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Medicinas Complementárias
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1.
Ther Drug Monit ; 44(1): 198-214, 2022 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-34654030

RESUMEN

PURPOSE: Reduced exposure to echinocandins has been reported in specific patient populations, such as critically ill patients; however, fixed dosing strategies are still used. The present review examines the accumulated evidence supporting echinocandin therapeutic drug monitoring (TDM) and summarizes available assays and sampling strategies. METHODS: A literature search was conducted using PubMed in December 2020, with search terms such as echinocandins, anidulafungin, caspofungin, micafungin, or rezafungin with pharmacology, pharmacokinetics (PKs), pharmacodynamics (PDs), drug-drug interactions, TDM, resistance, drug susceptibility testing, toxicity, adverse drug reactions, bioanalysis, chromatography, and mass spectrometry. Data on PD/PD (PK/PD) outcome markers, drug resistance, PK variability, drug-drug interactions, assays, and TDM sampling strategies were summarized. RESULTS: Echinocandins demonstrate drug exposure-efficacy relationships, and maximum concentration/minimal inhibitory concentration ratio (Cmax/MIC) and area under the concentration-time curve/MIC ratio (AUC/MIC) are proposed PK/PD markers for clinical response. The relationship between drug exposure and toxicity remains poorly clarified. TDM could be valuable in patients at risk of low drug exposure, such as those with critical illness and/or obesity. TDM of echinocandins may also be useful in patients with moderate liver impairment, drug-drug interactions, hypoalbuminemia, and those undergoing extracorporeal membrane oxygenation, as these conditions are associated with altered exposure to caspofungin and/or micafungin. Assays are available to measure anidulafungin, micafungin, and caspofungin concentrations. A limited-sampling strategy for anidulafungin has been reported. CONCLUSIONS: Echinocandin TDM should be considered in patients at known risk of suboptimal drug exposure. However, for implementing TDM, clinical validation of PK/PD targets is needed.


Asunto(s)
Antifúngicos , Mycobacterium tuberculosis , Antifúngicos/efectos adversos , Monitoreo de Drogas/métodos , Equinocandinas/efectos adversos , Humanos , Lipopéptidos/efectos adversos , Lipopéptidos/farmacocinética , Pruebas de Sensibilidad Microbiana
2.
J Med Chem ; 63(6): 3161-3171, 2020 03 26.
Artículo en Inglés | MEDLINE | ID: mdl-32097000

RESUMEN

Increased usage of daptomycin to treat infections caused by Gram-positive bacterial pathogens has resulted in emergence of resistant mutants. In a search for more effective daptomycin analogues through medicinal chemistry studies, we found that methylation at the nonproteinogenic amino acid kynurenine in daptomycin could result in significant enhancement of antibacterial activity. Termed "kynomycin," this new antibiotic exhibits higher antibacterial activity than daptomycin and is able to eradicate methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE) strains, including daptomycin-resistant strains. The improved antimicrobial activity of kynomycin was demonstrated in in vitro time-killing assay, in vivo wax worm model, and different mouse infection models. The increased antibacterial activity, improved pharmacokinetics, and lower cytotoxicity of kynomycin, compared to daptomycin, showed the promise of the future design and development of next-generation daptomycin-based antibiotics.


Asunto(s)
Antibacterianos/uso terapéutico , Depsipéptidos/uso terapéutico , Lipopéptidos/uso terapéutico , Infecciones Estafilocócicas/tratamiento farmacológico , Animales , Antibacterianos/síntesis química , Antibacterianos/farmacocinética , Antibacterianos/toxicidad , Permeabilidad de la Membrana Celular/efectos de los fármacos , Daptomicina/química , Daptomicina/uso terapéutico , Depsipéptidos/síntesis química , Depsipéptidos/farmacocinética , Depsipéptidos/toxicidad , Farmacorresistencia Bacteriana/efectos de los fármacos , Enterococcus/efectos de los fármacos , Femenino , Células HEK293 , Humanos , Lepidópteros/efectos de los fármacos , Lepidópteros/microbiología , Lipopéptidos/síntesis química , Lipopéptidos/farmacocinética , Lipopéptidos/toxicidad , Masculino , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Metilación , Ratones Endogámicos BALB C , Ratones Endogámicos ICR , Pruebas de Sensibilidad Microbiana
3.
Artículo en Inglés | MEDLINE | ID: mdl-28739797

RESUMEN

Intra-abdominal candidiasis (IAC) is a prominent invasive fungal infection associated with high mortality. Prompt antifungal therapy and source control are crucial for successful treatment. Echinocandin antifungal drugs are first-line agents; however, their clinical effectiveness is highly variable, with known potential for breakthrough resistance, and little is known about drug exposure at the site of infection. Using matrix-assisted desorption ionization mass spectrometry imaging technology, we investigated the spatial and quantitative distribution in tissue lesions for two echinocandin drugs, micafungin and CD101, in a clinically relevant IAC mouse model. Drug accumulation within lesions was observed with both drugs at their humanized therapeutic doses. CD101, but not micafungin, accumulated in lesions at levels above the mutant prevention concentration of the infecting strain. These findings indicate that current echinocandin drugs are limited by penetration at the site of infection and have implications for clinical outcomes and emergence of resistance in patients with IAC.


Asunto(s)
Absceso Abdominal/tratamiento farmacológico , Antifúngicos/uso terapéutico , Candida albicans/efectos de los fármacos , Candidiasis/tratamiento farmacológico , Equinocandinas/farmacocinética , Lipopéptidos/farmacocinética , Animales , Modelos Animales de Enfermedad , Farmacorresistencia Fúngica/fisiología , Equinocandinas/uso terapéutico , Femenino , Lipopéptidos/uso terapéutico , Micafungina , Ratones , Pruebas de Sensibilidad Microbiana , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción
4.
Artículo en Inglés | MEDLINE | ID: mdl-28584152

RESUMEN

Candida auris is an emerging multidrug-resistant threat. The pharmacodynamics of three antifungal classes against nine C. auris strains was explored using a murine invasive candidiasis model. The total drug median pharmacodynamic (PD) target associated with net stasis was a fluconazole AUC/MIC (the area under the concentration-time curve over 24 h in the steady state divided by the MIC) of 26, an amphotericin B Cmax/MIC (maximum concentration of drug in serum divided by the MIC) of 0.9, and a micafungin AUC/MIC of 54. The micafungin PD targets for C. auris were ≥20-fold lower than those of other Candida species in this animal model. Clinically relevant micafungin exposures produced the most killing among the three classes.


