Lenka A. Vodstrcil

Macrolide resistance and azithromycin failure in a Mycoplasma genitalium-infected cohort, and response of azithromycin failures to alternative antibiotic regimens

BACKGROUND Our aim was to determine the efficacy of 1 g azithromycin and alternative antibiotic regimens in a prospective cohort of Mycoplasma genitalium-infected participants, and factors associated with azithromycin failure. METHODS Consecutive eligible M. genitalium-infected men and women attending the Melbourne Sexual Health Centre between July 2012 and June 2013 were treated with 1 g of azithromycin and retested by polymerase chain reaction (PCR) on days 14 and 28. Cure was defined as PCR negative on day 28. Cases failing azithromycin were treated with moxifloxacin, and those failing moxifloxacin were treated with pristinamycin. Pre- and posttreatment samples were assessed for macrolide resistance mutations (MRMs) by high-resolution melt analysis. Mycoplasma genitalium samples from cases failing moxifloxacin were sequenced for fluoroquinolone resistance mutations. Multivariable analysis was used to examine associations with azithromycin failure. RESULTS Of 155 participants treated with 1 g azithromycin, 95 (61% [95% confidence interval {CI}, 53%-69%]) were cured. Pretreatment MRM was detected in 56 (36% [95% CI, 28%-43%]) participants, and strongly associated with treatment failure (87% [95% CI, 76%-94%]; adjusted odds ratio, 47.0 [95% CI, 17.1-129.0]). All 11 participants who had MRM detected in posttreatment samples failed azithromycin. Moxifloxacin was effective in 53(88% [95% CI, 78%-94%]) of 60 cases failing azithromycin; all failures had gyrA and parC mutations detected in pretreatment samples. Six of 7 patients failing moxifloxacin treatment received pristinamycin, and all were PCR negative 28 days after pristinamycin treatment. CONCLUSIONS We report a high azithromycin failure rate (39%) in an M. genitalium-infected cohort in association with high levels of pretreatment macrolide resistance. Moxifloxacin failure occurred in 12% of patients who received moxifloxacin; all had pretreatment fluoroquinolone mutations detected. Pristinamycin was highly effective in treating macrolide- and quinolone-resistant strains.

Oral Human Papillomavirus in Men Having Sex with Men: Risk-Factors and Sampling

Background Human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma is becoming more common. We examined prevalence and risk factors for oral HPV among men who have sex with men (MSM) and compared sampling and transport methods. Methods In 2010, 500 MSM (249 HIV-positive) attending Melbourne Sexual Health Centre answered a questionnaire, swabbed their mouth and throat and collected a gargled oral rinse sample. Half the oral rinse was transported absorbed in a tampon (to enable postage). HPV was detected by polymerase chain reaction, and genotyped by Roche Linear Array®. Men with HPV 16 or 18 were retested after six months. Results Any HPV genotype was detected in 19% (95% confidence intervals (CI) 15–25%) of HIV-infected men and 7% (95% CI 4–11%) of HIV-negative men (p<0.001), and HPV 16 was detected in 4.4% (95% CI 2–8%) of HIV-infected men and 0.8% (0.1–2.8%) of HIV-negative men. Oral HPV was associated with: current smoking (adjusted odds ratio (aOR) 2.2 (95%CI: 1.2–3.9)), time since tooth-brushing (aOR per hour 0.87, 95%CI: 0.8–0.96) and number of lifetime tongue-kissing partners aOR 3.2 95%CI: (1.2–8.4) for 26–100 partners and 4.9 95%CI: (1.9–12.5) for>100 partners. Lifetime oral-penile sex partner numbers were significantly associated in a separate model: aOR 2.8(1.2–6.3) for 26–100 partners and 3.2(1.4–7.2) for>100 partners. HPV 16 and 18 persisted in 10 of 12 men after a median six months. Sensitivities of sampling methods compared to all methods combined were: oral rinse 97%, tampon-absorbed oral rinse 69%, swab 32%. Conclusions Oral HPV was associated with HIV infection, smoking, recent tooth-brushing, and more lifetime tongue-kissing and oral sex partners. The liquid oral rinse sample was more sensitive than a tampon-absorbed oral rinse or a self-collected swab.

