Macrólidos para el tratamiento de la infección por Haemophilus ducreyi en población sexualmente activa: Una revisión sistemática
Autor: Romero Gómez, Laura Viviana
Asesor: Alzate, Juan Pablo (Thesis advisor)
Fecha: 2017
Programa: Bogotá - Medicina - Especialidad en Anestesiología y Reanimación
Facultad: Facultad de Medicina

Resumen: Chancroide es una enfermedad ulcerativa genital, endémica en países de bajos recursos;  su reconocimiento como una enfermedad susceptible de control y erradicación, puede  reducir la tasa de infecciones de transmisión sexual (ITS). Los Macrólidos pueden usarse  en esta situación, con buena efectividad y seguridad, en diferentes esquemas, por lo que  pueden reemplazar otro tratamiento antibiótico.  No existe una diferencia estadísticamente significativa entre las alternativas terapéuticas,  excepto para la tasa de cura clínica entre la primera y segunda semana, donde los  Macrólidos pueden tener cierta ventaja cuando se implementan como primera línea de  tratamiento para adultos sexualmente activos con úlceras genitales compatibles con  chancroide. La frecuencia de efectos adversos menores puede no ser diferente entre los  grupos.  En la actualidad, la calidad de la evidencia de la efectividad y seguridad del uso de  Macrólidos para el tratamiento de la infección por H. ducreyi, es baja y muy baja, lo que  implica que el efecto del tratamiento es incierto.  La decisión de prescribir un macrólido sobre otro, debe estar basada en las preferencias  locales en cuanto a tratamiento y costos. Sin embargo, evidencia de muy baja calidad  sugiere que la Azitromicina puede ser considerada como primera línea de tratamiento,  basado en su administración oral en mono dosis, con perfil de seguridad y efectividad  similar, comparado con el uso de Eritromicina.

Macrólidos para el tratamiento de la infección
por Haemophilus ducreyi en población
sexualmente activa: Una revisión
sistemática
Laura Viviana Romero Gómez
Universidad Nacional de Colombia
Facultad de Medicina, Departamento de Obstetricia y Ginecología
Bogotá D.C, Colombia
2017Macrólidos para el tratamiento de la
infección por Haemophilus ducreyi
en población sexualmente activa:
Una revisión sistemática
Laura Viviana Romero Gómez
Tesis presentada como requisito parcial para optar al título de:
Especialista en Obstetricia y Ginecología
Director:
MD, MSc Carlos Fernando Grillo Ardila
Grupo de Investigación:
Enfermedades infecciosas Departamento Obstetricia y Ginecología
Universidad Nacional de Colombia
Facultad de Medicina, Departamento de Obstetricia y Ginecología
Bogotá D.C, Colombia
2017Agradecimientos
Al grupo de investigación de Enfermedades infecciosas Departamento Obstetricia y
Ginecología por su apoyo.Resumen
Chancroide es una enfermedad ulcerativa genital, endémica en países de bajos recursos;
su reconocimiento como una enfermedad susceptible de control y erradicación, puede
reducir la tasa de infecciones de transmisión sexual (ITS). Los Macrólidos pueden usarse
en esta situación, con buena efectividad y seguridad, en diferentes esquemas, por lo que
pueden reemplazar otro tratamiento antibiótico.
No existe una diferencia estadísticamente significativa entre las alternativas terapéuticas,
excepto para la tasa de cura clínica entre la primera y segunda semana, donde los
Macrólidos pueden tener cierta ventaja cuando se implementan como primera línea de
tratamiento para adultos sexualmente activos con úlceras genitales compatibles con
chancroide. La frecuencia de efectos adversos menores puede no ser diferente entre los
grupos.
En la actualidad, la calidad de la evidencia de la efectividad y seguridad del uso de
Macrólidos para el tratamiento de la infección por H. ducreyi, es baja y muy baja, lo que
implica que el efecto del tratamiento es incierto.
La decisión de prescribir un macrólido sobre otro, debe estar basada en las preferencias
locales en cuanto a tratamiento y costos. Sin embargo, evidencia de muy baja calidad
sugiere que la Azitromicina puede ser considerada como primera línea de tratamiento,
basado en su administración oral en mono dosis, con perfil de seguridad y efectividad
similar, comparado con el uso de Eritromicina.
Palabras clave: Chancroide, Macrólidos, Haemophilus ducreyi.VI
Abstract
Chancroid is a genital ulcerative disease endemic in some low-income countries.
Recognition of Chancroid as a susceptible disease for control and eradication, could reduce
STI transmission rates. Macrolides could be use in this situation, with good effectiveness
and safety in different schemes, therefore, could replace other antibiotic treatment.
There is no statistically significant difference between the therapeutic alternatives, except
for the rate of clinical cure between first and second week, where macrolides could have
some advantage when it is implemented as first line therapy for treatment of sexually-active
adults with genital ulcers clinically compatible with chancroid. The frequency of minor
adverse effects could be not different between the groups.
At present, the quality of the evidence on the effectiveness and safety of macrolides for
treatment of H. ducreyi infection is low and very low, implying that we are uncertain about
the estimated treatment effect.
The decision to prescribe one macrolide over another one, should based on the local costs
and treatment preferences. However, very low quality of evidence suggest that,
Azithromycin could be considered as the first therapeutic alternative, based on their mono-
dose oral administration, with a similar safety and effectiveness profile, when it is compared
with long Erythromycin use.
Keywords: Chancroid, Macrolides, Haemophilus ducreyiTABLE OF CONTENTS
ABSTRACT VI
SUMMARY 8
PLAIN LANGUAGE SUMMARY 10
BACKGROUND 11
OBJECTIVES 15
METHODS 15
RESULTS 24
DISCUSSION 32
AUTHORS’ CONCLUSIONS 34
REFERENCES 35
CHARACTERISTICS OF STUDIES 40
SUMMARY OF FINDINGS 56
DATA AND ANALYSES 598 Macrólidos para el tratamiento de la infección por Haemophilus ducreyi en población
sexualmente activa
SUMMARY
Background
Chancroid is a genital ulcerative disease caused by Haemophilus ducreyi. This
microorganism is endemic in Africa, where it can cause up to 10% of genital ulcers.
Macrolides may be an effective alternative to treat chancroid and, based on their oral
administration and duration of therapy, could be considered as first line therapy.
Objectives
To assess the effectiveness and safety of macrolides for treatment of H ducreyi infection in
sexually active adults.
Search methods
We searched the Cochrane STI Group Specialized Register, CENTRAL, MEDLINE,
Embase, LILACS, WHO ICTRP, ClinicalTrials.gov and Web of Science to 30 October 2017.
We also handsearched conference proceedings and reference lists of retrieved studies.
Selection criteria
Randomized controlled trials (RCTs) comparing macrolides in different regimens or with
other therapeutic alternatives for chancroid.
Data collection and analysis
Two review authors independently assessed trials for inclusion, extracted data and
assessed risk of bias. We resolved disagreements through consensus. We used the
GRADE approach to assess the quality of the evidence.
Main results
Seven RCTs (875 participants) met our inclusion criteria, of which four were funded by
industry. Five studies (664 participants) compared macrolides with ceftriaxone,
ciprofloxacin, spectinomycin or thiamphenicol. Low quality evidence suggested there was
no difference between the groups after treatment in terms of clinical cure (risk ratio (RR)
1.09, 95% confidence interval (CI) 0.97 to 1.21; 2 studies, 340 participants with syndromic
approach and RR 1.06, 95% CI 0.98 to 1.15; 5 studies, 348 participants with aetiological
diagnosis) or improvement (RR 0.89, 95% CI 0.52 to 1.52; 2 studies, 340 participants with
syndromic approach and RR 0.80, 95% CI 0.42 to 1.51; 3 studies, 187 participants with9 Macrólidos para el tratamiento de la infección por Haemophilus ducreyi en población
sexualmente activa
aetiological diagnosis). Based on low and very low quality evidence, there was no difference
between macrolides and any other antibiotic treatments for microbiological cure (RR 0.93,
95% CI 0.74 to 1.16; 1 study, 45 participants) and minor adverse effects (RR 1.34, 95% CI
0.24 to 7.51; 3 studies, 412 participants).
Two trials (269 participants) compared erythromycin with any other macrolide type. Low
quality evidence suggested that, compared with azithromycin or rosaramicin, long courses
of erythromycin did not increase clinical cure (RR 1.00, 95% CI 0.91 to 1.10; 2 studies, 269
participants with syndromic approach and RR 1.04, 95% CI 0.93 to 1.16; 2 studies, 211
participants with aetiological diagnosis), with a similar frequency of minor adverse effects
between the groups (RR 1.14, 95% CI 0.63 to 2.06; 1 trial, 101 participants). For this
comparison, subgroup analysis found no difference between HIV-positive participants (RR
1.02, 95% CI 0.73 to 1.43; 1 study, 38 participants) and HIV-negative participants (RR 1.04,
95% CI 0.94 to 1.14; 1 study, 89 participants). We downgraded the quality of evidence to
low, because of imprecision, some limitations on risk of bias and heterogeneity.
None of the trials reported serious adverse events, cost effectiveness and participant
satisfaction.
Authors' conclusions
At present, the quality of the evidence on the effectiveness and safety of macrolides for
treatment of H ducreyi infection in sexually active adults is low, implying that we are
uncertain about the estimated treatment effect. There is no statistically significant difference
between the available therapeutic alternatives for the treatment of sexually active adults
with genital ulcers compatible with chancroid. Low quality evidence suggests that
azithromycin could be considered as the first therapeutic alternative, based on their mono-
dose oral administration, with a similar safety and effectiveness profile, when it is compared
with long-term erythromycin use.
Due to sparse available evidence about the safety and effectiveness of macrolides to treat
H ducreyi infection in people with HIV, these results should be taken with caution.10 Macrólidos para el tratamiento de la infección por Haemophilus ducreyi en población
sexualmente activa
PLAIN LANGUAGE SUMMARY
Review question
In this Cochrane Review, we assess the effectiveness and safety of macrolides in different
regimens or with other treatments for H ducreyi infection in adults.
Background
Chancroid is a sexually transmitted infection (STI) caused by infection with a bacteria called
Haemophilus ducreyi. It causes ulcers in the genital area and is endemic in some low-
income countries. Control and eradication of chancroid could reduce transmission of the
STI from one sexual partner to another. Macrolides are antibiotics that could be effective
and safe for treating H ducreyi infection.
Trial characteristics
We searched the available literature up to 30 October 2017 and we included seven trials
with 875 participants. The trials recruited men and non-pregnant women over the age of 16
years who presented with genital ulcers compatible with chancroid. Three studies included
people with high-risk sexual behaviour as migrant mine workers, sex workers and men with
prostitute contact. All the trials tested for other STIs, and discarded people who were also
infected with syphilis and herpes simple virus. One study included people with HIV. The
most frequent antibiotic treatment was erythromycin with azithromycin as an alternative.
They were compared with ceftriaxone, ciprofloxacin, spectinomycin or thiamphenicol. Five
studies compared two types of antibiotic and two studies compared different ways of
treating with macrolides. Four trials were funded by pharmaceutical companies.
Key results
There was no difference between the types of antibiotics in sexually active adults with
genital ulcers compatible with chancroid. Erythromycin is usually the first choice for
treatment but low quality evidence suggested that azithromycin (as a single dose, oral (by
mouth) administration) had similar safety and effectiveness.
Because of sparse evidence about the safety and effectiveness of macrolides to treat
Haemophilus ducreyi infection in people with HIV, these results should be taken with
caution.
Quality of evidence
The quality of evidence was low as there was a risk of bias due to poor methods, people
dropping out of the study and pharmaceutical companies sponsored four studies.1 Macrólidos para el tratamiento de la infección por Haemophilus ducreyi en población
1 sexualmente activa
BACKGROUND
Description of the condition
Chancroid is a genital ulcerative disease caused by Haemophilus ducreyi (Spinola 2002),
which is a Gram-negative, facultatively anaerobic coccobacillus. This bacterium is from the
family Pasteurellaceae, and was identified in 1889 by August Ducrey (Lewis 2003).
Currently, the prevalence of H ducreyi is unknown. However, in the late 1990s, worldwide
absolute frequency was estimated at around seven million cases (Steen 2001). It is
endemic in some Africa countries, where H ducreyi infection can cause up to 10% of genital
ulcer cases (González-Beiras 2016; Mohammed 2008). The infection can occur in sporadic
outbreaks in vulnerable populations, such as sex workers or between cocaine users (Bong
2002; Steen 2001).
