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1.
BMC Infect Dis ; 21(1): 375, 2021 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-33882845

RESUMO

BACKGROUND: Cryptococcal meningitis (CM) is a common HIV-associated opportunistic-infection worldwide. Existing literature focusses on hospital-based outcomes of induction treatment. This paper reviews outpatient management in integrated primary care clinics in Yangon. METHOD: This retrospective case note review analyses a Myanmar HIV-positive patient cohort managed using ambulatory induction-phase treatment with intravenous amphotericin-B-deoxycholate (0.7-1.0 mg/kg) and oral fluconazole (800 mg orally/day). RESULTS: Seventy-six patients were diagnosed between 2010 and 2017. The median age of patients diagnosed was 35 years, 63% were male and 33 (45%) were on concurrent treatment for tuberculosis. The median CD4 count was 60 at the time of diagnosis. Amphotericin-B-deoxycholate infusions precipitated 56 episodes of toxicity, namely hypokalaemia, nephrotoxicity, anaemia, febrile reactions, phlebitis, observed in 44 patients (58%). One-year survival (86%) was higher than existing hospital-based treatment studies. CONCLUSION: Ambulation of patients in this cohort saved 1029 hospital bed days and had better survival outcomes when compared to hospital-based studies in other resource constrained settings.


Assuntos
Infecções Oportunistas Relacionadas com a AIDS/complicações , Anfotericina B/administração & dosagem , Antifúngicos/administração & dosagem , Cryptococcus neoformans/imunologia , Ácido Desoxicólico/administração & dosagem , Fluconazol/administração & dosagem , HIV , Meningite Criptocócica/complicações , Meningite Criptocócica/tratamento farmacológico , Atenção Primária à Saúde , Infecções Oportunistas Relacionadas com a AIDS/epidemiologia , Infecções Oportunistas Relacionadas com a AIDS/virologia , Administração Intravenosa , Administração Oral , Adolescente , Adulto , Anfotericina B/efeitos adversos , Antifúngicos/efeitos adversos , Cryptococcus neoformans/isolamento & purificação , Ácido Desoxicólico/efeitos adversos , Combinação de Medicamentos , Quimioterapia Combinada , Feminino , Fluconazol/efeitos adversos , Humanos , Masculino , Meningite Criptocócica/epidemiologia , Meningite Criptocócica/microbiologia , Pessoa de Meia-Idade , Mianmar/epidemiologia , Flebite/induzido quimicamente , Estudos Retrospectivos , Resultado do Tratamento , Adulto Jovem
2.
Isr Med Assoc J ; 23(2): 116-120, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33595218

RESUMO

BACKGROUND: Extremely preterm infants are at high risk for mortality and morbidity including neurodevelopmental impairment from invasive Candida infections. Prophylactic antifungal therapy has been shown to reduce both colonization and invasive candidemia in high-risk preterm infants. Prophylactic treatment should be started in the first 48 to 72 hours after birth to extremely low birth weight (ELBW) infants (weighing ≤ 1000 grams at birth) or below 27 weeks gestation age with risk factors, or in any NICU with moderate (5-10%) or high (≥ 10%) rates of invasive candidiasis. Studies demonstrated the benefits of fluconazole prophylaxis regarding its safety of the short-term and long-term without the development of fungal resistance. Empiric antifungal therapy may lower mortality and improve outcomes.


Assuntos
Antifúngicos/administração & dosagem , Candidíase Invasiva/prevenção & controle , Doenças do Prematuro/prevenção & controle , Antifúngicos/efeitos adversos , Candidíase Invasiva/mortalidade , Farmacorresistência Fúngica , Fluconazol/administração & dosagem , Fluconazol/efeitos adversos , Humanos , Recém-Nascido de Peso Extremamente Baixo ao Nascer , Recém-Nascido , Recém-Nascido Prematuro , Doenças do Prematuro/microbiologia , Doenças do Prematuro/mortalidade , Unidades de Terapia Intensiva Neonatal , Seleção de Pacientes
3.
BMJ ; 369: m1494, 2020 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-32434758

