Poloxamer-enhanced solubility of griseofulvin and its related antifungal activity against Trichophyton spp

Abstract Poorly water-soluble drugs, such as the antifungal drug griseofulvin (GF), exhibit limited bioavailability, despite their high membrane permeability. Several technological approaches have been proposed to enhance the water solubility and bioavailability of GF, including micellar solubilization. Poloxamers are amphiphilic block copolymers that increase drug solubility by forming micelles and supra-micellar structures via molecular self-association. In this regard, the aim of this study was to evaluate the water solubility increment of GF by poloxamer 407 (P407) and its effect on the antifungal activity against three Trichophyton mentagrophytes and two T. rubrum isolates. The GF water solubility profile with P407 revealed a non-linear behavior, well-fitted by the sigmoid model of Morgan-Mercer-Flodin. The polymer promoted an 8-fold increase in GF water solubility. Fourier-transform infrared (FT-IR) spectroscopy, differential scanning calorimetry (DSC), and 2D nuclear magnetic resonance (NMR Roesy) spectroscopy suggested a GF-P407 interaction, which occurs in the GF cyclohexene ring. These results were supported by an increase in the water solubility of the GF impurities with the same molecular structure. The MIC values recorded for GF ranged from 0.0028 to 0.0172 mM, except for T. Mentagrophytes TME34. Notably, the micellar solubilization of GF did not increase its antifungal activity, which could be related to the high binding constant between GF and P407.

Efficacy of topical clotrimazole vs. topical tolnaftate in the treatment of otomycosis. A randomized controlled clinical trial / Eficácia do clotrimazol tópico versus tolnaftato tópico no tratamento da otomicose: um ensaio clínico controlado randomizado

Abstract Introduction: Otomycosis, an infection of the ear canal by fungi, is prevalent in hot and humid weather. Nevertheless, there is not sufficient evidence for the effectiveness of different topical antifungal treatments. Tolnaftate, is a topical antifungal agent described to be effective in the treatment of otomycosis. Currently there are not sufficient studies that prove its efficacy. Objectives: To compare the efficacy of clotrimazole and tolnaftate administration in the treatment of otomycosis. Material and methods: A controlled, randomized and open clinical trial included patients diagnosed with fungal external otitis who were treated with topical antifungals, randomized into two treatment groups: (1) clotrimazole cream; (2) tolnaftate solution. They were microscopically evaluated at one and two weeks of treatment to determine resolution of disease. Recurrence and complications were recorded. Demographic and clinical variables were collected and analyzed. Follow-up and final outcomes (absence of infection) were compared between groups. Results: Forty eight patients were included, 28 in the clotrimazole group and 20 in the tolnaftate group. Spring was the weather most commonly associated with otomycosis, while otic manipulation was the risk factor more common in both groups. Predominant symptoms were itching and otic fullness. Aspergillus niger organism was isolated most frequently. Treatment with clotrimazole resulted in 75% resolution vs 45% resolution with treatment with tolnaftate at one week of treatment (p = 0.007). The Tolnaftate treatment group demonstrated higher recurrence rates and treatment failures, 20% and 15% respectively. Conclusions: Clotrimazole cream treatment is more effective than tolnaftate for uncomplicated otomycosis. More studies are needed to corroborate our results.

Resumo Introdução: Otomicose, uma infecção fúngica do canal auditivo externo, é prevalente em climas quentes e úmidos. No entanto, a literatura não apresenta evidências suficientes sobre os diferentes tratamentos antifúngicos tópicos. O tolnaftato é um antifúngico tópico descrito como eficaz no tratamento da otomicose; entretanto, sua eficácia não está suficientemente comprovada. Objetivo: Comparar a eficácia do uso de clotrimazol e tolnaftato no tratamento da otomicose. Material e método: Ensaio clínico controlado e randomizado; incluiu pacientes diagnosticados com otite externa fúngica tratados com antifúngicos tópicos, randomizados em dois grupos de tratamento: 1) clotrimazole (creme); 2) solução de tolnaftato. Eles foram avaliados microscopicamente uma e duas semanas após o início do tratamento para avaliar a resolução da doença. Recorrência e intercorrências foram registradas; além disso, as variáveis demográficas e clínicas foram coletadas e analisadas. Os dados do acompanhamento e desfechos finais (ausência de infecção) foram comparados entre os grupos. Resultados: O estudo incluiu 48 pacientes, 28 dos quais foram alocados ao grupo clotrimazole e 20 ao grupo tolnaftato. A primavera foi a estação mais comum; a manipulação foi o fator de risco mais comum em ambos os grupos. Os sintomas mais comuns foram coceira e plenitude auricular. Aspergillus niger foi o micro-organismo mais comumente isolado. Após uma semana, o tratamento com clotrimazol apresentou uma taxa de resolução de 75% vs. 45% com o tratamento com tolnaftato (p = 0,007). O tratamento com tolnaftato apresentou maiores taxas de recidiva e falhas: 20% e 15%, respectivamente. Conclusões: Em casos de otomicose não complicada, o uso de clotrimazol (creme) é mais eficaz do que o de tolnaftato. Mais estudos são necessários para corroborar os presentes resultados.

