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1.
J Enzyme Inhib Med Chem ; 38(1): 36-50, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36305289

RESUMO

The increasing resistance of fungi to conventional antifungal drugs has prompted worldwide the search for new compounds. In this work, we investigated the antifungal properties of acylated Temporin L derivatives, Pent-1B and Dec-1B, against Candida albicans, including the multidrug-resistant strains. Acylated peptides resulted to be active both on reference and clinical strains with MIC values ranging from 6.5 to 26 µM, and they did not show cytotoxicity on human keratinocytes. In addition, we also observed a synergistic or additive effect with voriconazole for peptides Dec-1B and Pent-1B through the checkerboard assay on voriconazole-resistant Candida strains. Moreover, fluorescence-based assays, NMR spectroscopy, and confocal microscopy elucidated a potential membrane-active mechanism, consisting of an initial electrostatic interaction of acylated peptides with fungal membrane, followed by aggregation and insertion into the lipid bilayer and causing membrane perturbation probably through a carpeting effect.


Assuntos
Antifúngicos , Candida albicans , Farmacorresistência Fúngica Múltipla , Humanos , Antifúngicos/farmacologia , Peptídeos Catiônicos Antimicrobianos/farmacologia , Candida albicans/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Voriconazol/farmacologia
2.
J Infect Chemother ; 29(1): 87-89, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36162644

RESUMO

Thermothelomyces thermophila (formerly Myceliophthora thermophila) is usually found in soil and specifically compost as an environmental dematiaceous fungus. Here, we report the first case of invasive pulmonary infection caused by T. thermophila in a pediatric patient with acute lymphoblastic leukemia. T. thermophila was serially cultured from bronchoalveolar lavage (BAL) fluid and sputum samples obtained from this patient with respiratory symptoms. The patient received antifungal treatment with liposomal amphotericin B (160 mg daily) and itraconazole (200 mg daily) combination therapy, but she died. By the antifungal susceptibility testing, low minimum inhibitory concentrations (MIC) were observed for itraconazole (MIC 0.06 µg/mL), voriconazole (MIC 0.12 µg/mL), and posaconazole (MIC 0.03 µg/mL) but high MIC was observed with amphotericin B (MIC 4.0 µg/mL). Since T. thermophila is usually found in the environment, it can be considered as a contaminant and may cause difficulties in diagnosis. Therefore, it is necessary to confirm the potential of pathogen through repeated culture and to conduct an antifungal susceptibility testing to find a suitable antifungal agent.


Assuntos
Antifúngicos , Pneumonia , Feminino , Humanos , Criança , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Itraconazol/farmacologia , Itraconazol/uso terapêutico , Voriconazol/farmacologia , Testes de Sensibilidade Microbiana
3.
BMJ Case Rep ; 15(11)2022 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-36414342

RESUMO

Aspergillus osteomyelitis (AO) is a rare and often lethal opportunistic infection in predominantly immunocompromised patients. Treatment has shifted from amphotericin therapy to voriconazole monotherapy due to increased effectiveness and less toxicity. We report a case of an immunocompetent woman with vertebral osteomyelitis due to Aspergillus flavus who was successfully treated with surgery (requiring hardware implantation) and monotherapy posaconazole (following intolerance and hepatitis due to voriconazole). She remained well at follow-up post cessation of 12 months of antifungal therapy. We provide an updated literature review examining the role of azole monotherapy as the gold standard of treatment for AO.


Assuntos
Hepatite A , Osteomielite , Feminino , Humanos , Aspergillus flavus , Voriconazol/uso terapêutico , Osteomielite/tratamento farmacológico , Azóis
4.
J Med Case Rep ; 16(1): 429, 2022 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-36345027

RESUMO

BACKGROUND: Opportunistic infections are frequent in people living with the human immunodeficiency virus who either do not have access to antiretroviral therapy (ART) or use it irregularly. Tuberculosis is the most frequent infectious disease in PLHIV and can predispose patients to severe fungal infections with dire consequences. CASE PRESENTATION: We describe the case of a 35-year-old Brazilian man living with human immunodeficiency virus (HIV) for 10 years. He reported no adherence to ART and a history of histoplasmosis with hospitalization for 1 month in a public hospital in Natal, Brazil. The diagnosis was disseminated Mycobacterium tuberculosis infection. He was transferred to the health service in Recife, Brazil, with a worsening condition characterized by daily fevers, dyspnea, pain in the upper and lower limbs, cough, dysphagia, and painful oral lesions suggestive of candidiasis. Lymphocytopenia and high viral loads were found. After screening for infections, the patient was diagnosed with tuberculous pericarditis and esophageal candidiasis caused by Candida tropicalis. The isolated yeasts were identified using the VITEK 2 automated system and matrix-assisted laser desorption/ionization time-of-flight-mass spectrometry. Antifungal microdilution broth tests showed sensitivity to fluconazole, voriconazole, anidulafungin, caspofungin, micafungin, and amphotericin B, with resistance to fluconazole and voriconazole. The patient was treated with COXCIP-4 and amphotericin deoxycholate. At 12 days after admission, the patient developed sepsis of a pulmonary focus with worsening of his respiratory status. Combined therapy with meropenem, vancomycin, and itraconazole was started, with fever recurrence, and he changed to ART and tuberculostatic therapy. The patient remained clinically stable and was discharged with clinical improvement after 30 days of hospitalization. CONCLUSION: Fungal infections should be considered in patients with acquired immunodeficiency syndrome as they contribute to worsening health status. When mycoses are diagnosed early and treated with the appropriate drugs, favorable therapeutic outcomes can be achieved.


