RESUMO
Breakthrough invasive infections occurs during the use of antifungals both in prophylaxis and therapy, it favors the emergence of new pathogens in the fungal landscape. Hormographiella aspergillata is considered a rare but emerging pathogen in the era of broad-spectrum antifungal use in patients with hematological malignancies. Here, we present a case report of invasive sinusitis due to Hormographiella aspergillata, manifesting as a breakthrough infection in a patient with severe aplastic anemia under treatment with voriconazole for invasive pulmonary aspergilosis. Also, we make a review of H. aspergillata breakthrough infections published in the literature.
Assuntos
Agaricales , Pneumopatias Fúngicas , Humanos , Voriconazol/uso terapêutico , Pneumopatias Fúngicas/tratamento farmacológico , Antifúngicos/uso terapêuticoRESUMO
RATIONALE: Talaromyces marneffei causes life-threatening opportunistic fungal infections in immunocompromised patients. It often has a poorer prognosis in non-human immunodeficiency virus (HIV)-infected than in HIV-infected individuals because of delayed diagnosis and improper treatment. PATIENT CONCERNS: A 51-year-old man presented with complaints of pyrexia, cough, and expectoration that had lasted for 15 day. This patient has been taking anti-rejection medication since kidney transplant in 2011. DIAGNOSIS: T marneffei pneumonia; post renal transplantation; renal insufficiency; hypertension. INTERVENTIONS: Intravenous moxifloxacin was administered on admission. After the etiology was established, moxifloxacin was discontinued and replaced with voriconazole. The tacrolimus dose was adjusted based on the blood concentration of tacrolimus and voriconazole. OUTCOMES: The patient was successfully treated and followed-up without recurrence for 1 year. LESSONS: A high degree of caution should be maintained for the possibility of T marneffei infection in immunodeficient non-HIV patients who live in or have traveled to T marneffei endemic areas. Early diagnosis and appropriate treatment can prevent progression of T marneffei infection and achieve a cure. Metagenomic next-generation sequencing (mNGS) can aid the physician in reaching an early pathogenic diagnosis. Close monitoring of tacrolimus and voriconazole blood levels during treatment remains a practical approach at this time.
Assuntos
Infecções por HIV , Transplante de Rim , Pneumonia , Antifúngicos/uso terapêutico , Infecções por HIV/tratamento farmacológico , Humanos , Transplante de Rim/efeitos adversos , Moxifloxacina , Micoses , Pneumonia/tratamento farmacológico , Tacrolimo/uso terapêutico , Talaromyces , Voriconazol/uso terapêuticoRESUMO
Aspergillus spp. osteoarticular infections are destructive opportunistic infections, while there is no clear consensus on their management. The purpose of this review is to investigate the current literature regarding Aspergillus spp. osteoarticular infections. An electronic search of the PubMed and Scopus databases was conducted considering studies that assessed osteoarticular infections from Aspergillus spp. We included only studies with biopsy proven documentation of positive cultures or histological findings for Aspergillus spp., and those with essential information for each case such as the anatomical location of the infection, the type of treatment (conservative, surgical, combination), the antifungal therapy, and the outcome. Overall, 148 studies from 1965 to 2021 including 186 patients were included in the review. One hundred and seven (57.5%) patients underwent surgical debridement in addition to antifungal therapy, while 79 (42.7%) patients were treated only conservatively. Complete infection resolution was reported in 107 (57.5%) patients, while partial resolution in 29 (15.5%) patients. Surgical debridement resulted in higher complete infection resolution rate compared to only antifungal therapy (70.0% vs. 40.5%, P < 0.001), while complete resolution rate was similar for antifungal monotherapy and combination/sequential therapy (58.3% vs. 54.5%; P = 0.76). Last, complete resolution rate was also similar for monotherapy with amphotericin B (58.1%) and voriconazole (58.6%; P = 0.95). The results of this study indicate that antifungal monotherapy has similar efficacy with combination/sequential therapy, while voriconazole has similar efficacy with amphotericin B. Moreover, surgical debridement of the infected focus results in better outcomes in terms of infection eradication compared to conservative treatment. LAY SUMMARY: Antifungal monotherapy has similar efficacy with combination/sequential therapy, and voriconazole has similar efficacy with amphotericin B for the treatment of Aspergillus spp. osteoarticular infections, while surgical debridement of the infected focus improves the infection eradication rate.
