Efficacy and safety of a combined treatment of sodium stibogluconate at 20mg/kg/day with upper maximum daily dose limit of 850mg and Paromomycin 15mg/kg/day in HIV negative visceral leishmaniasis patients. A retrospective study, northwest Ethiopia.

BACKGROUND: Visceral leishmaniasis (VL) is one of the most neglected tropical infectious diseases. It is fatal if left untreated. The objective of this study was to assess the efficacy and safety of 17-day injections of combined regimen of sodium stibogluconate and paromomycin (SSG/PM) in HIV-negative VL patients. METHODS: A retrospective analysis of medical records of VL patients treated in the University of Gondar Hospital during period 2012-2019 was carried out. RESULTS: A total of 2836 patients were treated for VL from 2012 to 2019. Of these 1233 were treated with SSG-PM, and 1000 of them were included in the study. Initial cure was achieved in 922 (92.2%) patients. The frequency of treatment failure, treatment interruptions, default and deaths respectively were 30 (3%), 20 (2%), 13 (1.3%) and 15 (1.5%). Among 280 patients who completed 6-month follow up, the final cure was 93.9% (263/280), 4 (1.4%) relapsed and 13 (4.6%) developed post-kala-azar dermal leishmaniasis (PKDL). The most common adverse events (AEs) were raised liver transaminases (35.1%; 351 patients), injection site pain (29.1%, 291 patients) and raised serum alpha-amylase (29.1%, 291 patients). Factors associated with poor treatment outcomes were sepsis, pneumonia, and adverse events. CONCLUSION: A combination of SSG at 20mg/kg with upper daily maximum dose of 850mg and PM was effective for achieving initial cure at end of treatment and safe for treatment of HIV negative VL patients in northwestern Ethiopia. Our data are consistent with previous reports and confirms effectiveness of SSG/PM treatment regimen in the Eastern African countries. Efficacy at 6-months (93.9%) was estimated on data derived from patients who completed follow up and needs to be interrogated by future studies.

Antileishmanial efficacy and tolerability of combined treatment with non-ionic surfactant vesicle formulations of sodium stibogluconate and paromomycin in dogs.

Infection with Leishmania infantum causes the disease visceral leishmaniasis (VL), which is a serious clinical and veterinary problem. The drugs used to treat canine leishmaniasis (CanL) do not cause complete parasite clearance; they can be toxic, and emerging drug resistance in parasite populations limits their clinical utility. Therefore, in this study we have evaluated the toxicity and efficacy of joint treatment with a 1:1 mixture of sodium stibogluconate-NIV (SSG-NIV, 10 mg Sbv/day) and paromomycin-NIV (PMM-NIV, 10 mg PMM/kg/day), given intravenously daily for seven days from day 270 post-infection, to nine-month-old female beagle dogs (n = 6) experimentally infected with Leishmania infantum. Treatment significantly improved the clinical symptoms of VL infection in all the treated dogs, reduced parasite burdens in lymph nodes and bone marrow, and all symptomatic treated dogs, were asymptomatic at 90 days post-treatment. Treatment was associated with a progressive and significant decrease in specific IgG anti-Leishmania antibodies using parasite soluble antigen (p < 0.01) or rK39 (p < 0.01) as the target antigen. In addition, all dogs were classified as parasite negative based on Leishmania nested PCR and quantitative real time PCR tests and as well as an inability to culture of promastigote parasites from lymph nodes and bone marrow tissue samples taken at day 90 post-treatment. However, treatment did not cure the dogs as parasites were detected at 10 months post-treatment, indicating that a different dosing regimen is required to cause long term cure or prevent relapse.

