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1.
BMJ Case Rep ; 14(8)2021 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-34446514

RESUMO

A 48-year-old male patient living with HIV presented to our hospital with fever and weight loss. On evaluation, he was found to have pancytopenia, deranged liver and kidney function. CD4 count was 13 cells/uL. Bone marrow examination done because of pancytopenia showed yeast forms of histoplasmosis. Although liposomal amphotericin B is preferred for induction, he was treated with deoxycholate amphotericin B despite poor kidney function because of financial constraints. He was treated for 12 days with intravenous amphotericin, during which his clinical condition significantly improved. He was discharged on oral itraconazole.


Assuntos
Anfotericina B , Histoplasmose , Anfotericina B/uso terapêutico , Antifúngicos/uso terapêutico , Ácido Desoxicólico , Histoplasmose/complicações , Histoplasmose/diagnóstico , Histoplasmose/tratamento farmacológico , Humanos , Rim , Masculino , Pessoa de Meia-Idade
4.
ACS Infect Dis ; 7(8): 2472-2482, 2021 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-34282886

RESUMO

Chemotherapy against the neglected tropical disease visceral leishmaniasis (VL) is suboptimal with only four licensed drugs. Amphotericin B (AmB), despite its toxicity, remained a second line drug for a long time. However, the demonstration that liposomal AmB is highly effective against VL propelled it, despite its cost, to a first line drug in many countries. While several ongoing efforts are aiming at finding cheaper and stable AmB-formulations, an alternative strategy is the development of less-toxic AmB derivatives. We show here that two less-toxic AmB derivatives with the carboxylate at position 16 of AmB derivatized to a methyl urea (AmB-MU) or amino urea (AmB-AU) are active in vitro against Leishmania donovani, both as free-living parasites as well as their intracellular form. Both less-toxic derivatives, similarly to AmB, target the ergosterol pathway of L. donovani. While the AmB-AU derivative showed female-specific liver toxicity in vivo, the AmB-MU derivative was well-tolerated and more effective than AmB against experimental VL. These studies are an important step for improving AmB-based therapy against a prevalent parasitic disease.


Assuntos
Antiprotozoários , Leishmania donovani , Leishmaniose Visceral , Anfotericina B/farmacologia , Anfotericina B/uso terapêutico , Antiprotozoários/farmacologia , Composição de Medicamentos , Feminino , Humanos , Leishmaniose Visceral/tratamento farmacológico
5.
J Infect Chemother ; 27(10): 1471-1476, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34183236

RESUMO

INTRODUCTION: Liposomal amphotericin B (L-AMB), a broad spectrum anti-fungicidal drug, is often administered to treat invasive fungal infections (IFIs). However, the most suitable time to initiate treatment in septic shock patients with IFI is unknown. METHODS: Patients with septic shock treated with L-AMB were identified from the Japanese Diagnosis Procedure Combination national database and were stratified according to L-AMB treatment initiation either at septic shock onset (early L-AMB group) or after the onset (delayed L-AMB group) to determine their survival rates following septic shock onset and the shock cessation period. RESULTS: We identified 141 patients administered L-AMB on the day of or after septic shock onset: 60 patients received early treatment, whereas 81 patients received delayed treatment. Survival rates after septic shock onset were higher in the early L-AMB group than in the delayed L-AMB group (4 weeks: 68.4% vs 57.9%, P = 0.197; 6 weeks: 62.2% vs 44.5%, P = 0.061; 12 weeks: 43.4% vs 35.0%, P = 0.168, respectively). The septic shock cessation period was shorter in the early L-AMB group than in the delayed L-AMB group (7.0 ± 7.0 days vs 16.5 ± 15.4 days, P < 0.001), with a significant difference confirmed after adjusting for confounding factors with propensity score matching (7.1 ± 7.2 days vs 16.7 ± 14.0 days, P = 0.001). CONCLUSION: Early L-AMB administration at septic shock onset may be associated with early shock cessation.


