Modelling treatment effects for gonorrhoea

Neisseria gonorrhoeae (NG) bacteria have evolved resistance to many of the antibiotics that have been used successfully to treat gonorrhoea infection. To gain a better understanding of potential treatment options for gonorrhoea, we extend a previously developed within-host mathematical model to integrate treatment dynamics by accounting for key pharmacokinetic (PK) and pharmacodynamic (PD) features. This extended model was used to investigate different treatment regimens for two potential treatment options, namely, monotreatment with gepotidacin, and dual treatment with gentamicin and azithromycin. The simulated treatment success rates aligned well with the, albeit limited, clinical trial data that are available. The simulation results indicated that antibiotic treatment failure is associated with failure to successfully clear intracellular NG (NG residing within epithelial cells and neutrophils) and that extracellular PK indices alone cannot differentiate between treatment success or failure. We found that the index defined by the ratio of area under the curve to minimum inhibitory concentration (AUC/MIC) index > 150h, evaluated using intracellular gepotidacin concentration, successfully distinguished between treatment success and failure. For the dual treatment regimen, AUC/MIC index > 140h evaluated using the simulated single drug concentration, representing the combined effect of gentamicin and azithromycin with the Loewe additivity concept, successfully differentiated between treatment success and failure. However, we found this PK threshold associated with dual treatment to be less informative than in the gepotidacin monotreatment case as a majority of samples below this threshold still resulted in infection clearance. Although previous experimental results on the killing of intracellular NG are scarce, our findings draw attention to the importance of further experiments on antibiotic killing of intracellular NG. This will be useful for testing putative new anti-gonorrhoea antibiotics. Author Summary Gonorrhoea is a sexually transmitted infection caused by bacteria of the species Neisseria gonorrhoeae (NG). Although gonorrhoea can be easily treated using antibiotics, due to the propensity of NG to acquire resistance to antimicrobials, available treatment options have greatly diminished and most of the antibiotics used to treat infection in the past are now removed from treatment recommendations. As clinical trials have limitations in terms of expense, duration and ethical constraints they are not ideal for optimising doses, regimens and drug combinations. In this case, simulations through within-host mathematical models are useful in determining the effective dosing regimens and to explore intracellular treatment effects for which there is little experimental evidence. Our simulations identified the importance of treating intracellular NG (NG residing within neutrophils and epithelial cells) and the importance of considering intracellular pharmacokinetic indices when differentiating treatment success and failure. With the use of this model, we can simulate a range of different treatment regimens and drug combinations to assess their effectiveness at various values of the minimum inhibitory concentration which can potentially be used to guide future clinical trial design. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported by funding from the National Health and Medical Research Council (NHMRC) [grant numbers APP1078068 and APP1071269]. Pavithra Jayasundara was supported by a UNSW Sydney PhD tuition fee scholarship. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study used only openly available data and data sources are provided in the manuscript. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All relevant data are within the paper and its Supporting Information files and the code is available on GitHub at . .