Assuntos
Anfotericina B , Aspergilose , Animais , Anfotericina B/uso terapêutico , Antifúngicos/uso terapêutico , Aspergilose/diagnóstico , Aspergilose/tratamento farmacológico , Aspergilose/cirurgia , Aspergilose/veterinária , Aspergillus , Testes de Sensibilidade Microbiana/veterinária , Resultado do Tratamento , Voriconazol/uso terapêuticoRESUMO
Terbinafine and itraconazole are the most commonly used oral antifungals to treat onychomycosis and superficial dermatomycoses. Recently, poor response to oral terbinafine has been reported. We have summarized the most appropriate dosing regimens of posaconazole, fosravuconazole, voriconazole, and oteseconazole (VT-1161) to treat onychomycosis and superficial fungal infections. A structured search on PubMed and Google Scholar was conducted. Additionally, the bibliographies of selected articles were searched to identify relevant records. The number of records identified from the searches was 463, with 50 articles meeting the inclusion criteria for review. None of the new azoles are US FDA approved for onychomycosis treatment; however, an increasing number of studies have evaluated these agents. The efficacies (complete cure and mycologic cure) of the antifungal agents for dermatophyte great toenail onychomycosis treatment are terbinafine 250 mg/day × 12 weeks (Phase III trial) (38%, 70%), itraconazole 200 mg/day × 12 weeks (Phase III trial) (14%, 54%), posaconazole 200 mg/day × 24 weeks (Phase IIB) (54.1%, 70.3%), fosravuconazole 100 mg/day ravuconazole equivalent × 12 weeks (Phase III) (59.4%, 82.0%), and oteseconazole 300 mg/day loading dose × 2 weeks (Phase II), followed by 300 mg/week × 10 weeks (maintenance dose) (45%, 70%). Guidelines for monitoring are also presented.
Assuntos
Terapias Complementares , Fármacos Dermatológicos , Dermatoses do Pé , Onicomicose , Humanos , Onicomicose/tratamento farmacológico , Antifúngicos/uso terapêutico , Terbinafina/uso terapêutico , Itraconazol/uso terapêutico , Voriconazol/uso terapêutico , Dermatoses do Pé/tratamento farmacológico , Naftalenos/uso terapêutico , Fármacos Dermatológicos/uso terapêutico , Resultado do TratamentoRESUMO
Limited data are available on antimicrobials exposure and microbiology evolution in pediatric acute myeloid leukemia (AML) patients underwent antimicrobials prophylaxis. To assess the effectiveness of antimicrobials prophylaxis, antibiotic susceptibilities of bacteria, and exposure of antimicrobials during intensive chemotherapy for AML patients, 90 consecutive de novo AML patients aged 0-18 years between January 1, 1997 and March 31, 2018 were enrolled. Vancomycin, ciprofloxacin and voriconazole prophylaxis was administered from January 1, 2010. During the preprophylaxis period, January 1997 to December 2009, 62 patients experienced a total of 87 episodes of bloodstream infection (BSI) and 17 episodes of invasive fungal infection (IFI) among 502 courses of chemotherapy. In contrast, 16 episodes of BSI occurred and no IFIs were reported to occur in 28 patients who received 247 courses of chemotherapy in the prophylaxis period. Patients who received antimicrobial prophylaxis had a significant reduction of BSI, IFI, and febrile neutropenia in comparison with patients without prophylaxis. Exposure to amikacin, carbapenem, amphotericin B was reduced in the prophylaxis period. Imipenem susceptibility of Enterobacter cloacae as well as vancomycin susceptibility of Enterococcus species were reduced in the prophylaxis period. At the time of the last follow up, patients with prophylaxis had a better subsequent 5-year overall survival rate than those without prophylaxis. Prophylactic antimicrobials administration in children with AML who undergo chemotherapy can significantly reduce the rates of life-threatening infection, exposure to antimicrobials, and might result in a better outcome.