Asunto(s)
Anfotericina B/farmacocinética , Anfotericina B/uso terapéutico , Antifúngicos/uso terapéutico , Candida/efectos de los fármacos , Candidiasis Invasiva/tratamiento farmacológico , Candidiasis/tratamiento farmacológico , Equinocandinas/farmacocinética , Equinocandinas/uso terapéutico , Fluconazol/farmacocinética , Fluconazol/uso terapéutico , Lipopéptidos/farmacocinética , Lipopéptidos/uso terapéutico , Anfotericina B/sangre , Animales , Antifúngicos/sangre , Antifúngicos/farmacocinética , Candida/aislamiento & purificación , Candida/patogenicidad , Candidiasis/microbiología , Candidiasis Invasiva/microbiología , Modelos Animales de Enfermedad , Farmacorresistencia Fúngica Múltiple , Equinocandinas/sangre , Fluconazol/sangre , Humanos , Lipopéptidos/sangre , Micafungina , Ratones , Pruebas de Sensibilidad Microbiana
5.
J Ind Microbiol Biotechnol ; 43(2-3): 195-204, 2016 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-26670919

RESUMEN

The primary challenge for treating Clostridium difficile infections (CDI) is maintenance of clinical response after the end of treatment (sustained clinical response). Disease recurrence following a positive clinical response occurs in approximately 6-25 % of patients after the first episode and in up to 65 % for subsequent recurrences. Surotomycin, a novel cyclic lipopeptide antibiotic with a core derived by Streptomyces roseosporus fermentation, disrupts C. difficile cellular membrane activity in both logarithmic and stationary phases and minimally disturbs normal gastrointestinal microbiota because of its lack of activity against Gram-negative anaerobes and facultative anaerobes. Preclinical and clinical evidence indicate that surotomycin has low oral bioavailability, allowing gastrointestinal tract concentrations to greatly exceed its minimum inhibitory concentration for C. difficile. Surotomycin is well tolerated and effective in hamster models of CDI. Phase 2 clinical evidence suggests that surotomycin (250 mg twice daily) is an effective CDI treatment, with statistically lower recurrence rates than vancomycin.


Asunto(s)
Antibacterianos/aislamiento & purificación , Antibacterianos/uso terapéutico , Clostridioides difficile/efectos de los fármacos , Infecciones por Clostridium/tratamiento farmacológico , Infecciones por Clostridium/microbiología , Lipopéptidos/aislamiento & purificación , Lipopéptidos/uso terapéutico , Péptidos Cíclicos/aislamiento & purificación , Péptidos Cíclicos/uso terapéutico , Animales , Antibacterianos/farmacología , Disponibilidad Biológica , Ensayos Clínicos Fase II como Asunto , Clostridioides difficile/citología , Microbioma Gastrointestinal/efectos de los fármacos , Humanos , Lipopéptidos/administración & dosificación , Lipopéptidos/farmacocinética , Lipopéptidos/farmacología , Pruebas de Sensibilidad Microbiana , Péptidos Cíclicos/administración & dosificación , Péptidos Cíclicos/farmacocinética , Péptidos Cíclicos/farmacología
6.
Clin Infect Dis ; 61 Suppl 6: S635-42, 2015 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-26567282

RESUMEN

The time the earth takes to rotate its axis (the day) has dictated how often pharmaceutical compounds are dosed. The scientific link between the 2 events is materia medica arcana. As an example, in the treatment of invasive candidiasis, antifungal therapy with intravenous micafungin is dosed daily. A literature review revealed population pharmacokinetic analyses, in vivo pharmacokinetics/pharmacodynamics studies, and maximum-tolerated-dose studies of micafungin that examined optimal micafungin dosing strategies. The half-life of micafungin in patient blood was 14 hours in several studies, but was even longer in different organs, so that the concentration will persist above minimum inhibitory concentrations of Candida species for several days. Studies in mice and rabbits with persistent neutropenia and disseminated candidiasis, otherwise fatal, demonstrated that a single large dose of micafungin could clear disseminated candidiasis, even though the micafungin half-life in such animals is shorter than in humans. Human pharmacokinetics/pharmacodynamics studies confirmed this link between micafungin efficacy and the ratio of the area under the concentration-time curve, and the optimal exposures initially identified in neutropenic animals. Maximum tolerated dose studies have demonstrated safety of 900 mg administered daily for several weeks, whereas case reports demonstrate efficacy and safety of single 1400-mg doses. Thus, a single dose of micafungin, or 2 such doses within a few days of each other, is not only logical, but might even lead to faster clearance of Candida.


