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Revista Colombiana de Obstetricia y Ginecología

Print version ISSN 0034-7434

Rev Colomb Obstet Ginecol vol.64 no.2 Bogotá Jan./June 2013

 

Clinical practice guideline for syndromic management of patients with sexually transmitted infections and other genital tract infections - 2013

Guía de práctica clínica para el manejo sindrómico de los pacientes con infecciones de transmisión sexual y otras infecciones del tracto genital - 2013

Hernando Guillermo Gaitán-Duarte, MD, MSc.1, Andrea Esperanza Rodríguez-Hernández, MD, MSc.2, Ingrid Arévalo-Rodríguez, PSc3, Edith Angel-Müller, MD.4, Hugo Enrique López-Ramos, MD Msc(c).5, Jesús Santiago Estrada-Mesa, MD.6 Syndromic management of STI and other GTI guideline development group*

Received: 10 June 2012 - Accepted: 11 June 2013

1 Hernando Guillermo Gaitán-Duarte, MD, MSc in Clinical Epidemiology, Professor in the Universidad Nacional de Colombia’s Faculty of Medicine’s Obstetrics and Gynaecology Department and Clinical Research Institute, Coordinator Sexually Transmitted Infection. Cochrane Review Group.

2 Andrea Esperanza Rodríguez Hernández, MD, specialist in Applied Statistics, MSc in Clinical Epidemiology, assistant teacher in the Universidad Nacional de Colombia. Clinical Research Institute, the Guidelines’ Methodological Coordinator.

3 Ingrid Arévalo Rodríguez, Psychologist, MSc Clinical Epidemiology, Universidad Nacional de Colombia, PhD (c) in Paediatrics, Obstetrics and Gynaecology, Preventative Medicine and Public Health, Universidad Autónoma, Barcelona.

4 Edith Angel Müller, MD, Fellow in Gyneco-obstetrics and Perinatal Infectology, Associate Professor Universidad Nacional de Colombia’s Obstetrics and Gynaecology Department, Federación Colombiana de Obstetricia y Ginecología (FECOLSOG) representative, member of the Sexually-Transmitted Infections Cochrane Review Group’s Editorial Committee.

5 Hugo Enrique López Ramos, MD, in Clinical Epidemiology (c), member of the Colombia society of Urology representative for preparing the guidelines.

6 Jesús Santiago Estrada Mesa, MD, Specialist in Microbiology and Parasitology. Clinical laboratory Director Obra de la Congregación Mariana, Medellin, Colombia. Asociación Colombiana de Infectología (ACIN) representative.

*Syndromic management of STI and other GTI guideline development group. Full list of collaborators at the end of the document

ABSTRACT

Objective: To reduce practice variability in the management of genital tract and sexuallytransmitted infections (GTI/STI) and provide health care practitioners caring for GTI/STI patients with the most recent evidence regarding the effectiveness and safety of primary, secondary and tertiary prevention interventions alongside creating indicators for tracking the implementation of the guidelines and their impact on public health.

Materials and methods: A multidisciplinary development team was set up consisting of professionals in health care and patient representatives. Relevant clinical questions were posed and a search was made of the national and international guideline data-bases. Existing guidelines were evaluated for quality and applicability. None of the guidelines met the criteria for adaptation, therefore it was decided to develop de novo guidelines. The Pubmed, Ovid, Embase, Cochrane and Lilacs databases were searched for systematic reviews and meta-analyses, clinical trials and observational studies. Tables of evidence and recommendations were prepared using the GRADE approach based on informal and formal consensus methodology.

Results: The “Clinical Practice Guidelines” we reproduced, including recommendations and supporting evidence for prevention, diagnosis and treatment in terms of effectiveness and safety, and follow-up for cervicitis, urethritis, genital ulcers, vaginal discharge, scrotal inflammation and inguinal buboes.

Conclusions: The guideline’s core recommendation concerns patient management using a single dose and expedited patient treatment regarding sexual partners whenever possible. The guidelines must be updated in three years.

Key words: Clinical practice guidelines, sexually-transmitted infection, reproductive tract infection, cervicitis, urethritis, vaginal discharge, genital ulcer.

PROPOSAL AND SCOPE

The current guidelines are aimed at supporting clinicians/personnel providing health care for patients of both genders who may be susceptible to contracting/presenting sexually-transmitted infections (STI) and other genital tract infections (GTI). Genital tract infections arising from medical/ surgical procedures were not included.

Recommendations were made for primary, secondary and tertiary health care levels. The primary level would involve prevention, risk assessment, early detection, and initial management and reference action. Secondary and tertiary levels would involve the management of STI/GTI complications as well as advice on preventing relapses or chronicity (secondary prevention). Managing specific conditions by sub-specialists recommendations are not covered within the scope of these guidelines.

The guidelines target the 14 to 74 year-old population residing in Colombia, regardless of a patient’s health insurance scheme or whether a patient actually has health insurance.

As well as reducing variability regarding current practice in managing of GTI and STI, these guidelines are aimed at supporting health care personnel attending GTI/STI patients using the most recent evidence available regarding the effectiveness and safety of primary, secondary and tertiary prevention interventions. They also seek to cut the STI transmission chain, reduce the burden of disease associated with GTI/STI in Colombia and provide indicators for implementing such guidelines and for their impact on public health.

The syndromes accompanying genital tract conditions (the target for these guidelines) are the following:

1. Cervical infection syndrome (females).

2. Urethral discharge syndrome (males and females).

3. Genital ulcer syndrome (males and females).

4. Vaginal discharge syndrome (females).

5. Scrotal inflammation syndrome (males).

6. Inguinal bubo syndrome (males and females).

The guidelines for managing pelvic inflammatory disease/disorder (PID) will be published separately because it follows a different methodological adaptation (i.e. not de novo like the aforementioned syndromes). These clinical practice guidelines update the Guidelines for Attending Sexually-Transmitted Diseases form an aging sexually-transmitted infections published in line with Colombian Ministry of Health Resolution 412 which proposed a syndromic approach to people suffering STI/GTI syndromes (1).

INTRODUCTION TO AND JUSTIFICACTION FOR THE GUIDELINES

GTI are caused by microorganisms which are normally present in the reproductive tract or went it have been introduced for sexual contact or during medical-surgical procedures. They affect both females and males (2, 3). GTI not sexually transmitted are more common in females, particularly bacterial vaginosis (BV), a type of vaginal infection which is more common amongst reproductive aged females and which also represents the commonest cause of vaginal discharge, followed by Candida albicans (4, 5). STI are caused by different organisms: bacteria such as Neisseria gonorrhoeae and Chlamydia trachomatis, protozoa such as Trichomonas vaginalis and viruses such as herpes simplex virus (HSV), human immune deficiency virus (HIV) and human papilloma virus (HPV)(4).

GTI and STI frequently present with symptoms such increased vaginal secretion, urethral secretion, genital ulcers, pruritus, irritation, the presence of foetid odour or pelvic pain (6, 7). The signs and symptoms of infection have been grouped into the aforementioned clinical syndromes, following the supposition that they are caused by groups of specific organisms and that such grouping will lead to greater effectiveness in diagnosis and treatment. This should ideally occur during a patient’s first contact with the health care services, especially when there is no access to laboratory services. The World Health Organisation (WHO) has recommended a syndromic management approach to treating STI and GTI (8).

The female syndromes proposed are vaginal discharge syndrome, which includes vaginitis caused by Candida sp, Trichomonas vaginalis and bacterial vaginosis; the cervicitis syndrome mainly caused by Neisseria gonorroheae, Chlamydia trachomatis and finally pelvic inflammatory disease (PID) syndrome caused by Neisseria gonorroheae, Chlamydia trachomatis, mycoplasma (9) and anaerobic organisms gaining access to the upper genital tract (10). The scrotal inflammation syndrome caused by Neisseria gonorroheae, Chlamydia trachomatis and gram-negative bacteria (9) are proposed in males. Syndromes affecting both sexes include the genital ulcer syndrome caused by Treponema pallidum, Haemophilus ducreyi, Chlamydia trachomatis serotypes 1, 2 and 3, Klebsiella granulomatis and Herpes simplex virus, the inguinal bubo syndrome caused by Chlamydia trachomatis and Haemophilus ducreyi and the urethral discharge syndrome caused by Neisseria gonorrhoeae, Chlamydia trachomatis and Trichomonas vaginalis (9).

STI represent one of the main causes of morbidity in developing countries and carries a significant burden, both socially and financially to the country’s health care system and its patients (11). A report dealing with STI in Colombia 1976-2000 concerned itself almost exclusively with the HIV/AIDS situation, reporting 406,722 years of potential life lost (YPLL) between 1991 and 1998 (12). The years of life lost and disability-adjusted life years (DALYs) due to STI (excluding HIV/AIDS) are secondary to the following complications: cancer (13), pelvic inflammatory disease (PID), pregnancy, infertility, chronic pelvic pain, complications of pregnancy such as ectopic pregnancy, chorioamnionitis or puerperal infection (11) and epididimitis and prostatitis in males (14). It is known that communities that have members who maintain an asymptomatic STI carrier state are associated with increased transmission and recurrence of community-acquired STI (11). Therefore greater importance should be given to identifying at-risk behaviour regarding STI transmission, alongside prevention, detection and management, including the treatment of sexual contacts/partners (8).

The available clinical practice guidelines for GTI/STI and their syndromic treatment will provide health care administrators and professionals throughout Colombia with unified, evidence based, cost-effective tool to help guide optimal care of GTI/STI patients in all health care settings.

MATERIALS AND METHODS

The Guideline Development Group (GDG) consisted of experts in STI, clinical epidemiology, primary attention, urologists, infectologists, gynaecologists, psychologists, nurses, pharmacists, communicators and experts on the topics of public health and policy design. Patient’s representatives were also included who gave their opinions during the different phases involved in developing the guidelines.

Once the clinical questions had been formulated, the GDG performed a systematic search of clinical practice guidelines (CPG) orientated towards identifying currently available national and international CPG. The systematic search for CPG was undertaken with the support of the Sexually trasmitted infections Cochrane review group at the following sites: AHRQ-Clearing house, NHS, Guia Salud, Guidelines International Network, Scottish Intercollegiate Guidelines Network, National Institute for Clinical Excellence, Australian National Health and Medical Research Council, New Zealand Guidelines Group, World Health Organisation, Pan-American Health Organisation, TRIP database, Medline via PubMed, Lilacs via BVS (Biblioteca Virtual de la Salud). A search was also made of grey literature and the web pages of the various region’s Ministries of Health via Google. The following terms were used in the search: Sexual* transmit* infection*; Sexual* transmit* disease*; Venereal*; STD*; enfermedades de transmisión sexual, using filters (Medline) “Practice Guideline”[ptyp] OR practice guideline*[tiab] OR guideline*[ti] OR recommendation*[ti] OR “Practice guidelines as topic” [MeSH].

The AGREE II instrument for evaluating the quality of the guidelines was utilised. The only guideline that was of relevance and fulfilled the quality criteria was that GPC for Pelvic inflammatory Disease of the Royal College of Obstetricians and Gynaecologists (RCOG). Therefore, it was decided to adapt this CPG and develop de novo guidelines regarding the other aforementioned syndromes. A search of systematic reviews and meta-analyses from the last 10 years was performed with the support of Sexually transmitted infections Cochrane review group on Pubmed, Ovid, Embase, Cochrane Library and Lilacs databases. No articles were identified within this timeframe, so the timeframe was broadened. Systematic reviews were assessed for quality using the AMSTAR tool. For clinical questions that were not addressed by SRs, or where available SRs were of inadequate quality, a search of primary studies was performed, initially looking for clinical trials (CT), followed by cohort, cases and control and descriptive studies. These trials and studies were evaluated using the Scottish Intercollegiate Guidelines Network (SIGN) tools. It was necessary to refer to recommendations made by other CPG for some topics (mainly low prevalence infections as the published evidence was extremely scarce). The evidence tables were prepared using GRADEpro software (version 3.6); the levels of evidence were rated according to GRADE classification (15) (table 1).

