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

Eligibility for Local Therapies in Adolescents and Adults with Cutaneous Leishmaniasis from Southwestern Colombia: A Cross-Sectional Study.

Local therapies have been proposed as safe and effective alternatives to systemic drugs in cutaneous leishmaniasis (CL), especially among less severe cases. However, they are not widely available and used in endemic places, including Colombia, which has a high burden of disease. Further complicating the uptake of local therapies is that different treatment guidelines have been established by the World Health Organization (WHO) and Pan American Health Organization (PAHO). Using data from a large referral center in Colombia, we determined the proportion of patients who would be eligible for and potentially benefit from local therapies according to both international guidelines. The sample included 1,891 confirmed cases of CL aged ≥ 12 years, mostly infected with Leishmania Viannia panamensis (91%, n = 601/660), between 2004 and 2014. Overall, 57% of the sample had one lesion, whereas another 31% had two to three lesions. For 74% of patients, all lesions were in an area other than head or neck. The maximum lesion size was ≤ 3 cm for 58% and < 5 cm for 88% of the sample. Based on our data, up to 56% of patients could have been eligible for local therapies according to the WHO criteria. By contrast, only 23% were eligible according to the more restrictive PAHO criteria. Regardless, these data suggest that a substantial proportion of CL patients in Colombia may benefit from local therapies given their relatively mild presentation of disease and low risk of complications. Individualized risk-benefit assessment and guideline adjustments may increase local therapy eligibility and benefit a large number of patients.

Curcumin: A promising treatment for Cryptosporidium parvum infection in immunosuppressed BALB/c mice.

Members of the genus Cryptosporidium are frequent protozoan pathogens in humans and a wide range of animals. There is no consistently effective treatment against cryptosporidiosis, especially in immunodeficient patients. The present study was carried out to study the therapeutic effects of curcumin against cryptosporidiosis in immunosuppressed BALB/c mice. Mice were divided into five groups and immunosuppressed by dexamethasone. Three groups were inoculated with C. parvum oocysts, administered with curcumin, paromomycin, and without treatment. The reminders were regarded as controls. The oocysts in the fecal smear were counted daily. At days 0, 3, 7, and 11 post-treatment, the mice were sacrificed, and the efficacy of drugs was evaluated by comparing the histopathological alterations in jejunum and ileum, measuring the total antioxidant capacity, and malondialdehyde in the affected tissues. The infection was completely eliminated in the curcumin-treated group, and oocyst shedding stopped with no recurrence after drug withdrawal. On the contrary, paromomycin was unable to eliminate C. parvum infection completely, and oocyst shedding continued even 10 days after the drug withdrawal. Based on these findings, curcumin can be a trustworthy compound for the elimination of infection in immunosuppressed hosts. Further evaluation to find its accurate mechanism of action should be considered.

A review of cutaneous leishmaniasis in Morocco: A vertical analysisto determine appropriate interventions for control and prevention.

Leishmaniasis is considered one of the most neglected diseases worldwide. In Morocco, cutaneous leishmaniasis is an important public health problem. Leishmania major and Leishmania tropica are the two major species in this country. Despite all efforts, monitoring and control of the cutaneous leishmaniasis is still challenging. We used for the first time a vertical analysis of the control of cutaneous leishmaniasis in Morocco from the document review and publications. This analysis allowed us to develop an epidemiological model that emphasized key possible interventions. No evaluation studies of these interventions in Morocco were done. Global Evidence underline the effectiveness of preventive interventions produced in integrate inter-sectorial strategy framework (e.g use of insecticide-treated bednets, indoor residual spraying and rodents' control) rather than treatments such as based thermotherapy, cryotherapy, photodynamic therapy, CO2 laser and paromomycin. Therefore, integrated vector management control (IVMC) with communityc participation is recommended as effective strategy. Strengthening of the IVMC with community involvement are necessary conditions to improve the program of cutaneous leishmaniasis and prevent epidemic foci appearance.

Comparative efficacy of curcumin and paromomycin against Cryptosporidium parvum infection in a BALB/c model.