Assuntos
Antibacterianos/uso terapêutico , Antibioticoprofilaxia/métodos , Antifúngicos/uso terapêutico , Bacteriemia/prevenção & controle , Neutropenia Febril/prevenção & controle , Leucemia Mieloide Aguda/microbiologia , Micoses/prevenção & controle , Antibacterianos/administração & dosagem , Antifúngicos/administração & dosagem , Bacteriemia/tratamento farmacológico , Criança , Ciprofloxacina/administração & dosagem , Ciprofloxacina/uso terapêutico , Neutropenia Febril/tratamento farmacológico , Feminino , Humanos , Imipenem/administração & dosagem , Imipenem/uso terapêutico , Leucemia Mieloide Aguda/complicações , Masculino , Micoses/tratamento farmacológico , Vancomicina/administração & dosagem , Vancomicina/uso terapêutico , Voriconazol/administração & dosagem , Voriconazol/uso terapêuticoRESUMO
PURPOSE: To report the clinical and confocal findings of a unique case of combined Phialemonium curvatum and Acanthamoeba keratitis and to highlight the role of the prompt diagnosis and specific medical treatment in preserving visual function. METHODS: A case report and literature review. RESULTS: A 54-year-old woman presented with a 3-day history of visual impairment, photophobia, and ocular pain in her right eye. Her best corrected visual acuity was 0.4 Logarithm of the Minimum Angle of Resolution scale, and the slit-lamp examination showed whitish corneal stromal infiltrate with satellite lesions. In vivo confocal microscopy evidenced Acanthamoeba cysts and fungal hyphae that resulted P. curvatum in the culture examination. The intensive medical treatment was started with topical 0.02% polyhexamethylene biguanide, voriconazole 1%, and moxifloxacin hydrochloride 0.5%. Progressive improvement of clinical and confocal pictures was registered with a complete recovery of visual function after 1 month. CONCLUSIONS: This is the first case report of combined P. curvatum and Acanthamoeba keratitis. The fast diagnosis with in vivo confocal microscopy allowed early and intensive specific treatment with recovery of corneal infection.
Assuntos
Ceratite por Acanthamoeba/diagnóstico , Ascomicetos/isolamento & purificação , Infecções Oculares Fúngicas/diagnóstico , Ceratite/diagnóstico , Micoses/diagnóstico , Ceratite por Acanthamoeba/tratamento farmacológico , Ceratite por Acanthamoeba/parasitologia , Administração Oftálmica , Antibacterianos/uso terapêutico , Antifúngicos/uso terapêutico , Biguanidas/uso terapêutico , Desinfetantes/uso terapêutico , Quimioterapia Combinada , Diagnóstico Precoce , Infecções Oculares Fúngicas/tratamento farmacológico , Infecções Oculares Fúngicas/microbiologia , Feminino , Humanos , Ceratite/tratamento farmacológico , Ceratite/microbiologia , Microscopia Confocal , Pessoa de Meia-Idade , Moxifloxacina/uso terapêutico , Micoses/tratamento farmacológico , Micoses/microbiologia , Soluções Oftálmicas , Microscopia com Lâmpada de Fenda , Voriconazol/uso terapêuticoRESUMO
Antifungal activity of anidulafungin, voriconazole, isavuconazole, and fluconazole in the treatment of Candida auris was determined in vitro and in vivo. MICs for anidulafungin, voriconazole, isavuconazole, fluconazole, and amphotericin B were 0.5, 1, >64, 0.25, and 4 µg/ml, respectively. Significant in vivo efficacy was observed in the anidulafungin- and voriconazole-treated groups in survival and reduction in kidney tissue fungal burden compared to that in the untreated group (P values of <0.001 and 0.044, respectively). Our data showed that anidulafungin and voriconazole had comparable efficacies against C. auris, whereas isavuconazole did not show significant in vivo activity.
Assuntos
Candidíase , Fluconazol , Anidulafungina , Animais , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Candida , Candidíase/tratamento farmacológico , Modelos Animais de Doenças , Fluconazol/farmacologia , Fluconazol/uso terapêutico , Camundongos , Testes de Sensibilidade Microbiana , Nitrilas , Piridinas , Triazóis , Voriconazol/farmacologia , Voriconazol/uso terapêuticoRESUMO
OBJECTIVES: To describe the first outbreak of Candida auris in Brazil, including epidemiological, clinical and microbiological data. METHODS: After the first Candida auris-colonised patient was diagnosed in a COVID-19 ICU at a hospital in Salvador, Brazil, a multidisciplinary team conducted a local C. auris prevalence investigation. Screening cultures for C. auris were collected from patients, healthcare workers and inanimate surfaces. Risk factors for C. auris colonisation were evaluated, and the fungemia episodes that occurred after the investigation were also analysed and described. Antifungal susceptibility of the C. auris isolates was determined, and they were genotyped with microsatellite analysis. RESULTS: Among body swabs collected from 47 patients, eight (n = 8/47, 17%) samples from the axillae were positive for C. auris. Among samples collected from inanimate surfaces, digital thermometers had the highest rate of positive cultures (n = 8/47, 17%). Antifungal susceptibility testing showed MICs of 0.5 to 1 mg/L for AMB, 0.03 to 0.06 mg/L for voriconazole, 2 to 4 mg/L for fluconazole and 0.03 to 0.06 mg/L for anidulafungin. Microsatellite analysis revealed that all C. auris isolates belong to the South Asian clade (Clade I) and had different genotypes. In multivariate analysis, having a colonised digital thermometer was the only independent risk factor associated with C. auris colonisation. Three episodes of C. auris fungemia occurred after the investigation, with 30-day attributable mortality of 33.3%. CONCLUSIONS: Emergence of C. auris in Salvador, Brazil, may be related to local C. auris clade I closely related genotypes. Contaminated axillary monitoring thermometers may facilitate the dissemination of C. auris reinforcing the concept that these reusable devices should be carefully cleaned with an effective disinfectant or replaced by other temperature monitoring methods.