Informal expert consensus was taken for preparing the recommendations. The GRADE method was used for preparing and rating the recommendations. The quality of the evidence, the risk-benefit balance, the costs and patients’ preferences were also taken into account when doing this (16). The clinical questions for which recommendations could not be produced by informal consensus were submitted to experts formal consensus (Table 2).

on polyurethane and other synthetic materials which provide effective protection against STI and unwanted pregnancy, having similar effectiveness to that of latex condoms (20). These condoms can be used by people who are allergic to latex. Natural membrane condoms made from animal tissue have 1,500 nm diameter pores which, in spite of not allowing sperm to pass, have a greater diameter than HIV and HBV, thereby allowing sexuallytransmitted viral diseases to become acquired (20). Therefore use of natural membrane condoms is not recommended for preventing STI (4) (level of evidence: very low).

GENERAL RECOMMENDATIONS

1. How should patients identified as being at highly likely of suffering from a GTI/STI be managed?

The effectiveness of syndromic management regarding an STI/GTI. Few clinical studies have evaluated the effectiveness of syndromic management of GTI/STI. A community-based randomised clinical trial has shown that a syndromic approach reduced the incidence ofactive syphilis (RR 0.58: 0.35–0.9695% IC) and the prevalence of infection caused by N. Gonorrhoeae (RR 0.28: 0.11–0.7095% IC) compared to other community strategies form an aging STI/GTI at population level (17). However, this was not statistically significant for C. Trachomatis infection (RR 0.99: 0.71–1.3995% CI). Grosskurth et al., carried out a clinical study involving 8,845 patients, and found that syndromic management reduced the incidence of HIV(RR 0.58: 0.42-0.7995% IC) (18), however, a reduction in the incidence and prevalence of other STI was not observed. There were flaws in this particular study, including sample size and only being selective in males (level of evidence: moderate).

2. How should care be provided to a patient consulting due to symptoms of GTI/STI?

This recommendation was made by the group of national experts (level of evidence: very low)

3. Which are the most effective population strategies for preventing STI/GTI?

Counselling: Family planning consultations can be utilised as opportunities to explore sexual health risk taking behaviour in patients. Patients involved in high risk behaviours should be offered advice, information and an examination for STI. Advice should include strategies for reducing the risk of contracting STI, such as abstinence, using a condom, limiting the number of sexual partners, modifying sexual practice and vaccination. Counselling should be empathetic and unprejudiced. Such an approach should be adopted by all health care-related professionals; extensive training is not required as a prerequisite, but the quality of counselling improves when the provider has received some training and has developed the necessary inter-personal skills (4) (Level of evidence: very low).

Preexposure vaccination: Pre-exposure vaccination represents one of the most effective strategies for preventing the transmission of some STI. Two vaccines against VPH and one against hepatitis B are currently available. Vaccination strategies and schemes do not come within the scope of these guidelines; however, readers are invited to consult the respective Guideline (4).

Male condom: The male condom is highly effective in preventing STI when used consistently and correctly. However it has been demonstrated that using a condom as part of population policy for preventing STI does reduce the prevalence of syphilis, Neisseria gonorrhoeae and Trichomonas vaginalis (19). The failure rate of condoms for protecting against STI or unwanted pregnancy is likely secondary to its inconsistent or incorrect use, rather than it rupturing (4). The male condom is usually made of latex; other condoms are based on polyurethane and other synthetic materials which provide effective protection against STI and unwanted pregnancy, having similar effectiveness to that of latex condoms (20). These condoms can be used by people who are allergic to latex. Natural membrane condoms made from animal tissue have 1,500 nm diameter pores which, in spite of not allowing sperm to pass, have a greater diameter than HIV and HBV, thereby allowing sexuallytransmitted viral diseases to become acquired (20). Therefore use of natural membrane condoms is not recommended for preventing STI (4) (level of evidence: very low).

Female condom: Sexual partners should consider using a female condom when a male condom cannot be used correctly or consistently. The female condom can be used for protecting against STI during receptive anal relations (21) (level of evidence: very low).

Nonoxinol 9: A systematic review of the literature (22) evaluated the safety and effectiveness when compared to a placebo, of nonoxinol-9 (N-9) for preventing any type of sexually-transmitted disease (except HIV) in females. The review included ten controlled clinical trials (5,909 patients). The review had an AMSTAR score of 9/11. The meta-analysis had a low risk of bias but high heterogeneity. No statistically significant differences were found regarding the risk of acquiring infection due to N. Gonorrhoeae (RR 0.91: 0.67-1.2495% CI), cervicitis (RR 1.01: 0.84-1.2295% CI), Trichomonas vaginalis (RR 0.84: 0.69-1.0295% CI), Chlamydia trachomatis (RR 0.88: 0.77-1.0195% CI), BV (RR 0.88: 0.74-1.0495% CI) or Candida sp. (RR 0.97: 0.84-1.1295% CI). The females who were receiving N-9, compared to those receiving the placebo, had greater genital lesion frequency (RR 1.17: 1.021.3595% CI). There is evidence that N-9 does not protect against STI and that it could be harmful as it increases the genital ulcer rate; this product cannot be recommended alone or in spermicides for preventing STI (level of evidence: moderate).

Contraceptive methods lacking a mechanical barrier do not provide protection against HIV and/or other STI. Sexually-active females using hormonal methods, an intrauterine device (IUD), who have undergone surgical sterilisation or have had a hysterectomy, should be counselled regarding the risk of acquiring STI and condom use. Genital hygiene methods such as vaginal douching and vaginal washing after unprotected sex are not effective in protecting against STI or HIV (4) (level of evidence: very low).

Treating a sexual partner: This refers to a continuum of activities designed to increase the number of infected people receiving treatment, aimed at interrupting the chain of infection transmission. There is limited evidence regarding the impact of notifying a sexual partner on the prevalence of these infections in the community (23). However, the probability of re-infection of the index/primary case is reduced, therefore health care providers must counsel patients on the importance of notifying their sexual partners and advise them on the need to seek medical evaluation and treatment (4). A systematic review (19) evaluated the effectiveness of mass treatment for STI in all members of a particular community, the distribution of contraceptives within the community, the syndromic management of STI and STI counselling. The review had an AMSTAR score of 9/11 and included four controlled clinical trials (57,000 patients). The review examined the reduction in the prevalence of STI, increasing health care service use, improving service quality and increasing safe sexual behaviour in the community, including condom use. It was found that the interventions significantly reduced the prevalence of syphilis (RR 0.88: 0.80-0.9695% CI), N. Gonorrhoeae (RR 0.49: 0.31-0.7795% CI) and trichomoniasis (RR 0.64: 0.54-0.7795% CI) but not C. trachomatis (RR 1.03: 0.77-1.3695% CI). A significant increase was found regarding frequency of condom use (RR 1.18: 1.04-1.3395% CI) and frequency of consultation when seeking treatment for a STI (RR 1.22: 1.13-1.3295% CI) compared to control. The sole adverse effect was a small increase in the number of sexual partners (RR 1.07: 1.01 - 1.1395% CI) the included studies had a moderate risk of bias and were highly heterogeneous (level of evidence: moderate).

Educational interventions for adolescents regarding reducing the risk of HIV and sexually-transmitted diseases: A systematic review (AMSTAR score of 8/11) evaluated the effectiveness of two educational group strategies in adolescents applied within a scholastic or community setting. The two strategies were education strategy for reducing risky sexual behaviour (64 controlled clinical trials) and education regarding abstinence (23 controlled clinical trials). They focused on implementing counselling for preventing STI, distributing contraceptives, STI screening and carrying out educational campaigns aimed at reducing the prevalence of HIV and other sexually-transmitted disease. The included trials focused on educating adolescents in decision-making and practical skills, taking into account their attitudes and beliefs to aid effective communication. The education strategy for reducing risky sexual behaviour was significantly associated with reduced sexual activity (OR 0.81: 0.72-0.9095% CI), fewer sexual partners (OR 0.83: 0.74-0.9395% CI), fewer unprotected sexual contacts (OR 0.70: 0.60-0.8295% CI) and lower STI frequency (OR 0.65: 0.47-0.9095% CI). Regarding education concerning abstinence, the educational intervention was associated with less sexual activity (OR 0.81: 0.70-0.9495% CI), but there were no statistically significant differences regarding the 2013number of sexual partners, the number of non-protected sexual contacts or condom use during sexual activity. This review did not make clear the included studies risk of bias and there was high heterogeneity for some of the assessed outcomes (24) (level of evidence: moderate).

4. Which risk factors are associated with STI?

Certain socio-demographic characteristics and types of sexual behaviour increase the risk of contracting an STI. Several cohort studies and cases and control studies have reported risk factors for acquiring STIs. The following risk factors (Table 3) were taken into account, based on the studies reviewed here (25-45) alongside risk factors referred to by different CPG such as WHO 2005 (2), CDC 2010 (4) and Canadian CPG (9).

RECOMMENDATIONS FOR MANAGING SPECIFIC SYNDROMES

Single dose: The recommendation regarding single dose treatment of STI syndromes, is based on the consensus of national experts. The recommendation is based on evidence supporting the use of azithromycin and ceftriaxone for the organisms mainly causing cervicitis, tynidazole and fluconazole for those causing vaginal discharge and penicillin G benzathine for syphilis in genital ulcer syndrome (level of evidence: very low).

Treating sexual contacts. A systematic review referring to the effectiveness of four strategies for notifying the partners of STI/GTI patients (10/11 AMSTAR score) included 26 RCT, involving 17,578 participants. The first strategy involved patients simply notifying their partners that they needed treatment (i.e. simple referral). If this method was accompanied by diagnostic leaflets or kits it was called “improved patient referral”. The second strategy was expedited partner therapy (EPT) and consisted of sending treatment to the partner of a patient who had consulted, thereby avoiding the need for a doctor to examine the partner. A third strategy, involved health care provider referral, and consisted of information about the need for treatment being given by health care personnel. The fourth strategy was contract-based referral which involved a patient being responsible for communicating to their partner the need for treatment; however, when no response was obtained during a given time, the provider then contacted the patient. Regarding the number of partners treated per index patient, EPT was better than simple notification for patients suffering any STI syndrome (difference of means = 0.5: 0.34-0.6795% CI). No reliable evidence was found concerning the benefit of referral by provider or contract-based referral, nor was there evidence of an increase in adverse events. There was a risk of selection bias due to problems in random assignment and a high risk of RCT performance bias arising from a lack of masking and more than 20% loss in 7 studies (46) (level of evidence: moderate). The recommendation about sexual health consultation was agreed upon by the experts (level of evidence: very low).

CERVICAL INFECTION SYNDROME (CERVICITIS)

5. Which aetiological agents have been associated with cervical infection syndrome?

Managing cervical infection has been based on diagnosing and treating the main aetiological agents, these being Chlamydia trachomatis and Neisseria gonorrhoeae (4).

