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Brazilian Protocol for Sexually Transmitted Infections, 2020: infections that cause urethral discharge

Leonor Henriette de Lannoy Roberto José de Carvalho da Silva Edilbert Pellegrini Nahn Júnior Eduardo Campos de Oliveira Pâmela Cristina Gaspar About the authors

Highlighted excerpt:

Associated factors with urethritis are: young age, low socioeconomic level, multiple partnerships or new sexual partnership, history of STI, irregular use of condoms, and lack of access to adequate diagnosis and treatment.

Abstract

This article approaches infections that cause urethral discharge. This theme is part of the Clinical Protocol and Therapeutic Guidelines for Comprehensive Care for People with Sexually Transmitted Infections, published by the Ministry of Health of Brazil in 2020. These guidelines were prepared based on scientific evidence and validated in discussions with experts. Urethritis can cause severe and even irreversible health damage when not properly treated, or when the microorganism develops antimicrobial resistance. It is noteworthy that the high levels of antimicrobial resistance grown by pathogens that cause urethritis comprises a global emergency in public health. This article presents epidemiological and clinical aspects, recommendations on diagnostic and treatment, and strategies for surveillance, prevention, and control actions for infections that cause urethral discharge, to contribute to managers' and health professionals' care qualification.

Keywords:
Urethritis; Neisseria gonorrhoeae; Chlamydia trachomatis; Clinical protocols; Public health

INTRODUCTION

The article addresses infections that cause urethral discharge. This subject composes the Clinical Protocol and Therapeutical Guidelines (PCDT) for Comprehensive Care for People with Sexually Transmitted Infections (STIs), published by the Health Surveillance Secretariat of the Brazilian Ministry of Health. For elaborating the PCDT, evidences available in the literature were selected, analysed and discussed by a panel of experts. The referred PCDT was approved by the National Committee for the Incorporation of Technologies in the Brazilian National Health System (Conitec)11. Brasil. Ministério da Saúde. Portaria MS/SCTIE nº 42, de 5 de outubro de 2018. Torna pública a decisão de aprovar o Protocolo Clínico e Diretrizes Terapêuticas para Atenção Integral às Pessoas com Infecções Sexualmente Transmissíveis (IST), no âmbito do Sistema Único de Saúde - SUS. [Internet]. Diário Oficial da União, Brasília (DF), 2018 out 8 [cited 2020 jun 28]; Seção 1:88. Available from: http://bvsms.saude.gov.br/bvs/saudelegis/sctie/2018/prt0042_08_10_2018.html
http://bvsms.saude.gov.br/bvs/saudelegis...
and updated by the team of experts in STI in 2020.

EPIDEMIOLOGICAL ASPECTS

Urethritis is defined as an inflammation of the urethra and can be infectious or not. Several agents can cause infectious urethritis in the context of condom-free sexual practices. Urethritis is classified according to the etiologic agent as gonococcal, caused by Neisseria gonorrhoeae, and non-gonococcal, caused mainly by Chlamydia trachomatis and Mycoplasma genitalium. Other agents, such as Trichomonas vaginalis, enterobacteria (in insertive anal relations), herpes simplex virus (HSV), adenovirus, and Candida sp., are less frequent22. Ministério da Saúde (BR). Secretaria de Vigilância em Saúde. Departamento de Doenças de Condições Crônicas e Infecções Sexualmente Transmissíveis. Protocolo clínico e diretrizes terapêuticas para atenção integral às pessoas com infecções sexualmente transmissíveis (IST) [Internet]. Brasília: Ministério da Saúde; 2020 [cited 2020 out 13]. 131p. Available from: http://www.aids.gov.br/pt-br/pub/2015/protocolo-clinico-e-diretrizes-terapeuticas-para-atencao-integral-pessoas-com-infeccoes
http://www.aids.gov.br/pt-br/pub/2015/pr...
,33. Buder S, Schöfer H, Meyer T, Bremer V, Kohl PK, Skaletz-Rorowski A, Brockmeyer N. Bacterial sexually transmitted infections. JDDG: J Deutsch Dermatol Gesellschaft [Internet]. 2019 Mar [cited 2020 Oct 13]; 17(3):287-315. Available from: https://doi.org/10.1111/ddg.13804
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The following factors are associated with urethritis: young age, low socioeconomic status, multiple partnerships or new sexual partnerships, history of STI and irregular condom use, and lack of access to adequate diagnosis and treatment22. Ministério da Saúde (BR). Secretaria de Vigilância em Saúde. Departamento de Doenças de Condições Crônicas e Infecções Sexualmente Transmissíveis. Protocolo clínico e diretrizes terapêuticas para atenção integral às pessoas com infecções sexualmente transmissíveis (IST) [Internet]. Brasília: Ministério da Saúde; 2020 [cited 2020 out 13]. 131p. Available from: http://www.aids.gov.br/pt-br/pub/2015/protocolo-clinico-e-diretrizes-terapeuticas-para-atencao-integral-pessoas-com-infeccoes
http://www.aids.gov.br/pt-br/pub/2015/pr...
,33. Buder S, Schöfer H, Meyer T, Bremer V, Kohl PK, Skaletz-Rorowski A, Brockmeyer N. Bacterial sexually transmitted infections. JDDG: J Deutsch Dermatol Gesellschaft [Internet]. 2019 Mar [cited 2020 Oct 13]; 17(3):287-315. Available from: https://doi.org/10.1111/ddg.13804
https://doi.org/10.1111/ddg.13804...
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The World Health Organization (WHO), through a systematic review study, estimated for the year 2016 the occurrence of 370.4 million new curable urogenital infections by chlamydia, gonorrhea, and trichomoniasis in women and men aged 15 to 4944. Rowley J, Vander Hoorn S, Korenromp E, Low N, Unemo M, Abud-Raddad L, et al. Chlamydia, gonorrhoea, trichomoniasis and syphilis: global prevalence and incidence estimates, 2016. Bull World Health Organ [Internet]. 2019 Aug [cited 2020 Jun 28]; 97(8):548-62. Available from: https://dx.doi.org/10.2471%2FBLT.18.228486
https://doi.org/10.2471%2FBLT.18.228486...
. The global incidence rate of chlamydia in 2016 was 34 cases per 1,000 women and 33 cases per 1,000 men; of gonorrhea, 20 cases per 1,000 women and 26 cases per 1,000 men; and of trichomoniasis, 40 cases per 1,000 women and 42 cases per 1,000 men44. Rowley J, Vander Hoorn S, Korenromp E, Low N, Unemo M, Abud-Raddad L, et al. Chlamydia, gonorrhoea, trichomoniasis and syphilis: global prevalence and incidence estimates, 2016. Bull World Health Organ [Internet]. 2019 Aug [cited 2020 Jun 28]; 97(8):548-62. Available from: https://dx.doi.org/10.2471%2FBLT.18.228486
https://doi.org/10.2471%2FBLT.18.228486...
. A systematic review and meta-analysis study on the prevalence of M. genitalium, which included three studies with 3,809 people, estimated this agent’s prevalence at 1.3% in developed countries and 3.9% in developing countries. The prevalence was similar in men and women55. Baumann L, Cina M, Egli-Gany D, Goutaki M, Halbeisen FS, Lohrer G, et al. Prevalence of Mycoplasma genitalium in different population groups: systematic review andmeta-analysis. Sex Transm Infect [Internet]. 2018 Jun [cited 2020 Jun 28]; 94(4):255-62. Available from: https://doi.org/10.1136/sextrans-2017-053384
https://doi.org/10.1136/sextrans-2017-05...
. Analyses of the European Centre for Disease Prevention and Control (ECDC) found that in 2018, among 17 countries that collected data on the mode of transmission of gonorrhea, 48% of all confirmed and reported cases occurred in men who have sex with men66. European Centre for Disease Prevention and Control - ECDC. Gonorrhoea: annual epidemiological report for 2018 [Internet]. Stockholm: ECDC; 2019 [cited 2020 Oct 13]. 8 p. Available from: https://www.ecdc.europa.eu/sites/default/files/documents/gonorrhoea-annual-epidemiological-report-2018.pdf
https://www.ecdc.europa.eu/sites/default...
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In Brazil, the epidemiological scenario of infections that cause urethral discharge follows the high worldwide rates. It is estimated that the prevalence of gonorrhea in the population between 15 and 49 years of age is approximately 1.4%. The incidence in the general population is around 500,000 new cases per year77. Ministério da Saúde (BR). Secretaria de Ciência, Tecnologia e Insumos Estratégicos. Ceftriaxona 500mg para tratamento da Neisseria gonorrhoeae resistente à ciprofloxacina: relatório de recomendação n. 154 [Internet]. Brasília: Ministério da Saúde; 2015 [cited 2020 out 13]. 29 p. Available from: http://conitec.gov.br/images/Relatorios/2015/Relatorio_Ceftriaxona_Gonorreia_final.pdf
http://conitec.gov.br/images/Relatorios/...
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Regarding the risk of transmission, N. gonorrhea has a chance of transmission from infected man to woman varying from 50% to 73%, regardless of the number of exposures. A man's chance of becoming infected from an infected woman varies from 20% to 35% in an exposure88. Edwards JL, Apicella MA. The molecular mechanisms used by Neisseria gonorrhoeae to initiate infection differ between men and women. Clin Microbiol Rev [Internet]. 2004 Oct [cited 2020 Jun 20]; 17(4):965-81. Available from: https://doi.org/10.1128/cmr.17.4.965-981.2004
https://doi.org/10.1128/cmr.17.4.965-981...
. Unprotected oral sex results in infection about 25% of the time since the pharynx is one of the pathogen's largest asymptomatic reservoirs99. Fuchs W, Brockmeyer NH. Sexually transmitted infections. J Dtsch Dermatol Ges [Internet]. 2014 Jun [cited 2020 Oct 13]; 12(6):451-63. Available from: https://doi.org/10.1111/ddg.12310
https://doi.org/10.1111/ddg.12310...
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In the case of C. trachomatis, the probability of a man contracting the infection from a woman is 32%, and a woman contracting the infection from a man, 40%; this transmission proportion refers to contact with an infected partner through unprotected sex1010. Tu W, Ghosh P, Katz BP. A stochastic model for assessing chlamydia trachomatis transmission risk using longitudinal observational data. J R Stat Soc Ser A Stat Soc [Internet]. 2011 Oct [cited 2020 Oct 13]; 174(4):975-89. Available from: https://doi.org/10.1111/j.1467-985x.2011.00691.x
https://doi.org/10.1111/j.1467-985x.2011...
. Although it is well established that M. genitalium is sexually transmitted, it is not known how many times this occurs per episode of unprotected intercourse1111. Smieszek T, White PJ. Apparently-different clearance rates from cohort studies of mycoplasma genitalium are consistent after accounting for incidence of infection, recurrent infection, and study design. PLoS One [Internet]. 2016 Feb [cited 2020 Oct 13]; 11(2):e0149087. Available from: https://doi.org/10.1371/journal.pone.0149087
https://doi.org/10.1371/journal.pone.014...
. Studies suggest that the transmission of M. genitalium is probably lower than that of C. trachomatis, consistent with these agents' infective load. Men with symptomatic non-gonococcal urethritis and presumably higher loads of M. genitalium are likely to be more infectious than men with asymptomatic infections1212. Thurman AR, Musatovova O, Perdue S, Shain RN, Baseman JG, Baseman JB. Mycoplasma genitalium symptoms, concordance and treatment in high-risk sexual dyads. Int J STD AIDS [Internet]. 2010 Mar [cited 2020 Oct 13]; 21(3):177-83. Available from: https://doi.org/10.1258/ijsa.2009.008485
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,1313. Walker J, Fairley CK, Bradshaw CS, Tabrizi SN, Chen MY, Twin J, et al. The difference in determinants of Chlamydia trachomatis and Mycoplasma genitalium in a sample of young Australian women. BMC Infect Dis [Internet]. 2011 [cited 2020 Oct 13]; 11:35. Available from: https://dx.doi.org/10.1186%2F1471-2334-11-35
https://doi.org/10.1186%2F1471-2334-11-3...
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The risk of men becoming infected from partners infected with T. vaginalis ranges from 22% to 72%. Since there is contamination in up to 5% of people who report recent receptive anal sex, it is necessary to clarify whether the rectum may be a reservoir for T. vaginalis infection1414. Francis SC, Kent CK, Klausner JD, Rauch L, Kohn R, Hardick A, et al. Prevalence of rectal Trichomonas vaginalis and Mycoplasma genitalium in male patients at the San Francisco STD clinic, 2005-2006. Sex Transm Dis [Internet]. 2008 Sep [cited 2020 Jul 10]:35(9):797-800. Available from: https://dx.doi.org/10.1097%2FOLQ.0b013e318177ec39
https://doi.org/10.1097%2FOLQ.0b013e3181...
. According to the Centers for Disease Control and Prevention (CDC), rectal and oral testing for T. vaginalis is not recommended due to the lack of evidence of such infections at these sites.