Farmacocinética da micafungina em pacientes tratados com oxigenação por membrana extracorpórea: um estudo observacional prospectivo / Pharmacokinetics of micafungin in patients treated with extracorporeal membrane oxygenation: an observational prospective study

RESUMO Objetivo: Determinar os níveis plasmáticos e o comportamento farmacocinético da micafungina em pacientes tratados com oxigenação por membrana extracorpórea. Métodos: As amostras foram colhidas por meio de pontos de acesso antes e depois da membrana, em dois hospitais espanhóis de nível terciário. Os momentos para o cálculo das curvas farmacocinéticas foram antes da administração do fármaco, e 1, 3, 5, 8, 18 e 24 horas após o início da infusão nos dias 1 e 4 de tratamento. Calcularam-se a área sob a curva, a depuração do fármaco, o volume de distribuição e a meia-vida plasmática por meio de análise farmacocinética não compartimental. Resultados: Os valores farmacocinéticos analisados no primeiro e quarto dias de tratamento não mostram qualquer diferença de concentração entre amostras colhidas antes da membrana e após a membrana, e o comportamento farmacocinético foi similar na vigência de diferentes falências de órgãos. A área sob a curva antes da membrana no dia 1 foi de 62,1 (IC95% 52,8 - 73,4) e a área sob a curva após a membrana nesse mesmo dia foi de 63,4 (IC95% 52,4 - 76,7), com p = 0,625. A área sob a curva antes da membrana no dia 4 foi de 102,4 (IC95% 84,7 - 142,8), enquanto a área sob a curva após a membrana nesse mesmo dia foi de 100,9 (IC95% 78,2 - 138,8), com p = 0,843. Conclusão: Os parâmetros farmacocinéticos da micafungina não foram alterados significantemente.

ABSTRACT Objective: To determine micafungin plasma levels and pharmacokinetic behavior in patients treated with extracorporeal membrane oxygenation. Methods: The samples were taken through an access point before and after the membrane in two tertiary hospitals in Spain. The times for the calculation of pharmacokinetic curves were before the administration of the drug and 1, 3, 5, 8, 18 and 24 hours after the beginning of the infusion on days one and four. The area under the curve, drug clearance, volume of distribution and plasma half-life time with a noncompartmental pharmacokinetic data analysis were calculated. Results: The pharmacokinetics of the values analyzed on the first and fourth day of treatment did not show any concentration difference between the samples taken before the membrane (Cin) and those taken after the membrane (Cout), and the pharmacokinetic behavior was similar with different organ failures. The area under the curve (AUC) before the membrane on day 1 was 62.1 (95%CI 52.8 - 73.4) and the AUC after the membrane on this day was 63.4 (95%CI 52.4 - 76.7), p = 0.625. The AUC before the membrane on day 4 was 102.4 (95%CI 84.7 - 142.8) and the AUC was 100.9 (95%CI 78.2 - 138.8), p = 0.843. Conclusion: The pharmacokinetic parameters of micafungin were not significantly altered.

Informe diário de evidências: COVID-19 busca realizada em 22 de abril de 2020 / Daily evidence report: COVID-19 search conducted on April 22, 2020

O objetivo da revisão sistemática foi investigar a eficácia e a segurança de tratamentos com antivirais para COVID-19, SARS e MERS. Ao todo, 22 estudos foram incluídos: 1 ensaio clínico, 16 séries de casos e 5 relatos de caso. Os antivirais mais utilizados foram lopinavir / ritonavir, oseltamivir, ribavirina e arbidol. Todos os estudos usaram outras terapias, como antibióticos, imunoglobulina, interferon, glicocorticoides, metilprednisolona e medicamentos antiparasitários e antifúngicos, além da terapia antiviral para pacientes com COVID-19. No único ECR incluído, os pacientes que receberam lopinavir / ritonavir tiveram um processo de recuperação semelhante aos pacientes que receberam tratamento padrão. Os desfechos de mortalidade em 28 dias e carga viral de RNA não foram significativamente diferentes entre os dois grupos. Dentre os achados dos demais estudos, vale destacar que estudos de séries e relatos de casos não avaliam a eficácia de medicamentos, e que em geral as amostras foram pequenas. O estudo de Guan, com 1099 pacientes, chegou a conclusão que oseltamivir foi ineficaz na diminuição da taxa de admissão na UTI, na necessidade de ventilação e na taxa de mortalidade entre os pacientes. O estudo de Shang, com 416 pacientes, indicou que medicamentos antivirais não têm efeito na taxa de mortalidade de pacientes com COVID-19. O estudo de Li, com cinco crianças com COVID-19, indicou que os agentes antivirais não alteraram o resultado ou a duração da internação. A revisão cita outros estudos que foram publicados com os pacientes ainda sob tratamento, sem o desfecho final dessas populações. Quanto a busca por ensaios clínicos para SARS e MERS, foram encontrados protocolos, mas nenhum resultado publicado.

