Directrices para el tratamiento de las leishmaniasis en la región de las américas - 2 ed / Guidelines for the treatment of leishmaniasis in the region of the Americas - 2 ed

Las leishmaniasis son enfermedades infecciosas desatendidas de gran importancia en la Región de las Américas debido a su morbilidad, mortalidad y amplia distribución geográfica. De las tres formas clínicas principales, la cutánea es la más común y la visceral es la forma más grave, ya que puede causar la muerte de hasta 90% de las personas que no reciban tratamiento. En el 2013, la Organización Panamericana de la Salud (OPS) elaboró recomendaciones para el tratamiento de las leishmaniasis en la Región de las Américas utilizando la metodología de clasificación de la valoración, la elaboración y la evaluación de las recomendaciones (GRADE, por su sigla en inglés). No obstante, dada la evidencia acumulada desde entonces, se hizo necesario revisar esas recomendaciones. En esta segunda edición se presentan las recomendaciones actualizadas sobre el tratamiento de las leishmaniasis, y se detallan los esquemas y los criterios de indicación del tratamiento en el contexto regional. Estas directrices presentan modificaciones sustanciales con respecto a la primera edición. En el caso de la leishmaniasis cutánea, se ha eliminado el ketoconazol de las opciones terapéuticas, el número de especies de Leishmania para las que hay evidencia sólida de la eficacia de la miltefosina ha aumentado de dos a cuatro y la recomendación de administrar antimoniales intralesionales ahora es fuerte. Con respecto a la leishmaniasis mucosa, se incluye una recomendación fuerte sobre el uso de antimoniales pentavalentes con o sin pentoxifilina oral. Por lo que respecta a la leishmaniasis visceral, la recomendación fuerte sobre el uso de antimoniales pentavalentes y desoxicolato de anfotericina B ahora es condicional. También hay evidencia contundente en contra del uso de miltefosina en pacientes con leishmaniasis causada por Leishmania infantum. Otros cambios importantes son el desglose de las recomendaciones según si se trata de pacientes adultos o pediátricos, la inclusión de las especies de Leishmania y, en el caso de los pacientes inmunocomprometidos, la introducción de una recomendación fuerte contra el uso de antimoniales pentavalentes. Esta segunda edición es una versión revisada de la publicación Leishmaniasis en las Américas: recomendaciones para el tratamiento: https://iris.paho.org/handle/10665.2/7704

Leishmaniasis: Opciones terapéuticas en la población pediátrica / Leishmaniasis: Therapeutic options in the pediatric population

Resumen La leishmaniasis es una enfermedad parasitaria crónica endémica en muchas partes del mundo. La variabilidad de cepas, su clínica y respuesta a tratamiento ha hecho que se clasifique en dos grandes grupos: la leishmaniasis del Nuevo Mundo y la del Viejo Mundo. Según esto, varían las recomendaciones respecto a manejo y seguimiento. En esta revisión se hace énfasis a la leishmaniasis de nuestro medio, revisando opciones terapéuticas y posibilidades principalmente en la población pediátrica.

Abstract Leishmaniasis is a chronic parasitic disease endemic in many parts of the world. The variability of strains, their clinic and response to treatment has led to their classification into two major groups: New World leishmaniasis and Old World leishmaniasis. According to this, the recommendations regarding management and follow-up vary. In this review, emphasis is placed on leishmaniasis in our environment, reviewing therapeutic options and possibilities mainly in the pediatric population.

Comparative study between the effect of nitazoxanide and paromomycine in treatment of cryptosporidiosis in hospitalized children

