A biomarker-based exclusion of ventilator-associated pneumonia : towards improved antibiotic stewardship

PhD ThesisVentilator-associated pneumonia (VAP) is a common complicating condition amongst patients mechanically ventilated in the Intensive Care Unit (ICU). It is a common reason for antibiotics to be administered. The diagnosis of VAP is challenging and amongst patients in whom VAP is suspected, approximately a third will have infection confirmed. Therefore many patients receive antibiotics for VAP despite the condition not being present. Antimicrobial resistance (AMR) is a growing global concern and the overuse of antibiotics is an important factor in increasing AMR. The ICU is an environment with high antibiotic use and improving antibiotic stewardship is a priority. Rapid biomarker-based diagnostics could achieve this by expediting the diagnostic process. In this thesis I present the findings of a multi-centre validation study of a novel bronchoalveolar lavage-based biomarker test. The diagnostic value of the measured biomarkers is discussed and the optimum biomarker-based diagnostic test for use in VAP is presented. I subsequently present a multi-centre randomised controlled trial in which the biomarker-based test is assessed in the clinical environment to determine whether it does indeed result in improved antibiotic stewardship. Trial outcomes are reported and implications are discussed

The Use of Interdisciplinary Approaches to Understand the Biology of Campylobacter jejuni

Funding Information: This work was supported by a scholarship grant from the University of Aberdeen and Curtin University.Peer reviewedPublisher PD

Prospects for the development of a subunit vaccine against Mycobacterium ulcerans disease (Buruli ulcer)

Buruli ulcer (BU) is a slow progressing disease of the skin and subcutaneous tissue caused by Mycobacterium ulcerans. It presents in different clinical forms ranging from small non-ulcerative nodules to large ulcers and sometimes multiple ulcerations. The highest prevalence of the focally occurring disease is found in rural areas of West African countries. Both the mode of transmission as well as the potential environmental reservoir of M. ulcerans remain unidentified to date. In Cameroon, the remote Mapé dam region has recently been identified as a new BU endemic area. To assess the age-adjusted prevalence and local geographic distribution of BU, a house-by-house survey in the Bankim health district was conducted. Results showed that children between the age of five to 15 and elderly people were over proportionally affected by BU. To confirm the clinical diagnosis of BU during and after the health survey in Bankim, fine needle aspirates and swabs from undermined ulcer edges were transported to the Swiss Tropical and Public Health Institute for laboratory confirmation by quantitative real time PCR. In parallel we developed a protocol for primary culture initiation of M. ulcerans from patient lesions after a long time span between sampling and processing in a BSL3 culture laboratory. The established two sets of Cameroonian patient isolates from the Mapé and the Nyong river valleys were used for a comparative genome sequencing study revealing the presence of two distinct phylogenetic clonal complexes in Cameroon. Despite the fact that BU can be treated with antibiotics, the socioeconomic impact of the disease on affected populations remains devastating. As long as it is not clearly known how the disease is contracted, interruption of transmission is not an option. A vaccine against M. ulcerans on the other hand could be used both as preventive measure and therapeutically. While sero-epidemiological studies imply the presence of protective immunity in some individuals, no vaccine is available to date. Within the framework of the EU funded collaborative project BuruliVac we investigated the potential for developing a protein subunit vaccine against M. ulcerans by delivering vaccine candidate antigens with three different systems: i. as recombinant proteins with an adjuvant, ii. as vesicular stomatitis virus replicon and iii. incorporated into a genetically modified mouse malaria parasite (Plasmodium berghei) in an infection - treatment - approach. All three formulations were assessed for their immunogenicity and their protective potential in a mouse model of BU. Although all three vaccination approaches elicited strong humoral immune responses, no full protection was observed for any of the formulations. However a slight partial protection was seen for a replicon - prime / recombinant protein boost regimen with a vesicular stomatitis virus replicon incorporating an expression cassette for the M. ulcerans protein MUL2232. Additionally, a transient delay of foot pad swelling was observed in mice receiving infection - treatment - vaccination with P. berghei expressing MUL4987. Despite the mainly extracellular nature of M. ulcerans in infected tissue, antibody production against the protein vaccine candidates thus does not seem to be sufficient for protection. Considering marked differences between the mouse footpad model of BU and the disease in humans, we aimed at developing an animal model that better reflects local pathogenesis and host-pathogen interactions in the human BU lesions. Hence, we developed the pig as novel animal model for BU and showed that the observed histopathological changes in the infected pig skin closely represent those of human BU. Therefore the pig model has great potential for the validation of new therapeutic and prophylactic interventions

Prevalence, burden and anthelmintic resistance of gastrointestinal nematodes in the south west region of Western Australia dairy herds

Anthelmintic resistance in gastrointestinal nematodes (GIN) of dairy cattle is of global importance. The objective of this study was to determine the prevalence of GIN among post-weaned replacement heifers and bull calves aged between 4 - 12 months old in Western Australia dairy farms and quantify the level of anthelmintic resistance. A secondary objective of this study was to explore pooling faecal samples for cost effective diagnostic purposes of faecal egg counts (FECs). Pre-treatment FECs were monitored on 14 dairy farms, anthelmintic resistance was assessed on 11 of the farms based on FEC of ≥500 eggs per gram (epg) in at least 10 - 15% of the samples. Control FECs were compared with anthelmintic FECs at 14 days post-treatment with doramectin (injectable), levamisole (oral), fenbendazole (oral) and, a levamisole/abamectin combination (Eclipse® combination pour-on). The results demonstrate a high level of anthelmintic resistance, with at least one class of anthelmintic failing to achieve a 95% reduction in FEC in one or more GIN species. Doramectin was fully effective against Ostertagia, but C. oncophora displayed resistance to it on 91% of the farms. Conversely, levamisole was fully effective against C. oncophora, but Ostertagia displayed resistance in 80% of the farms. Fenbendazole resistance was present in both C. onocphora and Ostertagia in 64% and 70% of the farms respectively. Trichostrongylus showed low resistance, only occurring in doramectin (14%) and levamisole/abamectin combination (14%) on the farms sampled. A high level of correlation between pooled groups of 5, 10 and 20 samples was recorded (R=0.947, 0.987, 0.972 and P=0.015, 0.002, and 0.006) respectively. This study confirms that anthelmintic resistance within Western Australian dairy farms is common and regular faecal egg count reduction testing is recommended to monitor and guide decision-making for appropriate anthelmintic usage. Utilisation of pooled FECs provides a potential cost-effective method for farmers to regularly monitor FECs

Ready or Not? Protecting the Public's Health From Diseases, Disasters, and Bioterrorism, 2008

Examines ten indicators to assess progress in state readiness to respond to bioterrorism and other public health emergencies. Evaluates the federal government's and hospitals' preparedness. Makes suggestions for funding, restructuring, and other reforms

Advances in Computer Science and Engineering

The book Advances in Computer Science and Engineering constitutes the revised selection of 23 chapters written by scientists and researchers from all over the world. The chapters cover topics in the scientific fields of Applied Computing Techniques, Innovations in Mechanical Engineering, Electrical Engineering and Applications and Advances in Applied Modeling