In vitro antifungal activity and phytochemical characterization of Eugenia uniflora, Libidibia ferrea and Psidium guajava

The aim of this study was evaluate the in vitro antifungal activity of crude extracts from Eugenia uniflora, Libidibia ferrea and Psidium guajava. The extracts were obtained by turbo-extraction using water (AQ) or acetone-water (AC-W) (7:3, v/v) as solvents and lyophilized to obtain the crude extracts (CE). The CE were characterized by UV-Vis, TLC and HPLC. The activity of CEs was investigated against clinical isolates of Candida spp. and the Minimum Inhibitory Concentration (MIC), MIC50 and MIC90 were determinated. The analysis by TLC showed that all CEs presented polyphenols (flavonoids and tannins). The CEs from E. uniflora showed higher amount of polyphenols (30.35 ± 2.15%, AC-W) and the HPLC analysis revealed the tannins in all extracts. The CEs of E. uniflora showed MIC range from 1.9 to 500.0 µg/mL, and lower values of MIC50 and MIC90 against non-albicans Candida isolates. Regarding L. ferrea and P. guajava, the results showing MIC from 3.9 to 1000.0 µg/mL (CE-AQ) against C. albicans. The results demonstrate antifungal performance from CE against various species of Candida spp., suggesting that the herbal species may be use as new potential antifungal agents. Additionally, the polyphenol content can play a pivotal role in the antifungal properties of CE.

Minimum concentration of Amphotericin B in serum according to the formulation, dose, and daily or prolonged intermittent therapeutic regimen

Abstract INTRODUCTION: The therapeutic efficacy of daily amphotericin B infusion is related to its maximum concentration in blood; however, trough levels may be useful in intermittent regimens of this antifungal drug. METHODS : High performance liquid chromatography (HPLC) was used to determine the minimum concentration (Cmin) of amphotericin B in the serum of patients receiving deoxycholate (D-Amph) or liposomal amphotericin B (L-AmB) for the treatment of cryptococcal meningitis (n=28), histoplasmosis (n=8), paracoccidioidomycosis (n=1), and leishmaniasis (n=1). RESULTS: Daily use of D-Amph 30 to 50 mg or L-AmB 50 mg resulted in a similar Cmin, but a significant increase ocurred with L-AmB 100 mg/day. The geometric mean Cmin tended to decrease with a reduction in the dose and frequency of intermittent L-AmB infusions: 357 ng/mL (100 mg 4 to 5 times/week) > 263 ng/mL (50 mg 4 to 5 times/week) > 227 ng/mL (50 mg 1 to 3 times/week). The impact on Cmin was variable in patients whose dose or therapeutic scheme was changed, especially when administered the intermittent infusion of amphotericin B. The mean Cmin for each L-AmB schedule of intermittent therapy was equal or higher than the minimum inhibitory concentration of amphotericin B against Cryptococcus isolates from 10/12 patients. The Cmin of amphotericin B in patients with cryptococcal meningitis was comparable between those that survived or died. CONCLUSIONS: By evaluating the Cmin of amphotericin B, we demonstrated the therapeutic potential of its intermittent use including in the consolidation phase of neurocryptococcosis treatment, despite the great variability in serum levels among patients.

Human fusariosis: An emerging infection that is difficult to treat

Abstract Fusarium spp. has been associated with a broad spectrum of emerging infections collectively termed fusariosis. This review includes articles published between 2005 and 2018 that describe the characteristics, clinical management, incidence, and emergence of these fungal infections. Fusarium solani and F. oxysporum are globally distributed and represent the most common complexes. Few therapeutic options exist due to intrinsic resistance, especially for the treatment of invasive fusariosis. Therefore, the use of drug combinations could be an important alternative for systemic antifungal resistance. Increase in the number of case reports on invasive fusariosis between 2005 and 2018 is evidence of the emergence of this fungal infection.