H ducreyi infects the stratified squamous epithelium of mucosal surfaces and the regional
lymph nodes (Mohammed 2008) through superficial abrasions that occur during sexual
intercourse (O'Farrell 2014). Chancroid usually does not exhibit prodromal symptoms and,
after an incubation period of three to seven days, generates a papule as the first clinical
manifestation (Bong 2002). This papule commonly goes unnoticed, except on some
occasions when it can cause local pain or burning (Mohammed 2008), and finally acquires
a pustule configuration that precedes the ulcerative disease (Bong 2002). H ducreyi
replication occurs during all these stages and is accompanied by intermittent bacterial
shedding even before ulceration, which suggests that the bacteria may be transmissible
before clinical manifestations (Lewis 2003).
Typically these ulcers are well-defined, painful, with rough raised edges that are not
indurated, but with a soft consistency. Hence, they are commonly known as soft chancres
(Min Salud 2013). Multiple ulcers occur at the same time and show a tendency to
coalescence, which is why they can acquire a giant (greater than 2 cm) or serpiginous
configuration (Mohammed 2008). The base of the ulcer is covered by a greyish or yellowish
necrotic, purulent exudate that frequently bleeds when scraped (Bong 2002). In men, the
most common ulcer sites are the prepuce, frenulum and coronal sulcus; in women, it is the
introitus (Lewis 2006). In most cases, ulcers can resolve and heal without any treatment
between four and six weeks after infection (Lewis 2006). However, in up to 50% of cases,
the ulcerative stage of the disease can be accompanied by tender inguinal
lymphadenopathies with pyogenic response in an ipsilateral location, named buboes (Lewis
2000). Spreading of ulceration, with destruction of both skin and underlying soft tissue can
also be followed up by bubo ulceration (Mohammed 2008).
The diagnosis of chancroid requires a high index of suspicion, since its clinical
manifestations may be indistinguishable from other infections such as herpes simplex virus
(HSV) or syphilis (Lewis 2000). For this reason, confirmation of H ducreyi infection may
require different diagnostic methods and includes some specific techniques (Steen 2001).
Various studies describe the usefulness of Gram staining and direct microscopy to
diagnose chancroid through the visualization of morphological forms, such as "schools of
fish" or "railroad tracks" (Lewis 2000; Zeballos 2002). However, Gram staining and direct12 Macrólidos para el tratamiento de la infección por Haemophilus ducreyi en población
sexualmente activa
microscopy are not recommended, given their limited accuracy due to contamination with
common flora (Lewis 2006). Serological studies are not useful either, because of their low
sensitivity and specificity, cross-reactions with other Haemophilus species, the inability to
distinguish recent infections from old ones, and scarce immunoglobulin G (IgG) serum
antibody responses (O'Farrell 2014). Initially, serial cultures with 5% (v/v) carbon dioxide
were considered the gold standard test to confirm diagnosis, despite their low accuracy,
given by a sensitivity and specificity lower than 80% (CDC 2015; Lewis 2006). However,
due to their low performance, requirement for highly qualified personnel, time-consuming
nature, requirement for stringent transport and that they are not widely available, cell culture
has been abandoned as a diagnostic method (Lewis 2003).
Other diagnostic tests, such as immunofluorescence (IFI), show quite similar accuracy to
in vitro cell culture, with a sensitivity of 89% and specificity of 81% (Lewis 2000). However,
the cost and maintenance of these techniques represents a major disadvantage for
populations that do not have the resources or technical capabilities for their development
(Lewis 2000; Mohammed 2008). The nucleic acid amplification test (NAAT) is considered
the gold standard for diagnosis of H ducreyi infection (Lewis 2000); it relegates other
diagnostic techniques, such as cell culture, in cases of therapeutic failure or where
susceptibility testing is needed to determine therapeutic management (Kemp 2011). The
advantage of the NAAT is that it detects genes even if they are in low abundance from
readily available samples (Chernesky 1999; Marrazzo 2001), and reflects a substantial
improvement in accuracy with a higher sensitivity (98.4%) and specificity (99.6%) compared
to other techniques (Mohammed 2008). However, the disadvantage of this approach is that
specimens could contain amplification inhibitors that cause false-negative results and test
results are not immediately available (CDC 2015), which requires the patient to schedule a
second appointment with the healthcare provider.
Based on the mentioned limitations for available diagnostic tests, the Centers for Disease
Control and Prevention (CDC) advises suspicion of H ducreyi infection when the person
presents with one or more painful genital ulcers, with or without regional lymphadenopathy,
ruling-out syphilis and HSV infections by examination of ulcer exudate, or, in the case of
syphilis, with negative serological tests, at least seven days after the onset of the ulcer
(CDC 2015). This approach has been adopted by the World Health Organization (WHO)
for low-income countries, proposing syndromic management of genital ulcers (Lewis 2000).
This approach does not require laboratory studies and promotes the use of single doses in
first-line regimens to assure adherence and reduce costs (WHO 2005).
Description of the intervention
During the 1980s and 1990s, the management of genital ulcers caused by H ducreyi
involved the prescription of trimethoprim-sulfamethoxazole, amoxicillin or tetracycline.
However, the emergence of resistant strains of H ducreyi in low-income countries, with the
subsequent worldwide increase of therapeutic failure rates forced a change in treatment
approach. Macrolides may be an effective alternative to treat chancroid, and may replace
the previously mentioned medications (BASSH 2014; CDC 2015; O'Farrell 2014).1 Macrólidos para el tratamiento de la infección por Haemophilus ducreyi en población
3 sexualmente activa
The CDC and some guidelines development groups recommend the use of mono-dose as
first therapeutic alternative to treat sexually transmitted infections (STIs), based on the
premise of effectiveness and adherence to the intervention (CDC 2015; Gaitán-Duarte
2013; Min Salud 2013). In concordance with this, macrolides, particularly azithromycin,
represent an attractive option for the syndromic management of genital ulcers (Kemp 2011).
Macrolides can be administered to pregnant or nursing women (CDC 2015; Min Salud
2013), or people who are allergic to cephalosporins (O'Farrell 2014). Guidelines
recommend as a first option a single oral dose of azithromycin 1 g or, if feasible, a long
treatment regimen of erythromycin 500 mg every eight hours for one week (CDC 2015; Min
Salud 2013). If treatment with macrolides is not available or not possible, a second line
could be the administration of ceftriaxone at a single intramuscular dose of 250 mg, or
ciprofloxacin 500 mg orally every 12 hours for three days, as an alternative regimen (CDC
2015).
How the intervention might work
The macrolides drug family includes azithromycin, erythromycin and clarithromycin; of
which azithromycin and erythromycin are used for chancroid treatment. Macrolides inhibit
bacterial protein synthesis by binding to the P site on the 50S subunit of the bacterial
ribosome (Flórez 2008), and exhibit a bacteriostatic or bactericidal effect depending on the
microorganism, tissue and bioavailability (Flórez 2008). Azithromycin is a second-
generation macrolide and is derived from erythromycin. It has a similar mode of action, but
achieves higher concentrations at the site of infection due to cell accumulation (especially
phagocytes) and to higher volume of distribution (Flórez 2008). Azithromycin has a half-life
of 68 hours, and its oral bioavailability is approximately 38%. The maximum plasma
concentration is achieved between 2.2 and 4.0 hours after administration (Micromedex
2014), and it is mainly eliminated by hepatic metabolism (75%) (Flórez 2008). The most
common adverse effects include diarrhoea (3.6%), nausea (2.5%), abdominal pain (2.5%),
headache, dizziness (1.3%) and elevation of transaminases (1.5%) (Flórez 2008).
A second line of treatment is ceftriaxone, which is a third-generation cephalosporin. Like
other beta-lactam drugs, it causes bacterial lysis by preventing cell wall synthesis through
the disruption of peptidoglycan synthesis (Flórez 2008). Common adverse effects include
diarrhoea (2.7% to 5.6%), eosinophilia (6%) and thrombocytosis (5.1%). Serious adverse
effects include erythema multiforme, Stevens-Johnson syndrome, toxic epidermal
necrolysis, haemolytic anaemia (less than 1%), hypersensitivity reaction (2.7% to 3.3%)
and renal failure (Micromedex 2014). Its half-life is 5.8 to 8.7 hours (Flórez 2008).
Ceftriaxone is eliminated primarily by renal excretion (33% to 67%) as the unmetabolized
drug (Dynamed 2014). Finally, if treatment with macrolides or ceftriaxone is not available
or not possible, the alternative is ciprofloxacin (CDC 2015). Ciprofloxacin is a
fluoroquinolone and it functions by inhibiting DNA gyrase, which an enzyme that is
necessary for cell division (Flórez 2008). Its half-life is four hours, and 40% to 50% of the
oral dose is excreted in the urine as the unmetabolized drug (Dynamed 2014). Adverse
effects include nausea (2.5%), diarrhoea (1.6%), abnormal liver function tests (1.3%),
vomiting (1%) and rash (1%) (Flórez 2008).14 Macrólidos para el tratamiento de la infección por Haemophilus ducreyi en población
sexualmente activa
Why it is important to do this review
Recognition of chancroid as a susceptible disease for control and eradication (Steen 2001)
could reduce STI transmission rates and burden in the community (Mutua 2012). Currently,
there are no published systematic reviews that compare the effectiveness and safety of
macrolides with any other antibiotic for treating H ducreyi infection in sexually active
populations. This systematic review will facilitate the synthesis of the current evidence, and
recognize its strengths and weakness, address the uncertainty of the current knowledge,
and make it possible to assess the effectiveness and safety of this intervention. Macrolides
could offer the advantages of oral and single-dose administration, improved treatment
adherence, and reduced adverse effects (CDC 2015).1 Macrólidos para el tratamiento de la infección por Haemophilus ducreyi en población
5 sexualmente activa
OBJETIVES
To assess the effectiveness and safety of macrolides for treatment of H ducreyi infection
in sexually active adults.
METHODS
Criteria for considering studies for this review
Types of studies
We included randomized controlled trials (RCTs) that compared macrolides as first-line
therapy with any other antibiotic treatment or any other symptomatic treatment. We also
included RCTs that compared different macrolides regimens (by macrolide type) for the
treatment of H ducreyi infection.
We excluded quasi-RCTs because this produces effect estimates that indicate more
extreme benefits when they are compared with RCTs (Higgins 2011). We excluded cross-
over and cluster trials, because of the nature of the condition and intervention (Higgins
2011). Finally, we excluded RCTs that assessed the effectiveness of trimethoprim-
sulfamethoxazole because several H ducreyi isolates with resistance to this medication
have been reported worldwide (CDC 2015).
Types of participants
We included men and non-pregnant women over the age of 16 years who presented with
purulent genital ulcers compatible with chancroid.
We divided participants into two groups: syndromic (based on the presence of common and
reasonably consistent signs and symptoms) and aetiological diagnosis (supporting on a
laboratory-confirmed).
Types of interventions
Macrolides (any dose, frequency, duration and administration route) versus:
 any other antibiotic treatment (any dose, frequency, duration and administration
route);
 any symptomatic treatment (e.g. buboes aspiration or analgesic treatment); or
 any other macrolide type (any dose, frequency, duration and administration route).
Types of outcome measures16 Macrólidos para el tratamiento de la infección por Haemophilus ducreyi en población
sexualmente activa
Primary outcomes
 Clinical cure (proportion of participants with complete healing of ulcer and buboes
after therapy). Syndromic and aetiological approaches.
 Clinical improvement (proportion of participants with decrease in the size of the ulcer
or buboes after intervention). Syndromic and aetiological approaches.
 Microbiological cure (proportion of participants with eradication of H ducreyi after
treatment, by in vitro cell culture or by polymerase chain reaction (PCR) test).
 Serious adverse event (proportion of participants who experience any adverse
effect requiring hospitalization or discontinuation of therapy, or both).
Secondary outcomes
 Minor adverse events (e.g. metallic taste, nausea, vomiting, diarrhoea, headache,
etc.).
 Participant satisfaction with treatment.
 Cost-effectiveness of the intervention.
Search methods for identification of studies
We conducted a systematic search of the literature to identify relevant RCTs irrespective of
their language of publication, publication date and publication status (published,
unpublished, in press, and in progress). We performed both electronic searches in
bibliographic databases and handsearches, as described in the Cochrane Handbook for
Systematic Reviews of Interventions (Higgins 2011).
Electronic searches
We contacted the Information Specialist of the Cochrane STI Group in order to implement
a comprehensive search strategy to identify as many relevant RCTs as possible in
electronic databases. We used a combination of controlled vocabulary (Medical Subject
Headings (MeSH), Emtree terms, DeCS, including exploded terms) and free-text terms
(considering spelling variants, synonyms, acronyms and truncation) for "Haemophilus
ducreyi infection" and "Macrolides," with field labels, proximity operators and boolean
operators. We listed our search strategies in Appendix 1.
