The pipeline for drugs for control and elimination of neglected tropical diseases: 2. Oral anti-infective drugs and drug combinations for off-label use.

In its 'Road map for neglected tropical diseases 2021-2030', the World Health Organization outlined its targets for control and elimination of neglected tropical diseases (NTDs) and research needed to achieve them. For many NTDs, this includes research for new treatment options for case management and/or preventive chemotherapy. Our review of small-molecule anti-infective drugs recently approved by a stringent regulatory authority (SRA) or in at least Phase 2 clinical development for regulatory approval showed that this pipeline cannot deliver all new treatments needed. WHO guidelines and country policies show that drugs may be recommended for control and elimination for NTDs for which they are not SRA approved (i.e. for 'off-label' use) if efficacy and safety data for the relevant NTD are considered sufficient by WHO and country authorities. Here, we are providing an overview of clinical research in the past 10 years evaluating the anti-infective efficacy of oral small-molecule drugs for NTD(s) for which they are neither SRA approved, nor included in current WHO strategies nor, considering the research sponsors, likely to be registered with a SRA for that NTD, if found to be effective and safe. No such research has been done for yaws, guinea worm, Trypanosoma brucei gambiense human African trypanosomiasis (HAT), rabies, trachoma, visceral leishmaniasis, mycetoma, T. b. rhodesiense HAT, echinococcosis, taeniasis/cysticercosis or scabies. Oral drugs evaluated include sparfloxacin and acedapsone for leprosy; rifampicin, rifapentin and moxifloxacin for onchocerciasis; imatinib and levamisole for loiasis; itraconazole, fluconazole, ketoconazole, posaconazole, ravuconazole and disulfiram for Chagas disease, doxycycline and rifampicin for lymphatic filariasis; arterolane, piperaquine, artesunate, artemether, lumefantrine and mefloquine for schistosomiasis; ivermectin, tribendimidine, pyrantel, oxantel and nitazoxanide for soil-transmitted helminths including strongyloidiasis; chloroquine, ivermectin, balapiravir, ribavirin, celgosivir, UV-4B, ivermectin and doxycycline for dengue; streptomycin, amoxicillin, clavulanate for Buruli ulcer; fluconazole and isavuconazonium for mycoses; clarithromycin and dapsone for cutaneous leishmaniasis; and tribendimidine, albendazole, mebendazole and nitazoxanide for foodborne trematodiasis. Additional paths to identification of new treatment options are needed. One promising path is exploitation of the worldwide experience with 'off-label' treatment of diseases with insufficient treatment options as pursued by the 'CURE ID' initiative.

Effectiveness of ivermectin-based multidrug therapy in severely hypoxic, ambulatory COVID-19 patients.

Aims: Ivermectin is a safe, inexpensive and effective early COVID-19 treatment validated in 20+ random, controlled trials. Having developed combination therapies for Helicobacter pylori, the authors present a highly effective COVID-19 therapeutic combination, stemming from clinical observations. Patients & methods: In 24 COVID-19 subjects refusing hospitalization with high-risk features, hypoxia and untreated moderate to severe symptoms averaging 9 days, the authors administered this novel combination of ivermectin, doxycycline, zinc and vitamins D and C. Results & conclusions: All subjects resolved symptoms (in 11 days on average), and oxygen saturation improved in 24 h (87.4% to 93.1%; p = 0.001). There were no hospitalizations or deaths, less than (p < 0.002 or 0.05, respectively) background-matched CDC database controls. Triple combination therapy is safe and effective even when used in outpatients with moderate to severe symptoms. Clinical Trial Registration: NCT04482686 (ClinicalTrial.gov).

The story of Lymphatic Filariasis elimination as a public health problem from Yemen.