Cryptosporidium is a ubiquitous protozoan parasite causing gastrointestinal disorder in various hosts worldwide. The disease is self-limiting in the immunocompetent but life-threatening in immunodeficient individuals. Investigations to find an effective drug for the complete elimination of the Cryptosporidium infection are ongoing and urgently needed. The current study was undertaken to examine the anti-cryptosporidial efficacy of curcumin in experimentally infected mice compared with that of paromomycin. Oocysts were isolated from a pre-weaned dairy calf and identified as Cryptosporidium parvum using a nested- polymerase chain reaction (PCR) on Small subunit ribosomal ribonucleic acid (SSU rRNA) gene and sequencing analysis. One hundred and ten female BALB/c mice were divided into five groups. Group 1 was infected and treated with curcumin; Group 2 infected and treated with paromomycin; Group 3 infected without treatment; Group 4 included uninfected mice treated with curcumin, and Group 5 included uninfected mice treated with distilled water for 11 successive days, starting on the first day of oocyst shedding. The oocyst shedding was recorded daily. At days 0, 3, 7, and 11 of post treatments, five mice from each group were killed humanly; jejunum and ileum tissue samples were processed for histopathological evaluation and counting of oocyst on villi, simultaneously. Furthermore, total antioxidant capacity (TAC) and malondialdehyde (MDA) concentrations in affected tissues were also measured in different groups. By treatments, tissue lesions and the number of oocyst on villi of both jejunum and ileum were decreased with a time-dependent manner. In comparison with Group 3, oocyst shedding was stopped at the end of treatment period in both groups 1 and 2 without recurrence at 10days after drug withdrawal. Also, TAC was increased and the MDA concentrations were decreased in Group 1. Moreover, paromomycin showed acceptable treatment outcomes during experiment and its anti-cryptosporidial activity was faster than curcumin. The results confirmed the anti-cryptosporidial and antioxidant activity of curcumin against C. parvum and further evaluation of immunosuppressed animal models needs to be carried out.

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.

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.

The lack of effectiveness of hyperbaric oxygenation as a treatment for Leishmania major in a mouse model.

We aimed to study the effectiveness of hyperbaric oxygen therapy (HOT) (100% oxygen at 2 ATA for 70 minutes each session for 20 consecutive days) on BALB/c male mice infected with Leishmania major. Fifty-one mice were assigned to six groups. Group 1 was treated with HOT from 1 day after the inoculation. In Groups 2-5, treatment began when the cutaneous lesions appeared. Group 2 received HOT only, Group 3 received topical therapy with Leshcutan only, Groups 4 and 5 received a combination of HOT and Leshcutan for 5 and 10 days respectively, and Group 6 did not receive any treatment (control group). When comparing the control group with Group 1, treatment with HOT in Group 1 did not significantly affect the time of the appearance of the lesions. In contrast, mice treated with Leshcutan demonstrated a significant difference in lesion size and spleen dimensions as compared to the rest of the mice (p<0.001). The results show that HOT treatment has no positive effect on the course of Leishmaniasis in a BALB/c mice model infected with Leishmania major. Further studies are needed with a mouse model closer to humans and with different HOT protocols.

Amoebic liver abscess with negative serologic markers for Entamoeba histolytica: mind the gap!

A 38-year-old male German traveller returning from Asia presented with fever, night sweats and abdominal complaints. Abdominal ultrasonography revealed several fast-growing abscesses of the liver. Three blood cultures as well as serologic investigations for the detection of antibodies to Entamoeba histolytica, performed on day 3 and 7 after the onset of clinical symptoms, remained negative. Stool microscopy revealed the presence of amoeba cysts compatible with E. histolytica infection. Taking both the amoebic and bacterial etiology of the abscesses into consideration, the patient was treated with metronidazole and ciprofloxacin followed by paromomycin. Antibodies to E. histolytica tested positive shortly after anti-amoebic therapy was initiated. The patient fully recovered, and ultrasound follow-up showed complete resolution of the abscesses within 50 days. This case leads to the conclusion that amoebic liver abscess should be considered despite negative amoeba serology and that ultrasonography is an important diagnostic tool for the early diagnosis of extraintestinal amoebiasis.

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/l glutamine, 20 mg zinc acetate once a day and vitamin A supplementation (200,000 IU) once a day for 2 weeks. For cryptosporidiosis treatment, G1 received Mirazid (10 mg/kg for 2 weeks), G2 received Paromomycin (500 mg qid for 2 weeks), and G3 received a combination of Mirazid (10 mg/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 & 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 G1 & G2 in the 1st week (p = .036, 0.025 respectively), no significant difference in 2nd week, a significantly higher difference than in G1 (0.003), & G2 (0.006) in 3rd week, and a significantly higher difference than G1 (0.014), & G2 (0.01) in 4th week, but without significant differences in oocyst shedding in the 3 groups.

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.

Cutaneous leishmaniasis.

Cutaneous leishmaniasis is a widespread tropical infection caused by numerous different species of Leishmania protozoa that are transmitted by sandflies. Its clinical presentations are extremely diverse and dependent on a variety of parasite and host factors that are poorly understood. Diagnosis should aim to identify the exact species involved, but this requires laboratory investigations that are not widely available. No single ideal treatment has been identified, and those available are limited by variable success rates and toxicity. Clinical guidelines are needed to make better use of the investigations and treatments that do exist. Prevention is currently limited to bite prevention measures.

