Low efficacy of azithromycin to treat cutaneous leishmaniasis in Manaus, AM, Brazil

An open trial to evaluate the azithromycin efficacy in cutaneous leishmaniasis patients was carried out in Manaus (AM), where Leishmania (Viannia) guyanensis is the main etiologic agent. Forty-one patients with skin lesions of less than 12 weeks duration, without specific treatment for the last three months and a positive imprint to Leishmania sp. were included. From these, 31 (75.6%) were male with median age of 30.2. All of them received a daily-single oral dose of 500 mg of azithromycin for ten days. At 25th day, 16 (39%) presented therapeutic failure and received intramuscular pentavalent antimonial, four were considered lost, 21, that had improved or were inaltered received another ten-day series of azithromycin and were monthly followed, but nine (21.9%) of them presented a poor clinical response and switched to intramuscular pentavalent antimonial on day 55. Of the 12 remaining cases evaluated on day 55, despite of clinical improvement, three asked for antimony therapy and 9 (21.9%) continued the follow-up but, only three were cured on 55th, 85th and 115 th days, and six did not come back for final evaluation. The intention-treatment overall response rate was 22% and whole cure was seen in three (7.3%) of cases. Thus, azithromycin showed a low efficacy to treat cutaneous leishmaniasis in Manaus.     

Evidence for leishmania (viannia) parasites in the skin and blood of patients before and after treatment

BACKGROUND: American cutaneous leishmaniasis is considered to be a zoonotic disease transmitted by sand flies that feed on infected sylvatic mammals. However, the "domestication" of transmission and the increase in treatment failure with antimonial drugs have raised the suspicion of anthroponotic transmission of American cutaneous leishmaniasis. METHODS: The objective of the present study was to explore the potential of humans as a source of infection for sand flies. Biological (xenodiagnosis and culture) and molecular (polymerase chain reaction/Southern blot) detection methods were used to evaluate peripheral-blood monocytes and tissue fluids from sites accessible to sand flies from 59 adult patients with parasitologically confirmed American cutaneous leishmaniasis. RESULTS: Overall, 44.1% of patients (26/59) presented biological and/or molecular evidence of Leishmania parasites in normal skin, peripheral-blood monocytes, lesion scars, or lesion border (by xenodiagnosis) before (18/59 [30.5%]) or after (10/27 [37.0%]) treatment. Leishmania parasites were cultured from the unaffected skin of 2 (3.6%) of 55 patients, and xenodiagnosis gave positive results for 5 (8.8%) of 57 patients before treatment. CONCLUSIONS: The presence of Leishmania parasites in the unaffected skin and peripheral-blood monocytes of a high proportion of patients even after treatment and the acquisition of infection by sand flies support the plausibility of anthroponotic transmission of American cutaneous leishmaniasis.     

Action of p-(4-amidino-phenoxy)-benzaldehyde-p-amidino-phenylhydrazone dihydrochloride on Leishmania donovani infections in the golden hamster.

The chemotherapeutic effect of a new diamidine, HOE 668, the p-(4-amidino-phenoxy)-benzaldehyde-p-amidino-phenylhydrazone dihydrochloride, was compared with that of known anti-leishmanial drugs in golden hamsters infected with Leishmania donovani. The effect of HOE 668 against visceral leishmaniasis proved superior to that of pentamidine isethionate and the pentavalent antimonial drugs, sodium stibogluconate and N-methylglucamine antimoniate. However, HOE 668 can be used only experimentally because of its toxicity. Its very good anti-leishmanial action qualifies HOE 668 as a standard compound in screening tests.     

Oral miltefosine treatment in children with visceral leishmaniasis: a brief review.

Visceral leishmaniasis (VL) or kala-azar is an infection disease caused by hemiflagellate protozoan parasites (Leishmania donovani) and transmitted to humans by the phlebotomine sandfly. Leishmaniasis is distributed worldwide and 13 million people are estimated to be infected, with about 1.8 million new cases each year. All antileishmanial drugs are toxic and most have to be used parenterally for prolonged period. The therapy has been further complicated by large number of infected children and declining effectiveness of pentavalent antimonial compounds. Although the lipid formulations of amphotericin B are an important advance in therapy, their high cost precludes their use. Miltefosine, a phosphocholine analogue originally developed as antimalignant drug, has been found to be highly active against Leishmania in vitro and in animal model. Based on these experiences this drug was tried against human visceral leishmaniasis and found to be highly effective in children. The aim of this review is to evidence the pharmacodymamic and pharmacokinetic characteristics and the safety, tolerance and efficacy of this drug for treatment of visceral leishmaniasis in children.     