Figure 1 presents a summary of risks offered by each infectious agent that cause urethral discharge.

FIGURE 1:
Risk of transmission of infectious agents that cause urethral discharge in unprotected sexual practices.

CLINICAL ASPECTS

Urethral discharge is a clinical syndrome characterized by the appearance of discharge ranging from mucoid to purulent, with variable volume, which may be associated with urethral pain (regardless of urination), dysuria, stranguria (slow and painful urination), urethral pruritus, and urethral meatus erythema. Purulent urethral discharge corresponds to 75% of urethritis caused by N. gonorrhoeae and 11% to 33% of non-gonococcal urethritis. In contrast, the mucoid aspect is seen in about 25% of gonococcal urethritis cases and 50% of non-gonococcal urethritis cases22. Ministério da Saúde (BR). Secretaria de Vigilância em Saúde. Departamento de Doenças de Condições Crônicas e Infecções Sexualmente Transmissíveis. Protocolo clínico e diretrizes terapêuticas para atenção integral às pessoas com infecções sexualmente transmissíveis (IST) [Internet]. Brasília: Ministério da Saúde; 2020 [cited 2020 out 13]. 131p. Available from: http://www.aids.gov.br/pt-br/pub/2015/protocolo-clinico-e-diretrizes-terapeuticas-para-atencao-integral-pessoas-com-infeccoes
http://www.aids.gov.br/pt-br/pub/2015/pr...
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Gonococcal urethritis is an infectious and inflammatory process of the urethral mucosa. After the incubation period, which lasts an average of two to five days, ranging from one to 10 days, the infection progresses symptomatically. Dysuria is defined as the sensation of tingling and intraurethral itching followed by pain at urination. The discharge, initially mucoid, becomes purulent in one to two days, with larger volume and accompanied by urethral meatus edema. Some men may present fever, as well as manifestations of an acute systemic infection. About 95% of cases become asymptomatic in three months, and a proportion of untreated patients may evolve to spontaneous healing in a few weeks1515. Penna GO, Hajjar LA, Braz TM. Gonorreia. Rev Soc Bras Med Trop [Internet]. 2000 out [cited 2020 jul 25]; 33(5):451-64. Available from: https://doi.org/10.1590/S0037-86822000000500007
https://doi.org/10.1590/S0037-8682200000...
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The clinical complications from not receiving immediate treatment occur in up to 50% of the cases due to infection progression to the posterior urethra. Acute epididymitis is the most frequent complication and may evolve with epididymal duct's obstruction, determining oligozoospermia, azoospermia, and sterility. Other consequences of gonococcal urethritis are prostatitis, orchitis, penile edema (particularly of the foreskin), balanoposthitis, and also lesions of the sebaceous and acinar glands of the genital region, tysonitis (Tyson glands), cowperitis (Cowper glands), and littritis (Littré glands)1515. Penna GO, Hajjar LA, Braz TM. Gonorreia. Rev Soc Bras Med Trop [Internet]. 2000 out [cited 2020 jul 25]; 33(5):451-64. Available from: https://doi.org/10.1590/S0037-86822000000500007
https://doi.org/10.1590/S0037-8682200000...
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Non-gonococcal urethritis is symptomatic urethritis whose bacterioscopy by Gram staining, culture, and molecular detection of specific nucleic acid is negative for gonococcus. Human chlamydia infection is responsible for approximately 50% of cases of non-gonococcal urethritis. The incubation period in humans is 14 to 21 days. It is estimated that two-thirds of stable female partners of men with non-gonococcal urethritis host C. trachomatis in the endocervix, thus being able to reinfect their sexual partners and evolve into pelvic inflammatory disease if no treatment is carried out1616. Gaydos C, Maldeis NE, Hardick A, Hardick J, Quinn TC. Mycoplasma genitalium compared to chlamydia, gonorrhoea and trichomonas as an aetiological agent of urethritis in men attending STD clinics. Sex Transm Infect [Internet]. 2009 Oct [cited 2020 Jul 25]; 85(6):438-40. Available from: https://doi.org/10.1136/sti.2008.035477
https://doi.org/10.1136/sti.2008.035477...

