The origin, composition, and significance of the distal male urethral microbiome are unclear, but vaginal mi-crobiome dysbiosis is linked to new sex partners and several urogynecological syndromes. We characterized 110 urethral specimens from men without urethral symptoms, infections, or inflammation using shotgun metagenomics. Most urethral specimens contain characteristic lactic acid bacteria and Corynebacterium spp. In contrast, several bacteria associated with vaginal dysbiosis were present only in specimens from men who reported vaginal intercourse. Sexual behavior, but not other evaluated behavioral, demographic, or clinical variables, strongly associated with inter-specimen variance in urethral microbiome composition. Thus, the male urethra supports a simple core microbiome that is established independent of sexual exposures but can be re-shaped by vaginal sex. Overall, the results suggest that urogenital microbiology and sexual behavior are inexorably intertwined, and show that the male urethra harbors female urogenital pathobionts.

To prepare for the development of the 2021 Centers for Disease Control and Prevention (CDC) sexually transmitted infections treatment guidelines, the CDC convened a committee of expert consultants in June 2019 to discuss recent abstracts and published literature on the epidemiology, diagnosis, and management of sexually transmitted infections.This paper summarizes the key questions, evidence, and recommendations for the diagnosis and management of uncomplicated Chlamydia trachomatis (CT) infections in adolescents and adults that were reviewed and discussed for consideration in developing the guidelines. The evidence reviewed mostly focused on efficacy of doxycycline and azithromycin for urogenital, rectal, and oropharyngeal CT infection, CT risk factors in women, performance of CT nucleic acid amplification tests on self-collected meatal specimens in men, and performance of newer CT point-of-care tests.

ObjectivesChlamydia trachomatis(CT) andMycoplasma genitalium(MG) cause the majority of non-gonococcal urethritis (NGU). The role ofUreaplasma urealyticum(UU) in NGU is unclear. Prior case–control studies that examined the association of UU and NGU may have been confounded by mixed infections and less stringent criteria for controls. The objective of this case–control study was to determine the prevalence and aetiology of mixed infections in men and assess if UU monoinfection is associated with NGU.MethodsWe identified 155 men with NGU and 103 controls. Behavioural and clinical information was obtained and men were tested forNeisseria gonorrhoeaeand CT, MG, UU andTrichomonas vaginalis(TV). Men who were five-pathogen negative were classified as idiopathic urethritis (IU).ResultsTwelve per cent of NGU cases in which a pathogen was identified had mixed infections, mostly UU coinfections with MG or CT; 27% had IU. In monoinfected NGU cases, 34% had CT, 17% had MG, 11% had UU and 2% had TV. In controls, pathogens were rarely identified, except for UU, which was present in 20%. Comparing cases and controls, NGU was associated with CT and MG monoinfections and mixed infections. UU monoinfection was not associated with NGU and was almost twice as prevalent in controls. Men in both the case and control groups who were younger and who reported no prior NGU diagnosis were more likely to have UU (OR 0.97 per year of age, 95% CI 0.94 to 0.998 and OR 6.3, 95% CI 1.4 to 28.5, respectively).ConclusionsMixed infections are common in men with NGU and most of these are UU coinfections with other pathogens that are well-established causes of NGU. UU monoinfections are not associated with NGU and are common in younger men and men who have never previously had NGU. Almost half of NGU cases are idiopathic.

Chlamydia trachomatis is the leading cause of sexually transmitted infections that may progress to pelvic inflammatory disease and infertility. No effective vaccine exists for Chlamydia, nor are there biomarkers available that readily predict disease progression. In this cross-sectional pilot study, we recruited symptomatic and asymptomatic women with C. trachomatis (CT) infection and asymptomatic, uninfected control women from an urban sexually transmitted disease clinic to determine if there were differences in microRNA (miRNA) expression. Infected women with signs and/or symptoms (CTSS) have distinct miRNA profiles compared to asymptomatic infected women (CTNS). In the CTSS group, miR-142 and -147 showed 2.2- to 6.9-fold increases in expression. In the CTNS group, miR-449c, -6779, -519d, -449a, and -2467 showed 3.9- to 9.0-fold increases in expression. In the CTNS group, cyclins and cell cycle regulation and IL-17 pathways were likely downregulated, while the same signaling pathways were upregulated in the CTSS group. In addition, in the CTSS group, additional inflammatory pathways associated with TNFR1 and IL-8 appear to be upregulated. The miRNA expression patterns differ between CT-infected symptomatic and asymptomatic women, and these differences may warrant further study.