In 2000, Yemen joined the WHO global efforts to eliminate lymphatic filariasis (LF) as a public health problem by initiating a National LF Elimination Programme (NLFEP), that was fully integrated with the National Leprosy Elimination Programme (NLEP), the Ministry of Public Health and Population. This article reviews the NLFEP extensive efforts and interventions to eliminate LF in Yemen. LF mapping was started in 2000, followed by five annual rounds of mass drug administration (MDA) with ivermectin and albendazole in 8 implementation units (IUs) during 2002-2006. The epidemiological coverage for all MDA rounds was ≥80%. Based on WHO guidelines of 2005, MDA was stopped in 7 IUs, additional MDA rounds were continued in one IU until 2011. Microfilaremia monitoring and evaluation, and MDA stopping surveys were conducted based on WHO guidelines of 2005 and 2011. Information about the presence of patients suffering from lymphoedema/elephantiasis and hydrocele was collected, and basic care provided to all chronic cases by NLEP coordinators, trained on LF morbidity management and disability prevention (MMDP). As of 2017, a total of 610 lymphoedema patients were trained on self-management, and 31 hydrocele patients were referred to local General Hospitals for surgery. The NLFEP made excellent progress due to integration with NLEP, strong collaboration with national and international bodies, intensive training and supervision, and the use of robust advocacy for mobilization of endemic communities. Transmission assessment surveys (TAS), conducted in 2013 and 2016, indicated 0% antigenemia levels in schoolchildren in the 8 IUs. Thus, after almost two decades of sustained effort, Yemen met the WHO criteria for successful elimination of LF as a public health problem. In 2019, WHO validated Yemen as the second country in the WHO' Eastern Mediterranean Region to successfully eliminate LF as a public health problem.

Case Report: Nasal Myiasis in an Elderly Patient with Atrophic Rhinitis and Facial Sequelae of Leprosy.

We describe a case of nasal myiasis in an 89-year-old Brazilian patient affected by leprosy with severe nasal sequelae. An initial treatment comprising sinusectomy combined with nasal endoscopy removed more than 300 larvae, supplemented by systemic treatment using oral and topical ivermectin and levofloxacin. Infestation recurred after 2 months, was treated similarly, and resolved completely. The case could be attributed to severe nasal leprosy sequelae, with a lack of sneezing reflex, painless ulceration, atrophic rhinitis (ozena), and inability to clean the nose properly due to hand and nose impairment. This case illustrates the importance of long-term medical follow-up of patients with leprosy sequelae.

Management of severe strongyloidiasis attended at reference centers in Spain.

INTRODUCTION: Strongyloides stercoralis is a globally distributed nematode that causes diverse clinical symptoms in humans. Spain, once considered an endemic country, has experienced a recent increase in imported cases. The introduction of serology helps diagnosis and is currently replacing microbiological techniques in some settings, but its sensitivity is variable and can be low in immunocompromised patients. Diagnosis can only be confirmed by identification of larvae. Often, this "gold standard" can only be achieved in severe cases, such as disseminated S.stercoralis infection, or S.stercoralis hyperinfection syndrome, where parasite load is high. In addition, these clinical presentations are not well-defined. Our aim is to describe severe cases of S.stercoralis, their epidemiological profile, and their clinical details. METHODS: An observational retrospective study of disseminated S.stercoralis infection, or hyperinfection syndrome. Inclusion criteria: aged over 18, with a diagnosis of disseminated S.stercoralis infection, or hyperinfection syndrome, confirmed by visualization of larvae. Patients were identified through revision of clinical records for the period 2000-2015, in collaboration with eight reference centers throughout Spain. RESULTS: From the period 2000-2015, eighteen cases were identified, 66.7% of which were male, with a median age of 40 (range 21-70). Most of them were foreigners (94.4%), mainly from Latin America (82.3%) or Western Africa (17.6%). Only one autochthonous case was identified, from 2006. Immunosuppressive conditions were present in fourteen (77%) patients, mainly due steroids use and to retroviral coinfections (four HIV, two HTLV). Transplant preceded the clinical presentation in four of them. Other comorbidities were coinfection with HBV, Trypanosoma cruzi, Mycobacterium leprae or Aspergillus spp. All presented with digestive disorders, with 55.6% also presenting malaise. 44.4% of cases had fever, 27.8% skin complaints, and 16.7% respiratory or neurological disorders. One patient presented anemia, and one other nephrotic syndrome. Diagnosis was confirmed by identification of larvae in fresh stool samples (n = 16; 88.9%), concentration techniques (n = 6; 33.3%), larval culture (n = 5; 29.4%), or digestive biopsies (n = 8; 44%). S.stercoralis forms were identified during necropsy in one case. In addition, ten (55%) had a positive serology. All the cases were treated with ivermectin, six (33%) also received albendazole and one case received thiabendazole followed by ivermectin. All needed inpatient management, involving a mean hospitalization stay of 25 days (range 1-164). Two cases received intensive care and eventually died. CONCLUSIONS: Only eighteen cases of disseminated S.stercoralis infection/hyperinfection syndrome were identified from the 15-year period, most of which were considered to have been imported cases. Among those, immunosuppression was frequent, and mortality due to S.stercoralis was lower than previously described.