17. Daley GM, Russell DB, Tabrizi SN, McBride J. Mycoplasma genitalium: a review. Int J STD AIDS [Internet]. 2014 Jun [cited 2020 Jul 25]:25(7):475-87. Available from: https://doi.org/10.1177/0956462413515196
https://doi.org/10.1177/0956462413515196...
-1818. Lis R, Rowhani-Rahbar A, Manhart LE. Mycoplasma genitalium infection and female reproductive tract disease: a meta-analysis. Clin Infect Dis [Internet]. 2015 Aug [cited 2020 Oct 13]; 61(3):418-26. Available from: https://doi.org/10.1093/cid/civ312
https://doi.org/10.1093/cid/civ312...
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In men, non-gonococcal urethritis is usually characterized by discrete mucoid discharge, with slight and intermittent dysuria. Subacute urethritis is the form of presentation in approximately 50% of men with urethritis caused by C. trachomatis1919. Brígido HAZ, Mourão JRM. Corrimentos uretrais. In: Leão RNQ (coord.), Bichara CNC, Fraiha NH, Vasconcelos PFC. Medicina tropical e infectologia da Amazônia. Belém: Samauma Editorial; 2013. p. 245-50.. However, in some cases, discharges from non-gonococcal urethritis can clinically simulate those from gonorrhea. Urethritis caused by C. trachomatis may evolve into prostatitis, epididymitis, balanitis, conjunctivitis (by autoinoculation), urethral-conjunctive-synovial syndrome, or Reiter's syndrome.

Women with urethritis present mild dysuria, which may be accompanied by vaginal discharge or bleeding. Physical examination may reveal the presence of mucopurulent cervicitis or even vulvovaginal herpetic-like lesions2020. Rimawi BH, Soper DE. Infectious diseases of the female reproductive and urinary tract. In: Hacker N, Gambone J, Hobel C. Hacker & Moore's essentials of obstetrics and gynecology [Internet]. Philadelphia: Elsevier; 2016 [cited 2020 Oct 13]. p. 276-90. Available from: http://med-mu.com/wp-content/uploads/2018/07/Hacker-Moore-s-Essentials-of-Obstetrics-and-Gynecology-6E-PDF-UnitedVRG-1-.pdf
http://med-mu.com/wp-content/uploads/201...
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In persistent urethritis cases, the evaluation must be performed mainly through clinical history, considering the possibility of reinfection or inadequate treatment for chlamydia and gonorrhea. If such situations are ruled out, agents not susceptible to the previous treatment (e.g., M. genitalium and T. vaginalis), as well as the occurrence of antimicrobial resistance, must be investigated22. Ministério da Saúde (BR). Secretaria de Vigilância em Saúde. Departamento de Doenças de Condições Crônicas e Infecções Sexualmente Transmissíveis. Protocolo clínico e diretrizes terapêuticas para atenção integral às pessoas com infecções sexualmente transmissíveis (IST) [Internet]. Brasília: Ministério da Saúde; 2020 [cited 2020 out 13]. 131p. Available from: http://www.aids.gov.br/pt-br/pub/2015/protocolo-clinico-e-diretrizes-terapeuticas-para-atencao-integral-pessoas-com-infeccoes
http://www.aids.gov.br/pt-br/pub/2015/pr...
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Other non-infectious causes of urethritis, such as trauma (constant urethral milking), instrumentation, insertion of intraurethral or paraurethral foreign bodies (piercings), and chemical irritation (use of lubricants and spermicides), must be considered in the differential diagnosis of persistent urethritis22. Ministério da Saúde (BR). Secretaria de Vigilância em Saúde. Departamento de Doenças de Condições Crônicas e Infecções Sexualmente Transmissíveis. Protocolo clínico e diretrizes terapêuticas para atenção integral às pessoas com infecções sexualmente transmissíveis (IST) [Internet]. Brasília: Ministério da Saúde; 2020 [cited 2020 out 13]. 131p. Available from: http://www.aids.gov.br/pt-br/pub/2015/protocolo-clinico-e-diretrizes-terapeuticas-para-atencao-integral-pessoas-com-infeccoes
http://www.aids.gov.br/pt-br/pub/2015/pr...
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DIAGNOSIS

The treatment of urethral discharge can be performed through syndromic management for situations where there is no laboratory support22. Ministério da Saúde (BR). Secretaria de Vigilância em Saúde. Departamento de Doenças de Condições Crônicas e Infecções Sexualmente Transmissíveis. Protocolo clínico e diretrizes terapêuticas para atenção integral às pessoas com infecções sexualmente transmissíveis (IST) [Internet]. Brasília: Ministério da Saúde; 2020 [cited 2020 out 13]. 131p. Available from: http://www.aids.gov.br/pt-br/pub/2015/protocolo-clinico-e-diretrizes-terapeuticas-para-atencao-integral-pessoas-com-infeccoes
http://www.aids.gov.br/pt-br/pub/2015/pr...
,2121. Moherdaui F, Vuylsteke B, Siqueira LF, dos Santos Júnior MQ, Jardim ML, de Brito AM, et al. Validation of national algorithms for the diagnosis of sexually transmitted diseases in Brazil: results from a multicentre study. Sex Transm Infect [Internet]. 1998 Jun [cited 2020 Jun 5]; 74(Suppl 1):S38-43. Available from: https://pubmed.ncbi.nlm.nih.gov/10023352/.,2222. Menezes Filho JR, Sardinha JCG, Galbán E, Saraceni V, Talhari C. Effectiveness of syndromic management for male patients with urethral discharge symptoms in Amazonas, Brazil. An Bras Dermatol [Internet]. 2017 Nov-Dec [cited 2020 Jun 3]; 92(6):779-84. Available from: https://doi.org/10.1590/abd1806-4841.20175453.
https://doi.org/10.1590/abd1806-4841.201...
(Figure 2). For cases of male urethral discharge, it is estimated that the syndromic management has a sensitivity ranging from 84% to 95%2323. Wi TE, Ndowa FJ, Ferreyra C, Kelly-Cirino C, Taylor MM, Toskin I, et al. Diagnosing sexually transmitted infections in resource-constrained settings: challenges and ways forward. J Int AIDS Soc [Internet]. 2019 Aug [cited 2020 Jun 20]; 22(Suppl 6):e25343. Available from: https://doi.org/10.1002/jia2.25343.
https://doi.org/10.1002/jia2.25343...
.

FIGURE 2:
Recommendations for management of urethral discharge.