Assuntos
Candidíase , Esofagite , Micoses , Pericardite Tuberculosa , Masculino , Humanos , Adulto , Fluconazol/uso terapêutico , Voriconazol/uso terapêutico , Pericardite Tuberculosa/complicações , Pericardite Tuberculosa/diagnóstico , Pericardite Tuberculosa/tratamento farmacológico , Candidíase/tratamento farmacológico , Micoses/tratamento farmacológico , Antifúngicos/uso terapêutico , Esofagite/tratamento farmacológico , HIV
5.
Pan Afr Med J ; 42: 306, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36425541

RESUMO

Fungal necrotizing external otitis (NEO) is a rare disease. It is an aggressive and potentially fatal infection. The most commonly reported pathogen is Candida. We aim through this study to share our experience in the management of fungal necrotizing external otitis and discuss its diagnosis tools, anti-fungal treatment choice, and outcomes. We included fifteen patients with diagnosis criteria of fungal NEO; clinical features of NEO with positive culture swabs and/or positive serologic test to a fungal pathogen. The mean age was of 70 years with a prevalence of males. The main symptoms were otalgia (n=15) and otorrhea (n=7). Facial palsy was observed in four cases. Fungal pathogens were Candida(n=10) and Aspergillus (n=5). Complications were observed in eight cases: extension to the temporo-mandibular (n=4), abscess in the retropharyngeal space (n=2), abscess in the parapharyngeal space (n=1) and thrombophlebitis of the internal jugular vein (n=1). Six patients were treated with fluconazole, eight with voriconazole, and one patient with itraconazole. After a mean duration of 52 days of antifungal therapy, fourteen patients have been cured with normalization of the ear symptoms, biological, and imaging features. One patient died of septic shock. No recurrence of the disease was observed after a follow-up of 12 months in all cases.


Assuntos
Otite Externa , Otomicose , Masculino , Humanos , Idoso , Feminino , Otite Externa/diagnóstico , Otite Externa/tratamento farmacológico , Otite Externa/microbiologia , Antifúngicos/uso terapêutico , Abscesso/tratamento farmacológico , Otomicose/diagnóstico , Otomicose/tratamento farmacológico , Voriconazol/uso terapêutico , Candida
6.
Medicine (Baltimore) ; 101(40): e30958, 2022 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-36221387

RESUMO

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 terapêutico
7.
J Zoo Wildl Med ; 53(3): 605-612, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36214247

RESUMO

This report documents cases of fatal pulmonary mycosis caused by entomopathogenic fungi in the genera Metarhizium and Beauveria (Order Hypocreales) in a loggerhead sea turtle (Caretta caretta), a Chinese alligator (Alligator sinensis), two gopher tortoises (Gopherus polyphemus), a Cuvier's dwarf caiman (Paleosuchus palpebrosus), a false gharial (Tomistoma schlegelii), a green sea turtle (Chelonia mydas), and a Kemp's ridley sea turtle (Lepidochelys kempii), and a case of granulomatous coelomitis in a hawksbill sea turtle (Eretmochelys imbricata). Fungi identified in these cases included Beauveria bassiana, Beauveria brongniartii, Metarhizium anisopliae, Metarhizium robertsii, and one case of infection by a novel Metarhizium species. The animals were either housed at zoos or brought into rehabilitation from the wild. Although the majority of animals had comorbidities, the fungal infections were believed to be the primary cause of death. Fungal susceptibility testing was performed on two Beauveria spp. isolates, and revealed lower minimum inhibitory concentrations for itraconazole and voriconazole when compared to terbinafine and fluconazole. This case series demonstrates that a variety of reptile species from different orders are vulnerable to infection with Metarhizium, and multiple species of sea turtle are susceptible to infection with Beauveria.