Assuntos
Choque Séptico , Anfotericina B/uso terapêutico , Antifúngicos/uso terapêutico , Humanos , Choque Séptico/tratamento farmacológico
6.
N Z Med J ; 134(1536): 41-51, 2021 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-34140712

RESUMO

BACKGROUND: Azole resistance in Aspergillus fumigatus (A. fumigatus) is increasing globally. A pan-azole-resistant isolate prompted genetic analysis of local azole-resistant isolates to determine resistance genotypes. METHODS: All A. fumigatus complex isolates were tested by the broth colorimetric micro-dilution method, Sensititre® YeastOne® (SYO) (TREK Diagnostic Systems, West Sussex, England). Epidemiological cutoff values derived from the Clinical & Laboratory Standards Institute method were used to determine the proportion of non-wild-type (non-WT) isolates (ie, those with an increased likelihood to harbour acquired mechanisms of resistance). Non-WT isolates were identified by ß-tubulin gene sequencing and the genotype for azole resistance was determined. The history of the patient with the first pan-resistant isolate was reviewed along with the treatment history of patients with azole-resistant strains. RESULTS: From January 2001 to August 2020, antifungal susceptibility testing was performed on 260 A. fumigatus complex isolates: six isolates were non-WT for one or more azole agent, two A. fumigatus sensu stricto and four other members within the species complex: two A. fischeri and two A. lentulus. There were three non-WT isolates for amphotericin B, three for itraconazole, five for posaconazole and five for voriconazole. All six non-WT strains were isolated in the past nine years (P<0.01), and four in the past three years. Azole-resistance genotyping for the A. fumigatus sensu stricto isolates detected amino acid changes at hot spots in the cyp51A gene: one at G54E and one at G138C. All six isolates were WT for caspofungin. Five of the six patients with azole-resistant strains had previous azole treatment, and the patient with the pan-azole-resistant strain had been on continuous azole treatment for 42 months preceding strain isolation. CONCLUSIONS: New Zealand can be added to the growing list of countries with azole-resistant A. fumigatus complex isolates, including pan-azole resistance in A. fumigatus sensu stricto. While uncommon and mostly found in cryptic species within the complex, azole resistance is increasing. The results provide a baseline for monitoring this emerging antifungal resistance trend in A. fumigatus in New Zealand.


Assuntos
Antifúngicos/farmacologia , Aspergilose/microbiologia , Aspergillus fumigatus/efeitos dos fármacos , Azóis/farmacologia , Farmacorresistência Fúngica , Anfotericina B/farmacologia , Anfotericina B/uso terapêutico , Antifúngicos/uso terapêutico , Aspergilose/tratamento farmacológico , Aspergilose/patologia , Aspergillus fumigatus/genética , Azóis/uso terapêutico , Humanos , Pulmão/patologia , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Nova Zelândia , Estudos Retrospectivos
7.
PLoS Negl Trop Dis ; 15(5): e0009318, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33956817

RESUMO

The Republic of Congo (RoC) is one of the African countries with the most histoplasmosis cases reported. This review summarizes the current status regarding epidemiology, diagnostic tools, and treatment of histoplasmosis in the RoC. A computerized search was performed from online databases Medline, PubMed, HINARI, and Google Scholar to collect literature on histoplasmosis in the RoC. We found 57 cases of histoplasmosis diagnosed between 1954 and 2019, corresponding to an incidence rate of 1-3 cases each year without significant impact of the AIDS epidemic in the country. Of the 57 cases, 54 (94.7%) were cases of Histoplasma capsulatum var. duboisii (Hcd) infection, African histoplasmosis. Three cases (5.3%) of Histoplasma capsulatum var. capsulatum infection were recorded, but all were acquired outside in the RoC. The patients' ages ranged between 13 months to 60 years. An equal number of cases were observed in adults in the third or fourth decades (n = 14; 24.6%) and in children aged ≤15 years. Skin lesions (46.3%), lymph nodes (37%), and bone lesions (26%) were the most frequent clinical presentations. Most diagnoses were based on histopathology and distinctive large yeast forms seen in tissue. Amphotericin B (AmB) was first line therapy in 65% of the cases and itraconazole (25%) for maintenance therapy. The occurrence of African histoplasmosis in apparently normal children raises the possibility that African histoplasmosis is linked to environmental fungal exposure.