The use of diagnostic tests is indicated for screening asymptomatic urethritis cases and investigating symptomatic patients22. Ministério da Saúde (BR). Secretaria de Vigilância em Saúde. Departamento de Doenças de Condições Crônicas e Infecções Sexualmente Transmissíveis. Protocolo clínico e diretrizes terapêuticas para atenção integral às pessoas com infecções sexualmente transmissíveis (IST) [Internet]. Brasília: Ministério da Saúde; 2020 [cited 2020 out 13]. 131p. Available from: http://www.aids.gov.br/pt-br/pub/2015/protocolo-clinico-e-diretrizes-terapeuticas-para-atencao-integral-pessoas-com-infeccoes
http://www.aids.gov.br/pt-br/pub/2015/pr...
. Good test performance depends on strict compliance with all the manufacturers' steps, including collection, transportation, and storage of samples2424. World Health Organization - WHO. Laboratory diagnosis of sexually transmitted infections, including human immunodeficiency virus [Internet]. Geneva: World Health Organization; 2013 [cited 2020 Jun 20]. 228 p. Available from: https://apps.who.int/iris/bitstream/handle/10665/85343/9789241505840_eng.pdf;jsessionid=89BC7AF948F36261070A5DB66F3CF2BA?sequence=1
https://apps.who.int/iris/bitstream/hand...
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Screening of asymptomatic urethritis cases must be performed using molecular biology techniques, including methods with high sensitivity and specificity, such as polymerase chain reaction and transcription-mediated amplification. These tests, which are based on nucleic acid amplification test (NAAT), allow the usage of male urethral discharge samples or urine, or both, and the identification of one or more pathogens simultaneously in a single sample, depending on the manufacturer. Results are issued discriminating the detected pathogens2424. World Health Organization - WHO. Laboratory diagnosis of sexually transmitted infections, including human immunodeficiency virus [Internet]. Geneva: World Health Organization; 2013 [cited 2020 Jun 20]. 228 p. Available from: https://apps.who.int/iris/bitstream/handle/10665/85343/9789241505840_eng.pdf;jsessionid=89BC7AF948F36261070A5DB66F3CF2BA?sequence=1
https://apps.who.int/iris/bitstream/hand...

25. Taylor-Robinson D. Diagnosis and antimicrobial treatment of Mycoplasma genitalium infection: sobering thoughts. Expert Rev Anti Infect Ther [Internet]. 2014 Jun [cited 2020 Oct 13]; 12(6):715-22. Available from: https://doi.org/10.1586/14787210.2014.919220
https://doi.org/10.1586/14787210.2014.91...

26. Bazzo ML, Golfetto L, Gaspar PC, Pires AF, Ramos MC, Franchini M, et al. First nationwide antimicrobial susceptibility surveillance for Neisseria gonorrhoeae in Brazil, 2015-16. J Antimicrob Chemother [Internet]. 2018 Jul [cited 2020 Jun 12]; 73(7):1854-61. Available from: https://doi.org/10.1093/jac/dky090
https://doi.org/10.1093/jac/dky090...
-2727. Unemo M, Seifert HS, Hook EW, Hawkes S, Ndowa F, Dillon JR. Gonorrhoea. Nat Rev Dis Primers 5 [Internet]. 2019 Nov [cited 2020 Jun 15]; 5(1):79. Available from: https://doi.org/10.1038/s41572-019-0136-6
https://doi.org/10.1038/s41572-019-0136-...
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For symptomatic urethritis, several tests can be helpful to determine the etiological agents22. Ministério da Saúde (BR). Secretaria de Vigilância em Saúde. Departamento de Doenças de Condições Crônicas e Infecções Sexualmente Transmissíveis. Protocolo clínico e diretrizes terapêuticas para atenção integral às pessoas com infecções sexualmente transmissíveis (IST) [Internet]. Brasília: Ministério da Saúde; 2020 [cited 2020 out 13]. 131p. Available from: http://www.aids.gov.br/pt-br/pub/2015/protocolo-clinico-e-diretrizes-terapeuticas-para-atencao-integral-pessoas-com-infeccoes
http://www.aids.gov.br/pt-br/pub/2015/pr...
. Bacterioscopy, culture, and molecular biology methods are incorporated into the Brazilian National Health System (SUS) and are available in a varying manner at different levels of health-care service.

In gonococcal urethritis, intracellular Gram-negative diplococci in polymorphonuclear leukocytes can be visualized by bacterioscopy. This method has high sensitivity and specificity in male urethral discharge samples22. Ministério da Saúde (BR). Secretaria de Vigilância em Saúde. Departamento de Doenças de Condições Crônicas e Infecções Sexualmente Transmissíveis. Protocolo clínico e diretrizes terapêuticas para atenção integral às pessoas com infecções sexualmente transmissíveis (IST) [Internet]. Brasília: Ministério da Saúde; 2020 [cited 2020 out 13]. 131p. Available from: http://www.aids.gov.br/pt-br/pub/2015/protocolo-clinico-e-diretrizes-terapeuticas-para-atencao-integral-pessoas-com-infeccoes
http://www.aids.gov.br/pt-br/pub/2015/pr...
,2424. World Health Organization - WHO. Laboratory diagnosis of sexually transmitted infections, including human immunodeficiency virus [Internet]. Geneva: World Health Organization; 2013 [cited 2020 Jun 20]. 228 p. Available from: https://apps.who.int/iris/bitstream/handle/10665/85343/9789241505840_eng.pdf;jsessionid=89BC7AF948F36261070A5DB66F3CF2BA?sequence=1
https://apps.who.int/iris/bitstream/hand...
,2727. Unemo M, Seifert HS, Hook EW, Hawkes S, Ndowa F, Dillon JR. Gonorrhoea. Nat Rev Dis Primers 5 [Internet]. 2019 Nov [cited 2020 Jun 15]; 5(1):79. Available from: https://doi.org/10.1038/s41572-019-0136-6
https://doi.org/10.1038/s41572-019-0136-...
. Sample culture in selective medium (e.g., Thayer-Martin or similar) is a technique with good sensitivity and high specificity for the diagnosis of N. gonorrhoeae in optimized circumstances with methodological rigor2727. Unemo M, Seifert HS, Hook EW, Hawkes S, Ndowa F, Dillon JR. Gonorrhoea. Nat Rev Dis Primers 5 [Internet]. 2019 Nov [cited 2020 Jun 15]; 5(1):79. Available from: https://doi.org/10.1038/s41572-019-0136-6
https://doi.org/10.1038/s41572-019-0136-...
. Briefly, biological samples are cultivated in selective culture medium for Neisseria sp. As the culture medium also allows the growth of other Neisseria species, it is essential to perform the Gram stain of typical colonies (visualization of Gram-negative diplococci) and oxidase and catalase tests, which should present positive results when it comes to N. gonorrhoeae. For a definitive diagnosis, the colonies may be submitted to biochemical tests (manual or automated) as the particular behavior of bacteria in the presence of several substrates allows the identification of Neisseria species22. Ministério da Saúde (BR). Secretaria de Vigilância em Saúde. Departamento de Doenças de Condições Crônicas e Infecções Sexualmente Transmissíveis. Protocolo clínico e diretrizes terapêuticas para atenção integral às pessoas com infecções sexualmente transmissíveis (IST) [Internet]. Brasília: Ministério da Saúde; 2020 [cited 2020 out 13]. 131p. Available from: http://www.aids.gov.br/pt-br/pub/2015/protocolo-clinico-e-diretrizes-terapeuticas-para-atencao-integral-pessoas-com-infeccoes
http://www.aids.gov.br/pt-br/pub/2015/pr...
,2828. Murray GL, Bradshaw CS, Bissessor M, Danielewski J, Garland SM, Jensen JS, et al. Increasing macrolide and fluoroquinolone resistance in mycoplasma genitalium. Emerg Infect Dis [Internet]. 2017 May [cited 2020 Oct 13]; 23(5):809-12. Available from: https://dx.doi.org/10.3201%2Feid2305.161745
https://doi.org/10.3201%2Feid2305.161745...
,2929. Workowski KA, Bolan GA; Centers for Disease Control and Prevention - CDC. Sexually transmitted diseases treatment guidelines, 2015. MMWR Recomm Rep [Internet]. 2015 Jun [cited 2020 Jun 20]:64(RR-03):1-137. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5885289/.. The culture also allows the investigation of the gonococcus susceptibility profile to antimicrobials employing techniques for determining the minimum inhibitory concentration (MIC) and has great utility for surveillance purposes and establishing treatment guidelines2424. World Health Organization - WHO. Laboratory diagnosis of sexually transmitted infections, including human immunodeficiency virus [Internet]. Geneva: World Health Organization; 2013 [cited 2020 Jun 20]. 228 p. Available from: https://apps.who.int/iris/bitstream/handle/10665/85343/9789241505840_eng.pdf;jsessionid=89BC7AF948F36261070A5DB66F3CF2BA?sequence=1
https://apps.who.int/iris/bitstream/hand...
,2929. Workowski KA, Bolan GA; Centers for Disease Control and Prevention - CDC. Sexually transmitted diseases treatment guidelines, 2015. MMWR Recomm Rep [Internet]. 2015 Jun [cited 2020 Jun 20]:64(RR-03):1-137. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5885289/.. Besides bacterioscopy and culture, molecular biology techniques, such as NAAT, are available in SUS, which present excellent performance for the etiological diagnosis of symptomatic urethritis and are strongly recommended in the etiological treatment of urethral discharge.

