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Objective: Although Chlamydia trachomatis (CT) and Mycoplasma genitalium (MG) are major causes of non-gonococcal urethritis (NGU), up to 50% of cases are of unknown aetiology. We sought to identify urethral exposures at last sexual episode associated with NGU and non-CT/non-MG NGU to identify anatomical sites from which aetiologically relevant micro-organisms may be acquired., Methods: We enrolled STD clinic patients with and without NGU assigned male sex at birth and age ≥16 into a cross-sectional study. NGU was urethral symptoms or visible discharge plus ≥5 polymorphonuclear leucocytes without Neisseria gonorrhoeae . Urine was tested for CT and MG (Aptima). We used logistic regression to estimate the association between urethral exposures at last sex and NGU separately among cisgender men and transgender women who have sex with men (MSM/TGWSM) and cisgender men who have sex with women (MSW)., Results: Between 8 August 2014 and 1 November 2017, we enrolled 432 patients, including 183 MSM/TGWSM (118 NGU+, 65 NGU-) and 249 MSW (126 NGU+, 123 NGU-). The mean age was 34; 59% were white. CT and MG were detected in 72 (30%) and 49 (20%) NGU+ participants, respectively. Compared with MSM/TGWSM reporting only non-urethral exposures at last sex, those reporting insertive anal intercourse (IAI) only (adjusted OR (AOR)=4.46, 95% CI 1.09 to 18.19) and IAI with insertive oral sex (IOS) (AOR=7.88, 95% CI 2.67 to 23.26) had higher odds of NGU. MSM/TGWSM reporting IOS only had no significant increased odds (AOR=1.67, 95% CI 0.58 to 4.85). Compared with MSW whose only urethral exposure at last sex was vaginal sex (VS), MSW reporting IOS and VS had similar odds of NGU (OR=0.84, 95% CI 0.50 to 1.41). The results were similar for non-CT/non-MG NGU., Conclusions: Among MSM/TGWSM, IAI may lead to transmission of yet-unidentified rectal micro-organisms that cause non-CT/non-MG NGU, in addition to transmission of known pathogens. Sites of urethral exposure appear less important for understanding NGU risk among MSW due to minimal variation in behaviour., Competing Interests: Competing interests: CMK and LEM have received donations of test kits and reagents from Hologic. All other authors declare that they have no conflict of interest., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Ureaplasma urealyticum biovar 2 (UU-2), but not Ureaplasma parvum (UP), has been associated with non-gonococcal urethritis (NGU), but little is known about species-specific responses to standard therapies. We examined species-specific treatment outcomes and followed men with treatment failure for 9 weeks., Methods: From May 2007 to July 2011, men aged ≥16 attending a sexually transmitted disease (STD) clinic in Seattle, Washington, with NGU (urethral discharge or urethral symptoms plus ≥5 polymorphonuclear leucocytes /high-powered field) enrolled in a double-blind, randomised trial. Participants received active azithromycin (1 g) + placebo doxycycline or active doxycycline (100 mg twice a day ×7 days) + placebo azithromycin. Ureaplasma were detected in culture followed by species-specific PCR. Outcomes were assessed at 3, 6 and 9 weeks. At 3 weeks, men with persistent Ureaplasma detection received 'reverse therapy' (e.g., active doxycycline if they first received active azithromycin). At 6 weeks, persistently positive men received moxifloxacin (400 mg×7 days)., Results: Of 490 men, 107 (22%) and 60 (12%) were infected with UU-2 and UP, respectively, and returned at 3 weeks. Persistent detection was similar for UU-2-infected men initially treated with azithromycin or doxycycline (25% vs. 31%; p=0.53), but differed somewhat for men with UP (45% vs. 24%; p=0.11). At 6 weeks, 57% of UU-2-infected and 63% of UP-infected men who received both drugs had persistent detection. Failure after moxifloxacin occurred in 30% and 36%, respectively. Persistent detection of UU-2 or UP was not associated with signs/symptoms of NGU., Conclusions: Persistent detection after treatment with doxycycline, azithromycin and moxifloxacin was common for UU and UP, but not associated with persistent urethritis., Trial Registration Number: NCT00358462., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Background: Azithromycin or doxycycline is recommended for nongonococcal urethritis (NGU); recent evidence suggests their efficacy has declined. We compared azithromycin and doxycycline in men with NGU, hypothesizing that azithromycin was more effective than doxycycline., Methods: From January 2007 to July 2011, English-speaking males ≥16 years, attending a sexually transmitted diseases clinic in Seattle, Washington, with NGU (visible urethral discharge or ≥5 polymorphonuclear leukocytes per high-power field [PMNs/HPF]) were eligible for this double-blind, parallel-group superiority trial. Participants received active azithromycin (1 g) + placebo doxycycline or active doxycycline (100 mg twice daily for 7 days) + placebo azithromycin. Urine was tested for Chlamydia trachomatis (CT), Mycoplasma genitalium (MG), Ureaplasma urealyticum biovar 2 (UU-2), and Trichomonas vaginalis (TV) using nucleic acid amplification tests. Clinical cure (<5 PMNs/HPF with or without urethral symptoms and absence of discharge) and microbiologic cure (negative tests for CT, MG, and/or UU-2) were determined after 3 weeks., Results: Of 606 men, 304 were randomized to azithromycin and 302 to doxycycline; CT, MG, TV, and UU-2 were detected in 24%, 13%, 2%, and 23%, respectively. In modified intent-to-treat analyses, 172 of 216 (80%; 95% confidence interval [CI], 74%-85%) receiving azithromycin and 157 of 206 (76%; 95% CI, 70%-82%) receiving doxycycline experienced clinical cure (P = .40). In pathogen-specific analyses, clinical cure did not differ by arm, nor did microbiologic cure differ for CT (86% vs 90%, P = .56), MG (40% vs 30%, P = .41), or UU-2 (75% vs 70%, P = .50). No unexpected adverse events occurred., Conclusions: Clinical and microbiologic cure rates for NGU were somewhat low and there was no significant difference between azithromycin and doxycycline. Mycoplasma genitalium treatment failure was extremely common. Clinical Trials Registration.NCT00358462.