Assuntos
Antifúngicos/uso terapêutico , Candida/efeitos dos fármacos , Candidíase/diagnóstico , Candidíase/tratamento farmacológico , Candidíase/epidemiologia , Transmissão de Doença Infecciosa , Termômetros/microbiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Anidulafungina/uso terapêutico , Brasil/epidemiologia , COVID-19/complicações , COVID-19/microbiologia , Cuidados Críticos , Surtos de Doenças , Feminino , Fluconazol/uso terapêutico , Humanos , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Prevalência , SARS-CoV-2 , Voriconazol/uso terapêuticoRESUMO
We previously reported a 39-year-old man who presented with pulmonary and cerebral Cryptococcus gattii (genotype VGIIa) infection and was successfully treated with liposomal amphotericin B and flucytosine induction therapy. Following induction therapy, oral fluconazole treatment was initiated as consolidation therapy. However, the patient complained of progressively worsening headache, presenting an elevated cerebrospinal fluid (CSF) cell count. The minimum inhibitory concentrations of the CSF isolate were 8 and 0.12 µg/mL for fluconazole and voriconazole, respectively. The oral administration of voriconazole for more than 18 months alleviated his symptoms. Voriconazole might be useful for controlling refractory cases of C. gattii infection.
Assuntos
Criptococose , Cryptococcus gattii , Cryptococcus neoformans , Adulto , Antifúngicos/uso terapêutico , Criptococose/diagnóstico , Criptococose/tratamento farmacológico , Fluconazol/uso terapêutico , Humanos , Masculino , Testes de Sensibilidade Microbiana , Voriconazol/uso terapêuticoRESUMO
BACKGROUND: Infectious keratitis is the main cause of preventable blindness worldwide, with about 1.5-2.0 million new cases occurring per year. This inflammatory response may be due to infections caused by bacteria, fungi, viruses or parasites. Fungal keratitis is a poorly studied health problem. OBJECTIVES: This study aimed to identify a new fungal species by molecular methods and to explore the possible efficacy of the three most common antifungals used in human keratitis in Mexico by performing in vitro analysis. The capacity of this pathogen to cause corneal infection in a murine model was also evaluated. METHODS: The fungal strain was isolated from a patient with a corneal ulcer. To identify the fungus, taxonomic and phylogenetic analyses (nrDNA ITS and LSU data set) were performed. An antifungal susceptibility assay for amphotericin B, itraconazole and voriconazole was carried out. The fungal isolate was used to develop a keratitis model in BALB/c mice; entire eyes and ocular tissues were preserved and processed for histopathologic examination. RESULTS AND CONCLUSION: This fungal genus has hitherto not been reported with human keratitis in Mexico. We described a new species Purpurecillium roseum isolated from corneal infection. P roseum showed resistance to amphotericin B and itraconazole and was sensitive to voriconazole. In vivo study demonstrated that P roseum had capacity to developed corneal infection and to penetrate deeper corneal tissue. The global change in fungal infections has emphasised the need to develop better diagnostic mycology laboratories and to recognise the group of potential fungal pathogens.
Assuntos
Antifúngicos/uso terapêutico , Hypocreales/classificação , Hypocreales/efeitos dos fármacos , Hypocreales/isolamento & purificação , Ceratite/microbiologia , Idoso , Anfotericina B/uso terapêutico , Animais , Córnea , DNA Fúngico , Farmacorresistência Fúngica/efeitos dos fármacos , Feminino , Humanos , Hypocreales/patogenicidade , Itraconazol/uso terapêutico , Ceratite/tratamento farmacológico , Ceratite/patologia , México , Camundongos , Camundongos Endogâmicos BALB C , Testes de Sensibilidade Microbiana , Técnicas de Tipagem Micológica , Micoses/tratamento farmacológico , Micoses/microbiologia , Filogenia , Voriconazol/uso terapêuticoRESUMO
The genera Acremonium and Sarocladium comprise a high diversity of morphologically and genetically related fungi generally found in the environment, although a few species, mainly Sarocladium kiliense and Acremonium egyptiacum, can also be involved in many human infections. Clinical management of opportunistic infections caused by these fungi is very complex, since their correct identification is unreliable, and they generally show poor antifungal response. More than 300 clinical cases involving a broad range of Acremonium/Sarocladium infections have so far been published, and with this review we aim to compile and provide a detailed overview of the current knowledge on Acremonium/Sarocladium human infections in terms of presentation, diagnosis, treatments and prognoses. We also aim to summarise and discuss the data currently available on their antifungal susceptibility, emphasising the promising results obtained with voriconazole as well as their impact in terms of animal infections.