Prescripción inapropiada de antifúngicos y la necesidad de programas para su uso racional / Inappropriate antifungal prescription and the need for antifungal stewardship programs

Resumen La enfermedad fúngica invasora (EFI) es una entidad que afecta pacientes inmunocomprometidos y críticamente enfermos. En los últimos años, el número de pacientes con riesgo de presentarla viene en aumento, con el consecuente incremento de la formulación de antifúngicos de manera profiláctica, anticipada o empírica. Algunos estudios que evaluaron el uso adecuado de antifúngicos han mostrado que hasta 72% de las formulaciones pueden ser inapropiadas, exponiendo a los pacientes al riesgo de efectos adversos e interacciones medicamentosas, con mayores costos de la atención. Se han recomendado diferentes intervenciones para el control y el uso racional de antimicrobianos, conocidas como "antimicrobial stewardship", las que se pueden aplicar al uso de antifúngicos denominándose "antifungal stewardship"". Se presenta una revisión de la literatura médica sobre el uso apropiado de antifúngicos y el impacto de la implementación de programas de optimización del uso de estos medicamentos en algunos centros.

Invasive fungal disease (IFD) is a condition affecting immunosuppressed and critically ill patients. Recently there has been an increase in the amount of patients at risk for IFD, which implies an increase in the prescription of antifungal agents as prophylactic, pre-emptive or empiric therapy. Some studies evaluating appropriateness of antifungal prescription have shown that inappropriate formulations reach 72%, exposing patients to side effects, pharmacological interactions and rising costs. Some groups have recommended many interventions to control and make a rational use of antimicrobials, into strategies known as "antimicrobial stewardship", these interventions are useful also for antifungal agents and it has been named "antifungal stewardship". Here we present a narrative review of the scientific literature showing published articles about appropriate use of antifungal agents and the experience of some centers after implementing antifungal stewardship programs.

Neurohistoplasmosis y leishmaniasis cutánea en paciente inmunocompetente / Neurohistoplasmosis and cutaneous leishmaniasis in an immunocompetent patient

La histoplasmosis y la leishmaniasis son enfermedades olvidadas, endémicas en Argentina, y generalmente se asocian a inmunocompromiso. Presentamos el caso de un varón de 16 años, inmunocompetente, con histoplasmosis del sistema nervioso central y leishmaniasis cutánea. Inicialmente, el paciente presentó una lesión en la pierna de un mes de evolución seguida de paraparesia leve, diagnosticada como un proceso de desmielinización mediante estudios de imágenes. El cuadro fue tratado con altas dosis de corticoides y en 72 horas evolucionó a paraparesia grave con lesiones nodulares en las vértebras cervicales, observadas en las imágenes de resonancia magnética nuclear. Se aisló Histoplasma capsulatum de líquido cefalorraquídeo, genotípicamente identificado como perteneciente a la especie filogenética LamB. El paciente recibió tratamiento intravenoso con anfotericina B deoxicolato durante 30 días y posteriormente fluconazol e itraconazol oral durante un año. A los tres meses de iniciado el tratamiento con antifúngicos se reactivó la lesión de la pierna y en el examen directo se observaron amastigotes de Leishmania. La leishmaniasis cutánea fue tratada con antimoniato de meglumina intramuscular. La respuesta clínica al tratamiento de ambas enfermedades fue favorable.

Histoplasmosis and leishmaniasis are neglected and endemic diseases in Argentina, and generally are found associated with immunosuppression. We report the case of an immunocompetent 16-years-old man with simultaneous occurrence of central nervous system histoplasmosis and cutaneous leishmaniasis. Upon admission, the patient showed a one-month old skin lesion in a leg and mild paraparesis. Imaging studies detected thickening and edema in the spinal cord and the cerebrospinal fluid analysis was within normal range. The case was diagnosed as a demyelinating disorder and treated with high-dose short-term steroids. Seventy-two hours later the patient showed severe paraparesis and nuclear magnetic resonance imaging revealed nodular lesions in the spinal cord. Histoplasma capsulatum belonging to the phylogenetic species LamB was isolated from cerebrospinal fluid samples. The patient received intravenous antifungal therapy with amphotericin B for 30 days, followed by oral fluconazole and itraconazole for one year. Three months after initiation of antifungal treatment, the cutaneous lesion recrudesced and Leishmania amastigotes were observed on microscopic examination. The cutaneous leishmaniasis was treated with intramuscular meglumine antimoniate. The patient´s outcome was favorable after treatment for both diseases.

Fusarium solani keratitis: role of antifungal susceptibility testing and identification to the species level for proper management

ABSTRACT We report a patient with fungal keratitis caused by a multiresistant Fusarium solani in a tertiary care hospital located in southern Brazil. A 55-year-old man with a history of ocular trauma presented with keratitis in left eye. The patient has a complicated clinical course and failed to respond to local and systemic antifungal treatment, and required eye enucleation. Despite multiple topical, intraocular and systemic antifungal treatments, hyphal infiltration persisted in the corneal transplant causing continuous recurrences. The cultures of corneal biopsy scrapings were positive for Fusarium spp. The organism was identified to species level by multi-locus sequencing for translation elongation factor 1 alpha (EF-1α), and RNA polymerase II subunit (RPB2). In vitro antifungal susceptibility testing of the isolate by the broth microdilution method, according to CLSI M38-A2, disclosed susceptibility to natamycin and resistance to amphotericin B, voriconazole, itraconazole and fluconazole. Considering previous unsuccessful antifungal treatments due to multiple drug resistance, the eye was enucleated. Our case report illustrates that management of fungal keratitis remains a therapeutic challenge. Optimal treatment for F. solani infection has not yet been established and should include susceptibility testing for different antifungal agents.