We searched the following electronic databases:
 Cochrane STI Group's Specialized Register, which includes RCTs and controlled
clinical trials, from 1944 to 2017, located through: electronic searches of CENTRAL,
MEDLINE and Embase; online handsearching of journals not indexed in MEDLINE
or Embase, according to the journals' master list of the Cochrane STI Group;
 Cochrane Central Register of Controlled Trials (CENTRAL), Ovid: inception to 30
October 2017;1 Macrólidos para el tratamiento de la infección por Haemophilus ducreyi en población
7 sexualmente activa
 MEDLINE, Ovid: inception to 30 October 2017;
 MEDLINE In-Process & Other Non-Indexed Citations, Ovid: inception to 30 October
2017;
 MEDLINE Daily Update, Ovid: inception to 30 October 2017;
 Embase (Emabase.com): inception to 30 October 2017;
 LILACS, IAHx interface: inception to 30 October 2017.
For MEDLINE, we used the Cochrane highly sensitive search strategy for identifying RCTs:
sensitivity and precision maximizing version (2008 revision), Ovid format (Higgins 2011).
We combined the LILACS search strategy with an RCT filter of IAHx interface.
Searching other resources
We searched the following resources for additional trials:
 trials registers:
o WHO International Clinical Trials Registry Platform (ICTRP) portal
(apps.who.int/trialsearch/): inception to 30 October 2017;
o ClinicalTrials.gov (clinicaltrials.gov/): inception to 30 October 2017;
 Web of Science: inception to 30 October 2017.
Grey literature
We searched the System for Information on Grey Literature in Europe "OpenGrey"
(www.opengrey.eu/) from inception to 30 October 2017.
Handsearching
We handsearched the conference proceeding abstracts of the following events:
 International Society for Sexually Transmitted Diseases Research (ISSTDR)
(www.isstdr.org/): 2007, 2009, 2011, 2013 and 2015;
 British Association for Sexual Health and HIV (BASHH) (www.bashh.org/): 2014
and 2015;
 International Congress on Infectious Diseases (ICID) (www.isid.org/): 2010, 2012
and 2014;
 International Union against Sexually Transmitted Infections (IUSTI) (www.iusti.org/):
2011, 2012, 2013, 2014 and 2015;
 International Society for Infectious Diseases (ISID) (www.isid.org/): 2011, 2012,
2013, 2014 and 2015;
 International Meeting on Emerging Diseases and Surveillance (IMED)
(www.isid.org/): 2007, 2009, 2011, 2013 and 2014;
 Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC)
(www.icaac.org/): 2011, 2012, 2013, 2014 and 2015;
 International Federation of Gynecology and Obstetrics (FIGO)
(www.figo2012.org/home/): 2009, 2012 and 2015.18 Macrólidos para el tratamiento de la infección por Haemophilus ducreyi en población
sexualmente activa
We handsearched other relevant publications on the same topic and the reference lists of
all relevant studies identified.
Data collection and analysis
Selection of studies
LR and CFG-A independently screened all the titles and abstracts retrieved from the search
strategy to determine which trials we should assessed further. LR and CFG-A
independently investigated the full-text articles of all potentially relevant articles and we
resolved any disagreements through discussion. We presented a PRISMA flow diagram to
show the process of trial selection (Figure 1). We listed all articles excluded after full-text
assessment and the reasons for exclusion in the Characteristics of excluded studies table.
Data extraction and management
We designed a data extraction form, which was pilot tested, to extract data from the
included studies. For eligible studies, LR and CFG-A independently extracted data. We
resolved any disagreements through discussion until we reached a consensus.
We extracted data on the following:
 location of the study and setting;
 study design;
 power calculation performed;
 inclusion and exclusion criteria;
 syndromic or aetiological diagnosis.
 baseline information of the participants to ensure comparable intervention groups
at entry (number of women, number of men, age, prior treatment for ulcer, presence
of buboes, site and number of lesions, HIV coinfection);
 total number of intervention groups;
 types of interventions: macrolide type, concentration, frequency and duration of
treatment;
 types of comparison: any other antibiotic treatment (any dose, frequency, duration
and administration route) or any symptomatic treatment (e.g. buboes aspiration or
analgesic treatment);
 methods used to generate random allocation and maintain allocation concealment;
 use of any method of blinding of researchers or participants to evaluate outcomes;
 number of participants enrolled, randomized, excluded after randomization, and
analyzed;
 adherence to the planned intervention and other interventions in the groups under
evaluation;
 how the trial authors defined outcomes;
 time of follow-up of participants to measure outcomes;
 use of intention-to-treat (ITT) analysis;
 funding sources;1 Macrólidos para el tratamiento de la infección por Haemophilus ducreyi en población
9 sexualmente activa
 ethical issues: use of signed informed consent and ethics approval.
For eligible studies, two review authors (CFG-A and LR) entered data into Review Manager
5 (RevMan 2014), and checked for accuracy. When information regarding any of the above
was unclear, we attempted to contact the authors of the original trial reports for further
details. For a single RCT report, we extracted data directly into a data collection form; in
cases of multiple reports, we extracted data from each report separately and then combined
information across data collection forms.
Assessment of risk of bias in included studies
Two review authors (LR and CFG-A) independently assessed the risk of bias for each
included trial using the criteria outlined in the Cochrane Handbook for Systematic Reviews
of Interventions (Higgins 2011). We resolved any disagreements by consensus or by
consulting a third review author (CH). The review authors who assessed the risk of bias in
the included studies were theme and methodology experts.
1. Random sequence generation (checking for possible selection bias)
For each included study, we described the method used to generate the allocation
sequence in sufficient detail to allow an assessment of whether it should produce
comparable groups. We assessed the method as:
 low risk of bias (any truly random process, e.g. random number table; computer
random number generator);
 high risk of bias (any non-random process, e.g. odd or even date of birth; hospital
or clinic record number); or
 unclear risk of bias.
2. Allocation concealment (checking for possible selection bias)
For each included study, we described the method used to conceal allocation to
interventions prior to assignment and assessed whether intervention allocation could have
been foreseen in advance of, or during, recruitment or changed after assignment. We
assessed the methods as:
 low risk of bias (e.g. telephone or central randomization; consecutively numbered
sealed opaque envelopes);
 high risk of bias (open random allocation; unsealed or non-opaque envelopes,
alternation; date of birth); or
 unclear risk of bias.
3.1. Blinding of participants and personnel (checking for possible performance bias)
For each included study, we described the methods used, if any, to blind study participants
and personnel from the knowledge of which intervention a participant received. We
considered that studies were at low risk of bias if they were blinded, or if we judged that the20 Macrólidos para el tratamiento de la infección por Haemophilus ducreyi en población
sexualmente activa
lack of blinding would have been unlikely to affect results. We assessed blinding separately
for different outcomes or classes of outcomes. We assessed the methods as at:
 low, high or unclear risk of bias for participants;
 low, high or unclear risk of bias for personnel.
3.2. Blinding of outcome assessment (checking for possible detection bias)
For each included study, we described the methods used, if any, to blind outcome
assessors from the knowledge of which intervention a participant received. We assessed
blinding separately for different outcome or classes of outcomes. We assessed methods
used to blind outcome assessment as:
 low, high or unclear risk of bias.
4. Incomplete outcome data (checking for possible attrition bias due to the amount,
nature and handling of incomplete outcome data)
For each included study and for each outcome or class of outcomes, we described the
completeness of the data including attrition and exclusions from the analysis. We stated
whether attrition and exclusions were reported and the number of participants included in
the analysis at each stage (compared with the total number of randomized participants),
reasons for attrition or exclusion where reported, and whether missing data were balanced
across groups or were related to outcomes. Where sufficient information was reported, or
could be supplied by the trial authors, we reincluded missing data in the analyses that we
undertook. We assessed methods as:
 low risk of bias (e.g. no missing outcome data; missing outcome data balanced
across groups);
 high risk of bias (e.g. numbers or reasons for missing data imbalance across groups;
'as treated' analysis done with substantial departure of intervention received from
that assigned at randomization); or
 unclear risk of bias.
We used a cut-off point of 20% to determine whether a study was at low or high risk of bias
according to the level of missing data.
5. Selective reporting (checking for reporting bias)
For each included study, we described how we investigated the possibility of selective
outcome reporting bias and what we found. We assessed the methods as:
 low risk of bias (where it was clear that the study authors reported all the study's
prespecified outcomes and all expected outcomes of interest to the review);
 high risk of bias (where not all the study's prespecified outcomes had been reported;
one or more reported primary outcomes were not prespecified; outcomes of interest
were reported incompletely and so could not be used; the study failed to include
results of a key outcome that would have been expected to had been reported); or2 Macrólidos para el tratamiento de la infección por Haemophilus ducreyi en población
1 sexualmente activa
 unclear risk of bias.
6. Other bias (checking for bias due to problems not covered by (1) to (5) above)
For each included study, we described any important concerns we had about other possible
sources of bias (e.g. stopped early, extreme baseline imbalance, claimed to have been
fraudulent or funded by industry). We assessed whether each study was free of other
problems that could put it at risk of bias. We assessed methods as:
 low risk of other bias;
 high risk of other bias; or
 unclear risk of other bias.
7. Overall risk of bias
To summarize the quality of the evidence, we considered sequence generation, blinding of
outcome assessor, incomplete outcome data and selective reporting domains to classify
each study as:
 low risk of bias when we judged all the four criteria as at low risk of bias;
 high risk of bias when we judged at least one criterion as at high risk of bias;
 unclear risk of bias when we judged all the four criteria as at unclear risk of bias and
moderate risk of bias in the remaining cases (Tramacere 2015).
We explored the impact of the level of bias through undertaking sensitivity analyses (see
Sensitivity analysis).
Measures of treatment effect
For dichotomous data, we presented the results as risk ratios (RRs) with 95% confidence
intervals (CIs). The RR was used as a relative effect measure, which works well with a low
or high rate of events, and is easy to interpret and use in clinical practice.
We performed meta-analysis separately for participants with syndromic and aetiological
diagnosis. Syndromic management implies an approach in which clinic diagnostic was
based on the presence of common and reasonably consistent signs and symptoms without
resorting to techniques for laboratory confirmation (WHO 2005).
Unit of analysis issues
Where we identified a clinical trial that randomized participants to several intervention
groups, we determined which intervention groups were relevant. To avoid confusion for the
reader, we included all intervention groups of the study in the Characteristics of included
studies table, and provided a detailed description only of the intervention groups that were
relevant to the review, and we only used these groups in the analyses.22 Macrólidos para el tratamiento de la infección por Haemophilus ducreyi en población
sexualmente activa
Finally, to overcome a unit-of-analysis error for a study that could contribute multiple,
correlated comparisons, we combined all relevant experimental intervention groups of the
studies into a single group and combined all relevant control intervention groups into a
single control group, to create a single pair-wise comparison (Higgins 2011).
The unit of analysis was the participant who received treatment. We performed separate
analyses for participants who had microbiological and clinical cure and clinical improvement
at first week, between first and second week, or after the second week.
Dealing with missing data
We reported the percentage of observations with missing data of each included trial. For all
outcomes, we performed analyses, as far as possible, on an ITT basis (i.e. we attempted
to include all participants randomized to each group in the analyses, and we analyzed all
participants in the group to which they were allocated, regardless of whether or not they
received the allocated intervention). In case that this was not possible, the denominator for
each outcome in each trial was the number randomized minus any participants whose
outcomes were missing. We contacted the study investigators to request the missing data.
Assessment of heterogeneity
We assessed statistical heterogeneity in each meta-analysis using the I² statistic and Chi²
test values (Higgins 2011). We regarded heterogeneity as substantial if the I² statistic value
was greater than 40% and if we found a low P value (less than 0.10) in the Chi² test for
heterogeneity, which we plotted in a forest plot (RevMan 2014).
Assessment of reporting biases
We planned to explored publication bias through assessment of funnel plot asymmetry and
formal tests. For continuous outcomes, we planned to use the test proposed by Egger 1997,
and for dichotomous outcomes we planned to use the test proposed by Harbord 2006.
However, we included fewer than 10 trials in the meta-analysis, so we did not perform these
analyses.