Background Syndromic management remains the standard nongonococcal urethritis (NGU) treatment approach. Whether pathogen-specific signs/symptoms inform treatment decisions remains unclear. We identified men with single- and mixed-pathogen NGU and assessed for the presence of pathogen-specific signs or symptoms to improve syndromic management. Methods As part of an ongoing cohort study (the Idiopathic Urethritis Men’s Project [IUMP]), we recruited men with NGU. NGU was diagnosed by signs and/or symptoms of urethritis, and a urethral Gram stain with ≥5 neutrophils per high-power field without evidence of gram negative intracellular diplococci. Participants underwent a clinical history and physical exam, which documented specific self-reported symptoms and clinician observed signs. Single- and mixed-infections were identified by NAAT testing of first-catch urine for Neisseria gonorrhoeae (NG), Chlamydia trachomatis (CT), Mycoplasma genitalium (MG), Trichomonas vaginalis (TV), and Ureaplasma urealyticum (UU); five-pathogen-negative cases were classified as idiopathic urethritis (IU). Results One hundred fifty-five men with NGU are included in this analysis. The median age was 28 (range 18–63), 101 (65%) were African American, and 135 (87%) self-identified as heterosexual. The most commonly reported symptom was urethral discharge (92%), followed by burning/tingling (37%), and dysuria (28%). Over half of these men reported more than one symptom (58%). Single-pathogen NGU was detected in 99 (64%) men, mixed-pathogen in 14 (9%), and IU in 42 (27%). For single pathogen NGU, 53 (34%) had CT, 26 (17%) had MG, 3 (2%) had TV, and 17 (11%) had UU. We compared single-pathogen NGU, mixed-infection and IU for differences in signs or symptoms and found no pathogen-specific differences. Conclusion In men with NGU, no pathogen-specific signs and symptoms were identified that could inform treatment decisions. Pathogen-specific point-of-care tests are needed. Disclosure No significant relationships.

Background Persistent NGU occurs when symptoms persist after empiric NGU treatment and has been associated with Mycoplasma genitalium (MG) infection. The prevalence and etiology of persistent NGU in men remains largely unknown. Methods Within the Idiopathic Urethritis Men’s Project cohort study, we recruited men with NGU. NGU was diagnosed by the presence of urethritis signs and/or symptoms and urethral Gram stain with ≥5 PMN/HPF. Men were treated with 1 gm azithromycin and returned for a 1-month test-of-cure visit. At the test-of-cure visit, men were asked about post-treatment symptom outcomes and partner treatment. A first-catch urine specimen was obtained at both visits for five-pathogen testing for Neisseria gonorrhoeae (NG),Chlamydia trachomatis (CT), MG, Trichomonas vaginalis (TV), and Ureaplasma urealyticum (UU). NG-positive cases were excluded and five-pathogen-negative cases were classified as idiopathic urethritis (IU). Post-treatment symptom outcomes were: (1) resolved, (2) resolved then recurred, or (3) persisted unchanged. Results One hundred twenty-four men are included in this study. The median age was 28, 52% were African American, and 86% self-identified as heterosexual. All men reported urethral symptoms and 98% had a discharge on exam at baseline. Symptoms resolved completely in 91 (73%) men. Symptoms resolved then recurred or persisted unchanged in 12 (10%) and 21 (17%) men, respectively. Excluding men with untreated partners (N = 9, 28%), a different pathogen was identified in 5 (50%) and 4 (25%) men with recurrent and persistent symptoms, respectively. In men with the same pathogen identified (N = 15), 53% were IU, 33% were MG, 7% were CT, and 7% were UU. Conclusion Persistent NGU occurs in approximately 25% of azithromycin-treated men and is related to a new infection in up to 50% of cases. In men with persistent symptoms and the same infection identified at the test-of-cure visit, MG and IU comprised 86% of cases, which suggests that MG and IU-associated organisms may be resistant to azithromycin. Disclosure No significant relationships.