RESUMO

OBJECTIVE: To examine the risk of congenital malformations associated with exposure to oral fluconazole at commonly used doses in the first trimester of pregnancy for the treatment of vulvovaginal candidiasis. DESIGN: Population based cohort study. SETTING: A cohort of pregnancies publicly insured in the United States, with data from the nationwide Medicaid Analytic eXtract 2000-14. PARTICIPANTS: Pregnancies of women enrolled in Medicaid from three or more months before the last menstrual period to one month after delivery, and infants enrolled for three or more months after birth. INTERVENTIONS: Use of fluconazole and topical azoles was established by requiring one or more prescriptions during the first trimester of pregnancy. MAIN OUTCOME MEASURES: Risk of musculoskeletal malformations, conotruncal malformations, and oral clefts (primary outcomes), associated with exposure to oral fluconazole, diagnosed during the first 90 days after delivery, were examined. RESULTS: The study cohort of 1 969 954 pregnancies included 37 650 (1.9%) pregnancies exposed to oral fluconazole and 82 090 (4.2%) pregnancies exposed to topical azoles during the first trimester. The risk of musculoskeletal malformations was 52.1 (95% confidence interval 44.8 to 59.3) per 10 000 pregnancies exposed to fluconazole versus 37.3 (33.1 to 41.4) per 10 000 pregnancies exposed to topical azoles. The risks of conotruncal malformations were 9.6 (6.4 to 12.7) versus 8.3 (6.3 to 10.3) per 10 000 pregnancies exposed to fluconazole and topical azoles, respectively; risks of oral clefts were 9.3 (6.2 to 12.4) versus 10.6 (8.4 to 12.8) per 10 000 pregnancies, respectively. The adjusted relative risk after fine stratification of the propensity score was 1.30 (1.09 to 1.56) for musculoskeletal malformations, 1.04 (0.70 to 1.55) for conotruncal malformations, and 0.91 (0.61 to 1.35) for oral clefts overall. Based on cumulative doses of fluconazole, the adjusted relative risks for musculoskeletal malformations, conotruncal malformations, and oral clefts overall were 1.29 (1.05 to 1.58), 1.12 (0.71 to 1.77), and 0.88 (0.55 to 1.40) for 150 mg of fluconazole; 1.24 (0.93 to 1.66), 0.61 (0.26 to 1.39), and 1.08 (0.58 to 2.04) for more than 150 mg up to 450 mg of fluconazole; and 1.98 (1.23 to 3.17), 2.30 (0.93 to 5.65), and 0.94 (0.23 to 3.82) for more than 450 mg of fluconazole, respectively. CONCLUSIONS: Oral fluconazole use in the first trimester was not associated with oral clefts or conotruncal malformations, but an association with musculoskeletal malformations was found, corresponding to a small adjusted risk difference of about 12 incidents per 10 000 exposed pregnancies overall.


Assuntos
Antifúngicos/efeitos adversos , Candidíase Vulvovaginal/tratamento farmacológico , Fluconazol/efeitos adversos , Complicações Infecciosas na Gravidez/tratamento farmacológico , Anormalidades Induzidas por Medicamentos/epidemiologia , Administração Oral , Adulto , Antifúngicos/uso terapêutico , Candidíase Vulvovaginal/etnologia , Fissura Palatina/induzido quimicamente , Fissura Palatina/epidemiologia , Anormalidades Congênitas/epidemiologia , Anormalidades Congênitas/etiologia , Síndrome de DiGeorge/induzido quimicamente , Síndrome de DiGeorge/epidemiologia , Feminino , Fluconazol/uso terapêutico , Humanos , Recém-Nascido , Anormalidades Musculoesqueléticas/induzido quimicamente , Anormalidades Musculoesqueléticas/epidemiologia , Gravidez , Complicações Infecciosas na Gravidez/epidemiologia , Primeiro Trimestre da Gravidez , Risco , Sensibilidade e Especificidade , Estados Unidos/epidemiologia
4.
Gen Dent ; 68(2): 50-54, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32105227

RESUMO

Erythema multiforme (EM) is an acute hypersensitivity reaction that affects the skin and/or mucosa. EM induced by fluconazole is extremely rare, with only 2 previously published case reports. The aims of this article are to report a rare case of severe EM induced by fluconazole in an immunocompetent patient and to review all similar published cases. A 35-year-old man presented with multiple painful superficial ulcerated lesions on the lips, superficial ulcers on the right and left ocular mucosa, and erythematous macules on the right cervical region. Moreover, multiple painful superficial ulcers covered by a serofibrinous pseudomembrane were located on the oral mucosa. The lesions appeared after the initial oral use of fluconazole (100 mg) 3 weeks previously for the treatment of onychomycosis. The clinical diagnosis was EM associated with fluconazole. The antifungal medication was discontinued, and a single dose of intramuscular Diprospan (5 mg of betamethasone dipropionate/2 mg of betamethasone disodium phosphate) was prescribed. Complete healing of all lesions at the 7-day follow-up was observed.


Assuntos
Eritema Multiforme/induzido quimicamente , Eritema Multiforme/diagnóstico , Fluconazol/efeitos adversos , Fluconazol/uso terapêutico , Adulto , Humanos , Masculino , Mucosa Bucal , Úlcera , Cicatrização
5.
Adv Neonatal Care ; 20(1): E3-E8, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31306235