Comparison of cutaneous leishmaniasis due to Leishmania (Viannia) braziliensis and L. (V.) guyanensis in Brazil: clinical findings and diagnostic approach.

We compared the clinical findings and diagnostic methods for 66 patients with cutaneous leishmaniasis in the state of Bahia, Brazil, who were infected by Leishmania (Viannia) braziliensis (group A), with those for 68 patients in the state of Amazonas, Brazil, who were mainly infected by Leishmania (Viannia) guyanensis (group B). Differences were observed with regard to number, size, and location of skin lesions and to the pattern of lymphatic involvement. Patients in group B had smaller and more numerous lesions, which were frequently located above the waist, versus the larger but less numerous lesions among patients in group A, which were usually located on the lower limbs. Lymphatic involvement was present in 55 (83.3%) of the 66 patients in group A and in 42 (61.8%) of the 68 patients in group B (P=0.005). The positivity rates of imprints and skin culture procedures were higher in group B. Sensitivity of in vitro culture of skin aspirates was 47.0% and 91.2% for groups A and B, respectively (P<.001). Although hamster inoculation showed similar results in both groups, the interval before development of disease was shorter in group B. Our data provide substantial evidence that indicate that the disease caused by these species differs with regard to clinical presentation and diagnostic approach.     

Recommendations for treating leishmaniasis with sodium stibogluconate (Pentostam) and review of pertinent clinical studies.

Pentavalent antimonial compounds have been the mainstay of the treatment of visceral, cutaneous, and mucosal leishmaniasis for approximately half a century. Pentostam (sodium stibogluconate) is the pentavalent antimonial compound available in the United States (through the Centers for Disease Control). As dosage regimens for treating leishmaniasis have evolved, the daily dose of antimony and the duration of therapy have been progressively increased to combat unresponsiveness to therapy. In the 1980s, the use of 20 mg/kg/day (instead of 10 mg/kg/day) of antimony was recommended, but only to a maximum daily dose of 850 mg. The authors have concluded on the basis of recent efficacy and toxicity data that this 850-mg restriction should be removed; the evidence to date, which is summarized here, suggests that a regimen of 20 mg/kg/day of pentavalent antimony, without an upper limit on the daily dose, is more efficacious and is not substantially more toxic than regimens with lower daily doses. We recommend treating all forms of leishmaniasis with a full 20 mg/kg/day of pentavalent antimony. We treat cutaneous leishmaniasis for 20 days and visceral and mucosal leishmaniasis for 28 days. Our judgment of cure is based on clinical criteria.     

Potential utility of hyperbaric oxygen therapy and propolis in enhancing the leishmanicidal activity of glucantime

In this study we investigated the efficacy of hyperbaric oxygen (HBO) therapy, alone or combined with the pentavalent antimonial glucantime on Leishmania amazonensis infection. In parallel, the effect of Brazilian red propolis gel (propain) alone or combined with glucantime on L. amazonensis infection was evaluated. The inhibition of the infection in macrophages treated with glucantime in combination with HBO exposition was greater than that of macrophages treated with glucantime alone or HBO alone. The susceptible mouse strain BALB/c infected in the shaved rump with L. amazonensis treated with glucantime and exposed to HBO showed: time points in the course of the disease in which lesions were smaller than those of mice treated with glucantime alone and revascularization of the skin in the lesion site; interferon-gamma (IFN-g) levels were not elevated in lymph node cells from these animals. Propain alone was not efficient against lesions, although less exudative lesions were observed in animals treated with propain alone or combined with glucantime. These results reveal the potential value of HBO and red propolis in combination with glucantime for treating cutaneous leishmaniasis and encourage further studies on the effect of more aggressive HBO, propolis and glucantime therapies on different mouse models of leishmaniasis.     

Localized mucosal leishmaniasis due to Leishmania (Leishmania) infantum: clinical and microbiologic findings in 31 patients