Background The ability to quantify the organism load of Chlamydia trachomatis (CT) using a commercial assay could expand insights from epidemiological studies. This approach can be applied to routine diagnostic testing, and multiple specimen types. Approximate CT organism load was determined in urine from men with NGU, with and without co-infections, by comparing the results from each positive sample to a set of CT standards using the Abbott Realtime m2000 (m2000) platform. Methods Urine specimens, collected from men participating in the Idiopathic Urethritis Men’s Project (IUMP), were tested on the m2000 for CT. Additional testing included Neisseria gonorrhoeae, Mycoplasma genitalium, Trichomonas vaginalis, and Ureaplasma urealyticum. Standards were prepared by diluting CT elementary bodies (EB) into the collection device at six concentrations. CT organism load was determined by comparing the instrument generated delta cycle (DC) value from each CT positive urine to the standard curve. Calculated means were compared by t-test (p<0.05). Results Two hundred and six men were tested for CT and 83 (40.3%) were positive. The DC values for 81/83 (97.3%) CT positive samples fell within the range of the standard curve. The mean DC value was 12.15 (range 0.19–16.96) which equated to a mean CT organism load of 1.4×106 EB/ml urine (range 2.22×102-9.97×106). There was no difference between the mean organism load in specimens from men who did and did not have co-infections with other STIs, 2.04×106 versus 1.38×106 EB/ml, (p≥0.05). Conclusion CT load determination can be performed on urine specimens using the m2000. This could facilitate straightforward load determination in settings where routine testing is performed. In men with NGU, the CT organism load is high and no difference in CT load was observed in men with CT mono-infections and men co-infected with CT and other STIs. Disclosure No significant relationships.

Background Rectal infection with Chlamydia trachomatis (CT) is frequent in women who deny receptive anal sex and is thought to arise from autoinoculation of the rectum from vaginal secretions. An alternate hypothesis is that oral sex inoculates and establishes gastrointestinal tract infection. Distinguishing these hypotheses is difficult in women. In men, autoinoculation is unlikely and heterosexual men frequently perform oral sex, but rarely participate in receptive anal exposure behaviors. Methods We enrolled high-risk men with and without nongonococcal urethritis who presented to a sexually transmitted infection clinic in Indianapolis, Indiana. Urine and rectal swabs were collected and tested for urogenital and rectal CT, Neisseria gonorrhoeae (NG), and Mycoplasma genitalium (MG). Men completed surveys concerning symptoms, sexual orientation, and detailed recent and lifetime oral and anal sexual behaviors. Results Rectal CT was detected in 2/84 (2.4%) heterosexual men who reported cunnilingus, but no lifetime receptive anal behaviors. All of the men who denied receptive anal behaviors were negative for rectal NG and MG. In homosexual and bisexual men, rectal CT prevalence was high (9.7%), and rectal NG (4.8%) and MG (4.8%) were also detected. Conclusions We detected rectal CT infections in heterosexual men who reported cunnilingus but denied receptive anal behaviors. Oral sex may be a risk factor for rectal CT infection via oral inoculation of the gastrointestinal tract.

Background Antibiotic-resistant Neisseria gonorrhoeae has prompted the development of new therapies. Zoliflodacin is a new antibiotic that inhibits DNA biosynthesis. In this multicenter, phase 2 trial, zoliflodacin was evaluated for the treatment of uncomplicated gonorrhea. Methods We randomly assigned eligible men and women who had signs or symptoms of uncomplicated urogenital gonorrhea or untreated urogenital gonorrhea or who had had sexual contact in the preceding 14 days with a person who had gonorrhea to receive a single oral dose of zoliflodacin (2 g or 3 g) or a single 500-mg intramuscular dose of ceftriaxone in a ratio of approximately 70:70:40. A test of cure occurred within 62 days after treatment, followed by a safety visit 312 days after treatment. The primary efficacy outcome measure was the proportion of urogenital microbiologic cure in the microbiologic intention-to-treat (micro-ITT) population. Results From November 2014 through December 2015, a total of 179 participants (167 men and 12 women) were enrolled. Among the 141 participants in the micro-ITT population who could be evaluated, microbiologic cure at urogenital sites was documented in 55 of 57 (96%) who received 2 g of zoliflodacin, 54 of 56 (96%) who received 3 g of zoliflodacin, and 28 of 28 (100%) who received ceftriaxone. All rectal infections were cured in all 5 participants who received 2 g of zoliflodacin and all 7 who received 3 g, and in all 3 participants in the group that received ceftriaxone. Pharyngeal infections were cured in 4 of 8 participants (50%), 9 of 11 participants (82%), and 4 of 4 participants (100%) in the groups that received 2 g of zoliflodacin, 3 g of zoliflodacin, and ceftriaxone, respectively. A total of 84 adverse events were reported: 24 in the group that received 2 g of zoliflodacin, 37 in the group that received 3 g of zoliflodacin, and 23 in the group that received ceftriaxone. According to investigators, a total of 21 adverse events were thought to be related to zoliflodacin, and most such events were gastrointestinal. Conclusions The majority of uncomplicated urogenital and rectal gonococcal infections were successfully treated with oral zoliflodacin, but this agent was less efficacious in the treatment of pharyngeal infections.

