CHANCROID IS one of the classic ulcer-producing sexually transmitted diseases (STDs) of the genitalia characterized by painful ulceration(s) and frequent bubo formation. It is the commonest cause of genital ulcers in many parts of India.1 This is followed by herpes progenitalis and primary chancre. Its diagnosis has been primarily based on clinical features with support of Gram's stain and exclusion of other STDs.
Several antimicrobials have been used in treatment of chancroid including sulfonamides, tetracyclines, beta-lactams, aminoglycosides, and quinolones. Antimicrobial susceptibility varies markedly from one geographic area to another.2 Resistance to penicillin,3 sulfonamides,4 and tetracyclines5 have been reported. However, ciprofloxacin,6 erythromycin,7 azithromycin,8 and ceftriaxone9 have been found to be extremely effective for treatment of chancroid.
This study compares the efficacy of ciprofloxacin, erythromycin, and cotrimoxazole therapy in clinically diagnosed chancroid patients.
Material and Methods
Forty-six patients with a clinical diagnosis of chancroid attending the outpatient Department of Dermatology and Venereology at an institution in India over a 12-month period were taken up for the study.
Syphilis was excluded by dark ground illumination (DGI) and Venereal Diseases Research Laboratory (VDRL) test. Herpes genitalis was excluded by Tzanck's smear from ulcer and donovanosis was ruled out by tissue smear examination stained with Giemsa for intracellular bodies. Enzyme-linked immunosorbent assay (ELISA) test was performed to exclude human immunodeficiency virus (HIV) infection after informed consent. Only HIV serology-negative patients having chancroid were included.
The diagnosis of chancroid was made primarily by the classical clinical presentation. It was supplemented by direct Gram-stained smear showing gram-negative bacilli in a “school of fish” pattern and/or culture methods with confirmatory biochemical tests. For culture of the organisms, the patient's own clotted blood and selective solid medium were used. The latter contained chocolate agar consisting of gonococcal agar base, 1% hemoglobin, 5% fetal calf serum, 1% Isovitalex, and 3 μg/ml of vancomycin. In vitro susceptibility test was performed by the disc diffusion method of Kirby Bauer. The patients were assigned into three groups in a randomized manner; group 1 had 16 patients, whereas groups 2 and 3 had 15 patients each. Patients in group A received ciprofloxacin, 500 mg twice daily for 3 days, followed by placebo therapy for the next 4 days. Group 2 patients were given erythromycin, 500 mg four times daily for 7 days. Cotrimoxazole therapy (sulfamethoxazole 800 mg + trimethoprin 160 mg), twice daily for 7 days, was administered to patients in group 3. Chemotherapy in all the three groups was administered orally. Patients received follow-up on day 7, day 14, and if needed, day 21.
For purpose of evaluation of response to treatment, the clinical outcomes were defined as by Naamara et al.6
- Cure (complete healing of ulcer) was epithelization of the ulcer before day 21.
- Improvement was an objective decrease in the size of the ulcer compared with the size during a previous visit in patients who failed to make requisite follow-up visit to document complete resolution.
- Failure was the absence of objective improvement in any ulcer by day 7 or if there was an objective progression after day 7.
Response of the buboes, if any, was noted. However, resolution of inguinal bubo was not used as a criterion for the clinical efficacy of an antimicrobial agent since temporary progression of existing buboes with or without fluctuation may occur during the course of adequate and effective antimicrobial chemotherapy.10
Statistical analysis of the response rate to the three different therapeutic regimens was performed by Bio Medical Data Processing (BMDP Statistical Software, Inc., Los Angeles, CA) package, in consultation with a professor of Biostatistics at our institution. Pearson Chi square test was applied for the discrete variables and t test was applied for the continuous variables and significance of differences expressed as probability values (p value). Results of continuous variables were expressed as mean ± standard deviation while results of discrete variables were expressed in terms of number and percentage of patients evaluated. A p value < 0.05 was taken as significant.
Forty-four of the 46 patients were men. Forty-three patients completed the study. Three patients did not come for regular follow-up to document complete healing of lesions, although they showed improvement in initial follow-up visits. In 14 patients, direct Gram-stained smear showed gram-negative bacilli in a “school of fish” appearance suggestive of Haemophilus ducreyi. In 6 patients, organism could be grown on liquid culture medium, whereas in 4 patients positive culture was obtained on selective solid medium.
Response to Ciprofloxacin
Cure of the ulcers was observed in 15 patients, and improvement occurred in 1 patient. There were no failures. Of those cured, ulcers healed by day 7 in 8 patients, by day 14 in 6 patients, and by day 21 in 1 patient. Six of these 16 patients had buboes. Complete resolution and improvement of buboes were seen in 2 patients each. Worsening of buboes was noted in 2 other patients, where aspiration of fluctuant buboes had to be performed. No adverse effects of therapy were observed.
