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1.
Med Mycol J ; 61(3): 49-53, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32863328

RESUMO

BACKGROUND: Cerebral aspergillosis usually affects immunocompromised hosts and may rarely occur in immunocompetent individuals. Due to its angio-invasive nature, Aspergillus may cause various vascular complications, particularly mycotic aneurysms and infarcts. CASE PRESENTATION: A 22-year-old immunocompetent male with diagnosed case of sino-cerebral aspergillosis was taking voriconazole for two months. His headache worsened and repeat imaging showed an increase in the size of the lesion. The patient was managed with right frontal craniotomy and surgical debridement, and voriconazole was continued. After ten days of uneventful post-operative course, the patient developed left-sided hemispheric infarct. The patient is doing well at nine months' follow-up, and he is off voriconazole for three months after the follow-up imaging showed complete resolution of disease. CONCLUSION: Treatment of choice for cerebral aspergillosis is voriconazole. Surgical debridement may be a useful adjunct in patients not responding to voriconazole alone.


Assuntos
Aspergilose/complicações , Aspergilose/terapia , Aspergillus/patogenicidade , Infecções Fúngicas do Sistema Nervoso Central/complicações , Infecções Fúngicas do Sistema Nervoso Central/terapia , Infarto Cerebral/etiologia , Imunocompetência , Adulto , Craniotomia , Desbridamento , Seguimentos , Humanos , Masculino , Voriconazol/administração & dosagem , Adulto Jovem
2.
Am J Trop Med Hyg ; 103(4): 1473-1479, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32876006

RESUMO

Phaeohyphomycosis causes a wide spectrum of systemic manifestations and can affect even the immunocompetent hosts. Involvement of the central nervous system is rare. A 48-year-old farmer presented with chronic headache, fever, and impaired vision and hearing. Serial MRIs of the brain showed enhancing exudates in the basal cisterns, and lesions in the sella and perichiasmatic and cerebellopontine angle regions along with enhancement of the cranial nerves and leptomeninges. Cerebrospinal fluid (CSF) showed lymphocytic pleocytosis with elevated protein and decreased glucose on multiple occasions. Clinical, imaging, and CSF abnormalities persisted despite treatment with antitubercular drugs and steroids for 2 years. Biopsy of the dura mater at the cervicomedullary junction revealed necrotizing granulomatous lesions, neutrophilic abscesses, and giant cells containing slender, pauci-septate, pigmented fungal hyphae. Fungal culture showed growth of Fonsecaea pedrosoi, which is classically known to cause brain abscesses. Here, we report the diagnostic odyssey in a patient with chronic meningitis from a region endemic for tuberculosis and describe the challenges in establishing the accurate diagnosis. Lack of therapeutic response to an adequate trial of empirical antitubercular therapy warrants search for alternative causes, including fungal meningitis. We highlight the uncommon manifestation of F. pedrosoi with chronic meningitis as well as the protracted clinical course despite not receiving antifungal therapy.


Assuntos
Abscesso Encefálico/microbiologia , Diagnóstico Diferencial , Meningite Fúngica/diagnóstico , Meningite/patologia , Tuberculose Meníngea/diagnóstico , Anfotericina B/administração & dosagem , Anfotericina B/uso terapêutico , Antifúngicos/administração & dosagem , Antifúngicos/uso terapêutico , Antituberculosos/uso terapêutico , Ascomicetos/isolamento & purificação , Encéfalo/patologia , Abscesso Encefálico/patologia , Humanos , Masculino , Meningite Fúngica/tratamento farmacológico , Pessoa de Meia-Idade , Feoifomicose/diagnóstico , Esteroides/uso terapêutico , Tuberculose Meníngea/tratamento farmacológico , Voriconazol/administração & dosagem , Voriconazol/uso terapêutico
3.
J Infect Chemother ; 26(8): 847-850, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32414688