Asunto(s)
Antifúngicos/administración & dosificación , Candidiasis Invasiva/tratamiento farmacológico , Equinocandinas/administración & dosificación , Lipopéptidos/administración & dosificación , Animales , Antifúngicos/farmacocinética , Candida/efectos de los fármacos , Candidiasis Invasiva/microbiología , Ensayos Clínicos como Asunto , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Equinocandinas/farmacocinética , Semivida , Humanos , Lipopéptidos/farmacocinética , Dosis Máxima Tolerada , Micafungina , Ratones , Pruebas de Sensibilidad Microbiana , Conejos
7.
Int J Antimicrob Agents ; 46(6): 631-41, 2015 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-26602452

RESUMEN

This study aimed to investigate the cumulative fraction of response of various echinocandin (caspofungin, micafungin and anidulafungin) dosing regimens against Candida spp. in paediatric patients with invasive fungal infections (IFIs). Monte Carlo simulations were performed using previously published pharmacokinetic parameters and pharmacodynamic data to evaluate the ability of each echinocandin regimen in terms of fAUC/MIC (free drug area under the concentration-time curve/minimum inhibition concentration ratio) targets of caspofungin, micafungin and anidulafungin. Pharmacodynamic targets were attained in paediatric patients by both caspofungin regimens as well as by a high micafungin dosing regimens against Candida albicans and Candida glabrata. However, the results for anidulafungin suggested that the dosing regimens recommended were not optimal for paediatric patients. In addition, the predicted efficacy of all of the echinocandins against Candida parapsilosis was low. This is the first study to assess caspofungin, micafungin and anidulafungin therapy using Monte Carlo simulation. These results rationalise and optimise the dosage regimens of caspofungin, micafungin and anidulafungin against C. albicans, C. glabrata and C. parapsilosis for paediatric patients with IFIs.


Asunto(s)
Antifúngicos/farmacocinética , Antifúngicos/uso terapéutico , Candida/efectos de los fármacos , Candidiasis Invasiva/tratamiento farmacológico , Equinocandinas/farmacocinética , Equinocandinas/uso terapéutico , Adolescente , Adulto , Anidulafungina , Caspofungina , Niño , Preescolar , Relación Dosis-Respuesta a Droga , Humanos , Lipopéptidos/farmacocinética , Lipopéptidos/uso terapéutico , Micafungina , Pruebas de Sensibilidad Microbiana , Método de Montecarlo
8.
Expert Rev Anti Infect Ther ; 13(6): 799-815, 2015 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-25947367

RESUMEN

Echinocandins belong to the class of antifungal agents. Currently, three echinocandin drugs are licensed for intravenous treatment of invasive fungal infections: anidulafungin, caspofungin and micafungin. While their antifungal activity overlaps, there are substantial differences in pharmacokinetics (PK). Numerous factors may account for variability in PK of echinocandins including age (pediatrics vs adults), body surface area and body composition (normal weight vs obesity), disease status (e.g., critically ill and burn patients) and organ dysfunction (kidney and liver impairment). Subsequent effects of altered exposure might impact efficacy and safety. Knowledge of PK behavior is crucial in optimal clinical utilization of echinocandin in a specific patient or patient population. This review provides up-to-date information on PK data of anidulafungin, caspofungin and micafungin in special patient populations. Patient populations addressed are neonates, children and adolescents, obese patients, patients with hepatic or renal impairment, critically ill patients (including burn patients) and patients with hematological diseases.


Asunto(s)
Antifúngicos/uso terapéutico , Equinocandinas/farmacocinética , Lipopéptidos/farmacocinética , Adolescente , Adulto , Anidulafungina , Candida/efectos de los fármacos , Caspofungina , Niño , Enfermedad Crítica , Interacciones Farmacológicas , Equinocandinas/efectos adversos , Enfermedades Hematológicas/fisiopatología , Humanos , Recién Nacido , Riñón/fisiopatología , Lipopéptidos/efectos adversos , Hígado/fisiopatología , Micafungina , Pruebas de Sensibilidad Microbiana , Obesidad
9.
Expert Opin Drug Deliv ; 12(1): 27-39, 2015 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-25141765

RESUMEN

INTRODUCTION: Nucleic acid delivery is a complex process that requires transport across numerous extracellular and intracellular barriers, whose impact is often neglected during optimization studies. As such, the development of nonviral vectors for efficient delivery would benefit from an understanding of how these barriers relate to the physicochemical properties of lipoplexes and polyplexes. AREAS COVERED: This review focuses on the evaluation of parameters associated with barriers to delivery such as blood and immune cells compatibility which, as a collective, may serve as a useful prescreening tool for the advancement of nonviral vectors in vivo. An outline of the most relevant rationally developed polyplexes and lipoplexes for clinical application is also given. EXPERT OPINION: The evaluation of scientifically recognized parameters enabled the identification of systemic delivered nonviral vectors' behavior while in blood as one of the key determinants of vectors function and activity both in vitro and in vivo. This multiparametric approach complements the use of in vitro efficacy results alone for prescreening and improves in vitro-in vivo translation by minimizing false negatives. Further, it can aid in the identification of meaningful structure-function-activity relationships, improve the in vitro screening process of nonviral vectors before in vivo use and facilitate the future development of potent and safe nonviral vectors.


Asunto(s)
Materiales Biocompatibles/química , Materiales Biocompatibles/farmacocinética , Técnicas de Transferencia de Gen , Vectores Genéticos/química , Vectores Genéticos/farmacocinética , Ácidos Nucleicos/administración & dosificación , Supervivencia Celular/efectos de los fármacos , Citocinas/biosíntesis , Evaluación Preclínica de Medicamentos , Hemólisis/efectos de los fármacos , Histocompatibilidad/inmunología , Lipopéptidos/química , Lipopéptidos/farmacocinética , Nanopartículas/química , Polímeros/química , Relación Estructura-Actividad
10.
J Antimicrob Chemother ; 69(6): 1624-32, 2014 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-24505092