RESUMO

BACKGROUND: Because Candida spp is a major cause of mortality and morbidity in preterm infants, fluconazole prophylaxis has been suggested by some experts and hospital policy. In our hospital, fluconazole prophylaxis was used in eligible preterm infants and set as the neonatal intensive care unit (NICU) practice in 2014. PURPOSE: This study focused on fungal bloodstream infections and aimed to evaluate the benefit and harm of fluconazole prophylaxis. METHODS/SEARCH STRATEGY: This retrospective, descriptive study involved medical record reviews in our hospital from April 2005 to October 2016. NICU patients were included if Candida species, yeast-like organisms, or Malassezia species were cultured from their venous catheter tips or blood cultures. FINDINGS/RESULTS: After fluconazole prophylaxis, cases of Candida spp decreased and those of Malassezia furfur emerged. We reviewed 19 cases of catheter-related M furfur colonization and 1 case of M furfur fungemia. The gestational age was 27.3 ± 2.0 weeks and birth weight was 959.2 ± 229.8 g. Hyperalimentation with lipid infusion was used in all cases. All of the neonates survived with antifungal agent use. IMPLICATIONS FOR PRACTICE: This study highlights that prophylactic fluconazole may be an associated factor of Malassezia colonization; M furfur remains a potential concern for fungemia in the care of premature infants and thus requires our attention. IMPLICATIONS FOR RESEARCH: Future studies should further investigate the incidence and impact of noncandidal fungal infections with fluconazole prophylaxis use in premature infants.


Assuntos
Candidemia/diagnóstico , Candidemia/tratamento farmacológico , Fluconazol/efeitos adversos , Fluconazol/normas , Fluconazol/uso terapêutico , Fungemia/induzido quimicamente , Fungemia/tratamento farmacológico , Unidades de Terapia Intensiva Neonatal/normas , Antifúngicos/normas , Antifúngicos/uso terapêutico , Candidemia/epidemiologia , Feminino , Previsões , Fungemia/epidemiologia , Humanos , Lactente , Recém-Nascido , Unidades de Terapia Intensiva Neonatal/tendências , Masculino , Guias de Prática Clínica como Assunto , Prevalência , Estudos Retrospectivos , Taiwan/epidemiologia
6.
Int J Gynaecol Obstet ; 148(1): 6-13, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31691277

RESUMO

OBJECTIVE: To assess the risk of adverse fetal outcomes after exposure to oral antifungal agents during pregnancy. SEARCH STRATEGY: PubMed, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) were searched up to October 2018. SELECTION CRITERIA: Cohort studies and case-control studies investigating fetal outcomes following maternal exposure to oral antifungal agents. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed studies for inclusion, assessed risk of bias, and extracted data. Pooled estimates were calculated for the frequency of adverse fetal outcomes. MAIN RESULTS: Overall, eight cohort studies and one case-control study were included. The oral antifungal agents used during pregnancy were fluconazole and itraconazole. The data indicated that oral fluconazole exposure during pregnancy might slightly increase the risk of congenital heart defects and limb defects relative to the general population; oral itraconazole during pregnancy might increase the risk of eye defects. No difference was found between oral fluconazole/itraconazole exposure and non-exposure in the risk of other birth defects, spontaneous abortion, or stillbirth. CONCLUSION: Oral fluconazole or itraconazole may not increase the risk of birth defects. Nonetheless, the risk of congenital heart defects and limb defects after fluconazole exposure and eye defects after itraconazole exposure should be cautiously investigated.


Assuntos
Antifúngicos/efeitos adversos , Fluconazol/efeitos adversos , Itraconazol/efeitos adversos , Aborto Espontâneo/epidemiologia , Aborto Espontâneo/etiologia , Estudos de Casos e Controles , Estudos de Coortes , Anormalidades Congênitas/epidemiologia , Anormalidades Congênitas/etiologia , Feminino , Humanos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Natimorto/epidemiologia
7.
JAMA ; 322(17): 1673-1681, 2019 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-31688884

RESUMO

Importance: Children, adolescents, and young adults with acute myeloid leukemia are at high risk of life-threatening invasive fungal disease with both yeasts and molds. Objective: To compare the efficacy of caspofungin vs fluconazole prophylaxis against proven or probable invasive fungal disease and invasive aspergillosis during neutropenia following acute myeloid leukemia chemotherapy. Design, Setting, and Participants: This multicenter, randomized, open-label, clinical trial enrolled patients aged 3 months to 30 years with newly diagnosed de novo, relapsed, or secondary acute myeloid leukemia being treated at 115 US and Canadian institutions (April 2011-November 2016; last follow-up June 30, 2018). Interventions: Participants were randomly assigned during the first chemotherapy cycle to prophylaxis with caspofungin (n = 257) or fluconazole (n = 260). Prophylaxis was administered during the neutropenic period following each chemotherapy cycle. Main Outcomes and Measures: The primary outcome was proven or probable invasive fungal disease as adjudicated by blinded central review. Secondary outcomes were invasive aspergillosis, empirical antifungal therapy, and overall survival. Results: The second interim efficacy analysis and an unplanned futility analysis based on 394 patients appeared to have suggested futility, so the study was closed to accrual. Among the 517 participants who were randomized (median age, 9 years [range, 0-26 years]; 44% female), 508 (98%) completed the trial. The 23 proven or probable invasive fungal disease events (6 caspofungin vs 17 fluconazole) included 14 molds, 7 yeasts, and 2 fungi not further categorized. The 5-month cumulative incidence of proven or probable invasive fungal disease was 3.1% (95% CI, 1.3%-7.0%) in the caspofungin group vs 7.2% (95% CI, 4.4%-11.8%) in the fluconazole group (overall P = .03 by log-rank test) and for cumulative incidence of proven or probable invasive aspergillosis was 0.5% (95% CI, 0.1%-3.5%) with caspofungin vs 3.1% (95% CI, 1.4%-6.9%) with fluconazole (overall P = .046 by log-rank test). No statistically significant differences in empirical antifungal therapy (71.9% caspofungin vs 69.5% fluconazole, overall P = .78 by log-rank test) or 2-year overall survival (68.8% caspofungin vs 70.8% fluconazole, overall P = .66 by log-rank test) were observed. The most common toxicities were hypokalemia (22 caspofungin vs 13 fluconazole), respiratory failure (6 caspofungin vs 9 fluconazole), and elevated alanine transaminase (4 caspofungin vs 8 fluconazole). Conclusions and Relevance: Among children, adolescents, and young adults with acute myeloid leukemia, prophylaxis with caspofungin compared with fluconazole resulted in significantly lower incidence of invasive fungal disease. The findings suggest that caspofungin may be considered for prophylaxis against invasive fungal disease, although study interpretation is limited by early termination due to an unplanned interim analysis that appeared to have suggested futility. Trial Registration: ClinicalTrials.gov Identifier: NCT01307579.


