Assessing the antibiotic potential of essential oils against Haemophilus ducreyi.

BACKGROUND: Haemophilus ducreyi is the bacterium responsible for the genital ulcer disease chancroid, a cofactor for the transmission of HIV, and it is resistant to many antibiotics. With the goal of exploring possible alternative treatments, we tested essential oils (EOs) for their efficacy as antimicrobial agents against H. ducreyi. METHODS: We determine the minimum inhibitory concentration (MIC) of Cinnamomum verum (cinnamon), Eugenia caryophyllus (clove) and Thymus satureioides (thyme) oil against 9 strains of H. ducreyi using the agar dilution method. We also determined the minimum lethal concentration for each oil by subculturing from the MIC plates onto fresh agar without essential oil. For both tests, we used a 2-way ANOVA to evaluate whether antibiotic-resistant strains had a different sensitivity to the oils relative to non-resistant strains. RESULTS: All 3 oils demonstrated excellent activity against H. ducreyi, with MICs of 0.05 to 0.52 mg/mL and MLCs of 0.1-0.5 mg/mL. Antibiotic-resistant strains of H. ducreyi were equally susceptible to these 3 essential oils relative to non-resistant strains (p=0.409). CONCLUSION: E. caryophyllus, C. verum and T. satureioides oils are promising alternatives to antibiotic treatment for chancroid.

Epidemiology, clinical features, diagnosis and treatment of Haemophilus ducreyi - a disappearing pathogen?

Chancroid, caused by Haemophilus ducreyi, has declined in importance as a sexually transmitted pathogen in most countries where it was previously endemic. The global prevalence of chancroid is unknown as most countries lack the required laboratory diagnostic capacity and surveillance systems to determine this. H. ducreyi has recently emerged as a cause of chronic skin ulceration in some South Pacific islands. Although no antimicrobial susceptibility data for H. ducreyi have been published for two decades, it is still assumed that the infection will respond successfully to treatment with recommended cephalosporin, macrolide or fluoroquinolone-based regimens. HIV-1-infected patients require careful follow-up due to reports of treatment failure with single dose regimens. Buboes may need additional treatment with either aspiration or excision and drainage.

In vitro and in vivo activity of combination antimicrobial agents on Haemophilus ducreyi.

OBJECTIVES: Development of single dose antibiotic treatments for chancroid has been followed by drug-resistant Haemophilus ducreyi in endemic areas. We examined the activity and interactions of antimicrobial agents and combinations against H. ducreyi. METHODS: We evaluated the in vitro susceptibility of three virulent strains of H. ducreyi to ceftriaxone, azithromycin, rifabutin and streptomycin, and each two-drug combination by the agar dilution method. We then tested each two-antibiotic combination for activity by the chequerboard method. Lastly, we chose the antibiotic combination with the lowest fractional inhibitory concentration index (FICI) and tested combined sub-therapeutic doses, the highest doses which had no effect alone on lesion healing compared with controls, for in vivo interaction in the temperature-dependent rabbit model of H. ducreyi infection. RESULTS: Each H. ducreyi strain was susceptible in vitro to each antibiotic and two-antibiotic combination, and combined ceftriaxone and streptomycin had the lowest FICI at 0.63. In five treated animals versus three untreated controls, combined sub-therapeutic doses of ceftriaxone (0.05 mg/kg) and streptomycin (10 mg/kg) reduced mean (SD) duration of culture positivity from 7.3 (1.1) to 2.6 (1.7) days (P<0.001), time to 50% reduction in lesion size from 9.7 (1.5) to 5.8 (0.8) days (P<0.005), and time to resolution of ulcer from 11.7 (2.3) to 6.6 (1.7) days (P<0.05). CONCLUSIONS: Ceftriaxone and streptomycin have in vivo synergic interaction against H. ducreyi lesions in the temperature-dependent rabbit model of infection. Antibiotic combinations may be evaluated clinically as single-dose therapy for chancroid.