RESUMEN

OBJECTIVES: To explore the pharmacokinetics (PK) and pharmacodynamics (PD) of micafungin in patients undergoing continuous venovenous haemofiltration (CVVH). PATIENTS AND METHODS: Ten patients receiving CVVH treated with 100 mg/day micafungin were included (April-December 2012). CVVH was performed using polyethersulphone or polysulphone haemofilters. Dialysis membranes were not changed on sampling days. On Days 1 and 2, blood samples from arterial pre-filter and venous post-filter ports and ultrafiltrate samples were collected at the start and end of the infusion and at 3, 5, 8, 18 and 24 h. Concentrations were determined using HPLC. Values for the area under the concentration-time curve (AUC0-24) were calculated. Monte Carlo simulations were performed using pre-filter and post-filter AUC0-24/MIC ratios on Days 1 and 2. The probability of target attainment (PTA) was calculated using AUC0-24/MIC cut-offs: 285 (C. parapsilosis), 3000 (all Candida spp.) and 5000 (non-parapsilosis Candida spp.). Cumulative fraction responses (CFRs) were calculated using EUCAST MIC distributions. RESULTS: Mean post-filter AUC0-24 (mg·h/L) values were higher than pre-filter values on Day 1 (83.31 ±â€Š15.87 versus 71.31 ±â€Š14.24; P = 0.008) and Day 2 (119.01 ±â€Š27.20 versus 104.54 ±â€Š21.23; P = 0.005). PTAs were ≥90% for MICs of 0.125 mg/L (cut-off = 285), 0.016 mg/L (cut-off = 3000) and 0.008 mg/L (cut-off = 5000) on Day 1, and for MICs of 0.25 mg/L (cut-off = 285) and 0.016 mg/L (cut-off = 3000 and 5000) on Day 2, without differences between pre- and post-filter values. On Day 2, CFRs >90% were obtained for C. albicans (cut-off = 3000 and 5000) and C. glabrata (cut-off = 3000), but not for C. parapsilosis. CONCLUSIONS: There was no removal of micafungin by CVVH or need for dose adjustment, and there was optimal PK/PD coverage for non-parapsilosis Candida and equivalence of pre- and post-filter PD.


Asunto(s)
Antifúngicos/farmacocinética , Candida/efectos de los fármacos , Candidiasis Invasiva/tratamiento farmacológico , Enfermedad Crítica/terapia , Equinocandinas/farmacocinética , Hemofiltración , Lipopéptidos/farmacocinética , Anciano , Anciano de 80 o más Años , Antifúngicos/uso terapéutico , Candidiasis Invasiva/diagnóstico , Candidiasis Invasiva/microbiología , Equinocandinas/uso terapéutico , Femenino , Hemofiltración/efectos adversos , Humanos , Unidades de Cuidados Intensivos , Lipopéptidos/uso terapéutico , Masculino , Micafungina , Pruebas de Sensibilidad Microbiana , Persona de Mediana Edad , Método de Montecarlo
11.
Radiat Res ; 177(5): 628-42, 2012 May.
Artículo en Inglés | MEDLINE | ID: mdl-22175300

RESUMEN

To date, there are no safe and effective drugs available for protection against ionizing radiation damage. Therefore, a great need exists to identify and develop non-toxic agents that will be useful as radioprotectors or postirradiation therapies under a variety of operational scenarios. We have developed a new pharmacological agent, CBLB613 (a naturally occurring Mycoplasma-derived lipopeptide ligand for Toll-like receptor 2/6), as a novel radiation countermeasure. Using CD2F1 mice, we investigated CBLB613 for toxicity, immunogenicity, radioprotection, radiomitigation and pharmacokinetics. We also evaluated CBLB613 for its effects on cytokine induction and radiation-induced cytopenia in unirradiated and irradiated mice. The no-observable-adverse-effect level of CBLB613 was 1.79 mg/kg and 1 mg/kg for single and repeated doses, respectively. CBLB613 significantly protected mice against a lethal dose of (60)Co γ radiation. The dose reduction factor of CBLB613 as a radioprotector was 1.25. CBLB613 also mitigated the effects of (60)Co γ radiation on survival in mice. In both irradiated and unirradiated mice, the drug stimulated induction of interleukin-1ß (IL-1ß), IL-6, IL-10, IL-12, keratinocyte-derived chemokine, granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, and tumor necrosis factor-1α. CBLB613 also reduced radiation-induced cytopenia and increased bone marrow cellularity in irradiated mice. Our immunogenicity study demonstrated that CBLB613 is not immunogenic in mice, indicating that it could be developed as a radioprotector and radiomitigator for humans against the potentially lethal effects of radiation exposure.


Asunto(s)
Citocinas/sangre , Rayos gamma/efectos adversos , Lipopéptidos/uso terapéutico , Mycoplasma/química , Pancitopenia/prevención & control , Traumatismos Experimentales por Radiación/tratamiento farmacológico , Protectores contra Radiación/uso terapéutico , Receptor Toll-Like 2/agonistas , Receptor Toll-Like 6/agonistas , Animales , Médula Ósea/efectos de los fármacos , Médula Ósea/patología , Médula Ósea/efectos de la radiación , Citocinas/biosíntesis , Citocinas/genética , Relación Dosis-Respuesta a Droga , Relación Dosis-Respuesta en la Radiación , Esquema de Medicación , Evaluación Preclínica de Medicamentos , Células HEK293/efectos de los fármacos , Células HEK293/efectos de la radiación , Humanos , Lipopéptidos/inmunología , Lipopéptidos/farmacocinética , Lipopéptidos/toxicidad , Masculino , Ratones , FN-kappa B/metabolismo , Pancitopenia/sangre , Pancitopenia/etiología , Traumatismos Experimentales por Radiación/sangre , Traumatismos Experimentales por Radiación/prevención & control , Protectores contra Radiación/farmacocinética , Protectores contra Radiación/toxicidad , Bazo/efectos de los fármacos , Bazo/patología , Bazo/efectos de la radiación
12.
Antimicrob Agents Chemother ; 55(7): 3075-83, 2011 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-21502627

