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Guidelines recommend wound care and/or local therapy as first-line treatment for cutaneous leishmaniasis. An analysis of a referral treatment program in 135 travelers showed that this approach was feasible in 62% of patients, with positive outcome in 83% of evaluable patients.Background. Cutaneous leishmaniasis (CL) is a disfiguring but not life-threatening disease. Because antileishmanial drugs are potentially toxic, the World Health Organization (WHO) recommends simple wound care or local therapy as first-line treatment, followed or replaced by systemic therapy if local therapy fails or cannot be performed.Methods. To determine the feasibility and impact of the recommended approach, we analyzed the results of a centralized referral treatment program in 135 patients with parasitologically proven CL.Results. Infections involved 10 Leishmania species and were contracted in 29 different countries. Eighty-four of 135 patients (62%) were initially treated without systemic therapy. Of 109 patients with evaluable charts, 23 of 25 (92%) treated with simple wound care and 37 of 47 (79%) treated with local antileishmanial therapy were cured by days 42–60. In 37 patients with large or complex lesions, or preexisting morbidities, or who had not been cured with local therapy, the cure rate with systemic antileishmanial agents was 60%. Systemic adverse events were observed in 15 patients, all receiving systemic therapy.Conclusions. In this population of CL patients displaying variable degrees of complexity and severity, almost two-thirds of patients could be initially managed without systemic therapy. Of these, 60 were cured before day 60. The WHO-recommended stepwise approach favoring initial local therapy therefore resulted in at least 44% of all patients being cured without exposure to the risk of systemic adverse events. Efforts are needed to further simplify local therapy of CL and to improve the management of patients with complex lesions and/or preexisting comorbidities. [ABSTRACT FROM AUTHOR]

Background. Mucormycosis is a deadly invasive fungal infection whose characteristics are only partially understood. Methods. Data on mucormycosis obtained in France between 2005 and 2007 from 2 notification systems were merged. The 2008 European Organisation for Research and Treatment of Cancer/Mycoses Study Group definition criteria were applied and risk factors for death were analyzed by hazard ratios (HRs) calculated from the Cox proportional hazards regression model. Results. A total of 101 cases (60 proven, 41 probable), mostly in men (58%) .50 years (mean age, 50.7 ± 19.9) were recorded. Hematological malignancies represented 50% (median time for occurrence, 8.8 months after disease onset), diabetes 23%, and trauma 18% of cases. Sites of infection were lungs (28%; 79% in hematology patients), rhinocerebral (25%; 64% in diabetic patients), skin (20%), and disseminated (18%). Median time between first symptoms and diagnosis was 2 weeks. The main fungal species were Rhizopus oryzae (32%) and Lichtheimia species (29%). In cases where the causative species was identified, R. oryzae was present in 85% of rhinocerebral forms compared with only 17% of nonrhinocerebral forms (P <.001). Treatment consisted of surgery in 59% and antifungals in 87% of cases (liposomal amphotericin B in 61%). Ninety-day survival was 56%; it was reduced in cases of dissemination compared with rhinocerebral (HR, 5.38 [2.0-14.1]; P, .001), pulmonary (HR, 2.2 [1.0-4.7]; P = .04), or skin localization (HR, 5.73 [1.9-17.5]; P = .002); survival was reduced in cases of hematological malignancies compared with diabetes mellitus (HR, 2.3 [1.0-5.2]; P < .05) or trauma (HR, 6.9 [1.6-28.6], P =.008) and if &ges;2 underlying conditions (HR, 5.9 [1.8-19.0]; P = .004). Mucormycosis localization remained the only independent factor associated with survival. Conclusions. This 3-year study performed in one country shows the diverse clinical presentation of mucormycosis with a high prevalence of primary skin infection following trauma and a prognosis significantly influenced by localization. [ABSTRACT FROM AUTHOR]