A randomized, double-blind, placebo-controlled trial of single-dose ciprofloxacin versus erythromycin for the treatment of chancroid in Nairobi, Kenya.

A randomized, double-blind, placebo-controlled clinical trial was conducted in Nairobi, Kenya, to compare single-dose ciprofloxacin with a 7-day course of erythromycin for the treatment of chancroid. In all, 208 men and 37 women presenting with genital ulcers clinically compatible with chancroid were enrolled. Ulcer etiology was determined using culture techniques for chancroid, serology for syphilis, and a multiplex polymerase chain reaction for chancroid, syphilis, and herpes simplex virus (HSV). Ulcer etiology was 31% unmixed chancroid, 23% unmixed syphilis, 16% unmixed HSV, 15% mixed etiology, and 15% unknown. For 111 participants with chancroid, cure rates were 92% with ciprofloxacin and 91% with erythromycin. For all study participants, the treatment failure rate was 15%, mostly related to ulcer etiologies of HSV infection or syphilis, and treatment failure was 3 times more frequent in human immunodeficiency virus-infected subjects than in others, mostly owing to HSV infection. Ciprofloxacin is an effective single-dose treatment for chancroid, but current recommendations for empiric therapy of genital ulcers may result in high treatment failure due to HSV infection.

A comparative study of therapeutic response of patients with clinical chancroid to ciprofloxacin, erythromycin, and cotrimoxazole.

BACKGROUND AND OBJECTIVES: Cotrimoxazole has traditionally been used as first drug for treatment of chancroid in India. With reports of increasing resistance to the drug, this study was conducted to compare treatment response of clinical chancroid between ciprofloxacin, 500 mg twice daily for 3 days, erythromycin, 500 mg four times daily for 7 days, and double-strength cotrimoxazole (trimethoprim 160 mg + sulfamethoxazole 800 mg), twice daily for 7 days. STUDY DESIGN: Forty-six patients with a clinical diagnosis of chancroid were randomly divided into 3 groups. Sixteen patients received ciprofloxacin, whereas 15 each received erythromycin and cotrimoxazole. Patients were seen on day 7, 14, and if needed day 21. Clinical response was noted in terms of cure, improvement, or failure. RESULTS: Excellent response was observed to both ciprofloxacin and erythromycin therapy with cure rates of 93.7% and 93.3%, respectively. Improvement was observed in 6.7% cases in both groups. There were no failures with either ciprofloxacin or erythromycin. Poor response to cotrimoxazole therapy was observed with 53.3% cure rates and a high failure rate of 46.7%. CONCLUSION: Ciprofloxacin and erythromycin are equally effective in chancroid. Ciprofloxacin is better in terms of dosage schedule, duration of treatment, and low cost. Cotrimoxazole should be discontinued as drug of choice because of high failure rates.

Failure of treatment for chancroid in Rwanda is not related to human immunodeficiency virus infection: in vitro resistance of Haemophilus ducreyi to trimethoprim-sulfamethoxazole.

A comparative open study was performed to evaluate the efficacy of single doses of ciprofloxacin (500 mg) and trimethoprim-sulfamethoxazole (TMP-SMZ; 640 mg/3,200 mg) for the treatment of culture-proven chancroid. Clinical cure or improvement was observed 7 days after treatment in 32 (76.2%) of the 42 patients who received ciprofloxacin and 21 (52.5%) of the 40 patients who received TMP-SMZ (P = .04). Cultures for one (4.5%) of 22 patients not cured with ciprofloxacin and 16 (59.3%) of 27 patients not cured with TMP-SMZ were still positive for Haemophilus ducreyi 7 days after treatment (P < .001). Although 77 (71.3%) of the 108 patients tested were seropositive for HIV-1 antibody, HIV infection and the degree of CD4+ lymphocyte depletion had no effect on clinical and bacteriologic outcome. All isolates of H. ducreyi were highly susceptible to ciprofloxacin (MIC, 0.004-0.06 mg/L). In contrast, resistance to TMP-SMZ (MIC, > or = 4/76 micrograms/mL) was observed in 48.9% of isolates (22 of 45) and was significantly associated with treatment failure. Therefore, the administration of TMP-SMZ, in single or multiple doses, is no longer indicated for the treatment of chancroid in Rwanda.

