Macrolides for treatment of Haemophilus ducreyi infection in sexually active adults.

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 with 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.

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.

An Ulcer by Any Other Name: Non-herpes and Non-syphilis Ulcerative Sexually Transmitted Infections.

The myriad presentations of ulcerative sexually transmitted infections, other than genital herpes and syphilis, challenge even the most astute clinician given the considerable overlap in clinical presentation and lack of widely available diagnostic resources, such as nucleic acid testing, to confirm the diagnosis. Even so, case prevalence is relatively low, and incidence of chancroid and granuloma inguinale are declining. These diseases still cause substantial morbidity and increased chance for HIV acquisition, and with the recent advent of mpox as a cause, it remains imperative to identify and treat accurately.

Genital ulcer disease treatment for reducing sexual acquisition of HIV.

BACKGROUND: Genital ulcer disease by virtue of disruption of the mucosal surfaces may enhance HIV acquisition. Genital ulcer disease treatment with resolution of the ulcers may therefore contribute in reducing the sexual acquisition of HIV. OBJECTIVES: To determine the effects of treatment of genital ulcer disease on sexual acquisition of HIV. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, EMBASE, LILACS, NLM Gateway, Web of Science, WHO International Clinical Trials Registry Platform, ClinicalTrials.gov, and reference lists of relevant publications for eligible studies published between 1980 and August 2011. SELECTION CRITERIA: Randomized controlled trials of any treatment intervention aimed at curing genital ulcer disease compared with an alternative treatment, placebo, or no treatment. We included only trials whose unit of randomization was the individual with confirmed genital ulcer. DATA COLLECTION AND ANALYSIS: We independently selected studies and extracted data in duplicate; resolving discrepancies by discussion, consensus, and arbitration by third review author. We expressed study results as risk ratios (RR) with 95% confidence intervals (CI). MAIN RESULTS: There were three randomized controlled trials that met our inclusion criteria recruited HIV-negative participants with chancroid (two trials with 143 participants) and primary syphilis (one trial with 30 participants). The syphilis study, carried out in the US between 1995 and 1997, randomized participants to receive a single 2.0 g oral dose of azithromycin (11 participants); two 2.0 g oral doses of azithromycin administered six to eight days apart (eight participants); or benzathine penicillin G administered as either 2.4 million units intramuscular injection once or twice seven days apart (11 participants). No participant in the trial seroconverted during 12 months of follow-up. The chancroid trials, conducted in Kenya by 1990, found no significant differences in HIV seroconversion rates during four to 12 weeks of follow-up between 400 and 200 mg single oral doses of fleroxacin (one trial, 45 participants; RR 3.00; 95% CI 0.29 to 30.69), or between 400 mg fleroxacin and 800 mg sulfamethoxazole plus 160 mg trimethoprim (one trial, 98 participants; RR 0.33; 95% CI 0.04 to 3.09). Adverse events reported were mild to moderate in severity, and included Jarisch-Herxheimer reactions and gastrointestinal symptoms. The differences between the treatment arms in the incidence of adverse events were not significant. The quality of this evidence on the effectiveness of genital ulcer disease treatment in reducing sexual acquisition of HIV, according to GRADE methodology, is of very low quality. AUTHORS' CONCLUSIONS: At present, there is insufficient evidence to determine whether curative treatment of genital ulcer disease would reduce the risk of HIV acquisition. The very low quality of the evidence implies that the true effect of genital ulcer disease treatment on sexual acquisition of HIV may be substantially different from the effect estimated from currently available data. However, genital ulcer diseases are public health problems in their own right and patients with these conditions should be treated appropriately; whether the treatment reduces the risk of HIV infection or not.

Yaws, Haemophilus ducreyi, and Other Bacterial Causes of Cutaneous Ulcer Disease in the South Pacific Islands.

Cutaneous ulcers in the tropics are a painful and debilitating condition that anchors people into poverty. In rural regions of the South Pacific, infectious cutaneous ulcers are caused mainly by bacteria, including Treponema pallidum pertenue (yaws), Haemophilus ducreyi, and polymicrobial ulcers. For this group of infections the term cutaneous ulcer disease (CUD) is proposed. Some infections can cause malformations on the bone that have a permanent impact on lives in endemic communities. Better characterization of CUD may help design diagnostic tools and more effective antimicrobial therapies. This review updates the knowledge of CUD and discusses optimized terminology and syndromic management.

Cutaneous chancroid in a visitor from Vanuatu.

A 23-year-old woman from Vanuatu presented to an Australian hospital with a 3-week history of a non-healing ulcer on the lower leg. A swab was submitted for a multiplex polymerase chain reaction designed to investigate genital ulcerative conditions. Haemophilus ducreyi was detected and the gene product was subsequently sequenced, confirming the diagnosis of cutaneous chancroid. The lesion responded to intramuscular benzathine penicillin. This report adds further evidence that cutaneous chancroid should be considered in the evaluation of skin ulcers in the south Pacific.