Mycoplasma genitalium (MG) causes symptomatic nonchlamydial, nongonococcal urethritis in men, and cervicitis, pelvic inflammatory disease and infertility in women. We aimed to determine: prevalence and concordance of MG infection within heterosexual partnerships; MG detection by sample site in infected subjects; symptom association with MG infection; frequency of co-infection with Chlamydia trachomatis (CT), Neisseria gonorrhoeae (NG) and Trichomonas vaginalis (TV); and risk factors associated with MG infection and concordance. Data from two partnership studies were combined; both enrolled sexually active heterosexual couples between the ages of 14–24 years who were at high risk for CT, between April 10, 2000 and September 29, 2003 at a sexually transmitted infection (STI) clinic in Indianapolis, IN. MG was detected by nucleic acid amplification from specimens stored at −70°C for up to 48 months. MG was sought in urine and urethra in men and urine, vagina, and cervix in women. Symptoms evaluated were dysuria, discharge in men and discharge, dysuria, abdominal pain in women. Symptom association with MG infection was analyzed by Chi-square test and logistic regression was used for associations of demographic, behavioral and biologic factors with MG concordance. Microbiologic data were available from 200 men and 217 women, and demographic information from 188 men and 201 women in partnerships. 43/217 dyads contained an individual with MG infection, and both individuals were infected in 11/43 (26%) partnerships (concordant). In men and women MG detection was highest in urine (10%, 9%) specimens. Prevalence of MG was 14% in women and10% in men. Most infected men (79%) and women (62%) were African American. Mean age at first sex was 14 years for both genders. CT was the most frequent co-infection in both MG infected men (32%) and women (52%). MG infection without co-infection was associated with penile discharge in men (57%) P = 0.18. No symptoms in women were indicative of MG infection, and no demographic, behavioral or biologic factors were statistically associated with MG concordance. The prevalence of MG was substantial. Concordance in partnerships was 26%, less than observed with CT (~70%) in this study. Our study is limited due to small numbers of subjects with MG infection. All authors: No reported disclosures.

In this phase 2 study, single oral doses of gepotidacin were ≥95% effective for bacterial eradication in culture-proven uncomplicated urogenital gonorrhea. New antibiotics for drug-resistant Neisseria gonorrhoeae are urgently needed. With additional evaluation, gepotidacin may provide an alternative therapeutic option.

At a clinic in Indianapolis, Indiana, USA, we observed an increase in Neisseria gonorrhoeae-negative men with suspected gonococcal urethritis who had urethral cultures positive for N. meningitidis. We describe genomes of 2 of these N. meningitidis sequence type 11 complex urethritis isolates. Clinical evidence suggests these isolates may represent an emerging urethrotropic clade.