Comparison of in vitro Resistance of Wild Leishmania Isolates, Which are Resistant to Pentavalent Antimonial Compounds, Against Drugs Used in the Treatment of Leishmaniasis

Objective: Meglumine antimoniate (Glucantime®) and Sodium stibogluconate (Pentostam®) are used for the treatment of cutaneous leismaniasis in Turkey. There is a reported resistance to these drugs in recent years. The aim of the present study was to compare the in vitro sensitivities of resistant Leishmania isolates against Amphotericin B, Miltefosine, Meglumine Antimoniate, Paromomycin and Sodium Stibogluconate. Methods: Five Leishmania isolates of patients with cutaneous leishmaniasis, who showed no clinical recovery despite two consecutive meglumine antimoniate treatments, which were stored in the Parasite Bank in Manisa Celal Bayar University Medical Faculty were selected. They were genotyped with Real-Time PCR using specific primers and probes to ITS1 region. Drug resistance levels of each Leishmania isolate were analysed for Amphotericin B, Miltefosine, Meglumine Antimoniate, Paromomycin, and Sodium Stibogluconate at concentrations of 500, 250, 125, 50, 25 µg/mL with XTT method and hemocytometer. Results: It was observed that the resistant Leishmania tropica isolates showed no resistance to Amphotericin B, and were sensitive to Miltefosine, Sodium Stibogluconate, Paromomycin and Meglumin Antimonate, respectively. In addition, Leishmania tropica (MHOM/AZ/1974/SAF-K27) isolate of the control group could stay viable in none of the drug concentrations of five agents in the study. Conclusion: It was determined that none of the selected resistant L. tropica isolates showed resistance to Amphotericin B and that was also shown statistically (p<0.05). The results of this study are important in guiding clinicians and researchers who conduct studies on drugs and search for new drug molecules.

Highly sensitive UPLC-MS/MS method for the quantification of paromomycin in human plasma.

A highly sensitive method was developed to quantitate the antileishmanial agent paromomycin in human plasma, with a lower limit of quantification of 5 ng/mL. Separation was achieved using an isocratic ion-pair ultra-high performance liquid chromatographic (UPLC) method with a minimal concentration of heptafluorobutyric acid, which was coupled through an electrospray ionization interface to a triple quadrupole - linear ion trap mass spectrometer for detection. The method was validated over a linear calibration range of 5 to 1000 ng/mL (r2≥0.997) with inter-assay accuracies and precisions within the internationally accepted criteria. Volumes of 50 µL of human K2EDTA plasma were processed by using a simple protein precipitation method with 40 µL 20 % trichloroacetic acid. A good performance was shown in terms of recovery (100 %), matrix effect (C.V. ≤ 12.0 %) and carry-over (≤17.5 % of the lower limit of quantitation). Paromomycin spiked to human plasma samples was stable for at least 24 h at room temperature, 6 h at 35 °C, and 104 days at -20 °C. Paromomycin adsorbs to glass containers at low concentrations, and therefore acidic conditions were used throughout the assay, in combination with polypropylene tubes and autosampler vials. The assay was successfully applied in a pharmacokinetic study in visceral leishmaniasis patients from Eastern Africa.

Entamoeba histolytica liver abscess case: could stool PCR avoid it?

Background Liver abscess is the most common extraintestinal manifestation of Entamoeba histolytica. Clinical manifestations could appear after returning from an endemic area or several years after the exposure. The diagnosis usually requires microbiological confirmation. Case presentation We present a case of a 55-year-old woman diagnosed with Crohn's disease treated with immunosuppressive drugs, who was admitted to the Emergency Service with liver parenchyma abscesses. Computed tomography (CT)-guided puncture showed pus, and both Gram staining and fresh parasite visualization were negative. Hepatic pus bacteriological culture was reported as negative and parasite multiplex polymerase chain reaction (PCR) was performed, being positive for E. histolytica. The same PCR was performed on blood, pleural fluid and stool samples, all of them being positive for E. histolytica. Conclusions Reviewing the clinical history of this patient, it was observed that parasite detection in three stool samples was negative 2 months before the current admission. Due to the lack of sensitivity of the microscopy techniques, we propose to routinely perform parasite detection in stools using molecular techniques, especially in immunocompromised patients.

Evaluation of nephrotoxicity and ototoxicity of aminosidine (paromomycin)-allopurinol combination in dogs with leishmaniosis due to Leishmania infantum: A randomized, blinded, controlled study.