6. Which clinical manifestations of STI/GTI have been characterised for cervical infection syndrome?

According to the Canadian Guidelines form an aging STI, the signs and symptoms of cervical infection area mucopurulent discharge f lowing from the cervix, cervical friability, strawberry cervix and vaginal discharge (9). Dyspareunia and dysuria represent other associated signs and symptoms (47). Syndromic management of cervical infection has been controversial as Chlamydia trachomatis infection is asymptomatic in 50 to 70% of reproductive-aged females (48); and its signs and symptoms do not have the desired operational characteristics, leading to a high proportion of false negatives. A sensitivity of 13.3 % has been found for the syndromic management of cervical infection. Vaginal discharge reported by a patient and found during clinical examination is the most sensitive sign for syndromic diagnosis (49.7% sensitivity, 78.3% specificity) (49).

It has been reported that the sensitivity of the rapid tests for C. trachomatis applied in health care settings varies from 17% to 49%; these tests specificity varies between 90% and 100% (50-53). However, a cost effectiveness study carried out in Colombia has shown that using rapid tests for N. gonorrhoeae and C. trachomatis represent the most cost-effective strategy for managing cervicitis when compared to syndromic diagnosis (54) (level of evidence: low).

7. Which is the most effective and safest treatment for cervical infection syndrome?

Treatment of patients suffering C. Trachomatis infection: A meta-analysis (55) compared two treatments (azithromycin 1.0 g one dose versus doxycycline 100 mg every 12 hours for 7 days) evaluated 12 randomised clinical trials (RCT) involving 1,543 patients with urethral discharge or uterine cervicitis caused by C. trachomatis, (AMSTAR score 7/11). It was rated as being of very low quality due to a lack of rigour regarding the searches for information and the indirect comparisons made in the population. The authors stated that the quality of the studies included was doubtful due to the small sample sizes and lack of blinding in more than half the studies included, as well as losses to follow-up being greater than 20%. The outcome was microbiological cure or negative culture for C. trachomatis in follow-up ranging from 2 to 5 weeks post-treatment. It was found that the percentage of patients having an aetiological diagnosis of genital infection caused by C. Trachomatis treated with azithromycin in whom microbiological cure was identified at the end of 3.7 weeks follow-up, on average did not significantly differ from the percentage of patients having the same outcome and who had been treated with doxycycline (96.5% and 97.9% microbiological cure, respectively, difference between proportions 0.0014: -0.007–0.02295% CI; Z=1.05; p=0.296).

No differences were found regarding the presence of adverse effects in patients suffering genital infection caused by C. Trachomatis who had been treated with azithromycin (25%), compared to patients who had received treatment with doxycycline (22.9%; p = 0,533). Three randomised clinical trials were published following the publication of a systematic review by Lau et al. The first of them was carried out by Sendag et al.,(56); this study had serious methodological limitations (high risk of bias and imprecision). The study involved 131 females, 42 of them had a positive culture (n=21) and 54.5% of the females from the doxycycline group having a positive culture (n=23) were found to be free of clinical signs of cervicitis at 2 weeks follow-up. The authors did not report association estimators, just outcome frequency. Another RCT was conducted by Guven et al., (57) where the therapeutic effect of treatment with a single dose of 1 g azithromycin was compared to100 mg doxycycline every 12 hours for 7 days in females who had consulted due to different symptoms (not clarified by the authors) and who were positive for Chlamydia trachomatis, Ureaplasma urealyticum and/or Mycoplasma hominis according to immunoenzyme assays. Only 81 of the 533 females initially studied were positive for some of the aforementioned STI. They were randomly assigned to each treatment (the authors did not report the method). The eradication rate was reported to be 87.3% and 93.5% in the azithromycin and doxycycline groups, respectively. A clinical trial by Rustomjee et al.,(58) evaluated the effectiveness of treatment with azithromycin (n=45) compared to treatment with doxycycline plus ciprofloxacin (n=37) form an aging cervicitis caused by Chlamydia trachomatis or Neisseria gonorrhoeae, diagnosed by clinical exam, immunoassay and endocervical gram staining. Twenty-six of the females studied were infected by Chlamydia trachomatis, 19 had Chlamydia trachomatis and Neisseria gonorrhoeae infection and 37 were infected by Neisseria gonorrhoeae. The patients from both groups were comparable, except for their age and the presence of trichomoniasis. The groups were analysed according to the aetiological agent isolated, so that microbiological cure was reported according to the bacteria and not according to the randomised groups. The percentage of microbiological cure in the groups infected by Chlamydia trachomatis, Chlamydia trachomatis, Neisseria gonorrhoeae and Neisseria gonorrhoeae using azithromycin was 100%, 90% and 100%, respectively; 100% cure was achieved in the three groups for the same infections regarding the doxycycline plus ciprofloxacin group. The authors did not report association measures. No statistically significant differences were found regarding adverse event incidence (level of evidence: very low).

Treating patients suffering cervical infection caused by Neisseria gonorrhoeae: An RCT by Rehman et al., (59) evaluated a microbiological cure for patients of both genders having signs and symptoms of urethritis or cervicitis who had a positive aetiological diagnosis for Neisseria gonorrhoeae; 300 patients aged 14 to 55 years old were studied: 229 females and 71 males. They were randomly assigned to one of three treatment groups: a single dose of 500 mg ciprofloxacin, 500 mg IV ceftriaxone or2 g IM spectinomycin. Cure was determined by the absence of symptoms and Gram staining plus microscopy of prostatic fluid or vaginal secretion. Reported clinical efficacy was 90% in the ceftriaxone group, 94% in the spectinomycin group and 80% in the ciprofloxacin group. The authors only described proportions/percentages; they did not calculate measures of association (level of evidence: very low).

The CDC 2010 clinical practice guidelines (4) stated that ceftriaxone and cefixime were highly effective in treating urethritis and cervicitis caused by Neisseria gonorrhoeae and constituted the first-line treatment option. They also said that spectinomycin was an effective and useful treatment option for people who could not tolerate cephalosporins, however it is a costly, injectable drug which is not available in the USA therefore this antibiotic was not included in the CDC guidelines recommendations. However, other guidelines (i.e. Canadian 2008) recommended treatment with spectinomycin as an alternative drug to cephalosporins. The same guidelines did not recommend the use of ciprofloxacin for managing infections caused by N. Gonorrhoeae as this antibiotic is considered to induce resistance (9). The aforementioned two guidelines advised against using ciprofloxacin for infection caused by N. gonorrhoeae due to high bacterial resistance rates (level of evidence: very low).

8. Which complications are most frequently presented in cervical infection syndrome?

Ascend of the infection from the cervix to the upper genital tract causes complications as pelvic inflammatory disease (PID) which, in turn, can cause tubal infertility, ectopic pregnancy and chronic pelvic pain (60). The aetiological agents involved in developing cervicitis are also found in PID (C.trachomatis, N.gonorrhoeae, Mycoplasma genitalium) (61). A prospective cohort study which assessed long-termfollow-upfor treatment of C. Trachomatis infection was examined. The study involved 443 females who had signs and symptoms of moderate to severe PID who had been followed-up for an average of 84 months. It was shown that these females had close to a 20% risk of developing PID within the following 3 years (HR 2.48:1.00- 6.27 95% CI). It was also shown that this risk was cumulative in relation to the number of infections caused by C. trachomatis (62). However,it has still not been possible to determine whether sequelae were due to bio-pathological mechanisms characteristic of the infection and/orwhether they were attributable to limitations in the diagnosis (60).

9) Which type of followup is indicated for patients suffering from cervical infection syndrome?

This recommendation emerged from expert consensus (level of evidence: very low).

10. How effective and/or safe is the treatment for the partner of a patient suffering cervical infection syndrome?

Treating C. trachomatis patients’ partners. A systematic review by Ferreira et al. (46), which analysed notification strategies, showed that EPT was better in urethritis or cervicitis patients than patient notification in terms of lower reinfection rates (6 RCT; RR = 0.71:0.56-0.89 95% IC; I2= 39%). No benefit was found when analysis was restricted to C. trachomatis (2 RCT; RR= 0.90: 0.60-1.3595% IC; I2 = 22%). Regarding the number of sexual contacts treated per index patient, EPT was better than simple reference in C. trachomatis or N. Gonorrhoeae infection patients (difference between means =0.43: 0.28-0.5895% IC). However, EPT was not better than improved simple notification using leaflets in preventing reinfection (3 RCT;RR = 0.96:0.60-1.53 95% IC; I2 = 33%) (46) (level of evidence: moderate).

The CDC’s 2010 CPG (4) recommended that if apatientis infected by N. gonorrhoeae, then he/she should also be treated for C trachomatis. Treatment should be accompanied by sexual and reproductive health education. This document states that if a patient is symptomatic and no more than 60 days have passed since the last sexual relation, then the partner should receive treatment. Furthermore, if they are treated, the patients must be told not to 2013have sexual contact until the treatment has been completed and the symptoms have disappeared (level of evidence: very low).

11. Which treatment is the most effective and safest for a pregnant or breastfeeding women suffering from cervical infection syndrome?

Managing pregnant or breastfeeding women suspected as suffering or confirmed as having cervical infection caused by Chlamydia trachomatis: A systematic review by Brocklehurst (63) included 11 RCTs (1,449 females, AMSTAR score 10/11); comparing placebo or no treatment to antibiotic schemes in pregnant females suffering C trachomatis infection. The studies evaluated the microbiological cure and one neonatal adverse event. It was found that the treatment produced fewer microbiological failures compared to placebo or no treatment (OR 0.06:0.03–0.1295% IC). No statistically significant difference was found regarding the incidence of preterm birth (OR 0.89:0.51–1.5695% IC). Adverse events which required suspension of treatment were evaluated. The most frequently occurring adverse events were gastrointestinal (OR 4.83:0.60–38.6795% IC). Clindamycin and azithromycin appeared to be effective even though the studies sample sizes were small. Amoxicillin appeared to be equally effective as erythromycin regarding microbiological cure (OR 0.54:0.28–1.0295% IC). Clindamycin (600 mg threetimes aday for 10 days) appeared to be equally effective as erythromycin regarding microbiological cure (OR 0.40:0.13–1.1895% IC). A single dose of 1 g azithromycin appeared to be more effective then erythromycin regarding microbiological cure (OR 0.38:0.19–0.7495% IC). The estimation of effect showed risk of bias, indirectness and imprecision (level of evidence: low).

Managing pregnant or breastfeeding women suffering cervical infection (suspected or confirmed) caused by Neisseria gonorrhoeae: A systematic review by Brocklehurst (64) (9/11 AMSTAR score) which included 2 randomised clinical trials (346 patients), evaluated the maternal and neonatal morbidity of several treatment regimens for genital infection caused by Neisseria gonorrhoeae in pregnant women. The rates of failure of microbiological cure were similar in all treatment regimens: Amoxicillin plus probenecid versus spectinomycin (OR 2.29:0.74-7.0895% IC), ceftriaxone versus cefixime (OR 1.22:0.16-9.01 95% IC) and amoxicillinplus probenecid versus ceftriaxone (OR 2.29:0.74-7.08 95% IC). The author stated that the sample sizes were insufficient; therefore it is possible that the true effect regarding treatment effectiveness was not observed however he confirms the possibility of use ceftriaxone or cefixime in women with allergy to penicillin with a similar effectiveness regarding microbilogical cure. .Only one of the two studies included in the review (65) reported a case of treatment being suspended due to medication-associated adverse events. The reliability of the studies is affected by a high risk of bias and a high level of imprecision (very low level of evidence).