Asymptomatic rectal Chlamydia trachomatis (CT) infections are common among men who have sex with men (MSM),1 and frequently exist apart from urethral infections: up to 88% of those with rectal CT are negative at the urethra.2 The Centers for Disease Control (CDC) recommends rectal screening for CT among MSM at least yearly, and for those positive, rescreening in approximately 3 months due to a substantial rate of repeat infections.3 Currently, CDC treatment recommendations for asymptomatic rectal infections include either azithromycin 1 g orally as a single dose, or doxycycline 100 mg orally bid for 7 days.3 Treatment recommendations for symptomatic proctitis and severe proctocolitis differ because pathogens other than CT, including Neisseria gonorrhoeae and herpes simplex virus, can cause these syndromes. Severe disease also suggests lymphogranuloma venereum, caused by LGV strains of CT, for which 21 days of doxycycline is recommended. Notwithstanding the CDC guidelines, the best treatment for asymptomatic rectal infections in MSM is not clear. A number of observational studies, both retrospective and prospective, have been reported since 2009. A systematic review and meta-analysis of 8 of these studies estimated a pooled efficacy for azithromycin of 82.9%; 5 of the studies also included doxycycline, with an estimated pooled efficacy of 99.6%.4 The largest experience among these was a retrospective study in Seattle where among MSM with repeat CT testing within 90 days of treatment, the adjusted relative risk for persistence/recurrence among azithromycin treated men was 5.2 (95% confidence interval, 1.3–21).5 A follow-up report of one of the studies in the meta-analysis comprised 532 doxycycline-treated men and women with rectal CT, and reported an estimated failure rate of 0.9%.6 Finally, a recent retrospective experience among asymptomatic rectal CT in MSM reported an azithromycin efficacy of 83.6% among 171 azithromycin treated individuals. Of note, biomarkers including ompA sequencing and multilocus sequence typing and behavioral data were used to help discern treatment failure from reinfection.7 This study also suggests that organism load estimated at the index infection before treatment is associated with treatment failure. Another contribution to this literature is the report in this issue by Smith et al.8 In a prospective observational cohort within the REACT randomized trial in Australia, repeat CT infections were sought among men who have sex with women (MSW) (n = 89), women who have sex with men (WSM) (n = 100) and MSM (n = 101) who were CT-infected at baseline and treated with single-dose azithromycin. In MSW and WSM, urogenital sites were sampled, and among MSM, urogenital and rectal sites. The authors used an algorithm which included detailed behaviors, ompA genotyping and multilocus sequence typing to distinguish treatment failures from likely reinfections. They found that treatment failures differed between the pooled MSW/WSM groups (2.6%) as compared with MSM (8.9%); among MSM, most treatment failures were at the rectal site. Although the number of repeated infections evaluated was relatively small (n = 43), the analyses are detailed and carefully done. Initial organism load in MSM again was associated with treatment failure. As previously reported, CT genotype distributions differed between the pooled MSW/WSM groups and the MSM group—another research question is whether this is a product of a largely nonintersecting epidemiology, or of bacterial factors that provide a competitive advantage at the rectal site. Finally, the study result supports the contention that azithromycin is less effective at the rectal site as opposed to genital sites. The available literature, although observational in nature, points to the possibility of superior microbiological effectiveness of doxycycline over azithromycin in rectal CT infections in MSM. Recommendations for treatment of asymptomatic rectal CT have shifted to favor the doxycycline regimen in both Australian and European guidelines.9,10 Is this then a settled issue? The observational studies above have limitations. Most studies lacked biomarkers and many lacked detailed behavioral information to distinguish reinfection from treatment failure; some were noncomparative wherein only 1 treatment regimen was reported; several were retrospective; many had high loss-to-follow up rates; some included and pooled both men and women; and many included both symptomatic and asymptomatic persons. In addition, in some cases, diagnostic tests differed, important because culture is less sensitive than nucleic acid amplification tests (NAATs). Finally, with the exception of 1 study that compared azithromycin with doxycycline in a before-and-after comparison when clinic treatment policy was changed, treatments were not randomized or standardized, and the reasons that clinicians selected a regimen are not known. Despite the fact that the currently available retrospective and prospective observational studies all seem to point to a lower response rate to azithromycin, best evidence in the form of a randomized controlled trial (RCT) does not yet exist. The good news is that such an RCT of azithromycin versus doxycycline for the treatment of asymptomatic rectal infection in MSM is underway in Australia. The study protocol has been recently published.11 The Rectal Treatment Study aims to recruit 700 MSM with rectal detection of CT by NAAT, without symptoms of proctitis. Treatment will be randomized and double-blind. The primary outcome is CT detection by NAAT at 4 weeks. Secondary outcomes include use of behavioral and molecular analyses as methods for estimating repeated detections that are likely treatment failure as opposed to reinfection. The trial began recruiting in August 2016 with the goal of completing recruitment in 3 years. Should doxycycline prove more effective in an RCT setting, many providers would be concerned about adherence to the 7-day regimen, and fear that “use-effectiveness” in the real world may be less favorable and abrogate any advantage over single-dose therapy. Indeed, 2 studies using the Medication Event Monitoring System to assess adherence to 7-day doxycycline courses in the STD clinic setting suggested low rates (16–25%) of complete adherence.12,13 However, the Bachmann study13 reported a microbiological treatment success of 94% based on NAAT, despite poor adherence. More recently, in the context of an RCT comparing azithromycin and doxycycline in the treatment of NGU, a combination of written patient logs and computer-assisted self-interviews was used to assess adherence; a single missed dose was defined as nonadherence.14 Among men with chlamydial urethritis, 1 of 37 men with complete adherence failed doxycycline, as opposed to 2 of 10 with nonadherence; the 95% confidence interval of adjusted relative risk was very wide (1.00–89.2). Perhaps, reassuring is that doxycycline efficacy in the observational studies ranges from 90.5% to 100%, with 5 of the 6 studies clustered in the 96% to 100% range.4,6 Why might azithromycin be less effective than doxycycline at the rectal site, and why might azithromycin be less effective in eradicating CT detected at the rectal site, as opposed to urogenital sites? Although differential antibiotic tissue penetration or other factors may be involved, it is worth reconsidering the mode of transmission of CT which results in rectal shedding. The operative assumption that drives rectal screening recommendations is that asymptomatic rectal infections in MSM (and WSM) result from direct inoculation by insertive anal intercourse. Many undoubtedly are, but the possibility of acquisition of CT via oral sexual activity (fellatio, anilingus) causing asymptomatic gastrointestinal (GI) tract infection resulting in rectal shedding must also be considered. Rank and Yeruva15 reviewed the extensive available data for both experimental animal models and for natural chlamydial infections in veterinary animals; these demonstrate that an asymptomatic GI reservoir, commonly at the cecum, is present in every system studied. The immune response to GI involvement appears to wane rapidly despite presence of ongoing infection. Rank and Yeruva furthermore have shown that cecal infection in mice commonly fails treatment with azithromycin, whereas genital infection is eradicated; the reason for this disparity is not clear. Doxycycline treatment effectively clears both sites. The parallels with available clinical observations are striking. It is reasonable to hypothesize that an asymptomatic GI reservoir exists in humans as well and is supported by observations of rectal CT shedding in children with trachoma and in persistently infected children after perinatal acquisition. It is thus possible that rectal shedding in asymptomatic MSM are due to oral acquisition, and that a similar mechanism, distinct from genital to rectal autoinoculation, may underlie the surprisingly high rectal detection in women who do not report receptive anal intercourse.16 A corollary hypothesis is that MSW who engage in oral sexual practices, such as cunnilingus and anilingus with infected women, may acquire and shed CT at the rectal site, where direct and autoinoculation of the rectum are unlikely; a pilot study to examine this possibility is underway. Regardless, it is clear that much needs to be learned about the biological mechanisms involved, and whether GI colonization and rectal shedding requires a different treatment approach, not only among MSM but also among WSM. For now, if you practice in Australia and Europe, the standard recommendation is to use doxycycline as first choice for treatment of asymptomatic rectal infection in MSM. In the United States, until the result of the RCT is known, azithromycin and doxycycline are alternatives. A reasonable approach might include engaging the patient in the treatment decision process, favoring single-dose therapy for those considered unlikely to complete a 7-day course or who prefer a single-dose approach, and providing doxycycline for those who prefer what might be a more reliable therapy.