Assuntos
Hypocreales , Micoses , Infecções Oportunistas , Acremonium/classificação , Acremonium/efeitos dos fármacos , Acremonium/isolamento & purificação , Acremonium/patogenicidade , Animais , Antifúngicos/uso terapêutico , Artrite/tratamento farmacológico , Artrite/microbiologia , Sangue/microbiologia , Infecções do Sistema Nervoso Central/tratamento farmacológico , Infecções do Sistema Nervoso Central/microbiologia , Dermatomicoses/tratamento farmacológico , Farmacorresistência Fúngica , Endocardite/tratamento farmacológico , Endocardite/microbiologia , Infecções Oculares/tratamento farmacológico , Infecções Oculares/microbiologia , Humanos , Hypocreales/classificação , Hypocreales/efeitos dos fármacos , Hypocreales/isolamento & purificação , Hypocreales/patogenicidade , Infecções Fúngicas Invasivas/tratamento farmacológico , Infecções Fúngicas Invasivas/patologia , Micetoma/tratamento farmacológico , Micoses/tratamento farmacológico , Micoses/patologia , Micoses/veterinária , Onicomicose/tratamento farmacológico , Onicomicose/microbiologia , Infecções Oportunistas/tratamento farmacológico , Infecções Oportunistas/patologia , Infecções Oportunistas/veterinária , Osteomielite/tratamento farmacológico , Osteomielite/microbiologia , Peritonite/tratamento farmacológico , Peritonite/microbiologia , Infecções Respiratórias/tratamento farmacológico , Infecções Respiratórias/microbiologia , Voriconazol/uso terapêuticoRESUMO
When performed according to best-practice principles, therapeutic drug monitoring (TDM) can optimise anti-infective treatment and directly benefit clinical outcomes. We evaluated TDM performance and clinical decision-making for established anti-infective agents amongst Australian hospitals. A nationwide cross-sectional survey was conducted between August and September 2019. The survey consisted of multiple-choice questions regarding TDM of anti-infective agents in general as well as clinical vignettes specific to vancomycin, gentamicin and voriconazole. We sought to survey all Australian hospitals operating both in the public and private health sectors. Responses were captured from 85 unique institutions, from all Australian states and territories. Regarding guidelines, 26% of hospitals did not have endorsed guidelines to advise on the ordering, sampling and interpretation of TDM for any anti-infective agent. Admitting teams were predominantly responsible for ordering TDM (85%) and interpreting results (76%). Only 51% of hospitals had access to dose prediction software, with access generally better amongst principal referral (69%) (P = 0.01) and children's hospitals (100%) (P = 0.04). Whenever a laboratory-derived minimum inhibitory concentration (MIC) was not available to guide dosing decisions, a surrogate target MIC was assumed in 77% of hospitals. This was based on a 'worst-case' scenario infection in 11% of hospitals. The rates of clinical practice consistent with current guideline recommendations across all aspects of TDM were demonstrated to be 0% for vancomycin, 4% for gentamicin and 35% for voriconazole. At present, there is significant institutional variability in the clinical practice of TDM for anti-infective agents in Australia for established TDM drugs.