Assuntos
Jacarés e Crocodilos , Beauveria , Metarhizium , Micoses , Tartarugas , Animais , Fluconazol , Itraconazol , Micoses/veterinária , Controle Biológico de Vetores , Terbinafina , Voriconazol
8.
Indian J Ophthalmol ; 70(11): 4004-4009, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36308145

RESUMO

Purpose: The aim of this study was to present the signs, symptoms, management, and outcome of a series of cases of cluster endophthalmitis caused by a multi-drug resistant fungus, Trichosporon. Methods: This was a retrospective, non-randomized, consecutive interventional case series. Ten cases of postoperative endophthalmitis operated by a surgeon on three consecutive operation theater (OT) days presented 3-5 months after their surgery. All cases were microbiologically confirmed. The pathogen was found to be resistant to most antifungals, including amphotericin B. The cases had a latent period of around 45 days. Management of endophthalmitis included intravitreal injections, anterior chamber (AC) lavage, Pars Plana vitrectomy (PPV), posterior capsulotomy, IOL, and capsular bag removal. Multiple intravitreal injections were required due to recurrence of infections after initial improvement with voriconazole injections. Results: Structural integrity was maintained and infection-free status was achieved in all the eyes. The presenting vision ranged from 6/60 to PL (perception of light). Seven out of 10 had improvement in their final vision over the presenting vision. Final outcome of four patients had vision of 6/24 or better, 4 patients had vision in the range of 2/60 to 6/36 and 2 patients had PL. Conclusion: Trichosporon can cause devasting infections even in the immunocompetent, especially in association with implants and catheters. Triazoles form the mainstay of treatment of Trichosporon infection due to the high susceptibility of the organism in vitro. A regimen including voriconazole and amphotericin B may prove to be the most effective. This is the first report of an outbreak of cluster endophthalmitis caused by Trichosporon.


Assuntos
Catarata , Endoftalmite , Infecções Oculares Fúngicas , Trichosporon , Humanos , Anfotericina B/uso terapêutico , Voriconazol , Estudos Retrospectivos , Endoftalmite/diagnóstico , Endoftalmite/tratamento farmacológico , Endoftalmite/etiologia , Antifúngicos/uso terapêutico , Vitrectomia/efeitos adversos , Catarata/complicações , Infecções Oculares Fúngicas/diagnóstico , Infecções Oculares Fúngicas/tratamento farmacológico , Infecções Oculares Fúngicas/complicações
9.
Mycopathologia ; 187(5-6): 427-437, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36209322

RESUMO

Vulvovaginal candidiasis (VVC), which is most frequently caused by Candida albicans, is a common problem worldwide. Despite the fact that extensive epidemiological studies have been performed, the cause of recurrent VVC (RVVC) remains uncertain. The aims of this work were to compare the genotypes of C. albicans strains causing different conditions of VVC, and explore the relationship between the drug resistance and genotype of C. albicans strains. In our study, we collected 649 independent strains from VVC patients in China. Isolates were tested for in vitro susceptibility to fluconazole, itraconazole, voriconazole, amphotericin B and caspofungin in accordance with the Clinical Laboratory Standards Institute (CLSI) document M27-A3. Genotyping was performed using PCR targeting specific CAI locus marker. C. albicans is the main pathogen of VVC, but the proportion of non-candida albicans (NAC) infection is also increasing, and we also found increased cases of mixed infection. Some C. albicans are resistant to multiple drugs. The strains with the genotypes including 16-16, 18-18 and 22-22 was likely to be the dominant genotype of uncomplicated VVC (p < 0.05). The genotypes of complicated VVC are mainly distributed in 30-45, 33-45, 32-46 and 39-45. Strains of 30-45, 32-45, 30-47 and 30-46 genotypes showed resistance to fluconazole, itraconazole, voriconazole and amphotericin B respectively. Our work suggests that the dominant genotypes with higher repeat number of C. albicans strains were more prevalent in patients with RVVC and drug-resistant strains, however, strains with uncomplicated VVC were more likely to distribute in homozygous. Identification of specific genotypes that correlate with different conditions of VVC and drug resistant is also of diagnostic and therapeutic significance.


Assuntos
Candidíase Vulvovaginal , Humanos , Feminino , Candidíase Vulvovaginal/epidemiologia , Candidíase Vulvovaginal/tratamento farmacológico , Candida albicans , Fluconazol/uso terapêutico , Itraconazol/uso terapêutico , Voriconazol/uso terapêutico , Anfotericina B/uso terapêutico , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Genótipo , Testes de Sensibilidade Microbiana , Farmacorresistência Fúngica
10.
Mycopathologia ; 187(5-6): 517-526, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36219382

