RESUMEN
Therapeutic monitoring of antibiotics and antifungals based on pharmacokinetic and pharmacodynamic (PK/PD) parameters is a strategy increasingly used for the optimization of therapy to improve efficacy, reduce the occurrence of toxicities, and prevent the selection of antimicrobial resistance, particularly in vulnerable patients including neonates and the critical or immunocompromised paediatric host. In neonates and children, infections account for a high percentage of hospital admissions, and anti-infectives are the most used drugs. However, paediatric PK/PD studies and the evidence regarding the efficacy and safety of some newly marketed antibiotics and antifungals-usually used off-label in paediatrics-to determine the optimal drug dosage regimens are limited. It is widely known that this population presents important differences in the PK parameters (especially in drug clearance and volume of distribution) in comparison with adults that may alter antimicrobial exposure and, therefore, compromise treatment success. In addition, paediatric patients are more susceptible to potential adverse drug effects and they need closer monitoring. The aim of this document, developed jointly by the Spanish Society of Hospital Pharmacy and the Spanish Society of Paediatric Infectious Diseases, is to describe the available evidence on the indications for therapeutic drug monitoring (TDM) of antibiotics and antifungals in newborn and paediatric patients, and to provide practical recommendations for TDM in routine clinical practice to optimise their dosing, efficacy and safety. Of antibiotics and antifungals in the paediatric population.
Asunto(s)
Antibacterianos , Antifúngicos , Monitoreo de Drogas , Humanos , Recién Nacido , Antibacterianos/uso terapéutico , Antibacterianos/farmacocinética , Antibacterianos/administración & dosificación , Antibacterianos/efectos adversos , Antifúngicos/uso terapéutico , Antifúngicos/farmacocinética , Antifúngicos/efectos adversos , Antifúngicos/administración & dosificación , Niño , Lactante , Preescolar , España , Servicio de Farmacia en HospitalRESUMEN
Therapeutic monitoring of antibiotics and antifungals based on pharmacokinetic and pharmacodynamic parameters, is a strategy increasingly used for the optimization of therapy to improve efficacy, reduce the occurrence of toxicities, and prevent the selection of antimicrobial resistance, particularly in vulnerable patients including neonates and the critical or immunocompromised host. In neonates and children, infections account for a high percentage of hospital admissions and anti-infectives are the most used drugs. However, pediatric pharmacokinetic and pharmacodynamic studies and the evidence regarding the efficacy and safety of some newly marketed antibiotics and antifungals -usually used off-label in pediatrics- to determine the optimal drug dosage regimens are limited. It is widely known that this population presents important differences in the pharmacokinetic parameters (especially in drug clearance and volume of distribution) in comparison with adults that may alter antimicrobial exposure and, therefore, compromise treatment success. In addition, pediatric patients are more susceptible to potential adverse drug effects and they need closer monitoring. The aim of this document, developed jointly between the Spanish Society of Hospital Pharmacy (SEFH) and the Spanish Society of Pediatric Infectious Diseases (SEIP), is to describe the available evidence on the indications for therapeutic drug monitoring of antibiotics and antifungals in newborn and pediatric patients and to provide practical recommendations for therapeutic drug monitoring in routine clinical practice to optimize pharmacokinetic and pharmacodynamic parameters, efficacy and safety of antibiotics and antifungals in the pediatric population.
Asunto(s)
Antibacterianos , Antifúngicos , Monitoreo de Drogas , Humanos , Antifúngicos/uso terapéutico , Antifúngicos/farmacocinética , Antifúngicos/efectos adversos , Recién Nacido , Antibacterianos/uso terapéutico , Antibacterianos/farmacocinética , Niño , Lactante , España , Preescolar , Servicio de Farmacia en Hospital , Sociedades Médicas , PediatríaRESUMEN
Objective: To investigate the efficacy and safety of liposomal amphotericin B (L-AmB) for the salvage treatment of invasive fungal disease (IFD) in patients with hematological diseases. Methods: Data were retrospectively collected from 80 patients with hematological issues treated with L-AmB between June 2023 and December 2023 after failure of previous antifungal therapy. Baseline patient information, clinical efficacy, and factors affecting the efficacy of L-AmB were analyzed by logistic regression. Moreover, adverse effects associated with L-AmB were evaluated. Results: Among the 80 patients, 9 (11.2%) had proven IFD, 43 (53.8%) had probable IFD, and 28 (35.0%) had possible IFD. The efficacy rate of L-AmB salvage therapy for IFD was 77.5%, with a median daily dose of 3 (range: 1-5) mg·kg(-1)·d(-1) and a median dosing course of 14 (range: 8-25) days. Multivariate logistic regression analysis showed that the disease remission status (OR=4.337, 95% CI 1.167-16.122, P=0.029) and duration of medication (OR=1.127, 95% CI 1.029-1.234, P=0.010) were independent factors affecting the efficacy of L-AmB. The incidence of infusion reactions associated with L-AmB, including fever and chills, was 5.0%. The incidence of hypokalemia was 28.8% (predominantly grades 1-2), and the incidence of nephrotoxicity was 11.3% (predominantly grades 1-2) . Conclusion: L-AmB is safe and effective in the treatment of patients with IFD who are intolerant to or who have experienced no effect of previous antifungal therapy, with a low rate of adverse reactions.
