Chancroid in Emergency Medicine

Chancroid is a genital ulcerative disease and sexually transmitted infection characterized by soft (nonindurated) ulcers with irregular borders and tender inguinal lymphadenopathy, or buboes. The causative organism, Haemophilus ducreyi, is a gram-negative, anaerobic, coccobacillus that is notable for its complex growth requirements.[1]

The bacterium was first identified by Auguste Ducrey in 1889 following the autoinoculation of patients’ forearms with purulent material obtained directly from their genital ulcers. These studies provided the foundation for the differentiation of chancroid from syphilis, at least in etiology, as autoinoculation of the later did not result in ulcer formation.[2] H ducreyi is strictly a human pathogen, without an identified reservoir and mostly acts extracellularly.[3, 4]

H ducreyi enters the skin through a break in the epithelium, usually microabrasions, following minor trauma such as that experienced during sexual intercourse. Once the bacteria have breached the integument, they recruit a host of inflammatory cells to the inoculated area, including polymorphonuclear neutrophils (PMNs), macrophages, dendritic cells, natural killer cells, and CD4 and CD8 cells.[5] The bacteria also induce the secretion of interleukin 6 (IL-6) and interleukin 8 (IL-8) from cells of the epidermis and dermis (keratinocytes, fibroblasts, endothelial cells, and melanocytes). IL-8, in turn, induces PMNs and macrophages to form abscesses, appreciated clinically as intradermal pustules. Simultaneously, IL-6 stimulates CD4 cell activity in the area through the up-regulation of T-cell interleukin 2 (IL-2) receptor expression.

The formation of the characteristic ulcers seen in chancroid is facilitated by H ducreyi' s cytolethal distending toxin (HdCDT) that causes apoptosis and necrosis of human cells such as myeloid cells, epithelial cells, keratinocytes, and primary fibroblasts.[6] The clinical manifestation of these processes is exacerbated by H ducreyi ’s ability to evade phagocytosis, leading to slow healing.

Pustules and ulceration do not manifest in all infected patients. However, in instances when they do develop, it has been described that these individuals mount an exceptional inflammatory response, involving several proinflammatory molecules, namely interleukin 1-beta, at a local level.[5]

For an unknown reason, macrophages in ulcers have greater CCR5 and CXCR4 chemokine receptors, which are used for human immunodeficiency virus (HIV) entry, when compared with cells outside a region of infection. HIV transmission is also facilitated by H ducreyi' s characteristic ulceration and disruption of the epithelium.

Frequency

United States

Chancroid is noted to be endemic in certain regions of Africa, Asia, and Latin America. In the United States and other developed countries, however, it is essentially unseen at this time. (It is acknowledged that these data may be skewed by underdiagnosis, lack of reporting, and the difficulty in culturing H ducreyi.) In 2019, only 8 cases were reported in the United States involving 5 states. [7]

International

The global incidence of genital ulcer disease is more than 20 million cases per year, with a majority of these cases attributed to syphilis and herpes virus.[8] Even so, in 1997, the annual global incidence of chancroid was reported by the World Health Organization (WHO) and Joint United Nations Programme on HIV and AIDS (UNAIDS) to be about 6 million.[9]

Chancroid is more commonly diagnosed in heterosexual men, minority groups, or impoverished individuals. In addition, chancroid is associated with sexual exposure to a commercial sex worker, drug abuse, and/or alcohol abuse.[10]

Chancroid is more common in less developed areas, areas that are also notable for a greater prevalence of HIV (>8%). Chancroid infection is also commonly seen in individuals co-infected by syphilis or herpes simplex virus, both inside the United States (approximately 10% of patients) and, to a great extent, outside the United States.[8] Other risk factors are low education level, risky sexual behavior, the presence of other sexually transmitted diseases, older age, and male homosexuality.[11]

Given the absence of any determinant publications investigating circumcision and the prevalence of laboratory-diagnosed chancroid, there is still question as to the risk that noncircumcision imparts on these men. In some of these studies, genital ulcerative disease was diagnosed on the basis of clinical presentation without positive culture. In others, there was no direct comparison of study outcomes between uncircumcised and circumcised populations.[12]

Note that the frequency of chancroid, and other bacterial sexually transmitted diseases for that matter, has recently shifted away from bacterial infections and toward viral etiologies such as herpes simplex virus and HIV.