Azithromycin Versus Doxycycline for the Treatment of Genital Chlamydia Infection: A Meta-analysis of Randomized Controlled Trials

BACKGROUND There has been recent debate questioning the efficacy of azithromycin for the treatment of urogenital chlamydia infection. We conducted a meta-analysis to compare the efficacy of 1 g azithromycin with 100 mg doxycycline twice daily (7 days) for the treatment of urogenital chlamydia infection. METHODS Medline, PubMed, Embase, Cochrane Controlled Trials Register, Cochrane reviews, and Cumulative Index to Nursing and Allied Health Literature were searched until 31 December 2013. Randomized controlled trials comparing azithromycin with doxycycline for the treatment of genital chlamydia with evaluation of microbiological cure within 3 months of treatment were included. Sex, diagnostic test, follow-up time, attrition, patient symptomatic status, and microbiological cure were extracted. The primary outcome was the difference in efficacy at final follow-up. Study bias was quantitatively and qualitatively summarized. RESULTS Twenty-three studies were included evaluating 1147 and 912 patients for azithromycin and doxycycline, respectively. We found a pooled efficacy difference in favor of doxycycline of 1.5% (95% confidence interval [CI], -.1% to 3.1%; I(2) = 1.9%; P = .435; random effects) to 2.6% (95% CI, .5%-4.7%; fixed effects). Subgroup analyses showed that the fixed effects pooled efficacy difference for symptomatic men was 7.4% (95% CI, 2.0%-12.9%), and the random effects was 5.5% (95% CI, -1.4% to 12.4%). CONCLUSIONS There may be a small increased efficacy of up to 3% for doxycycline compared with azithromycin for the treatment of urogenital chlamydia and about 7% increased efficacy for doxycycline for the treatment of symptomatic urethral infection in men. However, the quality of the evidence varies considerably, with few double-blind placebo-controlled trials conducted. Given increasing concern about potential azithromycin failure, further well-designed and statistically powered double-blind, placebo-controlled trials are needed.

Recurrence of Bacterial Vaginosis Is Significantly Associated With Posttreatment Sexual Activities and Hormonal Contraceptive Use

BACKGROUND Bacterial vaginosis (BV) recurrence posttreatment is common. Our aim was to determine if behaviors were associated with BV recurrence in women in a randomized controlled trial (RCT). METHODS Symptomatic 18- to 50-year-old females with BV (≥3 Amsel criteria and Nugent score [NS] = 4-10) were enrolled in a 3-arm randomized double-blind RCT Melbourne Sexual Health Centre, Australia, in 2009-2010. All 450 participants received oral metronidazole (7 days) and were equally randomized to vaginal clindamycin, lactobacillus-vaginal probiotic or vaginal placebo. At 1, 2, 3, and 6 months, participants self-collected vaginal smears and completed questionnaires. Primary endpoint was NS = 7-10. Cox regression was used to estimate hazard ratios (HRs) for risk of BV recurrence associated with baseline and longitudinal characteristics. RESULTS Four hundred four (90%) women with postrandomization data contributed to analyses. Cumulative 6-month BV recurrence was 28% (95% confidence interval [CI], 24%-33%) and not associated with treatment. After stratifying for treatment and adjusting for age and sex frequency, recurrence was associated with having the same pre-/posttreatment sexual partner (adjusted HR [AHR] = 1.9; 95% CI, 1.2-3.0), inconsistent condom use (AHR = 1.9; 95% CI, 1.0-3.3), and being non-Australian (AHR = 1.5; 95% CI, 1.0-2.1), and halved with use of an estrogen-containing contraceptive (AHR = 0.5; 95% CI, .3-.8). CONCLUSIONS Risk of BV recurrence was increased with the same pre-/posttreatment sexual partner and inconsistent condom use, and halved with use of estrogen-containing contraceptives. Behavioral and contraceptive practices may modify the effectiveness of BV treatment. CLINICAL TRIALS REGISTRATION ACTRN12607000350426.

Hormonal Contraception Is Associated with a Reduced Risk of Bacterial Vaginosis: A Systematic Review and Meta-Analysis