Assuntos
Antifúngicos/uso terapêutico , Caspofungina/uso terapêutico , Fluconazol/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Micoses/prevenção & controle , Adolescente , Adulto , Antifúngicos/efeitos adversos , Aspergilose/epidemiologia , Aspergilose/prevenção & controle , Caspofungina/efeitos adversos , Criança , Pré-Escolar , Término Precoce de Ensaios Clínicos , Feminino , Fluconazol/efeitos adversos , Humanos , Lactente , Estimativa de Kaplan-Meier , Leucemia Mieloide Aguda/complicações , Masculino , Neutropenia/complicações , Adulto Jovem
9.
Am J Case Rep ; 20: 1378-1381, 2019 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-31530795

RESUMO

BACKGROUND Acute intermittent porphyria (AIP) is a rare autosomal dominant disorder that is part of a group of acute porphyria disorders usually found in females of reproductive age. Although clinically there is low penetrance, with 90% of genetically diagnosed individuals never experiencing an acute flair, consequences of acute flairs may lead to devastating results. Debilitating paresis, seizures, respiratory failure, and even death may result from AIP. Early detection is key in preventing these devastating manifestations. CASE REPORT A 67-year-old Hispanic man with a past medical history of pulmonary Coccidioides on fluconazole presented with bilateral thigh pain for 2 days. At baseline, the patient had no limitations, but now was limited to minimal walking due to his thigh pain subsequently progressing to diffuse weakness after the administration of IV Solumedrol. Over the next few months, EMG was notable for acute-on-chronic sensorimotor axonal denervation in upper and lower extremities, without evidence of myositis. Urine porphobilinogen was 58 mmol/L, which is 29 times the upper limit of normal. Treatment was started with hemin 4 mg/kg/day for 4 days. CONCLUSIONS Over our patient's clinical course, he was affected by a severe manifestation of repeated acute porphyria attacks, which started as anterior thigh pain and progressed to diffused weakness disproportionally affecting the muscles of the upper extremities. Although the patient was in his late 60's at the initial onset of AIP, his diffuse Coccidioides infection, use of azoles, and steroids likely contributed to his first AIP attack.


Assuntos
Antifúngicos/efeitos adversos , Coccidioidomicose/tratamento farmacológico , Fluconazol/efeitos adversos , Pneumopatias Fúngicas/tratamento farmacológico , Polineuropatias/etiologia , Porfiria Aguda Intermitente/diagnóstico , Idoso , Antifúngicos/administração & dosagem , Fluconazol/administração & dosagem , Humanos , Masculino , Porfobilinogênio/urina
10.
BJOG ; 126(13): 1546-1552, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31446677

RESUMO

BACKGROUND: Oral fluconazole is used to treat vulvovaginal candidiasis during pregnancy. However, there are concerns regarding the pregnancy outcomes following exposure to fluconazole. OBJECTIVES: To evaluate the pregnancy outcomes associated with exposure to oral fluconazole during the first trimester of pregnancy. SEARCH STRATEGY: A systematic literature search was conducted to identify relevant studies published from inception until April 2019. SELECTION CRITERIA: Relevant English-language citations using the terms oral fluconazole and pregnancy in humans. DATA COLLECTION: Two reviewers independently abstracted data and assessed study quality. MAIN RESULTS: Oral fluconazole use during the first trimester of pregnancy was marginally associated with an increased risk of congenital malformations (odds ratio [OR] 1.09, 95% CI 0.99-1.2, P = 0.088; n = 6 studies), whereas in the subgroup analysis, this association existed only for high-dose users (>150 mg) (OR 1. 19, 95% CI 1.01-1.4, P = 0.039; n = 2). Exposure to fluconazole also increased the risk of heart malformations (OR 1.31, 95% CI 1.09-1.57, P = 0.003; n = 4), cardiac septal defects (OR 1.3, 95% CI 1.1-1.67, P = 0.047; n = 3), and tetralogy of Fallot (OR 3.39 95% CI 1.71-6.74, P < 0.001; n = 2) in the offspring. In addition, exposure to fluconazole was significantly associated with an increased risk of spontaneous abortion (OR 1.99, 95% CI 1.38-2.88, P < 0.001; n = 3). CONCLUSIONS: Oral fluconazole use during the first trimester of pregnancy appears to be associated with heart malformations and spontaneous abortion, but a causal link cannot be proven. TWEETABLE ABSTRACT: Oral fluconazole during the first trimester of pregnancy may be associated with unfavourable pregnancy outcomes.