Canine leishmaniosis due to Leishmania infantum is a widespread zoonotic disease. Although aminosidine can be an effective treatment, current therapeutic recommendations do not advocate its use, mainly due to concerns regarding the potential nephrotoxicity and ototoxicity of this drug. The aim of this randomized, blinded, controlled study was to evaluate the nephrotoxicity and ototoxicity of aminosidine-allopurinol combination and compare it with that of meglumine antimonate-allopurinol combination in non-azotemic dogs with leishmaniosis. Forty dogs with leishmaniosis were randomly assigned to be treated with either aminosidine at 15 mg/kg, subcutaneously, once daily for 28 days (group A) or with meglumine antimonate at 100 mg/kg, subcutaneously, once daily for 28 days (group B). In addition to either drug, dogs in both groups were administered allopurinol at 10 mg/kg per os twice daily for 2 months. Kidney function was evaluated through measurement of serum creatinine, urea nitrogen, inorganic phosphorus, and cystatin-c concentrations and complete urinalysis, including protein-to-creatinine ratio, at baseline and after 14, 28, and 60 days from the beginning of the treatment. At the same time points, vestibular and auditory functions were evaluated through neurological examination and brainstem auditory evoked response (BAER) recordings of wave I, wave V, inter-wave I-V latencies, and minimum hearing thresholds. None of the dogs developed clinicopathological evidence of kidney disease during the study. Serum creatinine concentration increased >0.3 mg/dl over baseline in 2 dogs in group A and in 5 dogs in group B. Parameters of kidney function were not significantly different or were improved compared to baseline and the only difference between the two groups was the lower concentration of serum creatinine in group A. None of the dogs developed peripheral vestibular syndrome or hearing impairment. At the end of the study, parameters of auditory function were not significantly different or were improved compared to baseline and there were no differences between the two groups. The results of this study show that the nephrotoxicity and ototoxicity of aminosidine, when administered to non-azotemic dogs with leishmaniosis at 15 mg/kg subcutaneously once daily for 28 days along with allopurinol, is minimal and does not differ from that of meglumine antimonate.

Paromomycin-loaded mannosylated chitosan nanoparticles: Synthesis, characterization and targeted drug delivery against leishmaniasis.

Cutaneous leishmaniasis is the most common form of leishmaniasis caused by different species of Leishmania parasites. The emergence of resistance, toxicity, long term treatment, high cost of the current drugs, and intracellular nature of the parasite are the major difficulties for the treatment of leishmaniasis. Although the therapeutic effect of paromomycin (PM) on leishmaniasisLeishmania parasite). PM-loaded into mannosylated CS (MCS) nanoparticles using dextran (PM-MCS-dex-NPs) was prepared by ionic gelation and then characterized. The particle size and Zeta potential of PM-MCS-dex-NPs were obtained as 246 nm and + 31 mV, respectively. Mannosylation of CS was qualitatively evaluated by Fourier-transform infrared spectroscopy and quantitatively measured by CHNO elemental analysis; also, a mannosylation level of 17% (w) was attained. Encapsulation efficiency (EE), drug release profile, and THP-1 cell uptake potential were determined. A value of 83.5% for EE and a higher release rate in acidic media were achieved. THP-1 cell uptake level of PM-MCS-dex-NPs after 6 h was ˜2.8 and ˜3.9 times of non-mannosylated CS nanoparticles (PM-CS-dexIn vitroGlucantim, PM-CS-dex-NPs, and PM-MCS-dex-NPs after 48 h were obtained as 1846 ±â€¯158, 1234 ±â€¯93, 784 ±â€¯52 and 2714 ±â€¯126 µg mL-1Glucantim, PM-CS-dex-NPs, and PM-MCS-dex-NPs after 48 h were obtained as 105.0 ±â€¯14.0, 169.5 ±â€¯9.8, 65.8 ±â€¯7.3 and 17.8 ±â€¯1.0 µg mL-1Glucantim, PM-CS-dex-NPs and PM-MCS-dexGlucantim, PM-CS-dex-NPs, and PM-MCS-dex-NPs at a typical concentration of 20 µg mL-1 were 71.78, 69.94, 83.14 and 33.41%, respectively. While the effect of PM-CS-dex-NPs was more salient on amastigotes, PM-MCS-dex-NPs effectively affected both stages of the parasite, especially the amastigote one. This indicated that the mannosylated formulation acts as a targeted delivery system. The findings of this study revealed that this novel targeted formulation represented a strong anti-leishmanial activity.