Objective To examine the association between hormonal contraception (HC) and bacterial vaginosis (BV) by systematic review and meta-analysis. Methods Medline, Web of Science and Embase databases were searched to 24/1/13 and duplicate references removed. Inclusion criteria 1) >20 BV cases; 2) accepted BV diagnostic method; 3) measure of HC-use either as combined oestrogen-progesterone HC (combined), progesterone-only contraception (POC) or unspecified HC (u-HC); 4) ≥10% of women using HC; 5) analysis of the association between BV and HC-use presented; 6) appropriate control group. Data extracted included: type of HC, BV diagnostic method and outcome (prevalent, incident, recurrent), and geographical and clinic-setting. Meta-analyses were conducted to calculate pooled effect sizes (ES), stratified by HC-type and BV outcome. This systematic review is registered with PROSPERO (CRD42013003699). Results Of 1713 unique references identified, 502 full-text articles were assessed for eligibility and 55 studies met inclusion criteria. Hormonal contraceptive use was associated with a significant reduction in the odds of prevalent BV (pooled effect size by random-effects [reES] = 0.68, 95%CI0.63–0.73), and in the relative risk (RR) of incident (reES = 0.82, 95%CI:0.72–0.92), and recurrent (reES = 0.69, 95%CI:0.59–0.91) BV. When stratified by HC-type, combined-HC and POC were both associated with decreased prevalence of BV and risk of incident BV. In the pooled analysis of the effect of HC-use on the composite outcome of prevalent/incident/recurrent BV, HC-use was associated with a reduced risk of any BV (reES = 0.78, 95%CI:0.74–0.82). Conclusion HC-use was associated with a significantly reduced risk of BV. This negative association was robust and present regardless of HC-type and evident across all three BV outcome measures. When stratified by HC-type, combined-HC and POC were both individually associated with a reduction in the prevalence and incidence of BV. This meta-analysis provides compelling evidence that HC-use influences a woman’s risk of BV, with important implications for clinicians and researchers in the field.

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.

Trends in chlamydia and gonorrhea positivity among heterosexual men and men who have sex with men attending a large urban sexual health service in Australia, 2002-2009

BackgroundTo determine whether chlamydia positivity among heterosexual men (MSW) and chlamydia and gonorrhea positivity among men who have sex with men (MSM), are changing.MethodsComputerized records for men attending a large sexual health clinic between 2002 and 2009 were analyzed. Chlamydia and gonorrhea positivity were calculated and logistic regression used to assess changes over time.Results17769 MSW and 8328 MSM tested for chlamydia and 7133 MSM tested for gonorrhea. In MSW, 7.37% (95% CI: 6.99-7.77) were chlamydia positive; the odds of chlamydia positivity increased by 4% per year (OR = 1.04; 95% CI: 1.01-1.07; p = 0.02) after main risk factors were adjusted for. In MSM, 3.70% (95% CI: 3.30-4.14) were urethral chlamydia positive and 5.36% (95% CI: 4.82-5.96) were anal chlamydia positive; positivity could not be shown to have changed over time. In MSM, 3.05% (95% CI: 2.63-3.53) tested anal gonorrhea positive and 1.83% (95% CI: 1.53-2.18) tested pharyngeal gonorrhea positive. Univariate analysis found the odds of anal gonorrhea positivity had decreased (OR = 0.93; 95% CI: 0.87-1.00; p = 0.05), but adjusting for main risk factors resulted in no change. Urethral gonorrhea cases in MSM as a percentage of all MSM tested for gonorrhea also fell (p < 0.001).ConclusionsThese data suggest that chlamydia prevalence in MSW is rising and chlamydia and gonorrhea prevalence among MSM is stable or declining. High STI testing rates among MSM in Australia may explain differences in STI trends between MSM and MSW.

Computer-assisted self interviewing in sexual health clinics.

Background: This review describes the published information on what constitutes the elements of a core sexual history and the use of computer-assisted self interviewing (CASI) within sexually transmitted disease clinics. Methods: We searched OVID Medline from 1990 to February 2010 using the terms “computer assisted interviewing” and “sex,” and to identify published articles on a core sexual history, we used the term “core sexual history.” Results: Since 1990, 3 published articles used a combination of expert consensus, formal clinician surveys, and the Delphi technique to decide on what questions form a core sexual health history. Sexual health histories from 4 countries mostly ask about the sex of the partners, the number of partners (although the time period varies), the types of sex (oral, anal, and vaginal) and condom use, pregnancy intent, and contraceptive methods. Five published studies in the United States, Australia, and the United Kingdom compared CASI with in person interviews in sexually transmitted disease clinics. In general, CASI identified higher risk behavior more commonly than clinician interviews, although there were substantial differences between studies. CASI was found to be highly acceptable and individuals felt it allowed more honest reporting. Currently, there are insufficient data to determine whether CASI results in differences in sexually transmitted infection testing, diagnosis, or treatment or if CASI improves the quality of sexual health care or its efficiency. Conclusions: The potential public health advantages of the widespread use of CASI are discussed.

