DOI: 10.4081/aiua.2021.4.468 ORIGINAL PAPER Epidemiological, clinical and laboratory differences between male urethral infections due to Haemophilus spp. and those due to Neisseria gonorrhoeae, Chlamydia trachomatis, Mycoplasma genitalium and Ureaplasma urealyticum: A descriptive study Alvaro Vives, Marco Cosentino, Lluis Bassas, Carles Alonso, Felix Millan Sexually Transmitted Infection Department, Andrology Service, Fundació Puigvert, Universitat Autònoma de Barcelona, Barcelona, Spain. Summary Objective: To describe the epidemiological, coccal urethritis (GU), caused by Neisseria gonorrhoeae, or clinical and laboratory characteristics of non-gonococcal urethritis (NGU), caused by other aetiolog- male patients diagnosed with Haemophilus spp. urethral infec- ical agents, such as Chlamydia trachomatis, Mycoplasma tion and to compare them with the characteristics of male genitalium or Ureaplasma urealyticum (1). However, it is patients diagnosed with N. gonorrhoeae, C. trachomatis, estimated that the aetiology remains unknown in up to M. genitalium and U. urealyticum urethral infection. Over the 30%-40% of cases of NGU (2). past 2 years, an increase in urethral infections due to In recent years, new microorganisms have been described Haemophilus spp. was observed. as aetiological agents for NGU, with bacteria of the genus Materials and methods: All male patients who attended our Haemophilus taking on special importance (3, 4). Sexual Department of Sexually Transmitted Infections between January transmission to the urethra via insertive oral sex is recog- 2018 and February 2019 were retrospectively studied; they nized as a potential mode of transmission (5). However, underwent conventional bacteriological and multiplex PCR this mechanism has not been fully proven. studies in the urethra at the same time. We conducted a retrospective study to describe the epi- Results: Of the 86 patients studied, a unique microorganism was demiological, clinical and laboratory characteristics of detected in 76 cases, N. gonorrhoeae in 24, Haemophilus spp. in male patients diagnosed with urethral infections due to 21 (16 H. parainfluenzae and 5 H. influenzae), C. trachomatis Haemophilus spp. and to compare these characteristics in 19, M. genitalium in 8 and U. urealyticum in 4; 10 cases with those observed in male patients diagnosed with ure- presented more than one microorganism. In case of multiple thral infections due to N. gonorrhoeae, C. trachomatis, aetiological agents, sexual partnership was multiple. In the M. genitalium and U. urealyticum. Haemophilus group, 81% reported only unprotected oral insertive sex; symptoms lasted for more than one week in 62% of the patients. Conclusions: Haemophilus is an aetiological agent of non-gono- MATERIALS AND METHODS coccal urethritis whose incidence is clearly increasing; the main route of transmission is oral sex. The most common reason for Inclusion criteria consultation is dysuria and testicular pain, while urethral dis- The study population comprised all male patients who charge was predominant for the other causes of urethral infec- attended our Department of Sexually Transmitted Infections tion. Due to the high frequency of antibiotic resistance in the (STI) between January 2018 and February 2019 and Haemophilus group, it is necessary to confirm eradication by underwent conventional bacteriological and multiplex performing a test of cure. PCR studies in the urethra at the same time. The study was approved by our institutional medical and research KEY WORDS: Haemophilus spp.; Neisseria gonorrhoeae; ethics committee. Chlamydia trachomatis; Mycoplasma genitalium; Ureaplasma Demographic, behavioural, clinical and laboratory data urealyticum; Urethral infections; Males; Sexually transmitted were obtained by reviewing medical charts. The different infections. parameters under study were defined as follows: Submitted 15 August 2021; Accepted 7 October 2021 • Sexual orientation. • Type of sexual partner. • Number of sexual partners during the 90 days prior to INTRODUCTION the infection. One of the most common presentations of sexually trans- • Type of unprotected sex during the 90 days prior to the mitted infections (STI) among men is acute urethritis. infection. Classically, cases of sexually transmitted urethritis have • History of STIs: all patients were asked about their STI been classified according to their aetiology, as either gono- history. No conflict of interest declared. 