Ninety children infected with Cryptosporidium parvum attending Al Azhar University Teaching Hospital [Assuit] were chosen [60 males and 30 females] with age range from 6 months to ten years. The patients were divided into two groups of 45 patients for each [G1 and G2]. All patients suffered from chronic diarrhea for more than fifteen days. Cross-matched 45 children suffering from chronic diarrhea were used as a control group [G3]. Stool samples were collected and examined for detection of Cryptosporidium oocysts using Sheather's sugar and Modified Ziehl-Nelseen stain techniques. The first group [G1] received Nitazoxanide [100 mg and 200 mg every 12 hours for 3 days for children aged 6 months to 3 years, and children aged 4 to 10 years respectively], G2 received Parornomycin [25mg/kg/day for 2 weeks]. Third group received placebo. Significant improvement and shortening of the duration of diarrhea occur in G1; of 45 patients received Nitazoxanide 39 cases showed complete clinical and laboratory cure [86.6%], 5 cases showed clinical improvement with reduction in the number of oocysts and 1 case showed no cure. In G2 of 45 cases received Paromomycin 31 cases showed complete cure [68.8%], 8 cases showed clinical improvement with reduction of oocysts number and 6 cases were not cured. Nitazoxanide proved highly effective than Paromomycin in cryptosporidiosis

Leishmaniasis: current status of available drugs and new potential drug targets

The control of Leishmania infection relies primarily on chemotherapy till date. Resistance to pentavalent antimonials, which have been the recommended drugs to treat cutaneous and visceral leishmaniasis, is now widespread in Indian subcontinents. New drug formulations like amphotericin B, its lipid formulations, and miltefosine have shown great efficacy to treat leishmaniasis but their high cost and therapeutic complications limit their usefulness. In addition, irregular and inappropriate uses of these second line drugs in endemic regions like state of Bihar, India threaten resistance development in the parasite. In context to the limited drug options and unavailability of either preventive or prophylactic candidates, there is a pressing need to develop true antileishmanial drugs to reduce the disease burden of this debilitating endemic disease. Notwithstanding significant progress of leishmanial research during last few decades, identification and characterization of novel drugs and drug targets are far from satisfactory. This review will initially describe current drug regimens and later will provide an overview on few important biochemical and enzymatic machineries that could be utilized as putative drug targets for generation of true antileishmanial drugs.

Avanços no tratamento da leishmaniose tegumentar do novo mundo nos últimos dez anos: uma revisão sistemática da literatura / Advances in the treatment of cutaneous leishmaniasis in the new world in the last ten years: a systematic literature review

INTRODUÇÃO: O arsenal terapêutico contra a leishmaniose tegumentar é muito restrito. Os antimoniais pentavalentes permanecem como as drogas de escolha para seu tratamento há mais de 50 anos. Apesar da sua eficácia, necessita de injeções diárias, apresenta muitos efeitos colaterais e tempo de cura prolongado.

INTRODUCTION: The therapeutic arsenal against cutaneous leishmaniasis is very limited. Pentavalent antimonial compounds have been the drugs of choice for treatment of this disease for over 50 years. Despite their effectiveness, these drugs require daily injections, have many side effects and present prolonged healing time.

Efeito de uma formulação hidrofílica de paromomicina tópica na leishmaniose cutânea em pacientes com contra-indicações de tratamento com antimonial pentavalente / Effect of a hydrophilic formulation of topical paromomycin on cutaneous leishmaniasis among patients with contraindications for treatment with pentavalent antimonials

Descrevem-se o efeito terapêutico e os eventos adversos associados com o uso tópico de paromomicina 10 por cento em gel na leishmaniose cutânea. Quinze pacientes com leishmaniose cutânea cumpriram os critérios de inclusão descritos a seguir: contra-indicação para o uso de antimoniato de meglumina, intradermorreação de Montenegro positiva e até quatro lesões ulceradas. A fórmula foi prescrita duas vezes ao dia por 20 dias. Quatorze pacientes estiveram disponíveis para a avaliação do desfecho terapêutico e a proporção de cura foi de 21,4 por cento (3/14), 50 por cento melhoraram até a epitelização completa e a proporção de falha foi de 28,6 por cento. Nove pacientes que não apresentaram cura inicialmente foram re-tratados. Oito receberam uma nova série de paromomicina tópica e um foi tratado com antimoniato de meglumina. Dois pacientes não receberam novo tratamento e tiveram melhora lenta e contínua. Cinco de oito pacientes retratados com paromomicina tópica alcançaram a cura clínica, e três apresentaram falha, incluindo um paciente que tinha apresentado melhora com o primeiro tratamento. Os eventos adversos foram leves e locais em 53,3 por cento dos pacientes e nunca levaram à suspensão do tratamento.