Background: Complex cutaneous and muco-cutaneous leishmaniasis (CL and MCL) often requires systemic therapy. Liposomal amphotericin B (L-AmB) has a strong potential for a solid clinical benefit in this indication., Methods: We conducted a retrospective analysis of data from a French centralized referral treatment program and from the "LeishMan" European consortium database. All patients with parasitologically proven CL or MCL who received at least one dose of L-AmB were included. Positive outcome was based on ulcer closure as per recent WHO workshop guidelines., Results: From 2008 through 2016, 43 travelers returning from 18 countries (Old World n = 28; New World n = 15) were analyzed with a median follow-up duration of 79 days [range 28-803]. Main clinical forms were: localized CL with one or multiple lesions (n = 32; 74%) and MCL (n = 8; 19%). As per published criteria 19 of 41 patients (46%) were cured 90 days after one course of L-AmB. When the following items -improvement before day 90 but no subsequent follow-up, delayed healing (>3 months) and healing after a second course of L-AmB- were included in the definition of cure, 27 of 43 patients (63%) had a positive outcome. Five patients (MCL = 1; CL = 4) experienced a relapse after a median duration of 6 months [range 3-27] post treatment and 53% of patients (23/43) experienced at least one adverse event including severe hypokalaemia and acute cardiac failure (one patient each). In multivariate analysis, tegumentary infection with L. infantum was associated with complete healing after L-AmB therapy (OR 5.8 IC 95% [1.03-32]) while infection with other species had no impact on outcome., Conclusion: In conditions close to current medical practice, the therapeutic window of L-AmB was narrow in travellers with CL or MCL, with the possible exception of those infected with L. infantum. Strict follow-up is warranted when using L-AmB in patients with mild disease.

Tuberculosis (TB) is a deadly infectious disease, which kills millions of people every year. The causative pathogen, Mycobacterium tuberculosis (MTB), is estimated to have infected up to a third of the world's population; however, only approximately 10% of infected healthy individuals progress to active TB. Despite evidence for heritability, it is not currently possible to predict who may develop TB. To explore approaches to classify susceptibility to TB, we infected with MTB dendritic cells (DCs) from putatively resistant individuals diagnosed with latent TB, and from susceptible individuals that had recovered from active TB. We measured gene expression levels in infected and non-infected cells and found hundreds of differentially expressed genes between susceptible and resistant individuals in the non-infected cells. We further found that genetic polymorphisms nearby the differentially expressed genes between susceptible and resistant individuals are more likely to be associated with TB susceptibility in published GWAS data. Lastly, we trained a classifier based on the gene expression levels in the non-infected cells, and demonstrated reasonable performance on our data and an independent data set. Overall, our promising results from this small study suggest that training a classifier on a larger cohort may enable us to accurately predict TB susceptibility.

We report on 4 patients (1 immunocompetent, 3 immunosuppressed) in whom visceral leishmaniasis had become unresponsive to (or had relapsed after) treatment with appropriate doses of liposomal amphotericin B. Under close follow-up, full courses of pentavalent antimony were administered without life-threatening adverse events and resulted in rapid and sustained clinical and parasitological cure.

Background: Cutaneous leishmaniasis is caused by several Leishmania species that are associated with variable outcomes before and after therapy. Optimal treatment decision is based on an accurate identification of the infecting species but current methods to type Leishmania isolates are relatively complex and/or slow. Therefore, the initial treatment decision is generally presumptive, the infecting species being suspected on epidemiological and clinical grounds. A simple method to type cultured isolates would facilitate disease management., Methodology: We analyzed MALDI-TOF spectra of promastigote pellets from 46 strains cultured in monophasic medium, including 20 short-term cultured isolates from French travelers (19 with CL, 1 with VL). As per routine procedure, clinical isolates were analyzed in parallel with Multilocus Sequence Typing (MLST) at the National Reference Center for Leishmania., Principal Findings: Automatic dendrogram analysis generated a classification of isolates consistent with reference determination of species based on MLST or hsp70 sequencing. A minute analysis of spectra based on a very simple, database-independent analysis of spectra based on the algorithm showed that the mutually exclusive presence of two pairs of peaks discriminated isolates considered by reference methods to belong either to the Viannia or Leishmania subgenus, and that within each subgenus presence or absence of a few peaks allowed discrimination to species complexes level., Conclusions/significance: Analysis of cultured Leishmania isolates using mass spectrometry allows a rapid and simple classification to the species complex level consistent with reference methods, a potentially useful method to guide treatment decision in patients with cutaneous leishmaniasis.