Assuntos
Anti-Infecciosos/uso terapêutico , Tomada de Decisão Clínica , Gentamicinas/uso terapêutico , Vancomicina/uso terapêutico , Voriconazol/uso terapêutico , Austrália , Bactérias/efeitos dos fármacos , Infecções Bacterianas/tratamento farmacológico , Estudos Transversais , Monitoramento de Medicamentos/métodos , Fungos/efeitos dos fármacos , Pessoal de Saúde/psicologia , Humanos , Testes de Sensibilidade Microbiana , Micoses/tratamento farmacológico , Inquéritos e QuestionáriosRESUMO
Trichosporon asahii is a yeast-like fungus that is emerging as an important cause of invasive infections in tertiary medical centres. A 58-year-old Chinese man with no known medical illnesses presented with liver lacerations and multiple fractures following an alleged 12-foot fall at a construction site. The gravity of his injuries and poor haemodynamic status necessitated an intensive care unit (ICU) admission, during which several febrile episodes were detected and multiple antibiotics were administered. After being in the ICU for at least two weeks, a urease-positive yeast was isolated from the patient's blood. The yeast formed dry, fuzzy and wrinkled white colonies on Sabouraud dextrose agar following prolonged incubation, and produced blastoconidia, true hyphae, pseudohyphae and arthroconidia on slide culture. It was identified biochemically by the ID 32 C kit as T. asahii. The yeast had elevated minimal inhibitory concentration (MIC) values to fluconazole, amphotericin B, flucytosine and all echinocandins tested. In view of this, the patient was treated with voriconazole and was successfully transferred to the general medical ward.
Assuntos
Basidiomycota , Traumatismo Múltiplo/complicações , Tricosporonose/tratamento farmacológico , Voriconazol/uso terapêutico , Anfotericina B/farmacologia , Antibacterianos/efeitos adversos , Antifúngicos/farmacologia , Basidiomycota/efeitos dos fármacos , Basidiomycota/isolamento & purificação , Basidiomycota/patogenicidade , Farmacorresistência Fúngica Múltipla , Fungemia/tratamento farmacológico , Humanos , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Traumatismo Múltiplo/tratamento farmacológico , Voriconazol/farmacologiaRESUMO
OBJECTIVE: The present study was designed to discover novel biomarkers involved in voriconazole resistance in clinical isolates of Aspergillus flavus. MATERIALS AND METHODS: Two voriconazole non-wild-type and two voriconazole-wild-type A. flavus clinical isolates were selected to evaluate possible molecular mechanism involved in A. flavus resistance to voriconazole using the mutation assessment, Quantitative real- time PCR of cyp51A and cyp51C genes and complementary DNA- amplified fragment length polymorphism technique. RESULTS: No mutations were seen in the cyp51A and cyp51C genes in voriconazole non-wild-type isolates compared to wild- type and reference strains. Regarding to mRNA expression results, no changes were observed in expression fold of cyp51A and cyp51C mRNA expression level in first non- wild- type isolate compared to wild-type isolate. For second isolate cyp51C mRNA expression level was down regulated (5.6 fold). The set of genes including ABC fatty acid transporter XM- 002375835 and aldehydereductase XM- 002376518 and three unknown functional genes were identified. Based on results, the over-expression of AKR1 and ABC fatty acid transporter in the voriconazole non- wild- type isolates suggests these genes could represent a novel molecular marker linked to the voriconazole resistance in A. flavus. CONCLUSION: The results obtained in this study showed a novel finding as the authors identified AKR1 and ABC fatty acid transporter genes as possible voriconazole target genes in Iranian clinical isolates of A. flavus.
Assuntos
Aspergilose/microbiologia , Aspergillus flavus/genética , Farmacorresistência Fúngica/genética , Proteínas Fúngicas/genética , Voriconazol/uso terapêutico , Análise do Polimorfismo de Comprimento de Fragmentos Amplificados , Antifúngicos/uso terapêutico , Aspergilose/tratamento farmacológico , Aspergilose/genética , Aspergillus flavus/efeitos dos fármacos , Aspergillus flavus/isolamento & purificação , Biomarcadores/análise , Sistema Enzimático do Citocromo P-450/genética , Análise Mutacional de DNA/métodos , Regulação Fúngica da Expressão Gênica , Humanos , Testes de Sensibilidade Microbiana , Técnicas de Tipagem Micológica , Mutação Puntual , Esterol 14-Desmetilase/genéticaRESUMO
OBJECTIVE: To clarify the detailed pharmacokinetics (PK) of orally administered voriconazole in tear fluid (TF) of horses for evaluating the efficacy of voriconazole secreted into TF against equine keratomycosis. ANIMALS STUDIED: Five healthy Thoroughbred horses. PROCEDURES: Voriconazole was administrated through a nasogastric tube to each horse at a single dose of 4.0 mg/kg. TF and blood samples were collected before and periodically throughout the 24 hours after administration. Voriconazole concentrations in plasma and TF samples were analyzed using liquid chromatography-electrospray tandem-mass spectrometry. The predicted voriconazole concentration in both samples following multiple dosing every 24 hours was simulated by the superposition principle. RESULTS: The mean maximum voriconazole concentrations in plasma and TF were 3.3 µg/mL at 1.5 h and 1.9 µg/mL at 1.6 h, respectively. Mean half-life in both samples were 16.4 and 25.2 h, respectively. The ratio of predicted AUC0-24 at steady state in TF (51.3 µgâh/mL) to previously published minimum inhibitory concentration (MIC) of Aspergillus and Fusarium species was >100 and 25.7, respectively. CONCLUSIONS: This study demonstrated the detailed single-dose PK of voriconazole in TF after oral administration and simulated the predicted concentration curves in a multiple oral dosing. Based on the analyses of PK-PD, the simulation results indicated that repeated oral administration of voriconazole at 4.0 mg/kg/d achieves the ratio of AUC to MIC associated with treatment efficacy against Aspergillus species. The detailed PK-PD analyses against pathogenic fungi in TF can be used to provide evidence-based medicine for equine keratomycosis.