468 Archivio Italiano di Urologia e Andrologia 2021; 93, 4 Differences between male urethral infections • HIV status. Statistical analysis • Recreational drugs during the past year. Statistical analysis was conducted using Statistical Product • Main reason for consultation. and Service Solutions Version 18.0 (SPSS). Descriptive sta- • Duration of symptoms. tistics were used to evaluate the study outcomes. Mean • Presence of leukocytes. values and ranges are presented for continuous measure- • Types of treatment ments. Frequencies and percentages were reported for • Test of cure: This consists in the performance of a con- dichotomous and ordinal variables. Differences of dis- ventional bacteriological and/or multiplex PCR study 3 crete variables were analysed with unpaired two-tailed weeks after the end of the treatment. Student’s t test. Comparisons of proportions were per- • Clinical cure: in our STI Department patient is seen formed with Fisher’s exact test. Statistical significance was again 3 weeks after the end of the treatment. All set at p < 0.05. Multivariate binary logistic regressions patients without signs and symptoms at that time are were used to search for the better combination of vari- considered clinically cured. ables to predict the aetiology of Haemophilus spp, and the • Partner notification and treatment: We considered a pos- accuracy of the model was measured as the area under the itive result for partner notification when at least one of ROC curve (AUC). the sexual partners from the last 90 days had been advised and treated correctly. RESULTS According to the CDC STI guidelines, urethritis can be In total, 158 patients met the inclusion criteria, all had documented on the basis of any of the following signs or symptoms except for 5 who attended for screening. The laboratory tests: screening cases were men to whom a sexual partner of the 1) Mucoid, mucopurulent, or purulent discharge on last 90 days had warned a positive result for: N. gonor- examination. rhoeae, C. trachomatis, M. genitalium, U. urealyticum. 2) Gram stain of urethral secretions exist that demon- We obtained 86 (54%) positive results for the microor- strate ≥ 2 WBCs per oil immersion field. 3) Positive leukocyte esterase test on first-void urine or microscopic examination of sediment from a spun Table 1. first-void urine demonstrating ≥ 10 WBCs/HPF. Reasons for consultation. Reason for consultation Total Positive cases * Men evaluated in settings in which Gram stain or MB or Urethral secretion 69 55 (86.2%) GV smear is unavailable who meet at least one criterion for urethritis (i.e., urethral discharge, positive leukocyte Dysuria 47 20 (42.5%) esterase test on first void urine, or microscopic examina- Testicular pain 9 6 (66.7%) tion of first-void urine sediment with ≥ 10 WBCs/HPF) Balanitis 12 0 (0%) should be tested for C. trachomatis and N. gonorrhoeae by Meatitis 9 2 (22.2%) NAATs. Screening 5 2 (40%) Hematospermia 6 1 (16.7%) Laboratory studies Urethrorrhagia 1 0 (0%) Only urethral samples were obtained: the first sample for Total 158 86 (54.4%) culture and leukocyte counting while the second for mul- * Positive results for any of the following microorganisms: Haemophilus, Neisseria gonorrhoeae, tiple PCR. Conventional bacteriological study included Chlamydia trachomatis, Mycoplasma genitalium or Ureaplasma urealyticum. direct examination by Gram stain of the sample smear under 100× and 1000× magnification, and culture. Petri dishes of chocolate agar (BD), Martin-Lewis agar (BD), Table 2. Gardnerella agar (BD) and Sabouraud with gentamicin Classification of the isolated microorganisms. and chloramphenicol (BD) were used. Chocolate agar, Martin-Lewis agar and Gardnerella agar were incubated at Microorganism Number 35°C with enriched 7% CO2 atmosphere for 3 days Haemophilus spp. Haemophilus parainfluenzae 16 21 (chocolate and Martin-Lewis agar) or 2 days (Gardnerella Haemophilus influenzae 5 agar). Sabouraud was incubated at 35°C for 2 days at Neisseria gonorrhoeae 24 room air. N. gonorrhoeae and Haemophilus strains were Chlamydia trachomatis 19 identified by API NH test (bioMérieux). Multiplex PCR Mycoplasma genitalium 8 was performed by AnyplexTM II STI-7 assay (Seegene), Ureaplasma urealyticum 4 which detects five microorganisms in a single reaction: C. trachomatis + M. genitalium 1 Chlamydia trachomatis, Neisseria gonorrhoeae, Trichomonas vaginalis, Mycoplasma