Development of a within-host mathematical model of urethral gonorrhoea infection and application to treatment

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Copyright: Jayasundara, Pavithra
Background To understand the emergence and spread of drug resistance in the context of Neisseria gonorrhoeae (NG) it is first important to characterise the within-host dynamics that influence these events. However, in the context of NG, the within-host infection process is not well understood, with little investigation into the role of intracellular NG on the progression of natural infection and the dynamics of infection under treatment. This thesis aims to address this gap through the use of novel within-host mathematical models to describe symptomatic male urethral NG infection. Methods Initially, we developed a model to describe the progression of natural infection by considering the interaction between extracellular and intracellular NG with immune response through PMN. This initial model was then adopted to incorporate treatment of NG infection through pharmacokinetic (PK) and pharmacodynamic (PD) approaches for several antibiotics, examining both extracellular and intracellular dynamics after treatment. While this relatively simple treatment model with conventional approaches was successful in explaining the infection dynamics for the non-β-lactam drugs we test, using β-lactams the model struggled to describe infection dynamics consistent with the literature, leading to a revised approach applied to cefixime and ceftriaxone. This new approach incorporated a transition between bacteriostatic and bactericidal effects determined through threshold effects applied to the fraction of drug bound penicillin-binding-proteins. Parameter values were estimated by fitting to existing empirical data where sub-models to reflect different in vitro experimental conditions were adopted. Results Using the natural infection model, we successfully reproduced known phenomena on bacterial load and infection duration and found that the simulated natural infection was mainly driven by intracellular NG with ~80% of the total NG population internalised from day 5 on. In addition, we achieved realistic infection clearance times for each drug considered and simulations showed treatment failure to be largely driven by unsuccessful clearance of intracellular NG. We also identified relevant PK indices at the intracellular level that differentiated treatment success and failure. Although we investigated multiple dose strategies for orally administered drugs (gepotidacin, azithromycin and cefixime), we found little difference in treatment success for a fixed total dose. Discussion In this study we contribute new theoretical results tied to available observations in an area that has had limited experimental attention. In particular, this has involved development of a new mechanistic model of NG infection within-host and incorporation of realistic features of treatment. The study findings mainly emphasise the importance of the role of intracellular NG in prolonging natural infection and determining treatment success. The treatment model facilitates exploration of differing treatment regimens, the link between PK/PD indices and treatment success and where relevant incorporates mechanistic effects of drug-target binding. This work suggests the importance of intracellular infection in both persistence of infection and drug clearance, and presents and opportunity to investigate these predictions in future experiments. The approach taken here is flexible and has the potential to be expanded in various ways, including to other anatomical sites, consider the role of vaccines in clearance and to address the motivating questions around the emergence of drug resistance within-host.
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PhD Doctorate
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