Primer reporte de caso autóctono de tinea nigra en Chile / First autochthonous case report of tinea nigra in Chile

Resumen La tinea nigra es una infrecuente micosis superficial causada por el hongo dematiáceo Hortaea werneckii. Se presenta habitualmente en zonas costeras tropicales, siendo muy escasos los reportes en países sudamericanos con climas más templados. Habitualmente corresponde a infecciones importadas por viajeros. Se presenta el caso de una paciente adulta chilena, sin historia previa de viajes recientes, cursando con cuadro clínico y microbiológico compatible con tinea nigra palmar, tratado con itraconazol oral y sertaconazol tópico con respuesta favorable. Esta paciente corresponde al primer caso reportado en Chile de origen autóctono.

Abstract Tinea nigra is an infrequent superficial mycosis caused by the dematiaceous fungus Hortaea werneckii. It usually occurs in tropical coastal areas, with very few reports in South American countries with temperate climates, generally corresponding to infections imported by travelers. We present the case of a Chilean adult patient, with no previous history of recent trips, with clinical and microbiological background consistent with palmar tinea nigra, treated with oral itraconazole and topical sertaconazole with a favorable response. This article is the first case reported in Chile, of autochthonous origin.

Criptococosis cerebral, voriconazol, niveles plasmáticos y síndrome de reconstitución inmune: reporte de un caso / Cerebral cryptococcosis and immune reconstitution inflammatory syndrome: case report

We report a 45-year-old male with AIDS who had a Cryptococcus neoformans central nervous system infection. He was treated with amphotericin B deoxycholate subsequently changed to voriconazole due to systemic toxicity of the former. Plasma levels of voriconazole were insufficient with a standard dose (0.7 μg/mL), therefore, the dose was increased thereafter to reach appropriate levels (4.5 μg/mL). Anti-retroviral therapy was started five weeks after voriconazole initiation with non-interacting drugs and he was discharged after a favorable evolution. He was re-admitted three months later due to seizures; a brain magnetic resonance showed new sub-cortical nodules. After excluding alternative causes and demonstrating fungal eradication, an immune reconstitution inflammatory syndrome (IRIS) event was suspected and treated with a short course of steroids. His evolution was satisfactory.

Aspergillosis pulmonar / Pulmonary aspergillosis

RESUMEN Se presenta a una paciente de 50 años de edad, atendida durante 2 años por Consulta de Neumología, en la ciudad de Matanzas. Presentaba bronquitis crónica con tratamiento para la misma, hace 3 meses ingresa por Servicio de Medicina Interna por una neumonía de lenta resolución, asociada un síndrome general. Durante el ingreso se manejan varias posibilidades diagnósticas como: posible tuberculosis pulmonar, neoplasia de pulmón o neumonía a gérmenes atípicos. Se confirmó diagnóstico de aspergilosis pulmonar mediante lavado bronquial por broncoscopio. Se aplicó tratamiento con antifúngicos sistémicos y se logró mejoría clínica y radiológica. En esta paciente no existían evidencias de inmunosupresión (AU).

ABSTRACT We present a female patient aged 50 years, attended for two years in the Pulmonology consultation, in the city of Matanzas. She suffered chronic bronchitis with treatment; three months ago she was admitted in the Internal Medicine Service due to a low resolution pneumonia associated to a general syndrome. During her staying in the hospital several diagnostic possibilities were managed: possible pulmonary tuberculosis, lung neoplasia or pneumonia to atypical germs. The diagnosis of pulmonary aspergillosis was confirmed through bronchial lavage `per bronchoscope. no existían evidencias de inmunosupresión. The pronosis is Lung Aspergilosis due to a bronchial washing for bronchoscopy and the treatment begins with systemic antifúngicos, achieving clinical and radiological improvement. There is no evidence of inmunosupression in the patient (AU).