genitalium, Ureaplasma urealyticum. C. trachomatis + N. gonorrhoeae 1 Leukocytes and other elements were looked for in LPF C. trachomatis + H. parainfluenzae 3 microscopy (100x). Then, leukocytes in 20 fields of these C. trachomatis + H. influenzae 2 areas were observed at 1000x and the average was calcu- U. urealyticum + H. parainfluenzae 1 lated. The antimicrobial susceptibility of N. gonorrhoeae U. urealyticum + Gardnerella vaginalis 1 and Haemophilus spp. strains was analyzed according to N. gonorrhoeae + M. genitalium + U. urealyticum 1 2015 CLSI guidelines (6). Archivio Italiano di Urologia e Andrologia 2021; 93, 4 469 A. Vives, M. Cosentino, L. Bassas, C. Alonso, F. Millan ganisms under study however, when we focused the main demographic, behavioural, clinical and laboratory data reason for consultation. In patients with urethral dis- according to the germ obtained or multiple infection. charge the percentage of positives increased to 86.2% (55 cases) (Table 1). Demographic and behavioural differences Regarding the 86 positive results, a single microorganism Age: The mean age of the patients included in the study was detected in 76 cases; 24 cases of N. gonorrhoeae, 21 was 31.6 years (range 16-74). The lowest mean age (24.5 cases of Haemophilus spp. (16 H. parainfluenzae and 5 H. years) was observed in patients with infection by U. ure- influenzae), 19 cases of C. trachomatis, 8 cases of M. geni- alyticum while the highest was seen in those with N. gon- talium and 4 cases of U. urealyticum. orrhoeae infection (37.5 years); Haemophilus cases dis- Ten cases presented with more than one microorganism, played the second highest mean age. being C. trachomatis the most frequent, followed by Sexual orientation: For all microorganisms, including mul- Haemophilus spp. (Table 2). In Table 3 we described the tiple infections, most cases occurred in males having sex Table 3. Reasons for consultation. Aetiology Haemophilus Neisseria Chlamydia Mycoplasma Ureaplasma Multiple P* spp gonorrhoeae trachomatis genitalium urealyticum infection Number of cases 21 24 19 8 4 10 - Mean age (years) 35.6 (20–52) 37.5 (21–74) 29.8 (16–57) 32.6 (21–47) 24.5 (16–38) 30.1 (18–46) p = 0.315 Sexual orientation MSW 13 (62%) 14 (58%) 16 (84%) 7 (88%) 4 (100%) 7 (70%) p = 0.459 MSM 7 (33%) 10 (42%) 3 (16%) – – 1 (10%) p = 0.616 BSM 1 (5%) – – 1 (12%) – 2 (20%) p = 0.560 Type of sexual partner Single 5 (24%) 8 (33%) 9 (47%) 4 (50%) – 2 (20%) p = 0.381 Multiple 16 (76%) 16 (67%) 10 (53%) 4 (50%) 4 (100%) 8 (80%) p = 0.381 Number of sexual partners 3.5 (1–20) 2.5 (1–10) 2.4 (1–10) 3.,6 (1–20) 2.2 (1–4) 8.4 (1–20) p = 0.336 Type of unprotected sex durings UOIS 21 (100%) 24 (100%) 18 (95%) 8 (100%) 4 (100%) 10 (100%) p = 0.676 the past 90 day UVS 4 (19%) 9 (38%) 14 (74%) 7 (88%) 3 (75%) 7 (70%) p = 0.004 UAIS 1 (5%) 4 (17%) – 1 (12%) – 1 (10%) p = 0.922 Previous history of STI 9 (43%) 7 (29%) 8 (42%) 2 (22%) – 5 (50%) p = 0.477 HIV status Positive 2 (10%) – 2 (11%) – – 1 (10%) p = 0.651 Negative 14 (66%) 21 (87%) 16 (84%) 8 (100%) 3 (75%) 9 (90%) p = 0.081 Not available 5 (24%) 3 (13%) 1 (5%) – 1 (25%) – p = 0.182 Recreational drugs Alcohol 18 (86%) 22 (92%) 18 (95%) 8 (100%) 4 (100%) 8 (80%) p = 0.398 Tobacco 14 (66%) 11 (46%) 12 (63%) 5 (63%) 2 (50%) 6 (60%) p = 0.546 Other drugs 3 (14%) 3 (13%) 3 (16%) – 1 (25%) 4 (40%) p = 0.794 Main reason for consultation Discharge 7 (33%) 23 (96%) 13 (68%) 4 (50%) 1 (25%) 8 (80%) p = 0.003 Dysuria 8 (38%) 1 (4%) 4 (21%) 3 (38%) 2 (50%) 1 (10%) p = 0.132 Testicular pain 4 (19%) – 2 (11%) – – – p = 0.096 Meatitis 1 (5%) – – – – 1 (10%) Haematospermia 1 (5%) – – – – – Screening – – – 1 (12%) 1 (25%) – Duration of symptoms < 1 week 8 (38%) 22 (92%) 11 (58%) 6 (75%) 2 (50%) 8 (80%) p = 0.006 > 1 week 13 (62%) 2 (8%) 8 (42%) 1 (12%) 1 (25%) 2 (20%) p = 0.002 Not available – – – 1 (12%) 1 (25%) – Presence of leukocytes 5 (24%) 18 (75%) 8 (42%) – – 4 (40%) p = 0.124 Treatments Ceftriaxone (Ceft.) – 4 – – – – - Ceft. + doxycycline 2 16 8 – 2 4 - Ceft. + azithromycin 1 4 2 – – 1 - Doxycycline 2 – 4 – 2 4 - Azithromycin, single 1 g oral dose – – 5 – – – - Azithromycin 5-day course 3 – – 4 – 1 - Moxifloxacin – – – 4 – – - Other 13 – – – – – - Clinical cure Yes 19 (90%) 23 (96%) 17 (89%) 8 (100%) 3 (75%) 10 (100%) p = 0.968 Not known 2 (10%) 1 (4%) 2 (11%) – 1 (25%) – p = 0.968 Culture/PCR control 19 (90%) – – 8 (100%) – 10 (100%) - Partner notification and treatment – 23 (96%) 18 (95%) 