Topical paromomycin for New World cutaneous leishmaniasis.

BACKGROUND: Paromomycin-based topical treatments were shown to be effective in curing cutaneous leishmaniasis (CL) lesions caused by Leishmania major in Tunisia. Cure rates of an index lesion were approximately 80%. As a follow on, we conducted a similar Phase 3 trial in Panama to demonstrate the efficacy of these treatments against New World species. The primary objective was to determine if a combination topical cream (paromomycin-gentamicin) resulted in statistically superior final clinical cure rates of an index lesion compared to a paromomycin alone topical cream for the treatment of CL, primarily caused by Leishmania panamensis. METHODS: We conducted a randomized, double blind, Phase 3 trial of topical creams for the treatment of CL caused by Leishmania spp. Three hundred ninety nine patients with one to ten CL lesions were treated by topical application once daily for 20 days. The primary efficacy endpoint was percentage of subjects with clinical cure of an index lesion confirmed to contain Leishmania with no relapse. RESULTS: The clinical cure of the index lesion for paromomycin-gentamicin was 79% (95% CI; 72 to 84) and for paromomycin alone was 78% (95% CI; 74 to 87) (p = 0.84). The most common adverse events considered related to study cream application were mild to moderate dermatitis, pain, and pruritus. CONCLUSIONS: Superiority of paromomycin-gentamicin was not demonstrated. However, the approximately 80% cure rates for both topical creams were similar to those demonstrated in Tunisia and previously reported with parenteral antimonials.

Mannosylated thiolated paromomycin-loaded PLGA nanoparticles for the oral therapy of visceral leishmaniasis.

AIM: The present study evaluates the efficacy of paromomycin (PM)-loaded mannosylated thiomeric nanoparticles for the targeted delivery to pathological organs for the oral therapy of visceral leishmaniasis. MATERIALS & METHODS: Mannosylated thiolated chitosan (MTC)-coated PM-loaded PLGA nanoparticles (MTC-PLGA-PM) were synthesized and evaluated for morphology, drug release, permeation enhancing and antileishmanial potential. RESULTS: MTC-PLGA-PM were spherical in shape with a size of 391.24 ± 6.91 nm and an encapsulation efficiency of 67.16 ± 14%. Ex vivo permeation indicated 12.73-fold higher permeation of PM with MTC-PLGA-PM against the free PM. Flow cytometry indicated enhanced macrophage uptake and parasite killing in Leishmania donovani infected macrophage model. In vitro antileishmanial activity indicated 36-fold lower IC50 for MTC-PLGA-PM as compared with PM. The in vivo studies indicated 3.6-fold reduced parasitic burden in the L. donovani infected BALB/c mice model. CONCLUSION: The results encouraged the concept of MTC-PLGA-PM nanoparticles as promising strategy for visceral leishmaniasis.

Topical 15% Paromomycin-Aquaphilic for Bolivian Leishmania braziliensis Cutaneous Leishmaniasis: A Randomized, Placebo-controlled Trial.

BACKGROUND: Cutaneous leishmaniasis (CL) presents as 1 or more skin lesions, which makes local therapy inherently attractive compared to systemic therapy that exposes the whole body to a drug. For 30 years, 15% paromomycin topical formulations have been in clinical experimentation. Recently, 15% paromomycin in Aquaphilic, a complex base to facilitate adsorption into the lesion, was found superior to aquaphilic vehicle for Old World Leishmania major disease. METHODS: We performed a randomized trial of 15% paromomycin in Aquaphilic (40 patients) vs Aquaphilic vehicle (20 patients) vs a positive control (intralesional pentamidine; 20 patients) against L. braziliensis CL in Bolivia. RESULTS: Cure rates after 6 months of follow-up were 31 of 40 (77.5%, 95% confidence interval [CI] 62.5-88%) for paromomycin-Aquaphilic, 2 of 20 (10%, 95% CI 3-30%) for Aquaphilic vehicle (P < .0001 vs paromomycin-Aquaphilic), and 14 of 20 (70%, 95% CI 48-85.5%) for intralesional pentamidine. Both paromomycin-Aquaphilic and the Aquaphilic vehicle were very well tolerated, with only grade 1 adverse reactions in 5-10% of patients. CONCLUSIONS: Against L. braziliensis CL, a prevalent, aggressive form of New World CL, 15% paromomycin-aquaphilic was vastly superior to a negative vehicle control and was comparable in efficacy to a positive control. This study enlarges the potential use of 15% paromomycin-Aquaphilic from one form of Old World CL to CL more generally. CLINICAL TRIALS REGISTRATION: NCT03096457.