Haemophilus ducreyi cutaneous ulcer contracted at Seram Island, Indonesia, presented in the Netherlands.

OVERVIEW: We describe the first case of a cutaneous ulcer caused by Haemophilus ducreyi imported from Indonesia to the Netherlands. Skin infections caused by H. ducreyi are uncommon in travellers and have been described in just a few case reports and were all contracted on the Pacific Islands. THE CASE: A 22-year-old healthy male visited the Center of Tropical Medicine and Travel Medicine in February 2017 with a cutaneous ulcer of the right lateral malleolus 4 weeks after returning from Indonesia (Seram and Ambon Islands). He had noticed a small skin abrasion on the right ankle after slipping on a rock during a jungle trip on Seram Island. Back in the Netherlands, a painful ulcer developed at the same body location, and despite treatment with flucloxacillin, his complaints worsened. A swab that was taken for culture showed growth of small grey colonies that were characterised as H. ducreyi with matrix-assisted laser desorption/ionisation time-of-flight (MALDI-TOF) mass spectrometry. Treatment with ciprofloxacin for the diagnosis of H. ducreyi cutaneous ulcer was started, and the ulcer clearly diminished, leaving only a small healing ulcer. DISCUSSION: H. ducreyi is normally the causative agent of genital ulcers but is increasingly recognised as a cause of chronic skin ulcers, e.g., in Papua New Guinea. In our patient, the infection was very likely contracted in the Maluku province of Indonesia and imported into the Netherlands. No reports of infection with H. ducreyi from Indonesia could be found in literature, but this case indicates that H. ducreyi is present in at least one of the northeastern islands of Indonesia, which is important for local healthcare. Additionally, it illustrates the role of this agent as a cause of cutaneous ulcers in previously healthy travellers.

First reported case of chancroid in the Czech Republic.

We describe the first case of chancroid seen in the Czech Republic, diagnosed in a 40-year-old heterosexual HIV-positive man. Despite genital localization of the ulcer, the transmission of Haemophilus ducreyi infection in our patient remains unclear, as he denied having sexual intercourse and he did not travel outside the Czech Republic for several months before the ulcer appeared. The correct diagnosis has been revealed by a multiplex nucleic acid amplification test. Physicians in countries in the eastern and central Europe region should be aware that chancroid can occur in their patients.

2017 European guideline for the management of chancroid.

Chancroid is a sexually acquired infection caused by Haemophilus ducreyi. The infection is characterized by one or more genital ulcers, which are soft and painful, and regional lymphadenitis, which may develop into buboes. The infection may easily be misidentified due to its rare occurrence in Europe and difficulties in detecting the causative pathogen. H. ducreyi is difficult to culture. Nucleic acid amplification tests can demonstrate the bacterium in suspected cases. Antibiotics are usually effective in curing chancroid.

First case of chancroid in 14 years at the largest STI clinic in Paris, France.

We report the first case of chancroid seen at our clinic in 14 years. It was diagnosed by nuclear acid amplification test in a male patient returning from Madagascar. Although the disease is considered on the verge of disappearance even in tropical countries, its real potential for reemergence - due to new strains of Haemophilus ducreyi, underreporting and a lack of widespread use of molecular testing - could be underestimated.

Phosphoethanolamine Transferase LptA in Haemophilus ducreyi Modifies Lipid A and Contributes to Human Defensin Resistance In Vitro.

Haemophilus ducreyi resists the cytotoxic effects of human antimicrobial peptides (APs), including α-defensins, ß-defensins, and the cathelicidin LL-37. Resistance to LL-37, mediated by the sensitive to antimicrobial peptide (Sap) transporter, is required for H. ducreyi virulence in humans. Cationic APs are attracted to the negatively charged bacterial cell surface. In other gram-negative bacteria, modification of lipopolysaccharide or lipooligosaccharide (LOS) by the addition of positively charged moieties, such as phosphoethanolamine (PEA), confers AP resistance by means of electrostatic repulsion. H. ducreyi LOS has PEA modifications at two sites, and we identified three genes (lptA, ptdA, and ptdB) in H. ducreyi with homology to a family of bacterial PEA transferases. We generated non-polar, unmarked mutants with deletions in one, two, or all three putative PEA transferase genes. The triple mutant was significantly more susceptible to both α- and ß-defensins; complementation of all three genes restored parental levels of AP resistance. Deletion of all three PEA transferase genes also resulted in a significant increase in the negativity of the mutant cell surface. Mass spectrometric analysis revealed that LptA was required for PEA modification of lipid A; PtdA and PtdB did not affect PEA modification of LOS. In human inoculation experiments, the triple mutant was as virulent as its parent strain. While this is the first identified mechanism of resistance to α-defensins in H. ducreyi, our in vivo data suggest that resistance to cathelicidin LL-37 may be more important than defensin resistance to H. ducreyi pathogenesis.