Background: Given recent increasing case rates of Chlamydia trachomatis infection, we evaluated trends in chlamydia rates and related health outcomes in women and men aged 15 to 44 years who were enrolled in a Pacific Northwest health plan., Methods: We identified chlamydia, pelvic inflammatory disease (PID), ectopic pregnancy, and male urethritis cases occurring annually during 1997-2007 using computerized health plan databases, calculating rates per 100,000 person-years (py) by gender and 5-year age groups. We also calculated annual chlamydia testing rates., Results: In women, chlamydia testing rates increased by approximately 23% (220 tests per 1000 py in 1997 to 270 tests per 1000 in 2007). Chlamydia diagnosis rates rose from 449 cases/100,000 py in 1997 to 806/100,000 in 2007, a 79% increase (P = 0.01). Increases were greatest during 2005-2007, also the period of major conversion to nucleic acid amplification test. PID rates in this interval declined steadily from 823 cases/100,000 py to 473/100,000 (P < 0.01). Ectopic pregnancy rates remained unchanged. In men, chlamydia testing rates increased nearly 3.5-fold, from 12 to 42 tests per 1000 py. Chlamydia rates for men also rose significantly throughout the study interval (from 91 cases/100,000 py to 218/100,000; P < 0.01) as did urethritis diagnosis rates (P < 0.01)., Conclusion: Between 1997 and 2007, annual health plan chlamydia rates increased significantly for both women and men. These trends may be due in part to increased testing rates and increased use of more sensitive tests, but they likely do not explain the increased urethritis rates. During this same interval, we observed steady declines in PID rates, consistent with other national data sources.

Background: Ureaplasmas have been inconsistently associated with nongonococcal urethritis (NGU). We evaluated the association of the newly differentiated species Ureaplasma urealyticum (UU) and Ureaplasma parvum (UP) with NGU using 2 separate control groups., Methods: Case patients were men who attended a sexually transmitted disease (STD) clinic in Seattle, Washington, during the period 2007-2009 with NGU (defined as visible urethral discharge and/or ≥5 polymorphonuclear neutrophils per high-powered field; n = 329). Control subjects were STD clinic attendees (n = 191) and emergency department (ED) attendees (n = 193) without NGU. Polymerase chain reaction assays detected UU and UP in ureaplasma culture-positive urine. Multivariable logistic regression was used to assess the associations of UU and UP with NGU., Results: UU was only marginally associated with NGU in aggregate multivariable analyses, irrespective of control group (adjusted odds ratio [aOR](STD-control), 1.6 [95% confidence interval {CI}, 0.9-2.8]; aOR(ED-control), 1.7 [95% CI, 0.97-3.0]). This association was significantly stronger when analyses were restricted to men with fewer lifetime sex partners (<10 vaginal partners: aOR(STD-control), 2.9 [95% CI, 1.2-6.7]; aOR(ED-control), 3.2 [95% CI, 1.3-7.6]; <5 vaginal partners: aOR(STD-control), 6.2 [95% CI, 1.8-21.0]; aOR(ED-control), 5.2 [95% CI, 1.3-20.2]). UP was not positively associated with NGU overall or among subgroups., Conclusions: The absence of an association of UU with NGU among men with more lifetime sex partners suggests that adaptive immunity may attenuate the clinical manifestation of UU infection. Similar relationships were not observed with UP, which suggests that it is not a urethral pathogen.