RESUMO

Aspergillus spp. is the most common clinical pathogen of invasive fungal infection with high mortality. Existing treatments for Aspergillus spp. infection are still inefficient and accompanied by drug resistance, so it is still urgent to find new treatment approaches. The antiarrhythmic drug amiodarone (AMD) has demonstrated antifungal activity against a range of fungi. This study evaluated the efficacy of AMD in combination with triazoles for Aspergillus spp. infection. We tested the combined effect of AMD and three triazole drugs, namely, itraconazole (ITR), voriconazole (VRC), and posaconazole (POS), on the planktonic cells and biofilms of 20 strains of Aspergillus spp. via a checkerboard microdilution assay derived from 96-well plate-based method. Our results reveal that the combination of AMD with ITR or POS against Aspergillus biofilms has synergistic fungicidal effects. By contrast, the combination of AMD with VRC exhibits no antagonistic and synergistic effects. In this way, the use of AMD in combination with ITR or POS could be an effective adjunctive treatment for Aspergillus spp. infection.


Assuntos
Amiodarona , Aspergilose , Azóis/farmacologia , Azóis/uso terapêutico , Plâncton , Amiodarona/farmacologia , Amiodarona/uso terapêutico , Testes de Sensibilidade Microbiana , Aspergillus , Voriconazol/farmacologia , Voriconazol/uso terapêutico , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Itraconazol/farmacologia , Itraconazol/uso terapêutico , Aspergilose/tratamento farmacológico , Aspergilose/microbiologia , Biofilmes
11.
Clin Pharmacokinet ; 61(11): 1595-1607, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36195807

RESUMO

BACKGROUND: Cytochrome P450 (CYP) 3A contributes to the metabolism of many approved drugs. CYP3A perpetrator drugs can profoundly alter the exposure of CYP3A substrates. However, effects of such drug-drug interactions are usually reported as maximum effects rather than studied as time-dependent processes. Identification of the time course of CYP3A modulation can provide insight into when significant changes to CYP3A activity occurs, help better design drug-drug interaction studies, and manage drug-drug interactions in clinical practice. OBJECTIVE: We aimed to quantify the time course and extent of the in vivo modulation of different CYP3A perpetrator drugs on hepatic CYP3A activity and distinguish different modulatory mechanisms by their time of onset, using pharmacologically inactive intravenous microgram doses of the CYP3A-specific substrate midazolam, as a marker of CYP3A activity. METHODS: Twenty-four healthy individuals received an intravenous midazolam bolus followed by a continuous infusion for 10 or 36 h. Individuals were randomized into four arms: within each arm, two individuals served as a placebo control and, 2 h after start of the midazolam infusion, four individuals received the CYP3A perpetrator drug: voriconazole (inhibitor, orally or intravenously), rifampicin (inducer, orally), or efavirenz (activator, orally). After midazolam bolus administration, blood samples were taken every hour (rifampicin arm) or every 15 min (remaining study arms) until the end of midazolam infusion. A total of 1858 concentrations were equally divided between midazolam and its metabolite, 1'-hydroxymidazolam. A nonlinear mixed-effects population pharmacokinetic model of both compounds was developed using NONMEM®. CYP3A activity modulation was quantified over time, as the relative change of midazolam clearance encountered by the perpetrator drug, compared to the corresponding clearance value in the placebo arm. RESULTS: Time course of CYP3A modulation and magnitude of maximum effect were identified for each perpetrator drug. While efavirenz CYP3A activation was relatively fast and short, reaching a maximum after approximately 2-3 h, the induction effect of rifampicin could only be observed after 22 h, with a maximum after approximately 28-30 h followed by a steep drop to almost baseline within 1-2 h. In contrast, the inhibitory impact of both oral and intravenous voriconazole was prolonged with a steady inhibition of CYP3A activity followed by a gradual increase in the inhibitory effect until the end of sampling at 8 h. Relative maximum clearance changes were +59.1%, +46.7%, -70.6%, and -61.1% for efavirenz, rifampicin, oral voriconazole, and intravenous voriconazole, respectively. CONCLUSIONS: We could distinguish between different mechanisms of CYP3A modulation by the time of onset. Identification of the time at which clearance significantly changes, per perpetrator drug, can guide the design of an optimal sampling schedule for future drug-drug interaction studies. The impact of a short-term combination of different perpetrator drugs on the paradigm CYP3A substrate midazolam was characterized and can define combination intervals in which no relevant interaction is to be expected. CLINICAL TRIAL REGISTRATION: The trial was registered at the European Union Drug Regulating Authorities for Clinical Trials (EudraCT-No. 2013-004869-14).


