Local amphotericin B therapy for Cutaneous Leishmaniasis: A systematic review.

BACKGROUND: Cutaneous leishmaniasis (CL) is characterized by potentially disfiguring skin ulcers carrying significant social stigma. To mitigate systemic drug exposure and reduce the toxicity from available treatments, studies addressing new local therapeutic strategies using available medications are coming up. This review systematically compiles preclinical and clinical data on the efficacy of amphotericin B (AmB) administered locally for cutaneous leishmaniasis. METHODOLOGY: Structured searches were conducted in major databases. Clinical studies reporting cure rates and preclinical studies presenting any efficacy outcome were included. Exclusion criteria comprised nonoriginal studies, in vitro investigations, studies with fewer than 10 treated patients, and those evaluating AmB in combination with other antileishmanial drug components. PRINCIPAL FINDINGS: A total of 21 studies were identified, encompassing 16 preclinical and five clinical studies. Preclinical assessments generally involved the topical use of commercial AmB formulations, often in conjunction with carriers or controlled release systems. However, the variation in the treatment schedules hindered direct comparisons. In clinical studies, topical AmB achieved a pooled cure rate of 45.6% [CI: 27.5-64.8%; I2 = 79.7; p = 0.002), while intralesional (IL) administration resulted in a 69.8% cure rate [CI: 52.3-82.9%; I2 = 63.9; p = 0.06). In the direct comparison available, no significant difference was noted between AmB-IL and meglumine antimoniate-IL administration (OR:1.7; CI:0.34-9.15, I2 = 79.1; p = 0.00), however a very low certainty of evidence was verified. CONCLUSIONS: Different AmB formulations and administration routes have been explored in preclinical and clinical studies. Developing therapeutic technologies is evident. Current findings might be interpreted as a favorable proof of concept for the local AmB administration which makes this intervention eligible to be explored in future well-designed studies towards less toxic treatments for leishmaniasis.

The cure rate after different treatments for mucosal leishmaniasis in the Americas: A systematic review.

BACKGROUND: Mucosal or mucocutaneous leishmaniasis is the most severe form of tegumentary leishmaniasis due to its destructive character and potential damage to respiratory and digestive tracts. The current treatment recommendations are based on low or very low-quality evidence, and pentavalent antimonial derivatives remain strongly recommended. The aim of this review was to update the evidence and estimate the cure rate and safety profile of the therapeutic options available for mucosal leishmaniasis (ML) in the Americas. METHODOLOGY: A systematic review was conducted in four different databases and by different reviewers, independently, to evaluate the therapeutic efficacy and toxicity associated with different treatments for ML. All original studies reporting cure rates in more than 10 patients from American regions were included, without restriction of design, language, or publication date. The risk of bias was assessed by two reviewers, using different tools according to the study design. The pooled cure rate based on the latest cure assessment reported in the original studies was calculated grouping all study arms addressing the same intervention. The protocol for this review was registered at the International Prospective Register of Systematic Reviews, PROSPERO: CRD42019130708. PRINCIPAL FINDINGS: Twenty-seven original studies from four databases fulfilled the selection criteria. A total of 1,666 patients with ML were treated predominantly with pentavalent antimonials in Brazil. Other interventions, such as pentamidine, miltefosine, imidazoles, aminosidine sulfate, deoxycholate and lipidic formulations of amphotericin B (liposomal, lipid complex, colloidal dispersion), in addition to combinations with pentoxifylline, allopurinol or sulfa were also considered. In general, at least one domain with a high risk of bias was identified in the included studies, suggesting low methodological quality. The pooled cure rate based on the latest cure assessment reported in the original studies was calculated grouping all study arms addressing the same intervention. It was confirmed that antimony is still the most used treatment for ML, with only moderate efficacy (possibly increased by combining with pentoxifylline). There is already evidence for the use of miltefosine for ML, with a cure rate similar to antimony, as observed in the only direct meta-analysis including 57 patients (OR: 1.2; 0.43-3.49, I2 = 0). It was possible to gather all descriptions available about adverse events reported during ML treatment, and the toxicity reflected the pattern informed in the manufacturers' technical information. CONCLUSIONS: This study provides an overview of the clinical experience in the Americas related to ML treatment and points out interventions and possible combinations that are eligible to be explored in future well-designed studies.