The therapeutic effect of and adverse events associated with topical use of 10 percent paromomycin gel on cutaneous leishmaniasis are described. Fifteen patients with cutaneous leishmaniasis fulfilled the following inclusion criteria: contraindication for the use of meglumine antimoniate, positive Montenegro skin test and up to four ulcerated lesions. The formula was prescribed twice a day for 20 days. Fourteen patients were available for the therapeutic outcome evaluation. The cure rate was 21.4 percent (3/14); 50 percent improved as far as complete epithelialization; and the failure rate was 28.6 percent. Nine patients who did not initially present cure were retreated. Eight received a new series of topical paromomycin and one was treated with meglumine antimoniate. Two patients did not receive any new treatment and had continuous slow improvement. Five out of the eight patients retreated with topical paromomycin achieved clinical cure, and three presented failure, including one patient who had shown any improvement with the first treatment. For 53.3 percent of the patients, the adverse events were mild and local and never led to treatment suspension.

Tetany in kala azar patients treated with paromomycin.

Paromomycin, an aminoglycoside, is known to cause several side effects like nephrotoxicity and ototoxicity like other aminoglycosides but tetany has not been reported. Three cases of tetany were detected in the patients of kala-azar treated with paromomycin. They were promptly treated with intravenous 10 per cent calcium gluconate and tetany was relieved immediately and treatment with paromomycin continued with oral calcium supplement. After completion of 21 days treatment with paromomycin patients' splenic aspirates were free of parasites. Paromomycin may cause temporary tubular damage leading to calcium wasting in urine and hypocalcaemia resulting in tetany. Prompt detection of symptoms and intravenous calcium gluconate treatment promptly reverse the situation.

Mirazid alone or combined with paromomycin in treating Cryptosporidiosis parvum in immunocompetent hospitalized patients

Sixty cryptosporidiosis patients from Mansoura University Hospitals, 36 males and 24 females, with age from few months to ten years [mean age 6.1] were divided into three cross-matched groups of 20 patients each. All patients received the glutamine-based oral rehydration solution with 111 mmol/1 glutamine, 20 mg zinc acetate once a day and vitamin A supplementation [200,000 IU] once a day for 2 weeks. For cryptosporidiosis treatment, Gl received Mirazid [10mg /kg for 2 weeks], G2 received Paromomycin [500 mg qid for 2 weeks], and G3 received a combination of Mirazid [10mg/kg] and Paromomycin [500 mg] for two weeks. The result was assessed according to the scales: 0= no improvement, 1= symptoms began improvement [reduction of diarrhea frequency and stool volume, less abdominal pain, less nausea and vomiting], 2= diarrhea eradication, 3= weight gain, 4= oocyst counts reduction, 5= reduction in diarrhea and oocyst counts, 6= eradication of diarrhea and oocysts. G3 showed significantly higher difference than Gl and G2 in the 1[st] week [p=.036, 0.025 respectively], no significant difference in 2[nd] week, a significantly higher difference than in Gl [0.003], and G2 [0.006] in 3[rd] week, and a significantly higher difference than Gl [0.014], and G2 [0.01] in 4[th] week, but without significant differences in oocyst shedding in the 3 groups

Immunochemotherapy for cryptosporidiosis in immunosuppressed mouse model

Immunochemotherapy as a dual regimen [Nitazoxanide NTZ and Interferon gamma INF-gamma] and a triple one [NTZ, INF- gamma and Paromomycin PRM], administered to immunosuppressed Cryptosporidium infected mice for 10 days [4[th]-13[th]] day post-infection] was evaluated during and after treatment by determination of parasite count in ileum, associated histopathological changes, oocyst count in Kinyoun's acid fast stained faecal smears, percent reduction in oocyst excretion and cure rate. Both regimens induced nearby efficacy [P>0.05] with significant reduction in parasite count in the ileum on 7[th] [P< 0.01] and 14[th] [P<0.001] P.I. days, partial regression of histopathological changes and reduction in oocyst count from the 2[nd] day post-treatment. Oocyst excretion reduction percent was reached zenith on 13[th] P.I. day in both dual [95.76%] and triple [94.86%] regimens [P>0.05]. Complete cure was not achieved. Three days post-treatment relapse occurred in both regimens [P<0.001] increase in oocyst count [P<0.01] increase in parasite count in ileum, more severe histopathological changes with rapid deterioration and then, death of all remaining treated mice

Visceral leishmaniasis (kala-azar): challenges ahead.

