Levels of evidence (I-IV) and grades of recommendation (A-C) are defined at the end of the "Major Recommendations" field.
Diagnosis
The main methods of diagnosis revolve around the identification of Haemophilus ducreyi (Van Dyck & Piot, 1994; Ronald & Albritton, 1999; Lewis, 2000) by:
(i) Culture of scrapings from the ulcer base or of pus aspirate from the bubo; culture media include Mueller-Hinton agar or gonococcal agar base enriched with 1% to 2% bovine haemoglobin, 5% fetal calf serum, 1% isovitalex and 3 mg/L vancomycin; modification of these techniques by substitution of 0.2% activated charcoal instead of fetal calf serum has proven equally effective and is much cheaper (Lockett et al., 1991); the use of more than one medium increases sensitivity (Dangor et al., 1992). Since Haemophilus ducreyi is a fastidious organism, patients' specimens should be plated out directly at the clinic or sent rapidly (within 4 hours) to the laboratory; calcium alginate or plastic swabs should be used for sample collection; unfortunately, special, not widely available, transport medium needs to be used.
or
(ii) Microscopy of a Gram stained smear (or other stains) of scrapings from the ulcer base or of pus aspirate from the bubo: demonstration of characteristic gram-negative coccobacilli, with occasional chaining.
or
(iii) Detection of nucleic acid (DNA) by amplification techniques such as polymerase chain reaction techniques, using nested techniques. (Trees & Morse, 1995; West et al., 1995; Webb et al., 1996)
Expert opinion has estimated that, in endemic areas, a positive Haemophilus ducreyi culture is achievable in 60% to 80% of patients considered to have chancroid on clinical grounds. Microscopy is only 50% sensitive compared with culture, and prone to multiple errors given the polymicrobial flora of many ulcers. Polymerase chain reaction is the most sensitive technique, and has been demonstrated to be 95% sensitive compared to culture; conversely culture may be only 75% sensitive relative to polymerase chain reaction. Yet polymerase chain reaction may be negative in a number of culture-proven chancroid cases, owing to the presence of Taq polymerase inhibitors in the DNA preparations extracted from genital ulcer specimens. (Lewis, 2000) A multiple polymerase chain reaction assay has also been developed for the simultaneous amplification of DNA targets from Haemophilus ducreyi, Treponema pallidum and herpes simplex virus types 1 and 2. (Orle et al., 1996) Unfortunately, it is not commercially available, except for research purposes.
Other Diagnostic Methods
Other diagnostic tests have included various antigen-detection techniques involving immunofluorescence or radio-isotopic probes. Serologic diagnosis of chancroid has been useful in a number of epidemiological studies, using enzyme-linked immunoassays (EIAs) using either lysed whole cell, lipo-oligosaccharide (LOS) or outer membrane proteins (OMPs) as antigen sources. (Museyi et al., 1988; Alfa et al., 1993) However, for the individual patient, the method lacks sensitivity, specificity (cross-reaction with other Haemophilus species) and cannot distinguish between remote and recent infection.
To circumvene the many problems of positive diagnosis of chancroid, the U.S. Centers for Disease Control (CDC) proposes that a "probable diagnosis", for both clinical and surveillance purposes, be made if the patient has one or more painful genital ulcers, and (a) no evidence of Treponema pallidum infection by dark field examination of ulcer exudate or by a serologic test for syphilis performed at least 7 days after onset of ulcers, and (b) the clinical presentation, appearance of the genital ulcers and regional lymphadenopathy, if present, is typical for chancroid and a test for herpes simplex virus is negative.
Management
General Advice
- Patients should be advised to avoid unprotected sexual
intercourse until they and their partners(s) have completed treatment and
follow-up.
- Patients should be given a detailed explanation of their condition with particular emphasis on the long-term implications for the health of themselves and their partners(s). This should be reinforced by giving them clear and accurate written information.
Further Investigations
Screening for other possible causes of genital ulcerative disease should be arranged, particularly the diagnosis of Treponema pallidum and genital herpes, but also sometimes the diagnosis of lymphogranuloma venereum (LGV) (see the related guideline titled 2002 National Guideline for the Management of Lymphogranuloma Venereum or donovanosis (see the related guideline titled 2002 National Guideline for the Management of Donovanosis [Granuloma Inguinale]). In addition screening for serological syphilis and possibly for HIV should be offered. Biopsy of lymph nodes may be required to exclude neoplasia.
Treatment
Successful treatment of chancroid should cure infection, resolve clinical symptoms, and prevent transmission to sexual partners.