In the absence of the methods mentioned above, it is possible to use tests that suggest the presence of infection but do not specify the infectious agent, such as the positive test for leukocyte esterase in first-void urine or the microscopic examination of first-voided urine sediment presenting more than ten polymorphonuclear leukocytes per field (an increase of 1,000 times)22. Ministério da Saúde (BR). Secretaria de Vigilância em Saúde. Departamento de Doenças de Condições Crônicas e Infecções Sexualmente Transmissíveis. Protocolo clínico e diretrizes terapêuticas para atenção integral às pessoas com infecções sexualmente transmissíveis (IST) [Internet]. Brasília: Ministério da Saúde; 2020 [cited 2020 out 13]. 131p. Available from: http://www.aids.gov.br/pt-br/pub/2015/protocolo-clinico-e-diretrizes-terapeuticas-para-atencao-integral-pessoas-com-infeccoes
http://www.aids.gov.br/pt-br/pub/2015/pr...
.

TREATMENT

The recommended treatment for urethritis may or may not depend on laboratory support22. Ministério da Saúde (BR). Secretaria de Vigilância em Saúde. Departamento de Doenças de Condições Crônicas e Infecções Sexualmente Transmissíveis. Protocolo clínico e diretrizes terapêuticas para atenção integral às pessoas com infecções sexualmente transmissíveis (IST) [Internet]. Brasília: Ministério da Saúde; 2020 [cited 2020 out 13]. 131p. Available from: http://www.aids.gov.br/pt-br/pub/2015/protocolo-clinico-e-diretrizes-terapeuticas-para-atencao-integral-pessoas-com-infeccoes
http://www.aids.gov.br/pt-br/pub/2015/pr...
(Figure 2). In the presence of urethral discharge complaints, after anamnesis and physical examination, with confirmed urethral discharge and without laboratory support (urethritis without etiological agent identification), the treatment of chlamydia and gonorrhea with azithromycin 1g orally, single-dose, and ceftriaxone 500mg, intramuscular (IM), single-dose, is indicated. In the possibility of performing bacterioscopy (Gram), with visualization of Gram-negative intracellular diplococci, gonorrhea and chlamydia must be treated as described above (ceftriaxone 500mg, IM, single-dose, and azithromycin 1g, orally, single-dose). The presence of Gram-negative intracellular diplococci indicates a gonococcal infection, but does not exclude the possibility of chlamydia infection. In the absence of these findings, only chlamydia must be treated, with azithromycin 1g orally, single-dose. When biological material collection for culture or molecular biology is possible, this must occur at first consultation. The treatment must be instituted immediately, and test results may be analyzed at return visit22. Ministério da Saúde (BR). Secretaria de Vigilância em Saúde. Departamento de Doenças de Condições Crônicas e Infecções Sexualmente Transmissíveis. Protocolo clínico e diretrizes terapêuticas para atenção integral às pessoas com infecções sexualmente transmissíveis (IST) [Internet]. Brasília: Ministério da Saúde; 2020 [cited 2020 out 13]. 131p. Available from: http://www.aids.gov.br/pt-br/pub/2015/protocolo-clinico-e-diretrizes-terapeuticas-para-atencao-integral-pessoas-com-infeccoes
http://www.aids.gov.br/pt-br/pub/2015/pr...
.

It is noteworthy that, based on results of the SenGono Project 2015-2017 (described in the subtopic Antimicrobial resistance), the Brazilian treatment guideline recommends nationally dual therapy of ceftriaxone 500mg, IM, single-dose, associated with azithromycin 1g, orally, single-dose, for uncomplicated anogenital gonococcal infection (urethra, cervix, and rectum)22. Ministério da Saúde (BR). Secretaria de Vigilância em Saúde. Departamento de Doenças de Condições Crônicas e Infecções Sexualmente Transmissíveis. Protocolo clínico e diretrizes terapêuticas para atenção integral às pessoas com infecções sexualmente transmissíveis (IST) [Internet]. Brasília: Ministério da Saúde; 2020 [cited 2020 out 13]. 131p. Available from: http://www.aids.gov.br/pt-br/pub/2015/protocolo-clinico-e-diretrizes-terapeuticas-para-atencao-integral-pessoas-com-infeccoes
http://www.aids.gov.br/pt-br/pub/2015/pr...
.

After seven days of treatment, an appointment must be made to reassess signs and symptoms and to deliver results of culture or molecular biology tests, or both, when performed. Remission of symptoms characterizes healing. In the persistence of symptoms, it is crucial to exclude reinfection, inadequate treatment for chlamydia and gonorrhea, antimicrobial resistance (mainly related to gonococcus and M. genitalium), trauma, chemical irritation, or insertion of foreign bodies. In addition, T. vaginalis must be treated with metronidazole 500mg, two pills, orally, twice a day, for seven days, and the exams' results must be analyzed to assess the need to institute new treatment in accordance with findings. An appointment for reevaluation must be scheduled after seven days, followed by discharge in the absence of signs and symptoms and referral to specialized services if they persist. Treatment options for urethritis are presented in Figure 3 22. Ministério da Saúde (BR). Secretaria de Vigilância em Saúde. Departamento de Doenças de Condições Crônicas e Infecções Sexualmente Transmissíveis. Protocolo clínico e diretrizes terapêuticas para atenção integral às pessoas com infecções sexualmente transmissíveis (IST) [Internet]. Brasília: Ministério da Saúde; 2020 [cited 2020 out 13]. 131p. Available from: http://www.aids.gov.br/pt-br/pub/2015/protocolo-clinico-e-diretrizes-terapeuticas-para-atencao-integral-pessoas-com-infeccoes
http://www.aids.gov.br/pt-br/pub/2015/pr...
.

FIGURE 3:
Treatment for urethritis.

SURVEILLANCE, PREVENTION, AND CONTROL

STIs are among the most common public health problems in Brazil and the world. Primary health care is the first point for STI care, with preventive actions, diagnosis, timely and adequate treatment, and referral of cases that do not fit this care level. To allow integrality of care, services must be organized to promote access to other care levels when necessary3030. Ministério da Saúde (BR). Secretaria de Atenção à Saúde. Departamento de Atenção Básica. Cadernos de atenção básica: HIV/Aids, hepatites e outras DST [Internet]. Brasília: Ministério da Saúde; 2006 [cited 2020 out 13]. 196 p. Available from: http://bvsms.saude.gov.br/bvs/publicacoes/abcad18.pdf .
http://bvsms.saude.gov.br/bvs/publicacoe...
.

Anamnesis, identification of different vulnerabilities, and physical examination are essential elements in addressing people with STI. To guarantee the quality of assistance, adherence to treatment, and retention at health care service, the health professional needs to establish a relationship of trust with the person with STI, ensuring privacy and information confidentiality. Professionals must be available for dialogue and provide information on health education, addressing issues such as etiological agents of STI, possible forms of transmission, prevention, diagnosis, and the importance of treatment adherence. In addition, definition of a follow-up strategy, attention to sexual partnerships and access to prevention inputs must be ensured3131. Barberá, MJ , Serra-Pladevall J. Infección gonocócica: un problema aún sin resolver. Enferm Infecc Microbiol Clin [Internet]. 2019 Feb [cited 2020 Jun 3]; 37(7):458-66. Available from: https://doi.org/10.1016/j.eimc.2018.12.008..

