Interactions Amongst the Community of Endemic Pathogens of African Cattle: A Longitudinal Study in South East Uganda

The work presented in this thesis is focused upon the community of endemic pathogens of African cattle in Sub-Saharan Africa, which has long constrained livestock production in these areas. The first aim of this work is to investigate whether the pathogen community as a whole shapes the ensuant epidemiology and morbidity which are currently attributed to any of its individual pathogens. The second aim is to determine if a greater understanding of the interactions present amongst genetically distinct parasites of the same species can be used to better explain epidemiological features that are at present poorly understood. Emphasis is placed on examining spatial variation in the epidemiology of Theileria parva, a tick-transmitted protozoan that causes East Coast Fever. To achieve these aims, this work examines field data collected from a large and comprehensive study conducted in south east Uganda. Through application of apposite statistical techniques and mathematical modelling, aspects of the complex relations amongst the pathogen community and their environment are explored. Evidence is presented that demonstrates the paramount role of the pathogen community as a whole in shaping the infection dynamics and pathogenicity of any of its individual components. By focusing on a single member of this pathogen community (Theileria parva), some of the influences of host, vector, geographical location, temporal dynamics and intra-species pathogen interactions are elucidated. Application of a polymorphic molecular marker to Theileria parva infected blood samples and the use of Cox proportional hazard analysis, show variability in the survival of infections in cattle in high and low tick challenge areas. Moreover infection survival, which plays a pivotal role in parasite transmission, is shown to be a function of the interactions established amongst genetically distinct co-infective parasites. In consequence, vector intensity alone is insufficient to develop reliable transmission models which can accurately predict the epidemiology of the parasite inside and outside enzootic belts. Finally, a theoretical model is developed which, based upon the field evidence obtained throughout this work, provides a possible explanation for the mechanics of T. parva survival in cattle. In summary, this thesis makes a case that consideration of both inter- and intra-species pathogen interactions, can greatly augment understanding of the epidemiology of these pathogen communities. An integrated approach to pathogen dynamics can better equip an integrated approach to control of important diseases of African cattle

Frequent Undetected Ward-Based Methicillin-Resistant Staphylococcus aureus Transmission Linked to Patient Sharing Between Hospitals.

Background: Recent evidence suggests that hospital transmission of methicillin-resistant Staphylococcus aureus (MRSA) is uncommon in UK centers that have implemented sustained infection control programs. We investigated whether a healthcare-network analysis could shed light on transmission paths currently sustaining MRSA levels in UK hospitals. Methods: A cross-sectional observational study was performed in 2 National Health Service hospital groups and a general district hospital in Southeast London. All MRSA patients identified at inpatient, outpatient, and community settings between 1 November 2011 and 29 February 2012 were included. We identified genetically defined MRSA transmission clusters in individual hospitals and across the healthcare network, and examined genetic differentiation of sequence type (ST) 22 MRSA isolates within and between hospitals and inpatient or outpatient and community settings, as informed by average and median pairwise single-nucleotide polymorphisms (SNPs) and SNP-based proportions of nearly identical isolates. Results: Two hundred forty-eight of 610 (40.7%) MRSA patients were linked in 90 transmission clusters, of which 27 spanned multiple hospitals. Analysis of a large 32 patient ST22-MRSA cluster showed that 26 of 32 patients (81.3%) had multiple contacts with one another during ward stays at any hospital. No residential, outpatient, or significant community healthcare contacts were identified. Genetic differentiation between ST22 MRSA inpatient isolates from different hospitals was less than between inpatient isolates from the same hospitals (P ≤ .01). Conclusions: There is evidence of frequent ward-based transmission of MRSA brought about by frequent patient admissions to multiple hospitals. Limiting in-ward transmission requires sharing of MRSA status data between hospitals

Population-level faecal metagenomic profiling as a tool to predict antimicrobial resistance in Enterobacterales isolates causing invasive infections: an exploratory study across Cambodia, Kenya, and the UK

Background: Antimicrobial resistance (AMR) in Enterobacterales is a global health threat. Capacity for individual-level surveillance remains limited in many countries, whilst population-level surveillance approaches could inform empiric antibiotic treatment guidelines. Methods: In this exploratory study, a novel approach to population-level prediction of AMR in Enterobacterales clinical isolates using metagenomic (Illumina) profiling of pooled DNA extracts from human faecal samples was developed and tested. Taxonomic and AMR gene profiles were used to derive taxonomy-adjusted population-level AMR metrics. Bayesian modelling, and model comparison based on cross-validation, were used to evaluate the capacity of each metric to predict the number of resistant Enterobacterales invasive infections at a population-level, using available bloodstream/cerebrospinal fluid infection data. Findings: Population metagenomes comprised samples from 177, 157, and 156 individuals in Kenya, the UK, and Cambodia, respectively, collected between September 2014 and April 2016. Clinical data from independent populations included 910, 3356 and 197 bacterial isolates from blood/cerebrospinal fluid infections in Kenya, the UK and Cambodia, respectively (samples collected between January 2010 and May 2017). Enterobacterales were common colonisers and pathogens, and faecal taxonomic/AMR gene distributions and proportions of antimicrobial-resistant Enterobacterales infections differed by setting. A model including terms reflecting the metagenomic abundance of the commonest clinical Enterobacterales species, and of AMR genes known to either increase the minimum inhibitory concentration (MIC) or confer clinically-relevant resistance, had a higher predictive performance in determining population-level resistance in clinical Enterobacterales isolates compared to models considering only AMR gene information, only taxonomic information, or an intercept-only baseline model (difference in expected log predictive density compared to best model, estimated using leave-one-out cross-validation: intercept-only model = -223 [95% credible interval (CI): -330,-116]; model considering only AMR gene information = -186 [95% CI: -281,-91]; model considering only taxonomic information = -151 [95% CI: -232,-69]). Interpretation: Whilst our findings are exploratory and require validation, intermittent metagenomics of pooled samples could represent an effective approach for AMR surveillance and to predict population-level AMR in clinical isolates, complementary to ongoing development of laboratory infrastructures processing individual samples