Performance differences among commercially available antigen rapid tests for COVID-19 in Brazil.

A rapid and accurate diagnosis is a crucial strategy for containing the coronavirus disease (COVID-19) pandemic. Considering the obstacles to upscaling the use of RT-qPCR, rapid tests based on antigen detection (Ag-RDT) have become an alternative to enhance mass testing, reducing the time for a prompt diagnosis and virus spreading. However, the performances of several commercially available Ag-RDTs have not yet been evaluated in several countries. Here, we evaluate the performance of eight Ag-RDTs available in Brazil to diagnose COVID-19. Patients admitted to tertiary hospitals with moderate or mild COVID-19 symptoms and presenting risk factors for severe disease were included. The tests were performed using a masked protocol, strictly following the manufacturer's recommendations and were compared with RT-qPCR. The overall sensitivity of the tests ranged from 9.8 to 81.1%, and specificity greater than 83% was observed for all the evaluated tests. Overall, slight or fair agreement was observed between Ag-RDTs and RT-PCR, except for the Ag-RDT COVID-19 (Acro Biotech), in which moderate agreement was observed. Lower sensitivity of Ag-RDTs was observed for patients with cycle threshold > 25, indicating that the sensitivity was directly affected by viral load, whereas the effect of the disease duration was unclear. Despite the lower sensitivity of Ag-RDTs compared with RT-qPCR, its easy fulfillment and promptness still justify its use, even at hospital admission. However, the main advantage of Ag-RDTs seems to be the possibility of increasing access to the diagnosis of COVID-19 in patients with a high viral load, allowing immediate clinical management and reduction of infectivity and community transmission.

Diagnostic performance of commercially available COVID-19 serology tests in Brazil.

Timely and accurate laboratory testing is essential for managing the global COVID-19 pandemic. Reverse transcription polymerase chain reaction remains the gold-standard for SARS-CoV-2 diagnosis, but several practical issues limit the test's use. Immunoassays have been indicated as an alternative for individual and mass testing. OBJECTIVES: To access the performance of 12 serological tests for COVID-19 diagnosis. METHODS: We conducted a blind evaluation of six lateral-flow immunoassays (LFIAs) and six enzyme-linked immunosorbent assays (ELISAs) commercially available in Brazil for detecting anti-SARS-CoV-2 antibodies. RESULTS: Considering patients with seven or more days of symptoms, the sensitivity ranged from 59.5% to 83.1% for LFIAs and from 50.7% to 92.6% for ELISAs. For both methods, the sensitivity increased with clinical severity and days of symptoms. The agreement among LFIAs performed with digital blood and serum was moderate. Specificity was, in general, higher for LFIAs than for ELISAs. Infectious diseases prevalent in the tropics, such as HIV, leishmaniasis, arboviruses, and malaria, represent conditions with the potential to cause false-positive results with these tests, which significantly compromises their specificity. CONCLUSION: The performance of immunoassays was only moderate, affected by the duration and clinical severity of the disease. Absence of discriminatory power between IgM/IgA and IgG has also been demonstrated, which prevents the use of acute-phase antibodies for decisions on social isolation.

A new nanoemulsion formulation improves antileishmanial activity and reduces toxicity of amphotericin B.

This work aimed to optimise a new nanoemulsion (NE) formulation loaded with Amphotericin B (AmB) and to evaluate its in vivo antileishmanial activity and in vitro haemolytic toxicity. The influence of gradual increases in pressure, using a high-pressure homogeniser, was evaluated. The NE was characterised for droplet size, polydispersity index, zeta potential and encapsulation efficiency (EE). For antileishmanial activity studies, AmB-NE was administered intravenously in mice infected by Leishmania infantum chagasi, which causes Visceral Leishmaniasis (VL). When the NE was submitted to gradual increases in pressure, the PI values and droplet size decreased. The droplet size (∼145 nm) was lower than that obtained in previous studies. The zeta potential was negative and the EE was almost 100%. The haemolytic toxicity, evaluated on human red blood cells, for AmB-loaded NE was lower than that observed for the conventional AmB (C-AmB). C-AmB at 2 mg/kg was very toxic. In contrast, administration of the AmB-loaded NE, at same dose, did not result in any sign of acute toxicity, promoting a significant reduction in parasite burden as compared to the C-AmB. These findings suggest that this new AmB-loaded NE constitutes an attractive alternative for the treatment of VL due to improved efficacy and lower toxicity.