RESUMO

Aspergillus empyema is treated with either systemic administration of antifungal drugs or surgery, but the mortality rate is very high. Here, we report a case of Aspergillus empyema successfully treated using combined intrathoracic and intravenous administration of voriconazole (VRCZ). Treatment success was achieved by monitoring VRCZ plasma trough concentration. The patient was a 71-year-old Japanese woman diagnosed with Aspergillus empyema whom we started on intravenous administration of VRCZ. Although penetration of VRCZ into the pleural effusion was confirmed, the level was below 1 µg/mL, which is the minimum inhibitory concentration for Aspergillus fumigatus determined by antifungal susceptibility testing in pleural effusion culture. Therefore, we initiated combination therapy with intrathoracic and intravenous administration of VRCZ. VRCZ 200 mg was first dissolved in 50-100 mL of saline and administered into the thoracic cavity via a chest tube. The chest tube was clamped for 5-6 h, and then VRCZ solution was excreted though the chest tube. When a single dose of the VRCZ was administered into the intrathoracic space, the plasma concentration before intravenous administration increased from 1.45 µg/mL on day 27 to 1.53 µg/mL on day 28. Although intravenous administration was continued, the VRCZ plasma trough concentration decreased to 1.36 µg/mL on day 29. We therefore decided on an intrathoracic administration schedule of 2-3 times a week. Intrathoracic administration was performed 14 times in total until fenestration surgery on day 64. Our case suggests that combined intrathoracic and intravenous administration of VRCZ may be a valid treatment option for Aspergillus empyema.


Assuntos
Antifúngicos/administração & dosagem , Aspergilose/tratamento farmacológico , Aspergillus fumigatus/isolamento & purificação , Empiema/tratamento farmacológico , Voriconazol/administração & dosagem , Administração Intravenosa , Idoso , Tubos Torácicos , Monitoramento de Medicamentos , Quimioterapia Combinada , Empiema/microbiologia , Feminino , Humanos , Derrame Pleural/microbiologia , Resultado do Tratamento
5.
Int J Infect Dis ; 93: 345-352, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32109625

RESUMO

OBJECTIVES: To characterize the pharmacokinetics (PK) of intravenous voriconazole (VRC) in critically ill patients with liver dysfunction. METHODS: Patients with liver dysfunction in the intensive care unit (ICU) were included prospectively. The Child-Pugh score was used to categorize the degree of liver dysfunction. The initial intravenous VRC dosing regimen comprised a loading dose of 300 mg every 12 h for the first 24 h, followed by 200 mg every 12 h. The first PK curves (PK curve 1) were drawn within one dosing interval of the first dose for 17 patients; the second PK curves (PK curve 2) were drawn within one dosing interval after a minimum of seven doses for 12 patients. PK parameters were estimated by non-compartmental analysis. RESULTS: There were good correlations between the area under the curve (AUC0-12) of PK curve 2 and the corresponding trough concentration (C0) and peak concentration (Cmax) (r2 = 0.951 and 0.963, respectively; both p < 0.001). The median half-life (t1/2) and clearance (CL) of patients in Child-Pugh class A (n = 3), B (n = 5), and C (n = 4) of PK curve 2 were 24.4 h and 3.31 l/h, 29.1 h and 2.54 l/h, and 60.7 h and 2.04 l/h, respectively. In the different Child-Pugh classes, the CL (median) of PK curve 2 were all lower than those of PK curve 1. The apparent steady-state volume of distribution (Vss) of PK curve 1 was positively correlated with actual body weight (r2 = 0.450, p = 0.004). The median first C0 of 17 patients determined on day 5 was 5.27 (2.61) µg/ml, and 29.4% of C0 exceeded the upper limit of the therapeutic window (2-6 µg/ml). CONCLUSIONS: The CL of VRC decreased with increasing severity of liver dysfunction according to the Child-Pugh classification, along with an increased t1/2, which resulted in high plasma exposure of VRC. Adjusted dosing regimens of intravenous VRC should be established based on Child-Pugh classes for these ICU patients, and plasma concentrations should be monitored closely to avoid serious adverse events.