Assuntos
Antifúngicos/administração & dosagem , Candidíase Vulvovaginal/tratamento farmacológico , Anormalidades Craniofaciais/induzido quimicamente , Fluconazol/administração & dosagem , Anormalidades Induzidas por Medicamentos , Administração Oral , Antifúngicos/efeitos adversos , Feminino , Fluconazol/efeitos adversos , Humanos , Segurança do Paciente , Gravidez , Primeiro Trimestre da Gravidez
11.
Comp Med ; 69(3): 221-239, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30971325

RESUMO

Over 18 mo, adult female pigtailed macaques (Macaca nemestrina) housed at a breeding facility in Arizona were monitored every 6 mo for alopecia. The study period coincided with the movement of a majority of animals from primarily outdoor housing to continuous indoor housing and a corresponding decrease in available space. These changes were made due to the newly recognized prevalence of coccidioidomycosis at this site. The effects of pregnancy status, changes in outdoor access or space, and administration of fluconazole for the treatment of coccidioidomycosis on alopecia were explored. In this group of pigtailed macaques pregnancy did not appear to affect alopecia, in contrast to findings from a closely related species, rhesus macaques. Fluconazole administration increased alopecia in older animals but not in the youngest age group. Conversely, the effects of limited outdoor access or decreased space on increasing alopecia were greatest in the youngest group of animals.


Assuntos
Alopecia/veterinária , Macaca nemestrina , Doenças dos Macacos/etiologia , Complicações na Gravidez/veterinária , Prenhez , Fatores Etários , Alopecia/complicações , Alopecia/etiologia , Animais , Antifúngicos/efeitos adversos , Cruzamento , Coccidioidomicose/complicações , Coccidioidomicose/tratamento farmacológico , Coccidioidomicose/veterinária , Feminino , Fluconazol/efeitos adversos , Abrigo para Animais , Macaca mulatta , Doenças dos Macacos/tratamento farmacológico , Gravidez , Complicações na Gravidez/tratamento farmacológico , Especificidade da Espécie
12.
Regul Toxicol Pharmacol ; 106: 152-168, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31026541

RESUMO

Mefentrifluconazole (trade name: Revysol®) is an agrochemical active ingredient from the new sub-class of isopropanol-triazole fungicides, with high selective fungicide activity. A full program of toxicity testing conducted according to OECD guidelines has shown mefentrifluconazole (MFZ) to be non-genotoxic and non-carcinogenic. Repeated dose studies in rats, mice and dogs identified the liver as the main target organ. Prenatal developmental toxicity studies in rats and rabbits did not indicate treatment-related embryofetal toxicity or teratogenicity up to the highest dose levels tested. In a two-generation dietary study in rats, the high dose level resulted in reduced food consumption and body weight gain throughout the dosing-period. Mating performance and fertility, estrous cycles, gestation length and pre-and post-natal survival of offspring were essentially unaffected and there was no evidence of masculinization of female pups or feminization of male pups. The screening strategy that led to the selection of MFZ was aimed to identify candidates with both high fungicidal activity and minimal likelihood of adverse side effects thought to arise from aromatase inhibition. The success of the selection strategy has been illustrated for MFZ by the absence in toxicity studies of effects that would indicate an endocrine disrupting potential.


Assuntos
Antifúngicos/efeitos adversos , Antifúngicos/toxicidade , Fluconazol/análogos & derivados , Animais , Peso Corporal/efeitos dos fármacos , Cães , Relação Dose-Resposta a Droga , Feminino , Fluconazol/efeitos adversos , Fluconazol/toxicidade , Humanos , Fígado/efeitos dos fármacos , Masculino , Camundongos , Coelhos , Ratos
13.
J Low Genit Tract Dis ; 23(3): 226-229, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30893271