8 (100%) 3 (75%) 10 (100%) - UOIS: unprotected oral insertive sex; UVS: unprotected vaginal sex; UAIS: unprotected anal insertive sex. HIV STATUS: at the time of the consultation or during the 3 months preceding the consultation. Treatments: Ceftriaxone 500 mg single intramuscular dose. Ceftriaxone 500 mg single intramuscular dose + doxycycline 100 mg every 12 h, orally, for 7 days. Ceftriaxone 500 mg single intramuscular dose + azithromycin 1 g single dose, orally. Doxycycline 100 mg every 12 h, orally, for 7 days. Azithromycin 1 g orally, single dose. Azithromycin 5-day course: 500 mg–250 mg–250 mg–250 mg–250 mg orally. Moxifloxacin 400 mg oral single dose daily for 7 days. Other treatments: ciprofloxacin, levofloxacin, amoxicillin and clavulanic acid. * P: Comparison of the most important aspects between single infections by Haemophilus spp and the other single infections combined (excluding multiple infections). Fisher test for comparison of proportions. 470 Archivio Italiano di Urologia e Andrologia 2021; 93, 4 Differences between male urethral infections with women (MSW). Of the cases of Haemophilus spp. and meatitis and haematospermia in 5%. The Haemophilus N. gonorrhoeae, 33% and 42% respectively occurred in spp. group showed greater variability in the reasons for males having sex with males (MSM). No cases of infection consultation. Of the 5 asymptomatic patients who con- by U. urealyticum or M. genitalium were found in MSM. sulted for screening, in one case we found M. genitalium Type of sexual partner: For most aetiological agents, the and in another, U. urealyticum. type of sexual partner was multiple; an exception was M. Duration of symptoms: The duration of the symptoms was genitalium infection, for which 50% of patients reported a less than 1 week for the majority of infections (N. gonor- single partner and 50% multiple partners. rhoeae, M. genitalium, U. urealyticum and multiple infec- Number of sexual partners: The highest mean number of tions). For C. trachomatis, the distribution was more homo- sexual partners in the last 90 days was observed in the mul- geneous. In case of Haemophilus spp. infection, the duration tiple infection group (8.4), followed by M. genitalium (3.6) was more than 1 week in the majority of cases, with statis- and Haemophilus spp. (3.5), with a range from 1 to 20. tically significant differences compared with the other Type of unprotected sex: between 95 and 100% of all infections (p = 0.002). patients had unprotected oral insertive sex, being the Type of treatment: The type of treatment was empirical, most frequent risk sexual practice, without differences before cultures or PCR results (46 of 86 cases, 53%), or between the different germs. On the other hand, only based on the antibiogram for the isolated microorganism 19% of the Haemophilus spp reported unprotected vaginal which usually became available after 4 days (40 of 86 sex, which is statistically significant in relation to the cases, 47%). other germs (p = 0.004) (Table 3). Clinical cure: Globally we achieved a high percentage of History of STIs: Between 22% and 50% of the patients had clinical cures, without significant differences between the a history of STIs, without significant differences accord- microorganisms. In 6 cases (2 Haemophilus spp., 2 C. tra- ing to the microorganism, with the exception of patients chomatis, 1 N. gonorrhoeae and 1 U. urealyticum) patients with U. urealyticum infection, who had no history of STIs. went lost at follow up. HIV status: In 76 of the 86 cases (88%) the HIV status Test of cure: PCR was done in all M. genitalium infections, was known; only 5 patients were HIV+, and all of them as stated in the guidelines (7), and in all the results were were under treatment with negative viral load. negative. Bacteriological study (Gram stain and culture) Recreational drugs: Between 80% and 100% of the patients was done in 90% of the cases of Haemophilus spp. infec- consumed alcohol on a regular basis and between 46% tion cases, and in all the results were negative. We also and 66% used tobacco, without significant differences performed a PCR test in all cases of multiple infections, between the various groups. Use of other drugs ranged and they were also all negative. between 13% and 40%, being higher in patients with Partner notification and treatment: We carried out the noti- multiple infections. fication and treatment of sexual partners between 75 