibiotic resistance than broadly- distributed, low-intensity use. First, we characterized the distribution of outpatient antibiotic use across US states, finding that antibiotic use is uneven and that repeated use of antibiotics makes up a minority of antibiotic use. Second, we compared antibiotic use with resistance for 72 pathogen-antibiotic combinations across states. Finally, having partitioned total use into extensive and intensive margins, we found that intense use had a weaker association with resistance than extensive use. If the use-resistance relationship is causal, these results suggest that reducing total use and selection intensity will require reducing broadly-distributed, low- intensity use.

epidemiology↗

bioRxiv2018

Outpatient prescribing of four major antibiotic classes and prevalence of antimicrobial resistance in US adults

BackgroundThere is limited information on the relation between antibiotic use and antibiotic resistance in the US.\n\nMethodsWe used multivariable logistic regression to relate state-specific rates of outpatient prescribing overall for fluoroquinolones, penicillins, macrolides, and cephalosporins between 2011-2014 to state-specific prevalence of resistance for select combinations of antibiotics/bacteria among catheter-associated urinary tract infections (CAUTIs) in the CDC Patient Safety Atlas data between 2011-2014 for adults aged 65+y and 19-64y, adjusting for potential confounders.\n\nResultsRates of fluoroquinolone prescribing were positively associated with prevalence of fluoroquinolone resistance in Escherichia coli and Pseudomonas aeruginosa (both age groups), resistance to extended-spectrum (ES) cephalosporins in E. coli (aged 19-64y), and resistance to methicillin in Staphylococcus aureus (aged 19-64y). Rates of penicillin prescribing were positively associated with prevalence of resistance to fluoroquinolones in E. coli (aged 65+) and P. aeruginosa (both age groups), and resistance to ES cephalosporins in Klebsiella spp. (both age groups). Rates of cephalosporin prescribing were negatively associated with prevalence of resistance to fluoroquinolones in E. coli and resistance to ES cephalosporins in Klebsiella spp. (both age groups). Average annual temperature was positively associated with prevalence of resistance to ES cephalosporins in E. coli and P. aeruginosa, and resistance to fluoroquinolones in E. coli.\n\nConclusionsOur results suggest that prescribing of fluoroquinolones and penicillins to US adults is associated with prevalence of antibiotic resistance, including ESBLs and MRSA. Further work is needed to understand the potential benefit of replacing fluoroquinolones and penicillins by other antibiotics for reducing prevalence of antibiotic resistance.

epidemiology↗

bioRxiv2018

Rates of increase of antibiotic resistance and ambient temperature in Europe: a cross-national analysis of 28 countries between 2000-2016

BackgroundWidely recognized as a major public health threat globally, the rapid increase of antibiotic resistance in bacteria could soon render our most effective method to combat infections obsolete. Factors influencing the burden of resistance in human populations remain poorly described, though temperature is known to play an important role in mechanisms at the bacterial level.\n\nMethodsWe performed an ecologic analysis of country level antibiotic resistance prevalence in 3 common bacterial pathogens across 28 countries in Europe, and used multivariable models to evaluate associations with minimum temperature and other predictors over a 17-year period (2000-2016). We quantified the effects of minimum temperature, population density, and antibiotic consumption on the rate of change of antibiotic resistance across geographies.\n\nFindingsFor three common bacterial pathogens and four classes of antibiotics, we found evidence of a long-term effect of ambient minimum temperature on rates of increase of antibiotic resistance across 28 countries in Europe between 2000-2016. Specifically, we show that across all antibiotic classes for the pathogens E. coli and K. pneumoniae, European countries with 10{degrees}C warmer ambient temperatures have experienced more rapid increases in antibiotic resistance over the 17-year period, ranging between 0.33%/year (95% CI 0.2, 0.5) and 1.2%/year (0.4, 1.9), even after accounting for recognized drivers of resistance including antibiotic consumption and population density. We found a decreasing relationship for S. aureus and methicillin of -0.4%/year (95% CI -0.7, 0.0), reflecting widespread declines in MRSA across Europe over the study period.\n\nInterpretationAmbient temperature may be an important modulator of the rate of change of antibiotic resistance. Our findings suggest that rising temperatures globally may hasten the spread of resistance and complicate efforts to mitigate it.\n\nFundingCanadian Institutes of Health Research Fellowship (D.R.M.).