Assuntos
Antifúngicos/farmacocinética , Unidades de Terapia Intensiva , Hepatopatias/metabolismo , Voriconazol/farmacocinética , Administração Intravenosa , Adulto , Idoso , Idoso de 80 Anos ou mais , Área Sob a Curva , Estado Terminal , Feminino , Meia-Vida , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Voriconazol/administração & dosagem
6.
AAPS PharmSciTech ; 21(3): 82, 2020 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-31989357

RESUMO

The mainstay treatment of pulmonary disorders lies around the direct drug targeting to the lungs using a nebulizer, metered-dose inhaler, or dry powder inhaler. Only few inhalers are available in the market that could be used for inhalational drug delivery in rodents. However, the available rodent inhalers invariably require high cost and maintenance, which limits their use at laboratory scale. The present work, therefore, was undertaken to develop a simple, reliable, and cost-effective nose-only inhalation chamber with holding capacity of three mice at a time. The nebulized air passes directly and continuously from the central chamber to mouthpiece and maintains an aerosol cloud for rodents to inhale. Laser diffraction analysis indicated volume mean diameter of 4.02 ± 0.30 µm, and the next-generation impactor studies, however, revealed mean mass aerodynamic diameter of 3.40 ± 0.27 µm, respectively. An amount of 2.05 ± 0.20 mg of voriconazole (VRC) was available for inhalation at each delivery port of the inhaler. In vivo studies indicated the deposition of 76.12 ± 19.50 µg of VRC in the mice lungs when nebulized for a period of 20 min. Overall, the developed nose-only inhalation chamber offers a reliable means of generating aerosols and successfully exposing mice to nebulization.


Assuntos
Nebulizadores e Vaporizadores , Administração por Inalação , Aerossóis/administração & dosagem , Animais , Análise Custo-Benefício , Desenho de Equipamento , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Nebulizadores e Vaporizadores/economia , Nariz , Voriconazol/administração & dosagem
7.
Ocul Immunol Inflamm ; 28(3): 471-478, 2020 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-30810429

RESUMO

Purpose: Candida endophthalmitis represents a therapeutic challenge, considering the inability of many antifungals to achieve adequate concentrations in the vitreous. Intravitreal injection (IVI) of antifungals (amphotericin b deoxycholate or voriconazole) is therefore recommended. Whereas amphotericin b IVI is well documented, clinical data on voriconazole IVI are limited.Methods: This was a retrospective review IRB approved of patients receiving voriconazole IVI for Candida endophthalmitis. Complete ophthalmological examination was completed at baseline and during follow-up.Results: Five patients were treated with a mean four injections [range: 2-9] of voriconazole (100 µg/0.1 mL saline). Improvement of visual acuity and disappearance of signs of infection were obtained in all patients. Safety concern including photoreceptor toxicity was not attributed to voriconazole IVI.Conclusions: Voriconazole IVI demonstrated to be safe and led to a favorable clinical outcome. Thus, voriconazole IVI must be performed if Candida endophthalmitis is suspected to increase the chance of clinical success.


Assuntos
Candida albicans/isolamento & purificação , Endoftalmite/tratamento farmacológico , Infecções Oculares Fúngicas/tratamento farmacológico , Voriconazol/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Antifúngicos/administração & dosagem , Candidíase/diagnóstico , Candidíase/microbiologia , Endoftalmite/diagnóstico , Endoftalmite/microbiologia , Infecções Oculares Fúngicas/diagnóstico , Infecções Oculares Fúngicas/microbiologia , Feminino , Humanos , Injeções Intravítreas , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Tomografia de Coerência Óptica
9.
Pharm Dev Technol ; 25(4): 440-453, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31851857