The clinical and microbiologic characteristics of 31 patients with mucosal leishmaniasis due to Leishmania (Leishmania) infantum are described. Twenty-eight (90%) patients were male. Mean age at presentation was 48 +/- 14 years. Thirteen (42%) patients had no underlying disease, while 18 (58%) patients had several other medical conditions. Fifteen (48%) patients were immunocompromised, 7 patients were infected with human immunodeficiency virus (HIV), and 3 were graft recipients. The primary location of lesions was the larynx in 11 (35%) patients, oral mucosa in 10 (32%) patients, and the nose in 5 (16%) patients. Mucosal lesions were painless in all patients but 2 and consisted of whitish, red, or violaceous nodular swelling or tumorlike masses. Ulceration was reported in 6 patients. Pathologically, the lesions showed a chronic inflammatory infiltrate. Granuloma may be seen.The localization of the lesions determined the symptomatology of the disease. Symptoms included hoarseness, difficulty swallowing, and nasal obstruction. The disease presentation was usually protracted, with a mean time from the onset of symptoms to diagnosis of 13 months (range, 3 wk-4.5 yr), and the clinical diagnosis was usually mistaken for neoplasia of the upper aerodigestive tract. No laboratory abnormalities were found in these patients due to the localized disease, apart from those attributed to underlying diseases.Parasites were easily identified in smears or sections by Giemsa stain or hematoxylin-eosin stain. Leishmania was grown in culture in 12 (60%) patients; culture was negative in 8 (40%) patients. Leishmania (Leishmania) infantum was identified in only 9 instances. The following zymodemes were reported: MON-1 (2 patients), MON-24 (2 patients), MON-27 (1 patient), and MON-34 (1 patient). Serologic test results were known in 25 patients. Serology was usually positive at low titer; 6 (24%) patients had negative serologic test results.Twenty patients were treated with antimonial compounds for between 3 and 36 days. Three patients were given drugs other than antimonial drugs. Five patients were treated only locally, by surgery (3 patients) or topical medical therapy. One patient received no therapy, and treatment was not reported in 2 cases. Patients were cured in 25 (89%) cases, and sequelae were uncommon (14%). Relapse was detected in 2 individuals and 1 patient developed visceral leishmaniasis after treatment. Two HIV-coinfected patients died of causes unrelated to leishmaniasis.The results of the present report stress the clinical importance of searching for the presence of Leishmania in patients with suspected neoplasia of the upper respiratory tract if they have visited or resided in zones endemic for Leishmania (Leishmania) infantum. The treatment of choice for these patients is not established yet, but most patients respond to antimonial compounds given for 28 days or less.     

A species-specific approach to the use of non-antimony treatments for cutaneous leishmaniasis

We used a species-specific approach to treat 10 patients with cutaneous leishmaniasis diagnosed using polymerase chain reaction. Non-antimony treatments (oral miltefosine, ketoconazole, and liposomal amphotericin B) were chosen as an alternative to pentavalent antimony drugs based on likely or proven drug efficacy against the infecting species. Leishmania Viannia panamensis was diagnosed in three patients and treated successfully with oral ketoconazole. Miltefosine treatment cured two patients with L. infantum chagasi. A wide variety of Leishmania responded to liposomal amphotericin B administered for 5-7 days. Three patients with L. V. braziliensis, one patient with L. tropica, and two patients with L. infantum chagasi were treated successfully. One person with L. V. braziliensis healed slowly because of a resistant bacterial superinfection, and a second patient with L. infantum chagasi relapsed and was retreated with miltefosine. These drugs were reasonably well-tolerated. In this limited case series, alternative non-antimony-based regimens were convenient, safe, and effective.     

Rapid clearance of circulating Leishmania kinetoplast DNA after treatment of visceral leishmaniasis

With the aim of evaluating the utility of the detection of Leishmania kDNA in peripheral blood for the cure assessment of visceral leishmaniasis (VL), a PCR based method was performed in patients with confirmed VL at three follow-up periods after specific chemotherapy with pentavalent antimonial. In 16 out of 17 (94.1%) patients with pre-treatment detectable kDNA that were clinically cured, the PCR turned negative up to 37 days after the initiation of treatment, remaining negative over 90 days after treatment. The clearance of Leishmania kDNA from peripheral blood of patients with VL hints to occur during or shortly after treatment concurring or preceding clinical recovery.     

Randomized controlled clinical trial to access efficacy and safety of miltefosine in the treatment of cutaneous leishmaniasis Caused by Leishmania (Viannia) guyanensis in Manaus, Brazil

Miltefosine has been used in the treatment of several new world cutaneous leishmaniasis (CL) species with variable efficacy. Our study is the first evidence on its clinical efficacy in Leishmania (Viannia) guyanensis. In this phase II/III randomized clinical trial, 90 CL patients were randomly allocated (2:1) to oral miltefosine (2.5 mg/kg/day/28 days) (N = 60) or parenteral antimony (15-20 mg/Sb/kg/day/20 days) (N = 30) according to age groups: 2-12 y/o and 13-65 y/o. Patients were human immunodeficiency virus (HIV) noninfected parasitological proven CL without previous treatment. Definitive cure was accessed at 6 months follow-up visit. No severe adverse events occurred. Vomiting was the most frequent adverse event (48.3%) followed by nausea (8.6%) and diarrhea (6.7%). Cure rates were 71.4% (95% confidence interval [CI] = 57.8-82.7) and 53.6% (95% CI = 33.9-72.5) (P = 0.05) for miltefosine and antimonial, respectively. There were no differences in cure rates between age groups within the same treatment arms. Miltefosine was safe and relatively well tolerated and cure rate was higher than antimony.     

