Important considerations regarding the widespread use of doxycycline chemoprophylaxis against sexually transmitted infections.

Rates of sexually transmitted infections (STIs) continue to rise across the world and interventions are essential to reduce their incidence. Past and recent studies have indicated this may be achieved using doxycycline post-exposure prophylaxis (PEP) and this has sparked considerable interest in its use. However, many unanswered questions remain as to its long-term effects and particularly potentially negative impact on human microbiomes and antimicrobial resistance among STIs, other pathogens, and commensals. In this review, we discuss seven areas of concern pertaining to the widespread use of doxycycline PEP.

Sexual behaviour during COVID-19: a repeated cross-sectional survey in Victoria, Australia.

BACKGROUND: During 2020, the State of Victoria (Australia) experienced two COVID-19 waves. Both resulted in community lockdowns followed by eased restrictions. We examined variation of sexual behaviour in Victorians over time during COVID-19. METHODS: We conducted a repeated online survey at four timepoints corresponding with two lockdown (LD1, LD2) and two reduced restriction (RR1, RR2) periods in Victoria. A convenience sample of participants aged ≥18years was recruited via social media and asked about their recent (past 4weeks) sexual behaviour. Using multivariable logistic regression, we investigated variation in sexual behaviour between surveys. RESULTS: A total of 1828 surveys were completed; 72% identified as female, 69% were aged 18-29years, 90% were metropolitan residents. The proportion reporting recent partnered sex ranged from 54.9% (LD2) to 70.2% (RR1). Across all timepoints, the most common sexual partners were regular (81.5%, n =842) and 10.8% (n =111) reported casual partners (e.g. hook-ups). Compared with LD1, respondents were >2-fold more likely to report casual partner(s) during reduced restrictions (RR1: aOR 2.0; 95% CI 1.1-3.7; RR2: aOR 2.8; 95% CI 1.3-5.9). Across all timepoints, 26.6% (n =486) reported using dating apps. Compared with LD1, dating app use for face-to-face activities (e.g. dates, hook-ups) was >4-fold higher during reduced restrictions (RR1: aOR 4.3; 95% CI 2.3-8.0; RR2: aOR 4.1; 95% CI 1.9-8.8). App use for distanced activities (e.g. sexting, virtual dates) was highest during LD1 (48.8%) than other periods. CONCLUSIONS: In this convenience sample, self-reported sexual behaviours fluctuated between lockdowns and reduced restrictions. While dating apps may provide a mechanism for virtual connections, this may be temporary until physical connections are possible.

Treatment efficacy for rectal Neisseria gonorrhoeae: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Rectal gonorrhoea is a common sexually transmitted infection with increasing antimicrobial resistance requiring optimization of available treatments. OBJECTIVES: This systematic review aimed to assess the efficacy of current treatments, previously trialled treatments and new emerging treatments for rectal Neisseria gonorrhoeae (NG). METHODS: Online bibliographic databases were search from 1 January 1946 to 14 August 2020. All randomized controlled trials (RCTs) with rectal NG data among participants aged 15 years or above and published in English were included. Random effects meta-analyses were used to estimate overall treatment efficacy, defined as microbiological cure. Sub-group analyses included stratifying by diagnostic assay, by dual versus monotherapy, and by currently recommended treatments (e.g. ceftriaxone ± azithromycin) versus previously trialled but not recommended treatments (e.g. amoxicillin) versus emerging treatments (e.g. zoliflodacin). The study protocol was registered on PROSPERO (CRD42020202998). RESULTS: 54 studies including 1813 participants and 44 treatment regimens were identified. The overall summary treatment efficacy for rectal NG was 100.0% (95% CI: 99.9%-100.0%; I2 = 0.0%; P = 0.86). Efficacy estimates for monotherapies (100.0%; 95% CI: 99.88%-100.0%; I2 = 0.00%; P = 0.97) and dual therapies (100.0%; 95% CI: 97.65%-100.0%; I2 = 56.24%; P = 0.03) were similar. Efficacy was highest for current treatments (100.00%; 95% CI: 99.96%-100.00%; I2 = 0.00%; P = 0.98) versus emerging treatments (97.16%; 95% CI: 86.79%-100.00%; I2 = 0.00%; P = 0.84). There were no trials exclusively investigating rectal NG and small sample size was a limitation in most trials. CONCLUSIONS: Currently recommended treatments containing ceftriaxone, as mono or dual therapy, are effective. Emerging drugs such as zoliflodacin may be potentially useful for rectal NG but further data are needed.

Modelling the contribution that different sexual practices involving the oropharynx and saliva have on Neisseria gonorrhoeae infections at multiple anatomical sites in men who have sex with men.