Mortality/Morbidity

If chancroid is diagnosed and treated early, it can be cured easily and quickly. H ducreyi produces painful genital ulcers and tender, enlarged inguinal lymph nodes known as buboes. These may rupture, after forming abscesses, and subsequent scarring may be permanent. Open sores secondary to H ducreyi infection also facilitate the transmission of HIV. Immunocompromised patients, such as those infected by HIV, have lower cure rates and can have more serious complications.[13]

Sex

The male-to-female ratio is between 3 and 25:1,[9] depending on the geographic region being studied. Although males are affected more often, female sex workers appear to harbor the disease.

Age

Mean patient age is 30 years.

Chancroid can be cured with early antibiotic treatment in immunocompetent patients. If chancroid has already progressed to later stages, or if the host is immunocompromised, treatment may fail, resulting in any of the aforementioned complications.

Topics of patient education should include, but are not limited to, condom use, regular genital self-examination, risky behaviors, and informing past and present partners. 

Patients with chancroid may report painful papules, pustules, or ulcers with associated dyspareunia, vaginal discharge, fever, or weakness. Patients also can have tender inguinal lymphadenopathy. 

HIV-positive and other immunocompromised patients may present atypically.

The organisms enter through breaks in the skin on the genitals. Approximately 3-7 days following inoculation, tender, erythematous papules form. The papules are most often seen on the prepuce or frenulum in males and on the vulva, cervix, or perianal region in females. The papules commonly develop into pustules, which ulcerate after several weeks. These ulcers are characterized by irregular borders, a possible ring of erythema, purulent exudate, and granulomatous bases.[14] Painful inguinal lymphadenopathy or bubo formation is present in 50% of patients and may present around the time of ulceration.[15] Lymphadenopathy is usually unilateral, and lymph nodes may rupture themselves. Note the images below.

This photograph shows an early chancroid on the penis, along with accompanying regional lymphadenopathy. Courtesy of the CDC/Dr. Pirozzi.

Chancroid usually starts as a small papule that rapidly becomes pustular and eventually ulcerates. The ulcer enlarges, develops ragged undermined borders, and is surrounded by a rim of erythema. Unlike syphilis, lesions are tender and the border of the ulcer is not indurated. Courtesy of Hon Pak, MD.

This patient shows the characteristic lesions of chancroid. The bubo on the right side drained spontaneously. The bubo in the left inguinal canal required needle aspiration.

H ducreyi, a gram-negative coccobacillus, is the causative organism.

Scarring, phimosis, balanoposthitis, ruptured buboes with severe pain, and fistula formation are complications. Sexual dysfunction due to scar formation may also occur.

Per CDC guidelines (2015), a diagnosis of chancroid requires satisfaction of all of the following conditions:[13]

• The patient has one or more painful genital ulcers.
• The clinical presentation, appearance of genital ulcers, and, if present, regional lymphadenopathy are typical of chancroid.
• The patient has no evidence of T pallidum infection on darkfield examination of ulcer exudate or on a serologic test for syphilis performed at least 7 days after the onset of ulcers.
• The HSV PCR test or HSV culture results performed on the ulcer exudate are negative.

Physical examination findings should include both of the following to suggest a diagnosis of chancroid:[16]

• Painful genital ulcer
• Tender suppurative inguinal adenopathy

Microbiological diagnosis should be obtained in all cases of suspected chancroid, if possible.[10]

For definitive diagnosis of chancroid by H ducreyi, obtain the following:[10, 13]

• Gram stain of the ulcer exudate
• Culture of ulcer exudate on special media (if possible, multiple cultures should be obtained to enhance the likelihood of recovering the organism)
• If possible, antibiotic sensitivity testing from the culture

Other necessary tests to obtain include the following:[13]

• Syphilis serology, darkfield examination, or PCR testing, if available
• Culture or PCR testing for genital herpes
• Serologic testing for type-specific HSV antibody
• HIV testing

Culture is unreliable and insensitive. Sensitivities have been found to be between 50% and 100%.[17] Use of a special medium is required to culture H ducreyi due to its heme dependence. The growth temperature is also lower (33°C) than most organisms. If cultures are going to be positive, they usually grow organisms within 3 days.

