Genomic and clinical characteristics of campylobacteriosis in Australia.

Campylobacter spp. are a common cause of bacterial gastroenteritis in Australia, primarily acquired from contaminated meat. We investigated the relationship between genomic virulence characteristics and the severity of campylobacteriosis, hospitalisation, and other host factors.We recruited 571 campylobacteriosis cases from three Australian states and territories (2018-2019). We collected demographic, health status, risk factors, and self-reported disease data. We whole genome sequenced 422 C. jejuni and 84 C. coli case isolates along with 616 retail meat isolates. We classified case illness severity using a modified Vesikari scoring system, performed phylogenomic analysis, and explored risk factors for hospitalisation and illness severity.On average, cases experienced a 7.5 day diarrhoeal illness with additional symptoms including stomach cramps (87.1 %), fever (75.6 %), and nausea (72.0 %). Cases aged ≥75 years had milder symptoms, lower Vesikari scores, and higher odds of hospitalisation compared to younger cases. Chronic gastrointestinal illnesses also increased odds of hospitalisation. We observed significant diversity among isolates, with 65 C. jejuni and 21 C. coli sequence types. Antimicrobial resistance genes were detected in 20.4 % of isolates, but multidrug resistance was rare (0.04 %). Key virulence genes such as cdtABC (C. jejuni) and cadF were prevalent (>90 % presence) but did not correlate with disease severity or hospitalisation. However, certain genes (e.g. fliK, Cj1136, and Cj1138) appeared to distinguish human C. jejuni cases from food source isolates.Campylobacteriosis generally presents similarly across cases, though some are more severe. Genotypic virulence factors identified in the literature to-date do not predict disease severity but may differentiate human C. jejuni cases from food source isolates. Host factors like age and comorbidities have a greater influence on health outcomes than virulence factors.

The Cost of Foodborne Illness and Its Sequelae in Australia Circa 2019.

Foodborne illnesses cause a significant health burden, with Campylobacter and norovirus the most common causes of illness and Salmonella a common cause of hospitalization and occasional cause of death. Estimating the cost of illness can assist in quantifying this health burden, with pathogen-specific costs informing prioritization of interventions. We used a simulation-based approach to cost foodborne disease in Australia, capturing the cost of premature mortality, direct costs of nonfatal illness (including health care costs, medications, and tests), indirect costs of illness due to lost productivity, and costs associated with pain and suffering. In Australia circa 2019, the cost in Australian Dollars (AUD) of foodborne illness and its sequelae was 2.44 billion (90% uncertainty interval 1.65-3.68) each year, with the highest pathogen-specific costs for Campylobacter, non-typhoidal Salmonella, non-Shiga toxin-producing pathogenic Escherichia coli, and norovirus. The highest cost per case was for Listeria monocytogenes (AUD 776,000). Lost productivity was the largest component cost for foodborne illness due to all causes and for most individual pathogens; the exceptions were pathogens causing more severe illness such as Salmonella and L. monocytogenes, where premature mortality was the largest component cost. Foodborne illness results in a substantial cost to Australia; interventions to improve food safety across industry, retail, and consumers are needed to maintain public health safety.

Lymphatic filariasis endgame strategies: Using GEOFIL to model mass drug administration and targeted surveillance and treatment strategies in American Samoa.