Assuntos
Osso e Ossos/microbiologia , Histoplasma/isolamento & purificação , Histoplasmose/tratamento farmacológico , Histoplasmose/epidemiologia , Linfonodos/microbiologia , Pele/microbiologia , Adolescente , Adulto , Anfotericina B/uso terapêutico , Antifúngicos/uso terapêutico , Osso e Ossos/patologia , Criança , Pré-Escolar , Congo/epidemiologia , Exposição Ambiental/efeitos adversos , Feminino , Histoplasma/classificação , Histoplasma/efeitos dos fármacos , Histoplasmose/diagnóstico , Humanos , Lactente , Itraconazol/uso terapêutico , Linfonodos/patologia , Masculino , Pessoa de Meia-Idade , Pele/patologia , Adulto Jovem
8.
J Infect Chemother ; 27(9): 1319-1322, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33994091

RESUMO

PURPOSE: To determine the intraocular penetration of amphotericin B (AMPH-B) after an intravenously injection of liposomal amphotericin B (L-AMB) in inflamed human eyes. METHODS: Seven eyes of 5 patients with fungal eye diseases (endophthalmitis in 6 eyes and keratitis in 1 eye) were treated with intravenous injections of 100-250 mg/day of L-AMB. Samples of blood, corneal button, aqueous humor, and vitreous humor were collected and assessed for AMPH-B. RESULTS: The AMPH-B level in the cornea (604.0 µg/g) of the case with fungal keratitis exceeded the minimum inhibitory concentration. However, the levels in the aqueous and vitreous humors of the cases with fungal endophthalmitis were lower, e.g., 0.02 ± 0.01 µg/ml (0.09% of serum level) in the aqueous humor and 0.05 ± 0.08 µg/ml (0.17% of serum level) in the vitreous humor. CONCLUSIONS: The AMPH-B levels administered intravenously were very low in the aqueous and vitreous humors. Our findings indicate that intravenous L-AMB can be considered only for patients with mild endogenous fungal endophthalmitis, e.g., isolated chorioretinitis without vitreous extensions.


Assuntos
Anfotericina B , Endoftalmite , Anfotericina B/uso terapêutico , Antifúngicos/uso terapêutico , Endoftalmite/tratamento farmacológico , Humanos , Injeções Intravenosas
9.
Int J Biol Macromol ; 182: 1310-1321, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-34000308

RESUMO

Cutaneous leishmaniasis (CL) is a significant public health problem caused by different species of Leishmania parasites. Due to low skin permeability, the development of an effective system for delivery of Amphotericin B (AMB), the common effective drug for leishmaniasis treatment, is required to replace the unpleasant and problematic injections. To overcome this problem, a dissolvable microneedle (MN) patch was developed, using biodegradable polymers (a mixture of polyvinylpyrrolidone and carboxymethyl cellulose) for AMB's transdermal delivery. Scanning electron microscopy and fluorescent images showed successful fabrication of the MNs and homogeneous dispersion of the drug into the needles. MNs showed good mechanical properties with the ability to penetrate the rat skin and reach the lower layers. After insertion to the skin, the MNs were rapidly dissolved to release the encapsulated drug, and the resulted micropores in the skin were quickly resealed within 30 min. MN patches showed non-toxicity as exposed to HT-29 cell line. Flow cytometry results showed a potent in vitro leishmanicidal activity of AMB-loaded MN patches against the Leishmania parasites (up to 86% of the parasites' death). Taken together, MN patches might represent a new, efficient and clinically translational approach for transdermal AMB delivery to treat CL.


