Massey Documents by Type

Permanent URI for this communityhttps://mro.massey.ac.nz/handle/10179/294

Browse

Start date: 2021Subject: search.filters.subject.Antibiotics

Search Results

Now showing 1 - 4 of 4
  • Thumbnail Image
    Item
    Is early life antibiotic-use a risk factor for the development of Type 1 diabetes? : a longitudinal data linkage study : a thesis with publications presented in partial fulfillment to the requirements for the degree of Doctor of Philosophy in Public Health (Epidemiology), Massey University, Wellington, New Zealand
    (Massey University, 2025-09-01) Ram, Sharan
    Introduction: Early-life antibiotic-use may disrupt the gut microbiota, potentially increasing the risk of Type 1 diabetes (T1D). This thesis assessed associations between prenatal and early childhood antibiotic exposure and T1D. Methods: A meta-analysis of 14 studies (2006-2020), encompassing 3,066,063 participants, assessed associations between early-life antibiotic-use and T1D. Subsequently, a longitudinal nation-wide linkage study examined this association in 315,789 New Zealand children born between 2005-2010 and followed until 2021, using Cox proportional hazards regression controlled for potential confounders. Patterns of antibiotic-use during pregnancy and early childhood were also analysed across demographic characteristics. Associations between both pre and post natal antibiotic exposure were assessed, including analyses by antibiotic class and spectrum, and stratification by delivery mode. T1D was identified using insulin dispensing and hospitalisation records. Results: The meta-analysis, showed a pooled risk estimates for prenatal exposure of 1.10 (95% CI: 1.00–1.21); for postnatal antibiotic-use a pooled risk estimate of 1.11 (95%CI 1.04–1.18) was found, with ≥5 courses resulting in a pooled estimate of 1.36 (95%CI 1.15–1.61). Broad-spectrum antibiotics were associated with higher risk (HR: 1.13, 95% CI: 1.03–1.23). In New Zealand, 30% of pregnant women received antibiotics, predominantly penicillin (73.7%). Higher usage was observed among Pacific (38.7%) and Māori (35.7%) women, those most deprived (i.e. those from the lowest socio-economic group) (39.5%). Those who had caesarean deliveries had higher rates of antibiotic use, with incidence rate ratios (IRRs) of 1.27 for elective and 1.09 for emergency procedures. By age five, 96% of children had received antibiotics, with similar subgroup patterns as observed for pregnant women. Prenatal antibiotic-use was associated with an increased T1D risk in a dose-dependent fashion (≥3 courses, HR 1.86; 95%CI:1.44–2.39), with the highest risk for broad-spectrum antibiotics (HR: 1.30; 95%CI: 1.12–1.57). Postnatal antibiotic-use was associated, also in a dose-dependent way, with T1D (≥13 courses, HR 1.93; 95%CI 1.18–3.17; broad-spectrum antibiotics, HR 1.74; 95%CI 1.10-2.78). Stratified analyses by delivery mode resulted in mixed results across different analyses. Conclusion: These findings show high antibiotic-use in New Zealand and among specific ethnic and socio-economic subgroups. It also showed clear associations with the development of childhood T1D, which is consistent with international studies as shown in the meta-analysis, underscoring the need for judicious antibiotic stewardship
  • Thumbnail Image
    Item
    The maintenance and evolution of antibiotic resistance genes in the absence of antibiotic selection : a thesis submitted in partial fulfilment of the requirements for the degree of Doctor of Philosophy in Microbiology & Genetics at Massey University, Albany Campus, New Zealand
    (Massey University, 2023) Lai, Huei-Yi
    The rise of new antibiotic resistance in pathogenic bacteria combined with the stagnation of drug development has led to a crisis in treating bacterial infection. An understanding of factors that can influence the development and prevalence of antibiotic resistance in bacteria can help combat resistance. Bacteria can acquire antibiotic resistance via two types of genetic changes— antibiotic resistance mutations (ARMs) and acquisition of antibiotic resistance genes (ARGs). In the presence of antibiotics, these genetic changes are beneficial to bacteria but in the absence of antibiotic any fitness cost of the resistance genotype imposed on the bacteria is uncovered. The fitness cost of a resistance genotype creates a fitness difference between resistant and susceptible bacteria leading to purifying selection against resistant bacteria. As a result, the fitness cost of a resistance genotype can play an important role in the maintenance of resistant bacteria in a population, especially when the antibiotic selection is absent or weak. Previous studies have focused on the degree and mechanistic basis of the fitness cost of ARMs and of ARGs embedded in mobile genetic elements (MGEs), such as plasmids. Little is known about the fitness cost of individual ARGs, let alone its mechanistic basis. Moreover, ARGs are often associated with MGEs, which subject ARGs to frequent gene flow between bacteria. Because of this movement between host strains, any variation in the fitness cost of an ARG between different strains can influence its prevalence at the population level. Despite the potential importance of this effect in determining the success of ARGs, direct measurements of host specific fitness costs have been made for only a few distinct ARGs. Finally, compensatory evolution can alleviate the fitness cost of resistance genotypes so that both immediate and longterm costs of ARGs must be considered. In this thesis, I aim to investigate the fitness cost of individual ARGs and test its evolutionary significance. In Chapter 2, I quantify the fitness costs of six ARGs prevalent in published Escherichia coli genomes and determine the variation in costs across twelve Escherichia strains. While on average the fitness cost of the six