Relaxin mediates uterine artery compliance during pregnancy and increases uterine blood flow

Normal pregnancy involves dramatic remodeling of the uterine vasculature, with abnormal vascular adaptations contributing to pregnancy diseases such as preeclampsia. The peptide hormone relaxin is important for the renal and systemic hemodynamic adaptations to pregnancy, and has been shown to increase arterial compliance and outward hypertrophic remodeling. Therefore, we investigated the possibility that relaxin acts on its receptor, RXFP1, to mediate uterine artery compliance in late pregnancy and increase uterine blood flow velocity in rats. RXFP1 was predominantly localized to the tunica media vascular smooth muscle cells in the uterine artery, although receptors were also detected in endothelial cells. Highest expression of Rxfp1 in the uterine artery occurred in estrus and early pregnancy. Isolated uterine arteries from late pregnant rats treated with a monoclonal antibody against circulating relaxin (MCA1) had significantly increased vessel wall stiffness compared with controls, with no reduction in wall thickness. Chronic infusion of relaxin (4 μg/h, osmotic minipump) for 5 d in nonpregnant rats significantly increased uterine artery blood flow velocity. Overall, these data demonstrate a functional role for relaxin in mediating uterine artery compliance in pregnant rats, which may be necessary to maintain adequate uterine blood flow to the uterus and placenta.—Vodstrcil, L. A., Tare, M., Novak, J., Dragomir, N., Ramirez, R. J., Wlodek, M. E., Conrad, K. P., Parry, L. J. Relaxin mediates uterine artery compliance during pregnancy and increases uterine blood flow. FASEB J. 26, 4035–4044 (2012). www.fasebj.org

Efficacy of Oral Metronidazole with Vaginal Clindamycin or Vaginal Probiotic for Bacterial Vaginosis: Randomised Placebo-Controlled Double-Blind Trial

Background To determine if oral metronidazole (MTZ-400mg bid) with 2% vaginal clindamycin-cream (Clind) or a Lactobacillus acidophilus vaginal-probiotic containing oestriol (Prob) reduces 6-month bacterial vaginosis (BV) recurrence. Methods Double-blind placebo-controlled parallel-group single-site study with balanced randomization (1∶1∶1) conducted at Melbourne Sexual Health Centre, Australia. Participants with symptomatic BV [Nugent Score (NS) = 7–10 or ≥3 Amsels criteria and NS = 4–10], were randomly allocated to MTZ-Clind, MTZ-Prob or MTZ-Placebo and assessed at 1,2,3 and 6 months. MTZ and Clind were administered for 7 days and Prob and Placebo for 12 days. Primary outcome was BV recurrence (NS of 7–10) on self-collected vaginal-swabs over 6-months. Cumulative BV recurrence rates were compared between groups by Chi-squared statistics. Kaplan-Meier, log rank and Cox regression analyses were used to compare time until and risk of BV recurrence between groups. Results 450 18–50 year old females were randomized and 408 (91%), equally distributed between groups, provided ≥1 NS post-randomization and were included in analyses; 42 (9%) participants with no post-randomization data were excluded. Six-month retention rates were 78% (n = 351). One-month BV recurrence (NS 7–10) rates were 3.6% (5/140), 6.8% (9/133) and 9.6% (13/135) in the MTZ-Clind, MTZ-Prob and MTZ-Placebo groups respectively, p = 0.13. Hazard ratios (HR) for BV recurrence at one-month, adjusted for adherence to vaginal therapy, were 0.43 (95%CI 0.15–1.22) and 0.75 (95% CI 0.32–1.76) in the MTZ-Clind and MTZ-Prob groups compared to MTZ-Plac respectively. Cumulative 6-month BV recurrence was 28.2%; (95%CI 24.0–32.7%) with no difference between groups, p = 0.82; HRs for 6-month BV recurrence for MTZ-Clind and MTZ-Prob compared to MTZ-Plac, adjusted for adherence to vaginal therapy were 1.09(95% CI = 0.70–1.70) and 1.03(95% CI = 0.65–1.63), respectively. No serious adverse events occurred. Conclusion Combining the recommended first line therapies of oral metronidazole and vaginal clindamycin, or oral metronidazole with an extended-course of a commercially available vaginal-L.acidophilus probiotic, does not reduce BV recurrence. Trial Registration ANZCTR.org.au ACTRN12607000350426