The CDC 2010 CPG (4) stated that all pregnant women from an area of high prevalence of Neisseria gonorrhoeae infection, should undergo routine screening for the infection at the first prenatal consultation. Women aged under 25 years of age, who have risk factors for Neisseria gonorrhoeae infection, should be screened again during the third trimester. Dual treatment for Neisseria gonorrhoeae and Chlamydia trachomatis was recommended, bearing co-infection in mind. The same document recommended administering a single IM dose 250 mg ceftriaxone alongside a single oral dose 400 mg cefixime and/or another single dose cephalosporin, accompanied by treatment with single dose oral 1 g azithromycin for infection caused by Chlamydia trachomatis (very low level of evidence).

12. Which complications present most frequently in pregnant females suffering from cervical infection syndrome?

Complications arising from C. trachomatis infection during pregnancy are related to the pathogen’s vertical transmission when giving birth. If intra-partum infection occurs, the neonate could develop complications ranging conjunctivitis to pneumonia. A narrative review by Hammerschlag concluded that prenatal screening and antenatal treatment of cervical infection syndrome was effective for preventing gonococcal ophthalmia neonatorum and C. Trachomatis infection during the neonatal period (66) (level of evidence: very low).

13. How is persistent or recurrent cervical infection managed?

Managing women suffering from persistent or recurrent cervical infection (suspected or confirmed) caused by Chlamydia trachomatis: The group of experts has suggested the use of the doxycycline in cases of suspected recurrence. The treatment of partners, adherence to treatment and completing the course of treatment should be explored with women, alongside the importance of condom use with all sexual partners throughout treatment (Very low level of evidence).

Managing women suffering persistent or recurrent cervical infection (suspected or confirmed) caused by Neisseria gonorrhoeae: The group of experts has suggested using Ceftriaxone in cases of suspected recurrence. The treatment of partners, adherence to treatment and completing the course of treatment should be explored with women, alongside the importance of condom use with all sexual partners throughout treatment. (Very low level of evidence).

URETHRAL DISCHARGE SYNDROME

14) Which aetiological agents are associated with urethral discharge syndrome?

N. gonorrhoeae, C. trachomatis, Mycoplasma genitalium, Ureaplasma urea lyticum and Trichomonas vaginalis are the pathogens most frequently responsible for urethral discharge syndrome (9).

15) Which clinical manifestations of STI/GTI are characterised by Urethral Discharge Syndrome (UDS)?

The signs and symptoms characterising this syndrome are dysuria, irritation in the distal urethra or urinary meatus accompanied (sometimes) by erythema and urethral secretion (9). Initial syndromic management does not include laboratory tests.

16. Which treatment is the most effective and safest for Urethral Discharge Syndrome (UDS)?

C. trachomatis infection: The evidence supporting the recommendation for treating C. trachomatis has already been described when answering the question about which is the safest and most effective treatment for cervical infection. A meta-analysis by Lau et al., (55) compared two treatments (single dose 1 g azithromycin compared to 100 mg doxycycline every 12 hours for 7 days) for managing urethral discharge or cervicitis caused by Chlamydia trachomatis. There was no significant difference found between the microbiological cure rate of genital infection caused by Chlamydia trachomatis at an average of 3.7 weeks follow up, of patients who received azithromycin (96.5%) opposed to doxycycline (97.9%)(0.0014: -0.007-0.022 95% CI) (level of evidence: very low).

N. gonorrhoeae infection: The evidence supporting the recommendation for treating N. gonorrhoeae has already been described when answering the question about which is the safest and most effective treatment for cervical infection. An RCT which evaluated the microbiological cure rate of patients having signs and symptoms of urethritis due to N. gonorrhoeae was analysed. Patients were assigned to one of three treatment groups: single IM dose 500 mg ciprofloxacin, 500 mg ceftriaxone or 2 g spectinomycin. The percentage of patients diagnosed with urethritis or cervicitis caused by N. gonorrhoeae in which microbiological cure was identified after 5-day follow-up was 90% in the ceftriaxone group, 80% in the ciprofloxacin group and 94% in the group treated with spectinomycin (59). There was a high risk of bias and indirect evidence (level of evidence: very low).

17. Which complications are associated with urethral discharge syndrome?

Urethritis in males can complicate acute epidi-dimitis. Acute proctitis is frequently associated with venereal lymphogranuloma; however, there is no evidence concerning causal association between infection caused by C. Trachomatis and the development of prostatitis or male infertility (67). Reiter’s syndrome (urethritis, conjunctivitis, arthritis and mucocutaneous lesions) as well reactive arthritis have been associated with genital infection caused by C. trachomatis (68) .

18. How should patients with Urethral Discharge Syndrome be followed up?

This recommendation arose from expert consensus (level of evidence: very low).

19. How should the partner of a patient suffering Urethral Discharge Syndrome be treated?

These recommendations have been based on indirect evidence regarding the effectiveness of treating partners of patients suffering cervical infection caused by C. Trachomatis and N. Gonorrhoeae (see the section dealing with cervicitis).

GENITAL ULCER SYNDROME

20. Which aetiological agents are associated with genital ulcer syndrome?

The agents responsible for genital ulcer syndrome (GUS) are T. pallidum causing syphilis, H. ducreyi, C. Trachomatis serotypes 1, 2 and 3, Klebsiella granulomatis and Herpes simplex virus (HSV) (9).

21. What are the clinical manifestations of genital ulcers?

GUS is characterised by ulcerative, pustular or vesicular genital lesions, often accompanied by regional lymphadenopathy. These lesions are located on the surface of the prepuce and the glans, scrotum, perineum and perianal region in men and the vulva, perineum, perianal region and the rest of the mucous surfaces (vagina and neck of the womb) in women (69). The characteristics of the ulcers is dependent upon the causative agent. In GUS caused by HSV infection, the ulcers develop following the rupture of vesicles or blisters and tend to be circular, erythematous and have diffuse edges and base. HSV often causes multiple small ulcers which might converge to form larger ulcers. The ulcers can be painful, and a patient could present with systemic symptoms of infection such as fever and inguinal lymphadenopathy. GUS secondary to primary syphilis often presents as a single ulcer or chancre, which characteristically appears round, firm, painless, has indurated borders and a clean base and ispossibly accompanied by lymphadenopathy. Alternatively, two or more painful necrotic ulcers can present in chancre related infections, accompanied by erythema and oedema in the surrounding area. The ulcer, which presents as a protuberance initially, may be accompanied by inguinal lymphadenopathy and abscesses called buboes. Venereal lymphogranuloma infection often presents with the signs and symptoms of urethritis, alongside single self-limiting papules followed by femoral lymphadenopathy, inguinal distension and/or proctocolitis. The clinical picture of inguinal granuloma infection presents with a single ulcerative lesion or multiple highly vascularised, non-painful ones which bleed easily oncontact, located in 50% in the anal area. As time elapses, the initial protuberances become red nodules called granulation tissue which can extend to inguinal folds (4,9,69). It should be stressed that an initial syndromic approach to genital ulcers does not include laboratory tests.

A systematic review of diagnostic tests which evaluated rapid test sensitivity and specificity for diagnosing syphilis in STI clinics and during the prenatal period estimated a mean sensitivity of 86% (IQR: 0.75-0.94) and a specificity of 99% (IQR:0.98-0.99). However, the included studies (13 cross-sectional studies) were focused on identifying any/all types of syphilis and thus test performance regarding primary syphilis could not be ascertained (70). No evidence was found referring to the tests operational characteristics or effectiveness for penicillin allergy concerning primary syphilis health care (level of evidence: low).

22. Which is the most effective and safest treatment for genital ulcer syndrome in females and males?

Treating primary syphilis: The effectiveness of penicillin (in its different forms) has been established more by clinical experience than the availability of RCTs evaluating its usefulness. One RCT with 326 patients which brought together clinical experience of treating primary syphilis with penicillin, presented a high risk of bias related to follow-up, adherence to treatment and co-interventions. The RCT included all types of syphilis as well as patients who had confirmed HIV. The results showed that patients diagnosed as having primary syphilis who were treated with penicillin G benzathine did not have a greater risk of failure of cure (confirmed by serology) compared to patients who had received additional treatment with amoxicillin and probenecid: 17.8 and 17.2% failure incidence, respectively (OR 1.11: 0.6–2.295% IC) (71)(level of evidence: very low).

Other options to penicillin have been studied, revealing a similar effectiveness profile. A meta-analysis which included four RCT and 476 patients (AMSTAR score 8/11) showed that patients diagnosed with primary syphilis who had been treated with azithromycin had a similar serological cure rate when compared to patients who were treated with penicillin G benzathine (OR 0.68: 0.29-1.6195% IC) (72). Another meta-analysis (AMSTAR score 10 /11) included three RCTs which compared penicillin benzathine to azithromycin. There were no significant differences in terms of clinical cure (OR 1.04:0.69-1.5695% IC) not three months after the beginning of treatment, nor were there any differences regarding adverse events between azithromycin and penicillin benzathine (OR 1.43:0.42-4.9595% CI). The aforementioned studies involved a risk of reporting bias and limited precision; heterogeneity was high for evaluating adverse events (73) (level of evidence: moderate).

However, given that azithromycin-resistant T. Pallidum has been found in different parts of the world, it is recommended that this antibiotic is used only in cases where penicillin or doxycycline is not available (4, 9). An RCT which studied ceftriaxone treatment in patients suffering primary syphilis did not reveal any differences regarding clinical or serological cure rates compared to patients treated with penicillin G benzathine (RR 0.8:0.32-1.99 95% IC). This RCT had insufficient sample size and important losses regarding follow-up and indirectness due only male patients were included (74). The optimum treatment dose and timing of Ceftriaxone treatment was not defined (4) (level of evidence: low).

Managing patients with a penicillin allergy: A retrospective cohort study of patients treated with doxycycline/tetracycline was found. This study revealed no differences regarding serological cure rate in patients diagnosed with syphilis who had been treated with doxycycline/ tetracycline after 12-24 months, compared to patients treated with penicillin G benzathine (RR 1.0: 0.95-1.0695% IC). There was no difference in the time taken to serological cure between the two treatments. (Median 43 and 72, respectively; p=0.16). This study had a high risk of bias regarding selection, confounding and evaluating adherence to treatment. It was not clear whether patients having documented penicillin allergy were included or which criteria were used for prescribing doxycycline (75) (level of evidence: very low).

Treating chancroid: An RCT, which included 184 men suspected of suffering chancroid infection (127 had a positive culture for H ducreyi) with 83% follow-up, compared treatment with azithromycin to erythromycin. There was no difference in clinical cure rates between the two treatments. (OR 0.97: 0.86-1.1095% CI) (76). This study had a high risk of bias related to unclear random assignment and concealment methods and because it was un-blinded. Another RCT with risk of bias (performance and detection bias unclear and lack of adherence to the assignment of treatment), which included 133 patients suffering Haemophilus ducreyi infection, also did not show differences between azithromycin or ceftriaxone use of in terms of clinical cure (RR 1.13: 0.98-1.3095% CI) or adverse events (RR 2.02: 0.92-4.4395% CI) (77) (level of evidence: moderate).

An RCT involving 208 men and 37 women with confirmed H. ducreyi infection compared treatment with Ciprofloxacin (500mg single oral dose) to erythromycin (500mg 3 times a day for 7 days). The ciprofloxacin group had 19% treatment failure compared to 12% for the erythromycin group. No significant differences were found in terms of the clinical cure rates 21 days after beginning the treatment (RR 0.97: 0.68-1.3695% CI) (78) (high level of evidence).