RESUMO

In this study, voriconazole (VCZ) incorporated polyvinyl alcohol/sodium alginate electrospun nanofibers were produced and, then crosslinked with glutaraldehyde for topical antifungal treatment. The nanofibers were characterized in terms of fiber size, surface morphology, and compatibility between drug-polymer and polymer-polymer using scanning electron microscopy, atomic force microscopy, attenuated total reflection-Fourier transform infrared spectroscopy, and high pressure liquid chromatography. After optimization studies, in vitro drug release, skin penetration, and deposition studies were performed using Franz diffusion cells. Antifungal activities of the nanofiber formulations against Candida albicans, Candida tropicalis, and Candida parapysilosis strains were evaluated using susceptibility test and subsequently time-kill study was performed against C. albicans. The cytotoxicity study was performed using 4-succinate dehydrogenase viability assay on mouse fibroblast cell line. The release rate of VCZ from crosslinked nanofibers was slower than that of non-crosslinked nanofibers and Higuchi kinetic model best fitted to the in vitro release data of both of formulations. VCZ deposited in deeper skin layers from nanofiber formulations was higher than that of the control formulation (VCZ solution in propylene glycol (1% (w/v)). According to the susceptibility and time-kill studies, all of the nanofiber formulations showed antifungal activity against C. albicans with confirming no cytotoxicity on mouse fibroblast cells.


Assuntos
Antifúngicos/administração & dosagem , Candida/efeitos dos fármacos , Sistemas de Liberação de Medicamentos , Nanofibras/química , Voriconazol/administração & dosagem , Administração Tópica , Alginatos/química , Animais , Antifúngicos/farmacocinética , Antifúngicos/farmacologia , Candidíase/tratamento farmacológico , Linhagem Celular , Liberação Controlada de Fármacos , Humanos , Camundongos , Álcool de Polivinil/química , Absorção Cutânea , Suínos , Voriconazol/farmacocinética , Voriconazol/farmacologia
10.
Int J Pharm ; 576: 118991, 2020 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-31884059

RESUMO

Strategies to enhance corneal penetration of voriconazole (VOR) could improve the treatment of fungal keratitis. Here, we evaluated the use of iontophoresis for ocular VOR delivery from either: (i) a cyclodextrin inclusion complex (CD VOR), (ii) a liposome (LP VOR), and (iii) a chitosan-coated liposome (LP VOR CS). LP VOR CS presented mean diameter of 139.2 ±â€¯1.3 nm and zeta potential equal to + 3.3 ±â€¯1.5 mV compared to 134.6 ±â€¯1.7 and -8.2 ±â€¯3.0 mV of LP VOR, which, together with mucin mucoadhesion study, confirmed chitosan-coating. Both drug and liposomal formulations were stable under the influence of an applied electric current. Interestingly, in vitro studies in Candida glabrata culture indicated a decrease in VOR MIC values following iontophoresis (from 0.28 to 0.14 µg/mL). Iontophoresis enhanced drug penetration into the cornea. After 10 min of a 2 mA/cm2 applied current, corneal retained amounts were 45.4 ±â€¯11.2, 30.4 ±â€¯2.1 and 30.6 ±â€¯2.9 µg/cm2 for, respectively, CD VOR, LP VOR, and LP VOR CS. In conclusion, iontophoresis increases drug potency and enhances drug penetration into the cornea, showing potential to be used as "an emergency burst delivery approach".


Assuntos
Antifúngicos/administração & dosagem , Candida glabrata/efeitos dos fármacos , Córnea/metabolismo , Iontoforese , Voriconazol/administração & dosagem , Administração Oftálmica , Animais , Antifúngicos/química , Antifúngicos/metabolismo , Candida glabrata/crescimento & desenvolvimento , Quitosana/química , Ciclodextrinas/química , Composição de Medicamentos , Lipídeos/química , Lipossomos , Testes de Sensibilidade Microbiana , Nanopartículas , Sus scrofa , Distribuição Tecidual , Voriconazol/química , Voriconazol/metabolismo
11.
Indian J Ophthalmol ; 68(1): 35-38, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31856462

