Quantitative modeling predicts mechanistic links between pre-treatment microbiome composition and metronidazole efficacy in bacterial vaginosis

Bacterial vaginosis is a condition associated with adverse reproductive outcomes and characterized by a shift from a Lactobacillus-dominant vaginal microbiota to a polymicrobial microbiota, consistently colonized by strains of Gardnerella vaginalis. Metronidazole is the first-line treatment; however, treatment failure and recurrence rates remain high. To understand complex interactions between Gardnerella vaginalis and Lactobacillus involved in efficacy, here we develop an ordinary differential equation model that predicts bacterial growth as a function of metronidazole uptake, sensitivity, and metabolism. The model shows that a critical factor in efficacy is Lactobacillus sequestration of metronidazole, and efficacy decreases when the relative abundance of Lactobacillus is higher pre-treatment. We validate results in Gardnerella and Lactobacillus co-cultures, and in two clinical cohorts, finding women with recurrence have significantly higher pre-treatment levels of Lactobacillus relative to bacterial vaginosis-associated bacteria. Overall results provide mechanistic insight into how personalized differences in microbial communities influence vaginal antibiotic efficacy. Bacterial vaginosis (BV) is typically caused by a shift in the vaginal microbiota from a Lactobacillus-dominant community to one colonised by strains of Gardenerella vaginalis and treatment with the antibiotic metronidazole (MNZ) often results in failure and recurrence. Here, the authors use modelling and in vitro assays to show that sequestration of MNZ by Lactobacillus is critical in reducing efficacy and women with a higher pre-treatment Lactobacillus/Gardnerella ratio are more likely to recur.