Comparison of the recovery rate of otomycosis using betadine and clotrimazole topical treatment / Comparação da taxa de recuperação de otomicose com o uso de tratamento tópico com betadina e clotrimazol

Abstract Introduction Otomycosis is a common diseases that can be associated with many complications including involvement of the inner ear and mortality in rare cases. Management of otomycosis can be challenging, and requires a close follow-up. Treatment options for otomycosis include local debridement, local and systemic antifungal agents and utilization of topical antiseptics. Objective This study was designed to compare the recovery rate of otomycosis using two therapeutic methods; topical betadine (Povidone-iodine) and clotrimazole. Methods In this single-blind clinical trial, 204 patients with otomycosis were selected using a non-probability convenient sampling method and were randomly assigned to two treatment groups of topical betadine and clotrimazole (102 patients in each group). Response to treatment was assessed at 4, 10 and 20 days after treatment. Data were analyzed using the independent t-test, Chi-Square and Fisher exact test in SPSS v.18 software, at a significance level of p < 0.05. Results The results showed that out of 204 patients with otomycosis, fungi type isolated included Aspergillus in 151 cases (74%), and Candida albicans in 53 patients (26%). On the fourth day after treatment, 13 patients (13.1%) in the group treated with betadine and 10 patients (9.8%) in the group treated with clotrimazole showed a good clinical response to treatment (p = 0.75). A good response to treatment was reported for 44 (43.1%) and 47 patients (46.1%) on the tenth day after the treatment (p = 0.85); and 70 (68.6%) and 68 patients (67.6%) on the twentieth day after treatment (p = 0.46) in the groups treated with betadine and clotrimazole, respectively. The response to treatment was thus not significantly different in the two groups. Conclusion In the present study the efficacy of betadine and clotrimazole was the same for the treatment of otomycosis. The result of this study supports the use of betadine as an effective antifungal in otomycosis treatment, helping to avoid the emergence of resistant organisms.

Resumo Introdução A otomicose é uma das doenças comuns associadas a muitas complicações, como envolvimento da orelha interna e mortalidade em casos raros. O tratamento da otomicose pode ser realmente desafiador e requer um acompanhamento rigoroso. As opções de tratamento para otomicose podem incluir desbridamento local, agentes antifúngicos locais e sistêmicos e uso de antissépticos tópicos, os medicamentos tópicos recomendados para o tratamento da otomicose. Objetivo Comparar a taxa de recuperação de otomicose utilizando dois métodos terapêuticos de betadina tópica (povidona-iodo) e clotrimazol. Método Neste ensaio clínico simples cego, 204 pacientes com otomicose foram selecionados utilizando-se método de amostragem de não probabilidade conveniente e randomizados para dois grupos de tratamento, com betadina tópica e com clotrimazol (102 pacientes em cada grupo). A resposta ao tratamento foi avaliada aos 4, 10 e 20 dias após o tratamento. Os dados foram analisados utilizando o teste t independente, qui-quadrado e teste de Fisher no software SPSS v.18, com nível de significância de p < 0,05. Resultados Os resultados mostraram que dos 204 pacientes com otomicose, os tipos de fungos isolados incluíram Aspergillus em 151 casos (74%) e Candida albicans em 53 pacientes (26%). No quarto dia após o tratamento, 13 pacientes (13,1%) no grupo tratado com betadina e 10 pacientes (9,8%) no grupo tratado com clotrimazol apresentaram boa resposta ao tratamento (p = 0,75). Uma boa resposta ao tratamento foi relatada para 44 (43,1%) e 47 pacientes (46,1%) no décimo dia após o tratamento (p = 0,85); e 70 (68,6%) e 68 pacientes (67,6%) no vigésimo dia após o tratamento (p = 0,46) no grupo tratado com betadina e clotrimazol, respectivamente. Assim, a resposta ao tratamento não foi significativamente diferente nos dois grupos. Conclusão No presente estudo, a eficácia da betadina e do clotrimazol foi a mesma no tratamento da otomicose. O resultado deste estudo apoia o uso de betadina como um antifúngico eficaz no tratamento da otomicose que pode ajudar a evitar o surgimento de organismos resistentes.

Uso de posaconazol en niños: experiencia en un hospital pediátrico de alta complejidad / Use of posaconazole in children: Experience in a tertiary pediatric hospital

La información sobre el uso de posaconazol en niños es escasa. Se realizó este estudio descriptivo retrospectivo entre agosto de 2010 y marzo de 2017 para evaluar las características clínicas, microbiológicas y la evolución de los pacientes tratados con posaconazol. Se incluyeron 16 niños. Mediana de edad: 161 meses (rango intercuartílico -RIC- 69-173 m). Todos tenían enfermedad subyacente y presentaban infección fúngica invasiva probada. Los aislamientos más frecuentes fueron Mucor spp. y Aspergillus spp. La dosis media de posaconazol fue 600 mg/día (400-800 mg/día) y la mediana de duración del tratamiento, 223 días (RIC 48-632). Diez pacientes presentaron efectos adversos, pero solo uno requirió suspensión del antifúngico debido a alteraciones hidroelectrolíticas.