Injectable PLA-based in situ forming implants for controlled release of Ivermectin a BCS Class II drug: solvent selection based on physico-chemical characterization.

In situ forming implants (ISI) prepared from biodegradable polymers such as poly(D,L-lactide) (PLA) and biocompatible solvents can be used to obtain sustained drug release after parenteral administration. The aim of this work was to study the effect of several biocompatible solvents with different physico-chemical properties on the release of ivermectin (IVM), an antiparasitic BCS II drug, from in situ forming PLA-based implants. The solvents evaluated were N-methyl-2-pyrrolidone (NMP), 2-pyrrolidone (2P), triacetine (TA) and benzyl benzoate (BB). Hansen's solubility parameters of solvents were used to explain polymer/solvent interactions leading to different rheological behaviours. The stability of the polymer and drug in the solvents were also evaluated by size exclusion and high performance liquid chromatography, respectively. The two major factors determining the rate of IVM release from ISI were miscibility of the solvent with water and the viscosity of the polymer solutions. In general, the release rate increased with increasing water miscibility of the solvent and decreasing viscosity in the following order NMP>2P>TA>BB. Scanning electron microscopy revealed a relationship between the rate of IVM release and the surface porosity of the implants, release being higher as implant porosity increased. Finally, drug and polymer stability in the solvents followed the same trends, increasing when polymer-solvent affinities and water content in solvents decreased. IVM degradation was accelerated by the acid environment generated by the degradation of the polymer but the drug did not affect PLA stability.

Comparative efficacy and safety of topical permethrin, topical ivermectin, and oral ivermectin in patients of uncomplicated scabies.

BACKGROUND: Ivermectin has opened a new era in the management of scabies as orally effective drug. However, topical route has been little explored for ivermectin. AIMS: To compare the efficacy and safety of topical permethrin, oral ivermectin, and topical ivermectin in the treatment of uncomplicated scabies. METHODS: This was an open-label, randomized, comparative, parallel clinical trial conducted in 315 patients, randomly allocated to 3 groups. First group received permethrin 5% cream as single application, second group received tablet ivermectin 200 mcg/kg as single dose, and third group received ivermectin 1% lotion as single application. All the patients received anti-histaminic for pruritus. The patients were followed up at intervals of 1, 2, 3, and 4 weeks. If there were no signs of cure, the same intervention was repeated at each follow up. Primary efficacy variable was clinical cure of lesions. Statistical analysis was done by chi square test and one way ANOVA test using SPSS version 12. RESULTS: At the end of first week, cure rate was 74.8% in permethrin group, 30% in oral ivermectin group, and 69.3% in topical ivermectin group (P < 0.05). At the end of second week, cure rate was 99% in permethrin group, 63% in oral ivermectin group, and 100% in topical ivermectin group (P < 0.05). At the end of third week, 100% cure rate was observed in permethrin and topical ivermectin group while 99% in oral ivermectin group (P = 0.367). No serious adverse events were observed. CONCLUSIONS: Permethrin and topical ivermectin were equally effective against scabies while oral ivermectin was significantly less effective up to 2 weeks. Topical ivermectin can be used as an alternative to permethrin.

Successful treatment of Strongyloides stercoralis hyperinfection in a case of systemic lupus erythematosus - review of the literature regarding various treatment schedules.