Visceral leishmaniasis (kala-azar) as an opportunistic infection in patients infected with the human immunodeficiency virus in Spain

In an area endemic for visceral leishmaniasis, 16 patients with human immunodeficiency virus (HIV) infection developed the disease. All belonged to populations at risk for AIDS (15 were intravenous drug abusers). Five patients fulfilled the criteria for full-blown AIDS, and two more fulfilled them after diagnosis of leishmaniasis. All presented with the classic manifestations of visceral leishmaniasis, but leishmania serology was negative in 15 patients (93%). Leishmania donovani amastigotes were identified in the bone marrow in all cases. Most patients responded initially to treatment with pentavalent antimonial drugs, but seven (43%) followed a chronic course, with multiple relapses in five, despite alternative treatments. Visceral leishmaniasis occurred in patients with different levels of depression of the CD4 to CD8 lymphocyte ratio. Mortality was 37% (six patients) and was independent of the chronic-relapsing course of the disease. In no case was leishmaniasis the primary cause of death. Our data establish that visceral leishmaniasis is an opportunistic infection in HIV-infected patients, and we suggest that in endemic areas it should be considered an indicator disease for the diagnosis of AIDS.     

Successful treatment of cutaneous leishmaniasis with lipid formulations of amphotericin B in two immunocompromised patients

Pentavalent antimonial drugs are habitually the first choice for treating leishmaniasis, although they possess well-known toxicity and may present some therapeutic failure. Lipid formulations of amphotericin B (LFAB) have been increasingly used for treating several types of leishmaniasis. However, the administration of such lipid formulations specifically to patients with cutaneous leishmaniasis (CL) is still rare, including immunocompromised patients to whom standard treatments are more frequently contraindicated. We describe here two cases of immunocompromised patients with CL, one of them with AIDS, representing the first case of AIDS and CL co-infection treated with LFAB described in the literature. The patient achieved therapeutic success with a total 1.500 mg dose of amphotericin B colloidal dispersion. The other had diabetes mellitus as well as kidney failure and was under dialysis, having obtained the healing of lesion with a total dose of 600 mg of liposomal amphotericin B. Thus, the authors suggest that LFAB can represent a safe, efficient and less toxic therapeutic alternative to pentavalent antimonials, as well as to the so-called second line drugs, pentamidine and amphotericin B deoxycholate.     

A randomized clinical trial comparing oral azithromycin and meglumine antimoniate for the treatment of American cutaneous leishmaniasis caused by Leishmania (Viannia) braziliensis

Azithromycin was compared with meglumine antimoniate for treatment of patients with cutaneous leishmaniasis. Patients were randomized to receive oral azithromycin, 500 mg/day (22 patients) or intramuscular meglumine antimoniate, 10 mg Sb/kg/day (23 patients), both for 28 days, with a second cycle of 15 days if necessary, and followed-up for one year after completion of treatment. Efficacy, defined as complete re-epithelization without relapse for 12 months after completing therapy, was 82.6% (95% confidence interval [CI] = 67-98%) for meglumine antimoniate and 45.5% (95% CI = 25-66%) for azithromycin. All patients who failed treatment with azithromycin were treated with meglumine antimoniate and clinically cured. Azithromycin was well tolerated; meglumine antimoniate caused arthralgias and local symptoms in 78% of the patients. In 17 cases, species identification was obtained; Leishmania (Viannia) braziliensis was identified in all of them. For the treatment of American cutaneous leishmaniasis caused by L. (V.) braziliensis, meglumine antimoniate is significatively more efficacious than azithromycin, which was clinically curative in almost half of the patients and well-tolerated.     