Anticryptosporidial prophylactic efficacy of enrofloxacin and paromomycin in chickens.

Two battery tests were conducted to study the anticryptosporidial prophylactic efficacy of the 2 commercially available antibiotics, enrofloxacin and paromomycin. The efficacy of enrofloxacin was 52% at the recommended level, which could not be increased, using twice the recommended dose. At the recommended levels, paromomycin reduced the oocyst output of birds by 67-82%, showing the highest efficacy of all drugs tested against avian cryptosporidiosis thus far. Moreover, the patent period was shortened by 12-23%. The body weight gain of paromomycin-treated chickens was almost identical with that of uninfected, untreated control birds irrespective of dosage, indicating the lack of toxicity. Although paromomycin is not registered for use in birds, in combination with sanitary procedures and disinfection, it may help in the control of cryptosporidiosis in some bird facilities.

Early bactericidal activity of paromomycin (aminosidine) in patients with smear-positive pulmonary tuberculosis.

The early bactericidal activity of the aminoglycoside paromomycin (aminosidine) in doses of 7.5 and 15 mg/kg of body weight was measured in 22 patients with previously untreated smear-positive pulmonary tuberculosis. The fall in log(10) CFU per milliliter of sputum per day during the first 2 days of treatment for 7 patients receiving a paromomycin dosage of 7.5 mg/kg/day was 0.066, with a standard deviation (SD) of 0.216 and confidence limits from -0.134 to 0.266, and that for 15 patients receiving 15 mg/kg/day was 0.0924, with an SD of 0.140 and confidence limits from 0.015 to 0.170. The difference between the mean and zero was not significant for the 7. 5-mg/kg dose group but was significant for the 15-mg/kg dose group (t = 2.55, P = 0.023). Since paromomycin has no cross-resistance with streptomycin and has no greater toxicity than other aminoglycosides, these results suggest that it has the potential to substitute for streptomycin in antituberculosis regimens and may be a particularly valuable addition to the drug armamentarium for the management of multidrug-resistant tuberculosis.

Therapeutic trial in experimental tegumentary leishmaniasis caused by Leishmania (Leishmania) amazonensis. A comparative study between mefloquine and aminosidine.

One hundred and eighty-two male inbred C57/BL/6 mice were infected with 3 x 10(6) Leishmania (Leishmania) amazonensis promastigotes of the MHOM/BR/PH8 strain by means of a subcutaneous injection in the right ear. The animals were separated in three groups: 1) oral mefloquine hydrochloride treatment (16 mg/kg/day/10 days), 2) intramuscular aminosidine (Paromomycin) treatment (20 mg/kg/20 days) and 3) control. Twenty-six mice of each treated group were sacrificed, one at the end of treatment (nine weeks after inoculation), and one six weeks later (fifteen weeks after inoculation). Control Group animals were sacrificed at weeks six, nine and fifteen after inoculation. There was no significant difference between Group 1 (mefloquine) and Group 3 (control) subjects. Group 2 animals (aminosidine) presented the smallest differences of all, both at the end of the treatment and six weeks later. The histopato-logical parameters have shown the following findings: a) there was no significant difference between the mefloquine treated group and the control group; the group treated with aminosidine showed fewer of vacuolated macrophages than the control group, at week 9 (end of treatment). b) both at the end of treatment and six weeks later, evaluation of tissue necrosis and tissue fibrosis revealed no differences between the treated groups. It was found that six weeks after the end of treatment, mice in the control group presented significantly more severe degrees of fibrosis than mice in the other groups. It can be concluded that mefloquine showed limited therapeutic effect in this experimental model, whereas aminosidine had a significant effect. Nevertheless, neither of them resulted in cure of the lesions.

Comparison of the efficacy of free and non-ionic-surfactant vesicular formulations of paromomycin in a murine model of visceral leishmaniasis.

Non-ionic-surfactant vesicular (NIV) formulations of paromomycin have been tested in-vitro and in-vivo for their activity against Leishmania donovani. Production of NIV was dependent both on the surfactant used and on the concentration of paromomycin; only two of the surfactants studied formed vesicles at the highest paromomycin concentration (9 mg mL(-1)). At surfactant-lipid concentrations > or = 1.5 mM, suspensions of NIV (drug- or glucose-loaded) were cytotoxic to macrophages infected with L. donovani; high levels of nitrite were produced in cell supernatants. At surfactant-lipid concentrations < 1.5 mM, drug-loaded NIV were more effective than the same dose of free drug, in terms of the percentage of cells infected and the number of parasites/cell. At surfactant-lipid concentrations < or = 0.15 mM, drug-loaded NIV were ineffective in-vitro. In-vivo, treatment with decaethylene glycol mono n-hexadecyl ether paromomycin NIV was more effective than hexaethylene glycol mono n-hexadecyl ether paromomycin NIV, in terms of suppression of liver and spleen parasite burdens. Against liver parasites, both types of paromomycin-loaded NIV were more effective than free drug. Neither the NIV nor free forms of paromomycin caused significant suppression of bone-marrow parasites. The study shows that entrapment of paromomycin in NIV can be used to increase its antileishmanial activity in-vitro and in-vivo.