Polymerase chain reaction (PCR) is 96-100% sensitive and 97-98% specific.[8] However, PCR is not usually performed on site, thereby causing a delay in making the diagnosis. The expense is another factor. PCR directed against 1 of 2 genomic segments (either the ribosomal RNA gene, rrs-rrl ribosomal intergenic spacer region, or the GroEL gene, which encodes a heat shock protein) can be used.

Gram stain is similar to PCR in the time it takes and the delay in diagnosis and treatment. Microbiologists have described H ducreyi as looking like "schools of fish", "railroad tracks", and "fingerprints".[15] Histologic findings include neutrophils, fibrin, erythrocytes, and necrotic tissue.

Immunochromatography is a rapid diagnostic test that usually takes approximately 15 minutes to perform. Immunochromatography tests use monoclonal antibodies to the hemoglobin receptor of H ducreyi, hgbA, an outer membrane protein. Patterson reported this test to have a specificity of 100%.[17] Furthermore, these tests are easily performed, relatively inexpensive, and stable in several climates. The downside, however, is that the sensitivity has been found to be comparably poor. Availability of this test is limited by this.

Patients with chancroid, along with all of their sexual partners within 10 days of contact preceding the onset of symptoms, should receive treatment.[13]

CDC treatment guidelines for chancroid recommend one of the following options[13] :

• Azithromycin 1 g orally as a single dose
• Ceftriaxone 250 mg IM as a single dose
• Ciprofloxacin 500 mg orally twice a day for 3 days
• Erythromycin base 500 mg orally three times a day for 7 days

Resistance to ciprofloxacin and erythromycin has been reported.

Ciprofloxacin should be avoided in pregnant breastfeeding patients.[13]

In pregnancy, ceftriaxone and azithromycin are preferred treatment regimens. 

A longer course of treatment may be necessary in the following patients[13] :

• Uncircumcised males
• Patients with HIV infection
• Patients with fluctuant lymphadenopathy

Other, more common, causes of painful genital ulcers and tender suppurative inguinal adenopathy should be considered, and patients should be treated for other STDs as well, including HSV and syphilis.[13] In endemic areas, patients should be treated for granuloma inguinale. Therapy for lymphogranuloma venereum should be given if inguinal buboes are present.

Streptomycin and ceftriaxone have been shown to be synergistic in the treatment of chancroid.

Single-dose ciprofloxacin (92% cure rate) and azithromycin are effective. These treatment options also offer the advantage of directly observed, single-dose therapy. Several isolates have showed intermediate resistance to single-dose therapy. The prevalence of these isolates is not known at this time.[13]

Encourage abstinence until ulcer has healed. Sexual partners of patients with chancroid should be treated if there has been sexual contact within 10 days of symptom presentation. 

Fluctuant lymphadenopathy may require incision and drainage or needle aspiration.[13] Incision and drainage is preferred, as it decreases the likelihood of repeat drainage.

Scarring, phimosis, balanoposthitis, ruptured buboes with severe pain, and fistula formation are complications. Sexual dysfunction due to scar formation may also occur.

Patients need to be educated about safe sex practices.[13]

Patients should be educated about the increased risk of HIV transmission in the presence of genital ulcers.[10]

Treatment of partners is similar to the source patient. All sexual partners encountered 10 days preceding the onset of symptoms should be treated.[13]

Considerations in cases of treatment failure include the following[13] :

• Incorrect diagnosis
• Coinfection with other STDs
• Coinfection with HIV
• Treatment noncompliance
• Resistance of the H ducreyi strain

Follow-up should occur within 3-7 days after treatment initiation.[13]

Ulcers should symptomatically improve within 3 days and objectively within 7 days.[13]

Factors associated with treatment-resistant chancroid include the following[10, 13] :

• HIV infection
• Large ulcer
• Uncircumcised male
• Fluctuant lymphadenopathy

Single-dose therapy may fail in HIV-positive patients, warranting close monitoring.[13]