Assuntos
Antifúngicos/uso terapêutico , Infecções Oculares Fúngicas/veterinária , Doenças dos Cavalos/tratamento farmacológico , Voriconazol/uso terapêutico , Administração Oral , Animais , Antifúngicos/administração & dosagem , Antifúngicos/farmacocinética , Antifúngicos/farmacologia , Área Sob a Curva , Aspergillus/efeitos dos fármacos , Infecções Oculares Fúngicas/tratamento farmacológico , Feminino , Doenças dos Cavalos/sangue , Cavalos/metabolismo , Masculino , Testes de Sensibilidade Microbiana , Lágrimas/metabolismo , Voriconazol/administração & dosagem , Voriconazol/farmacocinética , Voriconazol/farmacologiaRESUMO
This study aimed to describe the effect of initial antifungal therapy on patient mortality and to detail the current distribution and resistance patterns of Candida spp. among patients with candidaemia. A prospective observational study was performed among consecutive patients with candidaemia from 10 Turkish medical centres between January 2015 and November 2018. The primary outcome was 10-day mortality. Species were identified using MALDI-TOF/MS. A total of 342 patients with candidaemia were included, of which 175 (51.2%) were male and 68 (19.9%) were aged <18 years. The most common species were Candida albicans (47.4%), Candida parapsilosis (26.6%), Candida tropicalis (9.6%) and Candida glabrata (7.6%). Among all Candida spp., the 10-day case fatality rate (CFR) was 32.2%. The CFR was highest in patients with C. albicans (57.3%) and lowest in patients with C. parapsilosis (21.8%). The resistance rate to fluconazole was 13% in C. parapsilosis, with no significant effect on mortality. No resistance to echinocandins was detected. In the multivariate analysis, being in the ICU [OR = 2.1 (95% CI 1.32-3.57); P = 0.002], renal failure [OR = 2.4 (1.41-3.97); P = 0.001], total parenteral nutrition [OR = 2 (1.22-3.47); P = 0.006], C. albicans infection [OR = 1.7 (1.06-2.82); P = 0.027] and echinocandin as primary agent [OR = 0.6 (0.36-0.99); P = 0.047] were significantly associated with mortality. Candidaemia is a deadly infection. Fluconazole resistance is emerging, although it was not significantly related to mortality. Using an echinocandin as the primary agent could be life-saving.
Assuntos
Antifúngicos/uso terapêutico , Candida/efeitos dos fármacos , Candidemia/tratamento farmacológico , Candidemia/mortalidade , Equinocandinas/uso terapêutico , Fluconazol/uso terapêutico , Adulto , Anfotericina B/uso terapêutico , Candida/classificação , Candida/genética , Candida albicans/efeitos dos fármacos , Candida glabrata/efeitos dos fármacos , Candida parapsilosis/efeitos dos fármacos , Candida tropicalis/efeitos dos fármacos , Farmacorresistência Fúngica Múltipla/genética , Feminino , Humanos , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Estudos Prospectivos , Turquia , Voriconazol/uso terapêuticoRESUMO
Antifungal susceptibility profiles of rare Saccharomycotina yeasts remain missing, even though an increase in prevalence of such rare Candida species was reported in candidemia. Majority of these rare yeast species carry intrinsic resistances against at least one antifungal compound. Some species are known to be cross-resistant (against multiple drugs of the same drug class) or even multi-drug resistant (against multiple drugs of different drug classes). We performed antifungal susceptibility testing (AFST) according to EUCAST broth microdilution for 14 rare species (Clavispora lusitaniae, Candida intermedia, Candida auris, Diutina rugosa, Wickerhamiella pararugosa, Yarrowia lipolytica, Pichia norvegensis, Candida nivariensis, Kluyveromyces marxianus, Wickerhamomyces anomalus, Candida palmioleophila, Meyerozyma guilliermondii, Meyerozyma caribbica, and Debaryomyces hansenii) known to cause candidemia. In total, 234 isolates were tested for amphotericin B, fluconazole, itraconazole, voriconazole, posaconazole, anidulafungin, micafungin, and caspofungin. Amphothericin B had the broadest efficiency against the 14 tested rare yeast species, while high minimum inhibitory concentrations (MICs) against azole drugs and echinocandins were common. Voriconazole was the most efficient azole drug. Multidrug resistance was observed for the species C. auris and K. marxianus. Multidrug resistant individual isolates were found for Y. lipolytica and M. caribbica. In conclusion, the observed high MIC values of the rare Saccharomycotina species tested limit antifungal treatment options, complicating the management of such infections.