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.

Fleroxacin in the treatment of chancroid: an open study in men seropositive or seronegative for the human immunodeficiency virus type 1.

Fleroxacin was prescribed to treat both HIV-negative and HIV-positive men with proven chancroid in an open study. HIV-negative men were treated with a single 400-mg dose of fleroxacin, and HIV-positive men were treated with 400 mg daily for 5 days. Three of the 58 evaluable HIV-negative men were clinical and microbiologic failures, and two of the 22 evaluable HIV-positive men had persisting infection with Haemophilus ducreyi. Both regimens were well tolerated. Fleroxacin is an acceptable alternative to existing treatment regimens for chancroid in men.

Problems in the treatment of bacterial sexually transmitted diseases.

Although most bacterial sexually transmitted diseases (STDs) can be effectively treated, currently available regimens are far from ideal. Increasingly widespread plasmid-mediated resistance to the penicillins limits the use of these agents in the treatment of Neisseria gonorrhoeae and Hemophilus ducreyi infections. Chromosomally mediated antimicrobial resistance to the tetracyclines, penicillins, erythromycins, and sulfonamides further limits therapeutic options in the treatment of gonorrhea, and plasmid-mediated resistance to sulfonamides and tetracyclines is frequent in H. ducreyi infections. In patients with Chlamydia trachomatis infections, effective regimens that can more easily be complied with (shorter duration, less frequent dosing) are needed, as are effective alternative regimens for use in pregnancy and in infants. In selected STDs that are polymicrobial (pelvic inflammatory disease and bacterial vaginosis, for example) or that often present simultaneously (gonorrhea-chlamydia, gonorrhea-syphilis, chancroid-syphilis), single-drug regimens that are effective against several genital pathogens would be ideal. Only limited therapeutic alternatives are available for some STDs, especially in pregnant women or in patients with penicillin allergy. Thus, antimicrobial resistance, drug toxicity, poor compliance, limited alternatives in pregnancy or allergy, and the lack of single agents possessing a broad spectrum of activity against multiple genital pathogens limit currently available therapy.

Erosions and ulcers of the vulva: diagnosis, incidence, and management.

In a study of 877 patients with disorders of the vulva seen at a vulva clinic, 375 (43%) presented with an erosion or ulceration or a condition in which an erosion or ulceration developed as a complicating feature. One hundred sixty-one of these patients had a sexually transmitted disease. This report identifies the conditions associated with erosions and ulcerations of the vulva by incidence and provides a simple clinical classification of them as an aid in diagnosis. Methods of study of this group of diseases and their management are discussed.

The impact of antimicrobial resistance on the treatment of sexually transmitted diseases.

The focus of this article is to review the development of antimicrobial resistance among several sexually transmitted diseases (STDs) and to discuss the frequency and mechanisms of resistance and recommendations for treatment of selected STDs in which resistance to certain antimicrobial agents has increased. For a number of STDs, such as Chlamydia trachomatis and syphilis, no evidence of antimicrobial resistance has developed over the years, although management of these diseases, such as in the case of pelvic inflammatory disease or syphilis in HIV-infected individuals, requires intensive treatment and follow-up to ensure effectiveness of treatment.

Treatment of chancroid with spectinomycin or co-trimoxazole.

Chancroid, the third most prevalent venereal disease in Thailand, was treated with a single 2-gm dose of spectinomycin, or two tablets of co-trimoxazole (trimethoprim-sulfamethoxazole) twice daily for seven days. The differences in cure rates between the two groups were statistically significant. The chancroidal ulcers were cured in 93.7% of 175 patients treated with spectinomycin, and in 48.2% of 168 co-trimoxazole-treated patients (P less than 0.01). The in vitro susceptibility of Haemophilus ducreyi to spectinomycin was 4 to 16 micrograms/ml and to co-trimoxazole 32 micrograms/ml or higher. Thus we found that a single-dose regimen of spectinomycin was significantly more effective than the standard seven-day regimen of co-trimoxazole for the treatment of chancroid.

Clinical efficacy of antimicrobial therapy in Haemophilus ducreyi infections.

Ulcerative genital disease in the United States is commonly due to herpes simplex or syphilis. Until recently, chancroid, an infection caused by the gram-negative streptobacillus Haemophilus ducreyi, was infrequently diagnosed. Continuing immigration, however, has reintroduced the disease into this country, and urban outbreaks have been associated with contact with infected prostitutes. Extensive resistance has made previous antimicrobial agents ineffective. Evaluations of multiple antibiotics and varied dosing schedules have been undertaken in an effort to circumvent this resistance. Clinicians treating patients with genital ulcerations must be aware of this disease and its geographically variable antibiotic sensitivities. Recent evidence demonstrating an association between seropositivity for the human immunodeficiency virus and ulcerative genital disease places additional importance on the timely diagnosis and appropriate treatment of chancroidal ulcers.