and 100% of the cases (7). Clinical differences Main reason for consultation: Of the 158 cases analysed, all Laboratory differences were symptomatic except for 5 who consulted for screen- Presence of leukocytes: We observed the presence of leuko- ing. Among patients with single infections other than cytes in 75% of N. gonorrhoeae infections, in 42% of C. tra- Haemophilus spp., urethral discharge was the main reason chomatis infections and in 40% of multiple infections, but for consultation with a statistically significant difference in only 24% of Haemophilus spp. infections; the differences observed in relation to the Haemophilus spp. group (p = were not statistically significant. We did not observe leuko- 0.003); dysuria was the main reason for consultation in cytes in any M. genitalium or U. urealyticum infections. 38%, urethral discharge in 33%, testicular pain in 19%, Antibiotic resistance Table 4. Antibiotic resistance was analysed only in cases in which Antibiotic resistance in patients with H. parainfluenzae the cultures were positive for N. gonorrhoeae or and H. influenzae infections. Haemophilus spp. Of the 26 cases positive for N. gonor- rhoeae (24 single infections plus 2 multiple infections), Antibiotic H. parainfluenzae * H. influenzae ** we did not observe any case of resistance to ceftriaxone. Cases Sensitive Resistant Cases Sensitive Resistant Of the 27 cases positive for Haemophilus spp. (including Ampicillin 20 13 (65%) 7 (35%) 7 7 (100%) – those with multiple infections), 20 were positive for H. Amoxicillin + clavulanic ac 20 18 (90%) 2 (10%) 7 7 (100%) – parainfluenzae, of which 70% were resistant to cotrimox- Cefuroxime 20 16 (80%) 4 (20%) 7 7 (100%) – azole, 60% resistant to tetracyclines and 40% resistant to Cefotaxime 20 20 (100%) – 7 7 (100%) – azithromycin. By comparison, among the 7 cases positive Meropenem 20 20 (100%) – 7 7 (100%) – for Haemophilus influenzae we found 43% resistance to Cipro/Levoflox 20 16 (80%) 4 (20%) 7 7 (100%) – cotrimoxazole, 29% to tetracyclines and rifampicin and Cotrimoxazole 20 6 (30%) 14 (70%) 7 4 (57%) 3 (43%) 14% to azithromycin. We observed a 20% resistance to Azithromycin 20 12 (60%) 8 (40%) 7 6 (86%) 1 (14%) quinolones in cases of Haemophilus parainfluenzae, with- Tetracyclines 20 8 (40%) 12 (60%) 7 5 (71%) 2 (29%) out such resistance in Haemophilus influenzae (Table 4). Rifampicin 20 17 (85%) 3 (15%) 7 5 (71%) 2 (29%) * H. parainfluenzae: 16 cases of single and 4 of multiple infections. Multivariate analysis ** H. influenzae: 5 cases of single and 2 of multiple infections. Multivariate logistic regression was used to build a pre- dictive model of assignment to the Haemophilus group, Archivio Italiano di Urologia e Andrologia 2021; 93, 4 471 A. Vives, M. Cosentino, L. Bassas, C. Alonso, F. Millan using a combination of clinical variables. A backward H. influenzae in 1.12% of the samples. Probably the fre- stepwise (conditional) method was used to drop insignifi- quency of infection by Haemophilus spp. must be related cant terms. The final model included as significant pre- to the sexual habits of the population, and the increasing dictors the type of unprotected sex being exclusively oral, practice of unprotected oral sex potentially explains these the main reasons for consultation (testicular pain, no ure- differences in incidence. In our series, H. parainfluenzae thral discharge), the duration of symptoms more than was more frequent than H. influenzae (74% vs 26%), one week, and the lack of leukocytes in the urethral sam- which is in concordance with the literature review (4, 8, ple. The accuracy of the logistic function, measured as the 14). Another discrepant finding in comparison to previ- calculated AUC on a ROC curve was 0.834 (0.717- ously published studies, such as Rane’s review in 2014, 0.951), and OR of 8.076 (3.391-19.234), showing a sen- which showed a higher prevalence of Haemophilus ure- sitivity of 76% and a specificity of 90%. thritis in MSM, is that in our series most infections were in MSW (62%), with only 33% in MSM (15). This may be because in our city MSM have access to regular screening DISCUSSION and treatment in specific community settings. To our knowledge this is the first study to compare the In our series, C. trachomatis, M. genitalium and U. ure- characteristics of Haemophilus infections with those of the alyticum were less common in MSM than MSW with other sexually transmitted urethral