The best treatment for urogenital infections with Chlamydia trachomatis (CT) is not clear. Accumulating evidence suggests that azithromycin is less efficacious than doxycycline, but no study has been sufficient to prompt a widespread change in practice or sexually transmitted disease (STD) treatment guidelines. Recently, Geisler and colleagues1 published the results of a randomized controlled trial (RCT) of azithromycin versus doxycycline for the treatment of urogenital CT infections among adolescents in youth correctional facilities. The efficacy of doxycycline was 100% and azithromycin 96.8%, but the confidence intervals around the 3.2% difference did not meet the study's prespecified threshold to establish the noninferiority of azithromycin. Most of the men included in the Geisler study were asymptomatic, and some evidence suggests that men with symptomatic urethritis have a poorer response to azithromycin. In a meta-analysis of trials that compared azithromycin with doxycycline for the treatment of urogenital chlamydial infection, Kong and colleagues2 estimated a 7% increased efficacy for doxycycline compared with azithromycin for the treatment of symptomatic urethral infection in men. Indeed, Geisler and colleagues found a similar, though nonsignificant, differential efficacy in a subanalysis of their study data: 10% (2 of 20) of men who reported painful urination failed azithromycin compared with 2% (2 of 82) of men who did not report painful urination (P = 0.17). Three recent prospective studies have assessed azithromycin treatment failure among men with symptomatic chlamydial urethritis treated with single-dose azithromycin, 2 of which compared azithromycin with doxycycline. In 2011, Schwebke and colleagues3 reported the results of an RCT for the treatment of nongonococcal urethritis (NGU) with doxycycline plus or minus tinidazole versus azithromycin plus or minus tinidazole. In that study, azithromycin was significantly less effective than doxycycline for the treatment of urogenital CT infections in men (77% vs 95%, P = 0.01). In 2013, Manhart and colleagues4 reported the results of an RCT for the treatment of NGU, but found no significant difference between azithromycin and doxycycline (86% vs 90%, P = 0.56). Also, in 2013, Kissinger and colleagues5 reported the results of a prospective study that retested men 4 to 6 weeks after treatment for CT urethritis. They reported a 94% success rate with azithromycin treatment, but over half of the men with CT redetection reported sexual exposure in the interim between treatment and retesting. This result suggested that a high proportion of putative treatment failures in the other 2 studies could have been explained by reinfection from reexposure to a prior partner or from a new partner. In an exemplary instance of scientific cooperation, the authors who conducted the 3 studies described above collaborated to reanalyze their data with harmonized methods to generate a more precise estimate of azithromycin treatment failure for the treatment of symptomatic urethritis in men who have sex with women (MSW).6 They were thus able to examine the degree to which reexposure, and likely reinfection, or detection of remnant chlamydial DNA due to early (<3 weeks) test-of-cure sampling accounted for redetection of CT in each of the studies and how differential classification of uncertain cases affected the results. The study found that, overall, 6.2% to 12.8% of urethral CT infections failed treatment. This is higher than the 5% threshold considered acceptable by the World Health Organization for a medication used to treat a sexually transmitted infection (STI).7 The analysis by Kissinger and colleagues raises a number of important questions. First, what causes azithromycin treatment failure? Antimicrobial resistance is one potential explanation, but macrolide resistance in human chlamydial strains has not been conclusively demonstrated.8 One report described an isolate with high-level resistance to azithromycin in vitro,9 but this was later shown to be due to heterotypic survival of the organism rather than true resistance.10 That is, some organisms survived in the presence of azithromycin and others did not, but there was no difference in the minimum inhibitory concentration to azithromycin between surviving and non-surviving strains. The same phenomenon was observed with 44 other CT isolates from patients whose infections were successfully treated with azithromycin, and thus, could not account for treatment failure. Antimicrobial susceptibility in CT is difficult to assess or monitor because in vitro testing does not correlate well with clinical persistence.11,12 Treatment failure of an infectious disease can be due to several other factors besides antimicrobial resistance, including inadequate tissue penetration of the antibiotic, subject variability in bioavailability, or inadequate concentration or duration of the antibiotic for the pathogen's level of susceptibility. Although the development of decreased susceptibility to azithromycin among CT remains a possibility, it is unlikely that antimicrobial resistance accounts for many treatment failures at present. Redetection of CT after treatment can also result from reexposure, and disentangling treatment failure from reinfection is a perennial challenge for STI clinical researchers. Even with successful treatment, men with chlamydial urethritis are at substantial risk of reinfection. The findings of the Kissinger study provide a reminder of the importance of retesting to detect reinfection. Comprehensive treatment of a patient with chlamydial urethritis is not limited to a dose of azithromycin or a course of doxycycline, but must also include partner treatment and a plan for retesting in 3 months. In many, perhaps most, areas of the United States, health departments do not contact the sex partners of persons diagnosed with CT infection because there are insufficient resources to do so in the context of competing STD/human immunodeficiency virus disease control priorities. Thus, medical providers who diagnose chlamydia must address partner treatment, including through the use of expedited partner therapy where legal and available. Has azithromycin treatment failure of chlamydial urethritis become more common over time? As Kissinger and colleagues6 point out, a meta-analysis from 2002 estimated the failure rate to be 3% and another in 2014 estimated it to be 6%.2 The current study finds a lower limit of treatment failure of 6.2% (95% confidence interval [CI], 3.2–9.2%). In the absence of consistent data with which to monitor chlamydia treatment failure over time, it is impossible to answer this question with certainty. However, almost all of the studies in the earlier meta-analysis used culture for detection of CT, and several studies in the latter meta-analysis used more sensitive molecular methods. Furthermore, rates of CT redetection observed in earlier studies are within the range of treatment failure reported by Kissinger and colleagues. The key study demonstrating the equivalence of azithromycin and doxycycline for the treatment of non-gonococcal urethritis was an RCT in 11 US STD Clinics published in 1995.14 Among men with chlamydial urethritis in that study, the microbiological cure rates were 83% for azithromycin (95% CI, 65–94%) and 90% (95% CI, 68–98%) for doxycycline. To us, this suggests that we are not identifying an emerging problem, but rather are more clearly recognizing the long-standing problem of azithromycin treatment failure. What are the implications of the azithromycin treatment failure prevalence being higher than the World Health Organization 5% threshold? Although the 5% level does not have a specific clinical or epidemiological implication in and of itself, it does serve as a clear guideline to treating providers and to our field more broadly. In general, if we have the option of a treatment with greater efficacy at comparable or superior safety and cost it should be the preferred therapy. Patient adherence to therapy is another important aspect of treatment decisions. Azithromycin has the major advantage of being administered as a single dose, whereas doxycycline is given as a twice daily 7-day regimen. On this basis alone, many providers prefer azithromycin and question whether the efficacy of doxycycline observed in trials translates into effectiveness in practice. However, we do not know what level of adherence to doxycycline is necessary for effective treatment. Studies of chlamydial treatment with less frequent doxycycline dosing (eg, 200 mg on day 1 followed by 100 mg daily for 6–9 days) have shown high efficacy,13 and with a half-life of 18 hours, it is plausible that incomplete adherence to doxycycline could still achieve cure. Although practitioners tend to prefer single dose therapy for STIs, it is worth examining that preference closely when the adequacy of single dose therapy is in question. Many patients with chlamydia will not have difficulty adhering to doxycycline for a week. A reasonable treatment approach would be to use doxycycline preferentially, but use azithromycin when a patient's ability to adhere to treatment is in doubt. The studies of focus in the Kissinger paper were conducted in MSW. This is important to note because men who have sex with men are at risk for rectal CT infection, for which retrospective data suggest azithromycin treatment is substantially less effective than doxycycline.15,16 These retrospective studies are inherently limited, and a prospective RCT is needed to definitively address this question. For MSW with chlamydial urethritis, however, the evidence is clear: about 6% to 13% will fail treatment with azithromycin, and this level is higher than the standard we generally accept for treatment of an STI.