The main treatment options are presented in Table 1 (summarised below) and most are similar to the 1997 U.S. Centers for Disease Control and Prevention guidelines (Guidelines for treatment of sexually transmitted diseases. MMWR Morbid Mortal Wkly Rep 1997:1-116). Evidence of their clinical efficacy has been obtained in randomised controlled trials for most (Level of Evidence Ib), however grading of recommendation will also take account of ease of administration, side effects and compliance.
Recommended Regimens
- Azithromycin 1 g orally in a single dose (Level of
Evidence Ib, Grade of Recommendation A)
or
- Ceftriaxone 250 mg intramuscularly in a single dose
(Level of Evidence Ib, Grade of Recommendation B)
or
- Ciprofloxacin 500 mg orally in a single dose (Level of
Evidence Ib, Grade of Recommendation B)
or
- Ciprofloxacin 500 mg orally two times a day for 3 days
(Level of Evidence Ib, Grade of Recommendation B/A)
or
- Erythromycin base 500 mg orally four times a day for 7 days (Level of Evidence Ib, Grade of Recommendation B/A)
Table 1. Drugs Shown to be Effective in the Treatment of Chancroid
|
Drug |
Dose |
Route |
Grading of Recommendation |
Level of Evidence |
|
Azithromycin* |
1 g STAT |
Oral |
A |
Ib |
|
Ceftriaxone* |
250 mg STAT |
Intramuscular |
B |
Ib |
|
Ciprofloxacin* |
500 mg twice daily for 3 days*
or |
Oral |
B/A |
Ib |
|
500 mg STAT |
Oral |
B |
Ib |
|
Erythromycin* |
500 mg four times daily for 7 days*
or |
Oral |
B/A |
Ib
|
|
500 mg three times daily for 7 days
or |
Oral |
A |
Ib |
|
250 mg three times daily for 5 days |
Oral |
C |
III |
|
Fleroxacin |
400 mg STAT
or |
Oral
|
B
|
Ib
|
|
400 mg once daily for 5 days# |
Oral |
C |
III |
|
Spectinomycin |
2 g STAT |
Intramuscular |
B |
IIa |
*Recommended by U.S. Centers for Disease Control and Prevention (Centers for Disease Control and Prevention (CDC), 1997).
#Proposed for HIV-positive patients
Azithromycin and ceftriaxone offer the advantage of single dose therapy. They have excellent in vitro activity against Haemophilus ducreyi with no reported resistance to date. (Ronald & Albritton, 1999) Erythromycin given at high doses for 7 days is the World Health Organization (WHO)-recommended first line treatment for chancroid. (World Health Organization, 1994) Although efficacious (with cure rates of 93% noted in Kenya [Tyndall et al., 1994] and India [D'Souza et al., 1998]), poor compliance and gastrointestinal intolerance make alternative therapy desirable (Level of Evidence Ib, Grade of Recommendation B). Lower dosage and simpler regimens of erythromycin have been evaluated in two separate trials in Kenya. Cure rates of 91% were achieved in a randomised double blind trial of erythromycin 500 mg three times daily for 7 days (versus a single dose of ciprofloxacin) (Malonza et al., 1999) (Level of Evidence Ib, Grade of Recommendation B). The efficacy of an even shorter regimen (250 mg three times daily for 5 days) was reportedly high in a small trial conducted by the same team, but this was not a randomized comparative trial (Kimani et al., 1995) (Level of Evidence III, Grade of Recommendation C). Worldwide, several isolates with intermediate resistance to either ciprofloxacin or erythromycin have been reported, thus single dose ciprofloxacin and the shorter (5-day) regimen of erythromycin may not be effective, as has been reported by teams in Rwanda and Malawi. (Bogaerts et al., 1995; Behets et al., 1995) However, the recent double-blind randomised-controlled trial conducted in Nairobi showed comparable cure rates for single dose ciprofloxacin (92%) and the standard 7-day course of erythromycin (91%) (Malonza et al., 1999). The single dose nature and relatively lower cost of the ciprofloxacin regimen makes it an attractive option for many low-income countries. Widespread resistance to trimethoprim-sulfamethoxazole (TMP-SMX) renders this cheap and once effective alternative almost useless, even using high dosages, outside specific settings where susceptibility has still recently been documented (Knapp et al., 1993; Van Dyck et al., 1994).
Alternative regimens:
- Oral single dose fluoroquinolones such as fleroxacin
400 mg (Plourde et al., 1992; Tyndall et al., 1993b) or norfloxacin 800 mg
(Schmid, 1989) (Level of Evidence Ib, Grade of Recommendation B)
- Injectable single dose aminoside such as spectinomycin 2 g intramuscularly (Fransen et al., 1987; Guzman, Guzman, & Bernal, 1992) (Level of Evidence IIa, Grade of Recommendation B)
Allergy
Patients allergic to quinolones or cephalosporins should be treated with the erythromycin regimen.