RESUMO

Purpose: To evaluate the efficacy of intrastromal voriconazole for the management of fungal keratitis not responding to conventional therapy. Methods: Patients having microbiologically proven fungal keratitis with poor response to 2 weeks of conventional topical therapy were included in the study. After obtaining informed consent, an intrastromal injection of voriconazole was administered around the ulcer. Response to treatment in the form reduction in the size of the ulcer and infiltration was recorded on regular follow-ups. Results: Out of a total of 20 patients, 14 responded to intrastromal treatment and resolved, whereas six patients progressed to perforation. Mean resolution time was 35.5 ± 9.2 days. The most common organism isolated was Fusarium in six patients while Aspergillus and Mucor were isolated in two each. The causative organism could not be isolated in eight patients. The size of the ulcer at presentation and height of hypopyon were found to be significant risk factors associated with treatment outcomes. Conclusion: Intrastromal voriconazole as an adjuvant therapy appeared to be effective in treatment of fungal keratomycosis not responding to conventional therapy, thus, reducing the need for therapeutic or tectonic keratoplasty.


Assuntos
Infecções Oculares Fúngicas/tratamento farmacológico , Ceratite/tratamento farmacológico , Voriconazol/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Antifúngicos/administração & dosagem , Substância Própria , Infecções Oculares Fúngicas/microbiologia , Feminino , Seguimentos , Fungos/isolamento & purificação , Humanos , Injeções Intraoculares , Ceratite/microbiologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Resultado do Tratamento
12.
BMC Infect Dis ; 19(1): 1051, 2019 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-31830905

RESUMO

BACKGROUND: Cryptococcal prostatitis is a rare clinical disease and has never been reported in China. CASE PRESENTATION: We report on a male HIV-infected patient with pulmonary and prostate cryptococcosis that was misdiagnosed (as tuberculosis) and delayed diagnosed. Although the patients accepted anti-fungal treatment and anti-retroviral treatment finally, the physician's mistakes reflect the rarity of this condition in China. CONCLUSION: Cryptococcal prostatitis is a rare disease that unusually presents in immunodeficient patients. Physicians should have a heightened awareness of this particular infection in the immunodeficient population.


Assuntos
Infecções Oportunistas Relacionadas com a AIDS/diagnóstico , Criptococose/diagnóstico , Cryptococcus neoformans/isolamento & purificação , Pneumonia por Pneumocystis/diagnóstico , Prostatite/diagnóstico , Retenção Urinária/diagnóstico , Retenção Urinária/microbiologia , Infecções Oportunistas Relacionadas com a AIDS/tratamento farmacológico , Antifúngicos/administração & dosagem , Antifúngicos/uso terapêutico , China , Criptococose/complicações , Criptococose/tratamento farmacológico , Diagnóstico Tardio , Erros de Diagnóstico , Fluconazol/administração & dosagem , Fluconazol/uso terapêutico , Flucitosina/administração & dosagem , Flucitosina/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Pneumonia por Pneumocystis/tratamento farmacológico , Pneumonia por Pneumocystis/microbiologia , Prostatite/tratamento farmacológico , Prostatite/microbiologia , Resultado do Tratamento , Voriconazol/administração & dosagem , Voriconazol/uso terapêutico
13.
Medicine (Baltimore) ; 98(41): e17535, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31593129

RESUMO

Scedosporium genus as a significant emerging opportunist causes a broad spectrum of disease in not only immunosuppressed but also immunocompetent patients. The lung is one of the most commonly encountered sites of Scedosporium infection. Due to its very high levels of antifungal resistance, surgery has been recommended as an important part in the treatment of pulmonary Scedosporium spp infection, even in immunocompetent cases. However, whether lung surgery could help to reduce the risk of death in immunocompetent patients is not clear.We retrospectively retrieved the records of pulmonary infections with Scedosporium species in immunocompetent patients through a comprehensive literature search. The association of surgery on all-cause mortality was explored using binary logistic regression (BLR). Receiver operating characteristic (ROC) curve analysis was carried out to evaluate the capability of the model.The comprehensive searching strategy yielded 33 case reports and 3 case series in total, with 40 individual patients being included. The overall mortality was 12.50%. The fatality rate was 9.09% (2/22) in cases with surgery and 16.67% (3/18) in cases without surgery (odds ratio, 0.50; 95% confidence interval, 0.07-3.38; P = .48). Consistently, BLR analysis identified no statistical association between surgery and reduced mortality (odds ratio, 1.19; 95% confidence interval, 0.09-15.64; P = .89), after adjusting for age, gender, and antifungal chemotherapy. The area under the ROC curve was 0.88.For immunocompetent patients with pulmonary Scedosporium spp infection, surgical therapy may not be associated with reduced mortality. Surgical excision could be considered but is not imperative in this group of patients.


