Pharmacokinetics of a single 1g dose of azithromycin in rectal tissue in men

Abstract

Chlamydia is the most common bacterial sexually transmitted infection among men who have sex with men. Repeat infection following treatment with 1g azithromycin is common and treatment failure of up to 22% has been reported. This study measured the pharmacokinetics of azithromycin in rectal tissue in men following a single 1g dose to assess whether azithromycin reaches the rectal site in adequate concentrations to kill chlamydia. Ten healthy men took a single oral dose of 1g azithromycin and provided nine self-collected swabs and one blood sample over 14 days. Participant demographics, medications, sexual behaviour, treatment side effects, lubricant use and douching practices were recorded with each swab. Drug concentration over time was determined using liquid chromatography–mass spectrometry and total exposure (AUC0-∞) was estimated from the concentration-time profiles. Following 1g of azithromycin, rectal concentrations peaked after a median of 24 hours (median 133mcg/g) and remained above the minimum inhibitory concentration for chlamydia (0.125mcg/mL) for at least 14 days in all men. AUC0-∞ was the highest ever reported in human tissue (13103((mcg/g).hr)). Tissue concentrations were not associated with weight (mg/kg), but data suggest that increased gastric pH could increase azithromycin levels and diarrhoea or use of water-based lubricants could decrease concentrations. High and sustained concentrations of azithromycin were found in rectal tissue following a single 1g dose suggesting that inadequate concentrations are unlikely to cause treatment failure. Factors effecting absorption (pH and diarrhoea) or drug depletion (douching and water-based lubricants) may be more important determinants of concentrations in situ.

Pharmacokinetic considerations regarding the treatment of bacterial sexually transmitted infections with azithromycin: a review

“…Rectal pH may also be changed by acid lowering drugs such as proton pump inhibitors. 37 Finally, the effects of biofilm formation and clumping of bacteria on treatments of infections in different anatomical sites with STI antimicrobials are mainly unexplored.…”

“…19 NG treatment trials using azithromycin 2 g as a single dose as monotherapy 44 or as part of dual therapies 45 reported vomiting in 6-7% of people. In the author's study of the rectal pharmacokinetics of azithromycin in men, the study found that men who experienced drug side effects such as diarrhoea had lower tissue concentrations, 37 which could contribute to treatment failure.…”

“…Pre-sex rectal douching with non-isotonic fluids such as water is a common practice among MSM 57 and the use hyperosmolar water-based lubricants have also been shown to cause damage to rectal tissue. Since azithromycin is likely to be found in rectal mucus and faeces, 37 it is plausible that douching may have a reduce treatment efficacy for rectal STIs because douching may reduce local tissue exposure to drug laden faeces or mucus or may remove rectal cells containing azithromycin. [58][59][60] The author's have previously shown that lower azithromycin rectal concentrations were found in men who practiced rectal douching.…”

“…[58][59][60] The author's have previously shown that lower azithromycin rectal concentrations were found in men who practiced rectal douching. 37 Observational studies also suggest that douching is associated with an increased risk of STIs. 57,61,62…”

“…with blood, mucus, other cells) that can lead to overestimation of drug concentrations. In the author's pharmacokinetics studies of 1 g azithromycin in rectal 37 and endocervical tissue, 68 the sampling methods were unable to differentiate both between intracellular and extracellular space and although the studies were able to report high concentrations of azithromycin, they were unable to report whether it was in the appropriate compartments for chlamydia infection. Further, the studies were unable to differentiate between azithromycin in mucus, blood or cervical/rectal epithelial cellular tissue.…”