Co-infections determine patterns of mortality in a population exposed to parasite infection

Many individual hosts are infected with multiple parasite species, and this may increase or decrease the pathogenicity of the infections. This phenomenon is termed heterologous reactivity and is potentially an important determinant of both patterns of morbidity and mortality and of the impact of disease control measures at the population level. Using infections with Theileria parva (a tick-borne protozoan, related to Plasmodium) in indigenous African cattle [where it causes East Coast fever (ECF)] as a model system, we obtain the first quantitative estimate of the effects of heterologous reactivity for any parasitic disease. In individual calves, concurrent co-infection with less pathogenic species of Theileria resulted in an 89% reduction in mortality associated with T. parva infection. Across our study population, this corresponds to a net reduction in mortality due to ECF of greater than 40%. Using a mathematical model, we demonstrate that this degree of heterologous protection provides a unifying explanation for apparently disparate epidemiological patterns: variable disease-induced mortality rates, age-mortality profiles, weak correlations between the incidence of infection and disease (known as endemic stability), and poor efficacy of interventions that reduce exposure to multiple parasite species. These findings can be generalized to many other infectious diseases, including human malaria, and illustrate how co-infections can play a key role in determining population-level patterns of morbidity and mortality due to parasite infections

Design and descriptive epidemiology of the Infectious Diseases of East African Livestock (IDEAL) project, a longitudinal calf cohort study in western Kenya

BACKGROUND: There is a widely recognised lack of baseline epidemiological data on the dynamics and impacts of infectious cattle diseases in east Africa. The Infectious Diseases of East African Livestock (IDEAL) project is an epidemiological study of cattle health in western Kenya with the aim of providing baseline epidemiological data, investigating the impact of different infections on key responses such as growth, mortality and morbidity, the additive and/or multiplicative effects of co-infections, and the influence of management and genetic factors. A longitudinal cohort study of newborn calves was conducted in western Kenya between 2007-2009. Calves were randomly selected from all those reported in a 2 stage clustered sampling strategy. Calves were recruited between 3 and 7 days old. A team of veterinarians and animal health assistants carried out 5-weekly, clinical and postmortem visits. Blood and tissue samples were collected in association with all visits and screened using a range of laboratory based diagnostic methods for over 100 different pathogens or infectious exposures. RESULTS: The study followed the 548 calves over the first 51 weeks of life or until death and when they were reported clinically ill. The cohort experienced a high all cause mortality rate of 16% with at least 13% of these due to infectious diseases. Only 307 (6%) of routine visits were classified as clinical episodes, with a further 216 reported by farmers. 54% of calves reached one year without a reported clinical episode. Mortality was mainly to east coast fever, haemonchosis, and heartwater. Over 50 pathogens were detected in this population with exposure to a further 6 viruses and bacteria. CONCLUSION: The IDEAL study has demonstrated that it is possible to mount population based longitudinal animal studies. The results quantify for the first time in an animal population the high diversity of pathogens a population may have to deal with and the levels of co-infections with key pathogens such as Theileria parva. This study highlights the need to develop new systems based approaches to study pathogens in their natural settings to understand the impacts of co-infections on clinical outcomes and to develop new evidence based interventions that are relevant

Evidence for Community Transmission of Community-Associated but Not Health-Care-Associated Methicillin-Resistant Staphylococcus Aureus Strains Linked to Social and Material Deprivation: Spatial Analysis of Cross-sectional Data

Supporting information for a paper titled "Evidence for Community Transmission of Community-Associated but Not Health-Care-Associated Methicillin-Resistant Staphylococcus Aureus Strains Linked to Social and Material Deprivation: Spatial Analysis of Cross-sectional Data". This includes: an MS Word document that describes the modelling approach (S1 Methods), Summary statistics for area-level variables in 513 LSOAs within catchment areas of the hospital cohort (S1 Table), data from the 2011 England and Wales census that outlines population structure of 513 LSOAs within catchment areas of the hospital cohort. (S2 Table), Individual patient-level metadata (S1 Text), and LSOA-level aggregated metadata (S2 Text

Interactions amongst the community of endemic pathogens of African cattle : a longitudinal study in south east Uganda