Background: Treatment of cutaneous leishmaniasis (CL) and mucosal leishmaniasis (ML) in travelers is still controversial. Over the last decade, national and international consortia have published recommendations for treating CL in travelers. These guidelines harmonize many issues, but there are some discrepancies., Methods: Leishmania parasites causing CL can now be genotyped by polymerase chain reaction techniques for detecting Leishmania DNA. Therefore, treatment recommendations can now be species based rather than based on geographical exposure. To review the evidence on which the recommendations were based, "LeishMan" (Leishmaniasis Management), a group of experts from 13 institutions in eight European countries, performed a PubMed MEDLINE) literature search and considered unpublished evidence and the experts' own personal experiences. The Oxford evidence grading system was used to evaluate the information., Results and Conclusion: In this article, the authors provide practical treatment recommendations for imported CL and ML in Europe, drawn up from the review by the European experts.

Patients under immunosuppressive therapy with tumor necrosis factor alpha (TNF-α) antagonists are vulnerable to various opportunistic infections including leishmaniasis. We present a case series of 8 travellers developing cutaneous leishmaniasis whilst on TNF-α antagonist treatment and review the literature on aspects of cutaneous leishmaniasis developing in patients treated with TNF-α antagonists. We make interim recommendations regarding the drug therapy used to maintain remission in travellers with rheumatoid disease travelling to leishmania prone areas. Despite having a medical condition requiring continued rheumatological review the interval to diagnosis appears not to be reduced compared to that described in non-rheumatoid patients. Rheumatologists and family doctors should be aware of the need for post-travel surveillance for leishmaniasis in rheumatoid patients on TNF-alpha antagonist treatment., (Copyright © 2013. Published by Elsevier Ltd.)

Background: There is a need for a simple and efficacious treatment for cutaneous leishmaniasis with an acceptable side-effect profile., Methods: We conducted a randomized, vehicle-controlled phase 3 trial of topical treatments containing 15% paromomycin, with and without 0.5% gentamicin, for cutaneous leishmaniasis caused by Leishmania major in Tunisia. We randomly assigned 375 patients with one to five ulcerative lesions from cutaneous leishmaniasis to receive a cream containing 15% paromomycin-0.5% gentamicin (called WR 279,396), 15% paromomycin alone, or vehicle control (with the same base as the other two creams but containing neither paromomycin nor gentamicin). Each lesion was treated once daily for 20 days. The primary end point was the cure of the index lesion. Cure was defined as at least 50% reduction in the size of the index lesion by 42 days, complete reepithelialization by 98 days, and absence of relapse by the end of the trial (168 days). Any withdrawal from the trial was considered a treatment failure., Results: The rate of cure of the index lesion was 81% (95% confidence interval [CI], 73 to 87) for paromomycin-gentamicin, 82% (95% CI, 74 to 87) for paromomycin alone, and 58% (95% CI, 50 to 67) for vehicle control (P<0.001 for each treatment group vs. the vehicle-control group). Cure of the index lesion was accompanied by cure of all other lesions except in five patients, one in each of the paromomycin groups and three in the vehicle-control group. Mild-to-moderate application-site reactions were more frequent in the paromomycin groups than in the vehicle-control group., Conclusions: This trial provides evidence of the efficacy of paromomycin-gentamicin and paromomycin alone for ulcerative L. major disease. (Funded by the Department of the Army; ClinicalTrials.gov number, NCT00606580.).

This review addresses the question of whether the risk of developing mucosal leishmaniasis (ML) warrants systemic treatment in all patients with New World cutaneous leishmaniasis (CL) or whether local treatment might be an acceptable alternative. The risk of patients with New World CL developing ML after the initial infection has been the main argument for systemic treatment. However, this statement needs re-evaluation and consideration of all the available data. The putative benefit of preventing ML should outweigh the toxicity of systemic antileishmanial therapy. To assess the need for and risk of systemic treatment the following factors were reviewed: the incidence and prevalence of ML in endemic populations and in travellers; the severity of mucosal lesions; the efficacy of current options to treat ML; the toxicity and, to a lesser extent, the costs of systemic treatment; the risk of developing ML after local treatment; and the strengths and limitations of current estimates of the risk of developing ML in different situations. Local treatment might be considered as a valuable treatment option for travellers suffering from New World CL, provided that there are no risk factors for developing ML such as multiple lesions, big lesions (>4 cm(2)), localisation of the lesion on the head or neck, immunosuppression or acquisition of infection in the high Andean countries, notably Bolivia.