Prevention and control of STIs that cause urethritis includes the correct usage of condoms during sexual intercourse; regular screening and testing of asymptomatic people in specific populations; investigation and management of symptomatic cases; institution of immediate treatment, when indicated; and treatment of sexual partners. The therapy, besides having a curative function, also aims at interrupting the chain of infection and preventing complications resulting from urethritis22. Ministério da Saúde (BR). Secretaria de Vigilância em Saúde. Departamento de Doenças de Condições Crônicas e Infecções Sexualmente Transmissíveis. Protocolo clínico e diretrizes terapêuticas para atenção integral às pessoas com infecções sexualmente transmissíveis (IST) [Internet]. Brasília: Ministério da Saúde; 2020 [cited 2020 out 13]. 131p. Available from: http://www.aids.gov.br/pt-br/pub/2015/protocolo-clinico-e-diretrizes-terapeuticas-para-atencao-integral-pessoas-com-infeccoes
http://www.aids.gov.br/pt-br/pub/2015/pr...
,3131. Barberá, MJ , Serra-Pladevall J. Infección gonocócica: un problema aún sin resolver. Enferm Infecc Microbiol Clin [Internet]. 2019 Feb [cited 2020 Jun 3]; 37(7):458-66. Available from: https://doi.org/10.1016/j.eimc.2018.12.008..

The screening of gonococcus and chlamydia in asymptomatic people is indicated in the following situations: pregnant women under 30 years old, at the first prenatal visit; people living with HIV, at the time of HIV infection diagnosis; people with indication of post-exposure prophylaxis to HIV; people with STI at the time of diagnosis; people who have suffered sexual violence, at the first visit and the four to six weeks afterward visit; people with receptive (passive) anal sex practice without condom use; and people in the use of pre-exposure prophylaxis to HIV, every six months22. Ministério da Saúde (BR). Secretaria de Vigilância em Saúde. Departamento de Doenças de Condições Crônicas e Infecções Sexualmente Transmissíveis. Protocolo clínico e diretrizes terapêuticas para atenção integral às pessoas com infecções sexualmente transmissíveis (IST) [Internet]. Brasília: Ministério da Saúde; 2020 [cited 2020 out 13]. 131p. Available from: http://www.aids.gov.br/pt-br/pub/2015/protocolo-clinico-e-diretrizes-terapeuticas-para-atencao-integral-pessoas-com-infeccoes
http://www.aids.gov.br/pt-br/pub/2015/pr...
.

It is essential that the sexual contacts of infected people be treated, even when asymptomatic, to interrupt the transmission chain of STIs33. Buder S, Schöfer H, Meyer T, Bremer V, Kohl PK, Skaletz-Rorowski A, Brockmeyer N. Bacterial sexually transmitted infections. JDDG: J Deutsch Dermatol Gesellschaft [Internet]. 2019 Mar [cited 2020 Oct 13]; 17(3):287-315. Available from: https://doi.org/10.1111/ddg.13804
https://doi.org/10.1111/ddg.13804...
. Therefore, this information must be passed on to the person with STI while providing communication and support tools until the end of treatment. Confidentiality, absence of coercion, and protection against discrimination must be guaranteed22. Ministério da Saúde (BR). Secretaria de Vigilância em Saúde. Departamento de Doenças de Condições Crônicas e Infecções Sexualmente Transmissíveis. Protocolo clínico e diretrizes terapêuticas para atenção integral às pessoas com infecções sexualmente transmissíveis (IST) [Internet]. Brasília: Ministério da Saúde; 2020 [cited 2020 out 13]. 131p. Available from: http://www.aids.gov.br/pt-br/pub/2015/protocolo-clinico-e-diretrizes-terapeuticas-para-atencao-integral-pessoas-com-infeccoes
http://www.aids.gov.br/pt-br/pub/2015/pr...
.

In men with gonococcus, C. trachomatis, or M. genitalium infection symptoms, all previous eight weeks sexual partners need to be examined and treated. In asymptomatic cases, this applies to all sexual partners for the past six months33. Buder S, Schöfer H, Meyer T, Bremer V, Kohl PK, Skaletz-Rorowski A, Brockmeyer N. Bacterial sexually transmitted infections. JDDG: J Deutsch Dermatol Gesellschaft [Internet]. 2019 Mar [cited 2020 Oct 13]; 17(3):287-315. Available from: https://doi.org/10.1111/ddg.13804
https://doi.org/10.1111/ddg.13804...
.

Urethritis are not a national compulsory notification condition; however, urethral discharge syndrome is a mandatory notification condition in some Brazilian states. The Brazilian Ministry of Health has also published an ordinance3232. Brasil. Ministério da Saúde. Portaria MS/GM nº 1.553, de 17 de junho de 2020. Altera a Portaria de Consolidação nº 5/GM/MS, de 28 de setembro de 2017, para instituir a Vigilância Sentinela da Síndrome do Corrimento Uretral Masculino (VSCUM) [Internet]. Diário Oficial da União , Brasília (DF), 2020 jun 18 [cited 2020 out 13]; Seção 1:61. Available from: http://bvsms.saude.gov.br/bvs/saudelegis/gm/2020/prt1553_18_06_2020.html .
http://bvsms.saude.gov.br/bvs/saudelegis...
that instituted sentinel surveillance sites for male urethral discharge syndrome, which should provide information for the production of official epidemiological data. Furthermore, the goal is to strengthen actions for prevention of STI that causes urethral discharge, subsidize national recommendations for the treatment of urethral discharge syndrome, monitor the gonococcus susceptibility to antimicrobials with the SenGono Project, and research etiological agents of urethral discharge and the antimicrobial resistance of M. genitalium3333. Ministério da Saúde (BR). Informe semanal sarampo - Brasil, semanas epidemiológicas 1 a 25, 2020. Bol Epidemiol [Internet]. 2020 Jul [cited 2020 out 13]; 51(27). Available from: https://antigo.saude.gov.br/images/pdf/2020/July/09/Boletim-epidemiologico-SVS-27-06.07.2020.pdf .
https://antigo.saude.gov.br/images/pdf/2...
.

Antimicrobial resistance

N. gonorrhoeae has developed progressive resistance to antibiotics throughout the history of antibiotic therapy, from sulfonamides to fluoroquinolones. After the spread of ciprofloxacin resistance, third-generation cephalosporins have been the basis of treatment in association with azithromycin. The emergence of cephalosporin-resistant gonorrhea will negatively impact the ability of professionals to treat gonorrhea effectively. Gonococcus strains considered multi-drug resistant and extensively resistant to drugs are already found in the Americas, Asia, several European countries, and Oceania3434. Allen VG, Mitterni L, Seah C, Rebbapragada A, Martin IE, Lee C, et al. Neisseria gonorrhoeae treatment failure and susceptibility to cefixime in Toronto, Canada. JAMA [Internet]. 2013 Jan [cited 2020 Jun 3]:309(2):163-70. Available from: https://doi.org/10.1001/jama.2012.176575.
https://doi.org/10.1001/jama.2012.176575...

35. Unemo M, Golparian D, Nicholas R, Ohnishi M, Gallay A, Sednaoui P. High-level cefixime- and ceftriaxone-resistant Neisseria gonorrhoeae in France: novel penA mosaic allele in a successful international clone causes treatment failure. Antimicrob Agents Chemother [Internet]. 2012 Mar [cited 2020 Jun 3]:56(3):1273-80. Available from: https://doi.org/10.1128/aac.05760-11
https://doi.org/10.1128/aac.05760-11...

36. Unemo M, Nicholas RA. Emergence of multidrug-resistant, extensively drug-resistant and untreatable gonorrhea. Future Microbiol [Internet]. 2012 Dec [cited 2020 Jun 3]:7(12):1401-22. Available from: https://doi.org/10.2217/fmb.12.117.
https://doi.org/10.2217/fmb.12.117...
-3737. Lewis DA. Global resistance of Neisseria gonorrhoeae: when theory becomes reality. Curr Opin Infect Dis [Internet]. 2014 Feb [cited 2020 Jun 3]:27(1):62-7. Available from: https://doi.org/10.1097/qco.0000000000000025.
https://doi.org/10.1097/qco.000000000000...
. Therefore, it is essential to continuously monitor antibiotic resistance and encourage research and development of new treatment regimens3838. World Health Organization - WHO. Global health sector strategy on Sexually Transmitted Infections, 2016-2021 [Internet]. Geneva: World Health Organization; 2016 [cited 2020 Jun 10]. Available from: https://www.who.int/reproductivehealth/publications/rtis/ghss-stis/en /.
https://www.who.int/reproductivehealth/p...
-3939. Centers for Disease Control and Precention - CDC. Antibiotic resistance threats in the United States, 2019. Atlanta, GA: U.S. Department of Health and Human Services, CDC; 2019 [cited 2020 Oct 13]. Available from: http://www.cdc.gov/DrugResistance/Biggest-Threats.html .
http://www.cdc.gov/DrugResistance/Bigges...
.