American Samoa underwent seven rounds of mass drug administration (MDA) for lymphatic filariasis (LF) from 2000-2006, but subsequent surveys found evidence of ongoing transmission. American Samoa has since undergone further rounds of MDA in 2018, 2019, and 2021; however, recent surveys indicate that transmission is still ongoing. GEOFIL, a spatially-explicit agent-based LF model, was used to compare the effectiveness of territory-wide triple-drug MDA (3D-MDA) with targeted surveillance and treatment strategies. Both approaches relied on treatment with ivermectin, diethylcarbamazine, and albendazole. We simulated three levels of whole population coverage for 3D-MDA: 65%, 73%, and 85%, while the targeted strategies relied on surveillance in schools, workplaces, and households, followed by targeted treatment. In the household-based strategies, we simulated 1-5 teams travelling village-to-village and offering antigen (Ag) testing to randomly selected households in each village. If an Ag-positive person was identified, treatment was offered to members of all households within 100m-1km of the positive case. All simulated interventions were finished by 2027 and their effectiveness was judged by their 'control probability'-the proportion of simulations in which microfilariae prevalence decreased between 2030 and 2035. Without future intervention, we predict Ag prevalence will rebound. With 3D-MDA, a 90% control probability required an estimated ≥ 4 further rounds with 65% coverage, ≥ 3 rounds with 73% coverage, or ≥ 2 rounds with 85% coverage. While household-based strategies were substantially more testing-intensive than 3D-MDA, they could offer comparable control probabilities with substantially fewer treatments; e.g. three teams aiming to test 50% of households and offering treatment to a 500m radius had approximately the same control probability as three rounds of 73% 3D-MDA, but used < 40% the number of treatments. School- and workplace-based interventions proved ineffective. Regardless of strategy, reducing Ag prevalence below the 1% target threshold recommended by the World Health Organization was a poor indicator of the interruption of LF transmission, highlighting the need to review blanket elimination targets.

Source attribution of campylobacteriosis in Australia, 2017-2019.

Campylobacter jejuni and Campylobacter coli infections are the leading cause of foodborne gastroenteritis in high-income countries. Campylobacter colonizes a variety of warm-blooded hosts that are reservoirs for human campylobacteriosis. The proportions of Australian cases attributable to different animal reservoirs are unknown but can be estimated by comparing the frequency of different sequence types in cases and reservoirs. Campylobacter isolates were obtained from notified human cases and raw meat and offal from the major livestock in Australia between 2017 and 2019. Isolates were typed using multi-locus sequence genotyping. We used Bayesian source attribution models including the asymmetric island model, the modified Hald model, and their generalizations. Some models included an "unsampled" source to estimate the proportion of cases attributable to wild, feral, or domestic animal reservoirs not sampled in our study. Model fits were compared using the Watanabe-Akaike information criterion. We included 612 food and 710 human case isolates. The best fitting models attributed >80% of Campylobacter cases to chickens, with a greater proportion of C. coli (>84%) than C. jejuni (>77%). The best fitting model that included an unsampled source attributed 14% (95% credible interval [CrI]: 0.3%-32%) to the unsampled source and only 2% to ruminants (95% CrI: 0.3%-12%) and 2% to pigs (95% CrI: 0.2%-11%) The best fitting model that did not include an unsampled source attributed 12% to ruminants (95% CrI: 1.3%-33%) and 6% to pigs (95% CrI: 1.1%-19%). Chickens were the leading source of human Campylobacter infections in Australia in 2017-2019 and should remain the focus of interventions to reduce burden.

Evaluating Molecular Xenomonitoring as a Tool for Lymphatic Filariasis Surveillance in Samoa, 2018-2019.

Molecular xenomonitoring (MX), the detection of filarial DNA in mosquitoes using molecular methods (PCR), is a potentially useful surveillance strategy for lymphatic filariasis (LF) elimination programs. Delay in filarial antigen (Ag) clearance post-treatment is a limitation of using human surveys to provide an early indicator of the impact of mass drug administration (MDA), and MX may be more useful in this setting. We compared prevalence of infected mosquitoes pre- and post-MDA (2018 and 2019) in 35 primary sampling units (PSUs) in Samoa, and investigated associations between the presence of PCR-positive mosquitoes and Ag-positive humans. We observed a statistically significant decline in estimated mosquito infection prevalence post-MDA at the national level (from 0.9% to 0.3%, OR 0.4) but no change in human Ag prevalence during this time. Ag prevalence in 2019 was higher in randomly selected PSUs where PCR-positive pools were detected (1.4% in ages 5-9; 4.8% in ages ≥10), compared to those where PCR-positive pools were not detected (0.2% in ages 5-9; 3.2% in ages ≥10). Our study provides promising evidence for MX as a complement to human surveys in post-MDA surveillance.

Modelling lymphatic filariasis elimination in American Samoa: GEOFIL predicts need for new targets and six rounds of mass drug administration.