Evaluation of paromomycin sulphate permeation using ex vivo human skin model.

Ex vivo evaluation of drug release and skin permeation from topical formulations of antileishmanial drug paromomycin sulphate was carried out using intact full thickness human skin. Potency-based microbiological assay was used for the analysis of paromomycin concentrations. A total percentage drug recovery of 86 ± 26% was obtained. Incubation periods of 1 and 3 h resulted in percentage drug permeation into deep skin layers ranging from 1.3 ± 0.04% to 5.3 ± 2.0% with paraffin-based ointment and from 1.6 ± 0.8% to 3.9 ± 1% with microemulsion-based emulgel. Although a small percentage, this is still significantly higher than those previously reported using animal skin models.

Field safety and effectiveness of new visceral leishmaniasis treatment regimens within public health facilities in Bihar, India.

BACKGROUND: In 2010, WHO recommended the use of new short-course treatment regimens in kala-azar elimination efforts for the Indian subcontinent. Although phase 3 studies have shown excellent results, there remains a lack of evidence on a wider treatment population and the safety and effectiveness of these regimens under field conditions. METHODS: This was an open label, prospective, non-randomized, non-comparative, multi-centric trial conducted within public health facilities in two highly endemic districts and a specialist referral centre in Bihar, India. Three treatment regimens were tested: single dose AmBisome (SDA), concomitant miltefosine and paromomycin (Milt+PM), and concomitant AmBisome and miltefosine (AmB+Milt). Patients with complicated disease or significant co-morbidities were treated in the SDA arm. Sample sizes were set at a minimum of 300 per arm, taking into account inter-site variation and an estimated failure risk of 5% with 5% precision. Outcomes of drug effectiveness and safety were measured at 6 months. The trial was prospectively registered with the Clinical Trials Registry India: CTRI/2012/08/002891. RESULTS: Out of 1,761 patients recruited, 50.6% (n = 891) received SDA, 20.3% (n = 358) AmB+Milt and 29.1% (n = 512) Milt+PM. In the ITT analysis, the final cure rates were SDA 91.4% (95% CI 89.3-93.1), AmB+Milt 88.8% (95% CI 85.1-91.9) and Milt+PM 96.9% (95% CI 95.0-98.2). In the complete case analysis, cure rates were SDA 95.5% (95% CI 93.9-96.8), AmB+Milt 95.5% (95% CI 92.7-97.5) and Milt+PM 99.6% (95% CI 98.6-99.9). All three regimens were safe, with 5 severe adverse events in the SDA arm, two of which were considered to be drug related. CONCLUSION: All regimens showed acceptable outcomes and safety profiles in a range of patients under field conditions. Phase IV field-based studies, although extremely rare for neglected tropical diseases, are good practice and an important step in validating the results of more restrictive hospital-based studies before widespread implementation, and in this case contributed to national level policy change in India. TRIAL REGISTRATION: Clinical trial is registered at Clinical trial registry of India (CTRI/2012/08/002891, Registered on 16/08/2012, Trial Registered Prospectively).

Using focused pharmacovigilance for ensuring patient safety against antileishmanial drugs in Bangladesh's National Kala-azar Elimination Programme.