Background: Nongonococcal urethritis (NGU) is common, yet up to 50% of cases have no defined etiology. The extent to which risk profiles and clinical presentations of pathogen-associated and idiopathic cases differ is largely unknown., Methods: Urethral swabs and urine specimens were collected from 370 NGU treatment trial participants who sought care at a sexually transmitted disease clinic in Seattle, WA from 2007 to 2009 and had a visible urethral discharge and/or microscopic evidence of urethral inflammation assessed by Gram-stain (≥5 polymorphonuclear leukocytes per high-powered field [PMNs/HPF]). Neisseria gonorrhoeae, Chlamydia trachomatis (CT), Mycoplasma genitalium (MG), Trichomonas vaginalis (TV), and Ureaplasma urealyticum (UU) were detected in urine, using nucleic acid amplification tests. Cases negative for all assessed pathogens were considered idiopathic. Bivariate and multivariate analyses identified clinical, sociodemographic, and behavioral factors associated with detection of specific pathogens., Results: After excluding 3 participants with gonococcal infection, pathogens were detected in only 50.7% of the 367 eligible cases: CT in 22.3%, MG in 12.5%, TV in 2.5%, and UU in 24.0%, with multiple pathogens detected in 9.5%. In all, 3.5% of cases were negative for CT, MG, and TV but lacked speciated ureaplasma results. The remaining cases (45.8%) were considered idiopathic. Pathogen detection was associated with young age, black race, risky sexual behaviors, cloudy or purulent discharge, and visible discharge plus≥5 PMNs/HPF. In contrast, idiopathic cases were more likely to report prior NGU, were older and less likely to be black, or have an abnormal urethral discharge on examination, compared to all other cases. These cases were not associated with any high risk behaviors., Conclusions: NGU is a heterogeneous condition. Pathogen detection was associated with a variety of traditional risk factors and clinical features; whereas, idiopathic cases tended to be diagnosed among lower-risk men.

Purpose: Since few men with chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) have culturable bacteria by traditional approaches, we used sensitive molecular methods to determine presence of fastidious microorganisms., Materials and Methods: We evaluated 135 men with CP/CPPS by standardized clinical evaluation, and by lower tract localization cultures and chamber counts of expressed prostatic secretions of leukocytes. We excluded from study patients with bacteriuria, bacterial prostatitis, urethritis or positive urethral cultures. Prostate biopsy was obtained using a double-needle technique to limit contamination. We chose molecular approaches because previous studies had used culture antigen detection in urine, urethral swabs and expressed prostatic secretions. However, interpretation of such studies is complicated because urogenital samples often acquire bacteria while passing through the urethra. We used specific and broad-spectrum polymerase chain reaction (PCR) assays., Results: Only 10 (8%) of the 135 subjects had positive specific PCR assays, including Mycoplasmia genitalium, Chlamydia trachomatis and Trichomonas vaginalis. Our findings suggested that C. trachomatis, T. vaginalis and M. genitalium may be identified in some patients with CP/CPPS, even among men with no evidence of urethritis and with negative urethral cultures and other assays. The broad-spectrum PCR assays provided the most provocative findings. DNA encoding tetracycline resistance was identified in 25% of subjects, and 77% of subjects had evidence of 16S rDNAs. The white blood cell concentration in the prostatic secretions correlated with identification of 16S rDNAs in prostate tissue (p <0.01)., Conclusions: Delineating the precise role of these organisms in the etiology of CP/CPPS may help define better diagnostic and treatment algorithms.

Background: Nonchlamydial nongonococcal urethritis (NGU) is a common sexually transmitted disease (STD) in heterosexual men. Prior studies have suggested that NGU may be acquired by insertive oral sex., Goal: To assess the association of oral sex and other sexual practices with nonchlamydial NGU in heterosexual men in order to better understand this syndrome and to guide its prevention and treatment. Risk factors for urethral gonorrhea and chlamydial infection were explored to contrast with NGU., Study Design: A retrospective case-control study was conducted among heterosexual men attending as STD clinic during 1993 and 1994. The study included 4,848 men who were sexually active within the prior 2 months and had urethral specimens obtained for Gram's stain, culture for Neisseria gonorrhoeae, and culture for Chlamydia trachomatis., Results: Insertive oral sex was not shown to be an independent risk factor for NGU. Independent predictors of nonchlamydial NGU by multivariate analysis included African-American race (odds ratio [OR] 3.71, 95% confidence interval [95% CI] 3.06 to 4.50) and having > or = two sex partners in the prior 2 months (OR 1.45, 95% CI 1.20 to 1.75). History of using condoms "always" was negatively associated with NGU (OR 0.59, 95% CI 0.43 to 0.79), gonorrhea (OR 0.31, 95% CI 0.17 to 0.56), and chlamydial infection (OR 0.67, 95% CI 0.44 to 1.03)., Conclusions: This study supports the sexually transmitted nature of nonchlamydial NGU but did not confirm an association with oral sex. However, the analysis was compromised by the rarity of insertive oral sex as patients' only sexual exposure. Consistent condom use protects against all causes of sexually acquired urethritis.

In a retrospective case-control study, gonococci with nutritional requirements for arginine, hypoxanthine, and uracil were recovered from 24 of 25 men with asymptomatic gonorrhea and 10 of 25 men with symptomatic gonorrhea (P = .0001). These strains represent a smaller proportion of gonococcal isolate from blacks than from whites. Asymptomatic urethral infection is important in the epidemiology of gonorrhea, particularly among whites.