Guideline sources The following summarized guidelines for the evaluation and management of non-gonococcal urethritis are prepared by our editorial team based on guidelines from the Japanese Association for Infectious Disease (JAID/JSC 2021), the Center for Disease Control (CDC 2021), the British Association for Sexual Health and HIV (BASHH 2018), and the International Union Against Sexually Transmitted Infections (IUSTI 2016). 1 2 3 4 Guidelines 1. Screening and diagnosis Diagnosis: Confirm urethritis by demonstrating polymorphonuclear leukocytes from the anterior urethra using a Gram or methylene-blue stained urethral smear, which should contain 5 polymorphonuclear leukocytes/high power microscopic field (averaged over 5 fields with the greatest concentration of polymorphonuclear leukocytes). Consider diagnosing urethritis based on the following criteria if microscopy is not available: presence of a mucopurulent or purulent urethral discharge on examination https://web.pathway.md/diseases/recmGxMQiP5GobwHH 1/5 6/30/23, 1:18 AM Non-gonococcal urethritis Pathway 1+ on a leukocyte esterase dipstick in a first void urine specimen threads in a first void urine specimen (threads may be physiological, such as semen). C 2. Classification and risk stratification Classification: classify urethritis into gonococcal and non-gonococcal depending on the causative microorganism. A Classify non-gonococcal urethritis further into chlamydial urethritis and non- chlamydial non-gonococcal urethritis. B 3. Diagnostic investigations Indication for testing: evaluate for urethritis in patients with symptoms or visible discharge. B Show 2 more First void urine: As per JAID 2021 guidelines, obtain Gram staining on urethral discharge or urinary sediment to determine whether the condition is gonococcal or non-gonococcal by confirming the presence or absence of gonococcus, a Gram-negative diplococcus. A Obtain NAATs using the first-foid urine if microscopy for gonococci is not possible. Obtain simultaneous testing for Neisseria gonorrhoeae and Chlamydia trachomatis. B As per BASHH 2018 guidelines: Test for Mycoplasma genitalium infection in patients with non-gonococcal urethritis. B Use the first void urine as the specimen of choice in cisgender males. B As per IUSTI 2016 guidelines: Consider obtaining a leukocyte esterase dipstick on the remains of the first void urine specimen to detect urethritis in symptomatic male patients with a negative urethral smear. C Consider examining the first void urine specimen for threads and, if present, staining and interpreting as for a spun deposit (10 polymorphonuclear leukocytes/high power microscopic field indicates urethritis). C Urethral smear: obtain a Gram or methylene-blue stained urethral smear from the anterior urethra to confirm urethritis by demonstrating polymorphonuclear leukocytes (5 polymorphonuclear leukocytes/high power microscopic field, averaged over 5 fields with greatest concentration of polymorphonuclear leukocytes). Show 4 more Vaginal smear: obtain vaginal swabs (clinician- or self-taken) as the specimen of choice for Mycoplasma genitalium infection in cisgender females. B Antimicrobial susceptibility testing: obtain testing for macrolide resistance mediating mutations in all Mycoplasma genitalium-positive specimens, if possible. B Assessment of sexual partners: https://web.pathway.md/diseases/recmGxMQiP5GobwHH 2/5 6/30/23, 1:18 AM Non-gonococcal urethritis Pathway As per JAID 2021 guidelines, advise abstaining from sexual contact without using a condom during treatment of male urethritis. A As per BASHH 2018 guidelines, test current sexual partners of patients with Mycoplasma genitalium infection. B As per IUSTI 2016 guidelines, obtain details of all sexual partners of the patient at the first visit. Obtain consent so that if Chlamydia trachomatis, Neisseria gonorrhea, or Mycoplasma genitalium are detected subsequently and the index patient does not reattend, the patient can be contacted and provider referral can be initiated for sexual contacts. B 4. Medical management Empirical therapy: do not initiate empirical treatment without verifying the presence of urethritis, as there is a risk of perpetuating the symptoms. D First-line therapy: As per CDC 2021 guidelines, administer doxycycline 100 mg PO BID for 7 days as first-line therapy in patients with non-gonococcal urethritis. E As per BASHH 2018 guidelines: Administer any of the following antibiotic regimens for the treatment of patients with uncomplicated Mycoplasma genitalium infection: doxycycline 100 mg BID for 7 days, followed by azithromycin 1 g PO as a single dose, then 500 mg PO once daily for 2 days if the organism is known to be macrolide-sensitive or resistance status is unknown