BACKGROUND: Adverse effects of antileishmanial drugs can affect patients' quality of life and adherence to therapy for visceral leishmaniasis (VL) and post-kala-azar dermal leishmaniasis (PKDL). In Bangladesh, there are 26 treatment centers that manage leishmaniasis cases coming from 100 endemic upazilas (subdistricts) of 26 districts (these include VL, PKDL, treatment failure, and relapse VL and cutaneous leishmaniasis cases). This study aimed to investigate the feasibility of using focused pharmacovigilance for VL (VLPV) in Bangladesh's National Kala-azar Elimination Programme for the early detection and prevention of expected and unexpected adverse drug reactions (ADRs). METHODS: This activity has been going on since December 2014. Activity area includes secondary public hospital or Upazila health complex (UHC) in hundred sub districts and Surya Kanta Kala-azar Research Center (SKKRC) in Mymensingh District, a specialized center for management of complicated VL and PKDL cases. Communicable Disease Control (CDC) of the Directorate General of Health Services (DGHS) assigned twenty five of hundred UHCs and SKKRC (total 26) as treatment centers depending on their suitable geographical location. This was implemented for better management of VL cases with Liposomal Amphotericin B (AmBisome®) to ensure patient convenience and proper utilization of this expensive donated drug. A VLPV expert committee and a UHC VLPV team were established, an operational manual and pharmacovigilance report forms were developed, training and refresher training of health personnel took place at UHCs and at the central level, collected information such as patient data including demographics, treatment history and response, adverse events were analyzed. This report includes information for the period from December 2014 to December 2016. RESULTS: From December 2014 to December 2016, 1327 leishmaniasis patients were treated and 1066 (80%) were available for VLPV. Out of these, 57, 33, 9, and 1% were new VL, PKDL, VL relapse, and other cases, respectively. Liposomal amphotericin B was mostly used (82%) for case management, followed by miltefosine (20%) and paromomycin (3%). Out of the 1066 patients, 26% experienced ADRs. The most frequent ADR was fever (17%, 176/1066), followed by vomiting (5%, 51/1066). Thirteen serious adverse events (SAEs) (eight deaths and five unexpected SAEs) were observed. The expert committee assessed that three of the deaths and all unexpected SAEs were possibly related to treatment. Out of the five unexpected SAEs, four were miltefosine-induced ophthalmic complications and the other was an AmBisome®-induced avascular necrosis of the nasal alae. The Directorate General of the Drug Administration entered the ADRs into the World Health Organization Uppsala Monitoring Centre (WHO-UMC) VigiFlow database. CONCLUSIONS: This study found that VLPV through NKEP is feasible and should be continued as a routine activity into the public health system of Bangladesh to ensure patient safety against anti-leishmanial drugs.

Amphotericin B for treatment of visceral leishmaniasis: systematic review and meta-analysis of prospective comparative clinical studies including dose-ranging studies.

OBJECTIVES: To evaluate the evidence for use of different formulations of amphotericin B (AmB), minimum effective dose for each formulation and its comparative efficacy against other drugs in achieving definitive cure of visceral leishmaniasis. METHODS: This systematic review and meta-analysis included following data sources: PubMed, Embase, Scopus, Web of Science and CINAHL. Controlled prospective clinical trials (randomized or nonrandomized, including dose-ranging studies) conducted between 1996 and 2017 with at least one treatment group receiving AmB were included (published data only). The primary outcome was definitive cure at 6 months. Adverse events and mortality were assessed as secondary outcomes. The PROSPERO registration number for this review is CRD42017067488. RESULTS: Thirty-one studies (26 from India) that enrolled 6903 patients into 84 study groups met the selection criteria. In India, liposomal AmB was not inferior to AmB deoxycholate (relative risk 1.00, 95% confidence interval (CI) 0.96-1.03, two randomized controlled trials (RCTs), 514 participants, high-quality evidence), and a single dose of the earlier formulation as low as 3.75 mg/kg achieved a cure rate of over 89% (95% CI 70.6-97.2). AmB deoxycholate was as effective as miltefosine (relative risk 0.99, 95% CI 0.95-1.03, two trials, 523 participants, high-quality evidence) and may be better than paromomycin (relative risk 1.04, 95% CI 1.02-1.07, one trial, 667 participants, low-quality evidence) in achieving definitive cure. CONCLUSIONS: AmB is an efficacious drug in the Indian subcontinent. Further evidence is needed from prospective clinical trials in other endemic geographical regions.