Asunto(s)
Anfotericina B , Antifúngicos , Enfermedades Hematológicas , Infecciones Fúngicas Invasoras , Terapia Recuperativa , Humanos , Anfotericina B/administración & dosificación , Anfotericina B/efectos adversos , Anfotericina B/uso terapéutico , Estudios Retrospectivos , Antifúngicos/administración & dosificación , Antifúngicos/efectos adversos , Antifúngicos/uso terapéutico , Terapia Recuperativa/métodos , Infecciones Fúngicas Invasoras/tratamiento farmacológico , Enfermedades Hematológicas/complicaciones , Resultado del Tratamiento , Masculino , Femenino , Persona de Mediana EdadRESUMEN
Objective: Hepatotoxicity is an important cause of early withdrawal of voriconazole (VCZ). The role of the plasma trough concentration of VCZ (C0) in hepatotoxicity is confusion. VCZ N-oxide is the primary metabolite of VCZ in plasma. We investigated the role of VCZ C0 and plasma trough concentration of VCZ N-oxide (CN) in hepatotoxicity in adult patients. Materials and Methods: This was a prospective study. VCZ C0 and CN were measured using liquid chromatography-tandem mass spectrometry. Results: In total, 601 VCZ C0 and CN from 376 adult patients were included. The percentage of grade 1 or higher adverse events for ALP, ALT, AST, γ-GT, and TBIL were 35.4%, 21.0%, 30.1%, 56.2%, and 22.2%, respectively. Compared with younger adult patients, elderly patients (≥65 years) had a higher rate of grade 1 or higher adverse events of ALP. In the multivariate analysis, VCZ C0 was a risk factor for grade 1 or higher adverse events of AST in elderly patients and TBIL in younger adult patients, and VCZ CN was a risk factor for grade 1 or higher adverse events of ALT, AST, and TBIL. Results of the receiver operating characteristic curve analysis indicated that when the VCZ C0 was higher than 4.0 µg/mL, or the VCZ CN was lower than 1.7 µg/mL, the incidence of grade 1 or higher adverse events of AST and TBIL increased. Conclusion: VCZ C0 and CN were associated with liver function-related adverse events. Measurement of VCZ CN should be considered for VCZ therapeutic drug monitoring.
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Antifúngicos , Enfermedad Hepática Inducida por Sustancias y Drogas , Voriconazol , Humanos , Voriconazol/efectos adversos , Voriconazol/sangre , Voriconazol/farmacocinética , Masculino , Femenino , Persona de Mediana Edad , Adulto , Estudios Prospectivos , Enfermedad Hepática Inducida por Sustancias y Drogas/sangre , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Anciano , Antifúngicos/efectos adversos , Antifúngicos/farmacocinética , Antifúngicos/sangre , Adulto Joven , Espectrometría de Masas en Tándem , Anciano de 80 o más Años , Monitoreo de DrogasRESUMEN
BACKGROUND Coccidioidomycosis is caused by the fungi Coccidioides immitis and Coccidioides posadasii, which are endemic to the southwestern United States and other countries of the Western Hemisphere. Pulmonary coccidioidomycosis is the most common form of coccidioidomycosis. Rarely, coccidioidal infection disseminates to meninges, bones, skin, and soft tissues. While fluconazole remains the first line of treatment and is used for most patients, voriconazole is used in selected refractory cases of coccidioidomycosis. Voriconazole has more fluorine molecules than other azoles, and over time the fluorine molecules in voriconazole can cause disorganized bone formation in the periosteal region (periostitis), causing generalized bony pain, and radiographically can mimic skeletal coccidioidomycosis. While voriconazole-induced periostitis has been noted in aspergillosis and other infections, it has not been reported commonly in patients with coccidioidomycosis. CASE REPORT We present a case of a 50-year-old female patient with a diagnosis coccidioidal meningitis who was refractory to fluconazole and was treated with voriconazole. She presented with bony pain, which was initially radiographically attributed to multifocal skeletal coccidioidal infection. Reflecting upon the patient's history and serum levels of fluoride and bone alkaline phosphatase, a diagnosis of voriconazole-induced periostitis was made. Discontinuation of the voriconazole resulted in resolution of the periostitis. CONCLUSIONS Voriconazole-induced periostitis should be considered in patients with musculoskeletal pain with a history of voriconazole treatment or with laboratory abnormalities, such as elevated fluoride levels and/or bone alkaline phosphatase. Discontinuation of voriconazole reverses the condition promptly.