B moxifloxacin 400 mg PO once daily for 10 days if the organism is known to be macrolide- resistant or treatment with azithromycin has failed. B Administer moxifloxacin 400 mg PO once daily for 14 days for the treatment of patients with complicated Mycoplasma genitalium infection. B As per IUSTI 2016 guidelines, administer doxycycline 100 mg PO BID or 200 mg PO once daily for 7 days as first-line therapy in patients with non-gonococcal urethritis. B Second-line therapy: As per CDC 2021 guidelines, administer any of the following regimens as second-line therapy in patients with non-gonococcal urethritis: azithromycin 1 g PO in a single dose azithromycin 500 mg in a single dose followed by 250 mg PO daily for 4 days. E As per BASHH 2018 guidelines, administer any of the following alternative antibiotic regimens for the treatment of patients with Mycoplasma genitalium infection: doxycycline 100 mg BID for 7 days, followed by pristinamycin 1 g PO QID for 10 days B pristinamycin 1 g PO QID for 10 days B doxycycline 100 mg PO BID for 14 days B minocycline 100 mg PO BID for 14 days. B https://web.pathway.md/diseases/recmGxMQiP5GobwHH 3/5 6/30/23, 1:18 AM Non-gonococcal urethritis Pathway As per IUSTI 2016 guidelines, consider administering any of the following regimens as second- line therapy for the treatment of patients with non-gonococcal urethritis: azithromycin 500 mg PO as a single stat dose followed nu 250 mg PO once daily for 4 days azithromycin 1 g PO as a single stat dose lymecycline 300 mg PO BID for 10 days tetracycline hydrochloride 500 mg PO BID for 10 days. C Show 2 more 5. Patient education Avoidance of sexual intercourse: As per JAID 2021 guidelines, evaluate and treat sexual partners of male patients with urethritis. A As per IUSTI 2016 guidelines, advise patients with non-gonococcal urethritis to abstain from sexual intercourse, including from oral sex, until both patient and current sexual partners have completed treatment. B 6. Follow-up and surveillance Follow-up testing: obtain a test of cure in all patients 5 weeks after the start of treatment (and no sooner than 3 weeks to avoid false negative results) to ensure microbiological cure and to help identify emerging resistance. B Evaluation of persistent/recurrent disease: advise patients with urethritis to return to the clinic in case of the persistence of any symptoms. Administer retreatment with appropriate regimens in patients with confirmed persistent urethritis and explore the possibility of reinfection. B Show 5 more Management of persistent/recurrent disease: Consider administering any of the following antibiotic regimens for the treatment of persistent/recurrent non-gonococcal urethritis after an initial course of treatment: azithromycin 500 mg PO single dose, then 250 mg PO for 4 days C plus metronidazole 400 mg PO BID for 5 days, C if doxycycline was prescribed as first-line therapy moxifloxacin 400 mg PO once daily for 7-14 days C plus metronidazole 400 mg PO BID for 5 days, if azithromycin was prescribed as first-line therapy. C Administer moxifloxacin 400 mg PO once daily for 7-14 days for the treatment of patients with non-gonococcal urethritis remaining symptomatic following a second course of treatment or having frequent recurrences after treatment. B Clinical findings https://web.pathway.md/diseases/recmGxMQiP5GobwHH 4/5 6/30/23, 1:18 AM Non-gonococcal urethritis Pathway Symptoms Past medical history Dysuria Chlamydia trachomatis infection Scrotal pain Human immunodeficiency virus infection Testicular pain Sexually transmitted diseases Urethral pruritus Trichomonas vaginalis infection Social history Genitourinary exam Unprotected sexual intercourse Epididymal tenderness Lab findings Urethral discharge Urethral meatal erythema urine WBCs urine Chlamydia trachomatis deoxyRNA urine leukocyte esterase urine mycoplasma genitalium deoxyRNA urine trichomonas vaginalis d RNA References 1. Suneeta Soni, Paddy Horner, Michael Rayment et al. British Association for Sexual Health and HIV national guideline for the management of infection with Mycoplasma genitalium 2018 . BASHH. 2018. Open 2. Patrick J Horner, Karla Blee, Lars Falk et al. 2016 European guideline on the management of non- gonococcal urethritis. Int J STD AIDS. 2016 Oct;27 11 928 37. Open 3. Ryoichi Hamasuna, Mitsuru Yasuda, Satoshi Takahashi et al. The JAID/JSC guidelines to Clinical Management of Infectious Disease 2017 concerning male urethritis and related disorders. J Infect Chemother. 2021 Apr;27 4 546 554. Open 4. Kimberly A Workowski, Laura H Bachmann, Philip A Chan et al. Sexually Transmitted Infections Treatment Guidelines, 2021. MMWR Recomm Rep. 2021 Jul 23;70 4 1 187. Open https://web.pathway.md/diseases/recmGxMQiP5GobwHH 5/5