RESUMO

OBJECTIVES: Vulvovaginal candidiasis (VVC) is an infection of the vagina's mucous membranes, caused by Candida albicans in more than 90% of acute VVC. Several topical and oral azole agents are available in a variety of formulations, and all seem to have similar effectiveness. Azoles are fungistatic, meaning that the fungi are inhibited from growth or replication but are not eradicated. Recurrent infection and developing azole resistance demonstrate a significant need for alternative treatments. MATERIALS AND METHODS: One hundred twenty-six women were randomized to 1 of the following 3 treatment cohorts: CD101 3% gel (n = 50) applied intravaginally on days 1 and 2, CD101 6% ointment (n = 50) applied intravaginally on day 1, or oral fluconazole 150 mg (n = 26) on day 1. Primary outcomes of clinical and mycological cure, as demonstrated by changes in the vaginal scores and mycological culture, were assessed on day 7 (±2 days), day 14 (±2 days), and day 28 (±7 days). Safety assessments included treatment-emergent adverse events. RESULTS: Ninety-nine women with positive Candida culture remained in the modified intent-to-treat population with 40 in each CD101 arm and 19 in the fluconazole arm. In the CD101 gel, CD101 ointment, and oral fluconazole groups, 35%, 30%, and 52.6% demonstrated clinical cure and 45%, 40%, and 57.9% had mycological cure at day 28, respectively. CONCLUSIONS: CD101 3% gel and CD101 6% ointment were well tolerated and produced similar rates of clinical and mycological cure in patients with an acute, moderate-to-severe episode of VVC. However, cure rates for these 2 formulations and regimens of CD101 were lower than those in patients treated with fluconazole.


Assuntos
Antifúngicos/administração & dosagem , Candidíase Vulvovaginal/tratamento farmacológico , Equinocandinas/administração & dosagem , Fluconazol/administração & dosagem , Administração Oral , Administração Tópica , Adulto , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Equinocandinas/efeitos adversos , Feminino , Fluconazol/efeitos adversos , Humanos , Resultado do Tratamento
14.
Br J Clin Pharmacol ; 85(7): 1464-1473, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30845347

RESUMO

AIMS: This phase I study evaluated the effects of the moderate cytochrome P450 (CYP) 3A inhibitor fluconazole and the strong CYP3A/P-glycoprotein (P-gp) inhibitor itraconazole on the pharmacokinetics of the investigational neural precursor cell expressed, developmentally downregulated 8 (NEDD8)-activating enzyme inhibitor pevonedistat in patients with advanced solid tumours. METHODS: Patients received single doses of intravenous pevonedistat 8 mg m-2 , alone and with fluconazole (loading: 400 mg; maintenance: 200 mg once daily), or pevonedistat 8, 15 or 20 mg m-2 , alone and with itraconazole 200 mg once daily. Serial blood samples for pevonedistat pharmacokinetics were obtained pre- and post-infusion on days 1 (alone) and 8 (with fluconazole/itraconazole). After completing the pharmacokinetic portion, patients remaining on study received pevonedistat with docetaxel or carboplatin and paclitaxel. RESULTS: The ratios of geometric mean area under the concentration-time curves (n; 90% confidence interval) of pevonedistat in the presence vs. absence of fluconazole or itraconazole were 1.11 (12; 1.03-1.19) and 1.14 (33; 1.07-1.23), respectively. Fifty patients (98%) experienced at least one adverse event (AE), with maximum severity of grade 1-2 in 28 patients (55%) and of grade ≥3 in 22 patients (43%). The most common drug-related AEs were vomiting (12%), diarrhoea (10%) and nausea (8%). No new safety findings were observed for pevonedistat. CONCLUSIONS: Fluconazole or itraconazole had insignificant effects on pevonedistat pharmacokinetics, indicating minor contributions of CYP3A/P-gp to pevonedistat clearance. The safety profile of single doses of pevonedistat plus steady-state fluconazole or itraconazole was consistent with prior clinical experience, with no new safety signals observed.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Ciclopentanos/farmacocinética , Inibidores do Citocromo P-450 CYP3A/farmacologia , Neoplasias/tratamento farmacológico , Pirimidinas/farmacocinética , Adulto , Idoso , Idoso de 80 Anos ou mais , Área Sob a Curva , Carboplatina/administração & dosagem , Ciclopentanos/administração & dosagem , Ciclopentanos/efeitos adversos , Inibidores do Citocromo P-450 CYP3A/administração & dosagem , Inibidores do Citocromo P-450 CYP3A/efeitos adversos , Docetaxel/administração & dosagem , Interações Medicamentosas , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/efeitos adversos , Inibidores Enzimáticos/farmacocinética , Feminino , Fluconazol/administração & dosagem , Fluconazol/efeitos adversos , Fluconazol/farmacologia , Humanos , Itraconazol/administração & dosagem , Itraconazol/efeitos adversos , Itraconazol/farmacologia , Masculino , Pessoa de Meia-Idade , Paclitaxel/administração & dosagem , Pirimidinas/administração & dosagem , Pirimidinas/efeitos adversos
16.
CMAJ ; 191(7): E179-E187, 2019 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-30782643

