Background:
Oral doxycycline (DOX) prophylaxis is a promising strategy to prevent bacterial sexually transmitted infections (STIs). Clinical trials demonstrated a 200 mg oral DOX dose taken by men who have sex with men (MSM) after sexual exposure can provide protection against STIs. However, mucosal pharmacokinetic data at the site of STI exposure and DOX activity are lacking. We examined mucosal DOX concentrations in men and women to better understand DOX efficacy and inform dose optimization for STI prevention.
Methods:
Eleven male and 9 female participants provided blood and mucosal swabs up to 7 days after receiving a 200 mg oral DOX dose. Rectal, vaginal and cervical biopsies as well as urethral swabs were collected 24 hours after dosing. DOX was measured by liquid chromatography-mass spectrometry with a lower limit of quantification of 10 ng/mL for plasma and 2.5 ng/sample for swabs and biopsies. Secretion concentrations were estimated using swab weight. Concentrations are reported as geometric mean and 95% confidence interval. Time above the 90% minimum inhibitory concentration (MIC90) was assessed for susceptible Neisseria gonorrhoeae (NG), Treponema pallidum (TP) and Chlamydia trachomatis (CT).
Results:
Rectal secretion DOX concentrations peaked at 48 hours, 8 hours in vaginal secretions, and 4 hours in plasma. Rectal and vaginal DOX exposure up to 96 hours were 2- and 3-times that of plasma, respectively. Rectal and vaginal secretion DOX concentrations remained above the MIC90 for 48, 72 and 96 hours, longer than in plasma, for NG, TP and CT, respectively. DOX concentrations in rectal (616 ng/g; 495 – 766 ng/g), vaginal (261 ng/g; 98 – 696 ng/g) and cervical tissue (410 ng/g; 193 – 870 ng/g) were only 1- to 2-times the MIC90 for NG, but at least 2- and 4-times greater than the MIC90 for TP and CT, respectively. Urethral secretion DOX was estimated to be at least 4-times the MIC90 for NG, TP and CT, and greater than plasma or mucosal concentrations.
Conclusions:
DOX efficiently distributes to mucosal sites and maintains inhibitory concentrations against TP and CT for 3-4 days after dosing, but only 2 days for NG which may impact level of protection. This study provides the first pharmacologic data on mucosal DOX exposures associated with STI protection among MSM, predicts high vaginal efficacy, and informs a rational DOX dose optimization for STI prevention in men and women.