RESUMEN
Rezafungin acetate is a novel echinocandin in clinical development for prevention and treatment of invasive fungal infections. Rezafungin is differentiated by a pharmacokinetic/pharmacodynamic (PK/PD) profile that includes a long half-life allowing once-weekly administration, front-loaded plasma drug exposures associated with antifungal efficacy, and penetration into deep-seated infections, such as intra-abdominal abscesses. In this series of in vivo studies, rezafungin demonstrated efficacy in the treatment of neutropenic mouse models of disseminated candidiasis, including infection caused by azole-resistant Candida albicans, and aspergillosis. These results contribute to a growing body of evidence demonstrating the antifungal efficacy and potential utility of rezafungin in the treatment of invasive fungal infections.
Asunto(s)
Antifúngicos/farmacocinética , Aspergilosis/tratamiento farmacológico , Candidiasis Invasiva/tratamiento farmacológico , Equinocandinas/farmacocinética , Administración Oral , Animales , Antifúngicos/administración & dosificación , Aspergilosis/inmunología , Aspergilosis/microbiología , Aspergillus fumigatus/efectos de los fármacos , Aspergillus fumigatus/aislamiento & purificación , Candida albicans/efectos de los fármacos , Candida albicans/aislamiento & purificación , Candidiasis Invasiva/sangre , Candidiasis Invasiva/inmunología , Candidiasis Invasiva/microbiología , Modelos Animales de Enfermedad , Esquema de Medicación , Equinocandinas/administración & dosificación , Femenino , Semivida , Humanos , Huésped Inmunocomprometido , Masculino , Ratones , Pruebas de Sensibilidad Microbiana , Neutropenia/inmunologíaRESUMEN
INTRODUCTION: The study objective was to evaluate the efficacy of different dosages of caspofungin in the treatment of invasive candidiasis and aspergillosis, in relation to the probability of pharmacokinetic/pharmacodynamic (PK/PD) target attainment, using modelling and Monte Carlo simulations in critically ill adult patients on continuous haemodiafiltration. METHODS: Critically ill adult patients on continuous venovenous haemodiafiltration treated with caspofungin were analysed. A population PK model was developed. Four caspofungin dosing regimens were simulated: the licensed regimen, 70 mg/day, 100 mg/day or 200 mg/day. A PK/PD target was defined as the ratio between the area under the caspofungin concentration-time curve over 24 hours and the minimal inhibitory concentration (AUC/MIC) for candidiasis or the minimal effective concentrations (AUC/MEC) for Aspergillus spp. Target attainment based on preclinical target for Candida and Aspergillus was assessed for different MIC or MEC, respectively. RESULTS: Concentration-time data were described by a two-compartment model. Body-weight and protein concentration were the only covariates identified by the model. Goodness-of-fit plots and bootstrap analysis proved the model had a satisfactory performance. As expected, a higher maintenance dose resulted in a higher exposure. Target attainment was >90% for candidiasis (MIC≤0.06 mg/L) and aspergillosis (MEC≤0.5 mg/L), irrespective of the dosing regimen, but not for C. parapsilosis. Standard regimen was insufficient to reach the target for C. albicans and C. parapsilosis with MIC≥0.1 mg/L. CONCLUSION: The licensed regimen of caspofungin is insufficient to achieve the PK/PD targets in critically ill patients on haemodiafiltration. The determination of MICs will enable dose scheme selection.