CDC guidelines (4) have indicated that reports of Haemophilus ducreyi resistance to ciprofloxacin and erythromycin are increasing, thereby suggesting that bacterial resistance studies should be undertakenin case where these drugs are used (level of evidence: low)

Treating venereal lymphogranuloma

(Chlamydia trachomatis serotypes L1, L2, L3): An RCT which compared different tetracyclines having a similar profile to that of doxycycline (chlortetracycline, oxytetracycline and sulfadiazine) to symptomatic treatment (aspirating the buboes plus aspirin), showed shorter lesion duration (31 cf 69 days) and greater serological cure rate in the patients who were treated with an antibiotic (RR 2.33: 1.4-4.1 95% CI). However, the risk of bias in this RCT was not clear since many evaluation elements were not present as this study was published in 1957 (79) (level of evidence: low).

Azithromycin for treating venereal lymphogranuloma has not been evaluated directly and the available evidence comes from other infections caused by C. trachomatis. In addition to the previously described evidence, two RCTs that compared Azithromycin with doxycycline which included 971 patients with Chlamydia trachomatis infection (mainly urethritis and cervicitis) did find differences in terms of clinical cure (RR range 1.03-1.06), However, there was no significant difference in terms of clinical cure or bacteriological cure (RR range 0.97-1.01) or regarding the presence of adverse events (RR range 0.89-1.1) compared to patients treated with doxycycline (80, 81). It is worth noting that these trials included patients with Chlamydia trachomatis infection in general, i.e. not specifically due to strains related to venereal lymphogranuloma: serovars L1, L2 and L3 (level of evidence: moderate).

Regarding erythromycin use, a report was found where 2 out of 3 patients treated with 1,600 mg daily improved after 12 and 14 months of treatment (82) (level of evidence: very low).

Treating inguinal granuloma: Little evidence is available regarding azithromycin and ciprofloxacin use. Two reports of cases involving ciprofloxacin treatment (83, 84) and an RCT pilot study concerning azithromycin use (85) were identified; no evidence was found regarding trimethoprimsulfamethoxazole use. Experts recommended the use of doxycycline as first line regime for this infection, followed by alternative regimes such as azithromycin, ciprofloxacin, erythromycin and trimethoprim-sulfamethoxazole (4) (level of evidence: very low).

Treating first HSV infection: The effectiveness of acyclovir for treatment of first HSV infection has been evaluated in 3 RCTs, involving 259 patients suffering their first episode of herpes simplex. The trials showed a reduction in the virulence period of the infection when treated with acyclovir when compared to placebo (86-88). The RCT data involving the greatest number of patients (150 patients: 119 of them having primary infection and 31 secondary infection) showed that acyclovir significantly reduced the time for lesions to become completely cured (12 cf14 days; p=0.005), reduced new lesion formation 48 hours after beginning the therapy (18% cf62%;p=0.001) and reduced the duration of pain (5 cf7 days; p=0.05) and viral shedding (2 cf9 days; p<0001) (87). However, two of the studies had low sample sizes (level of evidence: moderate).

A multicentre RCT compared valaciclovir (n= 323) to acyclovir (n= 320) as treatment for first HSV infection. It did not reveal any differences regarding the time taken until symptom resolution (HR 1.0: 0.85-1.1895% CI), virulence duration (HR 1.02: 0.85-1.2295% CI), duration of pain (HR 1.02: 0.84-1.1895% CI) or adverse events. This study had a low risk of bias (89) (level of evidence: high).

Treating recurrent herpes: Recurrent herpes has been defined as 6 or more episodes during a single year (9). A systematic review involving a meta-analysis of 14 RCTs (AMSTAR 9/11) showed that recurrent episodes of genital herpes were reduced with acyclovir (RR 0.46:0.43-0.4995% CI), valacyclovir (RR 0.56:0.53-0.5995% CI) or famciclovir treatment (RR 0.57: 0.5-0.6595% CI) (90) (level of evidence: high).

Experts have suggested that treatment with acyclovir or valacyclovir as prophylaxis for recurrent genital herpes must continue for 1 year(4) (level of evidence: very low).

23. Which complications are associated with GUS?

Complications related to treating genital ulcers do not occur very frequently, but when they arise, they may represent a failure to diagnose the initial infection and therefore modifications to the treatment may be required. Therapeutic failure is the main complication which may present when adopting a syndromic approach to treating genital ulcers; this can be assessed during follow-up or during patient consultation following initial prescription. An example of this would be the appearance of systemic infection (secondary or tertiary syphilis) (91). Factors such as initial syndromic diagnosis, co-infection with other STI/ GTI, the presence of HIV infection, adherence to treatment or the aetiological agent’s resistance to the recommended treatment must be considered when determining the next course of treatment. (4).

In some cases, the infection itself brings about complications, some of them related to the treatment used. The Jarisch-Herxheimer reaction is one of the most frequently occurring ones, involving an acute febrile illness, accompanied by severe headache and myalgia 24 hours after beginning treatment for syphilis; 50% incidence has been reported in patients suffering primary syphilis treated with penicillin G, with resolution occurring within 12-24 hours of its appearance (92). Recurrences may also be considered a complication. Recurrences occur relatively frequently in HSV infections and can be successfully treated as previously described with antivirals (93). Some symptoms, such as the presence of buboes in chancreid infection or venereal lymphogranuloma, might require another type of management in addition to pharmacological management in order to prevent the complications arising from lymphadenopathy (94, 95).

24. How are GUS patients followed up?

Optimum follow-up of patients suffering infections causing genital ulcers is based on expert opinion rather than clinical studies. Optimal follow-up represents a challenge for doctors dealing with these patients as often there are barriers to accessing care. The group of experts considered that clinical examination of patients was desirable at least 2 weeks after administering the recommended treatment when syndromic management of genital ulcers had been adopted. This is to ensure treatment had been effective and if not, to establish whether a different aetiological cause of the infection could be the cause (level of evidence: very low).

25. How are the partners of patients suffering from GUS treated?

Treating a sexual partner: Two recent CPGs have agreed on the importance of clinically reviewing the sexual partners of patients suffering from any of the infections which cause GUS (4, 9). Consultations are aimed at reviewing signs and symptoms and determining appropriate treatment. The CPGs concluded that treatment should be given in all cases, even in the absence of symptoms for sexual partners of those suffering from venereal lymphogranuloma, chancroid, inguinal granuloma and syphilis. The CPGs concluded that sexual partners of those suffering from herpes infection should be offered a consultation, but treatment was a priority only for patients with symptoms (level of evidence: very low).

A Systematic Review examining methods for notifying partners included an RCT of patients suffering syphilis infection. The RCT found that the contract notification method managed to locate more partners than the provider notification method (difference of means = 2.2:1.95-2.4595% CI); however, the group of partners receiving treatment was the same in both groups (46) (level of evidence: moderate).

26. How is gus treated in pregnant or breastfeeding women?

Treating early syphilis in pregnant women: A systematic review of observational studies (AMSTAR 6/11) which included studies on pregnant women referred to screening and the early treatment ofactive syphilis with 2,400,000 IU penicillin benzathine in different countries, having moderate heterogeneity, showed a reduction in the risk of congenital syphilis (RR = 0.03: 0.02-0.07 95% CI), foetal demise (RR = 0.18: 0.10-0.33 95% CI), preterm birth (RR = 0.36: 0.27-0.47 95% CI) and neonatal death (RR = 0.20: 0.13-0.32 95% CI) (96)(level of evidence: low).

A systematic review (AMSTAR 9/11) was evaluated which assessed antibiotic (AB) effectiveness with regards to treating syphilis during pregnancy (97). Even though 29 studies were localised, they did not fulfil quality and design criteria to be considered as candidates for the review.

Treatment of Chancroid. No evidence was found regarding how chancroid should be treated in pregnant women; only indirect information was available regarding effectiveness in other populations having limited external validity. No evidence concerning treatment of venereal lymphogranuloma or inguinal granuloma in pregnant or breastfeeding women was found; only the aforementioned evidence about treating the conditions in non-pregnant women. The Canadian guidelines (9) recommended the use of erythromycin for treating pregnant women suffering Lymphogranuloma venereum (LGV); however, our experts prioritised azithromycin to promote adherence (level of evidence: very low).

27. How are pregnant or breastfeeding women suffering their first episode of genital infection (suspected) caused by HSV type 1 or 2 treated?

No evidence was found regarding the treatment of HSV in pregnant women; only the aforementioned information was available regarding effectiveness in non-pregnant women, having limited external validity (level of evidence: very low).

28. Which complications most frequently present in pregnant women suffering from GUS?

In addition to the aforementioned complications, the most frequently occurring complications for pregnant women suffering genital ulcers are those related to giving birth and the newborn (98) the complications associated with the various medications commonly administered for treating different infectious agents have not been fully established. It is well-known that some reactions (such as the Jarisch-Herxheimer reaction) in maternal syphilis affect up to 40% of pregnant women and is associated with the appearance of uterine contractions, preterm birth and decele-ration of the foetal cardiac rate, with no serious outcomes at the end Using acetaminophen for managing pain and the associated fever has been shown to be useful (98).

When transmission of an infection to the foetus occurs during pregnancy or labour, it carries a high burden of morbidity and mortality for the newborn. Congenital syphilis is a multiple organ infection which impacts severely on neurological and skeletal development of the new born and can cause infant mortality (99). It is known that screening for the condition and early treatment of pregnant women can effectively avoid such transmission (96). Neonatal herpes is another example of a complication arising from transmission of the infection at birth, especially when the mother is affected in the last trimester of pregnancy (100).

VAGINAL DISCHARGE SYNDROME

29. Which aetiological agents are associated with vaginal discharge syndrome (VDS)?

Most patientssuffering vaginal discharged o not have a sexually-transmitted infection (5,101). There are three main causes of vaginal discharge syndrome (VDS): bacterial vaginosis, candidiasis and trichomoniasis. Concomitant infection by BV and Candida albicans has been described in 7.5% of patients (5). C. trachomatis and N. gonorrhoeae may also be causal agents in patients who have risk factors for STI (5) (level of evidence: moderate).

30. Which clinical manifestations of STI/GTI are characterised by VDS?

Various signs and symptoms have been described for diagnosing pathologies associated with VDS; these include foetid vaginal discharge (most frequently associated with bacterial vaginosis), yellow discharge in trichomoniasis and vaginal and/or vulvar pruritus and erythema and dysuria, most frequently associated with candidiasis (8, 49). Initial syndromic management does not include laboratory tests.

31. Which is the most effective and safest treatment for VDS?

Treating VDS: An RCT was analysed which compared single-dose syndromic management of vaginal discharge with tynidazole and fluconazole to syndromic management with methronidazole and clotrimazole lasting the conventional duration of treatment. The study recruited women attending primary care establishments from four countries in western Africa, including sex workers and HIV patients (random assignation was stratified according to whether subjects were sex workers). No statistically significant differences were found regarding the clinical improvement rates reported by patients after 14 days (66.3% cf 63.9%; p=0.26), or after 28 days (80.9% cf 81.1%;p=1.00). Analysis by subgroup according to HIV infection status did not reveal significant differences between both treatments with regards to clinical improvement reported after 14 days, in both sero negative patients and HIV infected patients. Loss of follow up: 20%. (102) (level of evidence: moderate).