Indian visceral leishmaniasis (VL) is a parasitic disease caused by a haemoflagellete Leishmania donovani and transmitted by the bite of sand fly Phlebotomus argentipes. It affects various age groups. In India about 1,00,000 cases of VL are estimated to occur annually; of these, the State of Bihar accounts for over than 90 per cent of the cases. Diagnosis of VL typically relies on microscopic examination of tissue smears but serology and molecular methods are better alternatives currently. Notwithstanding the growing incidence of resistance, pentavalent antimony complex has been the mainstay for the treatment of VL during the last several decades. The second line drugs such as amphotericin B, lipid formulations of amphotericin B, paromomycin and recently developed miltefosine are the other alternatives. In spite of significant development in various areas of Leishmania research, there is a pressing need for the technological advancement in the understanding of immune response, drug resistance and the pathogenesis of leishmaniasis that could be translated into field applicable and affordable methods for diagnosis, treatment, and control of the disease.

Current scenario of drug development for leishmaniasis.

Although three new drugs or drug formulations, liposomal amphotericin B (AmBisome), miltefosine and paromomycin should be available for the treatment of visceral leishmaniasis (VL) within the next year, they all suffer from limitations of either cost, specific toxicities or parenteral administration. As part of research to identify better treatments for VL and cutaneous leishmaniasis (CL), alternative and potentially cheaper formulations of amphotericin B, alklyphosphocholines other than miltefosine and improved formulations of paromomycin for CL have been identified. Other drugs or compounds that have demonstrated activity in experimental rodent models of infection include licochalcone derivatives, quinoline derivatives, bisphosphonates and a maesabalide; further chemistry based upon these leads is warranted. The process for discovery and development of new antileishmanials would also benefit from improved models, for example, transfected parasites, and non invasive methods of measuring parasite load in rodent models of infection.

Influence of the formulation type (o/w, w/o/w emulsions and ointment) on the topical delivery of paromomycin

Ointments containing paromomycin (PA) have been used for topical treatment of cutaneous leishmaniasis. Although influence of the vehicle on skin permeation is crucial for optimization of formulations containing PA, this aspect has not been investigated experimentally. In this study, we have evaluated the influence of the formulation type [oil-in-water (o/w), water-in-oil-in-water (w/o/w) emulsions and ointment] on in vitro release and skin permeation of PA and experiments were carried out on cellulose acetate membrane and skin biopsies from hairless mice, respectively. PA release from o/w emulsion (51.7 por cento ± 0.9 of dose applied) was faster than that observed for w/o/w emulsion (3.0 por cento ± 0.5)...

Cryptosporidium as a cause of diarrhoea

We herein describe 8 children [4 immunocompetent and 4 undergoing chemotherapy for acute lymphoblastic leukaemia] with severe diarrhoea and dehydration which was identified using modified Ziehl-Neelsen stain caused by Crytosporidium. The four immunocompetent children were treated with intravenous hydration only without specific antimicrobial therapy and they responded well. The other four immunocompromized children received intravenous hydration and antimicrobial chemotherapy. Two of them received paromomycin and responded well. One patient was started on paromomycin for 10 days, and although there was clinical improvement, his stool examination continued to be positive for Cryptosporidium. He then received azithromycin for 14 days to which he responded well and his stools became negative for Cryptosooridium. The fourth patient received azithromycin from the start and responded well. Cryptosporidium should be considered as a causative organism in children, especially those who are immunocompromized, and who present with severe or prolonged nonbloody diarrhoea. The organism is not seen in a routine 'ova and parasite' examination and the lab should be notified of its possibility in the differential diagnosis for diagnostic confirmation using modified Ziehl-Neelsen stain. Immunocompetent children with cryptosporidiosis will respond to intravenous hydration without specific antimicrobial therapy while immunocompromized children may benefit from paromomycin or azithromycin therapy. We wish to increase the awareness of this condition and its management in clinicians and microbiologists