Background Sexual transmission rates of Chlamydia trachomatis ( Ct ) cannot be measured directly; however, the study of concordance of Ct infection in sexual partnerships (dyads) can help to illuminate factors influencing Ct transmission. Methods Heterosexual men and women with Ct infection and their sex partners were enrolled and partner-specific coital and behavioral data collected for the prior 30 days. Microbiological data included Ct culture, and nucleic acid amplification testing (NAAT), quantitative Ct polymerase chain reaction, and ompA genotyping. We measured Ct concordance in dyads and factors (correlates) associated with concordance. Results One hundred twenty-one women and 125 men formed 128 dyads. Overall, 72.9% of male partners of NAAT-positive women and 68.6% of female partners of NAAT-positive men were Ct -infected. Concordance was more common in dyads with culture-positive members (78.6% of male partners, 77% of female partners). Partners of women and men who were NAAT-positive only had lower concordance (33.3%, 46.4%, respectively). Women in concordant dyads had significantly higher median endocervical quantitative Ct polymerase chain reaction values (3,032) compared with CT-infected women in discordant dyads (1013 inclusion forming units DNA equivalents per mL; P < 0.01). Among 54 Ct -concordant dyads with ompA genotype data for both members, 96.2% had identical genotypes. Conclusions Higher organism load appears associated with concordance among women. Same-genotype chlamydial concordance was high in sexual partnerships. No behavioral factors were sufficiently discriminating to guide partner services activities. Findings may help model coitus-specific transmission probabilities.