Response to Erythromycin
Cure of ulcer/s was observed in 14 patients, and improvement was seen in 1 patient. There were no failures. Of those cured, the ulcers healed by day 7 in 5 patients, by day 14 in 8 patients, and by day 21 in 1 patient. Six of these 15 patients had buboes. Complete resolution of buboe/s in 1 patient and improvement in 3 patients were observed. Worsening of buboes, where aspiration had to be performed, was seen in 1 patient. No change in bubo size was noted in 1 patient. Three patients complained of gastric irritation while on treatment.
Response to Cotrimoxazole
Cure of ulcers was observed in eight patients. Clinical failure was seen in seven patients. Of those cured, ulcers healed by day 7 and day 14 in four patients each. Of those patients who did not respond to cotrimoxazole therapy, four later received erythromycin, whereas 3 were given ciprofloxacin in the dosage described earlier. One patient on erythromycin did not show up for further follow-up. Two patients receiving erythromycin had complete healing of ulcers by day 14, whereas cure was achieved in 1 patient by day 21. The 3 patients receiving ciprofloxacin had complete healing of ulcers by day 14. Five of these 15 patients had buboes. Complete resolution, improvement, and worsening of buboes were observed in 1 patient each, whereas no change was seen in 2 patients. No adverse effects were observed.
The patients in the three treatment groups were comparable in demographic and clinical characteristics. Statistical analysis of therapeutic response of chancroid ulcers to three different drugs showed that there was no statistical difference in the response rate of chancroid ulcer/s between the ciprofloxacin and erythromycin group (Pearson's chi-square = 0.002; p = 0.9624). However, the difference in therapeutic response between the ciprofloxacin and cotrimoxazole group (Pearson's chi-square = 10.109; p = 0.0064) and between the erythromycin and cotrimoxazole group (Pearson's chi-square = 9.636; p = 0.0081) was statistically highly significant.
Response of chancroid to ciprofloxacin in the present study was excellent with 93.7% cure rate. The studies of Naamara et al6 from Kenya have also reported a similar response rate with cure observed in 93.0% patients. Bodhidatta and colleagues11 have reported 100% cure rates with ciprofloxacin, 500 mg, administered as a single dose. We have not come across any study from India evaluating the efficacy of ciprofloxacin in chancroid.
Very good response to erythromycin also was observed in the present study with a cure rate of 93.3%. Similar response has been reported by Kumar et al12 from Chandigarh, India, where 100% cure rate was observed in 30 patients treated with erythromycin. The studies of Duncan et al13 from South Africa have reported a 98% cure rate with erythromycin therapy.
The short duration (3 days) of treatment, twice daily dosage, absence of gastric irritation, and cost-effectiveness (approximately Rs. 72 or US$ 2.00 in India for 3 days) were significant advantages of ciprofloxacin over erythromycin, which had to be administered for 7 days in a dosage of four times a day, caused gastric irritation in four patients and cost approximately Rs. 168/- or US$ 4.75 in India for 7 days. Additionally, ciprofloxacin does not mask incubating syphilis. However, erythromycin can be an excellent agent for the treatment of chancroid in pregnant women,7 unlike ciprofloxacin, whose effects on the fetus are still unknown.6
The response to cotrimoxazole in the present study was disappointing with a high failure rate of 46.7%. Cotrimoxazole-resistant chancroid has been reported earlier in India.14 Studies from Taylor et al4 from Thailand and Plourde et al15 have also reported 45% and 30% failure rates, respectively. However, 100% and 96% cure rates with cotrimoxazole administered twice daily for 7 days and 3 days, respectively, have also been reported by Fast et al16 and Naamara et al.6
In the present study, in vitro sensitivity showed that the isolates were resistant to cotrimoxazole and uniformly sensitive to erythromycin and ciprofloxacin. This correlates well with the clinical response seen in our patients. The detailed data on in vitro sensitivity are being published elsewhere.
The Centers for Disease Control and Prevention in its 1993 STD Treatment Guidelines has not recommended cotrimoxazole even under alternative therapeutic regimens for the treatment of chancroid.8 We also believe that owing to the unacceptably high failure rate in the present study, cotrimoxazole can no longer be recommended as the first line of treatment of chancroid.
From the observations in this study it appears that both ciprofloxacin and erythromycin are equally effective for the treatment of chancroid. However, ciprofloxacin has certain advantages as discussed earlier, and we recommend ciprofloxacin as the first choice of treatment for chancroid except in pregnant women, in which case erythromycin should be preferred.
The response to buboes was not taken as a criterion for effectiveness of therapy in the present study. However, it was observed that most of the time buboes take longer to heal than ulcers, and patients did not come for follow-up once the ulcer has healed. In the present study only four patients with buboes had complete resolution during follow-up visits. Other workers who found that ulcers resolve earlier than buboes17 or that buboes may become fluctuant while ulcers are responding made similar observations.18
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