infections. Limitations NGU, which is consistent with the literature (15). All of of this study can be the small sample size and the lack of the Haemophilus group reported unprotected oral a representative control group. insertive sex and 81% of them denied having had anoth- Over the past 2 years we have observed an increase in er kind of unprotected sex, which was statistically signifi- urethral infections due to Haemophilus spp. in our STI cantly different compared with the other causes of ure- department for men, in keeping with other published thritis. These results were similar to the findings of Deza reviews (8). Motivated by this, we decided to perform a et al. (2015), who reported that all cases in their series retrospective study to identify the epidemiological, clini- had practiced unprotected insertive oral sex (4). cal and laboratory characteristics of these infections and Therefore, it seems clear that the main route of transmis- to compare them with urethral infections by N. gonor- sion of Haemophilus is via this route (16). These data sup- rhoeae, C. trachomatis, M. genitalium and U. urealyticum. port the contribution of oropharyngeal exposure to this All male patients who underwent conventional bacterio- syndrome. Colonization of the oral cavity by H. parain- logical and multiplex PCR studies in the urethra at the fluenzae and H. influenzae in different amounts in healthy same time between January 2018 and February 2019 individuals is very frequent (17). One aspect that we did were selected for inclusion in the study, yielding a total of not evaluate in men with recurrences, was the need to 158 cases. Of these, 86 tested positive for one or more of study partner’s oral flora in order to establish a direct these microorganisms, including 76 (88%) with infec- relation with oral sex and, also, to determine whether it is tions by a single microorganism and 10 (12%) with mul- necessary to treat sexual partners. tiple infections. This is consistent with the literature, In cases of Haemophilus infection the main reason for con- where dual infections have been identified in up to 10% sultation varied being the most common dysuria; the dif- of men in some studies, expecially among C. trachomatis ference was statistically significant compared with the and M. genitalium (9, 10). Taking into account that (a) all other causes of urethritis, for which urethral discharge 27 Haemophilus infections were symptomatic; (b) in 21 of was the main reason for consultation. In comparison, in the 27 cases a single microorganism was identified and; the study by Deza et al. the most common clinical pres- (c) all of these patients (except for 2 lost at follow up) had entation among cases of Haemophilus infection was remission of symptoms and negative cultures at control, mucopurulent urethral discharge, suggesting potential our first conclusion is that Haemophilus spp. are a sexual- difficulty in distinguishing causes of urethritis based on ly transmitted source of symptomatic urethral infection in symptomatology (4). We did not find any cases of men. Supporting this, we did not find any cases of Haemophilus infection in the 5 asymptomatic patients Haemophilus infection in the 5 asymptomatic patients who consulted for screening. Regarding the duration of who attended for screening. the symptoms, it was longer than one week in the Füzi was the first to report, in 1980, that Haemophilus Haemophilus group but usually less than one week in the could be a cause of sexually transmitted urethritis (11). other groups, the statistical difference being significant. The 2016 European Guideline on the management of Leukocytes were frequently present in infections due to NGU also refers to the fact that Haemophilus spp. are N. gonorrhoeae and C. trachomatis as well as multiple responsible for a small proportion of cases of NGU (7). In infections, but less frequent in infections due to our study, Haemophilus spp. were responsible for at least Haemophilus and absent in infections due to U. ure- 24.4% (21/86) of the cases and were the second most fre- alyticum and M. genitalium. In this regard it should be quent microorganism to be isolated alone, behind N. gon- noted that there is significant inter- and intra-observer orrhoeae but ahead of C. trachomatis and M. genitalium. error in counting polymorphonuclear leukocytes, espe- This result does not match previous reports, where C. tra- cially in samples with