Contact precautions may have an adverse effect on a patient's hospital experience and the delivery of care. This case-control study compared patient satisfaction scores between 70 patients isolated for MRSA and 139 non-isolated patients. Based on an adjusted analysis, there was no difference in patient satisfaction between the two groups. Age and educational status were found to affect patient satisfaction. (C) 2015 The Healthcare Infection Society. Published by Elsevier Ltd. All rights reserved.

Chlamydia trachomatis causes a high number of sexually transmitted infections worldwide, but reproducible and precise strain typing to link partners is lacking. We evaluated multilocus sequence typing (MLST) for this purpose by detecting sequence types (STs) concordant for the ompA genotype, a single-locus typing standard. We tested samples collected during April 2000-October 2003 from members of established heterosexual partnerships (dyads) in the Indianapolis, Indiana, USA, area who self-reported being coital partners within the previous 30 days. C. trachomatis DNA from 28 dyads was tested by MLST; sequences were aligned and analyzed for ST and phylogenetic relationships. MLST detected 9 C. trachomatis STs, 4 unique to Indianapolis; STs were identical within each dyad. Thirteen unique strains were identified; 9 (32%) dyads harbored novel recombinant strains that phylogenetically clustered with strains comprising the recombinants. The high rate of novel C. trachomatis recombinants identified supports the use of MLST for transmission and strain diversity studies among at-risk populations.