Assuntos
Anfotericina B/administração & dosagem , Anfotericina B/uso terapêutico , Carboximetilcelulose Sódica/química , Leishmaniose Cutânea/tratamento farmacológico , Agulhas , Povidona/química , Administração Cutânea , Anfotericina B/farmacologia , Animais , Morte Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células HT29 , Humanos , Masculino , Imagem Óptica , Ratos Sprague-Dawley , Pele/efeitos dos fármacos , Espectroscopia de Infravermelho com Transformada de Fourier , Adesivo Transdérmico
11.
ACS Appl Mater Interfaces ; 13(17): 19613-19624, 2021 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-33904311

RESUMO

Indwelling medical devices currently used to diagnose, monitor, and treat patients invariably suffer from two common clinical complications: broad-spectrum infections and device-induced thrombosis. Currently, infections are managed through antibiotic or antifungal treatment, but the emergence of antibiotic resistance, the formation of recalcitrant biofilms, and difficulty identifying culprit pathogens have made treatment increasingly challenging. Additionally, systemic anticoagulation has been used to manage device-induced thrombosis, but subsequent life-threatening bleeding events associated with all available therapies necessitates alternative solutions. In this study, a broad-spectrum antimicrobial, antithrombotic surface combining the incorporation of the nitric oxide (NO) donor S-nitroso-N-acetylpenicillamine (SNAP) with the immobilization of the antifungal Amphotericin B (AmB) on polydimethylsiloxane (PDMS) was developed in a two-step process. This novel strategy combines the key advantages of NO, a bactericidal agent and platelet inhibitor, with AmB, a potent antifungal agent. We demonstrated that SNAP-AmB surfaces significantly reduced the viability of adhered Staphylococcus aureus (99.0 ± 0.2%), Escherichia coli (89.7 ± 1.0%), and Candida albicans (93.5 ± 4.2%) compared to controls after 24 h of in vitro exposure. Moreover, SNAP-AmB surfaces reduced the number of platelets adhered by 74.6 ± 3.9% compared to controls after 2 h of in vitro porcine plasma exposure. Finally, a cytotoxicity assay validated that the materials did not present any cytotoxic side effects toward human fibroblast cells. This novel approach is the first to combine antifungal surface functionalization with NO-releasing technology, providing a promising step toward reducing the rate of broad-spectrum infection and thrombosis associated with indwelling medical devices.


Assuntos
Anfotericina B/uso terapêutico , Antifúngicos/uso terapêutico , Controle de Infecções/métodos , Óxido Nítrico/metabolismo , Trombose/prevenção & controle , Anfotericina B/administração & dosagem , Animais , Antifúngicos/administração & dosagem , Aderência Bacteriana/efeitos dos fármacos , Plaquetas/efeitos dos fármacos , Adesão Celular/efeitos dos fármacos , Humanos , Doadores de Óxido Nítrico/administração & dosagem , Nitroprussiato/administração & dosagem , Suínos
12.
BMC Infect Dis ; 21(1): 369, 2021 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-33874901

RESUMO

BACKGROUND: Visceral leishmaniasis (VL) is severe and potentially fatal. Brazil is one of the countries with the greatest endemicity for the disease in the world. The reduction of CD4+ T lymphocytes, B cells activation and high levels of inflammatory cytokines (IL-6/IL-8/TNF/IL-1ß), plasma LPS, soluble CD14, anti-Leishmania IgG3 and low leptin levels are involved in the immunopathogenesis of VL, most associated with severe VL. Despite relapses occurring in about 4-5% of patients with VL not associated with HIV infection, the factors underlying relapses are little known. Our aim was to identify clinical, laboratory and immunological parameters that may be associated with recurrences in VL. METHODS: Fifteen VL patients recruited from Hospital Eduardo de Menezes (BH-MG) were grouped into relapsing (R-VL, n = 5) and non-relapsing (NR-VL, n = 10) and evaluated during active disease, immediately after treatment (post-treatment) and 6 months post-treatment (6mpt). Clinical and laboratory data obtained from medical records were correlated with CD4+ and CD8+ T cell counts and anti-Leishmania Igs and IL-6 plasma levels and compared to those parameters of ten healthy controls. RESULTS: During the active phase of VL, despite similarity in the clinical symptoms, the rates of thrombocytopenia, elevated transaminases (AST and ALT) and hyperbilirubinemia were higher in the NR-VL group compared to R-VL (p < 0.05), a profile reversed during the post-treatment phase. All patients had low CD4+ T counts in active phase, however, NR-VL patients had a higher gain of this cell type than R-VL in the post-treatment (p < 0.05). There was a significant reduction in IgG3 levels during the follow-up in the NR-VL group compared to the R-VL, especially at 6mpt (p < 0.05). In addition, IgG3 levels were negatively correlated with CD4+ T counts in the R-VL group (r = - 0.52). Elevated levels of IL-6 were observed in active VL and correlated with clinical markers of severity. CONCLUSIONS: During active phase of VL, the NR-VL patients presented more severe laboratorial abnormalities compared to R-VL, probably because the latter had already received previous treatment. On the other hand, R-VL exhibited greater impairment of immune reconstitution and a high degree of B lymphocyte activation, which must be a factor that favored relapses.