Interventions for Old World cutaneous leishmaniasis.

BACKGROUND: Cutaneous leishmaniasis, caused by a parasitic infection, is considered one of the most serious skin diseases in many low- and middle-income countries. Old World cutaneous leishmaniasis (OWCL) is caused by species found in Africa, Asia, the Middle East, the Mediterranean, and India. The most commonly prescribed treatments are antimonials, but other drugs have been used with varying success. As OWCL tends to heal spontaneously, it is necessary to justify the use of systemic and topical treatments. This is an update of a Cochrane Review first published in 2008. OBJECTIVES: To assess the effects of therapeutic interventions for the localised form of Old World cutaneous leishmaniasis. SEARCH METHODS: We updated our searches of the following databases to November 2016: the Cochrane Skin Specialised Register, CENTRAL, MEDLINE, Embase, and LILACS. We also searched five trials registers and checked the reference lists of included studies for further references to relevant randomised controlled trials (RCTs). We wrote to national programme managers, general co-ordinators, directors, clinicians, WHO-EMRO regional officers of endemic countries, pharmaceutical companies, tropical medicine centres, and authors of relevant papers for further information about relevant unpublished and ongoing trials. We undertook a separate search for adverse effects of interventions for Old World cutaneous leishmaniasis in September 2015 using MEDLINE. SELECTION CRITERIA: Randomised controlled trials of either single or combination treatments in immunocompetent people with OWCL confirmed by smear, histology, culture, or polymerase chain reaction. The comparators were either no treatment, placebo/vehicle, and/or another active compound. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion and risk of bias and extracted data. We only synthesised data when we were able to identify at least two studies investigating similar treatments and reporting data amenable to pooling. We also recorded data about adverse effects from the corresponding search. MAIN RESULTS: We included 89 studies (of which 40 were new to this update) in 10,583 people with OWCL. The studies included were conducted mainly in the Far or Middle East at regional hospitals, local healthcare clinics, and skin disease research centres. Women accounted for 41.5% of the participants (range: 23% to 80%). The overall mean age of participants was 25 years (range 12 to 56). Most studies lasted between two to six months, with the longest lasting two years; average duration was four months. Most studies were at unclear or high risk for most bias domains. A lack of blinding and reporting bias were present in almost 40% of studies. Two trials were at low risk of bias for all domains. Trials reported the causative species poorly.Here we provide results for the two main comparisons identified: itraconazole (200 mg for six to eight weeks) versus placebo; and paromomycin ointment (15% plus 10% urea, twice daily for 14 days) versus vehicle.In the comparison of oral itraconazole versus placebo, at 2.5 months' follow up, 85/125 participants in the itraconazole group achieved complete cure compared to 54/119 in the placebo group (RR 3.70, 95% CI 0.35 to 38.99; 3 studies; 244 participants). In one study, microbiological or histopathological cure of skin lesions only occurred in the itraconazole group after a mean follow-up of 2.5 months (RR 17.00, 95% CI 0.47 to 612.21; 20 participants). However, although the analyses favour oral itraconazole for these outcomes, we cannot be confident in the results due to the very low certainty evidence. More side effects of mild abdominal pain and nausea (RR 2.36, 95% CI 0.74 to 7.47; 3 studies; 204 participants) and mild abnormal liver function (RR 3.08, 95% CI 0.53 to 17.98; 3 studies; 84 participants) occurred in the itraconazole group (as well as reports of headaches and dizziness), compared with the placebo group, but again we rated the certainty of evidence as very low so are unsure of the results.When comparing paromomycin with vehicle, there was no difference in the number of participants who achieved complete cure (RR of 1.00, 95% CI 0.86, 1.17; 383 participants, 2 studies) and microbiological or histopathological cure of skin lesions after a mean follow-up of 2.5 months (RR 1.03, CI 0.88 to 1.20; 383 participants, 2 studies), but the paromomycin group had more skin/local reactions (such as inflammation, vesiculation, pain, redness, or itch) (RR 1.42, 95% CI 0.67 to 3.01; 4 studies; 713 participants). For all of these outcomes, the certainty of evidence was very low, meaning we are unsure about these results.Trial authors did not report the percentage of lesions cured after the end of treatment or speed of healing for either of these key comparisons. AUTHORS' CONCLUSIONS: There was very low-certainty evidence to support the effectiveness of itraconazole and paromomycin ointment for OWCL in terms of cure (i.e. microbiological or histopathological cure and percentage of participants completely cured). Both of these interventions incited more adverse effects, which were mild in nature, than their comparisons, but we could draw no conclusions regarding safety due to the very low certainty of the evidence for this outcome.We downgraded the key outcomes in these two comparisons due to high risk of bias, inconsistency between the results, and imprecision. There is a need for large, well-designed international studies that evaluate long-term effects of current therapies and enable a reliable conclusion about treatments. Future trials should specify the species of leishmaniasis; trials on types caused by Leishmania infantum, L aethiopica, andL donovani are lacking. Research into the effects of treating women of childbearing age, children, people with comorbid conditions, and those who are immunocompromised would also be helpful.It was difficult to evaluate the overall efficacy of any of the numerous treatments due to the variable treatment regimens examined and because RCTs evaluated different Leishmania species and took place in different geographical areas. Some outcomes we looked for but did not find were degree of functional and aesthetic impairment, change in ability to detect Leishmania, quality of life, and emergence of resistance. There were only limited data on prevention of scarring.