The work presented in this thesis is focused upon the community of endemic pathogens of African cattle in Sub-Saharan Africa, which has long constrained livestock production in these areas. The first aim of this work is to investigate whether the pathogen community as a whole shapes the ensuant epidemiology and morbidity which are currently attributed to any of its individual pathogens. The second aim is to determine if a greater understanding of the interactions present amongst genetically distinct parasites of the same species can be used to better explain epidemiological features that are at present poorly understood. Emphasis is placed on examining spatial variation in the epidemiology of Theileria parva, a tick-transmitted protozoan that causes East Coast Fever. To achieve these aims, this work examines field data collected from a large and comprehensive study conducted in south east Uganda. Through application of apposite statistical techniques and mathematical modelling, aspects of the complex relations amongst the pathogen community and their environment are explored. Evidence is presented that demonstrates the paramount role of the pathogen community as a whole in shaping the infection dynamics and pathogenicity of any of its individual components. By focusing on a single member of this pathogen community (Theileria parva), some of the influences of host, vector, geographical location, temporal dynamics and intra-species pathogen interactions are elucidated. Application of a polymorphic molecular marker to Theileria parva infected blood samples and the use of Cox proportional hazard analysis, show variability in the survival of infections in cattle in high and low tick challenge areas. Moreover infection survival, which plays a pivotal role in parasite transmission, is shown to be a function of the interactions established amongst genetically distinct co-infective parasites. In consequence, vector intensity alone is insufficient to develop reliable transmission models which can accurately predict the epidemiology of the parasite inside and outside enzootic belts. Finally, a theoretical model is developed which, based upon the field evidence obtained throughout this work, provides a possible explanation for the mechanics of T. parva survival in cattle. In summary, this thesis makes a case that consideration of both inter- and intra-species pathogen interactions, can greatly augment understanding of the epidemiology of these pathogen communities. An integrated approach to pathogen dynamics can better equip an integrated approach to control of important diseases of African cattle.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Clustering of antimicrobial resistance outbreaks across bacterial species in the intensive care unit.

BACKGROUND: There are frequent reports of intensive care unit (ICU) outbreaks due to transmission of particular antibiotic-resistant bacteria. Less is known about the burden of outbreaks of resistance due to horizontal transfer of mobile genetic elements between species. Moreover, the potential of existing statistical software as a preliminary means for detecting such events has never been assessed. This study uses a software package to determine the burden of species and resistance outbreaks in 2 adjacent ICUs and to look for evidence of clustering of resistance outbreaks consistent with interspecies transmission of resistance elements. METHODS: A retrospective analysis of data from 2 adjacent 15-bed adult ICUs between 2002 and 2009 was undertaken. Detection of bacterial species-groups and resistance outbreaks was conducted using SaTScan and WHONet-SaTScan software. Resampling and permutation methods were applied to investigate temporal clustering of outbreaks. RESULTS: Outbreaks occurred for 69% of bacterial species-groups (18/26), and resistance outbreaks were detected against 63% of antibiotics (10/16). Resistance outbreaks against 7 of 10 antibiotics were observed in multiple species-groups simultaneously and there was evidence of inter-species-group dependence for 4 of 7 antibiotics; background temporal changes in resistance did not explain the temporal aggregation of outbreaks in 3 of 7 antibiotics. CONCLUSIONS: Species outbreaks occurred for the majority of bacteria commonly identified in the ICU. There was evidence for frequent temporal clustering of resistance outbreaks consistent with interspecies transmission of resistance elements. Wider application of outbreak detection software combined with targeted sequencing of bacterial genomes is needed to understand the contribution of interspecies gene transfer to resistance emergence

Infection prevention and control during the COVID-19 pandemic: Challenges and opportunities for Kenyan public hospitals

Background: Infection prevention and control, and water sanitation and hygiene have an essential role in ensuring the quality of care and patient outcomes in hospitals. Using a modification of the World Health Organization's water sanitation and hygiene facility improvement tool, we undertook assessments in 14 public hospitals in Kenya in 2018. The hospitals received written feedback on areas where they could make improvements. Following the first confirmed cases of COVID-19 in Kenya, we were drawn to ask whether the results of our pre-pandemic survey had led to action, and whether or not the threat of COVID-19 had focused more attention on infection prevention and control and water sanitation and hygiene. Methods: Using a semi-structured interview guide, we carried out phone interviews with key hospital leaders in 11 of the 14 hospitals. The data were transcribed and coded into thematic areas. We draw on these interviews to describe the status and awareness of infection prevention and control. Results: The infection prevention and control committee members are training health workers on infection prevention and control procedures and proper use of personal protective equipment and in addition, providing technical support to hospital managers. While some hospitals have also accessed additional funds to improve infection prevention and control, they tended to be small amounts of money. Long-standing challenges with supplies of infection prevention and control materials and low staff morale persist. Crucially, the reduced supply of personal protective equipment has led to fear and anxiety among health care personnel. Conclusions: As funds are mobilised to support care for COVID-19, we ask that funds prioritise infection prevention and control measures. This would have a profoundly positive effect on within hospital virus transmission, patient and staff safety but also lasting benefits beyond the COVID-19 pandemic