BACKGROUND: The spectrum of sexual practices that transmit Neisseria gonorrhoeae in men who have sex with men (MSM) is controversial. No studies have modelled potential Neisseria gonorrhoeae transmission when one sexual practice follows another in the same sexual encounter ('sequential sexual practices'). Our aim was to test what sequential practices were necessary to replicate the high proportion of MSM who have more than one anatomical site infected with gonorrhoea ('multisite infection'). METHODS: To test our aim, we developed eight compartmental models. We first used a baseline model (model 1) that included no sequential sexual practices. We then added three possible sequential transmission routes to model 1: (1) oral sex followed by anal sex (or vice versa) (model 2); (2) using saliva as a lubricant for penile-anal sex (model 3) and (3) oral sex followed by oral-anal sex (rimming) or vice versa (model 4). The next four models (models 5-8) used combinations of the three transmission routes. RESULTS: The baseline model could only replicate infection at the single anatomical site and underestimated multisite infection. When we added the three transmission routes to the baseline model, oral sex, followed by anal sex or vice versa, could replicate the prevalence of multisite infection. The other two transmission routes alone or together could not replicate multisite infection without the inclusion of oral sex followed by anal sex or vice versa. CONCLUSIONS: Our gonorrhoea model suggests sexual practices that involve oral followed by anal sex (or vice versa) may be important for explaining the high proportion of multisite infection.

Love during lockdown: findings from an online survey examining the impact of COVID-19 on the sexual health of people living in Australia.

INTRODUCTION: Australia recorded its first case of COVID-19 in late January 2020. On 22P March 2020, amid increasing daily case numbers, the Australian Government implemented lockdown restrictions to help 'flatten the curve'. Our study aimed to understand the impact of lockdown restrictions on sexual and reproductive health. Here we focus on sexual practices. METHODS: An online survey was open from the 23PP April 2020 to 11P May 2020. Participants were recruited online via social media and other networks and were asked to report on their sexual practices in 2019 and during lockdown. Logistic regression was used to calculate the difference (diff) (including 95% CIs) in the proportion of sex practices between time periods. RESULTS: Of the 1187 who commenced the survey, 965 (81.3%) completed it. Overall, 70% were female and 66.3% were aged 18-29 years. Most (53.5%) reported less sex during lockdown than in 2019. Compared with 2019, participants were more likely to report sex with a spouse (35.3% vs 41.7%; diff=6.4%; 95% CI 3.6 to 9.2) and less likely to report sex with a girl/boyfriend (45.1% vs 41.8%; diff=-3.3%; 95% CI -7.0 to -0.4) or with casual hook-up (31.4% vs 7.8%; 95% CI -26.9 to -19.8). Solo sex activities increased; 14.6% (123/840) reported using sex toys more often and 26.0% (218/838) reported masturbating more often. Dating app use decreased during lockdown compared with 2019 (42.1% vs 27.3%; diff= -14.8%; 95% CI -17.6 to -11.9). Using dating apps for chatting/texting (89.8% vs 94.5%; diff=4.7%; 95% CI 1.0 to 8.5) and for setting up virtual dates (2.6% vs 17.2%; diff=14.6%; 95% CI 10.1 to 19.2) increased during lockdown. CONCLUSION: Although significant declines in sexual activity during lockdown were reported, people did not completely stop engaging in sexual activities, highlighting the importance of ensuring availability of normal sexual and reproductive health services during global emergencies.

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

Rates of bacterial sexually transmitted infections (STIs) continue to rise, demanding treatments to be highly effective. However, curing infections faces significant challenges due to antimicrobial resistance in Neisseria gonorrhoeae and Mycoplasma genitalium and especially treating STIs at extragenital sites, particularly rectal chlamydia and oropharyngeal gonorrhoea. As no new antimicrobials are entering the market, clinicians must optimize the currently available treatments, but robust data are lacking on how the properties or pharmacokinetics of antimicrobials can be used to inform STI treatment regimens to improve treatment outcomes. This paper provides a detailed overview of the published pharmacokinetics of antimicrobials used to treat STIs and how factors related to the drug (tissue distribution, protein binding and t½), human (pH, inflammation, site of infection, drug side effects and sexual practices) and organism (organism load and antimicrobial resistance) can affect treatment outcomes. As azithromycin is commonly used to treat chlamydia, gonorrhoea and M. genitalium infections, and its pharmacokinetics are well studied, it is the main focus of this review. Suggestions are also provided on possible dosing regimens when using extended and/or higher doses of azithromycin, which appropriately balance efficacy and side effects. The paper also emphasizes the limitations of currently published pharmacokinetic studies including oropharyngeal gonococcal infections, where very limited data exist around ceftriaxone pharmacokinetics and its use in combination with azithromycin. In future, the different anatomical sites of infections may require alternative therapeutic approaches.

Factors associated with anorectal Chlamydia trachomatis or Neisseria gonorrhoeae test positivity in women: a systematic review and meta-analysis.