Assuntos
Pneumopatias Fúngicas/tratamento farmacológico , Pneumopatias Fúngicas/cirurgia , Infecções Respiratórias/tratamento farmacológico , Infecções Respiratórias/cirurgia , Scedosporium/efeitos dos fármacos , Adulto , Idoso , Idoso de 80 Anos ou mais , Antifúngicos/uso terapêutico , Farmacorresistência Fúngica/fisiologia , Feminino , Humanos , Hospedeiro Imunocomprometido/efeitos dos fármacos , Pneumopatias Fúngicas/microbiologia , Pneumopatias Fúngicas/mortalidade , Masculino , Pessoa de Meia-Idade , Mortalidade/tendências , Micoses/tratamento farmacológico , Micoses/epidemiologia , Micoses/microbiologia , Micoses/mortalidade , Estudos Observacionais como Assunto , Cuidados Pós-Operatórios , Infecções Respiratórias/microbiologia , Infecções Respiratórias/mortalidade , Estudos Retrospectivos , Scedosporium/isolamento & purificação , Voriconazol/administração & dosagem , Voriconazol/uso terapêutico
14.
BMJ Case Rep ; 12(9)2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31570348

RESUMO

A 10-year-old Saudi boy was diagnosed to have basidiobolomycosis after a stormy course of his ailment. Therapy was initiated with intravenous antifungal, voriconazole, which was well tolerated for 6 weeks except for local excoriation at the site of ileostomy. He developed drug-induced hepatitis on oral voriconazole, therefore, switched to oral itraconazole following which he experienced severe chest pain. Alternatively, co-trimoxazole (bactrim) an antibacterial with antifungal activity was prescribed but he had the intolerance to it as well. Unfortunately, posaconazole as an alternative antifungal was not available in our centre. We report here a Saudi boy who developed an intolerance to most common antifungals used clinically 6 weeks after the therapy was initiated.


Assuntos
Dor Abdominal/microbiologia , Antifúngicos/efeitos adversos , Doença de Crohn/fisiopatologia , Itraconazol/efeitos adversos , Voriconazol/efeitos adversos , Zigomicose/microbiologia , Administração Intravenosa , Antifúngicos/administração & dosagem , Criança , Doença de Crohn/microbiologia , Progressão da Doença , Humanos , Itraconazol/administração & dosagem , Masculino , Resultado do Tratamento , Voriconazol/administração & dosagem , Zigomicose/tratamento farmacológico , Zigomicose/fisiopatologia
16.
Int J Clin Oncol ; 24(11): 1449-1458, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31300904

RESUMO

BACKGROUND: The prevention of invasive fungal infections is important in patients with acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS) receiving cytoreductive chemotherapy. However, the role of oral voriconazole (VRCZ) in such patients has not been established. This study aimed to investigate the effectiveness of oral VRCZ compared to that of first-generation azoles prescribed within 7 days after the onset of chemotherapy in adult patients with AML/MDS using the Japanese administrative database. METHODS: This nationwide retrospective cohort study was conducted using the Diagnosis Procedure Combination/Per-Diem Payment System. The primary outcome was the proportion of patients who switched to intravenous antifungal agents. Analyses using the instrumental variable method were performed to address unmeasured confounding. RESULTS: In total, data on 5517 inpatients from 142 hospitals were analyzed. An oral VRCZ prescription was significantly associated with a reduction in the proportion of patients switching to intravenous antifungal agents compared to first-generation azole prescription (21.0% (95% confidence interval [CI] - 33.4 to - 8.6)). The impact of oral VRCZ in reducing the proportion of patients switching to intravenous antifungal agents was stronger in patients aged < 65 years than in those aged ≥ 65 years (- 40.6%, 95% CI - 63.2 to - 17.9; - 21.9%, 95% CI - 35.8 to - 8.1, respectively) and in patients prescribed oral azole within 3 days from the onset of chemotherapy than in those prescribed the same later (- 32.9%, 95% CI - 46.7 to - 19.2; - 9.0%, 95% CI - 33.7 to 15.7, respectively). CONCLUSION: Oral VRCZ administration may benefit adult patients with AML/MDS undergoing chemotherapy.