Data synthesis
We performed statistical analyses using Review Manager 5 (RevMan 2014). We conducted
separate analyses for syndromic and aetiological syndromic and diagnose. Because WHO
(WHO 2005) and other clinical practice guidelines (Min Salud 2013) recommend syndromic
management for low-income countries, we presented as primary analysis the effects of the
intervention based on those studies that implemented this approach and as secondary
analysis, the results from trials that used aetiological diagnosis.2 Macrólidos para el tratamiento de la infección por Haemophilus ducreyi en población
3 sexualmente activa
We used a fixed-effect meta-analysis for combining data where it was reasonable to
assume that studies were estimating the same underlying treatment effect (i.e. where trials
were examining the same intervention, and the trial populations and methods were judged
sufficiently similar). If there was clinical heterogeneity sufficient to expect that the underlying
treatment effects differed between trials, or if we detected substantial statistical
heterogeneity, we used a random-effects meta-analysis to produce an overall summary if
a mean treatment effect across trials was considered clinically meaningful. We treated the
random-effects summary as the mean range of possible treatment effects and we
discussed the clinical implications of treatment effects differing between trials. If the mean
treatment effect was not clinically meaningful, we did not combine trials.
If we used random-effects analyses, we presented the results as the mean treatment effect
with 95% CIs, and the estimates of the Tau² and I² statistics.
'Summary of findings' tables
We used the GRADE approach to produce a 'Summary of findings' table for each
comparison and by outcome (microbiological and clinical cure, clinical improvement, and
serious or minor adverse effects) (Guyatt 2011) We downgraded the quality of evidence
depending on the presence of the following factors:
 study limitations;
 inconsistency of results;
 indirectness of evidence;
 imprecision;
 publication bias.
Subgroup analysis and investigation of heterogeneity
We explored the following potential sources of heterogeneity using subgroup analyses:
 HIV status (positive versus negative participants);
 disease clinical stage (ulcer versus ulcer plus inguinal buboes).
We restricted subgroup analyses to the primary outcomes: microbiological and clinical cure,
clinical improvement and serious adverse events.
Sensitivity analysis
We performed sensitivity analyses to identify aspects of the review that might have affected
the results; for example, where there was risk of bias associated with the quality of some
of the included trials (low versus unclear or high risk of bias).24 Macrólidos para el tratamiento de la infección por Haemophilus ducreyi en población
sexualmente activa
RESULTS
Description of studies
Results of the search
We searched the available literature up to 30 October 2017. We retrieved 62
references, of which we screened 36 after we removed duplicates. Of these, we
screened the full-text of 10 references. Seven published trials met our inclusion
criteria (Ballard 1990; D'Souza 1998; Dos Santos 1994; Malonza 1999; Martin 1995;
Plummer 1983; Tyndall 1994). We excluded three studies (see the Characteristics
of excluded studies table). We presented a PRISMA diagram in Figure 1 to illustrate
the study selection process.
Included studies
The seven included trials had 875 participants with a sample size ranging from 46
to 245 people. Three trials were from Kenya (Malonza 1999; Plummer 1983; Tyndall
1994), and one trial each from India (D'Souza 1998), South Africa (Ballard 1990),
USA (Martin 1995), and Brazil (Dos Santos 1994), Two trials were multicentric (Dos
Santos 1994; Martin 1995), but only one of them used a method for sample size
calculation (Martin 1995). Four studies recruited their participants from STI clinics
(Ballard 1990; Dos Santos 1994; Malonza 1999; Martin 1995). Four studies were
sponsored by academic institutions with industry support (Malonza 1999; Martin
1995; Plummer 1983; Tyndall 1994), and three did not made a clear allusion to this
aspect (Ballard 1990; Dos Santos 1994; D'Souza 1998). All trials included
outpatients. Six trials were published in English and one in Portuguese (Dos Santos
1994).
Population
Included studies recruited sexually active people aged 16 to 60 years without recent
history of antibiotic treatment, who attended with genital ulcer disease with or
without inguinal or femoral lymphadenopathies. Three studies included men and
non-pregnant women (D'Souza 1998; Malonza 1999; Martin 1995), and four
recruited only men (Ballard 1990; Dos Santos 1994; Plummer 1983; Tyndall 1994).
Four trials implemented syndromic diagnosis for enrolling their population,
additionally presenting the effect of the intervention when the analysis was restricted
to participants with aetiological confirmation (Malonza 1999; Martin 1995; Plummer
1983; Tyndall 1994). The remaining studies recruited and reported exclusively
people with bacteriological confirmation (Ballard 1990; D'Souza 1998; Dos Santos2 Macrólidos para el tratamiento de la infección por Haemophilus ducreyi en población
5 sexualmente activa
1994). One study supplemented the diagnostic pathway with PCR (Malonza 1999),
two studies supplemented the diagnostic pathway by direct Gram-stained smear
looking for gram-negative bacilli with a "school of fish" pattern (D'Souza 1998; Dos
Santos 1994), and the remaining trials used media culture. The specimens were
taken from ulcer base or the buboes.
With the aim of identifying participants with Treponema pallidum coinfection, the
retrieved studies implemented dark field microscopy combined with serology
(Ballard 1990; D'Souza 1998; Dos Santos 1994; Martin 1995; Plummer 1983) or
PCR (Malonza 1999) or with microhaemaglutination (Tyndall 1994). HSV infection
was discarded using media culture (Ballard 1990; Martin 1995; Plummer 1983),
Tzanck smear (D'Souza 1998) or PCR (Malonza 1999). Two trials did not discarded
HSV and Chlamydia infection ( Dos Santos 1994; Tyndall 1994). Five trials
screened their participants for HIV (Ballard 1990; D'Souza 1998; Malonza 1999;
Martin 1995; Tyndall 1994); the remaining two did not (Dos Santos 1994; Plummer
1983). HIV seropositivity was not an exclusion criterion in only two trials (Malonza
1999; Tyndall 1994).
Some studies search for other STIs such as Chlamydia trachomatis (Ballard 1990),
Donovanosis (D'Souza 1998), or Neisseria gonorrhoeae (Plummer 1983), but this
was not consistent between trials. Three studies included populations with high-risk
sexual behaviour such as migrant mine workers (Ballard 1990), sex workers
(Malonza 1999), and men with prostitute contact (Tyndall 1994). One trial required
participants to refrain from sexual contact during treatment (Ballard 1990), and
another encouraged the participants to bring recent sexual contacts for evaluation
and treatment (Tyndall 1994). The remaining included trials did not make reference
to these aspects.
Interventions
The most frequent intervention was treatment with erythromycin (Ballard 1990;
D'Souza 1998; Dos Santos 1994; Malonza 1999; Plummer 1983), followed by
azithromycin (Martin 1995; Tyndall 1994). For erythromycin, two studies used 500
mg given orally four times a day (D'Souza 1998; Dos Santos 1994), and the other
two used 500 mg three times a day (Ballard 1990; Malonza 1999) with a duration
therapy of five (Ballard 1990), seven (D'Souza 1998; Malonza 1999; Tyndall 1994),
10 (Plummer 1983), or 15 days (Dos Santos 1994). The prescription of azithromycin
was more consistent, and was provided in a single dose of 1 g orally (Martin 1995;
Tyndall 1994).
Comparisons
All trials used antibiotic therapy as the comparison. Two studies prescribed
ciprofloxacin 500 mg orally as a single dose (Malonza 1999), or 500 mg orally twice
a day for three days (D'Souza 1998). One study administered thiamphenicol 5 g
orally as single dose or 500 mg three times a day for five days (Dos Santos 1994).26 Macrólidos para el tratamiento de la infección por Haemophilus ducreyi en población
sexualmente activa
Two studies provided the treatment through the intramuscular route as a single dose
of ceftriaxone 250 mg (Martin 1995) or spectinomycin 2 g (Ballard 1990).
Two studies compared two different macrolides regimens. One was the use of
azithromycin 1 g orally single dose versus erythromycin 500 mg four times daily for
seven days (Tyndall 1994), and the other compared erythromycin 500 mg orally four
times daily versus rosaramicin 250 mg orally four times daily for 10 days (Plummer
1983).
Outcomes
There were some differences in reporting and definition of the outcomes between
trials. All the studies repeated clinical assessments to determinate the evolution of
the lesions (ulcers and buboes) caused by chancroid, registering the change in the
healing processes, size and tenderness after treatment.
All studies reported clinical cure as the primary outcome defining this as the
complete epithelialization of the ulcers after the second treatment week. Three trials
included resolution of the buboes as part of clinical cure (Ballard 1990; Malonza
1999; Plummer 1983), while the other four did not mention this aspect. Four trials
reported clinical improvement defining it as the presence of a lesion without
complete epithelialization with or without decreased tenderness after the second
treatment week (Ballard 1990; D'Souza 1998; Malonza 1999; Martin 1995). One
study assessed the proportion of participants with microbiological cure at the end of
two weeks' follow-up, based on a negative isolation for the germ during a
microbiological examination (Dos Santos 1994).
Four trials reported the frequency of minor adverse events during treatment
capturing the information through symptoms reported by participants (D'Souza
1998; Malonza 1999; Martin 1995; Plummer 1983).
We obtained no data for the primary outcome of serious adverse events or for the
secondary outcomes of participant satisfaction with treatment and cost-
effectiveness of the intervention.
Excluded studies
We excluded three studies for the following reasons: one was not an RCT, one did
not provide a relevant comparison group (some participants were treated with
trimethoprim) and one did not provide a valid intervention group (macrolides as
prophylaxis to prevent an infection) (see Characteristics of excluded studies table).
Risk of bias in included studies2 Macrólidos para el tratamiento de la infección por Haemophilus ducreyi en población
7 sexualmente activa
We summarized the risk of bias assessment in Figure 2 and Figure 3.
Allocation (selection bias)
Random sequence generation (selection bias)
Two trials adequately reported the random sequence generation method by using
a computer-generated randomisation list, making selection bias at entry unlikely
(Malonza 1999; Tyndall 1994). The remaining included trials did not report the
random sequence generation method, making the risk of selection bias at entry
unclear.
Allocation concealment (selection bias)
Two studies adequately implemented a valid concealment of allocation method,
using sequentially numbered sealed envelopes or containers with a similar
appearance (Malonza 1999; Tyndall 1994), making selection bias at entry unlikely.
The remaining included trials did not report the method of allocation concealment,
so we judged them at unclear risk of bias of selection bias.
Blinding (performance bias and detection bias)
Five studies did not report the implemented methodology to blind study participants,
outcome assessors and personnel from knowledge of which intervention a
participant received (Ballard 1990; D'Souza 1998; Dos Santos 1994; Malonza 1999;
Tyndall 1994). However, we considered the studies at low risk for performance or
detection bias because the outcomes were objectively assessed, so the lack of
blinding would be unlikely to affect results. Two studies did not report the
methodology to blind study participants appropriately and so were at high risk for
performance and detection bias because some outcomes were subjectively
assessed and the lack of blinding would be likely to affect results (Martin 1995;
Plummer 1983).
Incomplete outcome data (attrition bias)
Two trials appropriately stated the attrition and exclusions at each stage; the
reasons were balanced across groups and the level of missing data was not over
20%, making attrition bias unlikely (D'Souza 1998; Malonza 1999). Four studies
were at high risk of bias because the level of missing data was over 20% or because
they used an 'as treated' analysis with substantial departure of intervention received
from that assigned at randomization (Ballard 1990; Martin 1995; Plummer 1983;
Tyndall 1994). One study did not provide enough information making the risk of
attrition bias unclear (Dos Santos 1994).28 Macrólidos para el tratamiento de la infección por Haemophilus ducreyi en población
sexualmente activa
Selective reporting (reporting bias)
The trial protocol was not available for all the included trials and it was unclear if the
published reports included all the expected outcomes, including those that were
prespecified. The report had insufficient information to permit judgement of 'yes' or
'no' (rated as unclear risk of bias).
Other potential sources of bias
Four studies were at high risks of bias because were sponsored by industry (Ballard
1990; Martin 1995; Plummer 1983; Tyndall 1994). The remaining retrieved trials
appeared to be free from other sources of bias and were at low risk of other bias.
Overall risk of bias
Because of some limitations on sequence generation, blinding of outcome
assessor, incomplete outcome data and selective reporting domains included
studies were classified as unclear (D'Souza 1998; Dos Santos 1994; Malonza 1999)
or high risk of bias (Ballard 1990; Martin 1995; Plummer 1983; Tyndall 1994).
Effects of interventions
See: Summary of findings table 1 for the main comparison 'Macrolides versus any
other antibiotic treatment' and Summary of findings table 2 Macrolides versus
macrolides (erythromycin versus other macrolide treatment).
1. Macrolides versus any other antibiotic treatment
Five trials including 664 participants compared macrolides versus any other
antibiotic treatment (Ballard 1990; D'Souza 1998; Dos Santos 1994; Malonza 1999;
Martin 1995). Not all contributed data to each outcome.
1.1a. Clinical cure: syndromic approach
Two trials reported the syndromic approach to clinical cure (Malonza 1999; Martin
1995). There was no evidence of a difference between macrolides and any other
antibiotic treatment (RR 1.09, 95% CI 0.97 to 1.21; 2 studies, 340 participants; I² =
0%; Analysis 1.1; Figure 4). The quality of the evidence was low due to limitations
on risk of bias.