BACKGROUND: As part of the global effort to eliminate the debilitating mosquito-borne disease lymphatic filariasis (LF), seven rounds of two-drug (diethylcarbamazine and albendazole) mass drug administration (MDA) were conducted in American Samoa over 2000-2006. However subsequent surveys demonstrated ongoing transmission prompting further rounds of three-drug (diethylcarbamazine, albendazole, and ivermectin) MDA starting in 2018. METHODS: We extend GEOFIL, a spatially-explicit agent-based model of LF transmission to predict the probability and timing of the local elimination or resurgence of LF for different MDA scenarios starting in 2018: two-drug vs. three-drug MDA, two to seven annual rounds, and population coverage rates of 55-75%. We developed an interactive visualisation comparing the effect of MDA strategies on different outcomes. RESULTS: At least six annual rounds of three-drug MDA treating 75% of the population were required to achieve LF elimination in American Samoa by 2035 in > 50% of simulations. In scenarios where MDA did not achieve elimination, prevalence doubled approximately every three years, even if MDA reduced antigen prevalence to <1% (the target recommended by the World Health Organisation). Prevalence in six- and seven-year-old children was approximately one quarter of the prevalence in the general population. CONCLUSION: The three rounds of three-drug MDA conducted in 2018, 2019, and 2021 may have come close to WHO targets but are unlikely to interrupt LF transmission in American Samoa without further interventions. The recommended post-MDA surveillance strategy of testing primarily six and seven-year-old children will delay detection of resurgence compared to population representative surveys. The recommended elimination targets (reducing antigen prevalence below 0.5%, 1%, or 2%) may not be sufficient to interrupt transmission in countries with LF epidemiology like American Samoa. Alternative surveillance strategies and interventions designed to identify and eliminate spatially localized residual transmission may need to be considered. Interactive visualisations may assist decision-makers to choose locally appropriate strategies.

Risk factors for campylobacteriosis in Australia: outcomes of a 2018-2019 case-control study.

BACKGROUND: We aimed to identify risk factors for sporadic campylobacteriosis in Australia, and to compare these for Campylobacter jejuni and Campylobacter coli infections. METHODS: In a multi-jurisdictional case-control study, we recruited culture-confirmed cases of campylobacteriosis reported to state and territory health departments from February 2018 through October 2019. We recruited controls from notified influenza cases in the previous 12 months that were frequency matched to cases by age group, sex, and location. Campylobacter isolates were confirmed to species level by public health laboratories using molecular methods. We conducted backward stepwise multivariable logistic regression to identify significant risk factors. RESULTS: We recruited 571 cases of campylobacteriosis (422 C. jejuni and 84 C. coli) and 586 controls. Important risk factors for campylobacteriosis included eating undercooked chicken (adjusted odds ratio [aOR] 70, 95% CI 13-1296) or cooked chicken (aOR 1.7, 95% CI 1.1-2.8), owning a pet dog aged < 6 months (aOR 6.4, 95% CI 3.4-12), and the regular use of proton-pump inhibitors in the 4 weeks prior to illness (aOR 2.8, 95% CI 1.9-4.3). Risk factors remained similar when analysed specifically for C. jejuni infection. Unique risks for C. coli infection included eating chicken pâté (aOR 6.1, 95% CI 1.5-25) and delicatessen meats (aOR 1.8, 95% CI 1.0-3.3). Eating any chicken carried a high population attributable fraction for campylobacteriosis of 42% (95% CI 13-68), while the attributable fraction for proton-pump inhibitors was 13% (95% CI 8.3-18) and owning a pet dog aged < 6 months was 9.6% (95% CI 6.5-13). The population attributable fractions for these variables were similar when analysed by campylobacter species. Eating delicatessen meats was attributed to 31% (95% CI 0.0-54) of cases for C. coli and eating chicken pâté was attributed to 6.0% (95% CI 0.0-11). CONCLUSIONS: The main risk factor for campylobacteriosis in Australia is consumption of chicken meat. However, contact with young pet dogs may also be an important source of infection. Proton-pump inhibitors are likely to increase vulnerability to infection.

Source attribution of salmonellosis by time and geography in New South Wales, Australia.