The study’s results suggested that there were no differences between single-dose treatment and conventional treatment when comparing them for the syndromic management of vaginal discharge (the difference between them being less than 10%). A single dose was suggested due to patient preference and the possibility of promoting better adherence to treatment, especially in disadvantaged populations; for example, it should be born in mind that sex workers activities and income are related to their ability to maintain an (extremely) active sex life. The validity of this recommendation will remain open until the CPG is next updated. Studies including subgroup analysis are required to improve the available evidence, specifically for sex workers and other vulnerable populations.

Treating bacterial vaginosis: A meta-analysis which included 24 controlled clinical trials (4,422 participants; AMSTAR score 8/11) which compared several treatments against placebo and between themselves in terms of clinical failure found that topical metronidazole was more effectiveness when compared to placebo (RR 0.59:0.44–0.79 95% CI), and Vaginal clindamycin was more effectiveness when compared to placebo (RR 0.19: 0.09–0.4195% CI). Comparing metronidazole to clindamycin revealed a similar clinical failure rate after 7 days (RR 1.06: 0.64-1.75 95% CI) and after 28 days (RR 0.97: 0.75-1.2795% CI). The metronidazole plus azithromycin combination compared to metronidazole alone was more effective for avoiding clinical failure after 7 days (RR 0.65: 0.46-0.9295% CI) and equally effective after 28 days (RR 1.22: 0.82-1.8395% CI). No differences were found between single dose tynidazole and metronidazole after 7 days treatment with regards to clinical failure (RR range 0.38-1.73) or adverse events (RR 0.62:0.13-2.9895% CI). There were no differences between methronidazole and clindamycin treatment with regards to discontinuing treatment, (RR 0.50 0.17-1.4795% CI), adverse events (RR 0.75: 0.54-1.0595% CI) or Candida albicans cell envelope (RR 1.11: 0.78– 1.5895% CI). There were fewer adverse events with clindamycin treatment opposed to metronidazole, which caused nausea (RR 0.27: 0.11–0.6995% CI). No evidence was found supporting the use of lactobacillus, triple sulphonamide vaginal cream, polyhexamethylene biguanide for shower use, oxygen peroxide, cephadroxyl (103).

One RCT did not find any differences between single dose secnidazole and metronidazole for 7 days with regards to clinical cure (RR 0.97: 0.881.0895% CI) or bacteriological cure (RR 1.03: 0.91-1.1795% CI) after 28 days. There was no difference with regards to adverse events (RR 0.94: 0.74-1.1495% CI)(104) (level of evidence: moderate).

Treating Trichomonas vaginalis: A meta-analysis (AMSTAR score 9/11) was evaluated which included 54 controlled clinical trials (5,201 patients) comparing several treatments to no treatment in terms of infection persistence after 4 to 14 days. Lower infection persistence was demonstrated in the treatment arm with inmidazol (RR 0.50: 0.43– 0.5695% CI). Short-term and long-term treatment with imidazole was also compared in terms of failure of cure; no differences were found between the two groups (RR 1.12: 0.58–2.1695% CI) involving follow-upfor up to 35 days. A lower risk of persistent infection after 21 days was demonstrated for the oral route when comparing oral to vaginal treatment aimed at cure (RR 0.20: 0.07–0.5695% CI). Comparing methronidazole to tynidazole revealed a higher percentage of clinical in favour of tynidazole, at to 21 days follow-up 3 (RR 3.81: 1.83–7.9095% CI) and parasitological cure (RR 3.24: 1.66–6.3295% CI). Secondary adverse effects were more common with metronidazole than with tynidazole treatment (RR 1.65: 1.35–2.0295% CI). This systematic review had a nunclear risk of bias with regards to the included studies and there was a high level of heterogeneity with regards to some of the comparisons (105) (level of evidence: low).

Treating Candida albicans: A meta-analysis of the literature was found which evaluated managing Candida albicans (AMSTAR score 9/11); it included 19 controlled clinical trials (2,579 patients). No statistically significant differences were found between oral and vaginal therapy (fluconazole vs clotrimazole) with regards to short-term microbiological cure (RR 1.02: 0.98–1.0795% CI) to long terms (RR 1.01: 0.93–1.0995% CI) orclinical improvement rates to short term (RR 0.92: 0.81–1.0595% CI) and clinical improvement to long terms (RR 1.00: 0.92–1.0895% CI). Just two of the 19 clinical trials included in this systematic review reported therapy being abandoned due to the presence of an adverse reaction to treatment; one case happened in each study (not specified). The review’s authors stated that no conclusion could be drawn concerning the safety of treatment involving oral or vaginal therapy for uncomplicated candidiasis. The included studies had a high risk of bias because there was no concealment, higher than 20% loss to follow-up and CCTs had often been funded by pharmaceutical companies (106) (level of evidence: low).

32. How are VDS patients followed up?

Routine follow-up of BV patients is not nece-ssary, unless the symptoms recur or the patient is pregnant. (4, 9).

33. How effective and/or safe is treating persistent or recurrent vaginal discharge?

Recurrent bacterial vaginosis. A multi-centre controlled clinical trial compared the efficacy of metronidazole vaginal gel to placebo in patients suffering recurrent bacterial vaginosis (112 patients). The trial revealed a reduced risk of recurrence of BV on ending treatment with metronidazole gel when compared to placebo (RR = 0.43: 0.25-0.7395% CI) and 3 months post-treatment (RR = 0.68: 0.49-0.9395% CI). A high risk of bias and imprecision was found (107) (level of evidence: low).

Recurrent Trichomonas vaginalis. Vaginitis caused by metronidazole-resistant Trichomonas vaginalis is an emergent problem, the incidence of which is yet to be established (108). However, recurrent infection caused by Trichomonas vaginalis can usually be explained by re-infection involving an untreated sexual partner or, to a lesser degree, by a relapse. Cases of relapse are most commonly secondary to inadequate initial treatment and is rarely secondary resistance to therapy (108). Treatment therefore consists of administering a larger dose of metronidazole or tynidazole (i.e. an oral dose of 500 mg methronidazole twice a day for 7 days or 500 mg tynidazole every 6 hours for 7 days). The use of a condom during treatment must be insisted on to guarantee suitable treatment of sexual partners. It should be stressed that tynidazole has potential advantages over metronidazole as it has more potent antimicrobial activity in vitro, a longer half-life and has fewer adverse effects (109) (level of evidence: very low). recurrent candidiasis. The presence of four or more episodes during a 12-month period is considered recurrent vulvovaginal candidiasis (vaginal thrush) (9). Fluconazole-resistant Candida albicans is usually not very frequent, having up to 13% estimated prevalence within some populations (110). However, recent epidemiological studies have indicated that non-albicans Candida species are usually found in 10% to 20% of patients suffering recurrent vulvovaginal candidiasis and it is well-known that conventional anti-fungicidal therapy is not effective against these species (9). Isolating and identifying the respective specie should thus be the rule in patients suffering recurrent or persistent vulvovaginal candidiasis, aimed at providing goal-directed therapy (9). (level of evidence: very low).

A clinical trial which included 494 women suffering microbiologically-confirmed recurrent vaginal candidiasis, compared sequential therapy which involved 150 mg fluconazole weekly for 6 months to placebo. 90.8% of the patients taking fluconazole remained recurrence free compared to 35.9% of the women managed with placebo after 6 months (risk of recurrence for placebo: RR = 2.53: 2.02-3.1795% CI). The average clinical recurrence time following the start of the trial was 10.2 months in the fluconazole group and 4.0 months in the placebo group (p < 0.001) (111) (high level of evidence).

Another clinical trial evaluated the effectiveness of intermittent, monthly, post-menstrual therapy involving 500 mg intravaginal clotrimazole compared to placebo in 62 patients. The trial found lower rates of vaginal candidiasis infection in the group who received treatment (30.3% prophylaxis cf.79.35% for the placebo: p < 0.001). This study had a high risk of bias and low precision (112) (level of evidence: low).

34. What is the effectiveness and safety of treating the partner of a patient suffering VDS?

No systematic reviews were found evaluating the effectiveness of treating sexual partners of women suffering Trichomonas vaginalis or vaginal Candidiasis infection.

Treating the partners of patients suffering Trichomonas vaginalis. A controlled clinical trial was found describing treatment for the sexual partners of 137 women suffering Trichomonas vaginalis; it compared the administration of tynidazole to placebo use. Tynidazole was more effective in reducing index case infection persistence or recurrence after 30 days (RR =4.66: 1.41-15.3995% CI) (113). The study had a low risk of bias and good precision. The SR about strategies for partner notification showed that expedited partner treatment increased the number of partners treated compared to provider notification in T. Vaginalis patients (RR= 0.51: 0.35-0.6795% CI) (46) (level of evidence: moderate).

Treating the partners of patients suffering candidiasis. A controlled clinical trial was found which compared treatment with itraconazole to no treatment in sexual partners of patients suffering candidiasis (39 patients). No statistically significant differences were found in terms of microbiological cure in the index case after7 days (RR 1.40: 0.36–5.4695% CI) nor after 30 days (RR 2.26: 0.22–22.5595% CI) nor in terms of clinical improvement from 7 to 30 days (RR 1.95: 0.61–6.1395% CI) (114) (level of evidence: high).

Treating the partners of patients suffering bacterial vaginosis. A systematic review which included six studies (4/11Amstar score) evaluated the effect of treatment with regards to BV recurrence. All 6 studies reported no benefit from treating the partners of patients suffering BV, however the studies had a high risk of bias and low precision, concluding that no evidence had been found to support any recommendation (115).

35. How effective and/or safe is the treatment for pregnant or breastfeeding patients suffering from VDS?

Treating BV in pregnant or breastfeeding women. A systematic review of the literature was found (AMSTAR score 8/11) which included 15 controlled clinical trials and involved 5,888 participants. Antibiotic therapy (amoxicillin or clindamycin or methronidazole) was more effective for eradicating BV in pregnant women compared to placebo (OR 0.17: 0.15-0.20 95% CI). The treatment did not reduce the risk of preterm birth (i.e. less than 37 weeks) (OR 0.91: 0.78-1.0695% CI), premature rupture of the membranes (PROM) before going into labour (OR 0.88: 0.61-1.2895% CI) and did not reduce the risk of puerperal infection (OR 0.67: 0.39-1.1795% CI). Treatment had no impact on the incidence of low birth-weight (OR 0.95: 0.77–1.1795% CI) or neonatal sepsis (OR 1.4: 0.45-4.3695% CI). The study showed that oral antibiotics were effective in reducing the incidence of therapeutic failure (OR 0.15: 0.13- 0.1795% CI), as was vaginal clindamycin (OR 0.27: 0.21-0.3595% CI). Early treatment (before 20 weeks had elapsed) had a beneficial effect on reducing the risk of pre-term birth before 37 weeks (OR 0.72: 0.55–0.9595% CI) and on the incidence of low birth weight (OR 0.31: 0.13- 0.5795% CI). The study did not find any differences regarding the percentage of serious adverse events which would have necessitated interrupting the treatment or non-serious adverse events. There was a high level of heterogeneity regarding some of this SR’s comparisons (116). A further systematic review published after this systematic review led to similar results (117) (level of evidence: moderate).

Treating Trichomonas vaginalis infection in pregnant women. A systematic review of the literature was evaluated which involved 842 patients (AMSTAR score 10/11) from two controlled clinical trials, one of them undertaken in a developing country involving symptomatic and a symptomatic women. Treatment was compared to no treatment and the results revealed lower infection persistence in the group being treated (RR = 0.11: 0.080.1795% CI). The studies had a high risk of bias (118) (level of evidence: moderate).