In its "Report on Global Sexually Transmitted Infection Surveillance 2018”, WHO prioritizes the control of gonococcal infections due to the imminent possibility of them becoming untreatable4040. Tien V, Punjabi C, Holubar MK. Antimicrobial resistance in sexually transmitted infections. J Travel Med [Internet]. 2020 Feb [cited 2020 Jun 3]; 27(1):taz101. Available from: https://doi.org/10.1093/jtm/taz101.
https://doi.org/10.1093/jtm/taz101...
-4141. World Health Organization - WHO. Report on global sexually transmitted infection surveillance [Internet]. Geneva: World Health Organization; 2018 [cited 2020 Jun 7]. Available from: https://www.who.int/reproductivehealth/publications/stis-surveillance-2018/en/ .
https://www.who.int/reproductivehealth/p...
. Brazil is one of the member countries of global gonococcus susceptibility surveillance program (Gonococcal Antimicrobial Surveillance Programme, GASP)4242. World Health Organization - WHO. The gonococcal antimicrobial surveillance programme (GASP) [Internet]. Geneva: World Health Organization; 2020 [cited 2020 Jun 15]. Available from: https://www.who.int/reproductivehealth/topics/rtis/gonococcal_resistance/en /.
https://www.who.int/reproductivehealth/t...
. The activities of GASP in Brazil take place within the SenGono Project, that consists a cooperation between the Ministry of Health, the National Reference Laboratory (Molecular Biology, Microbiology and Serology Laboratory of the Federal University of Santa Catarina), and sentinel sites distributed throughout the country (Figure 4)3333. Ministério da Saúde (BR). Informe semanal sarampo - Brasil, semanas epidemiológicas 1 a 25, 2020. Bol Epidemiol [Internet]. 2020 Jul [cited 2020 out 13]; 51(27). Available from: https://antigo.saude.gov.br/images/pdf/2020/July/09/Boletim-epidemiologico-SVS-27-06.07.2020.pdf .
https://antigo.saude.gov.br/images/pdf/2...
.

FIGURE 4:
Functions of the Ministry of Health, the National Reference Laboratory, and the Sentinel Sites under the SenGono Project.

In the first edition, from 2015 to 2017, high resistance to ciprofloxacin, close to and even higher than 50%, and high susceptibility to third-generation cephalosporins (cefixime and ceftriaxone) were observed in all country's regions2626. Bazzo ML, Golfetto L, Gaspar PC, Pires AF, Ramos MC, Franchini M, et al. First nationwide antimicrobial susceptibility surveillance for Neisseria gonorrhoeae in Brazil, 2015-16. J Antimicrob Chemother [Internet]. 2018 Jul [cited 2020 Jun 12]; 73(7):1854-61. Available from: https://doi.org/10.1093/jac/dky090
https://doi.org/10.1093/jac/dky090...
.

The surveillance performed in the SenGono Project has integrated the "National Plan to Combat Antimicrobial Resistance 2019-2023", and is in its second edition (2018-2020), with the expansion to new sentinel sites and evaluation of gonococcus susceptibility to two new antimicrobials (spectinomycin and gentamicin). Also, determination of male urethral discharge etiology and investigation of antimicrobial resistance of M. genitalium have been incorporated into this edition3333. Ministério da Saúde (BR). Informe semanal sarampo - Brasil, semanas epidemiológicas 1 a 25, 2020. Bol Epidemiol [Internet]. 2020 Jul [cited 2020 out 13]; 51(27). Available from: https://antigo.saude.gov.br/images/pdf/2020/July/09/Boletim-epidemiologico-SVS-27-06.07.2020.pdf .
https://antigo.saude.gov.br/images/pdf/2...
.

M. genitalium was first identified in 1980 and recognized as an important cause of non-gonococcal urethritis2525. Taylor-Robinson D. Diagnosis and antimicrobial treatment of Mycoplasma genitalium infection: sobering thoughts. Expert Rev Anti Infect Ther [Internet]. 2014 Jun [cited 2020 Oct 13]; 12(6):715-22. Available from: https://doi.org/10.1586/14787210.2014.919220
https://doi.org/10.1586/14787210.2014.91...
,4343. Horner P, Blee K, Adams E. Time to manage Mycoplasma genitalium as an STI: but not with azithromycin 1 g!. Curr Opin Infect Dis [Internet]. 2014 Feb [cited 2020 Oct 13]; 27(1):68-74. Available from: https://doi.org/10.1097/qco.0000000000000030.
https://doi.org/10.1097/qco.000000000000...

44. Manhart LE, Jensen JS, Bradshaw CS, Golden MR, Martin DH. Efficacy of antimicrobial therapy for mycoplasma genitalium infections. Clin Infec Dis [Internet]. 2015 Dec [cited 2020 Oct 13]; 61(Suppl 8):S802-17. Available from: https://doi.org/10.1093/cid/civ785.
https://doi.org/10.1093/cid/civ785...
-4545. Birger R, Saunders J, Estcourt C, Sutton AJ, Mercer CH, Roberts T, et al. Should we screen for the sexually-transmitted infection Mycoplasma genitalium? Evidence synthesis using a transmission-dynamic model. Sci Rep [Internet]. 2017 Nov [cited 2020 Oct 13]; 7(1):16162. Available from: https://dx.doi.org/10.1038%2Fs41598-017-16302-8.
https://doi.org/10.1038%2Fs41598-017-163...
. Because the bacteria has no cell wall, antibiotics such as beta-lactams (including penicillins and cephalosporins) are not effective2929. Workowski KA, Bolan GA; Centers for Disease Control and Prevention - CDC. Sexually transmitted diseases treatment guidelines, 2015. MMWR Recomm Rep [Internet]. 2015 Jun [cited 2020 Jun 20]:64(RR-03):1-137. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5885289/.. The introduction of azithromycin, used as single-dose therapy for chlamydia infections, has resulted in clearance of M. genitalium from the urogenital tract, eliminating the pathogen without the disease development2525. Taylor-Robinson D. Diagnosis and antimicrobial treatment of Mycoplasma genitalium infection: sobering thoughts. Expert Rev Anti Infect Ther [Internet]. 2014 Jun [cited 2020 Oct 13]; 12(6):715-22. Available from: https://doi.org/10.1586/14787210.2014.919220
https://doi.org/10.1586/14787210.2014.91...
,4343. Horner P, Blee K, Adams E. Time to manage Mycoplasma genitalium as an STI: but not with azithromycin 1 g!. Curr Opin Infect Dis [Internet]. 2014 Feb [cited 2020 Oct 13]; 27(1):68-74. Available from: https://doi.org/10.1097/qco.0000000000000030.
https://doi.org/10.1097/qco.000000000000...
,4646. Kikuchi M, Ito S, Yasuda M, Tsuchiya T, Hatazaki K, Takanashi M, et al. Remarkable increase in fluoroquinolone-resistant Mycoplasma genitalium in Japan. J Antimicrob Chemother [Internet]. 2014 Sep [cited 2020 Oct 13]; 69(9):2376-82. Available from: https://doi.org/10.1093/jac/dku164.
https://doi.org/10.1093/jac/dku164...

47. Salado-Rasmussen K, Jensen JS. Mycoplasma genitalium testing pattern and macrolide resistance: a Danish nationwide retrospective survey. Clin Infect Dis [Internet]. 2014 Jul [cited 2020 Oct 13]; 59(1):24-30. Available from: https://doi.org/10.1093/cid/ciu217.
https://doi.org/10.1093/cid/ciu217...

48. Jensen JS, Bradshaw C. Management of mycoplasma genitalium infections - can we hit a moving target? BMC Infect Dis [Internet]. 2015 Aug [cited 2020 Oct 13]; 15:343. Available from: https://doi.org/10.1186/s12879-015-1041-6.
https://doi.org/10.1186/s12879-015-1041-...