Assuntos
Citocromo P-450 CYP3A , Midazolam , Humanos , Midazolam/farmacocinética , Citocromo P-450 CYP3A/metabolismo , Voriconazol/farmacocinética , Rifampina , Administração Oral , Interações Medicamentosas , Preparações Farmacêuticas , Área Sob a Curva
12.
Antimicrob Agents Chemother ; 66(11): e0102822, 2022 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-36286491

RESUMO

We evaluated the in vitro activity of manogepix and comparator agents against 1,435 contemporary fungal isolates collected worldwide from 73 medical centers in North America, Europe, the Asia-Pacific region, and Latin America during 2020. Of the isolates tested, 74.7% were Candida spp.; 3.7% were non-Candida yeasts, including 27 Cryptococcus neoformans var. grubii (1.9%); 17.1% were Aspergillus spp.; and 4.5% were other molds. All fungal isolates were tested by reference broth microdilution according to CLSI methods. Based on MIC90 values, manogepix (MIC50/MIC90, 0.008/0.06 mg/liter) was 16- to 64-fold more active than anidulafungin, micafungin, and fluconazole against Candida spp. isolates and the most active agent tested. Similarly, manogepix (MIC50/MIC90, 0.5/1 mg/liter) was ≥8-fold more active than anidulafungin, micafungin, and fluconazole against C. neoformans var. grubii. Based on minimum effective concentration for 90% of the isolates tested (MEC90) and MIC90 values, manogepix (MEC90, 0.03 mg/liter) was 16- to 64-fold more potent than itraconazole, posaconazole, and voriconazole (MIC90s, 0.5 to 2 mg/liter) against 246 Aspergillus spp. isolates. Aspergillus fumigatus isolates exhibited a wild-type (WT) phenotype for the mold-active triazoles, including itraconazole (87.0% WT) and voriconazole (96.4% WT). Manogepix was highly active against uncommon species of Candida, non-Candida yeasts, and rare molds, including 11 isolates of Candida auris (MIC50/MIC90, 0.004/0.015 mg/liter) and 12 isolates of Scedosporium spp. (MEC50/MEC90, 0.06/0.12 mg/liter). Additional studies are in progress to evaluate the clinical utility of the manogepix prodrug fosmanogepix in difficult-to-treat resistant fungal infections.


Assuntos
Cryptococcus neoformans , Fluconazol , Anidulafungina/farmacologia , Micafungina/farmacologia , Fluconazol/farmacologia , Voriconazol/farmacologia , Itraconazol/farmacologia , Testes de Sensibilidade Microbiana , Antifúngicos/farmacologia , Candida , Aspergillus , Farmacorresistência Fúngica
13.
Int J STD AIDS ; 33(13): 1134-1141, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36214529

RESUMO

BACKGROUND: We describe 11 cases of refractory vulvovaginal yeast infections (RVVYI) treated using oral voriconazole with or without concomitant topical agents. METHODS: Retrospective case-note review of all women prescribed oral voriconazole to treat RVVYI in five Sexual Health Clinics from Jan 2010-March 2020. Demographic details, clinical features, diagnostic results and treatment outcomes were collected. RESULTS: 11 women with vulvovaginal symptoms for a median of 1 year were treated with voriconazole. RVVYI was diagnosed clinically and confirmed on microscopy and culture with speciation. 10/11 isolates were fluconazole resistant, 1 intermediately sensitive, 10/11 were either fully or intermediately sensitive to voriconazole. All had received prior fluconazole and clotrimazole and 10/11 had used at least 2-weeks of one or more second-line antifungals with non-clearance of the yeast. Oral voriconazole 400 mg BD day-1, then 200 mg BD 13-days was prescribed and 10/11 women completed the course. Concomitant topical treatment was used by 6/11. Liver and renal function were monitored at 0, 7, 14 days. One woman stopped voriconazole after 5-days due to perioral tingling. Other transient side-effects were nausea (n = 2), photosensitivity, muscle aches, hair thinning (all n = 1), peripheral visual disturbance (n = 2). 8/11 experienced both symptom reduction and yeast clearance. Two women had an initial partial response but experienced resolution of symptoms following a second course of voriconazole. CONCLUSIONS: Our observational data adds to the limited evidence to support voriconazole treatment for RVVYI. A 2-week course of voriconazole was tolerated and completed by 10/11 women. Eight women, five using concomitant topical agents, achieved mycological cure.