Assuntos
Antifúngicos/administração & dosagem , Infecções Fúngicas Invasivas/prevenção & controle , Leucemia Mieloide Aguda/tratamento farmacológico , Síndromes Mielodisplásicas/tratamento farmacológico , Voriconazol/administração & dosagem , Administração Intravenosa , Administração Oral , Idoso , Feminino , Mortalidade Hospitalar , Humanos , Infecções Fúngicas Invasivas/mortalidade , Japão/epidemiologia , Tempo de Internação/estatística & dados numéricos , Leucemia Mieloide Aguda/complicações , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/complicações , Síndromes Mielodisplásicas/mortalidade , Estudos Retrospectivos
17.
Int J Antimicrob Agents ; 54(4): 463-470, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31279853

RESUMO

Individualisation of the therapeutic strategy for the oral antifungal agent voriconazole (VCZ) is extremely important for treatment optimisation. To date, regulatory agencies include CYP2C19 as the only major pharmacogenetic (PGx) biomarker in their dosing guidelines; however, the effect of other genes might be important for VCZ dosing prediction. We developed an exploratory PGx study to identify new biomarkers related to VCZ pharmacokinetics. We first designed a 'clinical practice VCZ-AUC prediction model' based on CYP2C19 to be used as a reference model in this study. We then designed a multifactorial polygenic prediction model and found that genetic variability in FMO3, NR1I2, POR, CYP2C9 and CYP3A4 partially contributes to VCZ total area under the concentration-time curve (AUC0-∞) interindividual variability, and its inclusion in VCZ AUC0-∞ prediction algorithms improves model precision. To our knowledge, there are no PGx studies specifically relating POR, FMO3 and NR1I2 polymorphisms to VCZ pharmacokinetic variability. Further research is needed in order to test the model proposed here.


Assuntos
Antifúngicos/administração & dosagem , Antifúngicos/farmacocinética , Estudos de Associação Genética , Voriconazol/administração & dosagem , Voriconazol/farmacocinética , Administração Oral , Adulto , Feminino , Humanos , Masculino , Farmacogenética/métodos , Ensaios Clínicos Controlados Aleatórios como Assunto , Espanha , Adulto Jovem
18.
Crit Care Med ; 47(9): e767-e773, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31306179

RESUMO

OBJECTIVES: Little is known on the impact of continuous renal replacement therapy on antimicrobial dose requirements in children. In this study, we evaluated the pharmacokinetics of commonly administered antimicrobials in an ex vivo continuous renal replacement therapy model. DESIGN: An ex vivo continuous renal replacement therapy circuit was used to evaluate drug-circuit interactions and determine the disposition of five commonly used antimicrobials (meropenem, piperacillin, liposomal amphotericin B, caspofungin, and voriconazole). SETTING: University research laboratory. PATIENTS: None. INTERVENTIONS: Antimicrobials were administered into a reservoir containing whole human blood. The reservoir was connected to a pediatric continuous renal replacement therapy circuit programmed for a 10 kg child. Continuous renal replacement therapy was performed in the hemodiafiltration mode and in three phases correlating with three different continuous renal replacement therapy clearance rates: 1) no clearance (0 mL/kg/hr, to measure adsorption), 2) low clearance (20 mL/kg/hr), and 3) high clearance (40 mL/kg/hr). Blood samples were drawn directly from the reservoir at baseline and at 5, 20, 60, and 180 minutes during each phase. Five independent continuous renal replacement therapy runs were performed to assess inter-run variability. Antimicrobial concentrations were measured using validated liquid chromatography-mass spectrometry assays. A closed-loop, flow-through pharmacokinetic model was developed to analyze concentration-time profiles for each drug. MEASUREMENTS AND MAIN RESULTS: Circuit adsorption of antimicrobials ranged between 13% and 27%. Meropenem, piperacillin, and voriconazole were cleared by the continuous renal replacement therapy circuit and clearance increased with increasing continuous renal replacement therapy clearance rates (7.66 mL/min, 4.97 mL/min, and 2.67 mL/min, respectively, for high continuous renal replacement therapy clearance). Amphotericin B and caspofungin had minimal circuit clearance and did not change with increasing continuous renal replacement therapy clearance rates. CONCLUSIONS: Careful consideration of drug-circuit interactions during continuous renal replacement therapy is essential for appropriate drug dosing in critically ill children. Antimicrobials have unique adsorption and clearance profiles during continuous renal replacement therapy, and this knowledge is important to optimize antimicrobial therapy.


