Advancing Sexual Health for Cisgender Women: A Series of Studies Addressing Doxycycline Post-Exposure Prophylaxis, Vaginal Health, and Antimicrobial Resistance in Kenyan Women

Abstract

Globally, high rates of sexually transmitted infections (STIs) persist even in the face of effective antibiotic treatment, with young women living in Africa facing a disproportionate burden. Sexually transmitted infections can lead to dire reproductive health consequences for women, including severe complications and significant economic burdens related to lost productivity and quality of life. Among these infections, Trichomonas vaginalis stands as the most prevalent curable STI globally and can cause vaginitis, urethritis, pregnancy complications, and increased HIV susceptibility. Treatment relies solely on 5-nitroimidazole medications (metronidazole and tinidazole), but emerging resistance has necessitated extended treatment protocols, highlighting the urgent need for novel prevention strategies. Doxycycline post-exposure prophylaxis (doxy-PEP) has emerged as an innovative method for STI prevention. While laboratory evidence suggests doxycycline may effectively treat T. vaginalis by disrupting cellular metabolism, no studies have investigated doxyPEP’s potential in preventing T. vaginalis infections—an important gap in developing comprehensive STI prevention approaches for high-burden settings.The first study investigated the potential utility of doxyPEP in preventing the protozoal infection of T. vaginalis, a pathogen not traditionally targeted by doxycycline therapy. In this secondary analysis of a randomized clinical trial involving 449 cisgender Kenyan women followed for 12 months, the study assessed incident infections. There was no significant difference in T. vaginalis incidence when comparing the doxyPEP group to the standard of care group (RR: 0.96, 95% CI: 0.54-1.73, p=0.9). Low doxycycline use was reported in a subset of participants in the parent trial. Further studies are needed to investigate whether alternative dosing strategies, higher concentrations, or different administration schedules might enhance doxycycline’s efficacy against protozoal pathogens, potentially bridging the gap between promising in vitro mechanisms and clinical outcomes. Building on this doxyPEP research, the second study examined antimicrobial resistance patterns in Neisseria gonorrhoeae, which is ranked as the second most frequent bacterial STI globally, with Africa accounting for the highest incidence in 2020. Antimicrobial resistance (AMR), which refers to the ability of bacteria, including N. gonorrhoeae, to resist antimicrobial drugs, is widely acknowledged as a significant global public health issue that may impact Africa more profoundly, as the region had the highest number of deaths attributed to AMR in 2019. While doxyPEP represents one intervention to prevent bacterial STIs, the broader implications of doxyPEP, such as unintended consequences on non-target pathogens and its potential impact on AMR patterns, require further exploration. This study examined antimicrobial resistance patterns in N. gonorrhoeae among cisgender women participating in the same doxyPEP trial and identified associated demographic, behavioral, and clinical factors. Analysis of gonorrhea-positive samples revealed universal tetracycline resistance (100%) and high fluoroquinolone resistance (90.5%), while cephalosporin resistance remained low (2.6%), and no macrolide resistance was detected. No differences in resistance patterns were observed between study groups, although doxycycline use was low among those randomized to doxyPEP. These findings underscore the importance of ongoing surveillance as doxyPEP implementation expands globally. The third study shifted focus to examine the complex relationship between vaginal health and cervical inflammation. Bacterial vaginosis (BV), a condition characterized by a marked shift in vaginal microbiota from a Lactobacillus-dominated community to a more diverse community comprised of anaerobic and Gram-negative species, is the most common cause of vaginitis in cisgender women. While BV has been associated with various reproductive health complications, its relationship with cervicitis, a cervical inflammatory condition often caused by sexually transmitted pathogens, has been the subject of conflicting research findings, particularly regarding intermediate vaginal microbiota, a transitional state between normal microbiota and BV. Understanding this relationship is critical for developing nuanced therapeutic interventions to improve vaginal health and reduce cervicitis-related complications. This study examined the relationship between vaginal Nugent score categories and cervicitis among cisgender women engaged in transactional sex in Mombasa, Kenya. The intermediate vaginal microbiota demonstrated a significantly higher risk of cervicitis (adjusted RR=1.32, 95% CI: 1.18-1.48) compared to normal microbiota, a risk surpassing that associated with BV (adjusted RR=1.12, 95% CI: 1.01-1.25). This novel finding challenges conventional binary views of vaginal health and suggests that intermediate microbiota represents a distinct pathological state requiring targeted clinical attention. Furthermore, the study highlighted a progressive increase in cervicitis risk associated with the presence of both non–H₂O₂–producing lactobacilli and H₂O₂-producing lactobacilli, indicating a complex interplay between protective and potentially pathogenic vaginal bacterial species. These findings advocate for a nuanced understanding of vaginal microbiota and highlight the need for future mechanistic studies exploring the specific cytokine and chemokine profiles associated with intermediate vaginal microbiota states. The three studies analyzed in this dissertation collectively provide important insights into STI prevention among Kenyan cisgender women, investigating the efficacy of doxyPEP against T. vaginalis, documenting antimicrobial resistance in N. gonorrhoeae, and revealing complex relationships between vaginal microbiota and cervical inflammation. The findings underscore the need for multifaceted interventions that address vaginal health, antimicrobial stewardship, and pathogen-specific prevention strategies. Future research should explore microbiota-inflammation interactions, conduct long-term AMR surveillance in populations using prophylactic biomedical interventions, and develop innovative approaches tailored to diverse STI pathogens.