Evaluation of an animal model system for cryptosporidiosis: therapeutic efficacy of paromomycin and hyperimmune bovine colostrum-immunoglobulin.

Several immunodeficient rodent models currently exist in which persistent, largely asymptomatic, Cryptosporidium parvum infections can be established. Piglets, in contrast, develop a self-limiting diarrheal illness. We have consequently developed an animal model system in which scid mice were used to screen drugs for inhibitory activity against C. parvum, after which the drugs' therapeutic potential was evaluated with piglets. Paromomycin and hyperimmune bovine colostrum-immunoglobulin were selected to evaluate this system. C. paravum infections in suckling scid mice tended to be associated with villus surfaces, while in weaned and in older scid mice infections were more commonly localized in abscessed crypts. Rates of oocyst shedding in suckling scid mice were 50 to 200 times higher than in weaned mice and therefore made suckling mice a considerably more sensitive model for drug testing. Paromomycin given in high doses over 9 to 10 days was not toxic to either scid mice (3,000 mg/kg of body weight per day) or piglets (500 mg/kg/day). Paromomycin treatment was very effective against villus surface infections in suckling mice and considerably less effective against infections in inaccessible sites such as abscessed crypts and stomach pits seen in weaned and adult scid mice. The therapeutic efficacy of paromomycin in piglets depended on the severity of the diarrheal illness. Mild to moderate diarrhea and infection were cleared after paromomycin treatment of piglets infected with one C. parvum isolate. However, paromomycin had no impact on severely affected piglets infected with a second isolate, presumably because of a rapid transit time through the gut. In contrast to paromomycin hyperimmune bovine colostrum-immunoglobulin treatment reduced the rate of C. parvum infection moderately in scid mice and only slightly in piglets, again probably because of a rapid transit time through the gut and inactivation in the stomach. It was also clear that the impact of effective drugs against C. parvum can be detected within 5 days after the onset of treatment in either model.

Topical treatment of cutaneous leishmaniasis in Belize: in vitro and in vivo studies with Leishmania mexicana.

Strains of Leishmania mexicana isolated from Belizian patients were found to be highly susceptible to paromomycin sulphate (PR) treatment. This drug at 100 micrograms ml-1 destroyed 85-99.5% of in vitro cultivated Leishmania promastigotes within 4 days of exposure to the drug. Leishmania promastigotes inoculated into the base of the tail of Balb/c mice caused the development of local lesions several weeks after infection. These lesions were totally cleared of parasites after 20 days of topical treatment with PR ointment, comprised of 15% paromomycin sulphate and 12% methylbenzethonium chloride in soft white paraffin. Similar results were also obtained with L. braziliensis infections. Isoenzyme analysis was found to be the method of choice for parasite strain identification. Excreted factor serotyping was only partially effective and promastigote agglutination gave negative results.

Leishmania major: bacterial contamination of cutaneous lesions in experimental animals.

No bacterial contamination has been demonstrated in cutaneous leishmaniasis (CL) nodule and in lesions caused by Leishmania major in Balb/c mice up to 20 days after infection. However, although many phagocytic cells (polymorphonuclear leukocytes and macrophages) were present in the CL lesion, 80% of the lesions showed bacterial contamination that developed within the first 70 days of infection. Topical treatment of the lesion with an ointment containing 15% paromomycin and 12% methylbenzethonium chloride in soft white paraffin for 20 days eliminated all the Leishmania parasites and several of the associated bacteria including: Proteus vulgaris, Pasteurella multocida, Staphylococcus albus and Staphylococcus aureus. This treatment did not affect Escherichia coli, Klebsiella spp. and Pseudomonas aeruginosa. Total elimination of these bacteria was achieved only during the healing process, and within 20 days following termination of treatment. The rate of disappearance of bacteria inoculated alone into the base of the tail of normal uninfected Balb/c mice was much faster than that of bacteria inoculated into either the CL nodule or the CL lesion. This study suggests the development of local immunosuppression in the CL lesion that may be mediated by the Leishmania parasites and their metabolites.