There is limited information on the use of posaconazole in children. This retrospective and descriptive study was conducted to evaluate the clinical, microbiological characteristics and evolution of patients treated with posaconazole between August 2010 and March 2017. We included 16 children. Median age: 161 months (interquartile range -IQR-69-173m). All had underlying disease and a proven invasive fungal infection. The most frequent isolated were Mucor spp. and Aspergillus spp. The mean posaconazole dose was 600 mg /day (400-800 mg/day) and the median duration of treatment was 223 days (IQR 48-632). Ten patients had adverse effects, but only one required suspension of the antifungal treatment due to hydroelectrolytic disorders.

Combination of topical agents and oxybutynin as a therapeutic modality for patients with both osmidrosis and hyperhidrosis / Uso combinado de agentes tópicos e oxibutinina para tratamento de pacientes com osmidrose e hiper-hidrose

Summary Introduction: The association of osmidrosis and hyperhidrosis often causes emotional and social problems that may impair the patients' quality of life. The purpose of our study was to analyze the therapeutic results of oxybutynin and topical agents in 89 patients with both osmidrosis and hyperhidrosis. Method: We conducted an observational study at two specialized centers of hyperhidrosis between April 2007 and August 2013. Eighty-nine (89) patients with both osmidrosis and hyperhidrosis were treated with oxybutynin and topical agents. Patients were evaluated before treatment and at 3 and 6 weeks after treatment started, by using the Quality of Life Questionnaire and the Sweating Evolution Scale. Results: Before treatment, 98% of the patients presented with poor or very poor quality of life. After six weeks of treatment, 70% stated their quality of life as being slightly better or much better (p<0.001) and nearly 70% of the patients experienced a moderate or great improvement in sweating and malodor. Improvement in osmidrosis was significantly greater when the axillary region was the first most disturbing site of hyperhidrosis. Conclusion: There was a significant improvement in quality of life and a reduction in sweating and malodor after six weeks of treatment with topical agents and oxybutynin in patients with both hyperhidrosis and osmidrosis. Therefore, clinical treatment should be considered before invasive techniques.

Resumo Introdução: A associação entre osmidrose e hiper-hidrose com frequência causa problemas emocionais e sociais que podem deteriorar a qualidade de vida dos pacientes. O objetivo deste estudo foi analisar os resultados terapêuticos do uso de oxibutinina associada a agentes tópicos em 89 pacientes com osmidrose e hiper-hidrose. Método: Nós conduzimos um estudo observacional em dois centros especializados em hiper-hidrose entre abril de 2007 e agosto de 2013. Oitenta e nove (89) pacientes com osmidrose associada a hiper-hidrose foram tratados com oxibutinina e agentes tópicos. Os pacientes foram avaliados antes do tratamento e após 3 e 6 semanas do início do tratamento, por meio do Questionário de Qualidade de Vida e da Escala de Evolução da Sudorese. Resultados: Antes do tratamento, 98% dos pacientes apresentavam qualidade de vida ruim ou muito ruim. Após seis semanas de tratamento, 70% classificou sua qualidade de vida como sendo pouco ou muito melhor (p<0.001) e aproximadamente 70% dos pacientes relataram melhora moderada ou grande de sudorese e odor. Houve melhora significativamente maior da osmidrose quando a região axilar era o sítio em que a hiper-hidrose mais incomodava. Conclusão: Houve melhora significativa da qualidade de vida e uma redução da sudorese e do odor após seis semanas de tratamento com agentes tópicos e oxibutinina em pacientes com hiper-hidrose associada a osmidrose. Dessa maneira, a terapia clínica deve ser considerada antes de técnicas invasivas.

Fluconazole levels in serum and cerebrospinal fluid according to daily dosage in patients with cryptococcosis and other fungal infections

ABSTRACT Fluconazole is extensively used for the treatment of candidiasis and cryptococcosis. Among other factors, successful treatment is related to appropriate fluconazole levels in blood and cerebrospinal fluid. In the present study, fluconazole levels were determined in 15 patients, 14 of whom had AIDS and 13 had neurocryptococcosis. The only selection criterion was treatment with fluconazole, which was performed with a generic or similar form of the drug. Fluconazole level was determined by high performance liquid chromatography and the susceptibility profile of Cryptococcus spp. isolated from the patients was assessed by broth microdilution. Blood and cerebrospinal fluid fluconazole levels were found to be related to the fluconazole daily dose, and exceeded the minimum inhibitory concentration of this antifungal for the Cryptococcus spp. isolates. A good correlation was observed between serum and cerebrospinal fluid drug concentration. In conclusion, treatment with non-original fluconazole under usual medical practice conditions results in appropriate blood and cerebrospinal fluid levels of the drug for inhibiting Cryptococcus spp. susceptible to this antifungal drug. The relatively common failures of neurocryptococcosis treatment appear not to be due to insufficient fluconazole levels in the cerebrospinal fluid, especially with the use of daily doses of 400-800 mg.