OBJECTIVES: There has been considerable discussion about anorectal Chlamydia trachomatis (CT) in women, with some calling for anorectal CT screening, but little about anorectal Neisseria gonorrhoeae (NG). Given that urogenital NG is more strongly associated with pelvic inflammatory disease, this is an evidence gap. This systematic review and meta-analysis investigates the associations between anorectal CT in women and CT positivity at other sites (urogenital/oropharyngeal) and with anal intercourse, and compares these with anorectal NG within the same study populations. METHODS: Electronic databases were searched for English-language studies published to October 2018 using the following terms: ("Chlamydia" OR "Chlamydia trachomatis") AND (("anal" OR "rect*" OR "anorect*") OR ("extra?genital" OR "multi?site")). Studies were included if anorectal NG data were available. Random-effects meta-analyses calculated pooled estimates; heterogeneity was investigated using meta-regression. RESULTS: 25 studies were eligible. Anorectal CT positivity ranged from 0% to 17.5%, with a summary estimate of 8.0% (95% CI 7.0 to 9.1; I2=88.5%). Anorectal NG positivity ranged from 0% to 17.0%, with a summary estimate of 2.1% (95% CI 1.6 to 2.8; I2=92.7%). The association between urogenital and anorectal positivity was stronger for NG than CT (summary prevalence ratio (PR)=89.3 (95% CI 53.1 to 150.3; I2=80.1%), PR=32.2 (95% CI 25.6 to 40.7; I2=70.3%), respectively), and between oropharyngeal and anorectal positivity it was stronger for NG than CT (PR=34.8 (95% CI 10.2 to 118.2; I2=89.9%), PR=8.8 (95% CI 6.8 to 11.5; I2=58.1%), respectively). Anal intercourse was associated with anorectal NG (PR=4.3; 95% CI 2.2 to 8.6; I2=0.0%) but not with anorectal CT (PR=1.0; 95% CI 0.7 to 1.4; I2=0.0%). CONCLUSIONS: Anorectal CT is more common than anorectal NG, but anorectal NG is more strongly associated with anal intercourse, urogenital and oropharyngeal NG, suggesting that ongoing discussion about anorectal CT should also include NG. Longitudinal data are required to further understanding of the aetiology of anorectal STIs and assess whether anorectal screening is needed in women. TRIAL REGISTRATION NUMBER: CRD42df017080188.

The efficacy of azithromycin and doxycycline for the treatment of rectal chlamydia infection: a systematic review and meta-analysis.

BACKGROUND: There are increasing concerns about treatment failure following treatment for rectal chlamydia with 1 g of azithromycin. A systematic review and meta-analysis was conducted to investigate the efficacy of 1 g of azithromycin as a single dose or 100 mg of doxycycline twice daily for 7 days for the treatment of rectal chlamydia. METHODS: Medline, Embase, PubMed, Cochrane Controlled Trials Register, Australia New Zealand Clinical Trial Register and ClinicalTrials.gov were searched to the end of April 2014. Studies using 1 g of azithromycin or 7 days of doxycycline for the treatment of rectal chlamydia were eligible. Gender, diagnostic test, serovar, symptomatic status, other sexually transmitted infections, follow-up time, attrition and microbial cure were extracted. Meta-analysis was used to calculate pooled (i) azithromycin and doxycycline efficacy and (ii) efficacy difference. RESULTS: All eight included studies were observational. The random-effects pooled efficacy for azithromycin (based on eight studies) was 82.9% (95% CI 76.0%-89.8%; I(2) = 71.0%; P < 0.01) and for doxycycline (based on five studies) was 99.6% (95% CI 98.6%-100%; I(2) = 0%; P = 0.571), resulting in a random-effects pooled efficacy difference (based on five studies) of 19.9% (95% CI 11.4%-28.3%; I(2) = 48.5%; P = 0.101) in favour of doxycycline. CONCLUSIONS: The efficacy of single-dose azithromycin may be considerably lower than 1 week of doxycycline for treating rectal chlamydia. However, the available evidence is very poor. Robust randomized controlled trials are urgently required.

Treatment challenges for urogenital and anorectal Chlamydia trachomatis.

While true antimicrobial resistance to Chlamydia trachomatis is a rare occurrence, repeat chlamydia infections continue to be reported following treatment with a single 1 g dose of azithromycin or week long doxycycline - with considerable more concern about azithromycin treatment failure. While most repeat positive cases are likely to be reinfections, emerging evidence indicates treatment failure may play a role. Current data suggests that there may are differences in the efficacy of the drugs between rectal and non-rectal sites of infection and factors such as immune response, drug pharmacokinetics, organism load, auto-inoculation from rectum to cervix in women and the genital microbiome may play a role in treatment failure. Other possible reasons for repeat infection include the low discriminatory power of NAAT tests to differentiate between viable and nonviable organisms and failure to detect LGV infection. This review will present the current evidence regarding the management challenges for urogenital and anorectal chlamydia infections and provide some suggestions for where future research efforts are needed to address important knowledge gaps in this area and provide stronger evidence for the development of robust treatment guidelines.