low-grade inflammation (18). chomatis was the most frequent microorganism, followed An interesting finding was the multiple resistances to by N. gonorrhoeae and, thirdly, by M. genitalium (1, 12). antibiotics in the Haemophilus group, which suggests a In a cross-sectional study conducted by Orellana et al. need to reconsider which is the best empirical treatment (13), in which they analyzed 1248 male urethral samples as adjuvant to intramuscular ceftriaxone in patients con- over 3 years, H. parainfluenzae was isolated in 1.76% and sulting for urethritis. The most striking finding was that 472 Archivio Italiano di Urologia e Andrologia 2021; 93, 4 Differences between male urethral infections 60% of H. parainfluenzae and 29% of H. influenzae infec- Main limitation of the study is represented by the retro- tions were resistant to doxycycline and 40% of H. parain- spective nature of the paper and the absence of a control fluenzae and 19% of H. influenzae infections were resistant group; another is the number of patients of our study to azithromycin, both of which are recommended first- that, even if it is high for a single Centre in one year, line drugs for the treatment of NGU (19). These percent- could be implemented to increase statistical significance. ages are similar to those described in other areas of the Finally, our diagnostic work out was focused on the diag- world such as East Asia (20). Among the H. parainfluen- nosis of urethritis not including a screening for concomi- zae cases there was also a 20% rate of resistance to tant prostatic infections. quinolones, which exclude them as a therapeutic option. Another drug that may be of special interest in usual practice is amoxicillin in combination with clavulanic CONCLUSIONS acid, since we observed resistance to this combination in To our knowledge, this is the first study to compare the only 10% of H. parainfluenzae and none of H. influenzae characteristics of Haemophilus infections with those of the infections. In view of these findings and the high preva- other sexually transmitted urethral infections. lence of resistance either present prior to treatment or Haemophilus seems to be an aetiological agent of non- developing during treatment, it is important to perform a gonococcal urethritis whose incidence is clearly increas- test of cure to confirm microbiological healing, as recom- ing. Oral insertive sex is the main route of acquisition of mended in all guidelines for M. genitalium (21). We per- Haemophilus urethral infection. formed a test of cure in 100% of cases of M. genitalium In the Haemophilus group the main reason for consulta- and multiple infection, with clinical and microbiological tion varied; this could make diagnosis difficult and the cure confirmed in all cases. duration of symptoms was clearly longer than for other We also performed a test of cure in 90% (19/21) of the microorganisms. It is necessary to confirm eradication of cases of single Haemophilus infection and in all of them we infection due to the high rate of antibiotic resistance, for were able to confirm clinical and microbiological cure. An this reason, in the future we should update the guidelines explanation for this high percentage of clinical cures for empirical treatment of urethritis. could be that not all the positive cases were treated Finally, it would be interesting, in cases of recurrence, to empirically; in 40 of the 86 cases, we waited for the detect Haemophilus spp. in the couple’s oral cavity and to results, which normally took about 4 days, and then compare whether the strain coincides with that of the adjusted the antibiotic depending on the antibiogram of urethra, in order to ascertain whether it is necessary to the microorganism isolated. treat sexual partners. There is good evidence that U. urealyticum causes ure- thritis in some but not all men, the problem being that even the PCR test cannot distinguish between asympto- REFERENCES matic carriers and possible causality (22-24). On the 1. Ito S, Hanaoka N, Shimuta K, et al. 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Correspondence Alvaro Vives, MD avives@fundacio-puigvert.es Marco Cosentino, MD (Corresponding Author) doccosentino@gmail.com Lluis Bassas, MD lbassas@fundacio-puigvert.es Carles Alonso, MD calonso@fundacio-puigvert.es Felix Millan fmillan@fundacio-puigvert.es Fundacio Puigvert, Barcelona, Spain 474 Archivio Italiano di Urologia e Andrologia 2021; 93, 4