BACKGROUND: Salmonella is a major cause of zoonotic illness around the world, arising from direct or indirect contact with a range of animal reservoirs. In the Australian state of New South Wales (NSW), salmonellosis is believed to be primarily foodborne, but the relative contribution of animal reservoirs is unknown. METHODS: The analysis included 4543 serotyped isolates from animal reservoirs and 30,073 serotyped isolates from domestically acquired human cases in NSW between January 2008 and August 2019. We used a Bayesian source attribution methodology to estimate the proportion of foodborne Salmonella infections attributable to broiler chickens, layer chickens, ruminants, pigs, and an unknown or unsampled source. Additional analyses included covariates for four time periods and five levels of rurality. RESULTS: A single serotype, S. Typhimurium, accounted for 65-75% of included cases during 2008-2014 but < 50% during 2017-2019. Attribution to layer chickens was highest during 2008-2010 (48.7%, 95% CrI 24.2-70.3%) but halved by 2017-2019 (23.1%, 95% CrI 5.7-38.9%) and was lower in the rural and remote populations than in the majority urban population. The proportion of cases attributed to the unsampled source was 11.3% (95% CrI 1.2%-22.1%) overall, but higher in rural and remote populations. The proportion of cases attributed to pork increased from approximately 20% in 2009-2016 to approximately 40% in 2017-2019, coinciding with a rise in cases due to Salmonella ser. 4,5,12:i:-. CONCLUSION: Layer chickens were likely the primary reservoir of domestically acquired Salmonella infections in NSW circa 2010, but attribution to the source declined contemporaneously with increased vaccination of layer flocks and tighter food safety regulations for the handling of eggs.

Epidemiological Analysis of the 2019 Dengue Epidemic in Bhutan.

Bhutan experienced its largest and first nation-wide dengue epidemic in 2019. The cases in 2019 were greater than the total number of cases in all the previous years. This study aimed to characterize the spatiotemporal patterns and effective reproduction number of this explosive epidemic. Weekly notified dengue cases were extracted from the National Early Warning, Alert, Response and Surveillance (NEWARS) database to describe the spatial and temporal patterns of the epidemic. The time-varying, temperature-adjusted cohort effective reproduction number was estimated over the course of the epidemic. The dengue epidemic occurred between 29 April and 8 December 2019 over 32 weeks, and included 5935 cases. During the epidemic, dengue expanded from six to 44 subdistricts. The effective reproduction number was <3 for most of the epidemic period, except for a ≈1 month period of explosive growth, coinciding with the monsoon season and school vacations, when the effective reproduction number peaked >30 and after which the effective reproduction number declined steadily. Interventions were only initiated 6 weeks after the end of the period of explosive growth. This finding highlights the need to reinforce the national preparedness plan for outbreak response, and to enable the early detection of cases and timely response.

Antimicrobial Resistance of Campylobacter spp. Causing Human Infection in Australia: An International Comparison.

The study investigates the prevalence of antimicrobial resistance in Campylobacter jejuni and Campylobacter coli in gastroenteritis patients in the eight most populous regions in Australia and compares the prevalence of antimicrobial resistance in Europe and North America. A total of 164 Campylobacter isolates were collected from patients with campylobacteriosis and tested for susceptibility to six antimicrobials using ETEST® strips and compared with reports from Europe and the United States. Genomes were sequenced on Illumina NextSeq to identify genetic determinants of resistance. Phenotypically, 1.8%, 14.0%, 14.6%, and 20.1% of isolates were resistant to erythromycin (ERY), ampicillin, tetracycline (TET), and ciprofloxacin (CIP), respectively. Comparing published phenotypic results of antimicrobial resistance in several European countries and the United States with these Australian isolates reveals that rates observed in Australia are among the lowest observed for ERY, CIP, and TET for both C. coli and C. jejuni. For each antimicrobial tested, concordance between resistance phenotype and genotype ranged from 66.6% to 100.0%. This study highlights that, among industrialized countries, Portugal and Spain have very high levels of antimicrobial resistance in C. jejuni and C. coli, especially when compared with the United Kingdom, United States, and Australia.

Molecular characterization of Campylobacter spp. recovered from beef, chicken, lamb and pork products at retail in Australia.