1.1b. Clinical cure: aetiological approach2 Macrólidos para el tratamiento de la infección por Haemophilus ducreyi en población
9 sexualmente activa
Five trials reported the aetiological approach to clinical cure (Ballard 1990; D'Souza
1998; Dos Santos 1994; Malonza 1999; Martin 1995). There was no evidence of a
difference between macrolides and any other antibiotic treatment (RR 1.06, 95% CI
0.98 to 1.15; 5 studies, 348 participants; I² = 8%; Analysis 1.2; Figure 5). The quality
of the evidence was low due to limitations on risk of bias.
1.2a. Clinical improvement: syndromic approach
Two trials reported the syndromic approach to clinical improvement (Malonza 1999;
Martin 1995). There was no evidence of a difference between macrolides and any
other antibiotic treatment (RR 0.89, 95% CI 0.52 to 1.52; 2 studies, 340 participants;
I² = 62%; Analysis 1.3). The quality of the evidence was very low due to limitations
on precision, heterogeneity and risk of bias.
1.2b. Clinical improvement: aetiological approach
Three trials reported the aetiological approach to clinical improvement (D'Souza
1998; Malonza 1999; Martin 1995). There was no evidence of a difference between
macrolides and any other antibiotic treatment (RR 0.80, 95% CI 0.42 to 1.51; 3
studies, 187 participants; I² = 0%; Analysis 1.4). The quality of the evidence was
low due to limitations on precision and risk of bias.
1.3. Microbiological cure
One trial assessed microbiological cure (Dos Santos 1994). There was no evidence
of a difference between macrolides and any other antibiotic treatment (RR 0.93,
95% CI 0.74 to 1.16; 1 study, 45 participants; Analysis 1.5). The quality of evidence
was low due to limitations on imprecision.
1.4. Serious adverse events
None of the trials reported serious adverse events.
1.5. Minor adverse events
Three trials reported minor adverse effects (D'Souza 1998; Malonza 1999; Martin
1995). There was no evidence of a significance difference between macrolides and
any other antibiotic treatment (RR 1.34, 95% CI 0.24 to 7.51; 3 studies, 412
participants; I² = 62%; Analysis 1.6). The quality of the evidence was very low due
to limitations on precision, heterogeneity and risk of bias.
1.6. Participant satisfaction with treatment
None of the trials reported participant satisfaction with treatment.30 Macrólidos para el tratamiento de la infección por Haemophilus ducreyi en población
sexualmente activa
1.7. Cost-effectiveness of the intervention
None of the trials reported cost-effectiveness of the intervention.
2. Macrolides versus any symptomatic treatment
We found no trials comparing macrolides versus any symptomatic treatment.
23. Macrolides versus any other macrolide (erythromycin versus any other
macrolide type)
Two trials including 269 participants compared erythromycin versus azithromycin or
rosaramicin (Plummer 1983; Tyndall 1994). Not all contributed data to each
outcome.
23.1a. Clinical cure: syndromic approach
Two trials reported the syndromic approach to clinical cure (Plummer 1983; Tyndall
1994). There was no evidence of a difference between groups (RR 1.00, 95% CI
0.91 to 1.10; 2 studies, 269 participants; I² = 0%; Analysis 2.1; Figure 6). The quality
of the evidence was low due to limitations on risk of bias.
23.1b. Clinical cure: aetiological approach
Two trials reported the aetiological approach to clinical cure (Plummer 1983; Tyndall
1994). There was no evidence of a difference between the groups (RR 1.04, 95%
CI 0.93 to 1.16; 2 studies, 211 participants; I² = 0%; Analysis 2.2). The quality of the
evidence was low due to limitations on risk of bias.
23.2a. Clinical improvement: syndromic approach
Neither trial reported the syndromic approach to clinical improvement.
23.2b. Clinical improvement: aetiological approach
Neither trial reported the aetiological approach to clinical improvement.
23.3. Microbiological cure
Neither trial reported microbiological cure.
23.4. Serious adverse events
Neither trial reported serious adverse events.3 Macrólidos para el tratamiento de la infección por Haemophilus ducreyi en población
1 sexualmente activa
23.5. Minor adverse event
One trial reported minor adverse events (Plummer 1983). There were no significant
differences for minor adverse effects between groups (RR 1.14, 95% CI 0.63 to
2.06; 1 trial, 101 participants; Analysis 2.3). The quality of the evidence was very
low due to limitations on precision, heterogeneity and risk of bias.
23.6. Participant satisfaction with treatment
Neither trial reported participant satisfaction with treatment.
23.7. Cost-effectiveness of the intervention
Neither trial reported cost-effectiveness of the intervention.
Subgroup analysis and investigation of heterogeneity
We performed subgroup analyses to explore whether differences by HIV status
(positive versus negative participants) modified the observed results (Analysis 3.1).
We only retrieved information in the analyses of 'clinical cure' for the comparison
erythromycin versus any other macrolide. The tests for subgroup effect were not
significantly different between HIV-positive participants (RR 1.02, 95% CI 0.73 to
1.43; 1 study, 38 participants) and HIV-negative participants (RR 1.04, 95% CI 0.94
to 1.14; 1 study, 89 participants) (P = 0.94).
We could not analyze potential sources of heterogeneity using subgroup analysis
by disease clinical stage (ulcer versus ulcer plus inguinal buboes), because of lack
of information.
Sensitivity analysis
We could not carry out the planned sensitivity analyses based on the quality of the
included trials because all of the included studies were assessed at unclear or high
risk of bias.
DISCUSSION
Summary of main results
Seven RCTs (875 participants) met our inclusion criteria of which four were funded by
industry. Five trials (664 participants) compared macrolides with ceftriaxone, ciprofloxacin,
spectinomycin or thiamphenicol. Low quality evidence suggested that there was no
difference between the groups after treatment in terms of clinical cure (RR 1.09, 95% CI32 Macrólidos para el tratamiento de la infección por Haemophilus ducreyi en población
sexualmente activa
0.97 to 1.21; 2 studies, 340 participants with syndromic approach and RR 1.06, 95% CI
0.98 to 1.15; 5 studies, 348 participants with aetiological diagnosis) or improvement (RR
0.89, 95% CI 0.52 to 1.52; 2 studies, 340 participants with syndromic approach and RR
0.80, 95% CI 0.42 to 1.51; 3 studies, 187 participants with aetiological diagnosis). Based
on low and very low quality evidence, there could be no difference between macrolides and
any other antibiotic treatments for the outcomes microbiological cure (RR 0.93, 95% CI 0.74
to 1.16; 1 study, 45 participants) and minor adverse effects (RR 1.34, 95% CI 0.24 to 7.51;
3 studies, 412 participants).
Two trials (269 participants) compared erythromycin with any other macrolide type. Low
quality evidence suggested that, compared with azithromycin or rosaramicin, a long course
of erythromycin did not increase clinical cure (RR 1.00, 95% CI 0.91 to 1.10; 2 studies, 269
participants with syndromic approach and RR 1.04, 95% CI 0.93 to 1.16; 2 studies, 211
participants with aetiological diagnosis), with a similar frequency of minor adverse effects
between the groups (RR 1.14, 95% CI 0.63 to 2.06; 1 trial, 101 participants). For this
comparison, subgroup analysis did not suggest a significant difference between HIV-
positive participants (RR 1.02, 95% CI 0.73 to 1.43; 1 trial, 38 participants) and HIV-
negative participants (RR 1.04, 95% CI 0.94 to 1.14; 1 trial, 89 participants).
We downgraded the quality of evidence to low, because of imprecision, some limitations on
risk of bias and heterogeneity.
Overall completeness and applicability of evidence
We conducted a comprehensive search to retrieve all relevant RCTs. Most outcomes were
evaluated except for serious adverse events, cost effectiveness of the intervention and
participant satisfaction with treatment, as none of the trial reported these outcomes.
The applicability of the evidence is both broadly and narrowly related with clinical practice.
Broad because the studies included populations affected with more frequency by this
condition (men and non-pregnant women sexually active aged between 16 and 60 years,
with or without high-risk sexual behaviour, including people with HIV). Tightly related with
clinical practice, as trials recruited participants who had the presence of genital ulcers
consistent with a clinical diagnosis of chancroid (i.e. painful, non-indurated lesions with
purulent bases, with or without inguinal or femoral adenopathies). An aspect with high
relevance is that this evidence could be applied to vulnerable and economically
disadvantaged populations who live in high-income countries as well as in low-income
countries, where the syndromic approach is the recommended management for people with
genital ulcers, given the difficulty of perform an aetiological diagnosis. The interventions
analysed in this review encompass multiple clinical scenarios that are common in current
practice including various antibiotic regimens with different regimens from single doses to
10 days of therapy. Because there is sparse available evidence about the safety and
effectiveness of macrolides to treat H ducreyi infection in people with HIV, these results
should be taken with caution as they are based on small studies.
Quality of the evidence3 Macrólidos para el tratamiento de la infección por Haemophilus ducreyi en población
3 sexualmente activa
We rated the quality of the evidence for this systematic review according to the
recommendations of the GRADE Working Group (Higgins 2011). All included studies were
at high or unclear risk of bias and consequently were graded with low or very low confidence
on the estimate of effect. In addition, the design and execution limitations of retrieved trials,
exhibited flaws in terms of their consistency (heterogeneity) and imprecision (outcome
events with wide CIs and some optimal information size was not achieved). We could not
evaluate publication bias because there were too few included trials for each comparison.
All the results of this review should be taken with caution as they were based on low and
very low quality evidence (see Summary of findings table 1 and Summary of findings table
2).
Potential biases in the review process
This systematic review has some strengths as we adhered to the predefined objectives and
study eligibility criteria. Our search included an appropriate range of databases and
sources, including additional methods to identify eligible studies. We assessed all studies
for risk of bias and graded the quality of evidence using the GRADE approach. However,
we have some concerns about publication bias and related small-study effects. We were
unable to prepare a funnel plot to examine publication bias due to a lack of studies. Four of
the included trials were funded by industry and due to the limited number of trials for each
comparison our confidence on the estimate of effect was low and very low.
Agreements and disagreements with other studies or reviews
There are no previous systematic reviews published on this topic. Most outcomes of interest
in this review revealed that there were no differences between ceftriaxone, ciprofloxacin,
spectinomycin or thiamphenicol use against macrolides for the treatment of chancroid. The
evidence included in our systematic review supports the recommendations from guideline
development groups (CDC 2015; Gaitán-Duarte 2013), who proposed that azithromycin
single dose could be similar in terms of effectiveness, when this is compared with a long
course of erythromycin (CDC 2015) or against other therapeutic alternatives (Gaitán-Duarte
2013).
AUTHORS’ CONCLUSIONS
Implications for practice
As of October 2017, the quality of the evidence on the effectiveness and safety of
macrolides for treatment of Haemophilus ducreyi infection in sexually active adults is low,
implying that we are uncertain about the estimated treatment effect. We found no
statistically significant differences between the available therapeutic alternatives for the
treatment of sexually active adults with genital ulcers compatible with chancroid. Low quality
of evidence suggests that azithromycin could be considered as the first therapeutic34 Macrólidos para el tratamiento de la infección por Haemophilus ducreyi en población
sexualmente activa
alternative, based on mono-dose oral administration with a similar safety and effectiveness
profile when compared with long-term erythromycin use.
Because of the sparse available evidence about the safety and effectiveness of macrolides
to treat H ducreyi infection in people with HIV, these results should be considered with
caution.
Implications for research
There is a need for high-quality randomized controlled trials on treatments for chancroid.
Due to the low quality of evidence for most included outcomes in this Cochrane Review,
future studies that evaluate the same outcomes could change our conclusions. There are
uncertainties that need to be addressed in research in this area including serious adverse
effects, cost effectiveness of the intervention and participant satisfaction. Future
evaluations should include the use of different regimens of antibiotics (among them
macrolides) in different contexts including pregnancy and concurrent HIV infection, and
comparison with symptomatic treatment (aspiration of buboes or surgical excision of
ulcers).
REFERENCES
Included studies
Ballard 1990
Ballard RC, da L`Exposto F. A comparative study of spectinomycin and erythromycin in the
treatment of chancroid. Journal of Antimicrobial Chemotherapy 1990;26:429-434.
Dos Santos 1994
Published data only (unpublished sought but not used)
Dos Santos MF, Góes Siqueira LF. Multicentric comparative study Erythromycin,
Trimetoprim + Sulphamethoxazol, Thiamphenicol capsules and Thiamphenicol granules for
Chancroid treatment [Estudo multicêntrico comparativo da eficácia da eritromicina, do
sulfametoxazol + trimetoprima, tianfenicol càpsulas e tianfenicol granulado no tratamento
do cancro mole]. A Folha Mèdica 1994;109(1):219 - 223.