49. Sethi S, Zaman K, Jain N. Mycoplasma genitalium infections: current treatment options and resistance issues. Infect Drug Resist [Internet]. 2017 Sep [cited 2020 Oct 13]; 10:283-92. Available from: https://dx.doi.org/10.2147%2FIDR.S105469.
https://doi.org/10.2147%2FIDR.S105469...
-5050. Bissessor M, Tabrizi SN, Twin J, Abdo H, Fairley CK, Chen MY, et al. Macrolide resistance and azithromycin failure in a Mycoplasma genitalium-infected cohort and response of azithromycin failures to alternative antibiotic regimens. Clin Infect Dis [Internet]. 2015 Apr [cited 2020 Oct 13]; 60(8):1228-36. Available from: https://doi.org/10.1093/cid/ciu1162.
https://doi.org/10.1093/cid/ciu1162...
. However, recent studies indicate an upward trend in prevalence of macrolide-resistant M. genitalium infections (transmitted resistance) and cases of induced resistance after azithromycin therapy33. Buder S, Schöfer H, Meyer T, Bremer V, Kohl PK, Skaletz-Rorowski A, Brockmeyer N. Bacterial sexually transmitted infections. JDDG: J Deutsch Dermatol Gesellschaft [Internet]. 2019 Mar [cited 2020 Oct 13]; 17(3):287-315. Available from: https://doi.org/10.1111/ddg.13804
https://doi.org/10.1111/ddg.13804...
,4343. Horner P, Blee K, Adams E. Time to manage Mycoplasma genitalium as an STI: but not with azithromycin 1 g!. Curr Opin Infect Dis [Internet]. 2014 Feb [cited 2020 Oct 13]; 27(1):68-74. Available from: https://doi.org/10.1097/qco.0000000000000030.
https://doi.org/10.1097/qco.000000000000...
,5050. Bissessor M, Tabrizi SN, Twin J, Abdo H, Fairley CK, Chen MY, et al. Macrolide resistance and azithromycin failure in a Mycoplasma genitalium-infected cohort and response of azithromycin failures to alternative antibiotic regimens. Clin Infect Dis [Internet]. 2015 Apr [cited 2020 Oct 13]; 60(8):1228-36. Available from: https://doi.org/10.1093/cid/ciu1162.
https://doi.org/10.1093/cid/ciu1162...
. There is no evidence that azithromycin extended regimen (1.5g) is superior to a single-dose 1g regimen5151. Read TR, Fairley CK, Tabrizi SN, Bissessor M, Vodstrcil L, Chen MY, et al. Azithromycin 1.5g over 5 days compared to 1g single dose in urethral mycoplasma genitalium: impact on treatment outcome and resistance. Clin Infect Dis [Internet]. 2017 Feb [cited 2020 Oct 13]; 64(3):250-6. Available from: https://doi.org/10.1093/cid/ciw719.
https://doi.org/10.1093/cid/ciw719...
. Moxifloxacin remains highly active against most macrolide-resistant M. genitalium strains. However, first clinical cases of moxifloxacin treatment failure have been published33. Buder S, Schöfer H, Meyer T, Bremer V, Kohl PK, Skaletz-Rorowski A, Brockmeyer N. Bacterial sexually transmitted infections. JDDG: J Deutsch Dermatol Gesellschaft [Internet]. 2019 Mar [cited 2020 Oct 13]; 17(3):287-315. Available from: https://doi.org/10.1111/ddg.13804
https://doi.org/10.1111/ddg.13804...
,2828. Murray GL, Bradshaw CS, Bissessor M, Danielewski J, Garland SM, Jensen JS, et al. Increasing macrolide and fluoroquinolone resistance in mycoplasma genitalium. Emerg Infect Dis [Internet]. 2017 May [cited 2020 Oct 13]; 23(5):809-12. Available from: https://dx.doi.org/10.3201%2Feid2305.161745
https://doi.org/10.3201%2Feid2305.161745...
,4343. Horner P, Blee K, Adams E. Time to manage Mycoplasma genitalium as an STI: but not with azithromycin 1 g!. Curr Opin Infect Dis [Internet]. 2014 Feb [cited 2020 Oct 13]; 27(1):68-74. Available from: https://doi.org/10.1097/qco.0000000000000030.
https://doi.org/10.1097/qco.000000000000...
,4444. Manhart LE, Jensen JS, Bradshaw CS, Golden MR, Martin DH. Efficacy of antimicrobial therapy for mycoplasma genitalium infections. Clin Infec Dis [Internet]. 2015 Dec [cited 2020 Oct 13]; 61(Suppl 8):S802-17. Available from: https://doi.org/10.1093/cid/civ785.
https://doi.org/10.1093/cid/civ785...
,5050. Bissessor M, Tabrizi SN, Twin J, Abdo H, Fairley CK, Chen MY, et al. Macrolide resistance and azithromycin failure in a Mycoplasma genitalium-infected cohort and response of azithromycin failures to alternative antibiotic regimens. Clin Infect Dis [Internet]. 2015 Apr [cited 2020 Oct 13]; 60(8):1228-36. Available from: https://doi.org/10.1093/cid/ciu1162.
https://doi.org/10.1093/cid/ciu1162...

51. Read TR, Fairley CK, Tabrizi SN, Bissessor M, Vodstrcil L, Chen MY, et al. Azithromycin 1.5g over 5 days compared to 1g single dose in urethral mycoplasma genitalium: impact on treatment outcome and resistance. Clin Infect Dis [Internet]. 2017 Feb [cited 2020 Oct 13]; 64(3):250-6. Available from: https://doi.org/10.1093/cid/ciw719.
https://doi.org/10.1093/cid/ciw719...

52. Dionne-Odom J, Geisler WM, Aaron KJ, Waites KB, Westfall AO, Van Der Pol B, et.al. High prevalence of multidrug-resistant mycoplasma genitalium in human immunodeficiency virus-infected men who have sex with men in Alabama. Clin Infect Dis [Internet]. 2018 Feb [cited 2020 Oct 13]; 66(5):796-8. Available from: https://doi.org/10.1093/cid/cix853
https://doi.org/10.1093/cid/cix853...
-5353. Gratrix J, Plitt S, Turnbull L, Smyczek P, Brandley J, Scarrott R, et al. Prevalence and antibiotic resistance of Mycoplasma genitalium among STI clinic attendees in western Canada: a cross-sectional analysis. BMJ Open [Internet]. 2017 Jul [cited 2020 Oct 13]; 7(7):e016300. Available from: https://doi.org/10.1136/bmjopen-2017-016300
https://doi.org/10.1136/bmjopen-2017-016...
. Therefore, M. genitalium is an emerging problem, requiring frequent surveillance and studies with new diagnostic and treatment options2727. Unemo M, Seifert HS, Hook EW, Hawkes S, Ndowa F, Dillon JR. Gonorrhoea. Nat Rev Dis Primers 5 [Internet]. 2019 Nov [cited 2020 Jun 15]; 5(1):79. Available from: https://doi.org/10.1038/s41572-019-0136-6
https://doi.org/10.1038/s41572-019-0136-...
.

The increase in resistance during recent decades reinforces the importance of etiological diagnosis and adoption of appropriate treatments. In 2016, the World Health Assembly adopted the "Global health sector strategy on Sexually Transmitted Infections, 2016-2021"3838. World Health Organization - WHO. Global health sector strategy on Sexually Transmitted Infections, 2016-2021 [Internet]. Geneva: World Health Organization; 2016 [cited 2020 Jun 10]. Available from: https://www.who.int/reproductivehealth/publications/rtis/ghss-stis/en /.
https://www.who.int/reproductivehealth/p...
. This strategy includes the rapid expansion of evidence-based interventions and services to eliminate STI as a public health concern by 2030.

ACKNOWLEDGMENTS

The authors thank the technical group of experts responsible for developing the Clinical Protocol and Therapeutic Guidelines for Comprehensive Care for People with STI in 2020 for their substantial contribution to this work.

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Publication Dates

  • Publication in this collection
    17 May 2021
  • Date of issue
    2021

History

  • Received
    01 Feb 2021
  • Accepted
    10 Mar 2021
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