RESUMEN

The clinical utility of the echinocandins is potentially compromised by the emergence of drug resistance. We investigated whether Candida albicans with amino acid substitutions at position Ser645 in Fks1 can be treated with either a conventional or an elevated dosage of micafungin. We studied Candida albicans (wild-type SC5314; MIC, 0.06 mg/liter) and four fks1 mutants (one FKS1/fks1 heterozygote mutant [MIC, 0.5 mg/liter] and three fks1/fks1 homozygous mutants [MICs for all, 2 mg/liter]) with a variety of amino acid substitutions at Ser645. The pharmacokinetic and pharmacodynamic relationships were characterized in a persistently neutropenic murine model of disseminated candidiasis. A mathematical model was fitted to all pharmacokinetic and pharmacodynamic data. This mathematical model was then used to "humanize" the murine pharmacokinetics, and the predicted antifungal effect was determined. The estimated maximal rate of growth and ultimate fungal densities in the kidney for each of the strains were similar. The administration of micafungin at 1 mg/kg of body weight to the wild type resulted in moderate antifungal activity, whereas the administration of 5 and 20 mg/kg resulted in rapid fungicidal activity. In contrast, the FKS1/fks heterozygote was killed only with 20 mg/kg, and the homozygous fks1 mutants failed to respond to any dosage. The bridging study revealed that human dosages of 100 and 400 mg/day were active only against the wild type, with no activity against either the heterozygote or the homozygote mutants. Ser645 Fks1 Candida albicans mutants cannot be treated with either conventional or elevated dosages of micafungin and should be deemed resistant.


Asunto(s)
Antifúngicos/farmacología , Antifúngicos/uso terapéutico , Candida albicans/efectos de los fármacos , Candida albicans/metabolismo , Candidiasis/tratamiento farmacológico , Equinocandinas/metabolismo , Lipopéptidos/farmacología , Lipopéptidos/uso terapéutico , Sustitución de Aminoácidos , Animales , Antifúngicos/administración & dosificación , Antifúngicos/farmacocinética , Candida albicans/genética , Candida albicans/patogenicidad , Candidiasis/microbiología , Farmacorresistencia Fúngica/genética , Equinocandinas/administración & dosificación , Equinocandinas/química , Equinocandinas/genética , Equinocandinas/farmacocinética , Equinocandinas/farmacología , Equinocandinas/uso terapéutico , Proteínas Fúngicas/química , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Genotipo , Humanos , Lipopéptidos/administración & dosificación , Lipopéptidos/farmacocinética , Masculino , Micafungina , Ratones , Pruebas de Sensibilidad Microbiana
13.
Enferm Infecc Microbiol Clin ; 29 Suppl 2: 3-9, 2011 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-21420570

RESUMEN

The echinocandins anidulafungin, caspofungin, and micafungin have a broad and similar spectrum of in vitro and in vivo activity against most Candida spp. Minimal inhibitory concentrations (MICs) for Candida spp. are usually below 1 µg/mL for most isolates. The exceptions are Candidaparapsilosis and C. guilliermondii. Species-specific clinical breakpoints (CBPs) and epidemiologic cutoff values (ECVs) have been proposed by the Clinical and Laboratory Standards Institute (CLSI) for the eight most common Candida spp. versus each echinocandin; these values are useful to detect in vitro antifungal resistance (CBPs) and to identify isolates harboring fks mutations or having reduced susceptibility (ECVs). This paper presents a review of the literature (2006-2010) regarding the in vitro activity similarities or differences among the three echinocandins against Candida spp.; different parameters or measurements of in vitro potency were evaluated. The focus of the review is the non-Candida albicans species.


Asunto(s)
Candida/efectos de los fármacos , Equinocandinas/farmacología , Lipopéptidos/farmacología , Pruebas de Sensibilidad Microbiana/métodos , Anidulafungina , Candida/enzimología , Candida/genética , Candida/aislamiento & purificación , Candida/ultraestructura , Candidiasis/microbiología , Caspofungina , Evaluación Preclínica de Medicamentos , Farmacorresistencia Fúngica/genética , Farmacorresistencia Fúngica Múltiple , Equinocandinas/farmacocinética , Fluconazol/farmacología , Proteínas Fúngicas/genética , Proteínas Fúngicas/fisiología , Glucosiltransferasas/genética , Glucosiltransferasas/fisiología , Humanos , Técnicas In Vitro , Lipopéptidos/farmacocinética , Micafungina , Especificidad de la Especie , Equivalencia Terapéutica
14.
Enferm Infecc Microbiol Clin ; 29 Suppl 2: 23-8, 2011 Mar.
Artículo en Español | MEDLINE | ID: mdl-21420573

RESUMEN

Micafungin is an echinocandin approved by the European Medicines Evaluation Agency for the treatment of invasive candidiasis in children, including premature infants born before 29 weeks of pregnancy, and as prophylaxis in children undergoing hematopoietic stem-cell transplantation or patients at risk of prolonged neutropenia. This drug has good activity in several Candida spp., including those resistant to fluconazole. Although micafungin is active against Aspergillus spp., it has been used mainly in combination therapy for invasive aspergillosis. There is ample information on the use of micafungin in children, including neonates, and this drug is the only echinocandin approved for use in infants aged less than 3 months. The efficacy, pharmacokinetics and safety of micafungin have been evaluated in phase II and III clinical trials in children, in which its efficacy and safety were demonstrated in comparison with liposomal amphotericin B and fluconazole. The pharmacokinetic profile of micafungin in children allows once daily intravenous administration, with greater clearance than in adults, and consequently pediatric doses are relatively higher. The most appropriate dose in children weighing less than 40 kg is 2 mg/kg/day in the treatment of invasive candidiasis and 1 mg/kg/day as prophylaxis in children undergoing hematopoietic stem-cell transplantation. Doses in neonates should be higher. In premature infants, the most appropriate doses to achieve levels in the brain parenchyma are 7 mg/kg/day and 10 mg/kg/day in those weighing more and less than 1,000 g, respectively. Micafungin has few drug-drug interactions and an acceptable safety profile. Withdrawal of this drug due to adverse effects is rare, although transaminase monitoring is recommended during treatment, as well as evaluation of the risk-benefit balance in patients with liver disease or concomitant administration of hepatotoxic drugs.


