Modelling treatment effects for gonorrhoea

Abstract 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.