Strongyloides stercoralis hyperinfection poses a great challenge to physicians in the tropics due to their non-specific symptoms and signs. Early identification and initiation of treatment improves mortality rates. Reports of Strongyloides infection in Hansens disease, systemic lupus erythematosus (SLE), organ transplant recipients and malnourished individuals have been reported in the published literature. The outcomes were variable, which may be attributed to a lack of treatment protocol. Treatment has been individualized and reports available are based on individual case reports and small case series. We report a successfully treated case of hyperinfection in SLE and discuss the various treatment options available.

[Infection due to Strongyloides stercoralis: epidemiological, clinical, diagnosis findings and outcome in 30 patients]. / Infección por Strongyloides stercoralis: estudio epidemiológico, clínico, diagnóstico y terapéutico en 30 pacientes.

BACKGROUND: Strongyloides stercoralis is a nematode parasite, which is endemic in tropical and subtropical regions. Infection usually remains asymptomatic, but in immunocompromised hosts severe and life-threatening manifestations such as hyperinfection syndrome and disseminated disease might occur. METHODS: We retrospectively analyzed the epidemiological and clinical characteristics, including HIV co-infection, microbiological findings, and outcome in 30 patients with strongyloidiasis, who attended in the Infectious Diseases F. J. Muñiz Hospital in Buenos Aires from January 2004 to December 2008. RESULTS: The study included 20 men and 10 women with an average age of 33 years. HIV co-infection was present in 21 patients (70%) with a median CD4 T cell count of 50 cells/mm³ (range 7-355) (average 56 cells/mm³). Among HIV negative patients the following comorbidities were detected: tuberculosis (n = 3) and chronic alcoholism, leprosy treated with corticosteroids, immunosuppressive treatment for psoriasis, and diabetes mellitus (each in one patient). Two patients did not have any predisposing diseases or immunosuppressive treatments. Seventeen patients presented with diarrhea and were classified as chronic intestinal strongyloidiasis (57%), asymptomatic infection with peripheral eosinophilia was diagnosed in 7 (23%), and 6 patients (20%) developed hyperinfection syndrome. Seventeen patients (57%) presented peripheral eosinophilia. Diagnosis was achieved by direct visualization of larvae in feces by Baermann technique (n = 20), by multiple stool smears examinations (n = 2), by combination of both (n = 1), by visualization of the filariform larvae in duodenal fluid and stool (n = 1), and in fecal and bronchoalveolar lavage specimens (n = 6). Overall mortality in this series was 20% (6/30). There was no significant correlation between age and mortality. A significant inverse correlation between the survival rate and CD4 T-cell count as well as eosinophilia was observed. There was also a significant correlation between HIV co-infection and mortality. Twenty-two patients responded favorably to treatment with ivermectin.

Topical permethrin and oral ivermectin in the management of scabies: a prospective, randomized, double blind, controlled study.

BACKGROUND: Scabies is a highly contagious and intensely pruritic parasitic infestation. It is a re-emerging infection in the new millennium especially with HIV pandemic and a significant health problem in developing countries. Various treatment modalities have been used since time immemorial but the search for an ideal scabicide is ongoing. AIMS: In this study, we compared the therapeutic efficacy of single application of topical 5% permethrin with oral ivermectin (200 µg/kg/dose) in a single-dose and a two-dose regimen in patients with scabies. METHODS: 120 clinically diagnosed cases of scabies (>5 years of age and/or >15 kg) were randomized into three treatment groups A, B, C of 40 patients each; receiving either topical 5% permethrin (group A) or oral ivermectin (200 µg/kg/dose) in a single dose (group B) or double dose regimen (group C) repeated at 2 weeks interval. Patients were followed up at 1, 2, and 4 weeks interval. At each visit, cure rate (>50% improvement in lesion count and pruritus and negative microscopy) was assessed and compared. RESULTS: Cure rate in three treatment groups at the end of 4 weeks was 94.7% (A), 90% (B), 89.7% (C), and thus all three treatment modalities were equally efficacious. However, at 1 week follow up, group A patients reported better improvement in both lesion count and pruritus. CONCLUSIONS: Both permethrin and ivermectin in both single and two dose regimen are equally efficacious and well tolerated in scabies. However, permethrin has a rapid onset of action.