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Antifúngicos , Coccidioidomicosis , Periostitis , Voriconazol , Humanos , Periostitis/inducido químicamente , Coccidioidomicosis/tratamiento farmacológico , Coccidioidomicosis/diagnóstico , Voriconazol/efectos adversos , Persona de Mediana Edad , Femenino , Antifúngicos/efectos adversos , Diagnóstico DiferencialRESUMEN
BACKGROUND: Terbinafine has been successfully used in the treatment of human sporotrichosis; however, its effectiveness in the treatment of feline sporotrichosis is unknown. Therefore, this study aimed to describe the use of terbinafine in the treatment of feline sporotrichosis. METHODS: A cohort study was conducted in cats with sporotrichosis to assess the effectiveness and safety of terbinafine (30â60 mg/kg/day). Clinical examination and analysis of laboratory parameters were performed monthly until clinical signs resolved or terbinafine treatment was discontinued. RESULTS: Of the 54 cats with sporotrichosis included in the study, 19 were lost during follow-up and five were withdrawn from the study due to switching to treatment with another prescription drug. Of the remaining 30 cats, 10 achieved clinical cure, with a median treatment time of 18.5 weeks. Treatment failed in 18 cases, and two cats died. Twenty-two cats had adverse reactions to terbinafine treatment, and 10 cats showed elevation of serum transaminases. LIMITATION: Loss during follow-up was high, which makes it difficult to draw accurate conclusions regarding clinical outcomes. CONCLUSION: The low rate of clinical cure observed suggests that terbinafine does not represent an effective treatment option for cases of feline sporotrichosis.
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Antifúngicos , Enfermedades de los Gatos , Esporotricosis , Terbinafina , Gatos , Animales , Terbinafina/uso terapéutico , Enfermedades de los Gatos/tratamiento farmacológico , Esporotricosis/tratamiento farmacológico , Esporotricosis/veterinaria , Antifúngicos/uso terapéutico , Antifúngicos/efectos adversos , Resultado del Tratamiento , Masculino , Femenino , Estudios de CohortesRESUMEN
Voriconazole is the cornerstone of the treatment and prevention of fungal infections. While there is a good correlation between CYP2C19 genotype and voriconazole exposure during prophylactic treatment, no correlation was found in patients with invasive aspergillosis. Proinflammatory cytokines result in inhibition of CYP2C19 enzyme activity (and may result in phenoconversion). Here we investigated the relationship between inflammation, CYP2C19 genotype-predicted-phenotype, and CYP2C19 activity in patients receiving voriconazole. Data were obtained from two prospective studies investigating voriconazole treatment (NCT02074462 and NCT00893555). Dose-corrected voriconazole plasma concentration and C-reactive protein (CRP) were used as proxies for CYP2C19 activity and inflammation, respectively. After data extraction and synthesis, data from 39 patients with paired voriconazole and CRP measurements were available. The distribution of CYP2C19 genotype-predicted metabolizer phenotypes was 31% intermediate (IM), 41% normal (NM), and 28% rapid metabolizer (RM). During inflammation, dose-corrected voriconazole levels were increased by 245%, 278%, and 486% for CYP2C19 NMs IMs and RMs, respectively. Patients with moderate or high CRP levels (>50 mg/L) were phenoconverted to a lower metabolizer phenotype irrespective of their CYP2C19 genotype. In a subgroup analysis of eight patients with longitudinal data available with and without inflammation, the pattern of the dose-corrected voriconazole and CRP measurements were similar, with CYP2C19 activity following decreasing or increasing CRP levels. In conclusion, voriconazole plasma concentrations increase during inflammation due to downregulation of CYP2C19 activity. While this effect appears largest for CYP2C19 RMs, no clinically relevant differences were observed between the CYP2C19 genotypes.