Because it relies on potentially toxic, difficult-to-handle, or expensive compounds the therapy of leishmaniasis is still a complex issue in 2010, especially for visceral leishmaniasis in immuno-suppressed subjects, or in patients with cutaneous and mucosal involvement. This induces a wide diversity of observed therapeutic practices, some being sub-optimal. The Société de Pathologie Exotique organised a meeting dedicated to the therapy of leishmaniasis in France that led to the first consensus on therapeutic guidelines. Liposomal amphotericin B is the first-line option for visceral leishmaniasis both in immunocompetent, and immunosuppressed patients (cumulated doses of 20 mg/kg and 30-40 mg/kg, respectively). Secondary prophylaxis with either liposomal amphotericin B, pentamidine or meglumine antimoniate is proposed to patients with heavy immunosuppression until immunity has been restored for at least 6 months. While the efficacy of new topical formulations of paromomycin is being tested, patients with Old World cutaneous leishmaniasis may be left untreated, or be administered a combination of superficial cryotherapy plus intralesional antimony, or even--in complex situations--receive systemic therapy. The efficacy of a short course of pentamidine (L. guyanensis/L. panamensis) and a 20-day schedule of meglumine antimoniate (L. braziliensis) is solidly established. However, in well-defined situations, local therapy of New World cutaneous leishmaniasis is now considered acceptable., (Copyright © 2010 Elsevier Masson SAS. All rights reserved.)

Background: Cutaneous leishmaniasis (cl) is a disfiguring disease that confronts clinicians with a quandary: leave patients untreated or engage in a complex or toxic treatment. Topical treatment of CL offers a practical and safe option. Accordingly, the treatment of CL with WR279,396, a formulation of paromomycin and gentamicin in a hydrophilic base, was investigated in a phase 2 clinical study in Tunisia and France., Methods: A phase 2, randomized, double blind, vehicle-controlled study was conducted to assess the safety and efficacy of topical WR279,396 when applied twice a day for 20 days as treatment for parasitologically confirmed CL. The study protocol established the primary efficacy end point as complete clinical response (CCR) defined as 50% or greater reduction in the ulceration size of an index lesion by day 50 (D50) followed by complete re-epithelialization by D100, and no relapse through D180., Results: Ninety-two subjects were randomized. Leishmania major was identified in 66 of 68 isolates typed (97%). In the intent-to-treat population, 47 of 50 WR279,396 treated participants (94%) met the definition of CCR, compared with 30 of 42 vehicle-placebo participants (71%) [p = 0.0045]. Erythema occurred in 30% and 24% of participants receiving WR279,396 and placebo, respectively [p = 0.64]. There was no clinical or laboratory evidence of systemic toxicity., Conclusion: Application of WR279,396 for 20 days was found to be safe and effective in treating L. major CL, and offers great potential as a new, simple, easily applicable, and inexpensive topical therapy for this neglected disease., Trial Registration: ClinicalTrials.gov NCT00703924.

Background: Because topical therapy is easy and usually painless, it is an attractive first-line option for the treatment of localized cutaneous leishmaniasis (LCL). Promising ointments are in the final stages of development. One main objective was to help optimize the treatment modalities of human LCL with WR279396, a topical formulation of aminoglycosides that was recently proven to be efficient and safe for use in humans., Methodology/principal Findings: C57BL/6 mice were inoculated in the ear with luciferase transgenic L. major and then treated with WR279396. The treatment period spanned lesion onset, and the evolution of clinical signs and bioluminescent parasite loads could be followed for several months without killing the mice. As judged by clinical healing and a 1.5-3 log parasite load decrease in less than 2 weeks, the 94% efficacy of 10 daily applications of WR279396 in mice was very similar to what had been previously observed in clinical trials. When WR279396 was applied with an occlusive dressing, parasitological and clinical efficacy was significantly increased and no rebound of parasite load was observed. In addition, 5 applications under occlusion were more efficient when done every other day for 10 days than daily for 5 days, showing that length of therapy is a more important determinant of treatment efficacy than the total dose topically applied., Conclusions/significance: Occlusion has a significant adjuvant effect on aminoglycoside ointment therapy of experimental cutaneaous leishmaniasis (CL), a concept that might apply to other antileishmanial or antimicrobial ointments. Generated in a laboratory mouse-based model that closely mimics the course of LCL in humans, our results support a schedule based on discontinuous applications for a few weeks rather than several daily applications for a few days.