Assuntos
Anticorpos Antiprotozoários/sangue , Linfócitos T CD4-Positivos/citologia , Imunoglobulina G/sangue , Leishmania/imunologia , Leishmaniose Visceral/patologia , Adulto , Anfotericina B/uso terapêutico , Brasil , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Ácido Desoxicólico/uso terapêutico , Combinação de Medicamentos , Feminino , Infecções por HIV/complicações , Humanos , Interleucina-6/sangue , Leishmaniose Visceral/tratamento farmacológico , Leishmaniose Visceral/imunologia , Masculino , Pessoa de Meia-Idade , Recidiva
13.
BMJ Case Rep ; 14(4)2021 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-33906877

RESUMO

A middle-aged woman with diabetes presented with left-sided facial pain, complete ptosis and fever of short duration. On presentation, she had hyperglycaemia without ketosis. There was total ophthalmoplegia of the left eye with a visual acuity of 6/36. She incidentally tested positive for COVID-19. CT paranasal sinus and MRI brain revealed left-sided pansinusitis with acute infarct in the left parieto-occipital region without angioinvasion. An emergency functional endoscopic sinus procedure was done, which confirmed mucormycosis on histopathological examination. After 1 week of conventional amphotericin B and antibiotics, repeat CT brain showed improvement in mucosal thickening and sinusitis. This case is a rare presentation of mucormycosis associated with rapid progression to orbital apex syndrome with brain infarction in a patient with non-ketotic diabetes and COVID-19. Early diagnosis and treatment are essential to prevent further end-organ damage. It is also interesting that there was no angioinvasion and transient periarterial inflammation was attributed to brain infarction.


Assuntos
Blefaroptose/complicações , COVID-19/complicações , Complicações do Diabetes , Mucormicose/diagnóstico , Oftalmoplegia/complicações , Doenças Orbitárias/complicações , Doenças dos Seios Paranasais/complicações , Anfotericina B/uso terapêutico , Antifúngicos/uso terapêutico , Encéfalo/diagnóstico por imagem , Feminino , Humanos , Imageamento por Ressonância Magnética , Pessoa de Meia-Idade , Mucormicose/tratamento farmacológico , Doenças Orbitárias/diagnóstico por imagem , Doenças Orbitárias/etiologia , Doenças dos Seios Paranasais/diagnóstico por imagem , SARS-CoV-2 , Tomografia Computadorizada por Raios X , Resultado do Tratamento
15.
J Mycol Med ; 31(2): 101124, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33684835

RESUMO

Aspergillus infection is a well-known complication of severe influenza and severe acute respiratory syndrome coronavirus (SARS-CoV), and these infections have been related with significant morbidity and mortality even when appropriately diagnosed and treated. Recent studies have indicated that SARS-CoV-2 might increase the risk of invasive pulmonary aspergillosis (IPA). Here, we report the first case of Aspergillus ochraceus in a SARS-CoV-2 positive immunocompetent patient, which is complicated by pulmonary and brain infections. Proven IPA is supported by the positive Galactomannan test, culture-positive, and histopathological evidence. The patient did not respond to voriconazole, and liposomal amphotericin B was added to his anti-fungal regimen. Further studies are needed to evaluate the prevalence of IPA in immunocompetent patients infected with SARS-CoV-2. Consequently, testing for the incidence of Aspergillus species in lower respiratory secretions and Galactomannan test of COVID-19 patients with appropriate therapy and targeted anti-fungal therapy based on the primary clinical suspicion of IPA are highly recommended.