Treatment for pregnant or lactating mothers and children
The safety of azithromycin for pregnant and lactating women has not been established. Ciprofloxacin is contraindicated for pregnant and lactating women, children, and adolescents less than 18 years of age. The erythromycin or ceftriaxone regimens should be applied. No adverse effects of chancroid on pregnancy outcome or on the fetus have been reported.
Special Considerations
Human Immunodeficiency Virus (HIV) Infection
Patients co-infected with HIV should be closely monitored. There have been concerns that healing may be slower among HIV infected people (Behets et al., 1995; Kimani et al., 1995) and treatment failures have been frequently recorded in Kenya using azithromycin (Tyndall et al., 1994), ceftriaxone (Tyndall et al., 1993a), or single dose fleroxacin (Tyndall et al., 1993b), or in Malawi with low dose erythromycin or ciprofloxacin (Behets et al., 1995). A higher treatment failure rate among HIV infected patients has, however, not been observed by the same Kenyan team in a more recent study using low dose erythromycin or single dose ciprofloxacin (Malonza et al., 1999). In Rwanda, researchers found that HIV and the degree of immunosuppression as measured by CD4 counts had no effect on bacteriological and clinical outcomes and that treatment failures were entirely attributable to resistance of Haemophilus ducreyi to trimethoprim-sulfamethoxazole (TMP-SMX) (Bogaerts et al., 1995). Dosage and duration of the fleroxacin regimen also needed to be increased to treat HIV infected patients in Nairobi (Plourde et al., 1992). The U.S. Centers for Disease Control and Prevention recommends that "since data on therapeutic efficacy with the recommended ceftriaxone and azithromycin regimens among patients infected with HIV are limited, those regimens should be used among persons known to be infected with HIV only if follow-up can be assured." (CDC, 1997) Some experts suggest using the full dose erythromycin 7-day regimen for treating HIV infected persons.
Management of Fluctuant Buboes
The classic strategy has been to needle-aspirate fluctuant buboes from adjacent healthy skin. The procedure is simpler and safer than incision, which is prone to complications (sinus formations). A randomised study conducted during an outbreak of chancroid in the United States (Ernest, Marvez-Valls, & Martin, 1995) has shown that careful incision and drainage is an effective and safe method for treating fluctuant buboes and avoids frequent needle re-aspirations. This procedure should always be performed under effective antibiotic cover.
Follow-up
Patients should be re-examined 3-7 days after initiation of therapy. If treatment is successful, ulcers improve symptomatically within 3 days and substantial re-epithelialisation occurs within 7 days after onset of therapy. The time required for complete healing is related to the size of the ulcer (and perhaps HIV); large ulcers may require more than 2 weeks.
Treatment failures should warrant: (i) investigation of possible co-infections with Treponema pallidum or herpes simplex virus; or (ii) determination of possible resistance by isolation of Haemophilus ducreyi and susceptibility testing by the agar dilution technique or the equally effective but simpler E-test (Lewis, 1997).
Clinical resolution of fluctuant lymphadenopathy is slower than that of ulcers and may require frequent needle aspiration (or drainage).
Sexual Partner(s) Management
Persons who have had sexual contact with a patient who has chancroid within the 10 days before onset of the patient's symptoms should be examined, and treated even in the absence of symptoms, as asymptomatic carriage of Haemophilus ducreyi has been proved to occur (Plummer, 1989; Hawkes et al., 1995).
Definitions:
The following rating scheme was used for major management recommendations.
Levels of Evidence:
Ia
- Evidence obtained from meta-analysis of randomised controlled trials
Ib
- Evidence obtained from at least one randomised controlled trial
IIa
- Evidence obtained from at least one well designed controlled study without randomisation
IIb
- Evidence obtained from at least one other type of well designed quasi-experimental study
III
- Evidence obtained from well designed non-experimental descriptive studies such as comparative studies, correlation studies, and case control studies
IV
- Evidence obtained from expert committee reports or opinions and/or clinical experience of respected authorities
Grading of Recommendations:
A (Evidence Levels Ia, Ib)
- Requires at least one randomised controlled trial as part of the body of literature of overall good quality and consistency addressing the specific recommendation.
B (Evidence Levels IIa, IIb, III)
- Requires availability of well conducted clinical studies but no randomised clinical trials on the topic of recommendation.
C (Evidence Level IV)
- Requires evidence from expert committee reports or
opinions and/or clinical experience of respected authorities.
- Indicates absence of directly applicable studies of good quality.