Farmacocinética de posaconazol en la profilaxis y tratamiento de la infección fúngica invasora en niños inmunocomprometidos en un hospital pediátrico / Pharmacokinetics of posaconazol in the prophylaxis and treatment of invasive fungal infection in immunocompromised children in a pediatric hospital

Resumen Introducción En pediatría no existe consenso en la dosificación de posaconazol (PSC) para profilaxis y tratamiento de la infección fúngica invasora (IFI), usándose la medición de concentraciones plasmáticas (CPs) del fármaco. Objetivo Describir la experiencia de monitoreo de las CPs de PSC en niños inmunocomprometidos con IFI y determinar si las dosis recomendadas alcanzan CPs efectivas en profilaxis (≥ 0,7 µg/mL) y tratamiento (≥ 1,25 µg/mL). Método Análisis retrospectivo en niños que recibieron PSC suspensión como profilaxis o tratamiento entre enero de 2012 y octubre de 2016, en las unidades de Oncología y Trasplante de Médula Ósea del Hospital Calvo Mackenna. Resultados 78 CPs en seis pacientes (4 indicaciones de profilaxis y 4 tratamientos) fueron revisados. La mediana de dosis de PSC fue de 12,5 y 18,8 mg/kg/d para profilaxis y tratamiento, respectivamente, resultando CP mediana de 0,97 y 1,8 μg/mL, respectivamente. En profilaxis, se registraron 40/67 (60%) con CP ≥ 0,70 μg/mL recibiendo una mediana de dosis de 12,5 mg/kg/d. Mientras que para el tratamiento: 5/11 (46%), presentaron CP ≥ 1,25 μg/mL, recibiendo una mediana de dosis de 18 mg/kg/d. Conclusión Nuestros resultados se ajustan a lo recomendado para la dosificación de PSC, pero evidencian una necesidad de realizar una monitorización individualizada para mantener adecuadas CPs.

Background There is no consensus on the optimal dosage use of posaconazole (PSC) for invasive fungal infection (IFI) in pediatric patients and normally it is adjusted with drug levels (DLs) ≥ 0.7 μg/ml and ≥ 1.25 μg/ml for prophylaxis and treatment, respectively. Objective To describe the experience of monitoring DLs of PSC in immunocompromised pediatric patients with IFI and to determine if the recommended doses reach CP effective in prophylaxis (≥ 0.7 μg/mL) and treatment (≥ 1.25 μg/mL). Method A retrospective analysis in children who received PSC from January 2012 to October 2016, in the Oncology and Bone Marrow Transplant units at Hospital Calvo Mackenna was done Six patients with 78 DLs were reviewed (4 prophylaxis and 4 treatment). Median PSC dose was 12.5 and 18.8 mg/kg/d for prophylaxis and treatment, resulting in mean DLs of 0.97 and 1.8 μg/mL respectively. In prophylaxis 40/67 (60%) were recorded with DLs ≥ 0.70 μg/mL receiving a median dose of 12.5 mg/kg/d. While for treatment: 5/11 (46%) presented DLs ≥ 1.25 μg/mL, receiving a median dose of 18 mg/kg/d. Conclusion Our results are in line with the recommended for PSC dosage, but individualized monitoring is required to maintain adequate DLs.

Monitorización terapéutica de antimicrobianos en pediatría: revisión de la experiencia latinoamericana / Therapeutic monitoring of antimicrobial agents in pediatrics: review based on Latin American experiences

Resumen La presente revisión resume la evidencia sobre la monitorización terapéutica de tres antimicrobianos basada en datos regionales: vancomicina, amikacina y voriconazol en la población pediátrica. Estos datos coinciden con la literatura internacional en relación al requerimiento de dosis mayores que 40 mg/kg/día de vancomicina, la posibilidad de usar monodosis diarias de amikacina y el requerimiento de dosis mayores de voriconazol en relación a las iniciales recomendadas de 8 mg/kg/día. Contar con datos locales sobre el comportamiento farmacocinético/farmacodinámico de diversos antimicrobianos en la pediatría es de gran valor para adecuar la dosificación de los mismos en nuestra población. Se deberían incrementar los estudios de monitorización terapéutica en el uso de antimicrobianos en pediatría que permitan generar pautas de tratamiento adecuadas para este grupo etario.

This review summarizes recommendations of therapeutic monitoring of three antimicrobials based in regional data: vancomycin, amikacin and voriconazole in pediatric population. Regional evidence agrees with international literature regarding the requirement of higher daily doses than 40 mg/kg/day of vancomycin, as well as with the possibility of use one daily doses of amikacin and to recommend higher doses of voriconazole compared to the initially recommended doses of 8 mg/kg/day. Local data on the pharmacokinetic/pharmacodynamic behavior of various antimicrobials in pediatrics are of great value for dosing adjustment in our pediatric population. More studies in therapeutic monitoring in the use of antimicrobials in pediatrics should be performed in order to allow the generation of adequate treatment guidelines for this age group.