Assuntos
Aspergilose/complicações , Aspergillus ochraceus/isolamento & purificação , COVID-19/complicações , Infecções Fúngicas Invasivas/complicações , SARS-CoV-2/isolamento & purificação , Adulto , Anfotericina B/uso terapêutico , Antifúngicos/uso terapêutico , Aspergilose/diagnóstico por imagem , Aspergilose/tratamento farmacológico , Biomarcadores , Abscesso Encefálico/diagnóstico por imagem , Abscesso Encefálico/etiologia , Abscesso Encefálico/microbiologia , Líquido da Lavagem Broncoalveolar/microbiologia , COVID-19/diagnóstico por imagem , Teste de Ácido Nucleico para COVID-19 , Evolução Fatal , Humanos , Imunocompetência , Infecções Fúngicas Invasivas/diagnóstico por imagem , Infecções Fúngicas Invasivas/tratamento farmacológico , Infecções Fúngicas Invasivas/microbiologia , Pneumopatias Fúngicas/complicações , Pneumopatias Fúngicas/diagnóstico por imagem , Pneumopatias Fúngicas/microbiologia , Masculino , Mananas/sangue , Voriconazol/uso terapêutico
16.
PLoS Negl Trop Dis ; 15(3): e0009013, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33651812

RESUMO

BACKGROUND: There is a continued need to develop effective and safe treatments for visceral leishmaniasis (VL). Preclinical studies on pharmacokinetics and pharmacodynamics of anti-infective agents, such as anti-bacterials and anti-fungals, have provided valuable information in the development and dosing of these agents. The aim of this study was to characterise the pharmacokinetic and pharmacodynamic properties of the anti-leishmanial drugs AmBisome and miltefosine in a preclinical disease model of VL. METHODOLOGY / PRINCIPAL FINDINGS: BALB/c mice were infected with L. donovani (MHOM/ET/67/HU3) amastigotes. Groups of mice were treated with miltefosine (orally, multi-dose regimen) or AmBisome (intravenously, single dose regimen) or left untreated as control groups. At set time points groups of mice were killed and plasma, livers and spleens harvested. For pharmacodynamics the hepatic parasite burden was determined microscopically from tissue impression smears. For pharmacokinetics drug concentrations were measured in plasma and whole tissue homogenates by LC-MS. Unbound drug concentrations were determined by rapid equilibrium dialysis. Doses exerting maximum anti-leishmanial effects were 40 mg/kg for AmBisome and 150 mg/kg (cumulatively) for miltefosine. AmBisome displayed a wider therapeutic range than miltefosine. Dose fractionation at a total dose of 2.5 mg/kg pointed towards concentration-dependent anti-leishmanial activity of AmBisome, favouring the administration of large doses infrequently. Protein binding was >99% for miltefosine and amphotericin B in plasma and tissue homogenates. CONCLUSION / SIGNIFICANCE: Using a PK/PD approach we propose optimal dosing strategies for AmBisome. Additionally, we describe pharmacokinetic and pharmacodynamic properties of miltefosine and compare our findings in a preclinical disease model to available knowledge from studies in humans. This approach also presents a strategy for improved use of animal models in the drug development process for VL.


Assuntos
Anfotericina B/farmacocinética , Antiprotozoários/farmacocinética , Leishmaniose Visceral/tratamento farmacológico , Fosforilcolina/análogos & derivados , Anfotericina B/uso terapêutico , Animais , Antiprotozoários/uso terapêutico , Quimioterapia Combinada , Proteínas de Homeodomínio/genética , Humanos , Fígado/parasitologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Carga Parasitária , Fosforilcolina/farmacocinética , Fosforilcolina/uso terapêutico , Ligação Proteica/fisiologia
17.
PLoS Negl Trop Dis ; 15(3): e0009302, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33780461