The safety of metronidazole treatment during pregnancy. Another systematic review of the literature was found (AMSTAR score 6/11) which included 5 observational studies (four cohort studiesand acases and controls study) involving 199,451 pregnant women; It compared the risk of congenital malformations in pregnant women exposed to metronidazole during the first trimester. It demonstrated that treatment with metronidazole did not increase the frequency of any congenital malformation diagnosed at birth (OR 1.08: 0.90–1.29 95% CI) (119) (level of evidence: very low). No studies were found which evaluated the safety of using tynidazole during pregnancy.

Treatment of pregnant women suffering Candida infection. A systematic review of the literature was evaluated (AMSTAR score 9/11) which included 10 controlled clinical trials (830 patients). It showed that clotrimazole, terconazole and miconazole were more effective than nystatin in preventing persistent vaginal infection (RR 0.32: 0.25–0.4195% CI). Likewise, clotrimazole was more effective than the placebo in eradicating Candida infection (RR 0.2: 0.09–0.4595% CI). Two controlled clinical trials included in this review (81 pregnant females) demonstrated that fourday therapy was associated with greater infection persistence compared to seven-day treatment (RR 20.48: 2.89–145.1995% CI); however, seven-day treatment was no more effective than fourteen-day therapy (RR 0.54: 0.29–1.0195% CI). Terconazole was as effective as clotrimazole (RR 1.33: 0.34– 5.1695% CI) This SR includes RCT with high risk of bias and imprecision (120) (level of evidence: low).

36. Which complications most frequently present inpregnant or breastfeeding women suffering from VDS?

Bacterial vaginosis. (BV) associated complications in pregnant patients described to date have been preterm birth, chorioamnionitis, endometritis and premature rupture of the membranes (4,9). However, there is contradictory evidence concerning the true benefit of treating pregnant women suffering from BV with regards tothe complications described above. According to the literature, the sole benefit of treatment is relief from the signs and symptoms related to BV infection (4). However, the benefit of treating pregnant women suffering from BV who have a history of preterm birth has been shown. In these cases, treatment decreases the risk of preterm birth, the incidence of low birth weight and premature rupture of the membranes (9). Metronidazole and clindamycin are not contraindicated in pregnancy (9), however it is known that administering vaginal clindamycin after week 20 of pregnancy is associated with negative outcomes for neonates, such as low birth weight and neonatal infections (4,9).

Trichomonas vaginalis.Infection caused by Trichomonas vaginalis has been associated with adverse perinatal outcomes, particularly with the presence of premature rupture of membranes, such as preterm birth (OR 1.3: 1.1-1.4 95% CI), low birthweight (OR 1.3: 1.1-1.5 95% CI) (121) and neonatal infection (122). Despite this treating TV during pregnancy has not been shown to reduce perinatal morbidity (4). Some trials have suggested an increased risk of premature and low birth weight following treatment with metronidazole, however serious methodological limitations in these studies have not allowed solid conclusions to be drawn (4). TV is a sexually-transmitted disease which has unpleasant symptoms and is associated with adverse outcomes including facilitating transmission of HIV. Therefore it is prudent to offer treatment to women suffering TV infection in pregnancy. Clinicians should counsel their patients regarding the risks and benefits of treatment (118).

Candida albicans. Candida usually inhabits warm areas of the body, such as the mouth, vagina, perineum and groin. The infection is usually not troublesome and women are often asymptomatic. No evidence has been found suggesting that the infection should be treated in asymptomatic women. The safety and effectiveness of single dose treatments during pregnancy has not been proven (120). A clinical study evaluated the impact of Candida infection in pregnancy on neonatal health, however the significance of transmission of this infection is not completely understood at present. Vulvovaginal candidiasis during pregnancy has not been shown to be harmful for the foetus (123).

SCROTAL INFLAMMATION SYNDROME

37. Which aetiological agents are associated with scrotal inflammation syndrome?

Epididymitis is usually associated with C. trachomatis or N. Gonorrhoeae infection, however it can also arise secondary to infection from enteric organisms in men who engage in active penetrative anal sex without protection (9).

38. What are the clinical features of scrotal inflammation syndrome?

Scrotal inflammation syndrome includes the presence of epididimitis, which is characterised by swelling and/or unilateral testicular pain, with or without urethral discharge and an increase in local skin temperature. There may also be erythema and oedema of the scrotal skin (11). Scrotal inflammation syndrome is not always preceded by dysuria or urethral discharge. A slight increase in polymorphonuclear (PMN) cells in urethral secretion hasonly been demonstrated in some cases (124).

39. What is the most effective and safest treatment for scrotal inflammation syndrome?

The use of ceftriaxone has been found to be effective for treating scrotal inflammation syndrome caused by Neisseria gonorrhoeae from indirect evidence provided by studies analysing ceftriaxone treatment versus other antibiotics in similar syndromes caused by Neisseria gonorrhoeae. An RCT (59) evaluated the microbiological cure of patients with signs and symptoms of urethritis caused by Neisseria gonorrhoeae following treatment with either 500 mg DU ciprofloxacin, 500 mg ceftriaxone IV SD or 2 g spectinomycin IM SD. Clinical efficacy was reported to be 90% in the ceftriaxone group, 80% in the ciprofloxacin group and 94% in the spectinomycin group (there was no further statistic alanalysis) (Level of evidence: low).

The available evidence for making recommendations was insufficient, therefore the Canadian Healthcare Agency’s Sexually-Transmitted Infections Guidelines and the CDC guideline recommendations were adopted (Atlanta) (4,9). This decision was the consensus of experts on the topic (level of evidence: low).

Slow resolution of the symptoms and signs of scrotal inflammation, in spite of suitable treatment, should lead to a clinician to consider other diagnoses including g testicular torsion, which is a surgical emergency (125).

40. Which complications are most frequently associated with scrotal inflammation syndrome?

Scrotal inflammation syndrome has increasingly been associated with chronic epididimitis as a complication. Other complications have been described, such as chronic pain and infertility but incidence of these is very low (126).

41. What is the indicated follow-up for scrotal inflammation syndrome patients?

According to the consensus of experts, followup is recommended two weeks after beginning treatment (level of evidence: very low).

42. How effective and safe is the treatment for the partner of a patient suffering from scrotal inflammation syndrome?

The group of exper ts welcomed the recommendations for treating the sexual partners of patients suffering Neisseria gonorrhoeae and Chlamydia trachomatis infections, as well as the recommendation for treating the partners of patients affected by Gram-negative epididimitis (level of evidence: very low).

INGUINAL BUBO SYNDROME

43. Which aetiological agents are associated with inguinal bubo syndrome?

Inguinal bubo syndrome covers two separate pathologies: venereal lymphogranuloma and chancroid (4); the former results from infection by C. trachomatis serovars L1, L2 or L3 and the latter from H. Ducreyi infection (95).

44. What are the clinical features of inguinal bubo syndrome?

Inguinal bubo syndrome characteristically presents with 1 or more papules or ulcers in the inguinal region, accompanied by unilateral and bilateral lymphadenopathy, called buboes (95).

In the case of chancroid, the ulcer begins as a papule which evolves into one or more pustular lesions. When these rupture, painful ulcerations are produced with an associated purulent discharge and a granulomatous base which may or may not be accompanied by active bleeding. The location of the lesion varies according to the patient’s gender. In men, the lesions frequently occur on the prepuce, the balano prepucial groove and the base of the penis. In men and women, the lesions can occur on the external genitals (frequently found in the vaginal or cervical region) (127). Painful inguinal lymphadenopathy occurs in 30% of patients suffering chancroid. Chancroid can often be mistaken for syphilis during the soft chancre phase, however, the distinguishing feature is that a chancroid ulcer is painful, whereas a chancre is usually painless (9).

45. What is the most effective and safest treatment for inguinal bubo syndrome?

Insufficient evidence was found to make recommendations on the treatment of inguinal bubo syndrome, therefore the recommendations made by CDC (Atlanta) for sexually-transmitted infections (4), the Canadian Healthcare Agency (9) and expert consensus have been adopted (level of evidence: very low).

46. Which complications most frequently present in inguinal bubo syndrome?

Venereal lymphogranuloma responds well to antibiotic treatment, however if it is left untreated, an extensive lesion of the tissue can occur, leading to complicated abscesses, chronic fistula formation and chronic pelvic-abdominal pain (128). Proctitis caused by venereal lymphogranuloma is a complication of the infection which can occur in men and women. It can present with rectal ulcerations, bloody anal discharge, anal fissures and/or fistulas in the anal region which can trigger constitutional symptoms (129).

What type of follow-up is indicated for patients suffering inguinal bubo syndrome?

The panel of experts recommended follow-up two weeks after commencing treatment (level of evidence: very low).

48. How effective or safe is the treatment of the partner of a patient suffering inguinal bubo syndrome?

These recommendations are based on the available evidence on the syndromic management of genital ulcers (level of evidence: very low).

49. What is the most effective and safest treatment for pregnant or breastfeeding women suffering inguinal bubo syndrome?

This recommendation was based on the available evidence on the syndromic management of genital ulcers in pregnant women (level of evidence: very low).

50. What are the most frequently occurring complications of inguinal bubo syndrome in pregnant women?

Little has been described in the literature about the complications which may affect pregnant women suffering from inguinal bubo syndrome; however, if the data obtained regarding C. trachomatis infections is extrapolated, then the complications are related to ascending infection towards the uterus, leading to PID. If the infection is vertically transmitted, the neonate can develop an ophthalmological (trachoma) and/or pulmonary infection; in either of these cases it is recommended that Prenatal Control Guidelines should be referred to (130).

AUDIT INDICATORS

The indicators are given below, grouped by entity orthe entities in charge.

Colombian Ministry of Health

• The Colombian Ministry of Health must develop a form for reporting, a database and present reports concerning the analysis of the data so collected.

• Availability of rapid tests for C. trachomatis and N. Gonorrhoeae by institution and attention level.

• Percentages of strains resistant to the antibiotics mentioned in the recommendations.

Colombian Local Secretariats of Health

• Number of subjects receiving promotion and prevention activities per institution.

• Amount of user training activities per institution.

• Availability of rapid tests for C. trachomatis and N. gonorrhoeae per institution per attention level.

• Number of patients referred to regional public health laboratories or sentinel institutions due to recurrence for aetiological and resistance study.

• Percentage of strains resistant to the antibiotics mentioned in the recommendations.

Abbreviations appearing in health carerelated documents originally written in Spanish

• Healthcare-providing institution, Third party payers

• Sexual and reproductive health consultation available in institutions.

• Availability of genital tract infection consultation in the institutions.

• Opportunity for appointments regarding sexual and reproductive health.

• Opportunity for appointments regarding sexually- transmitted infections and other genital tract infections.

• Amount of user training activities per institution.

• Availability of rapid tests for C. trachomatis and N. gonorrhoeae per institution per attention level.

• Number of patients receiving medicaments for syndromic management, in the same institution the same day as the consultation.

• Amount of patients receiving medicaments for managing their partners by type of syndromic management (when required), in the same institution on the same day as the consultation.

• Amount of treatments for partners which were denied by third party payers.

• Amount of treatments for partners which were administered by third party payers.

•Amount of complaints regarding the non-availability oftreatment for patients and/or partners in entitiesrelated to the syndromic management of sexually-transmitted infections

• Amount of patients remitted to regional public health laboratories or sentinel institutions for aetiological study and assessment of resistance due to recurrence.

Patients

Amount of complaints arising from the lack of availability of treating a patient and/or couple in entities related to the syndromic management of sexually-transmitted infections.