Asunto(s)
Antifúngicos/uso terapéutico , Equinocandinas/uso terapéutico , Lipopéptidos/uso terapéutico , Micosis/tratamiento farmacológico , Adolescente , Adulto , Factores de Edad , Animales , Antifúngicos/administración & dosificación , Antifúngicos/efectos adversos , Antifúngicos/farmacocinética , Barrera Hematoencefálica , Peso Corporal , Niño , Preescolar , Ensayos Clínicos como Asunto/estadística & datos numéricos , Método Doble Ciego , Aprobación de Drogas , Evaluación Preclínica de Medicamentos , Equinocandinas/administración & dosificación , Equinocandinas/efectos adversos , Equinocandinas/farmacocinética , Humanos , Lactante , Recién Nacido , Recien Nacido Prematuro , Enfermedades del Prematuro/tratamiento farmacológico , Lipopéptidos/administración & dosificación , Lipopéptidos/efectos adversos , Lipopéptidos/farmacocinética , Metaanálisis como Asunto , Micafungina , Estudios Multicéntricos como Asunto/estadística & datos numéricos , Micosis/prevención & control , Conejos , Ensayos Clínicos Controlados Aleatorios como Asunto/estadística & datos numéricos
15.
Enferm Infecc Microbiol Clin ; 29 Suppl 2: 15-22, 2011 Mar.
Artículo en Español | MEDLINE | ID: mdl-21420572

RESUMEN

Micafungin is a semisynthetic lipopeptide developed from Coleophoma empetri, which blocks the synthesis of ß-1,3-D-glucan, an essential component of the fungal wall, though non-competitive inhibition of ß-1,3-D-glucan synthetase. Micafungin is a dose-dependent candidacidal agent with excellent in vitro efficacy against most Candida spp. including species resistant to amphotericin B, such as Candida lusitaniae, several azoles, such as C. glabrata or C. krusei, and isolates not susceptible to other echinocandins. Moreover, this drug is active against Candida biofilms. Micafungin is a first-line drug for the treatment of candidemias and invasive candidiasis in adults and children (including neonates). This drug is approved for use in the treatment of invasive candidiasis and Candida esophagitis, as well as in the prophylaxis of Candida infections in hematopoietic stem cell transplant recipients or those at risk of prolonged neutropenia. Micafungin can be used both in the treatment and prevention of candidiasis in neonates, children, adolescents, adults, and the elderly, making it highly useful in patient groups in which the use of other antifungal drugs has not been authorized.


Asunto(s)
Antifúngicos/uso terapéutico , Candidiasis Invasiva/tratamiento farmacológico , Equinocandinas/uso terapéutico , Lipopéptidos/uso terapéutico , Adolescente , Adulto , Anciano , Animales , Antifúngicos/efectos adversos , Antifúngicos/farmacocinética , Antifúngicos/farmacología , Biopelículas/efectos de los fármacos , Candida/efectos de los fármacos , Candida/enzimología , Candida/ultraestructura , Pared Celular/efectos de los fármacos , Niño , Preescolar , Ensayos Clínicos como Asunto , Método Doble Ciego , Evaluación Preclínica de Medicamentos , Equinocandinas/efectos adversos , Equinocandinas/farmacocinética , Equinocandinas/farmacología , Esofagitis/tratamiento farmacológico , Proteínas Fúngicas/antagonistas & inhibidores , Glucosiltransferasas/antagonistas & inhibidores , Humanos , Huésped Inmunocomprometido , Lactante , Recién Nacido , Lipopéptidos/efectos adversos , Lipopéptidos/farmacocinética , Lipopéptidos/farmacología , Micafungina , Ratones , Persona de Mediana Edad , Estudios Multicéntricos como Asunto , Complicaciones Posoperatorias/prevención & control , Especificidad de la Especie , Trasplante , Adulto Joven
16.
Antimicrob Agents Chemother ; 55(5): 2113-21, 2011 May.
Artículo en Inglés | MEDLINE | ID: mdl-21300835

RESUMEN

Echinocandins have become a first-line therapy for invasive candidiasis (IC). Using phase 3 trial data for patients with IC, pharmacokinetic-pharmacodynamic (PK-PD) relationships for efficacy for micafungin were examined. Micafungin exposures were estimated using a population pharmacokinetic model, and univariable and multivariable logistic regressions were used to identify factors associated with outcome, including the micafungin area under the concentration-time curve (AUC)/MIC ratio. Monte Carlo simulation was used to evaluate the probability of achieving AUC/MIC ratios associated with efficacy. Mycological and clinical success rates for evaluable cases were 89.4 and 90.9, respectively. MIC50s and MIC90s for Candida species inhibition were 0.008 and 0.5 mg/liter, respectively. The median AUC/MIC ratio was 15,511 (range, 41.28 to 98,716). Univariable analyses revealed a significant relationship between the AUC/MIC ratio and mycological response, with the worst response being among patients with lower (≤3,000) AUC/MIC ratios (P=0.005). For patients with Candida parapsilosis, AUC/MIC ratios of ≥285 were predictive of a higher mycological response (P=0.11). Multivariable logistic regression demonstrated the AUC/MIC ratio, APACHE II score, and history of corticosteroid use to be significant independent predictors of a favorable response. PK-PD target attainment analyses suggested that 76.7% and 100% of patients would achieve an AUC/MIC ratio of ≥3,000 for an MIC of 0.03 mg/liter and an AUC/MIC ratio of ≥285 for an MIC of <0.5 mg/liter, respectively. The identification of a lower AUC/MIC ratio target for C. parapsilosis than other Candida species suggests consideration of species-specific echinocandin susceptibility breakpoints and values that are lower than those currently approved by regulatory agencies.