RESUMO

BACKGROUND: Despite a historical association with poor tolerability, a comprehensive review on safety of antileishmanial chemotherapies is lacking. We carried out an update of a previous systematic review of all published clinical trials in visceral leishmaniasis (VL) from 1980 to 2019 to document any reported serious adverse events (SAEs). METHODS: For this updated systematic review, we searched the following databases from 1st Jan 2016 through 2nd of May 2019: PUBMED, Embase, Scopus, Web of Science, Cochrane, clinicaltrials.gov, WHO ICTRP, and the Global Index Medicus. We included randomised and non-randomised interventional studies aimed at assessing therapeutic efficacy and extracted the number of SAEs reported within the first 30 days of treatment initiation. The incidence rate of death (IRD) from individual treatment arms were combined in a meta-analysis using random effects Poisson regression. RESULTS: We identified 157 published studies enrolling 35,376 patients in 347 treatment arms. Pentavalent antimony was administered in 74 (21.3%), multiple-dose liposomal amphotericin B (L-AmB) in 52 (15.0%), amphotericin b deoxycholate in 51 (14.7%), miltefosine in 33 (9.5%), amphotericin b fat/lipid/colloid/cholesterol in 31 (8.9%), and single-dose L-AmB in 17 (4.9%) arms. There was a total of 804 SAEs reported of which 793 (including 428 deaths) were extracted at study arm level (11 SAEs were reported at study level only). During the first 30 days, there were 285 (66.6%) deaths with the overall IRD estimated at 0.068 [95% confidence interval (CI): 0.041-0.114; I2 = 81.4%; 95% prediction interval (PI): 0.001-2.779] per 1,000 person-days at risk; the rate was 0.628 [95% CI: 0.368-1.021; I2 = 82.5%] in Eastern Africa, and 0.041 [95% CI: 0.021-0.081; I2 = 68.1%] in the Indian Subcontinent. In 21 study arms which clearly indicated allowing the inclusion of patients with HIV co-infections the IRD was 0.575 [95% CI: 0.244-1.355; I2 = 91.9%] compared to 0.043 [95% CI: 0.020-0.090; I2 = 62.5%] in 160 arms which excluded HIV co-infections. CONCLUSION: Mortality within the first 30 days of VL treatment initiation was a rarely reported event in clinical trials with an overall estimated rate of 0.068 deaths per 1,000 person-days at risk, though it varied across regions and patient populations. These estimates may serve as a benchmark for future trials against which mortality data from prospective and pharmacovigilance studies can be compared. The methodological limitations exposed by our review support the need to assemble individual patient data (IPD) to conduct robust IPD meta-analyses and generate stronger evidence from existing trials to support treatment guidelines and guide future research.


Assuntos
Antiprotozoários/efeitos adversos , Antiprotozoários/uso terapêutico , Leishmaniose Visceral/tratamento farmacológico , Leishmaniose Visceral/mortalidade , Anfotericina B/efeitos adversos , Anfotericina B/uso terapêutico , Antimônio/efeitos adversos , Antimônio/uso terapêutico , Ácido Desoxicólico/efeitos adversos , Ácido Desoxicólico/uso terapêutico , Combinação de Medicamentos , Humanos , Fosforilcolina/efeitos adversos , Fosforilcolina/análogos & derivados , Fosforilcolina/uso terapêutico
19.
mBio ; 12(1)2021 02 23.
Artigo em Inglês | MEDLINE | ID: mdl-33622715