In vitro susceptibilities of isolates of Haemophilus ducreyi from Thailand and the United States to currently recommended and newer agents for treatment of chancroid.

We determined the in vitro susceptibilities of 54 isolates of Haemophilus ducreyi from Thailand (29 isolates) and San Francisco (25 isolates) to penicillin G, tetracycline, amoxicillin-clavulanic acid, ceftriaxone, cefixime, erythromycin, azithromycin, ciprofloxacin, ofloxacin, and trimethoprim-sulfamethoxazole. Isolates were susceptible to < or = 0.25 microgram of ceftriaxone per ml, < or less 0.5 microgram of cefixime per ml, < or = 0.125 microgram of ciprofloxacin per ml, and < or = 0.06 microgram of ofloxacin per ml. Erythromycin was active against all isolates (MIC for 90% of isolates tested, 0.25 microgram/ml), as was azithromycin (MIC, < or = micrograms/ml). In contrast, all but one isolate were resistant to > or = 8.0 micrograms of tetracycline per ml, 11.1% of the isolates were resistant to and 40.9% of the isolates were resistant to trimethoprim-sulfamethoxazole (MIC, > or = 4/76 microgram/ml.)

The role of fluoroquinolones in sexually transmitted diseases.

The management of sexually transmitted diseases (STDs) has reached a new level in the era of antibiotic resistance and human immunodeficiency virus infection. To date, no single antimicrobial is capable of eradicating the commonly encountered STD pathogens including Neisseria gonorrhoeae, Chlamydia trachomatis, and Treponema pallidum. Among the marketed fluoroquinolones, ciprofloxacin, ofloxacin, lomefloxacin, and enoxacin all provide excellent in vitro activity (MIC90 < 0.06 micrograms/ml) and excellent in vivo efficacy against N. gonorrhoeae, including multiply resistant isolates (penicillinase-producing N. gonorrhoeae and chromosomally mediated resistant N. gonorrhoeae). Ofloxacin is the only fluoroquinolone approved by the Food and Drug Administration for chlamydial infection. All of the quinolones lack reliable in vitro activity against Ureaplasma urealyticum, a cause of nongonococcal urethritis. Although limited data suggest the usefulness of ciprofloxacin and ofloxacin in the treatment of pelvic inflammatory disease, these drugs cannot currently be recommended for single-agent therapy. Haemophilus ducreyi infections, however, can be managed effectively with the fluoroquinolones. Although their role continues to evolve, this class of drugs cannot be used equally to treat all STDs, and notably, no quinolone to date inhibits T. pallidum.

Treatment of chancroid with a single dose of spectinomycin.

Fifty patients with lesions characteristic of chancroid were enrolled in an open-label prospective study to examine the efficacy of a single 2-gm dose of spectinomycin for treatment of chancroid. Only those patients (41 men; aged 18 to 49 years) with positive culture results for Haemophilus ducreyi were included in the analysis. Patients each received a single 2-gm dose of spectinomycin intramuscularly. The recovery process began on the third day of follow-up, as evidenced by the occurrence of epithelialization and a decrease in inflammation. By the seventh day after treatment, only one patient had ulcers; 40 patients experienced eradication of all ulcers (P less than 0.0001). The condition of nodes affected by infection also indicated efficacy of treatment (P less than 0.01); only one patient still had a swollen node by the fourteenth day after treatment. Of the 41 patients, 37 (90%) had negative culture results for H. ducreyi on the third day after treatment. Only 4 patients (10%) required a second dose of spectinomycin on the seventh day to affect a cure. Treatment with spectinomycin resulted in a 98% cure rate 14 days after treatment. The minimum inhibitory concentration (MIC) of spectinomycin was 1 microgram/mL to 3 micrograms/mL in the 15 strains studied. The drug was well tolerated and no adverse reactions were reported. It is concluded that a single 2-gm dose of spectinomycin is a safe and effective alternative drug for treatment of chancroid.