Antihelminthic therapy and antimony in cutaneous leishmaniasis: a randomized, double-blind, placebo-controlled trial in patients co-infected with helminths and Leishmania braziliensis

Helminth infections influence the clinical response to certain diseases and are associated with delayed healing time of patients with cutaneous leishmaniasis (CL) caused by Leishmania braziliensis. We conducted a randomized, double-blind, placebo-controlled clinical trial to examine the role of early versus deferred treatment of intestinal helminth infection on the clinical course of patients with CL treated with pentavalent antimony. (Clinicaltrials.gov number NCT00469495). A total of 90 patients were enrolled, 51.1% (N = 23) of control patients had persistent lesions at Day 90, compared with 62.2% (N = 28) in the treatment group (difference 11.1%, 95% confidence interval = -9.1-30.0%). There was no statistically significant difference in overall time to cure between groups, although there was a tendency for shorter cure times in the control group. This study shows that early introduction of antihelminthic therapy does not improve clinical outcome in patients co-infected with helminths and L. braziliensis.     

PCR-RFLP to identify Leishmania (Viannia) braziliensis and L. (Leishmania) amazonensis causing American cutaneous leishmaniasis

A PCR-RFLP based method was developed to diagnose and identify the Leishmania species causing American cutaneous leishmaniasis (ACL) in a panel of clinical samples obtained from an endemic region of Brazil. The comparison of the results obtained by PCR-RFLP and PCR-hybridization in the identification of Leishmania (Viannia) braziliensis and L. (Leishmania) amazonensis were highly concordant (kappa=91.5%). The PCR-RFLP method was reliable, fast and easy to conduct on biopsies and presents potential value of utmost importance for the diagnosis and identification of Leishmania in clinical specimens, infected reservoirs and vectors.     

Disseminated cutaneous leishmaniasis due to Leishmania(Leishmania) amazonensis in human immunodeficiency virus(HIV)-infected patients: A report of two cases

Rationale: Co-infection of human immunodeficiency virus(HIV) and Leishmania spp. has impact on clinical and therapeutic outcomes of leishmaniases. Most studies do not present the identification of Leishmania species causing American tegumentary leishmaniasis in co-infections. In the Americas, Leishmania(L.) Viannia(V.) braziliensis and L.(V.) guyanensis have been identified. Patient concerns: In this study, two cases of American tegumentary leishmaniasis in patients infected with HIV are described. Patients presented several lesions with rapid dissemination and mucosal involvement. Diagnosis: Disseminated cutaneous leishmaniasis caused by L. amazonensis was identified by molecular test. Interventions: The patients were treated with conventional therapies for HIV infection and American tegumentary leishmaniasis. Outcomes: In co-infection, the clinical manifestations are atypical and the treatment response can be impaired. Lessons: These cases show that HIV infection impacts L. amazonensis infection and point to the relevance of identifying Leishmania species, which can lead to a better patient management.     

Risk factors for relapse of visceral leishmaniasis in Georgia

The number of relapses in patients treated for visceral leishmaniasis (VL) has increased, thus identifying prognostic factors may aid decisions on treatment. Demographic and clinical information was abstracted from medical records of patients diagnosed and treated in Georgia from 2002 to 2004. The 300 persons with VL were primarily children <5 years (73.3%), and ～44% had delays in diagnosis of more than 30 days from symptom onset. All patients received standard therapy with pentavalent antimony (20 mg/kg/day), most for 20-25 days. Factors significantly associated with VL relapse were delay in diagnosis for >90 days (RR = 4.21, 95% CI: 1.58, 11.16), haemoglobin level <60 g/l (RR = 11.96, 95% CI: 4.12, 34.76) and age <1 year (RR = 2.36, 95% CI: 0.96, 5.80). Physician and public education is needed to reduce delays in diagnosis. Prolonging treatment for 30 days (e.g. WHO recommendation) or implementing new regimens may reduce the number of relapses.     

Treatment of cutaneous leishmaniasis with a topical antileishmanial drug (WR279396): phase 2 pilot study

We studied the efficacy of WR279396, a topical formulation of aminoglycosides that cures 100% of cutaneous leishmaniasis lesions in mice. We conducted what is to our knowledge the first controlled study of WR279396 therapy for clinical cutaneous leishmaniasis. A total of 45 Colombian soldiers, all men, were randomly assigned to treatment with WR279396 (33 patients) or placebo (12 patients). Each lesion was treated twice daily for 20 days. Lesions were measured at the end of therapy and at 45, 90, and 180 days after treatment began. A total of 17 (61%) of 28 assessable WR279396-treated patients were cured, and 5 (55%) of 9 assessable placebo-treated patients were cured (P = 0.9). For the 36 lesions treated with WR279396 that were cured, cure took a mean of 35 days, whereas for the 6 lesions that were cured in the group of patients receiving placebo, cure time took a mean of 56 days (P = 0.04). WR279396 is a nontoxic topical formulation that significantly accelerated cure time in patients with Leishmania panamensis cutaneous leishmaniasis.