RESUMO

Invasive fungal diseases cause millions of deaths each year. There are currently approximately 300,000 acute cases of aspergillosis, most of which result from a pulmonary infection of immunocompromised patients by the common soil organism and opportunistic pathogen Aspergillus fumigatus Patients are treated with antifungal drugs, such as amphotericin B (AmB). However, AmB has serious limitations due to human organ toxicity. AmB is slightly less toxic if loaded in liposomes, such as AmBisome or AmB-loaded liposomes (AmB-LLs). Even with antifungal therapy, recurrent infections are common, and 1-year fatality rates may exceed 50%. We have previously shown that coating AmB-LLs with the extracellular oligomannan-binding domain of the C-type lectin receptor Dectin-2 (DEC2-AmB-LLs) effectively targets DEC2-AmB-LLs to cell walls, exopolysaccharide matrices, and biofilms of fungal pathogens in vitro In vitro, DEC2-AmB-LLs reduce the effective dose of AmB for 95% inhibition and killing of A. fumigatus 10-fold compared to that of untargeted AmB-LLs. Herein we tested the antifungal activity of DEC2-AmB-LLs relative to that of untargeted AmB-LLs in immunosuppressed mice with pulmonary aspergillosis. Remarkably, DEC2-AmB-LLs bound 30-fold more efficiently to A. fumigatus at sites of infection in the lungs. Furthermore, Dectin-2-targeted liposomes delivering AmB at a dose of 0.2 mg/kg of body weight significantly reduced the fungal burden in lungs compared to results with untargeted AmB-LLs at 0.2 mg/kg and micellar voriconazole at 20 mg/kg and prolonged mouse survival. By dramatically increasing the efficacy of antifungal drugs at low doses, targeted liposomes have the potential to create a new clinical paradigm to treat diverse fungal diseases.IMPORTANCE Invasive aspergillosis (IA) generally results from a pulmonary infection of immunocompromised patients by the common soil organism and opportunistic pathogen Aspergillus fumigatus The susceptible population has expanded rapidly due to the increased number of cancer patients with immunocompromising chemotherapy and transplant patients taking immunosuppressants. Patients are treated with antifungals, such as liposomal amphotericin B, with per-patient costs exceeding $50,000 in the United States. However, AmB has serious side effects due to host toxicity, which limits its usage and contributes to the lack of fungal clearance in patients at safe doses. Fifty percent of IA patients die within a year. Herein, we employed liposomal amphotericin B coated with the innate immune receptor Dectin-2 to direct antifungals specifically to the fungal pathogen. Using two mouse models of pulmonary aspergillosis, we demonstrate that Dectin-2-targeted delivery of amphotericin B to A. fumigatus resulted in remarkably higher efficacy than that of the untargeted antifungal formulations.


Assuntos
Antifúngicos/uso terapêutico , Aspergillus fumigatus/efeitos dos fármacos , Parede Celular/metabolismo , Lectinas Tipo C/metabolismo , Lectinas Tipo C/uso terapêutico , Lipossomos/química , Aspergilose Pulmonar/tratamento farmacológico , Anfotericina B/metabolismo , Anfotericina B/uso terapêutico , Animais , Parede Celular/efeitos dos fármacos , Feminino , Lectinas Tipo C/genética , Lipossomos/uso terapêutico , Camundongos , Neutropenia
20.
Mycoses ; 64(8): 798-808, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33590551

RESUMO

Acute respiratory distress syndrome is a common complication of severe viral pneumonia, such as influenza and COVID-19, that requires critical care including ventilatory support, use of corticosteroids and other adjunctive therapies to arrest the attendant massive airways inflammation. Although recommended for the treatment of viral pneumonia, steroid therapy appears to be a double-edged sword, predisposing patients to secondary bacterial and invasive fungal infections (IFIs) whereby impacting morbidity and mortality. Mucormycosis is a fungal emergency with a highly aggressive tendency for contiguous spread, associated with a poor prognosis if not promptly diagnosed and managed. Classically, uncontrolled diabetes mellitus (DM) and other immunosuppressive conditions including corticosteroid therapy are known risk factors for mucormycosis. Upon the background lung pathology, immune dysfunction and corticosteroid therapy, patients with severe viral pneumonia are likely to develop IFIs like aspergillosis and mucormycosis. Notably, the combination of steroid therapy and DM can augment immunosuppression and hyperglycaemia, increasing the risk of mucormycosis in a susceptible individual. Here, we report a case of sinonasal mucormycosis in a 44-year-old woman with hyperglycaemia secondary to poorly controlled diabetes following dexamethasone therapy on a background of influenza pneumonia and review 15 available literatures on reported cases of influenza and COVID-19 associated mucormycosis.


Assuntos
Corticosteroides/uso terapêutico , COVID-19/complicações , Influenza Humana/complicações , Mucormicose/tratamento farmacológico , Mucormicose/etiologia , Pneumonia Viral/tratamento farmacológico , Adulto , Anfotericina B/uso terapêutico , Antifúngicos/uso terapêutico , Complicações do Diabetes , Feminino , Humanos , Lipossomos/uso terapêutico , Triazóis/uso terapêutico
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