Multiple sexually acquired diseases occurring concurrently in an HIV positive man: case report, diagnosis and management.

A case of an HIV positive man with multiple sexually acquired disease occurring concurrently is described. Risk behaviours that could have predisposed him to HIV infection are discussed. The factors which might have interacted to make the sexually acquired infections severe and difficult to treat are postulated.

PIP: The case of an HIV-seropositive man with gonorrhea, syphilis, genital warts, and chancroid is described. Multiple sexual partners, genital ulcer diseases, and lack of circumcision may have predisposed him to HIV infection. As indicated by his CD4/CD8 ratio of 0.5, his immunological status was not very compromised. Other factors were therefore probably behind these multiple sexually transmitted diseases (STD). This 30-year old man was inadequately treated for a long time for urethral discharge and genital ulcer disease, and ultimately collapsed on the job with a comprised central nervous system. Bacterial infection related to the multiple STDs could certainly have caused this collapse. The time demands of this man's work, the lack of medical facilities to diagnose and treat such conditions, his unprotected sexual behavior with multiple partners, and broader socioeconomic conditions which separate wage- earning males from their families in Africa conspire to produce multiply-afflicted cases such as these.

Treatment of chancroid, 1989.

Since recommendations for the treatment of chancroid were made in 1985, in vitro and in vivo data indicate that the two drugs recommended, erythromycin (500 mg four times a day for 7 days) and ceftriaxone (250 mg intramuscularly in a single dose), remain effective. The alternative therapies of trimethoprim-sulfamethoxazole (160/800 mg twice a day for 7 days) and amoxicillin-clavulanic acid (500/125 mg three times a day for 7 days) also appear to be effective, although there has been little experience with these drugs in the United States. Single-dose trimethoprim-sulfamethoxazole (640/3,200 mg) now lacks the efficacy of other regimens. The experience with ciprofloxacin (500 mg twice a day for 3 days) has been favorable, and other quinolones may prove useful. Concurrent infection with human immunodeficiency virus appears to result in an increased rate of failure of treatment for chancroid, and such cases may require more prolonged therapy.

[Diagnosis and therapy of ulcus molle today. Case report and review of the literature]. / Diagnose und Therapie des Ulcus molle heute. Kasuistik und Literaturübersicht.

Chancroid, an ulcerous disease of the genitalia caused by Haemophilus ducreyi, occurs rarely but regularly in Germany. Exact diagnosis is based on the clinical features and a direct smear, and in particular on cultivation of the organism, showing its unique macromorphological characteristics. The sensitivity of cultivation has increased due to the development of selective media for primary isolation. Resistance problems during the last decade meant that a change to new therapeutic strategies was unavoidable. The work presented here includes a case report and a review of the recent literature, it illustrates modern methods of diagnosis and treatment of Haemophilus ducreyi infections 100 years after the first description of the organism.

Evaluation of fleroxacin (RO 23-6240) as single-oral-dose therapy of culture-proven chancroid in Nairobi, Kenya.