Assuntos
Anti-Infecciosos/administração & dosagem , Anti-Infecciosos/farmacocinética , Terapia de Substituição Renal Contínua/métodos , Pediatria , Anfotericina B/administração & dosagem , Caspofungina/administração & dosagem , Caspofungina/farmacocinética , Relação Dose-Resposta a Droga , Humanos , Meropeném/administração & dosagem , Meropeném/farmacocinética , Taxa de Depuração Metabólica , Modelos Biológicos , Piperacilina/farmacocinética , Voriconazol/administração & dosagem , Voriconazol/farmacocinética
20.
J Infect Chemother ; 25(12): 1019-1025, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31239195

RESUMO

Flavin-containing monooxygenase (FMO) 3 together with cytochrome P450 (CYP) 2C19 play a significant role in voriconazole N-oxidation. This study aimed to evaluate the influence of FMO3 and CYP2C19 genotypes on the plasma disposition and adverse effects of voriconazole in immunocompromised patients. Sixty-five Japanese immunocompromised patients receiving oral voriconazole were enrolled. Predose plasma concentrations of voriconazole and N-oxide were determined at day 5 or later. The adverse effects of voriconazole and the FMO3 and CYP2C19 genotypes were investigated. The patients with FMO3 E158K/E308G had a lower plasma concentration of voriconazole. The metabolic ratio to N-oxide was significantly higher in the FMO3 E158K/E308G group than in the wild group. In contrast, FMO3 V257M was not associated with the plasma concentration of voriconazole. No significant difference was observed in the saturation index, defined as a correlation coefficient of the regression line between the absolute plasma concentration of voriconazole and the inverse value of the metabolic ratio to N-oxide, between the FMO3 genotypes. CYP2C19 phenotype did not affect the plasma concentration and metabolic ratio of voriconazole. The saturation index of voriconazole rose in the order of CYP2C19 extensive, intermediate, and then poor metabolizer groups. However, the FMO3 and CYP2C19 genotypes and their associated voriconazole pharmacokinetics did not have an effect on the incidence of adverse effects. In conclusion, FMO3 E158K/E308G decreased the plasma concentration of voriconazole through its higher metabolic activity. The FMO3 genotype altered the plasma exposure of voriconazole, while the CYP2C19 phenotype affected the metabolic capacity in immunocompromised patients.


Assuntos
Antifúngicos/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/epidemiologia , Citocromo P-450 CYP2C19/genética , Oxigenases/genética , Voriconazol/efeitos adversos , Administração Oral , Idoso , Antifúngicos/administração & dosagem , Antifúngicos/farmacocinética , Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Doença Hepática Induzida por Substâncias e Drogas/genética , Citocromo P-450 CYP2C19/metabolismo , Feminino , Genótipo , Humanos , Hospedeiro Imunocomprometido/efeitos dos fármacos , Hospedeiro Imunocomprometido/genética , Incidência , Japão/epidemiologia , Testes de Função Hepática , Masculino , Pessoa de Meia-Idade , Micoses/tratamento farmacológico , Oxigenases/metabolismo , Voriconazol/administração & dosagem , Voriconazol/farmacocinética
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