Assuntos
Candidíase Vulvovaginal , Fluconazol , Feminino , Humanos , Voriconazol/uso terapêutico , Fluconazol/uso terapêutico , Saccharomyces cerevisiae , Estudos Retrospectivos , Antifúngicos/uso terapêutico , Candidíase Vulvovaginal/tratamento farmacológico , Candidíase Vulvovaginal/diagnóstico
14.
Pharmazie ; 77(10): 307-310, 2022 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-36273254

RESUMO

Long-term voriconazole use may increase the risk of cutaneous squamous cell carcinoma (cSCC), especially in immunocompromised patients. However, relatively little is known regarding voriconazole-induced cSCC in Japan. Thus, the purpose of this study was to evaluate the association between voriconazole use and cSCC in Japan using different national pharmacovigilance databases. First, using the Japanese Adverse Drug Event Report (JADER) database, we evaluated the association between voriconazole use and cSCC in Japan. Second, using the U. S. Food and Drug Administration Adverse Event Reporting System (FAERS) database, we examined regional differences in the occurrence of voriconazole-induced cSCC between Japan and other countries. We calculated reporting odds ratios (RORs) as disproportionality analysis to evaluate voriconazole-induced cSCC. In this study, cases in which one or more of "Bowen's disease", "Carcinoma in situ of skin", "Keratoacanthoma", "Squamous cell carcinoma in skin", or "Squamous cell carcinoma" were reported as adverse events were considered to be cSCC cases. The analysis based on the JADER database showed an association between voriconazole use and cSCC in Japan, with a ROR (95% confidence interval) of 35.37 (25.60-48.87). Further, the analysis based on the FAERS database revealed that signals were detected in Japan as well as in Western countries and Australia. This study is the first in which the association between voriconazole use and cSCC in Japan is assessed using national pharmacovigilance databases. Healthcare providers need to be fully aware of the potential for cSCC development owing to voriconazole use and in all countries, including Japan, ensure careful follow-up of patients' skin.


Assuntos
Carcinoma de Células Escamosas , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Neoplasias Cutâneas , Humanos , Farmacovigilância , Sistemas de Notificação de Reações Adversas a Medicamentos , Voriconazol/efeitos adversos , Japão/epidemiologia , Carcinoma de Células Escamosas/induzido quimicamente , Carcinoma de Células Escamosas/epidemiologia , Neoplasias Cutâneas/induzido quimicamente , Neoplasias Cutâneas/epidemiologia , Bases de Dados Factuais , Mineração de Dados , Células Epiteliais
15.
Egypt J Immunol ; 29(4): 134-147, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36208042

RESUMO

Candida species resistant to fluconazole and voriconazole were screened for the presence of ERG11gene by polymerase chain reaction (PCR). Also, the association of this gene with the demonstration of Candida virulence factors; biofilm formation, phospholipase and proteinases activities were studied. A total of 61 Candida isolates were collected from urine specimens. Candida species were identified by API 20 C Aux test. Extracellular phospholipase, secretory aspartyl proteinase and biofilm formation were determined. ERG11 gene was detected by PCR. C. albicans was identified in 34.5%, C. glabrata in 29.5% and C. tropicalis and C. krusei in 18% each. Candida species was resistant to fluconazole and voriconazole in 55.7% and 27.9%, respectively. Seventeen (50%) of fluconazole resistant Candida isolates were sensitive to voriconazole. The most frequently Candida species revealed fluconazole resistance were C. glabrata (47.1%), C. krusei (29.4%), and C. tropicalis and C. albicans (11.8% each). Biofilm formation, phospholipase and proteinase activity were determined in 41.2%, 67.6% and 35.3% of fluconazole resistant Candida isolates, respectively. Erg 11 gene was determined in 82.4% of fluconazole resistant Candida isolates and prominent in C. glabrata (93.75%), followed by C. krusei (90%), C. tropicalis (75%) and C. albicans (25%). Erg 11 gene was detected in 64.7% (11/17) of fluconazole resistant-voriconazole sensitive Candida isolates. Regarding, correlation of Erg11 gene positivity and virulence factors among fluconazole resistant Candida isolates, 34.5% exhibited biofilm formation and 62.1% and 31% showed phospholipase and proteinase activities, respectively. There were statistically significant difference concerning the association of proteinase activities and Erg 11 gene expression among fluconazole resistance Candida isolates (P=0.04). The study emphasizes the high prevalence of Erg11 gene among fluconazole resistant Candida species. There was association between the proteinase activity, fluconazole resistance and the presence of Erg11 among Candida species. Voriconazole maintains better activity towards Candida species and represent an alternative therapy.


Assuntos
Ácido Aspártico Proteases , Sistema Enzimático do Citocromo P-450/genética , Fluconazol , Proteínas Fúngicas/genética , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Candida/genética , Candida albicans/genética , Fluconazol/farmacologia , Humanos , Testes de Sensibilidade Microbiana , Peptídeo Hidrolases , Fosfolipases , Fatores de Virulência/genética , Voriconazol/farmacologia
16.
Emerg Microbes Infect ; 11(1): 2264-2274, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36066554