Comparative study of the prophylactic and therapeutic effects of paromomycin, recombinant IL-12 alone or in combination against cryptosporidium parvum infection in immunosuppressed mice

The administration of paromomycin [100 mg/kg orally] for ten days, rIL-12 [0.5 ug/mouse s.c.] for three consecutive days or their combination was evaluated before and after infection with C. Parvum using immunosuppressed mice model. A total of 110 suckling albino mice were immunosuppressed by hydrocortisone acetate and infected with 106 Cryptosporidium oocysts. An assessment of drug efficacy was done by the estimation of the oocyst count in stool using modified Ziehl- Neelsen technique, histopathological examination of terminal ileum and determination of the serum level of IFN-gamma and calculation of the cure rate. The combination of paromomycin and rIL-12 was more effective than either drug alone. The cure rate was 86.7% when the regimen was used prophylactically and 73.3% when the combination was administered. Regression of the histopathological changes in comparison with the control group was noted

Intestinal giardiasis. Mini-review / Giardiasis intestinal. Mini-Revisión

Giardia intestinalis is a common parasite in our country and the rest of the world and is responsible for several clinical disturbances that include dysentery type diarrheas, recurrent abdominal pain, duodenitis, jejunitis, cholecystitis and in some cases toxemias and convulsions. In this paper we review recent concepts of intestinal giardiasis, considering the basic aspects of the biology and physiology of Giardia intestinalis, its morphology and its relationship the parasite pathogenicity. We detail the physiopathological mechanisms responsible for the different clinic manifestations of giardiasis, the specific laboratory and endoscopic methods of diagnosis and the most recent advances in the treatment and prophylaxis of this disease.

Tratamento tópico da leishmaniose cutânea experimental: avaliação de diferentes formulações contendo sulfato de paromomicina e da associação com imunoterapia / Topical therapy of experimental cutaneous leishmaniasis: assessment of different formulations containing paromomycin sulfate and the combination with immunotherapy

A leishmaniose é uma doença causada por protozoários do gênero Leishmania e nas Américas eles se agrupam em duas categorias: Leishmaniose Visceral Americana (LVA) e Leishmaniose Tegumentar Americana (LTA). A profilaxia da LTA baseia-se no combate aos transmissores, na redução das fontes de infecção e no tratamento de pacientes com agentes quimioterápicos, os quais são muito limitados, tóxicos e requerem um longo período de tratamento. Em virtude dos problemas associados ao tratamento convencional com antimoniais, uma grande diversidade de tratamentos alternativos, de uso tópico ou sistêmico, vem sendo estudados para essa doença. Dentre eles destaca-se a paromomicina que tem mostrado resultados surpreendentes no tratamento das várias formas da doença. Utilizamos a paromomicina em formulações de uso tópico para o tratamento de lesões ulceradas causadas por Leishmania major em camundongos BALB/c. Nossos resultados mostraram que das formulações utilizadas (emulsão e pomada), administradas duas vezes ao dia por doze dias, a emulsão foi mais eficaz que a pomada e que o tratamento conduzido com a remoção das crostas mostrou que essa formação funciona como uma barreira fisica interferindo na eficácia do tratamento. A associação com a uréia, como agente promotor da absorção cutânea, não aumentou a eficácia da pomada. O aumento da concentração de paromomicina nas formulações foi capaz de aumentar a eficiência do tratamento sendo insuficiente para a cura completa dos animais. A utilização da interleucina 12 como adjuvante ao tratamento foi fundamental para a modulação da resposta imunológica e para a cura clínica dos animais. Dessa forma, concluímos que o tratamento com a emulsão a 5 por cento de paromomicina associado a IL-12 durante e após o tratamento é eficaz para a cura clínica da doença neste modelo experimental.