Asunto(s)
Antifúngicos/farmacocinética , Candidemia/tratamiento farmacológico , Candidiasis/tratamiento farmacológico , Equinocandinas/farmacocinética , Lipopéptidos/farmacocinética , Antifúngicos/uso terapéutico , Candidemia/sangre , Candidiasis/sangre , Ensayos Clínicos Fase III como Asunto , Equinocandinas/uso terapéutico , Femenino , Humanos , Lipopéptidos/uso terapéutico , Masculino , Micafungina , Pruebas de Sensibilidad Microbiana , Persona de Mediana Edad , Método de Montecarlo , Ensayos Clínicos Controlados Aleatorios como Asunto
17.
Rev Iberoam Micol ; 26(1): 23-34, 2009 Mar 31.
Artículo en Español | MEDLINE | ID: mdl-19463274

RESUMEN

BACKGROUND: Invasive fungal infections are a significant cause of morbidity and mortality among immunocompromised patients. Although several new antifungal agents have been developed in the past few years, the management of serious fungal infections continues to be problematic. AIMS: To review the pharmacodynamics and pharmacokinetics of a new antifungal agent: micafungin. METHODS: A systematic review of biomedic databases (EBSCO Open Journals, Ovid Online, Proquest Medical Library, PubMed/Medline, Science Direct, Springer Links and Wiley Interscience) has been performed. Search was conducted from 2000 to 2008. Supplementary sources included abstracts from the Interscience Conference on Antimicrobial Agents (ICAAC) and Chemotherapy and the Infectious Diseases Society of America (IDSA) from 1998 to 2008. RESULTS: Micafungin has a potent mechanism of action: inhibits beta-1,3-D-glucan synthase interfering with fungal cell wall synthesis. This agent shares with caspofungin an identical spectrum of in vitro activity against Candida albicans, non-albicans Candida species, and Aspergillus. Due to the limited oral availability, micafungin is available for parenteral administration only. Micafungin is characterized by a linear pharmacokinetic profile and substantially fewer toxic effects. Micafungin is a poor substrate for the cytochrome P450 enzymes, and compared to azoles, fewer drug interactions have been described. No dose reduction is required in renal impairment or in mild to moderate liver failure. CONCLUSIONS: The pharmacodynamic and pharmacokinetic profiles of micafungin imply that this drug is a safe alternative for the treatment of fungal infections. Micafungin can be safely co-administered with most drugs without the need for dosage adaptation even in patients with renal o liver function impairment.


Asunto(s)
Antifúngicos/farmacología , Equinocandinas/farmacología , Proteínas Fúngicas/antagonistas & inhibidores , Glucosiltransferasas/antagonistas & inhibidores , Lipopéptidos/farmacología , Micosis/tratamiento farmacológico , Adolescente , Adulto , Anciano , Animales , Antifúngicos/efectos adversos , Antifúngicos/farmacocinética , Antifúngicos/uso terapéutico , Aspergillus/efectos de los fármacos , Aspergillus/enzimología , Biotransformación , Candida/efectos de los fármacos , Candida/enzimología , Niño , Preescolar , Evaluación Preclínica de Medicamentos , Interacciones Farmacológicas , Equinocandinas/efectos adversos , Equinocandinas/farmacocinética , Equinocandinas/uso terapéutico , Humanos , Recién Nacido , Lipopéptidos/efectos adversos , Lipopéptidos/farmacocinética , Lipopéptidos/uso terapéutico , Micafungina , Pruebas de Sensibilidad Microbiana , Persona de Mediana Edad , Estructura Molecular , Pneumocystis carinii/efectos de los fármacos , Pneumocystis carinii/enzimología , Adulto Joven
18.
Rev Iberoam Micol ; 26(1): 62-4, 2009 Mar 31.
Artículo en Español | MEDLINE | ID: mdl-19463279

RESUMEN

Micafungin is one of three echinocandins, a novel class of antifungal agents active against 1,3-beta-D glucan in the fungal cell wall. It is a favorable safety profile have made it an attractive option in the treatment of invasive Candida and Aspergillus infections. Available studies have shown that younger children have lower C(max), shorter t(1/2) and faster clearance than adults.


Asunto(s)
Antifúngicos/uso terapéutico , Aspergilosis/tratamiento farmacológico , Candidiasis/tratamiento farmacológico , Equinocandinas/uso terapéutico , Fungemia/tratamiento farmacológico , Lipopéptidos/uso terapéutico , Adolescente , Antifúngicos/farmacocinética , Niño , Preescolar , Ensayos Clínicos como Asunto , Interacciones Farmacológicas , Farmacorresistencia Fúngica Múltiple , Equinocandinas/farmacocinética , Femenino , Humanos , Lactante , Lipopéptidos/farmacocinética , Masculino , Micafungina , Pruebas de Sensibilidad Microbiana
19.
Rev Iberoam Micol ; 26(1): 81-9, 2009 Mar 31.
Artículo en Español | MEDLINE | ID: mdl-19463284

RESUMEN

BACKGROUND: Micafungin is a echinocandin. It inhibits beta-1,3-D-glucan synthesis, thus achieving fungicidal activity against virtually all Candida spp., including those resistant to fluconazole, and fungistatic activity against Aspergillus spp., as well as several but not all pathogenic molds. Results from in vitro studies, animal models, small clinical trials, hint at possible future indications such as invasive aspergillosis and empirical viantifungal therapy, although currently there is little information published. AIMS: To describe published data of micafungin as treatment against invasive mold infections, specially analysing its role in the inmunodepressed host and critical care setting. METHODS: A systematic review of literature using the principal medical search engines was performed. Terms such as micafungin, aspergillosis, zygomycosis, invasive fungal infections, emerging fungal infections, antifungal treatment or therapy, antifungal prophylaxis, empiric or pre-emptive therapy were crossed. Febrile neutropenia patients were excluded. RESULTS: Several studies in these setting were identified and were described in this review. Although there were no blinded randomized clinical trials published, treatment or prophylaxis of invasive aspergillosis and other invasive mould infections with micafungin described in open clinical studies were analyzed. CONCLUSIONS: Micafungin could play a future important role as a primary or rescue therapy, alone or in combination, in the treatment or prophylaxis of invasive fungal infections caused by moulds. New randomized clinical trials are needed to confirm their efficacy.