RESUMO

Patients presenting with severe COVID-19 are predisposed to acquire secondary fungal infections such as COVID-19-associated candidemia (CAC), which are associated with poor clinical outcomes despite antifungal treatment. The extreme burden imposed on clinical facilities during the COVID-19 pandemic has provided a permissive environment for the emergence of clonal outbreaks of multiple Candida species, including C. auris and C. parapsilosis. Here we report the largest clonal CAC outbreak to date caused by fluconazole resistant (FLZR) and echinocandin tolerant (ECT) C. parapsilosis. Sixty C. parapsilosis strains were obtained from 57 patients at a tertiary care hospital in Brazil, 90% of them were FLZR and ECT. Although only 35.8% of FLZR isolates contained an ERG11 mutation, all of them contained the TAC1L518F mutation and significantly overexpressed CDR1. Introduction of TAC1L518F into a susceptible background increased the MIC of fluconazole and voriconazole 8-fold and resulted in significant basal overexpression of CDR1. Additionally, FLZR isolates exclusively harboured E1939G outside of Fks1 hotspot-2, which did not confer echinocandin resistance, but significantly increased ECT. Multilocus microsatellite typing showed that 51/60 (85%) of the FLZR isolates belonged to the same cluster, while the susceptible isolates each represented a distinct lineage. Finally, biofilm production in FLZR isolates was significantly lower than in susceptible counterparts Suggesting that it may not be an outbreak determinant. In summary, we show that TAC1L518F and FKS1E1393G confer FLZR and ECT, respectively, in CAC-associated C. parapsilosis. Our study underscores the importance of antifungal stewardship and effective infection control strategies to mitigate clonal C. parapsilosis outbreaks.


Assuntos
COVID-19 , Candidemia , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Brasil/epidemiologia , COVID-19/epidemiologia , Candida parapsilosis/genética , Candidemia/tratamento farmacológico , Candidemia/epidemiologia , Candidemia/microbiologia , Surtos de Doenças , Equinocandinas/farmacologia , Equinocandinas/uso terapêutico , Fluconazol/farmacologia , Fluconazol/uso terapêutico , Humanos , Unidades de Terapia Intensiva , Testes de Sensibilidade Microbiana , Pandemias , Voriconazol/uso terapêutico
17.
Molecules ; 27(17)2022 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-36080374

RESUMO

The TDM of voriconazole which exhibits wide inter-individual variability is indispensable for treatment in clinic. In this study, a method that high-performance liquid chromatography tandem mass spectrometry cubed (HPLC-MS3) is first built and validated to quantify voriconazole in human plasma. The system is composed of Shimadzu Exion LCTM UPLC coupled with a Qtrap 5500 mass spectrometer. The separation of voriconazole is performed on a Poroshell 120 SB-C18 column at a flow rate of 0.8 mL/min remaining 7 min for each sample. The calibration curves are linear in the concentration range of 0.25-20 µg/mL. Intra-day and inter-day accuracies and precisions are within 8.0% at three concentrations, and the recoveries and matrix effect are all within accepted limits. In terms of stability, there is no significant degradation of voriconazole under various conditions. The HPLC-MS3 and HPLC-MRM (multiple reaction monitoring) methods are compared in 42 patients with Passing-Bablok regression and Bland-Altman plots, and the results show no significant difference between the two methods. However, HPLC-MS3 has a higher S/N (signal-to-noise ratio) and response than the MRM. Finally, the HPLC-MS3 assay is successfully applied to monitor the TDM (therapeutic drug monitoring) of voriconazole in human plasma, and this verifies that the dosing guidelines for voriconazole have been well implemented in the clinic and patients have received excellent treatment.


Assuntos
Monitoramento de Medicamentos , Espectrometria de Massas em Tandem , Cromatografia Líquida de Alta Pressão/métodos , Cromatografia Líquida/métodos , Monitoramento de Medicamentos/métodos , Humanos , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem/métodos , Voriconazol
18.
J Med Case Rep ; 16(1): 340, 2022 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-36068562

RESUMO

BACKGROUND: We present a case of fungal keratitis caused by Scedosporium apiospermum, which is a rare agent. Case description A 34-year-old Caucasian male patient was admitted to our clinic with complaints of pain and blurred vision in the left eye. The patient had a history of wearing contact lenses for 3 years. According to the Snellen chart, the patient's visual acuity was 20/20 and counting fingers at 30 cm, for right and left eyes, respectively. A 3 × 3 mm corneal abscess at the center of the cornea with hypopyon in the patient's left eye was observed. After the patient was hospitalized, fortified gentamicin and fortified cefazolin drops were started 24 times per day. Intravenous fluconazole 1 × 800 mg loading, 1 × 400 mg maintenance dose, intravenous vancomycin 4 × 500 mg and intravenous cefoperazone + sulbactam 2 × 2 g treatments were started. We observed S. apiospermum in the corneal scraping sample, which the identification was performed by combined phenotypic characteristics and matrix-assisted laser-desorption ionization time-of-flight mass spectrometry on the sixth day of treatment. The drops were revised as fortified vancomycin, ceftazidime, and voriconazole drops 24 times per day. Intravenous voriconazole 2 × 6 mg/kg loading and 2 × 4 mg/kg maintenance dose treatments were started. Three weeks later, left eye visual acuity increased to 20/40, and the corneal abscess regressed. On second-year follow-up, his visual acuity increased to 20/25 for the left eye and the cornea was transparent. CONCLUSION: Scedosporium group is an opportunistic filamentous fungus that is very rarely seen and causes severe keratitis infections. In the literature, to the best of our knowledge, three cases of keratitis due to S. apiospermum after contact lenses were reported, and all were treated with penetrating keratoplasty. In this case, unlike the others, only medical treatment was applied. In cases with suspected fungal keratitis, medical treatment should be started without waiting for the culture result, the findings should be followed and penetrating keratoplasty should be performed in the case of no response to treatment.