Asunto(s)
Antifúngicos , Proteína C-Reactiva , Citocromo P-450 CYP2C19 , Genotipo , Inflamación , Voriconazol , Voriconazol/administración & dosificación , Voriconazol/farmacocinética , Voriconazol/sangre , Humanos , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2C19/metabolismo , Masculino , Femenino , Inflamación/tratamiento farmacológico , Inflamación/genética , Persona de Mediana Edad , Antifúngicos/administración & dosificación , Antifúngicos/farmacocinética , Antifúngicos/sangre , Antifúngicos/efectos adversos , Antifúngicos/farmacología , Adulto , Proteína C-Reactiva/análisis , Proteína C-Reactiva/metabolismo , Anciano , Estudios Prospectivos , Aspergilosis/tratamiento farmacológico , Aspergilosis/genética , FenotipoRESUMEN
BACKGROUND: Acute kidney injury (AKI) and hypokalaemia are common adverse events after treatment with liposomal amphotericin B (L-AMB). OBJECTIVES: Because excess potassium (K) leakage occurs during renal tubular injury caused by L-AMB, measuring the decrease in rate of serum K concentration might be more useful to assess the renal impact of L-AMB than hypokalaemia identified from a one-point measurement. The effects of a decrease in K concentration and duration of hypokalaemia on AKI were investigated. METHODS: A ≥ 10% decrease in K concentration from the reference concentration within a 7-day timeframe was evaluated. The hypokalaemia index, which combines the duration of K concentration lower than the reference and a marked low K concentration, was calculated from the area over the concentration curve. RESULTS: Eighty-six patients were included in the study. The incidences of AKI and decrease in K concentration were 36.0% and 63.9%, respectively. Of patients who developed both adverse events, a decrease in K concentration occurred first in 22 of 26 patients, followed by AKI 7 days later. Hypokalaemia did not increase AKI risk whereas a decrease in K concentration was an independent risk factor for AKI. The hypokalaemia index in patients with AKI was significantly higher than those without AKI (5.35 vs. 2.50 points, p = 0.002), and ≥3.45 points was a significant predictor for AKI. CONCLUSION: A ≥ 10% decrease in the K concentration was a significant factor for AKI in patients receiving L-AMB therapy. In such patients, dose reduction or alternative antifungals could be considered based on the hypokalaemia index.
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Lesión Renal Aguda , Anfotericina B , Antifúngicos , Hipopotasemia , Potasio , Humanos , Hipopotasemia/inducido químicamente , Hipopotasemia/sangre , Anfotericina B/efectos adversos , Anfotericina B/administración & dosificación , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/sangre , Masculino , Potasio/sangre , Femenino , Persona de Mediana Edad , Anciano , Antifúngicos/efectos adversos , Antifúngicos/administración & dosificación , Adulto , Estudios Retrospectivos , Factores de Riesgo , Incidencia , Anciano de 80 o más AñosRESUMEN
Fingolimod is a sphingosine-1-phosphate receptor modulator used to treat multiple sclerosis. While fingolimod has been associated with an increased risk of cryptococcal meningitis, its correlation with other deep mycoses remains unclear. In this study, we conducted a scoping review of fingolimod associated with histoplasmosis, based on a case report, a literature review, and data from the FDA Adverse Events Reporting System (FAERS) as of January 24th, 2023. A 30-year-old Brazilian woman diagnosed with relapsing-remitting multiple sclerosis, receiving a daily dose of 0.5 mg of fingolimod, presented with a two-month history of fever and unintended weight loss, accompanied by lymphadenopathy, splenomegaly, and lung involvement was investigated. Biopsy of a lung nodule revealed fungal structures suggestive of Histoplasma sp. Additionally, serological testing yielded positive for Histoplasma capsulatum. Disseminated histoplasmosis should be considered in the differential diagnosis of febrile syndromes in patients undergoing fingolimod therapy for multiple sclerosis, particularly in the Americas, where this mycosis is endemic. Treatment with itraconazole and modification of immunotherapy can achieve excellent clinical outcomes.