Malonza 19993 Macrólidos para el tratamiento de la infección por Haemophilus ducreyi en población
5 sexualmente activa
Malonza IM, Tyndall MW. A Randomized, Double-Blind, Placebo-Controlled Trial of Single-
Dose Ciprofloxacin versus Erythromycin for the Treatment of Chancroid in Nairobi, Kenya.
The Journal of Infectious Diseases 1999;180:1886-93.
Martin 1995
Martin DH, Sargent SJ. Comparision of Azithromycin and Ceftriaxone for the Treatment of
Chancroid. Clinical Infectious Diseases August 1995;21(2):409-414.
Paschal D`Souza 1998
Paschal D`Souza, Ravinder K. A Comparative Study of Therapeutic Response of Patients
With Clinical Chancroid to Cirprofloxacin, Erythromycin, and Cotrimoxazole. Sexually
Transmitted Diseases July, 1998;25(6):293 - 295.
Plummer 1983
Plummer FA, Nsanze H. Short-Course and Single-Dose Antimicrobial Therapy for
Chancroid in Kenya: Studies with Rifampin Alone and in Combination with Trimethoprim.
Reviews of Infectious Diseases August 1983;5(3):S565-S572.
Tyndall 1994
Tyndall MW, Agoki E. Single Dose Azithromycin for the Treatment of Chancroid: A
Randomized Comparision With Erythromycin. Sexually Transmitted Diseases July.August
1994;21(4):231-234.
Excluded studies
Ballard 1996
Published and unpublished data
Ballard RC, Htun Ye. Treatment of chancroid with azithromycin. International Journal of
STD and AIDS 1996;7(1):9-12.
Kumar 1990
Kumar B, Sharma VK. Sulphaphenazole, streptomycin and sulphaphenazole combination,
trimethoprim, and erythromycin in the treatment of chancroid. Genitourinary Medicine
1990;66:105-107.
Thornton 1998
Thornton AC, O`Mara Jr EM. Prevention of Experimental Haemophilus ducreyi Infection: A
Randonmized, Controlled Clinical Trial. The Journal of Infectious Diseases 1988;177:1608-
13.36 Macrólidos para el tratamiento de la infección por Haemophilus ducreyi en población
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BASSH 2014
British Association for Sexual Health and HIV (BASSH). National Guideline for the
Management of Chancroid..
https://www.bashhguidelines.org/media/1059/chancroid_2014-ijstda.pdf
doi:10.1177/0956462414542988 (11 June, 2015).
Bong 2002
Bong CT, Bauer ME, Spinola SM. Haemophilus ducreyi: clinical features, epidemiology,
and prospects for disease control. Microbes and Infection 2002;4(11):1141–8.
CDC 2015
Workowski KA, Bolan GA; Centers for Disease Control and Prevention. Sexually
Transmitted Diseases Treatment Guidelines. June 5, 2015. Morbidity and Mortality Weekly
Report. Recommendations and Reports 2015;64(RR-03):1-137.
Chernesky 1999
Chernesky MA. Nucleic acid tests for the diagnosis of sexually transmitted diseases. FEMS
Immunology and Medical Microbiology 1999;24(4):437-46.
Dynamed 2014
Dynamed®. An evidence based medicine point of care tool. Mechanisms of action, dose,
interactions, drug pharmacokinetics. http://www.dynamed.com/home/ (15 October, 2015).
Egger 1997
Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a
simple, graphical test. BMJ 1997;315(7109):629–34.
Flórez 2008
Flórez J, Armijo JA, Mediavilla A. Farmacología Humana. 5th edition. Barcelona: Editorial-
Masson, 2008.
Gaitán-Duarte 2013
Gaitán-Duarte HG, Rodríguez-Hernández AE, Arévalo-Rodríguez I, Angel-Müller E, López-
Ramos HR, Estrada-Mesa JS, et al. Clinical practice guideline for syndromic management
of patients with sexually transmitted infections and other genital tract infections [Guía de
práctica clínica para el manejo sindrómico de los pacientes con infecciones de transmisión3 Macrólidos para el tratamiento de la infección por Haemophilus ducreyi en población
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sexual y otras infecciones del tracto genital]. Rev Colomb Obstet Ginecol 2013;64(2):126-
177.
González-Beiras 2016
González-Beiras C, Marks M, Chen CY, Roberts S, Mitjà O. Epidemiology of Haemophilus
ducreyi Infections. Emerging Infectious Diseases 2016;22(1):1-8.
Guyatt 2011
Guyatt G, Oxman AD, Akl EA, Kunz R, Vist G, Brozek J, et al. Introduction-GRADE
evidence profiles and summary of findings tables. Journal of Clinical Epidemiology
2011;64(4):383-94.
Harbord 2006
Harbord RM, Egger M, Sterne JA. A modified test for small-study effects in meta-analyses
of controlled trials with binary endpoints. Statistics in Medicine 2006;25(20):3443–57.
Higgins 2011
Higgins JPT, Green S, editor(s). Cochrane Handbook for Systematic Reviews of
Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011.
Available from handbook.cochrane.org.
Kemp 2011
Kemp M, Christensen JJ, Lautenschlager S, Vall-Mayans M, Moi H. European guideline for
the management of chancroid. International Journal of STD & AIDS 2011;22(5):241-4.
Lewis 2000
Lewis DA. Diagnostic tests for chancroid. Sexually Transmitted Infections 2000;76(2):137–
41.
Lewis 2003
Lewis DA. Chancroid: clinical manifestations, diagnosis, and management. Sexually
Transmitted Infections 2003;79(1):68-71.
Lewis 2006
Lewis DA, Ison CA. Chancroid. Sexually Transmitted Infections 2006;82(Suppl 4):iv19–20.
Marrazzo 2001
Marrazzo JM. Impact of new sexually transmitted disease diagnostics on clinical practice
and public health policy. Current Infectious Disease Reports 2001;3(2):147–51.38 Macrólidos para el tratamiento de la infección por Haemophilus ducreyi en población
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Micromedex® 2014
Micomedex®. Solutions 2.0. Mechanisms of action, dose, interactions, drug
pharmacokinetics [Mecanismos de acción, dosis, interacciones, farmacocinética de
medicamentos].
http://www.micromedexsolutions.com/micromedex2/librarian/deeplinkaccess?SearchTerm
=TEST (10 October, 2015).
Min Salud 2013
Ministerio de Salud y Protección Social. Clinical practice guidelines syndromic approach to
the diagnosis and treatment of patients with sexually transmitted infections and other
infections of the genital tract [Guía de Práctica Clínica para el abordaje sindrómico del
diagnóstico y tratamiento de los pacientes con infecciones de transmisión sexual y otras
infecciones del tracto genital]. Colciencias Guia No. 16 2013;16:1-79.
Mohammed 2008
Mohammed TT, Olumide YM. Chancroid and human immunodeficiency virus infection – a
review. International Journal of Dermatology 2008;47(1):1-8.
Mutua 2012
Mutua FM, M’Imunya JM, Wiysonge CS. Genital ulcer disease treatment for reducing
sexual acquisition of HIV. Cochrane Database of Systematic Reviews 2012, Issue 8. Art.
No.: CD007933. DOI: 10.1002/14651858.CD007933.pub2.
O’Farrell 2014
O’Farrell N, Lazaro N. UK National Guideline for the management of chancroid 2014.
International Journal of STD & AIDS 2014;25(14):975–83.
RevMan 2014
Review Manager 5 (RevMan 5) [Computer program]. Version 5.3. Copenhagen, Denmark:
Nordic Cochrane Centre, The Cochrane Collaboration, 2014.
Spinola 2002
Spinola SM, Bauer ME, Munson RS Jr. Immunopathogenesis of Haemophilus ducreyi
Infection (chancroid). Infection and Immunity 2002;70(4):1667–76.
Steen 2001
Steen R. Eradicating chancroid. Bulletin of the World Health Organization 2001;79(9):818-
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9 sexualmente activa
Tramacere 2015
Tramacere I, Del Giovane C, Salanti G, D’Amico R, Filippini G. Immunomodulators and
immunosuppressants for relapsing-remitting multiple sclerosis: a network meta-analysis.
Cochrane Database of Systematic Reviews 2015, Issue 9. Art. No.: CD011381. DOI:
10.1002/14651858.CD011381.pub2.
WHO 2005
World Health Organization. Infecciones de transmisión sexual y otras infecciones del tracto
reproductivo: una guía para la práctica básica. Switzerland: Salud Reproductiva e
Investigaciones Conexas, 2005.
Zeballos 2002
Zeballos P, Ara M, Sanz B. The chancroid [El chancroide]. Revista Piel 2002;17(6):16-33.
CHARACTERISTICS OF STUDIES
Characteristics of included studies
Ballard 1990
Methods Setting: South Africa, outpatient clinic.
Trial design: single-centre, parallel, randomized
controlled trial, 2 arms.
Funding sources: not mentioned.
Ethical issues: ethical board and signed consent.
Participants Age: mean 29 years.
Inclusion criteria: migrant mine workers with
genital ulcers consistent with a clinical diagnosis of
chancroid, i.e. painful, non-indurated lesions with
purulent bases. Genital examinations were
performed. If there was > 1 ulcer, the largest ulcer
was selected for study. Participants were included
if dark-field examination proved to be negative for
Treponema pallidum. In addition, they had to be
available for follow-up examination and should not
have received any antimicrobial chemotherapy
during the preceding 7 days40 Macrólidos para el tratamiento de la infección por Haemophilus ducreyi en población
sexualmente activa
Exclusion criteria: People were subsequently
excluded if either HSV or Chlamydia trachomatis
were isolated from their lesions, or if attempts to
isolate Haemophilus ducreyi from genital lesions at
the initial visit were unsuccessful.
Number: 116 men.
Baseline characteristics: aetiological diagnose.
Genital examination performed, and presence and
clinical details of any genital ulceration noted. The
characteristics of any associated inguinal or
femoral lymphadenopathy were recorded. After
material had was obtained for darkfield
microscopy, swabs were taken for isolation of H
ducreyi from the bases of lesions and, where
applicable, aspirates were obtained from fluctuant
lymph nodes. Swabs were also taken directly from
lesions for isolation of C trachomatis and HSV.
Blood was obtained by venepuncture for syphilis
(RPR and FT A-Abs tests) and chlamydial micro-IF
serology. All participants were asked to refrain
from sexual contact and to return for follow-up
examinations between day 7 and day 10 following
initiation of therapy and approximately 1 week later
(days 14-21).
Interventions 2 intervention groups.
Intervention 1: erythromycin base, 500 mg oral 3
times daily for 5 days (69 participants).
Intervention 2: spectinomycin single 2 g
intramuscularly (71 participants).
Outcomes At 7 and 10 days following initiation of therapy and
approximately 1 week later (days 14-21) repeated
clinical assessments were made and
microbiological investigations performed to assess
if the ulcer had not re-epithelialized, if the regional
lymph nodes had become fluctuant, or if an
inguinal or femoral ulcer had formed or persisted.
The trial authors defined clinical cure as the
presence of an ulcer re-epithelialized totally and
clinical improvement as regional lymph nodes
resolution. Adverse events were not reported.
Risk of bias table4 Macrólidos para el tratamiento de la infección por Haemophilus ducreyi en población
1 sexualmente activa
Authors'
Bias Support for judgement
judgement
Random sequence generation "Patients were randomly
U n c le a r ris k
(selection bias) assigned therapy".
Comment: insufficient
information to enable
judgement.
Allocation concealment (selection Comment: insufficient
U n c le a r ris k
bias) information to enable
judgement.
Blinding of participants and personnel Cure was objectively assessed
L o w ris k
(performance bias) and lack of blinding could have
affected results.
Blinding of outcome assessment There was no blinding or
L o w ris k
(detection bias) incomplete blinding, and the
outcome or outcome
measurement was likely to be
influenced by a lack of blinding.
Cure was objectively assessed
and lack of blinding could have
affected results.
Incomplete outcome data (attrition "As treated analyses" and the
H ig h ris k
bias) risk of bias was high according
to the level of missing data (>
20%).
Selective reporting (reporting bias) Comment: insufficient
U n c le a r ris k
information to enable
judgement.
Other bias The trial was sponsored by
H ig h ris k
industry.
D'Souza 1998
Methods Setting: India, outpatient clinic.
Trial design: single-centre, parallel, randomized
controlled trial, 3 arms.
Funding sources: not mentioned.
Ethical issues: ethical board and signed consent.
Participants Age: information not provided.42 Macrólidos para el tratamiento de la infección por Haemophilus ducreyi en población
sexualmente activa
Inclusion criteria: participants with confirmed
infection by Haemophilus ducreyi.