Asunto(s)
Antifúngicos/uso terapéutico , Equinocandinas/uso terapéutico , Fungemia/tratamiento farmacológico , Lipopéptidos/uso terapéutico , Micosis/tratamiento farmacológico , Adulto , Animales , Antifúngicos/efectos adversos , Antifúngicos/farmacocinética , Aspergilosis/tratamiento farmacológico , Candidiasis/tratamiento farmacológico , Niño , Ensayos Clínicos como Asunto , Método Doble Ciego , Evaluación Preclínica de Medicamentos , Equinocandinas/efectos adversos , Equinocandinas/farmacocinética , Fluconazol/uso terapéutico , Predicción , Trasplante de Células Madre Hematopoyéticas , Humanos , Huésped Inmunocomprometido , Lipopéptidos/efectos adversos , Lipopéptidos/farmacocinética , Micafungina , Estudios Multicéntricos como Asunto , Micosis/prevención & control , Trasplante de Órganos , Complicaciones Posoperatorias/prevención & control , Premedicación , Estudios Prospectivos , Ensayos Clínicos Controlados Aleatorios como Asunto , Cigomicosis/tratamiento farmacológico
20.
Rev. iberoam. micol ; 26(1): 23-34, mar. 2009. graf, tab
Artículo en Español | IBECS | ID: ibc-136101

RESUMEN

Antecedentes: Las infecciones fúngicas son una causa importante de morbilidad y mortalidad en los pacientes inmunodeficientes. A pesar que en los últimos años se han desarrollado nuevos fármacos antifúngicos, el tratamiento de estas infecciones sigue siendo problemático. Objetivos: Revisar la farmacodinamia y la farmacocinética de una nueva equinocandina: micafungina. Métodos: Se ha realizado una revisión simple utilizando una búsqueda bibliográfica en las fuentes habituales (EBSCO Open Journals, Ovid Online, Proquest Medical Library, PubMed/Medline, Science Direct, Springer Links y Wiley Interscience) desde el año 2000 hasta 2008. Adicionalmente, se han incluido los libros de resúmenes de Interscience Conference on Antimicrobial Agents and Chemotherapy and the Infectious Diseases Society of America celebradas desde 1998 hasta 2008. Resultados: La micafungina es una equinocandina con un potente mecanismo de acción: inhibe el enzima β-1,3-D-glucano sintasa e interfiere en la síntesis de la pared celular. Este fármaco comparte con la caspofungina un idéntico espectro in vitro frente a Candida albicans, especies de Candida diferentes de C. albicans y Aspergillus. Debido a la limitada biodisponibilidad oral, la micafungina se administra únicamente por vía parenteral. Se caracteriza por una farmacocinética lineal y por presentar pocos efectos adversos. La micafungina se metaboliza mínimamente por el citocromo P-450 y presenta pocas interacciones farmacológicas. No requiere reducir dosis en fracaso renal, ni en fracaso hepático leve o moderado. Conclusiones: La micafungina presenta un perfil farmacodinámico y farmacocinético que permite su administración de modo seguro, con mínimas interacciones medicamentosas y sin necesidad de ajuste de dosis en presencia de fracaso renal o hepático (AU)


Background: Invasive fungal infections are a significant cause of morbidity and mortality among immuno- compromised patients. Although several new antifungal agents have been developed in the past few years, the management of serious fungal infections continues to be problematic. Aims: To review the pharmacodynamics and pharmacokinetics of a new antifungal agent: micafungin. Methods: A systematic review of biomedic databases (EBSCO Open Journals, Ovid Online, Proquest Medical Library, PubMed/Medline,, Science Direct, Springer Links and Wiley Interscience) has been performed. Search was conducted from 2000 to 2008. Supplementary sources included abstracts from the Interscience Conference on Antimicrobial Agents (ICAAC) and Chemotherapy and the Infectious Diseases Society of America (IDSA) from 1998 to 2008. Results: Micafungin has a potent mechanism of action: inhibits β-1,3-D-glucan synthase interfering with fungal cell wall synthesis. This agent shares with caspofungin an identical spectrum of in vitro activity against Candida albicans, non-albicans Candida species, and Aspergillus. Due to the limited oral availability, micafungin is available for parenteral administration only. Micafungin is characterized by a linear pharmacokinetic profile and substantially fewer toxic effects. Micafungin is a poor substrate for the cytochrome P450 enzymes, and compared to azoles, fewer drug interactions have been described. No dose reduction is required in renal impairment or in mild to moderate liver failure. Conclusions: The pharmacodynamic and pharmacokinetic profiles of micafungin imply that this drug is a safe alternative for the treatment of fungal infections. Micafungin can be safely co-administered with most drugs without the need for dosage adaptation even in patients with renal o liver function impairment (AU)


Asunto(s)
Humanos , Animales , Recién Nacido , Preescolar , Niño , Adolescente , Adulto Joven , Adulto , Persona de Mediana Edad , Anciano , Antifúngicos/farmacología , Antifúngicos/farmacocinética , Equinocandinas/farmacología , Equinocandinas/uso terapéutico , Proteínas Fúngicas/antagonistas & inhibidores , Glucosiltransferasas/antagonistas & inhibidores , Micosis/tratamiento farmacológico , Lipopéptidos/farmacología , Lipopéptidos/farmacocinética , Pneumocystis carinii , Pneumocystis carinii/enzimología , Antifúngicos/efectos adversos , Antifúngicos/uso terapéutico , Equinocandinas/efectos adversos , Equinocandinas/farmacocinética , Lipopéptidos/efectos adversos , Lipopéptidos/uso terapéutico , Aspergillus , Aspergillus/enzimología , Candida , Candida/enzimología , Estructura Molecular , Biotransformación , Interacciones Farmacológicas , Pruebas de Sensibilidad Microbiana
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