RESUMO

BACKGROUND: While topical azoles are the first-line treatment for fungal infections, oral fluconazole is frequently used during pregnancy. We aimed to assess the effect of exposure to low and high doses of fluconazole during pregnancy on the occurrence of spontaneous abortions, major congenital malformations and stillbirths. METHODS: Within the Quebec Pregnancy Cohort (1998-2015), we identified women exposed to low- (≤ 150 mg) and high-dose (> 150 mg) fluconazole, and women who were not exposed. For each case of spontaneous abortion or stillbirth, up to 5 controls were randomly selected using an incidence density sampling method matched on gestational age at diagnosis of spontaneous abortion or stillbirth (index date) and the year of the last menstrual period. For cases of major congenital malformation, we considered all liveborn babies as controls. Generalized estimation equation models were used to analyze the 3 main outcomes separately. RESULTS: Within a cohort of 441 949 pregnancies, 320 868 pregnancies were included in the analyses of spontaneous abortions, 226 599 of major congenital malformations and 7832 of stillbirths. Most (69.5%) women exposed to fluconazole in pregnancy received the common single therapeutic dose of 150 mg (low dose); the remainder received a dose of > 150 mg (high dose). Use of oral fluconazole during early pregnancy was associated with an increased risk of spontaneous abortion compared with no exposure (adjusted odds ratio [OR] for 345 cases exposed to low-dose treatment 2.23, 95% confidence interval [CI] 1.96-2.54; adjusted OR for 249 cases exposed to high-dose treatment 3.20, 95% CI 2.73-3.75). Exposure to fluconazole during the first trimester did not increase the risk of overall major congenital malformations; however, exposure to a high dose during the first trimester was associated with an increased risk of cardiac septal closure anomalies (adjusted OR 1.81, 95% CI 1.04-3.14; 13 exposed cases) compared with no exposure. No association was found between exposure to fluconazole during pregnancy and the risk of stillbirth. INTERPRETATION: Any maternal exposure to fluconazole during pregnancy may increase risk of spontaneous abortion and doses higher than 150 mg during the first trimester may increase risk of cardiac septal closure anomalies.


Assuntos
Aborto Espontâneo/induzido quimicamente , Antifúngicos/efeitos adversos , Fluconazol/efeitos adversos , Defeitos dos Septos Cardíacos/induzido quimicamente , Exposição Materna/efeitos adversos , Natimorto/epidemiologia , Aborto Espontâneo/epidemiologia , Administração Oral , Adolescente , Adulto , Antifúngicos/administração & dosagem , Candidíase Vulvovaginal/tratamento farmacológico , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Fluconazol/administração & dosagem , Idade Gestacional , Defeitos dos Septos Cardíacos/epidemiologia , Humanos , Modelos Logísticos , Análise Multivariada , Gravidez , Complicações Infecciosas na Gravidez/tratamento farmacológico , Primeiro Trimestre da Gravidez , Quebeque/epidemiologia , Adulto Jovem
17.
J Clin Invest ; 129(3): 999-1014, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30688656

RESUMO

BACKGROUND: Cryptococcal meningitis (CM) causes an estimated 180,000 deaths annually, predominantly in sub-Saharan Africa, where most patients receive fluconazole (FLC) monotherapy. While relapse after FLC monotherapy with resistant strains is frequently observed, the mechanisms and impact of emergence of FLC resistance in human CM are poorly understood. Heteroresistance (HetR) - a resistant subpopulation within a susceptible strain - is a recently described phenomenon in Cryptococcus neoformans (Cn) and Cryptococcus gattii (Cg), the significance of which has not previously been studied in humans. METHODS: A cohort of 20 patients with HIV-associated CM in Tanzania was prospectively observed during therapy with either FLC monotherapy or in combination with flucytosine (5FC). Total and resistant subpopulations of Cryptococcus spp. were quantified directly from patient cerebrospinal fluid (CSF). Stored isolates underwent whole genome sequencing and phenotypic characterization. RESULTS: Heteroresistance was detectable in Cryptococcus spp. in the CSF of all patients at baseline (i.e., prior to initiation of therapy). During FLC monotherapy, the proportion of resistant colonies in the CSF increased during the first 2 weeks of treatment. In contrast, no resistant subpopulation was detectable in CSF by day 14 in those receiving a combination of FLC and 5FC. Genomic analysis revealed high rates of aneuploidy in heteroresistant colonies as well as in relapse isolates, with chromosome 1 (Chr1) disomy predominating. This is apparently due to the presence on Chr1 of ERG11, which is the FLC drug target, and AFR1, which encodes a drug efflux pump. In vitro efflux levels positively correlated with the level of heteroresistance. CONCLUSION: Our findings demonstrate for what we believe is the first time the presence and emergence of aneuploidy-driven FLC heteroresistance in human CM, association of efflux levels with heteroresistance, and the successful suppression of heteroresistance with 5FC/FLC combination therapy. FUNDING: This work was supported by the Wellcome Trust Strategic Award for Medical Mycology and Fungal Immunology 097377/Z/11/Z and the Daniel Turnberg Travel Fellowship.