Assuntos
Úlcera da Córnea , Infecções Oculares Fúngicas , Ceratite , Scedosporium , Abscesso/tratamento farmacológico , Adulto , Antifúngicos/uso terapêutico , Córnea , Úlcera da Córnea/tratamento farmacológico , Infecções Oculares Fúngicas/tratamento farmacológico , Humanos , Ceratite/tratamento farmacológico , Masculino , Vancomicina/uso terapêutico , Voriconazol/uso terapêutico
19.
Int J Mol Sci ; 23(18)2022 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-36142376

RESUMO

BACKGROUND: Fungal infections can pose great threat to sight. Immediate treatment is usually required; antifungal agents are widely accepted and are effective in most cases. The present experimental study aims to investigate the probable effects of intravitreal injection of antifungal agents on the structure and mechanical properties of the surface of peripheral blood erythrocytes. METHODS: Nine albino New Zealand white rabbits, aged five months old, were chosen for the experiment. Solutions of micafungin, voriconazole, or balanced salt solution (BSS) were injected into the midvitreous. Animals were divided into two experimental groups and one control group. Blood sampling from an intravenous (IV) line was performed after 10 days from the last IV injection. An atomic force microscope (AFM) was used to study the structural and mechanical properties of cell surfaces. RESULTS: The analysis results showed that the parameters of the cytoskeleton's spatial organization changed insignificantly with the antifungal drug treatment. CONCLUSIONS: Our findings suggest that locally administered antifungal drugs can cause significant changes to the structure and frictional properties of the erythrocyte surface. These effects occur in the long-term period after administration of the drugs and represent a potential possibility for violation of blood supply to tissues, and the further development of negative side effects.


Assuntos
Antifúngicos , Micoses , Animais , Antifúngicos/uso terapêutico , Eritrócitos , Micafungina/uso terapêutico , Micoses/tratamento farmacológico , Coelhos , Voriconazol/farmacologia
20.
J Pharm Biomed Anal ; 220: 114964, 2022 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-36084471

RESUMO

Linezolid, vancomycin, teicoplanin, tigecycline, imipenem, meropenem, voriconazole, and micafungin are eight special-grade antimicrobials commonly used for patients with severe infections. Changes in the pharmacodynamics and pharmacokinetics of critically ill patients severely affect the efficacy of antimicrobial drugs. Therefore, conventional or standard dosing regimens do not achieve satisfactory anti-infective effects. In the current study a simple and specific ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for simultaneously determining the concentrations of the above-mentioned eight antimicrobials in human plasma only 3 min after one-step magnetic solid phase extraction pre-treatment. Multiple-reaction monitoring and positive ion modes were used for detection. The calibration curves were established over a concentration range of 0.1-25.0 µg/mL for teicoplanin, linezolid, micafungin, voriconazole, imipenem, igecyclin, and meropenem, and 0.2-50.0 µg/mL for vancomycin; the coefficient of correlation was > 0.9971 for all the compounds. The inter- and intra-day coefficients of variation were < 6.88% at the lower limit of quantification and quality control (QC) levels (low concentration-QC, medium concentration-QC, and high-concentration QC). The UPLC-MS/MS method was successfully used for clinical therapeutic drug monitoring of linezolid, vancomycin, teicoplanin, tigecycline, imipenem, meropenem, voriconazole, and micafungin for critically ill patients.


Assuntos
Anti-Infecciosos , Monitoramento de Medicamentos , Teicoplanina , Anti-Infecciosos/sangue , Anti-Infecciosos/química , Cromatografia Líquida de Alta Pressão/métodos , Cromatografia Líquida/métodos , Estado Terminal , Monitoramento de Medicamentos/métodos , Humanos , Imipenem , Linezolida , Meropeném , Micafungina , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem/métodos , Tigeciclina , Vancomicina , Voriconazol
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