Infección por Strongyloides stercoralis: estudio epidemiológico, clínico, diagnóstico y terapéutico en 30 pacientes / Infection due to Strongyloides stercoralis: epidemiological, clinical, diagnosis findings and outcome in 30 patients

Background: Strongyloides stercoralis is a nematode parasite, which is endemic in tropical and subtropical regions. Infection usually remains asymptomatic, but in immunocompromised hosts severe and life-threatening manifestations such as hyperinfection syndrome and disseminated disease might occur. Methods: We retrospectively analyzed the epidemiological and clinical characteristics, including HIV co-infection, microbiological findings, and outcome in 30 patients with strongyloidiasis, who attended in the Infectious Diseases F. J. Muñiz Hospital in Buenos Aires from January 2004 to December 2008. Results: The study included 20 men and 10 women with an average age of 33 years. HIV co-infection was present in 21 patients (70 percent) with a median CD4 T cell count of 50 cells/mm³ (range 7-355) (average 56 cells/mm³). Among HIV negative patients the following comorbidities were detected: tuberculosis (n = 3) and chronic alcoholism, leprosy treated with corticosteroids, immunosuppressive treatment for psoriasis, and diabetes mellitus (each in one patient). Two patients did not have any predisposing diseases or immunosuppressive treatments. Seventeen patients presented with diarrhea and were classified as chronic intestinal strongyloidiasis (57 percent), asymptomatic infection with peripheral eosinophilia was diagnosed in 7 (23 percent), and 6 patients (20 percent) developed hyperinfection syndrome. Seventeen patients (57 percent) presented peripheral eosinophilia. Diagnosis was achieved by direct visualization of larvae in feces by Baermann technique (n = 20), by multiple stool smears examinations (n = 2), by combination of both (n = 1), by visualization of the filariform larvae in duodenal fluid and stool (n = 1), and in fecal and bronchoalveolar lavage specimens (n = 6). Overall mortality in this series was 20 percent (6/30). There was no significant correlation between age and mortality. A significant inverse correlation between the survival rate and CD4 T-cell count as well as eosinophilia was observed. There was also a significant correlation between HIV co-infection and mortality. Twenty-two patients responded favorably to treatment with ivermectin.

Antecedentes: Strongyloides stercoralis, parásito endémico de áreas tropicales y subtropicales del planeta, en sujetos inmunodeprimidos puede cursar con formas graves y aun mortales como el síndrome de hiperinfestación y la enfermedad diseminada. Métodos: Análisis retrospectivo de las características epidemiológicas, manifestaciones clínicas, co-infección por virus de inmunodeficiencia humana (VIH), hallazgos microbiológicos y evolución de 30 pacientes con estrongiloidiasis, atendidos en el Hospital de Enfermedades Infecciosas F. J. Muñiz de Buenos Aires, entre enero 2004 y diciembre 2008. Resultados: Se incluyeron en la evaluación 20 hombres y 10 mujeres con una mediana de edad de 33 años. Co-infección por VIH hubo en 21 pacientes (70 por ciento); la mediana de linfocitos T CD4+ en ellos al momento del diagnóstico de la parasitosis fue de 50 céls/mm³ (rango 7 a 355), (media de 56 céls/mm³). En los pacientes seronegativos para VIH, se comprobaron las siguientes co-morbilidades: tuberculosis (n: 3) y un caso de cada una de las siguientes afecciones: alcoholismo crónico, diabetes mellitus, reacción lepromatosa bajo corticotera-pia, y psoriasis en tratamiento inmunosupresor. Hubo dos pacientes sin aparentes enfermedades de base. Diecisiete pacientes presentaron enfermedad intestinal crónica con diarrea (57 por ciento), era asintomática y fue sospechada por la eosinofilia periférica (n: 7, 23 por ciento) y se clasificó como síndrome de hiperinfestación (n: 6, 20 por ciento) diagnosticado por la identificación de larvas en la materia fecal y secreciones broncopulmonares. Diecisiete pacientes (57 por ciento) presentaron eosinofilia periférica. El diagnóstico se efectuó por la visualización directa de las larvas en muestras de heces en fresco mediante la técnica de concentración de Baer-man (n: 20); por el examen copro-parasitológico seriado (n: 2) y por ambos métodos (n: 1); en líquido duodenal y materia fecal (n: 1) y por la identificación de larvas en materia fecal y secreciones respiratorias (n: 6). Letalidad global: 20 por ciento (6/30). Los pacientes con eosinofilia tuvieron una menor letalidad que aquellos sin esta respuesta (p < 0,001). No hubo correlación estadística entre la edad y la supervivencia. Sí fue significativa la correlación entre el recuento de CD4 y la letalidad, incluyendo 18 de los 21 pacientes seropositivos para VIH (p: 0,03). Finalmente, la correlación seropositividad para VIH y letalidad también fue significativa. Veintidós pacientes respondieron a la terapia antiparasitaria con ivermectina y evolucionaron favorablemente.