Visceral and cutaneous leishmaniases are heterogenous entities. The Leishmania species that a given patient harbors usually cannot be determined clinically, and this identification is essential to prescribe the best species-specific therapeutic regimen. Our diagnosis procedure includes a real-time PCR assay targeted at the 18S rRNA gene, which detects all Leishmania species but which is not specific for a given Leishmania species. We developed a species identification based on sequencing of the cytochrome b (cyt b) gene directly from the DNA extracted from the clinical specimen. The sequences were analyzed using the Sequence Analysis/Seqscape v2.1 software (Applied Biosystems). This software is designed to automatically identify the closest sequences from a reference library after analysis of all known or unknown polymorphic positions. The library was built with the Leishmania cyt b gene sequences available in GenBank. Fifty-three consecutive real-time PCR-positive specimens were studied for species identification. The cyt b gene was amplified in the 53 specimens. Sequencing resulted in the identification of six different species with >or=99% identity with the reference sequences over 872 nucleotides. The identification was obtained in two working days and was in accordance with the multilocus enzyme electrophoresis identification when available. Real-time PCR followed by sequencing of the cyt b gene confirmed the diagnosis of leishmaniasis and rapidly determined the infecting species directly from the clinical specimen without the need for the isolation of parasites. This technique has the potential to significantly accelerate species-adapted therapeutic decisions regarding treatment of leishmaniasis.

The efficacy of fluconazole was evaluated in 35 travelers with parasitologically proven imported Old World cutaneous leishmaniasis (CL). Leishmania major (mainly MON-25) was identified in 15 patients and strongly suspected given the transmission area in 12 of these patients. Daily oral fluconazole (200 mg/day for adults and 2.5 mg/kg/day for children) was prescribed for six weeks. Outcome definition was based on re-epithelialization rate at day 50. Of the 27 L. major-infected patients, 12 (44.4%) were cured. This cure rate is similar to the placebo cure rate from trials in L. major CL in which, as in the present report, the definition of outcome relied exclusively on re-epithelialization. These data question the assumption that oral fluconazole is consistently effective for treatment of CL caused by L. major.

Today no drug likely to be efficient on the majority of human-infecting species, well tolerated, and easy to administer is available for the treatment of human cutaneous leishmaniasis. But recent progress has been made. Efficient against visceral leishmaniasis, orally administered miltefosine may supplant pentavalent antimonials for the treatment of cutaneous leishmaniasis acquired in the New World. Right now, the reference treatment is still parenteral pentavalent antimonials 20 mg Sbv/kg/d for a duration that may probably be reduced from 20 to 10 days. The benefit/risk ratio of pentamidine still compares well with that of pentavalent antimonials for the treatment of lesions due to species belonging to the L. panamensis/L. guyanensis/L. shawi group. Pentamidine, which is easier to handle than antimonials, remains the reference treatment for cases from areas where these species predominate. Oral fluconazole is an improvement, readily available for cases from L. major foci. If its efficacy is confirmed in other foci and against other species, mechanisms will have to be implemented to make this therapeutic improvement affordable to poor patients in endemic countries. The development of an efficient and well tolerated topical treatment is still warranted. A new formulation of aminosidine is currently under evaluation. One can hope that the treatment of cutaneous leishmaniasis will soon become simpler, both for patients and doctors. For the benefits of this simplification to be rapidly affordable to all patients, the pharmaceutical and clinical research outlay must be maintained.