Australian rates of campylobacteriosis are among the highest in developed countries, yet only limited work has been done to characterize Campylobacter spp. in Australian retail products. We performed whole genome sequencing (WGS) on 331 C. coli and 285 C. jejuni from retail chicken meat, as well as beef, chicken, lamb and pork offal (organs). Campylobacter isolates were highly diverse, with 113 sequence types (STs) including 38 novel STs, identified from 616 isolates. Genomic analysis suggests very low levels (2.3-15.3%) of resistance to aminoglycoside, beta-lactam, fluoroquinolone, macrolide and tetracycline antibiotics. A majority (>90%) of isolates (52/56) possessing the fluoroquinolone resistance-associated T86I mutation in the gyrA gene belonged to ST860, ST2083 or ST7323. The 44 pork offal isolates were highly diverse, representing 33 STs (11 novel STs) and harboured genes associated with resistance to aminoglycosides, lincosamides and macrolides not generally found in isolates from other sources. Prevalence of multidrug resistant genotypes was very low (<5%), but ten-fold higher in C. coli than C. jejuni. This study highlights that Campylobacter spp. from retail products in Australia are highly genotypically diverse and important differences in antimicrobial resistance exist between Campylobacter species and animal sources.

Some simple rules for estimating reproduction numbers in the presence of reservoir exposure or imported cases.

For many diseases, the basic reproduction number (R0) is a threshold parameter for disease extinction or survival in isolated populations. However no human population is fully isolated from other human or animal populations. We use compartmental models to derive simple rules for the basic reproduction number in populations where an endemic disease is sustained by a combination of local transmission within the population and exposure from some other source: either a reservoir exposure or imported cases. We introduce the idea of a reservoir-driven or importation-driven disease: diseases that would become extinct in the population of interest without reservoir exposure or imported cases (since R0<1), but nevertheless may be sufficiently transmissible that many or most infections are acquired from humans in that population. We show that in the simplest case, R0<1 if and only if the proportion of infections acquired from the external source exceeds the disease prevalence and explore how population heterogeneity and the interactions of multiple strains affect this rule. We apply these rules in two case studies of Clostridium difficile infection and colonisation: C. difficile in the hospital setting accounting for imported cases, and C. difficile in the general human population accounting for exposure to animal reservoirs. We demonstrate that even the hospital-adapted, highly-transmissible NAP1/RT027 strain of C. difficile had a reproduction number <1 in a landmark study of hospitalised patients and therefore was sustained by colonised and infected admissions to the study hospital. We argue that C. difficile should be considered reservoir-driven if as little as 13.0% of transmission can be attributed to animal reservoirs.

Healthcare-Associated Clostridium difficile Infections are Sustained by Disease from the Community.

Clostridium difficile infections (CDIs) are some of the most common hospital-associated infections worldwide. Approximately 5% of the general population is colonised with the pathogen, but most are protected from disease by normal intestinal flora or immune responses to toxins. We developed a stochastic compartmental model of CDI in hospitals that captures the condition of the host's gut flora and the role of adaptive immune responses. A novel, derivative-based method for sensitivity analysis of individual-level outcomes was developed and applied to the model. The model reproduced the observed incidence and recurrence rates for hospitals with high and moderate incidence of hospital-acquired CDI. In both scenarios, the reproduction number for within-hospital transmission was less than 1 (0.67 and 0.44, respectively), but the proportion colonised with C. difficile at discharge (7.3 and 6.1%, respectively) exceeded the proportion colonised at admission (5%). The transmission and prevalence of CDI were most sensitive to the average length of stay and the transmission rate of the pathogen. Recurrent infections were most strongly affected by the treatment success rate and the immune profile of patients. Transmission within hospitals is substantial and leads to a net export of colonised individuals to the broader community. However, within-hospital transmission alone is insufficient to sustain endemic conditions in hospitals without the constant importation of colonised individuals. Improved hygiene practices to reduce transmission from symptomatic and asymptomatic individuals and reduced length of stay are most likely to reduce within-hospital transmission and infections; however, these interventions are likely to have a smaller effect on the probability of recurrence. Immunising inpatients against the toxins produced by C. difficile will reduce the incidence of CDI but may increase transmission.