Crusted scabies: clinical and immunological findings in seventy-eight patients and a review of the literature.

OBJECTIVES: To describe the clinical and immunological features of crusted scabies in a prospectively ascertained cohort of 78 patients. METHODS: All patients requiring inpatient treatment for crusted scabies in the 'top end' of the northern territory of Australia over a 10 year period were prospectively identified. Demographics, risk factors, and immunological parameters were retrospectively compiled from their medical records and pathology databases. RESULTS: More than half the patients with crusted scabies had identifiable immunosuppressive risk factors. Eosinophilia and elevated IgE levels occurred in 58% and 96% of patients, respectively, with median IgE levels 17 times the upper limit of normal. Seventeen percent had a history of leprosy but 42% had no identifiable risk factors. There was a decrease in mortality after the introduction of a treatment protocol consisting of multiple doses of ivermectin combined with topical scabicides and keratolytic therapy. CONCLUSIONS: Crusted scabies often occurs in patients with identifiable immunosuppressive risk factors. In patients without such risk factors, it is possible that the crusted response to infection results from a tendency to preferentially mount a Th2 response. The treatment regime described was associated with a reduction in mortality. This is the largest reported case series of crusted scabies.

Stigma associated with onchocercal skin disease among those affected near the Ofiki and Oyan Rivers in western Nigeria.

Skin diseases have been a major source of social stigma, whether they be infectious or not. The potential stigamtizing effect of skin disease associated with onchocerciasis is currently receiving attention because half of the 17 million victims of onchocerciasis in Africa live where the non-blinding form of the disease is prevalent. Some reports are available that onchocercal skin disease (OSD) is associated with social stigma including problems in finding a marriage partner. Previous studies have also implied positive effects of ivermectin treatment on OSD. Therefore a multi-country trial of ivermectin is underway to test the hypothesis that ivermectin treatment might affect perceptions of stigma associated with OSD. This paper presents the baseline stigma findings from the study site located in southwestern Nigeria. A total of 1032 persons living in villages near the Ofiki and Oyan Rivers were screened and interviewed and 500 (48%) were found to have an onchocercal skin lesion. A 13-item, 39-point stigma scale was used in interviews with affected persons. A mean score of 16.8 was obtained. No personal characteristics or disease factors were found to be associated with stigma score. The highest ranking items focused on issues of self-esteem such as feeling embarrassed, feelings of being pitied, thinking less of oneself, feeling that scratching annoys others, feeling that others thought less of the person and feeling that others had avoided the person. During the interviews it was discovered that only about half of those clinically diagnosed as having OSD labeled their own condition as onchocerciasis. Those who said their lesion was OSD had a lower stigma score than those who did not, conforming with previous studies wherein affected persons perceived less stigma from OSD than those without the disease. A broader community perspective on OSD was obtained through 50 interviews using paired comparisons of five skin-related local illnesses. Onchocerciasis placed midway in aversive responses between the higher end represented by leprosy and chicken pox and lower scoring papular rashes known locally as eela and ring worm. In-depth village based interviews yielded several case studies of how onchocerciasis had a negative social impact on its victims. While study on the cultural perceptions of OSD is recommended, the results indicate that with a fairly high prevalence of OSD, the community level effects of social stigma should be regarded as serious.