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Clorhidrato de Fingolimod , Histoplasmosis , Esclerosis Múltiple Recurrente-Remitente , Humanos , Histoplasmosis/tratamiento farmacológico , Histoplasmosis/diagnóstico , Clorhidrato de Fingolimod/efectos adversos , Femenino , Adulto , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Antifúngicos/efectos adversos , Antifúngicos/uso terapéutico , Inmunosupresores/efectos adversos , HistoplasmaRESUMEN
Conventional itraconazole (c-ITZ) can be used for a variety of fungal infections although variable absorption has been a significant limitation. Super-bioavailable itraconazole (SUBA-ITZ) is a novel formulation that overcomes absorption concerns by utilizing a polymer-matrix to disperse active drug and facilitate dissolution. The pH-driven matrix allows concurrent proton pump inhibitor administration without significant effects on drug concentrations. The enhanced bioavailability of SUBA-ITZ allows for lower dosing, while achieving similar serum concentrations as c-ITZ and SUBA-ITZ is now US FDA approved in the treatment of blastomycosis, histoplasmosis and aspergillosis. Common side effects of SUBA-ITZ include gastrointestinal disorders, peripheral edema and drug-induced hypertension. Given the significant differences in pharmacokinetics between the formulations, c-ITZ and SUBA-ITZ capsules are not considered interchangeable. It is important to note that drug errors may occur when transitioning a patient from one formulation to another.
Itraconazole is an antifungal agent used in the treatment of a number of mycoses. Prior formulations (versions) of itraconazole required strict dietary requirements and often had poor absorption. A new itraconazole formulation has since been developed super bioavailable itraconazole (SUBA-itraconazole). This has no food requirements, has superior absorption and maintains effectiveness against a number of fungal infections.
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Antifúngicos , Itraconazol , Humanos , Itraconazol/uso terapéutico , Itraconazol/farmacocinética , Itraconazol/administración & dosificación , Antifúngicos/uso terapéutico , Antifúngicos/farmacocinética , Antifúngicos/efectos adversos , Antifúngicos/administración & dosificación , Micosis/tratamiento farmacológico , Micosis/microbiología , Histoplasmosis/tratamiento farmacológico , Aspergilosis/tratamiento farmacológico , Aspergilosis/microbiología , Blastomicosis/tratamiento farmacológico , Infecciones Fúngicas Invasoras/tratamiento farmacológico , Infecciones Fúngicas Invasoras/microbiología , Disponibilidad BiológicaRESUMEN
Aspergillosis is a major cause of morbidity and mortality in penguins, with triazole antifungal drugs being commonly used for prophylaxis and treatment. This report describes 15 cases of fatal hemolysis associated with liquid itraconazole and voriconazole formulations administered to African penguins (Spheniscus demersus) from four institutions. All penguins underwent stressful events (e.g. relocation, induced molt) and were administered commercial liquid itraconazole formulations or compounded voriconazole liquid suspension. Observed clinical signs in affected penguins prior to death included hyporexia, weight loss, lethargy, dyspnea, red-tinged droppings, and obtunded mentation. Intra- and extravascular hemolysis and hemoglobinuric nephrosis were the primary pathologic manifestations on postmortem examination. The concentration-dependent hemolytic potentials of itraconazole, voriconazole, and commercial and compounded vehicle suspensions were evaluated in vitro by exposing chicken whole blood as a surrogate for penguin blood. Hemoglobin content in blood plasma was then measured by spectrophotometry. Neither itraconazole nor voriconazole alone induced hemolysis in vitro. The vehicle ingredients sorbitol and hydromellose induced hemolysis, but not at predicted plasma levels in chicken erythrocytes, suggesting neither the azole antifungals nor their major vehicles alone were likely to contribute to hemolysis in vivo in these penguins. Potential mechanisms of toxicosis include generation of an unmeasured reactive metabolite causing hemolysis, preexisting erythrocyte fragility, or species-specific differences in hemolytic thresholds that were not assessed in the chicken erythrocyte model. More research is needed on the potential for toxicosis of azole antifungal drugs and carrier molecules in this and other avian species.