Exclusion criteria: infection by HIV, donovanosis,
syphilis or herpes virus.
Number: 44 men and 2 women.
Baseline characteristics: aetiological diagnosis.
Infection by H ducreyi confirmed through clinical
approach supplemented by direct Gram-stained
smear showing Gram-negative bacilli in a "school
of fish" pattern or culture method with confirmatory
biochemical test (or both). All participants were HIV
negative. Syphilis was excluded by dark ground
illumination and VDRL test. Herpes genitalis was
excluded by Tzanck smear from ulcer and
donovanosis was ruled out by tissue smear
examination stained with giemsa for intracellular
bodies. ELISA test was performed to exclude HIV.
Interventions 3 intervention groups.
Intervention 1: erythromycin 500 mg 4 times daily
for 7 days (15 participants).
Intervention 2: ciprofloxacin 500 mg twice daily for
3 days, followed by placebo therapy for the next 4
days (16 participants).
Intervention 3: sulfamethoxazole 800 mg +
trimethoprim 160 mg twice daily for 7 days (15
participants).
Outcomes Outcomes were cure defined as complete healing
of ulcer before day 21; improvement characterized
by an objective decrease in the size of the ulcer
compared with the size during a previous visit and
failure catalogue as the absence of objective
improvement in any ulcer by day 7 or if there was
an objective progression after day 7.
Risk of bias table
Authors'
Bias Support for judgement
judgement4 Macrólidos para el tratamiento de la infección por Haemophilus ducreyi en población
3 sexualmente activa
Random sequence generation "The patients were assigned
U n c le a r ris k
(selection bias) into three group in a
randomised manner."
Comment: insufficient
information to enable
judgement.
Allocation concealment (selection Comment: insufficient
U n c le a r ris k
bias) information to enable
judgement.
Blinding of participants and personnel Cure and improvement were
L o w ris k
(performance bias) objectively assessed and lack
of blinding could have affected
results.
Blinding of outcome assessment No blinding or incomplete
L o w ris k
(detection bias) blinding, and the outcome or
outcome measurement was
likely to be influenced by a lack
of blinding. Cure and
improvement were objectively
assessed and lack of blinding
could have affected results.
Incomplete outcome data (attrition ≤ 20% participants excluded
L o w ris k
bias) and intention-to-treat analyses
were reported.
Selective reporting (reporting bias) Comment: insufficient
U n c le a r ris k
information to enable
judgement.
Other bias Trial was not sponsored by
Low risk
industry.
Dos Santos 1994
Methods Setting: Brazil, outpatient clinic.
Trial design: multicentre randomized clinical trial.
Funding sources: not mentioned.
Ethical issues: not mentioned.
Participants Age: 17-45 years.
Inclusion criteria: people with chancroid who had
not used antibiotics in the previous weeks or had
allergies to antibiotics.44 Macrólidos para el tratamiento de la infección por Haemophilus ducreyi en población
sexualmente activa
Exclusion criteria: not mentioned.
Number: 60 men.
Baseline characteristics: aetiological diagnose.
Specimens from the ulcer base were collected for
Gram stain. 1 of the hospitals used enriched media
culture. Infection by Treponema pallidum was
discarded with ulcer material and serology with
VDRL.
Interventions 4 intervention groups.
Intervention 1: erythromycin 500 mg at 6-hour
intervals for 10 days (15 participants).
Intervention 2: thiamphenicol granules 5 g single
dose (15 participants).
Intervention 3: thiamphenicol capsules 500 mg at
8-hour intervals for 5 days (15 participants).
Intervention 4: sulfamethoxazole-trimethoprim
960 mg every 12 hours for 10 days (15
participants).
Outcomes At 5, 10 and 15 days following intervention, repeat
clinical assessments were made and
microbiological investigations were performed.
Microbiological cure was defined as no H ducreyi
by culture or Gram stain. Clinical cure was defined
as the presence of an ulcer re-epithelialized totally
in presence of negative isolation.
Risk of bias table
Authors'
Bias Support for judgement
judgement
Random sequence generation "Through randomization it was
Unclear risk
(selection bias) possible to distribute the
patients in groups of 15."
Comment: insufficient
information to enable
judgement.4 Macrólidos para el tratamiento de la infección por Haemophilus ducreyi en población
5 sexualmente activa
Allocation concealment (selection Comment: insufficient
U n c le a r ris k
bias) information to enable
judgement.
Blinding of participants and personnel Cure was objectively assessed
Low risk
(performance bias) and lack of blinding could have
affected results.
Blinding of outcome assessment There was no blinding or
Low risk
(detection bias) incomplete blinding, and the
outcome or outcome
measurement was likely to
have been influenced by a lack
of blinding. Cure was
objectively assessed and lack
of blinding could have affected
results.
Incomplete outcome data (attrition Comment: insufficient
U n c le a r ris k
bias) information to enable
judgement.
Selective reporting (reporting bias) Comment: insufficient
Unclear risk
information to enable
judgement.
Other bias Trial was not sponsored by
L o w ris k
industry.
Malonza 1999
Methods Setting: Kenya, outpatient clinic.
Trial design: single-centre, randomized, double-
blind, placebo-controlled trial.
Funding sources: WHO Global Programme on
AIDS; Medical Research Council of Canada and
Roche Molecular Systems, who provided multiplex
PCR kits.
Ethical issues: ethical board and signed consent.
Participants Age: 18-60 years.
Inclusion criteria: men and women who
presented with purulent genital ulcers clinically
compatible with chancroid and willing to return to
the clinic for follow-up.
Exclusion criteria: not provided.46 Macrólidos para el tratamiento de la infección por Haemophilus ducreyi en población
sexualmente activa
Number: 245 men and women.
Baseline characteristics: syndromic and
aetiological diagnosis. Participants had a detailed
genital examination. Clinicians registered
information on the number, size and tenderness of
ulcers and buboes. Specimens from the ulcer base
were collected for Haemophilus ducreyi culture
and for H ducreyi, Treponema pallidum, and HSV
PCR. HIV was determined by EIA and confirmed
by a second EIA. Study included uncircumcised
men and female sex workers, and did not exclude
participants with mixed infections (H ducreyi and T
Pallidum or H ducreyi and HSV).
Interventions 2 intervention groups.
Intervention 1: erythromycin 500 mg 3 times daily
for 7 days (108 participants).
Intervention 2: ciprofloxacin 500 mg single dose
(105 participants).
Outcomes The response to treatment was evaluated at each
follow-up visit using an objective assessment
based on number of ulcers, size of largest ulcer
and tenderness. Ulcers were designated as
clinically cured, improved or not improved. Buboes,
if present, were evaluated by the same scoring
system. Weekly follow-up visits were arranged until
complete epithelialization of the ulcers (cure) had
occurred or the participant was designated as
having failed treatment (no improvement).
Improvement was defined as partial
epithelialization of the ulcer at the end of follow-up.
Risk of bias table
Authors'
Bias Support for judgement
judgement
Random sequence generation "Randomized, placebo-
L o w ris k
(selection bias) controlled, double-blind study.
Medications were then
dispensed using coded
envelopes, with the first dose of
medication taken under direct
supervision."4 Macrólidos para el tratamiento de la infección por Haemophilus ducreyi en población
7 sexualmente activa
Comment: this was probably
done.
Allocation concealment (selection "Identical packages of
L o w ris k
bias) medication were provided to
each participant."
Comment: this was probably
done.
Blinding of participants and personnel "Each participant received
L o w ris k
(performance bias) either 500 mg of active
ciprofloxacin with a 7-day
course of erythromycin
placebo, to be taken 3
times/day for 7 days, or
ciprofloxacin placebo with a 7-
day course of 500 mg of active
erythromycin to be taken 3
times/day for 7 days."
Comment: this was probably
done.
Blinding of outcome assessment "Each participant received
L o w ris k
(detection bias) either 500 mg of active
ciprofloxacin with a 7-day
course of erythromycin
placebo, to be taken 3
times/day for 7 days, or
ciprofloxacin placebo with a 7-
day course of 500 mg of active
erythromycin to be taken 3
times/day for 7 days."
Comment: this was probably
done.
Incomplete outcome data (attrition ≤ 20% participants excluded
L o w ris k
bias) and intention-to-treat analyses
were reported.
Selective reporting (reporting bias) Comment: insufficient
Unclear risk
information to enable
judgement.
Other bias Industry sponsored this trial.
L o w ris k
However, Roche Molecular
Systems only provided
multiplex PCR kits.
Martin 199548 Macrólidos para el tratamiento de la infección por Haemophilus ducreyi en población
sexualmente activa
Methods Setting: USA, outpatient clinic.
Trial design: multicentre, parallel, randomized
controlled trial.
Funding sources: Pfizer Laboratories, Groton,
CT.
Ethical issues: ethical board and signed consent.
Participants Age: ≥ 16 years.
Inclusion criteria: men and women with painful
genital ulcers, negative darkfield examination and
negative syphilis reagin test. People empirically
treated for syphilis with penicillin or ampicillin were
included in study.
Exclusion criteria: allergy to β-lactam or
macrolide antibiotics; significant underlying
medical disease; history of significant alcohol or
drug (or both) abuse; history of genital herpes;
known HIV infection; pregnancy; treatment with
another investigational drug within the previous 4
weeks; and treatment with antibiotics other than
ampicillin or penicillin within previous 7 days.
Number: 197 men and women.
Baseline characteristics: syndromic and
aetiological diagnose. Specimens for H ducreyi
culture were obtained by applying a cotton swab
to the base of the ulcer; the swab was inoculated
into 2 different cultures. A second swab was
applied to the base of the lesion to obtain a
specimen for HSV culture. Study included
uncircumcised and circumcised men.
Interventions 2 intervention groups.
Intervention 1: azithromycin 1 g single dose orally
(99 participants).
Intervention 2: ceftriaxone 250 mg single dose
intramuscular (98 participants).
Outcomes Participants returned for follow-up examination at
6-8 days. According to response at that time,
further follow-ups were scheduled at 12-16 days
and 19-23 days after treatment. Response was4 Macrólidos para el tratamiento de la infección por Haemophilus ducreyi en población
9 sexualmente activa
defined as healed, improved or not improved.
Healed was defined as complete epithelialization
of the ulcers, improved as lesion that decreased in
size with or without decreased tenderness, not
improved as ulcer that increased in size and
tenderness. Reported adverse effects were
nausea, pain, dyspepsia and vomiting, which were
self-reported.
Risk of bias table
Authors'
Bias Support for judgement
judgement
Random sequence generation "Patients were assigned
U n c le a r ris k
(selection bias) randomly to receive either a
single 1g oral dose of
Azithromycin or a 250mg IM
[intramuscular] dose of
Ceftriaxone."
Comment: insufficient
information to enable
judgement.
Allocation concealment (selection Comment: insufficient
U n c le a r ris k
bias) information to enable
judgement.
Blinding of participants and personnel Adverse effects were
H ig h ris k
(performance bias) subjectively assessed and lack
of blinding could have affected
results. Cure and improvement
were assessed objectively and
lack of blinding could not have
affected results.
Blinding of outcome assessment No blinding or incomplete
High risk
(detection bias) blinding, and the outcome or
outcome measurement was
likely to have been influenced
by a lack of blinding. Adverse
effects were subjectively
assessed and lack of blinding
could have affected results.
Cure and improvement were
assessed objectively and lack
of blinding could not have
affected results.50 Macrólidos para el tratamiento de la infección por Haemophilus ducreyi en población
sexualmente activa
Incomplete outcome data (attrition For adverse effects, the risk of
H ig h ris k
bias) bias was low (e.g. no missing
outcome data; missing
outcome data balanced across
groups). For cure and
improvement, the risk of bias
was high due to the level of
missing data (> 20%).
Selective reporting (reporting bias) Comment: insufficient
U n c le a r ris k
information to enable
judgement.
Other bias Trial was sponsored by
H ig h ris k
industry.
Plummer 1983
Methods Setting: Kenya.
Trial design: single-centre, parallel, randomized
controlled study.
Funding sources: grants from the Medical
Research Council of Canada, Canadian
International Development Agency, WHO and
Schering Corporation Canada.
Ethical issues: ethical board and signed consent.
Participants Age: 18-60 years.
Inclusion criteria: aged 18-60 years, otherwise
healthy, willing to return for follow-up visits and
their lesion specimens were negative on dark-field
microscopic examination.
Exclusion criteria: confirmed infection by syphilis,
Neisseria gonorrhoeae or previous antibiotic
treatment.
Number: 84 men.