Assuntos
Cryptococcus gattii , Cryptococcus neoformans , Farmacorresistência Fúngica/efeitos dos fármacos , Fluconazol/administração & dosagem , Meningite Criptocócica , Ploidias , Cryptococcus gattii/genética , Cryptococcus gattii/isolamento & purificação , Cryptococcus neoformans/genética , Cryptococcus neoformans/isolamento & purificação , Farmacorresistência Fúngica/genética , Feminino , Fluconazol/efeitos adversos , Humanos , Masculino , Meningite Criptocócica/líquido cefalorraquidiano , Meningite Criptocócica/tratamento farmacológico , Meningite Criptocócica/genética , Meningite Criptocócica/microbiologia
18.
Int J Dermatol ; 58(2): 250-253, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30229876

RESUMO

BACKGROUND: Fluconazole is the most commonly used antifungal treatment for various forms of coccidioidomycosis. Although we had anecdotally observed a high proportion of patients reporting cutaneous adverse effects associated with fluconazole treatment, this observation was not well described in the medical literature, and we were unsure of the additional effect of the arid desert environment of Arizona. METHODS: We performed a one-time, voluntary survey of patients with coccidioidomycosis and compared the responses of patients treated with fluconazole with those of untreated patients. RESULTS: From January 1, 2015, to August 22, 2017, 62 fluconazole-treated and 35 untreated patients with coccidioidomycosis provided consent and were enrolled in the study; demographics were similar between the two groups. Among the 62 fluconazole-treated patients, daily dosages ranged from 200 mg to 800 mg. However, most (44/62, 71%) took 400 mg daily, the typical dose for the treatment of coccidioidomycosis. The median fluconazole treatment duration at the time of study participation was 6 months. When compared with untreated patients, those taking fluconazole had more moderate to severe dry lips (74.2% [46/62] vs. 23.5% [8/34]; P < 0.001), dry skin (45.8% [27/59] vs. 22.9% [8/35]; P = 0.03), and alopecia (31.1% [19/61] vs. 11.4% [4/35]; P = 0.004). CONCLUSIONS: For the treatment of coccidioidomycosis, patients receiving fluconazole reported significantly more severe cutaneous effects, including dry lips, dry skin, and alopecia, than untreated patients. Our findings identify an association but do not prove causality.


Assuntos
Antifúngicos/efeitos adversos , Fluconazol/efeitos adversos , Doenças Labiais/epidemiologia , Dermatopatias/epidemiologia , Alopecia/epidemiologia , Arizona/epidemiologia , Clima , Coccidioidomicose/tratamento farmacológico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
19.
J Oncol Pharm Pract ; 25(8): 2004-2006, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30501378

RESUMO

Prolongation of the corrected QT interval can lead to the deadly arrhythmia torsades de pointes. There are many risk factors for corrected QT prolongation, one being medication. The goal of this case report is to add to the limited literature surrounding the possibility of torsades de pointes when levofloxacin and fluconazole are used concomitantly. Additionally, provide guidance for patient factors that need to be assessed when prescribing the two drugs.


Assuntos
Fluconazol/efeitos adversos , Levofloxacino/efeitos adversos , Torsades de Pointes/induzido quimicamente , Adulto , Eletrocardiografia , Feminino , Fluconazol/uso terapêutico , Humanos , Levofloxacino/administração & dosagem , Síndrome do QT Longo/induzido quimicamente , Fatores de Risco
20.
J Antimicrob Chemother ; 74(3): 768-771, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30535104

RESUMO

BACKGROUND: Fluconazole is a commonly prescribed first-generation triazole antifungal. Although the toxicity profile of fluconazole has been evaluated in clinical trials, there are scant data regarding its tolerability with long-term therapy. Treatment guidelines for coccidioidomycosis recommend fluconazole therapy and severe or disseminated infections can require lifelong treatment. OBJECTIVES: To assess the prevalence of long-term fluconazole adverse effects, their consequences for antifungal therapy, time to adverse effects and the association between dosing regimen or fluconazole serum level and adverse effect status. METHODS: We conducted a single-centre, retrospective study of adult patients (≥18 years) with proven or probable coccidioidomycosis receiving long-term fluconazole therapy for an intended duration of ≥28 days. RESULTS: Out of 124 patients included, 64 (51.6%) experienced adverse effects. The most common adverse effects were xerosis (16.9%), alopecia (16.1%) and fatigue (11.3%). Of the 64 patients experiencing adverse effects, 42 (65.6%) required a therapeutic intervention such as dose reduction, discontinuation or switch to a new antifungal. Patients experiencing adverse effects were prescribed higher total daily fluconazole doses (6.7 versus 5.7 mg/kg; P < 0.01). The median therapeutic drug levels did not differ significantly between patients who experienced adverse effects and those who did not (36.1 versus 28.1 mg/L; P = 0.35). CONCLUSIONS: A significant number of patients receiving long-term fluconazole therapy for coccidioidomycosis experienced adverse effects. Of these, around two-thirds required a therapeutic change. We believe these findings are representative of the adverse effect profile of long-term fluconazole therapy as it is used in clinical practice for coccidioidomycosis as opposed to use in clinical trials.


Assuntos
Antifúngicos/efeitos adversos , Antifúngicos/uso terapêutico , Coccidioidomicose/tratamento farmacológico , Fluconazol/efeitos adversos , Fluconazol/uso terapêutico , Adulto , Antifúngicos/administração & dosagem , Coccidioidomicose/microbiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/diagnóstico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Feminino , Fluconazol/administração & dosagem , Humanos , Masculino , Estudos Retrospectivos , Fatores de Tempo , Resultado do Tratamento
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