In patients with HIV infection, the same regimens may be used, but note that these patients are more likely to experience treatment failure, which may necessitate repeated or longer therapy.[13]

Patients should be tested for HIV at the time of diagnosis. If the screening test is negative, they should be retested for HIV and syphilis in 3 months.[18]

Per CDC guidelines (2015), a diagnosis of chancroid requires satisfaction of all of the following conditions[13] :

• The patient has one or more painful genital ulcers.
• The clinical presentation, appearance of genital ulcers, and, if present, regional lymphadenopathy are typical of chancroid.
• The patient has no evidence of  T pallidum infection on darkfield examination of ulcer exudate or on a serologic test for syphilis performed at least 7 days after the onset of ulcers.
• The HSV PCR test or HSV culture results performed on the ulcer exudate are negative.

CDC treatment guidelines for chancroid recommend one of the following options[13] :

• Azithromycin 1 g orally as a single dose
• Ceftriaxone 250 mg IM as a single dose
• Ciprofloxacin 500 mg orally twice a day for 3 days
• Erythromycin base 500 mg orally three times a day for 7 days

CDC treatment guidelines for chancroid recommend one of the following options[13] :

• Azithromycin 1 g orally as a single dose
• Ceftriaxone 250 mg IM as a single dose
• Ciprofloxacin 500 mg orally twice a day for 3 days
• Erythromycin base 500 mg orally three times a day for 7 days

Resistance to ciprofloxacin and erythromycin has been reported.

A 2017 Cochrane literature review comparing the efficacy of macrolides for the treatment of H ducreyi infection in sexually active adults found low-quality evidence to suggest there is no statistically significant difference between azithromycin and the available therapeutic alternatives and suggested that azithromycin could be considered as first-line therapy.[16]

The goal of therapy is to eradicate the microorganism. Since treatment of chancroid may accompany treatment of gonorrhea, it is important to be aware of the updated CDC guidelines for treating STDs. In April 2007, the CDC updated treatment guidelines for gonococcal infection and associated conditions.

Fluoroquinolone antibiotics are no longer recommended to treat gonorrhea in the United States. The recommendation was based on analysis of new data from the CDC's Gonococcal Isolate Surveillance Project (GISP). According to these data, the proportion of gonorrhea cases in heterosexual men that were fluoroquinolone-resistant (QRNG) reached 6.7%, an 11-fold increase from 0.6% in 2001. The data were published in the April 13, 2007, issue of the Morbidity and Mortality Weekly Report.[19] This limits treatment of gonorrhea to drugs in the cephalosporin class (eg, ceftriaxone 125 mg IM once as a single dose). Fluoroquinolones may be an alternative treatment option for disseminated gonococcal infection if antimicrobial susceptibility can be documented.

For more information see, the CDC’s Antibiotic-Resistant Gonorrhea Web site; CDC Updated Gonococcal treatment recommendations (April 2007); or Medscape Medical News on CDC Issues - New Treatment Recommendations for Gonorrhea.

Class Summary

These agents are always indicated in chancroid. Therapy must be aimed at covering all likely pathogens according to the clinical setting.

Azithromycin (Zithromax)

Used to treat mild to moderately severe infections caused by susceptible strains of microorganisms. Indicated for chlamydial and gonorrheal infections of genital tract.

Ceftriaxone (Rocephin)

Third-generation cephalosporin with broad-spectrum, gram-negative activity; lower efficacy against gram-positive organisms and higher efficacy against resistant organisms than earlier generation cephalosporins. Arrests bacterial growth by binding to 1 or more penicillin-binding proteins.

Erythromycin (EES, E-Mycin, Ery-Tab)

Blocks peptide bond formation by blocking peptidyl tRNA translocation from the A- to the P- site. Inhibits bacterial growth.

Ciprofloxacin (Cipro)

Bactericidal antibiotic that inhibits bacterial DNA synthesis, and consequently growth, by inhibiting DNA-gyrase in susceptible organisms. Indicated for pseudomonal infections and those due to multidrug-resistant gram-negative organisms. If co-infection with gonorrhea suspected, do not use fluoroquinolones. CDC no longer recommends fluoroquinolones for gonorrhea or related conditions because of resistance.