Baseline characteristics: syndromic and
aetiological diagnose. Ulcers were cultured for H
ducreyi, Neisseria gonorrhoeae, HSV and other
aerobic bacteria on selective media. Serum and
blood were obtained for syphilis serology,5 Macrólidos para el tratamiento de la infección por Haemophilus ducreyi en población
1 sexualmente activa
biochemistry and complete blood count. Study
included circumcised men.
Interventions 2 intervention groups.
Intervention 1: erythromycin base 500 mg orally 4
times a day for 10 days (45 participants).
Intervention 2: rosaramicin 250 mg orally 4 times
a day for 10 days (39 participants).
Outcomes At the time of enrolment, a standard history and
examination were performed. Ulcers were counted
and measured in 2 dimensions, and the associated
clinical features of tenderness, purulence and
induration were noted. Follow-up visits were
scheduled for days 3 or 4, 7, 10, 14 and 28. At each
follow-up visit, participants were questioned about
ulcer symptoms, sexual contact, therapeutic
compliance and adverse effects.
Ulcers were considered cured if completely
epithelialized, improved if less tender or smaller in
diameter (or both), unchanged if no improvement
was discernible, and worse if larger in diameter.
Failure was defined as no improvement or as
progression of ulcers by day 7. Buboes were
considered cured when no longer tender to
palpation or fluctuant. Analysed adverse effects
were gastrointestinal upset, dizziness, joint pain
and chest pain and were self-reported by
participants.
Risk of bias table
Authors'
Bias Support for judgement
judgement
Random sequence generation "Patients were assigned
U n c le a r ris k
(selection bias) according to a pre-constructed
random sequence."
Comment: insufficient
information to enable
judgement.
Allocation concealment (selection Comment: insufficient
Unclear risk
bias) information to enable
judgement.52 Macrólidos para el tratamiento de la infección por Haemophilus ducreyi en población
sexualmente activa
Blinding of participants and personnel Adverse effects were
H ig h ris k
(performance bias) subjectively assessed and lack
of blinding could have affected
results. Cure was assessed
objectively and lack of blinding
could not have affected results.
Blinding of outcome assessment There was no blinding or
H ig h ris k
(detection bias) incomplete blinding, and the
outcome or outcome
measurement was likely to be
influenced by a lack of blinding.
Adverse effects were
subjectively assessed and lack
of blinding could have affected
results. Cure was assessed
objectively and lack of blinding
could not have affected results.
Incomplete outcome data (attrition For adverse effects, risk of bias
H ig h ris k
bias) was low (e.g. no missing
outcome data; missing
outcome data balanced across
groups). For cure, risk of bias
was high according to the level
of missing data (> 20%).
Selective reporting (reporting bias) Comment: insufficient
U n c le a r ris k
information to enable
judgement.
Other bias Trial was sponsored by
H ig h ris k
industry.
Tyndall 1994
Methods Setting: Kenya, outpatient clinic.
Trial design: single-centre, parallel, randomized
controlled study.
Funding sources: Pfizer and WHO.
Ethical issues: ethical board and signed consent.
Participants Age: 18-60 years.
Inclusion criteria: aged 18-60 years, otherwise
healthy, willing to return for follow-up visits and5 Macrólidos para el tratamiento de la infección por Haemophilus ducreyi en población
3 sexualmente activa
their lesion specimens were negative on dark-field
microscopic examination.
Exclusion criteria: not provided.
Number: 127 men.
Baseline characteristics: syndromic and
aetiological diagnose. Men aged 18-60 years with
purulent genital ulcers. Swabs from the ulcer base
were obtained for Haemophilus ducreyi cultures.
Sera for syphilis and HIV-1 serology were
collected. Participants were encouraged to bring
recent sexual contacts to the clinic for evaluation
and treatment. The participants included HIV-
positive, VDRL-positive, uncircumcised men and
with sex workers contact.
Interventions 2 intervention groups.
Intervention 1: azithromycin 1 g orally single dose
(82 participants).
Intervention 2: erythromycin 500 mg 4 times daily
for 7 days (45 participants).
Outcomes Ulcers were measured and assessed for severity
using a semi-quantitative scale. Participants were
asked to return for assessment on day 7, day 14
and, if necessary, day 21. Ulcers were considered
cured if completely epithelialized. No other
outcomes were reported.
Risk of bias table
Authors'
Bias Support for judgement
judgement
Random sequence generation "The therapy was assigned
L o w ris k
(selection bias) using consecutive
randomization envelopes that
had a predetermined two to one
azithromycin to erythromycin
ratio."
Comment: this was probably
done.
Allocation concealment (selection "The therapy was assigned
Low risk
bias) using consecutive54 Macrólidos para el tratamiento de la infección por Haemophilus ducreyi en población
sexualmente activa
randomization envelopes that
had a predetermined two to one
azithromycin to erythromycin
ratio."
Comment: this was probably
done.
Blinding of participants and personnel Cure was objectively assessed
L o w ris k
(performance bias) and lack of blinding could have
affected results.
Blinding of outcome assessment No blinding or incomplete
L o w ris k
(detection bias) blinding, and the outcome or
outcome measurement was
likely to have been influenced
by a lack of blinding. Cure was
objectively assessed and lack
of blinding could have affected
results.
Incomplete outcome data (attrition For cure, risk of bias was high
H ig h ris k
bias) according to the level of missing
data (> 20%).
Selective reporting (reporting bias) Comment: insufficient
U n c le a r ris k
information to enable
judgement.
Other bias The trial was sponsored by
H ig h ris k
industry.
Footnotes
EIA: enzyme immunoassay; ELISA: enzyme-linked immunoabsorbent assay; FT A-Ab:
fluorescent treponemal antibody absorption; HSV: herpes simplex virus; micro-IF:
microimmunofluorescence; PCR: polymerase chain reaction; RPR: rapid plasma reagin;
VDRL: Venereal Disease Research Laboratory; WHO: World Health Organization.
Characteristics of excluded studies
Ballard 1996
Reason for exclusion Not a randomized controlled trial.
Kumar 1990
Reason for exclusion Did not implement a valid comparison.5 Macrólidos para el tratamiento de la infección por Haemophilus ducreyi en población
5 sexualmente activa
Thornton 1998
Reason for exclusion Did not implement a valid intervention.
SUMMARY OF FINDINGS
Macrolides compared to any other antibiotic for treatment of Haemophilus ducreyi
infection in sexually active adults
Patient or population: sexually active adults
Settings: -
Intervention: macrolides
Comparison: any other antibiotic
Anticipated absolute
effects* (95% CI)
Risk with Risk with
any other macrolides
antibiotic
Study population
735 per 1000 801 per 1000
(713 to 889)
Study population
835 per 1000 885 per 1000
(818 to 960)
Study population
139 per 1000 123 per 1000
(72 to 211)
Study population
175 per 1000 140 per 1000
(74 to 265)
Study population
933 per 1000 868 per 1000
(691 to 1000)
Study population
64 per 1000 86 per 1000
(15 to 481)56 Macrólidos para el tratamiento de la infección por Haemophilus ducreyi en población
sexualmente activa
*The risk in the intervention group (and its 95% confidence interval) is based on the
assumed risk in the comparison group and the relative effect of the intervention (and its
95% CI).
CI: confidence interval; RCT: randomized controlled trial; RR: risk ratio.
GRADE Working Group grades of evidence
High certainty: we are very confident that the true effect lies close to that of the estimate
of the effect.
Moderate certainty: we are moderately confident in the effect estimate: the true effect is
likely to be close to the estimate of the effect, but there is a possibility that it is substantially
different.
Low certainty: our confidence in the effect estimate is limited: the true effect may be
substantially different from the estimate of the effect.
Very low certainty: we have very little confidence in the effect estimate: the true effect is
likely to be substantially different from the estimate of effect.
Footnotes
1Downgraded by two levels for very serious limitations on blinding, incomplete outcome
data and other bias domains.
2Downgraded by one level for substantial heterogeneity (I² > 40%).
3Downgraded by one level for imprecision as the 95% CI crossed through 0.75 and 1.25.
4Downgraded by one level for serious limitations on blinding, incomplete outcome data and
other bias domains.
5Downgraded by two levels for imprecision as the 95% CI crossed through 0.75 and optimal
information size was not achieved.
2 Macrolide (erythromycin) compared to any other macrolide for Haemophilus
ducreyi infection in sexually active adults
Macrolide (erythromycin) compared to any other macrolide for Haemophilus ducreyi
infection in sexually active adults
Patient or population: sexually active adults
Settings: -
Intervention: macrolide
Comparison: any other macrolide
Anticipated absolute effects*
(95% CI)5 Macrólidos para el tratamiento de la infección por Haemophilus ducreyi en población
7 sexualmente activa
Risk with Risk with Relative No of evidence
macrolides macrolides effect participants (GRADE)
(erythromycin (95% CI) (studies)
Study population
888 per 1000 888 per 1000
(808 to 977)
Study population
860 per 1000 894 per 1000
(799 to 997)
Study population
286 per 1000 326 per 1000
(180 to 589)
*The risk in the intervention group (and its 95% confidence interval) is based on the
assumed risk in the comparison group and the relative effect of the intervention (and its
95% CI).
CI: confidence interval; RCT: randomized controlled trial; RR: risk ratio.
GRADE Working Group grades of evidence
High certainty: we are very confident that the true effect lies close to that of the estimate
of the effect.
Moderate certainty: we are moderately confident in the effect estimate: the true effect is
likely to be close to the estimate of the effect, but there is a possibility that it is substantially
different.
Low certainty: our confidence in the effect estimate is limited: the true effect may be
substantially different from the estimate of the effect.
Very low certainty: we have very little confidence in the effect estimate: the true effect is
likely to be substantially different from the estimate of effect.
Footnotes
1Downgraded by two levels for very serious limitations on blinding, incomplete outcome
data and other bias domains.
2Downgraded by one level for serious limitations on blinding, incomplete outcome data and
other bias domains.
3Downgraded by two levels for imprecision as the 95% CI crosses through 0.75 and 1.25
and optimal information size was not achieved.
DATA AND ANALYSES
1 Macrolides versus Any other antibiotic treatment58 Macrólidos para el tratamiento de la infección por Haemophilus ducreyi en población
sexualmente activa
Outcome or Subgroup Studies Participants Statistical Method Effect Estimate
1.1 Clinical cure: 2 340 Risk Ratio (M-H, Fixed, 1.09 [0.97, 1.21]
Syndromic approach. 95% CI)
1.2 Clinical cure: 5 348 Risk Ratio (M-H, Fixed, 1.06 [0.98, 1.15]
Etiological approach. 95% CI)
1.3 Clinical improvement: 2 340 Risk Ratio (M-H, Fixed, 0.89 [0.52, 1.52]
Syndromic approach. 95% CI)
1.4 Clinical improvement: 3 187 Risk Ratio (M-H, Fixed, 0.80 [0.42, 1.51]
Etiological approach. 95% CI)
1.5 Microbiological Cure 1 45 Risk Ratio (M-H, Fixed, 0.93 [0.74, 1.16]
95% CI)
1.6 Minor adverse effects 3 412 Risk Ratio (M-H, Random, 1.34 [0.24, 7.51]
95% CI)
2 Macrolides versus Macrolides (Erythromycin versus other Macrolide treatment)
Outcome or Subgroup Studies Participants Statistical Method Effect Estimate
2.1 Clinical cure: 2 269 Risk Ratio (M-H, Fixed, 1.00 [0.91, 1.10]
Syndromic approach. 95% CI)
2.2 Clinical cure: 2 211 Risk Ratio (M-H, Fixed, 1.04 [0.93, 1.16]
Etiological approach. 95% CI)
2.3 Minor adverse effects 1 101 Risk Ratio (M-H, Fixed, 1.14 [0.63, 2.06]
95% CI)
Macrolides versus Macrolides (Subgroup analysis by HIV status)
Outcome or Subgroup Studies Participants Statistical Method Effect Estimate
3.1 Clinical cure 1 127 Risk Ratio (M-H, Fixed, 1.03 [0.92, 1.16]
95% CI)
3.1.1 VIH positive 1 38 Risk Ratio (M-H, Fixed, 1.02 [0.73, 1.43]
95% CI)
3.1.2 VIH negative 1 89 Risk Ratio (M-H, Fixed, 1.04 [0.94, 1.14]
95% CI)5 Macrólidos para el tratamiento de la infección por Haemophilus ducreyi en población
9 sexualmente activa60 Macrólidos para el tratamiento de la infección por Haemophilus ducreyi en población
sexualmente activa6 Macrólidos para el tratamiento de la infección por Haemophilus ducreyi en población
1 sexualmente activa62 Macrólidos para el tratamiento de la infección por Haemophilus ducreyi en población
sexualmente activa6 Macrólidos para el tratamiento de la infección por Haemophilus ducreyi en población
3 sexualmente activa