[Leg ulcer revealing cutaneous leishmaniasis]. / Ulcère de jambe révélant la leishmaniose cutanée.

Leishmaniases are parasitic diseases occurring in endemic tropical and subtropical areas and caused by protozoa of the genus leishmania, transmitted by a diptera (sand fly). We here report a case of topical cutaneous leishmaniasis discovered in a 15-year old boy with painless ulcer on his left leg, who had been staying in South Africa. Clinical examination showed painless non-itchy ulcer, occurred 1 month before, on the antero-internal part of his left leg with crusts and scars caused by insect bites, all evolving in a context of patient's general health status, without mucosal or visceral lesions. Skin biopsy allowed specific parasitologic diagnosis revealing topical zoonotic cutaneous leishmaniasis caused by L. major. The patient underwent topical treatment based on paramomycin and oral fluconazole resulting in ulcer healing at the end of 2 months.

Occult Amebic Liver Abscess as Cause of Extensive Inferior Vena Cava and Hepatic Vein Thrombosis.

The most common extraintestinal complication of Entamoeba histolytica is amebic liver abscess (ALA). Hepatic vein and inferior vena cava (IVC) thrombosis are rare but well-documented complications of ALA, typically attributed to mechanical compression and inflammation associated with a large abscess. We present a case of a previously healthy 43-year-old Canadian man presenting with constitutional symptoms and right upper quadrant abdominal pain. He was found to have thrombophlebitis of the IVC, accessory right hepatic vein, and bilateral iliac veins. Extensive investigations for thrombophilia were negative. Magnetic resonance imaging of the liver demonstrated a 3.2-cm focal area of parenchymal abnormality that was reported as presumptive hepatocellular carcinoma, and a 1.9-cm lesion in the caudate lobe with diffusion restriction and peripheral rim enhancement. Despite multiple biopsy attempts, a histopathological diagnosis was not achieved. Abdominal pain and fever 4 months later prompted repeat ultrasound demonstrating a 10.4- × 12.0-cm rim-enhancing fluid attenuation lesion felt to represent a liver abscess. Thick dark "chocolate brown" drainage from the lesion and positive serology for E. histolytica confirmed the diagnosis of ALA acquired from a previous trip to Cuba. The patient was started on treatment with metronidazole and paromomycin and repeat abdominal ultrasound demonstrated resolution of the abscess. This case is the first to demonstrate extensive IVC thrombosis secondary to a relatively small occult ALA and emphasizes the thrombogenic potential of ALA. Amebic infection should be considered as a rare cause of IVC thrombosis in the correct clinical context.