ARGs is small, consistent with their high prevalence, the costs of most ARGs vary between hosts. I show that this variation can be consequential, resulting in host-dependent evolutionary dynamics of an ARG plasmid. In Chapter 3, I use whole genome sequencing and reverse genetics to dissect the genetic basis of the compensatory evolution observed in Chapter 2. I identify a mutation on a phage gene that can alleviate the fitness cost of a b-lactamase, and moreover, I demonstrate that the host-dependent cost of the b-lactamase is due to the negative interaction between the b-lactamase and the phage gene. Chapter 4 extends work on measuring ARG costs and determining their effect on ARG maintenance to investigate the influence of costs on the molecular evolution of an ARG. In Chapter 4, I examine if the host dependent fitness cost of the b-lactamase can influence the accumulation of genetic variation in that gene. Together, these chapters characterize the influence of the fitness cost of ARGs on their maintenance and evolution and demonstrate that, even without antibiotic selection, other selective forces continue to influence the persistence of antibiotic resistance genes in bacterial populations.
  • Thumbnail Image
    Item
    The role of emerging organic contaminants in the development of antimicrobial resistance
    (KeAi Communications Co. Ltd. Publishing services by Elsevier BV on behalf of KeAi Communications Co Ltd, 2021-08-05) Alderton I; Palmer BR; Heinemann JA; Pattis I; Weaver L; Gutiérrez-Ginés MJ; Horswell J; Tremblay LA
    Antimicrobial resistance (AMR) threatens human and ecological health worldwide. Unless major changes occur across the human, animal and environmental sectors, the problem will continue to expand. An important component of AMR that deserves greater attention is the influence of emerging organic contaminants (EOCs) – ubiquitous compounds found, amongst others, in pharmaceuticals, personal care products, food, industrial and agricultural products, plastics and building materials. EOCs are widely used and can accumulate in the environment from varied sources, predominantly via waste streams. EOCs can interact with microbial communities potentially leading to the emergence and spread of AMR. Biocides and pharmaceuticals have been demonstrated to promote AMR development. Antimicrobial resistance is a multi-faceted problem that requires input from all sectors, with robust strategies and policies needed to make headway with solving the issues of this important threat.
  • Thumbnail Image
    Item
    Synergistic triple combination antibiotic therapy for Gram-negative bacterial infections : a thesis presented in partial fulfilment of the requirements for the degree of Doctor of Philosophy in Microbiology and Genetics at Massey University, Manawatu, New Zealand
    (Massey University, 2021) Olivera, Catrina Diane
    The continuing emergence of multidrug-resistant bacteria and the slowing down of the discovery and development of novel antibiotics have made antimicrobial resistance an ominous threat to human health. As reflected in the World Health Organization’s priority pathogens list, this problem is notably more severe in multidrug-resistant Gram-negative bacteria. This situation needs to be rectified through alternative approaches, such as the revival of 'old' antibiotics and the development of combination therapies. This thesis focuses on the combination of the 'old' antibiotics, nitrofurans and vancomycin (VAN) with the secondary bile salt sodium deoxycholate (DOC). The synergistic interaction of these antibacterials was demonstrated in the in vitro growth inhibition and killing of Gram-negative bacteria, including the clinically relevant pathogens such as carbapenemase-producing Escherichia coli, Klebsiella pneumoniae, and Acinetobacter baumannii. The synergy increased the efficacy and reduced the doses of each of the components compared to monotherapy use, with the advantage of mitigating nitrofuran mutagenicity. Using a transcriptomics approach, underlying mechanisms of the individual and combined action of nitrofurans, VAN, and DOC in E. coli were elucidated. The nitrofuran antibiotic, furazolidone (FZ), and DOC elicited highly similar gene perturbations indicative of iron starvation response, decreased respiration and metabolism, and translational stress. VAN, on the other hand, induced extracytoplasmic stress response in agreement with its known role in peptidoglycan synthesis inhibition. Through genetic and biochemical approaches, Fur (ferric uptake regulator) protein inactivation was confirmed to be important in the synergy of FZ and DOC and to contribute to the synergy of the triple combination. Similarly, the SOS response to DNA damage was shown to be essential for the synergy between FZ and VAN and to also contribute to the synergy of the triple combination. Taken together, the findings of this thesis strongly suggest the presence of multiple interaction points, that leads to the triple synergy, and support the proposed mechanism of synergy where the combined effects lead to the amplification of damaging effects and suppression of resistance mechanisms. Overall, this thesis shows the synergistic triple combination of nitrofurans, DOC, and VAN as a promising therapy for Gram-negative infections. Furthermore, this work significantly increases the understanding of drug interaction mechanisms that lead to synergy, which is hoped to help advance this combination further into the development pipeline. Transcriptomics analyses and the follow-up experiments provide key fundamental insights into the physiological impact that these three antimicrobials have on enterobacterium E. coli and highlight the advantage of combined targets in bacterial killing. These findings, in turn, will help design novel antibiotics, mono- or combined therapies, against multidrug-resistant bacteria.