Chancroid is gaining importance as a sexually transmitted disease because of its association with transmission of human immunodeficiency virus type 1 (HIV-1). Effective, simply administered therapy for chancroid is necessary. Fleroxacin is effective against Haemophilus ducreyi in vitro. We performed an initial randomized clinical trial to assess the efficacy of fleroxacin for treatment of chancroid in Nairobi, Kenya. Fifty-three men with culture-positive chancroid were randomly assigned to receive either 200 mg (group 1) or 400 mg (group 2) of fleroxacin as a single oral dose. Groups 1 and 2 were similar with regard to severity of disease, bubo formation, and HIV-1 status. A satisfactory clinical response to therapy was noted in 23 of 26 patients (88%) in group 1 and 18 of 23 patients (78%) in group 2. Bacteriological failure occurred in 1 of 26 evaluable patients (4%) in group 1 and 4 of 23 evaluable patients (17%) in group 2. Two of 37 HIV-1-seronegative men (5%) and 3 of 11 HIV-1-infected men (27%) were bacteriological failures. Fleroxacin, 200 or 400 mg as a single oral dose, is efficacious therapy for microbiologically proven chancroid in patients who do not have concurrent HIV-1 infection. Among HIV-1-infected men, a single dose of 200 or 400 mg of fleroxacin is inadequate therapy for chancroid.

PIP: In Kenya, researchers enrolled 53, men aged 18-60 years with chancroid who enrolled at the Nairobi City Council Special Treatment Clinic in a clinical trial to test the efficacy of fleroxacin in clinical Haemophilus ducreyi infections. They randomly allocated the men the group receiving 200 mg of oral fleroxacin or the group receiving 400 mg of oral fleroxacin. 88% of the men receiving 200 mg oral fleroxacin (group 1) experienced either improvement in their clinical status or healing compared to 78% of the men receiving 400 mg oral fleroxacin. 2 of 7 (29%) patients who experienced delayed healing tested positive for HIV-1. 2 of 22 patients (9%) who healed right away were HIV-1 positive. The size of the genital ulcer had the most significant effect on healing time. The mean widest ulcer diameter was 9.5 mm in men who healed quickly while it was 18.5 mm in men who experienced a delay in healing (p .005). Microbiological cure occurred in 92% of men from group 1 and in 83% of those in group 2. The difference in microbiological failure rates of HIV-1 seropositive men and HIV-1 seronegative men approached significance (27% vs. 5%; p = .07). These results showed that a 200 or 400 mg single dose of oral fleroxacin is an efficacious treatment for men with microbiologically confirmed chancroid who are not HIV-1 infected. On the other hand, a single dose of neither 200 or 400 mg of oral fleroxacin adequately treats chancroid in HIV-1 infected men. Further study of chancroid treatment in HIV infected patients is needed, especially since chancroid may facilitate HIV transmission.

Evaluation of 500- and 1,000-mg doses of ciprofloxacin for the treatment of chancroid.

A randomized, double-blind study was performed comparing ciprofloxacin in a 500-mg single dose with 1,000 mg (500-mg doses given 12 h apart) for the treatment of chancroid in Thailand. Haemophilus ducreyi was isolated from 87 (48%) of 180 men with a clinical diagnosis of chancroid. For men with ulcers that were culture positive for H. ducreyi, rates of cure were 100% in the 500-mg group and 98% in the 1,000-mg group. For men with ulcers that were culture negative for H. ducreyi, rates of cure were 93% in the 500-mg group and 96% in the 1,000-mg group. The MIC of ciprofloxacin for 50% of isolates among 85 isolates of H. ducreyi was 0.007 micrograms/ml (range, 0.002 to 0.03 micrograms/ml). No significant adverse effects were detected in either group. These data indicate that both of these treatment regimens are equally effective therapies for chancroid in Thailand.

Efficacy and safety of a single dose therapy of a 500 mg ciprofloxacin tablet in chancroid patients.

A single dose therapy of 500 mg ciprofloxacin was sufficient to cure 15 of 18 chancroid patients within six days and the remaining three within 7, 11 and 20 days respectively. The drug was well tolerated, and no serious side effects were observed. The MICs of ciprofloxacin for the isolated Haemophilus ducreyi strains ranged from 0.0015 to 0.02 mg/l (mean 0.01 mg/l). It may therefore be concluded from our study that the oral administration of ciprofloxacin to chancroid patients with or without buboes is highly effective and free from side effects.