UPDATING THE GUIDELINES

The recommendations presented in these guidelines must be updated during the next three years or before hand in the case of new evidence becoming available which would modify the recommendations given here.

SOURCES OF FINANCING

The preparation of these guidelines has been financed by the Colombian Ministry of Health and Social Protection and by COLCIENCIAS (via contract 159/2010 with the Universidad Nacional de Colombia, the institution selected from those competing in the bidding for contract 500/2009 for preparing Integral Attention Guidelines (IAG) within the Colombian General Healthrelated Social Security System). These guidelines form part of a group of 25 evidence-based IAG incorporating financial considerations and implementability within the Colombian Healthrelated Social Security System (CHSSS) and which were developed following a Colombian Ministry of Health and Social Protection initiative regarding priority issues involving highly prevalent topics in Colombia through a contract awarded to the Universidad Nacional de Colombia (a member of the Centro Nacional de Investigacion en Evidencia y Tecnologías en Salud - CINETS alliance).

PEER REVIEW

The Guideline was reviewed by people from the International Health Central American Institute Foundation (IHCAI).

DECLARATION OF EDITORIAL INDEPENDENCE

The financing entities have accompanied the preparation of the present document, there by guaranteeing the transferability and applicability of its contents to the context of the Colombian SGSSS. The scientific research work and preparation of the recommendations included in the present document were conducted independently by the Universidad Nacional de Colombia’s GDG.

ALL MEMBERS OF THE GDG AND PEOPLE WHO HAVE PARTICIPATED IN THE EXPERT COLLABORATION AND EXTERNAL REVIEW HAVE DECLARED ANY CONFLICT OF INTEREST.

Main researcher – Guidelines’ leader Hernando Guillermo Gaitán-Duarte, MD, MSc in Clinical Epidemiology, Professor in the Universidad Nacional de Colombia’s Faculty of Medicine’s Obstetrics and Gynaecology Department and Clinical Research Institute, Coordinator Sexually Transmitted Infection. Cochrane Review Group.

Andrea Esperanza Rodríguez Hernández, MD, specialist in Applied Statistics, MSc in Clinical Epidemiology, assistant teacher in the Universidad Nacional de Colombia. Clinical Research Institute, the Guidelines’ Methodological Coordinator.

Ingrid Arévalo Rodríguez, Psychologist, MSc Clinical Epidemiology, Universidad Nacional de Colombia, PhD (c) in Paediatrics, Obstetrics and Gynaecology, Preventative Medicine and Public Health, Universidad Autónoma, Barcelona.

Edith Angel Müller, MD, Fellow in Gyneco-obstetrics and Perinatal Infectology, Associate Professor Universidad Nacional de Colombia’s Obstetrics and Gynaecology Department, Federación Colombiana de Obstetricia y Ginecología (FECOLSOG) representative, member of the Sexually-Transmitted Infections Cochrane Review Group’s Editorial Committee.

Hugo Enrique López Ramos, MD, in Clinical Epidemiology (c), member of the Colombia society of Urology representative for preparing the guidelines.

Jesús Santiago Estrada Mesa, MD, Specialist in Microbiology and Parasitology. Clinical laboratory Director Obra de la Congregación Mariana, Medellin, Colombia. Asociación Colombiana de Infectología (ACIN) representative.

Francisco Fernández, MD, Local Health Secretariat’s Sexual and Reproductive Health Coordinator, teacher in the Universidad Cooperativa de Colombia’s Faculty of Medicine, Primary Attention Expert.

Edwar Eugenio Hernández Vargas, Psychologist, Secretary for the Red Interuniversitaria por la Diversidad de Identidades Sexuales (REDDES) affiliated to the Sociedad Colombiana de Sexología, Psychology Expert.

Carol Zussandy Páez Canro, MD, teaching fellow in the Clinical Research Institute, Universidad Nacional de Colombia, Guidelines Monitor.

Carlos Fernando Grillo-Ardila, MD, MSc in Clinical Epidemiology, teacher in the Universidad Nacional de Colombia’s Gynaecology and Obstetrics Department, member of the Sexually-Transmitted Infections Cochrane Review Group’s Editorial Committee.

Juan Manuel Reyes Sánchez, Pharmaceutical Chemist, teaching fellow in the Universidad Nacional de Colombia’s Clinical Research Institute, Guidelines’ Monitor.

Miguel Hernando Díaz Ortega, BSc in Bacteriology and Clinical Laboratory. MSc in Clinical Epidemiology, Universidad Nacional de Colombia contractor, Guidelines’ Monitor, Sexually Transmitted Infections Cochrane Review Group. Trial Search Coordinator.

Constanza Collazos Vidal, MD, MSc Epidemiology, External Assessor Sociedad Colombiana de Anestesiología (SCA) Scientific Branch, specialist in Qualitative Research. Natalia Marcela Calderón Benitez, Chief Nurse, MSc Nursing, Assessor for the Colombian League for the Fight against AIDS. Nursing expert.

Javier H Eslava Schmalbach, MD MSc PhD, Professor in the Universidad Nacional de Colombia’s Faculty of Medicine’s Surgery Department and Clinical Research Institute.

Correspondence: Hernando G Gaitán-Duarte, e-mail: hgggaitand@unal.edu.co. Postal address: Instituto de Investigaciones Clínicas, Of 205, Facultad de Medicina, Ciudad Universitaria, Bogotá, Colombia.

ACKNOWLEDGEMENTS

Ministerio de salud y proteccion social Isabel Cristina Idárraga Vásquez, consultant regarding strategies for eliminating maternal-infant transmission of HIV and congenital syphilis, Direction General de Salud Pública, Ministerio de Salud y Proteccion Social.

Johana Castrillón, Gestión de la Demanda, Ministerio de Salud y Protección Social.

Daniel M. García, UNFPA, Ministerio de Salud y Protección Social.

Tevia Moreno, Observatorio de VIH, Ministerio de Salud y Protección Social.

Instituto Nacional de Salud

Amparo Sabogal, Vigilancia y Control en Salud, Grupo STI, Instituto Nacional de Salud.

Constanza Cuéllar, Vigilancia y Control en Salud, Grupo STI, Instituto Nacional de Salud.

Rubén Robayo, Vigilancia y Control en Salud, Grupo STI, Instituto Nacional de Salud.

Jeny Carolina Peralta, Vigilancia y Control en Salud, Grupo STI, Instituto Nacional de Salud.

Lida Martínez, Vigilancia y Control en Salud, Grupo STI, Instituto Nacional de Salud.

Secretaría Distrital de Salud, Bogotá

Manuel González, MD, MSc Public Health, Grupo Técnico Salud Sexual y Reproductiva, Secretaría Distrital de Salud.

Blanca Lilia Méndez, Grupo Técnico Salud Sexual y Reproductiva, Secretaría Distrital de Salud.

Asociación Colombiana de Empresas de Medicina Integral (ACEMI).

Juan Manuel Diaz Granados, executive president of ACEMI.

Asociación Nacional de Enfermeras de Colombia (ANEC)

Esperanza Morales Correa, chief nurse, president of the Asociación Nacional de Enfermeras de Colombia (ANEC).

Centro Internacional de Entrenamiento e Investigaciones Médicas (IDEIM)

Adriana Cruz, MD, dermatologist, research fellow in immunology, syphilis research coordinator, Centro Internacional de Entrenamiento e Investigaciones Médicas (IDEIM), Cali, Colombia.

Other professionals

Jorge Eliécer Duque Martinez, MD, MSc Public Health, UNICÁNCER.

Mercy Yolima Martínez Velásquez, MD, gynaecologist and obstetrician, obstetric ultrasound, Clínica Materno e Infantil, SaludCoop.

Nidia Patricia Espíndola, librarian, circulation and loan coordinator, Biblioteca Pública Virgilio Barco.

Escuela de Estudios de Género, Universidad Nacional de Colombia

Florence Thomas, psychologist, MSc Social Psychology, teacher and researcher Escuela de Estudios de Género, Universidad Nacional de Colombia.

Juan Simbaqueba Vargas, psychologist, MScPublic Health, director of the Red Colombiana de Personas Viviendo con VIH.

Juanita María Barreto Gama, social worker, MSc Social Policy, teacher and researcher Escuela de Estudios Género, Universidad Nacional de Colombia.

Martha Clemencia Buriticá Céspedes, teacher and researcher Escuela de Estudios de Género, Universidad Nacional de Colombia.

MANAGEMENT TEAM

Director General:

Rodrigo Pardo Turriago, MD, Clinical Neurologist, MSc Clinical Epidemiology, associate professor, Department of Internal Medicine and Clinical Research Institute, Faculty of Medicine, Universidad Nacional de Colombia.

Academic Coordinator:

Paola Andrea Mosquera Méndez, psychologist, specialist in epidemiology, MSc Social Policy, associate researcher, Clinical Research Institute, Universidad Nacional de Colombia.

Guideline Coordinator:

Edgar Cortés Reyes, physiotherapist-economist, MSc in Clinical Epidemiology, associate professor, Human Body Movement Department and Clinical Research Institute, Director of the Body Movement Department, Facultad de Medicina, Universidad Nacional de Colombia.

Administrative Manager:

Ricardo Losada Saenz, Industrial Engineer, MSc in Research Aptitude and MSc in Public Health, manager of the Federation Colombiana de Obstetricia y Ginecología.

Assessor:

Beatriz Stella Jiménez Cendales, MD, specialist in Health Auditing-IPS management, MSc in International Medical Technology Evaluation, researcher, Universidad Nacional de Colombia.

Documentalist:

Miguel Hernando Díaz Ortega, BSc Bacteriology and Clinical Laboratory, contractor Universidad Nacional de Colombia, Cochrane Group Sexually-Transmitted Infection Search Coordinator.

External Assessors:

Carlos Gomez Restrepo, psychiatrist, MSc Clinical Epidemiology, associate professor Epidemiology and Biostatistics Department, Pontificia Universidad Javeriana.

Paul Brown, economist, MSc Economics, PhD Economics, Professor University of California, Merced, School of Social Sciences, Humanities and Arts.

Cindy Farqhuar, MD, specialist in Gyneco-obstetrics, sub-specialist in Reproductive Endocrinology and Infertility, Auckland University, Editor Cochrane Group for Menstrual Disorders and Infertility.

Anne Lethaby, evidence-based medicine projects researcher, New Zealand Guidelines Group, editor Cochrane Group Menstrual Disorders and Infertility.

Reviewing pairs:

Mario Tristán, doctor epidemiologist. Director Foundation-Cochrane Central America & Caribbean Branch.

Participating Scientific Societies: Federación Colombiana de Obstetricia and Ginecología (FECOLSOG) Sociedad Colombiana de Urología (SCU) Asociación Colombiana de Infectología (ACIN)

Communications team

Vivian Molano, Leonardo Anchique

Patients’ guidelines team

Lina Bonilla, Jair Ospina

Equity Group

Javier H Eslava - Schmalbach

Translation and review of English Version

Dr. Sarah Armstrong. O&G Teaching and Research Registrar Auckland City Hospital

Monica Caicedo Clinical Epidemiology Master Degree student at Universidad Nacional de Colombia

BIBLIOGRAPHY

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Flowchart regarding STI/GTI management in females

Flowchart regarding STI/GTI management in males

Cervicitis syndrome flowchart

Urethral discharge syndrome flowchart

Genital ulcer syndrome flowchart

Vaginal discharge syndrome flowchart

Scrotal inflammation syndrome flowchart

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