Assuntos
Antifúngicos/uso terapêutico , Candidemia/tratamento farmacológico , Farmacorresistência Fúngica , Fluconazol/uso terapêutico , Testes de Sensibilidade Microbiana , Saccharomyces/efeitos dos fármacos , Saccharomyces/isolamento & purificação , Voriconazol/uso terapêutico , HumanosRESUMO
OBJECTIVES: Lomentospora prolificans is an emerging cause of serious invasive fungal infections. Optimal treatment of these infections is unknown, although voriconazole-containing treatment regimens are considered the treatment of choice. The objective of this study was to evaluate the role of combination antifungal therapy for L. prolificans infections. METHODS: We performed a retrospective review of medical records of patients with invasive L. prolificans infection diagnosed between 1 January 2008 and 9 September 2019 that were documented in the FungiScope® registry of rare invasive fungal infections. We compared clinical outcomes between antifungal treatment strategies. RESULTS: Over the study period, 41 individuals with invasive L. prolificans infection from eight different countries were documented in the FungiScope® registry. Overall, 17/40 (43%) had treatment response/stable disease and 21/40 (53%) had a fatal outcome attributed to invasive fungal infection. Combination antifungal therapy was associated with increased 28-day survival (15/24 survived versus 4/16 receiving monotherapy; p 0.027) and the combination voriconazole plus terbinafine trended to be associated with higher rates of treatment success (10/16, 63%, 95% CI 35%-85%) compared with other antifungal treatment regimens (7/24, 29%, 95% CI 13%-51%, p 0.053). In Kaplan-Meier survival analysis there was a higher survival probability in individuals receiving the voriconazole/terbinafine combination compared with other antifungal regimens (median survival 150 days versus 17 days). CONCLUSIONS: While overall mortality was high, combination antifungal treatment, and in particular combination therapy with voriconazole plus terbinafine may be associated with improved treatment outcomes compared with other antifungal regimens for the treatment of invasive L. prolificans infections.
Assuntos
Antifúngicos/uso terapêutico , Infecções Fúngicas Invasivas/tratamento farmacológico , Terbinafina/uso terapêutico , Voriconazol/uso terapêutico , Adulto , Idoso , Quimioterapia Combinada , Feminino , Humanos , Infecções Fúngicas Invasivas/sangue , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Sistema de Registros , Estudos Retrospectivos , Scedosporium/efeitos dos fármacos , Resultado do TratamentoRESUMO
Aspergillus fumigatus is the predominant etiological agent of invasive aspergillosis (IA), a difficult-to-manage fungal disease associated with a high case fatality rate. Azole antifungals, particularly voriconazole, have significantly improved the survival rate of patients with IA. However, the clinical advances made possible through the use of medical azoles could be threatened by the emergence of azole-resistant strains which has been reported in an ever-increasing number of countries over the last 10 years. The major resistance mechanism, that combines point mutation(s) in the coding sequence of cyp51A gene and an insertion of a tandem repeat in the promoter region of this gene which leads to its overexpression (TR34/L98H and TR46/Y121F/T289A), is presumed to be of environmental origin. However, the emergence of clinical and environmental azole-resistant strains without the cyp51A gene mutation suggests that other mechanisms could also be responsible for azole resistance (for example, overexpression of efflux pumps). The development of resistance may be linked to either long-term use of azole antifungals in patients with chronic aspergillosis (patient-acquired route) or selection pressure of the fungicides in the environment (environmental route). The fungicide-driven route could be responsible for resistance in azole-naive patients with IA. This literature review aims to summarize recent findings, focusing on the current situation of azole-resistance in A. fumigatus, and provides better understanding of the importance of the environmental route in resistance acquisition.