Treatment of chancroid with ciprofloxacin. A prospective, randomized clinical trial.

Chancroid is a major sexually transmitted disease in many developing countries. Although single-dose and short-course treatment of chancroid have been described, the increasing resistance of Hemophilus ducreyi to antimicrobial agents requires continuing evaluation of new therapies. Ciprofloxacin is a new quinolone antimicrobial agent with excellent in vitro efficacy against H. ducreyi. A double-blind, randomized clinical trial was conducted comparing a single-dose ciprofloxacin regimen (500 mg) and a three-day regimen of ciprofloxacin (500 mg twice daily) with a three-day regimen of trimethoprim-sulfamethoxazole (160 and 800 mg, respectively, twice daily) for the treatment of chancroid. The three-day ciprofloxacin regimen successfully eradicated H. ducreyi, and resulted in rapid clinical improvement in all 40 patients followed, with no failures. The other two regimens were also effective, but bacteriologic and clinical failure occurred in two and three patients following treatment with single-dose ciprofloxacin and three days of trimethoprim-sulfamethoxazole, respectively. All patients with buboes had resolution of lesions. There were no significant adverse effects associated with ciprofloxacin or trimethoprim-sulfamethoxazole. All three regimens are effective therapy for chancroid and H. ducreyi infections. If resistance to trimethoprim-sulfamethoxazole becomes widespread, ciprofloxacin may become a first-line therapy for chancroid. This study also demonstrates the efficacy of ciprofloxacin in soft tissue infection.

Trimethoprim sulphamoxole in the treatment of chancroid. Comparison of two single dose treatment regimens with a five day regimen.

In a prospective blinded study, 135 men with genital ulcers culture positive for Haemophilus ducreyi, were randomized to one of three regimens. Two single dose regimens, either the combination of sulphamoxole 3200 mg/trimethoprim 640 mg or trimethoprim 700 mg alone were compared to a five day regimen of sulphamoxole 800 mg/trimethoprim 160 mg twice daily. All 31 treated with a five day regimen of trimethoprim sulphamoxole healed without further treatment. Of 27 patients treated with the single dose sulphamoxole/trimethoprim regimen, only 21 were cured and of 34 treated with trimethoprim alone, 25 responded. Antibacterial susceptibilities were performed on 31 H. ducreyi isolates. The laboratory susceptibility of these strains to trimethoprim correlated with the clinical response to the single agent. Trimethoprim alone in a dose of 700 mg or the combination of sulphamoxole (3200 mg) and trimethoprim (640 mg) is not satisfactory for the single dose treatment of genital ulcer disease. However, when prescribed for five days, sulphamoxole/trimethoprim is effective and compares favourably with other treatment regimens.

Cefotaxime treatment of Haemophilus ducreyi infection in Kenya.

The authors conducted a double-blind randomized clinical trial comparing single-dose cefotaxime (1 g im) plus daily placebo injections with cefotaxime (1 g im on each of three days). Each regimen was given with probenicid (1 g orally) for the treatment of chancroid. Twenty Haemophilus ducreyi culture-positive men received the single-dose cefotaxime regimen; in eight patients ulcers or buboes failed to respond to therapy. Nineteen H. ducreyi culture-positive men received cefotaxime on each of three days; H. ducreyi was eradicated from all patients, but one had a continuing ulcer and another had a bubo that failed to respond. Thus cefotaxime (1 g im daily for three days) plus probenicid (1 g orally) is effective therapy for chancroid. The lack of efficacy for chancroid of the single-dose cefotaxime regimen is surprising, given the remarkable susceptibility of H. ducreyi to cefotaxime; presumably the half-life of cefotaxime is too short for predictable eradication of H. ducreyi from the ulcer with a single-dose regimen.