Eficácia pré-clínica do tratamento tópico da leishmaniose cutânea com gel hidrofílico de paromomicina em combinação com leishmanicidas de uso sistêmico e local

Os medicamentos disponíveis para o tratamento da leishmaniose cutânea apresentam eficácia insatisfatória, efeitos adversos frequentes e graves e requerem longos esquemas terapêuticos. Assim, a busca por novas alternativas de tratamento para a leishmaniose cutânea é considerada prioritária pela Organização Mundial da Saúde. O presente estudo teve como objetivo avaliar a eficácia pré-clínica do gel hidrofílico de paromomicina tópico (PA), da anfotericina B lipossomal intraperitoneal (AnfLipo) e do antimoniato de meglumina intralesional (Glu IL) em esquema de monoterapia e em combinação para o tratamento da leishmaniose cutânea causada por Leishmania (Viannia) braziliensis. O estudo foi composto pela avaliação de monoterapias por diferentes esquemas terapêuticos e por combinações binárias. Na avaliação dos medicamentos em monoterapia, os hamsters experimentalmente infectados na base a cauda com L. (V.) braziliensis, foram tratados com PA (duas vezes ao dia, durante 30 dias consecutivos), AnfLipo (dose única ou intervalar, ambas com dose total de 10 mg/kg) e Glu IL (infiltração única, semanal ou quinzenal). A eficácia clínica foi avaliada através da medida do tamanho da lesão e a eficácia parasitológica por diluição limitante de cultivo de parasitas. O grupo de animais tratados com PA apresentou tendência de redução do tamanho das lesões, sem diferença estatística significativa em relação ao grupo controle, mas não observou-se redução de carga parasitária na lesão e no baço dos animais (p>0,05). Para AnfLipo, não houve diferença estatística do tamanho das lesões entre os diferentes esquemas de tratamento, mas houve diferença entre os grupos tratados e o grupo controle (p<0,05). Já na avaliação parasitológica, este medicamento foi eficaz em reduzir a carga de parasitas no baço (p<0,05). O Glu IL, administrado semanalmente ou quinzenalmente, levou à cura completa de 80% e 100% dos animais, respectivamente. A infiltração única reduziu as lesões até 28 dias após tratamento, mas a partir daí houve reativação das mesmas. A redução do tamanho das lesões obtida com os esquemas de tratamento intralesional semanalmente ou quinzenalmente foi estatisticamente diferente do grupo controle (p<0,05). Na avaliação parasitológica com Glu IL, não houve redução significativa da carga de parasitas na lesão e no baço (p>0,05). No estudo de combinações binárias, os seguintes regimes de tratamentos foram adotados: PA (duas vezes ao dia, durante 30 dias consecutivos), AnfLipo (dose única - 10 mg/kg) e Glu IL (infiltração única). Os animais tratados com as combinações (PA+Glu IL, PA+AnfLip e Glu IL+AnfLipo) apresentaram 100% de redução do tamanho da lesão (p<0,05), enquanto os animais tratados por monoterapias apresentaram redução de 29% (PA), 50% (Glu IL) e 72% (AnfLipo). Redução significativa da carga parasitária no baço ocorreu nos grupos tratados com AnfLipo (p<0,05). Conclui-se que as combinações avaliadas foram mais efetivas na cicatrização das lesões do que os medicamentos em monoterapia e que essas combinações representam uma alternativa para o tratamento da leishmaniose cutânea causada por L. (V.) braziliensis e encorajam futuros ensaios clínicos.