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Antifúngicos , Enfermedades de las Aves , Hemólisis , Spheniscidae , Voriconazol , Animales , Enfermedades de las Aves/inducido químicamente , Enfermedades de las Aves/tratamiento farmacológico , Hemólisis/efectos de los fármacos , Antifúngicos/efectos adversos , Antifúngicos/uso terapéutico , Antifúngicos/administración & dosificación , Voriconazol/efectos adversos , Voriconazol/uso terapéutico , Itraconazol/efectos adversos , Itraconazol/uso terapéutico , Itraconazol/administración & dosificación , Triazoles/efectos adversos , Triazoles/uso terapéutico , Masculino , Femenino , Animales de ZoológicoRESUMEN
Azole antifungal drugs are commonly used to treat vulvovaginal candidiasis (VVC). The nephrotoxicity and developmental toxicity of azole drugs have not been systematically analyzed in the real world. We used the FDA Adverse Event Reporting System (FAERS) to investigate the adverse events (AEs) associated with imidazole therapy for VVC. FAERS data (from quarter 1 2004 to quarter 3 2022) were retrieved using OpenVigil 2.1, and AEs were retrieved and standardized according to the Medical Dictionary for Regulatory Activities (MedDRA). In the top 10 System Organ Class (SOC), all four drugs have been found to have kidney and urinary system diseases and pregnancy. We found significant signals, including clotrimazole [bladder transitional cell carcinoma, (report odds ratio, ROR = 291.66)], [fetal death, (ROR = 10.28)], ketoconazole[nephrogenic anemia (ROR = 22.1)], [premature rupture of membranes (ROR = 22.91 46.45, 11, 3)], Miconazole[hematuria (ROR = 19.03)], [neonatal sepsis (ROR = 123.71)], [spontaneous abortion (ROR = 5.98)], Econazole [acute kidney injury (ROR = 4.41)], [spontaneous abortion (ROR = 19.62)]. We also discovered new adverse reactions that were not reported. Therefore, when using imidazole drugs for treatment, it is necessary to closely monitor the patient's renal function, pay attention to the developmental toxicity of the fetus during pregnancy, and be aware of potential adverse reactions that may occur.
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Sistemas de Registro de Reacción Adversa a Medicamentos , Antifúngicos , Candidiasis Vulvovaginal , Imidazoles , United States Food and Drug Administration , Femenino , Humanos , Candidiasis Vulvovaginal/tratamiento farmacológico , Antifúngicos/efectos adversos , Antifúngicos/uso terapéutico , Imidazoles/efectos adversos , Estados Unidos , Embarazo , Adulto , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiología , Miconazol/efectos adversos , Miconazol/administración & dosificación , Clotrimazol/efectos adversosAsunto(s)
Antifúngicos , Erupciones por Medicamentos , Itraconazol , Humanos , Itraconazol/efectos adversos , Itraconazol/uso terapéutico , Antifúngicos/efectos adversos , Erupciones por Medicamentos/etiología , Erupciones por Medicamentos/patología , Erupciones por Medicamentos/diagnóstico , Masculino , Femenino , Persona de Mediana Edad , Exantema/inducido químicamenteRESUMEN
HRS9432(A) is a long-acting echinocandin antifungal medication primarily used to treat invasive fungal infections, particularly invasive candidiasis. The safety, tolerability, and pharmacokinetic characteristics of HRS9432(A) injection were investigated in a randomized, double-blind, placebo-controlled, single- and multiple-ascending-dose Phase I study involving 56 healthy adult subjects. Doses ranging from 200 to 1200 mg were administered. Safety was continually monitored, including adverse events, clinical laboratory examinations, vital signs, 12-lead electrocardiograms, and physical examinations, while the pharmacokinetic profile within the body was evaluated. The results indicated that concentrations of HRS9432 peaked immediately after infusion, demonstrating essentially linear pharmacokinetic characteristics within the dosage range of 200-1,200 mg. It exhibited a low clearance rate and an extended half-life, with a clearance of approximately 0.2 L/h, a volume of distribution of around 40 L, and a half-life of approximately 140h following a single dose. The accumulation index for AUC0-τ after multiple doses ranged from 1.41 to 1.75. No severe adverse events occurred during the study, and the severity of all adverse events was mild or moderate. Therefore, the intravenous administration of HRS9432(A) in healthy Chinese adult subjects, either as multiple infusions of 200 to 600 mg (once a week, four doses) or as a single infusion of 900-1,200 mg, demonstrated overall good safety and tolerability. The pharmacokinetic exhibited essentially linear characteristics in the body, supporting a weekly dosing frequency for clinical applications and providing additional options for the treatment or prevention of invasive fungal infections. CLINICAL TRIALS: This study is registered with the International Clinical Trials Registry Platform as ChiCTR2300073525.