epidemiology↗

bioRxiv2018

Lineage calling can identify antibiotic resistant clones within minutes

Surveillance of drug-resistant bacteria is essential for healthcare providers to deliver effective empiric antibiotic therapy. However, traditional molecular epidemiology does not typically occur on a timescale that could impact patient treatment and outcomes. Here we present a method called genomic neighbor typing for inferring the phenotype of a bacterial sample by identifying its closest relatives in a database of genomes with metadata. We show that this technique can infer antibiotic susceptibility and resistance for both S. pneumoniae and N. gonorrhoeae. We implemented this with rapid k-mer matching, which, when used on Oxford Nanopore MinION data, can run in real time. This resulted in determination of resistance within ten minutes (sens/spec 91%/100% for S. pneumoniae and 81%/100% N. gonorrhoeae from isolates with a representative database) of sequencing starting, and for clinical metagenomic sputum samples (75%/100% for S. pneumoniae), within four hours of sample collection. This flexible approach has wide application to pathogen surveillance and may be used to greatly accelerate appropriate empirical antibiotic treatment.

bioinformatics↗

bioRxiv2018

Antimicrobial resistance prevalence and rates of hospitalization with septicemia in the diagnosis in adults in different US states

ObjectivesRates of hospitalization with sepsis/septicemia and associated mortality in the US have risen significantly during the last two decades. Antibiotic resistance may contribute to the rates of sepsis-related outcomes through lack of clearance of bacterial infections following antibiotic treatment during different stages of infection. However, there is limited information about the relation between prevalence of resistance to various antibiotics in different bacteria and rates of sepsis-related outcomes. MethodsFor different age groups of adults (18-49y,50-64y,65-74y,75-84y,85+y) and combinations of antibiotics/bacteria, we evaluated associations between state-specific prevalence (percentage) of resistant samples for a given combination of antibiotics/bacteria among catheter-associated urinary tract infections in the CDC Antibiotic Resistance Patient Safety Atlas data between 2011-2014 and rates of hospitalization with septicemia (ICD-9 codes 038.xx present on the discharge diagnosis) reported to the Healthcare Cost and Utilization Project (HCUP), as well as rates of mortality with sepsis (ICD-10 codes A40-41.xx present on death certificate). ResultsAmong the different combinations of antibiotics/bacteria, prevalence of resistance to fluoroquinolones in E. coli had the strongest association with septicemia hospitalization rates for individuals aged over 50y, and with sepsis mortality rates for individuals aged 18-84y. A number of positive correlations between prevalence of resistance for different combinations of antibiotics/bacteria and septicemia hospitalization/sepsis mortality rates in adults were also found. ConclusionsOur findings, as well as our related work on the relation between antibiotic use and sepsis rates support the association between resistance to/use of certain antibiotics and rates of sepsis-related outcomes, suggesting the potential utility of antibiotic replacement.

epidemiology↗

bioRxiv2018

Trends in outpatient antibiotic prescribing practice among US older adults, 2011-2015: an observational study

Structured abstractO_ST_ABSObjectiveC_ST_ABSTo identify temporal trends in outpatient antibiotic use and antibiotic prescribing practice among older adults.\n\nDesignObservational study using United States Medicare administrative claims during 2011-2015. Trends in antibiotic use were estimated using multivariable regression adjusting for beneficiaries demographic and clinical covariates.\n\nSettingMedicare.\n\nParticipants4.6 million Medicare beneficiaries from a nationwide, 20% sample of fee-forservice Medicare beneficiaries [≥]65 years old.\n\nMain outcome measurementsOverall rates of antibiotic prescription claims, rates of appropriate and inappropriate prescribing, rates for each of the most frequently prescribed antibiotics, and rates of antibiotic claims associated with specific diagnoses.\n\nResultsAntibiotic claims fell from 1362.2 to 1361.6 claims per 1,000 beneficiaries per year during 2011-2015, an overall 0.2% decrease (95% CI 0.07-0.32). Inappropriate antibiotic claims fell from 552 to 533 claims per 1,000 beneficiaries, a 4.1% decrease (CI 3.9-4.3). Individual antibiotics had heterogeneous changes in use. For example, azithromycin claims per beneficiary decreased by 18.4% (CI 18.2-18.7) while levofloxacin claims increased by 28.1% (CI 27.5-28.6). Azithromycin use associated with each of the potentially appropriate and inappropriate respiratory diagnoses we considered decreased, while levofloxacin use associated with each of those diagnoses increased.\n\nConclusionAmong US Medicare beneficiaries, overall antibiotic use and inappropriate use declined modestly, but individual drugs experienced divergent changes in use. Trends in drug use across indications were stronger than trends in use for individual indications, suggesting that guidelines and concerns about antibiotic resistance were not major drivers of change in antibiotic use.

epidemiology↗