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Antifúngicos , Voluntarios Sanos , Humanos , Método Doble Ciego , Adulto , Masculino , Antifúngicos/farmacocinética , Antifúngicos/administración & dosificación , Antifúngicos/efectos adversos , Femenino , Adulto Joven , Semivida , Área Bajo la Curva , Micafungina/farmacocinética , Micafungina/administración & dosificación , Micafungina/efectos adversos , Persona de Mediana Edad , Pueblo Asiatico , Pueblos del Este de AsiaRESUMEN
INTRODUCTION: Rezafungin is a second-generation, once-weekly echinocandin antifungal approved for the treatment of invasive candidiasis, including candidemia. In phase II/III studies of rezafungin versus caspofungin, patients with severe hepatic impairment were excluded due to lack of caspofungin data in this population. This open-label, single-dose, phase I study evaluated the pharmacokinetics (primary objective) and safety of rezafungin in subjects with moderate or severe hepatic impairment versus matched, healthy subjects with normal hepatic function. METHODS: Eight subjects each with moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment were matched 1:1 with healthy subjects for age, sex, and body mass index. Each subject received a single 400-mg, intravenous, 1-h infusion of rezafungin. Plasma pharmacokinetic sampling was performed at various time points through 336 h postdose. Pharmacokinetic parameters were derived by non-compartmental analysis. Safety was assessed throughout. RESULTS: All 32 subjects received study treatment and were included in all analyses. Despite overlapping distributions of total plasma concentrations, based on geometric least-squares (LS) mean ratios, the area under the plasma concentration-time curve from time zero (prior to the start of infusion) to infinity (AUC0-∞) was 32% lower in subjects with moderate (LS mean ratio, 67.55; 90% confidence interval [CI]: 53.91, 84.65) and severe (LS mean ratio, 67.84; 90% CI: 57.49, 80.05) hepatic impairment versus matched healthy subjects. The maximum plasma concentration (Cmax) was 12% lower in moderate hepatic impairment and 28% lower in severe hepatic impairment groups. Linear regression showed no significant trend in the degree of hepatic impairment (based on Child-Pugh score) on AUC0-∞ or Cmax (p > 0.05). Treatment-emergent adverse events were reported in seven subjects (21.9%; three subjects in each of the hepatic impairment groups, and one healthy subject), none of which were severe, serious, or resulted in withdrawal. CONCLUSIONS: Rezafungin is well tolerated and can be administered to patients with moderate or severe hepatic impairment without the need for dose adjustment. The modest reduction in exposures in subjects with hepatic impairment is not clinically meaningful and is unlikely to impact efficacy.
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Antifúngicos , Equinocandinas , Humanos , Masculino , Femenino , Persona de Mediana Edad , Antifúngicos/farmacocinética , Antifúngicos/administración & dosificación , Antifúngicos/efectos adversos , Equinocandinas/farmacocinética , Equinocandinas/efectos adversos , Equinocandinas/administración & dosificación , Adulto , Anciano , Hepatopatías , Infusiones Intravenosas , Área Bajo la Curva , Índice de Severidad de la Enfermedad , Estudios de Casos y ControlesRESUMEN
BACKGROUND: Isavuconazole is a relatively new antifungal agent indicated for the management of various invasive fungal diseases (IFDs), including invasive aspergillosis. Information on real-world experience with isavuconazole is scarce. This retrospective observational study aimed to describe the usage of isavuconazole in clinical practice with an in-depth evaluation of individual isavuconazole exposure. METHODS: Patients treated with isavuconazole were evaluated based on retrospective data, including therapeutic drug monitoring (TDM) data and efficacy and safety data. Additionally, we calculated the individual isavuconazole exposure described by the average AUC24 over the first 7â days of treatment by means of non-linear mixed-effects modelling and compared this with the currently desired lower target AUC of 60â mg·h/L. RESULTS: Ninety-nine patients treated with isavuconazole were evaluated. In our real-life cohort, isavuconazole was often deployed off-label in patients with non-classical host factors and infections with non-Aspergillus and non-Mucorales species. Isavuconazole was most often chosen for its safety profile, even after prior triazole treatment with manifestations of toxicity. TDM and subsequent dosage adjustments were frequently performed. The individual average AUC24 over 7â days was above 60â mg·h/L in 29 out of 77 (37.7%) patients. CONCLUSIONS: This overview provides practical insights that can aid clinicians in the management of their patients with IFD. Our study shows that isavuconazole was used in a diverse patient population and was well tolerated overall. Individual isavuconazole exposure reflected by the average AUC24 over the first 7 days of treatment was generally low and variable. Dosage adjustments following TDM were frequently performed. Our experience shows that isavuconazole is a feasible alternative after prior azole treatment.
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Antifúngicos , Infecciones Fúngicas Invasoras , Nitrilos , Piridinas , Triazoles , Humanos , Piridinas/uso terapéutico , Piridinas/efectos adversos , Piridinas/administración & dosificación , Triazoles/uso terapéutico , Triazoles/efectos adversos , Triazoles/administración & dosificación , Nitrilos/uso terapéutico , Nitrilos/efectos adversos , Nitrilos/administración & dosificación , Antifúngicos/uso terapéutico , Antifúngicos/efectos adversos , Antifúngicos/administración & dosificación , Estudios Retrospectivos , Femenino , Infecciones Fúngicas Invasoras/tratamiento farmacológico , Infecciones Fúngicas Invasoras/prevención & control , Masculino , Persona de Mediana Edad , Anciano , Adulto , Monitoreo de Drogas , Anciano de 80 o más Años , Adulto JovenRESUMEN
INTRODUCTION: Terbinafine is considered the gold standard for treating skin fungal infections and onychomycosis. However, recent reports suggest that dermatophytes are developing resistance to terbinafine and the other traditional antifungal agents, itraconazole and fluconazole. When there is resistance to terbinafine, itraconazole or fluconazole, or when these agents cannot used, for example, due to potential drug interactions with the patient's current medications, clinicians may need to consider off-label use of new generation azoles, such as voriconazole, posaconazole, fosravuconazole, or oteseconazole. It is essential to emphasize that we do not advocate the use of newer generation azoles unless traditional agents such as terbinafine, itraconazole, or fluconazole have been thoroughly evaluated as first-line therapies. AREAS COVERED: This article reviews the clinical evidence, safety, dosage regimens, pharmacokinetics, and management algorithm of new-generation azole antifungals. EXPERT OPINION: Antifungal stewardship should be the top priority when prescribing new-generation azoles. First-line antifungal therapy is terbinafine and itraconazole. Fluconazole is a consideration but is generally less effective and its use may be off-label in many countries. For difficult-to-treat skin fungal infections and onychomycosis, that have failed terbinafine, itraconazole and fluconazole, we propose consideration of off-label voriconazole or posaconazole.
Asunto(s)
Antifúngicos , Azoles , Farmacorresistencia Fúngica , Onicomicosis , Humanos , Antifúngicos/administración & dosificación , Antifúngicos/efectos adversos , Antifúngicos/farmacología , Onicomicosis/tratamiento farmacológico , Onicomicosis/microbiología , Azoles/administración & dosificación , Azoles/farmacología , Dermatomicosis/tratamiento farmacológico , Dermatomicosis/microbiología , Uso Fuera de lo Indicado , Interacciones Farmacológicas , Arthrodermataceae/efectos de los fármacosRESUMEN
PURPOSE: We aimed to investigated the influencing risk factors of voriconazole-induced liver injury in Uygur pediatric patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT). METHODS: This was a prospective cohort design study. High-performance liquid chromatography-mass spectrometry was employed to monitor voriconazole concentration. First-generation sequencing was performed to detect gene polymorphisms. Indicators of liver function were detected at least once before and after voriconazole therapy. RESULTS: Forty-one patients were included in this study, among which, 15 patients (36.6%) had voriconazole-induced liver injury. The proportion of voriconazole trough concentration > 5.5 µg·mL-1 patients within the DILI group (40.0%) was significantly higher compared to the control group (15.4%) (p < 0.05). After administration of voriconazole, the values of ALT (103.3 ± 80.3 U/L) and AST (79.9 ± 60.6 U/L) in the DILI group were higher than that in the control group (24.3 ± 24.8 and 30.4 ± 8.6 U/L) (p < 0.05). There was no significant difference between the two groups in genotype and allele frequencies of CYP2C19*2, CYP2C19*3, CYP2C19*17, and UGT1A4 (rs2011425) (p > 0.05). CONCLUSION: There was a significant correlation between voriconazole-induced liver injury and voriconazole trough concentration in high-risk Uygur pediatric patients with allogeneic HSCT.