Asunto(s)
Candidiasis Invasiva/tratamiento farmacológico , Candidiasis/tratamiento farmacológico , Equinocandinas/administración & dosificación , Equinocandinas/uso terapéutico , Aspergilosis Pulmonar Invasiva/tratamiento farmacológico , Lipopéptidos/administración & dosificación , Lipopéptidos/uso terapéutico , Anciano , Anciano de 80 o más Años , Antifúngicos/farmacología , Aspergillus/efectos de los fármacos , Candida albicans/efectos de los fármacos , Candida glabrata/efectos de los fármacos , Candida parapsilosis/efectos de los fármacos , Caspofungina , Enfermedad Crítica , Femenino , Hemodiafiltración , Humanos , Masculino , Pruebas de Sensibilidad Microbiana , Persona de Mediana EdadRESUMEN
CD101 is a novel echinocandin with concentration-dependent fungicidal activity in vitro and a long half-life (â¼133 h in humans, â¼70 to 80 h in mice). Given these characteristics, it is likely that the shape of the CD101 exposure (i.e., the time course of CD101 concentrations) influences efficacy. To test this hypothesis, doses which produce the same total area under the concentration-time curve (AUC) were administered to groups of neutropenic ICR mice infected with Candida albicans R303 using three different schedules. A total CD101 dose of 2 mg/kg was administered as a single intravenous (i.v.) dose or in equal divided doses of either 1 mg/kg twice weekly or 0.29 mg/kg/day over 7 days. The studies were performed using a murine disseminated candidiasis model. Animals were euthanized at 168 h following the start of treatment. Fungi grew well in the no-treatment control group and showed variable changes in fungal density in the treatment groups. When the CD101 AUC from 0 to 168 h (AUC0-168) was administered as a single dose, a >2 log10 CFU reduction from the baseline at 168 h was observed. When twice-weekly and daily regimens with similar AUC values were administered, net fungal stasis and a >1 log10 CFU increase from the baseline were observed, respectively. These data support the hypothesis that the shape of the CD101 AUC influences efficacy. Thus, CD101 administered once per week demonstrated a greater degree of fungal killing than the same dose divided into twice-weekly or daily regimens.
Asunto(s)
Antifúngicos/uso terapéutico , Candida albicans/efectos de los fármacos , Candidiasis/tratamiento farmacológico , Equinocandinas , Animales , Antifúngicos/administración & dosificación , Antifúngicos/farmacocinética , Modelos Animales de Enfermedad , Esquema de Medicación , Equinocandinas/administración & dosificación , Equinocandinas/farmacocinética , Equinocandinas/uso terapéutico , Humanos , Ratones , Ratones Endogámicos ICR , Pruebas de Sensibilidad MicrobianaRESUMEN
Caspofungin (CAS) which is used as salvage therapy in patients with invasive pulmonary aspergillosis (IPA) inhibits the 1,3-ß-D-glucan synthesis in Aspergillus fumigatus. Inhibiting 1,3-ß-D-glucan synthesis induces a stress response and in an invertebrate model it was demonstrated that inhibiting this response with geldamycin enhanced the therapeutic efficacy of CAS. Since geldamycin itself is toxic to mammalians, the therapeutic efficacy of combining geldamycin with CAS was not studied in rodent models. Therefore in this study we investigated if the geldamycin derivate 17-(allylamino)-17-demethoxygeldanamycin (17-AAG) was able to enhance the therapeutic efficacy of CAS in vitro and in our IPA model in transiently neutropenic rats. In vitro we confirmed the earlier demonstrated synergy between 17-AAG and CAS in ten A. fumigatus isolates. In vivo we treated A. fumigatus infected neutropenic rats with a sub-optimal dose of 0.75 mg/kg/day CAS and 1 mg/kg/day 17-AAG for ten days. Survival was monitored for 21 days after fungal inoculation. It appeared that the addition 17-AAG delayed death but did not improve overall survival of rats with IPA. Increasing the doses of 17-AAG was not possible due to hepatic toxicity. This study underlines the need to develop less toxic and more fungal specific geldamycin derivatives and the need to test such drugs not only in invertebrate models but also in mammalian models.
Asunto(s)
Benzoquinonas/administración & dosificación , Equinocandinas/administración & dosificación , Aspergilosis Pulmonar Invasiva/tratamiento farmacológico , Lactamas Macrocíclicas/administración & dosificación , Lipopéptidos/administración & dosificación , Animales , Antifúngicos/administración & dosificación , Aspergillus fumigatus/efectos de los fármacos , Benzoquinonas/toxicidad , Caspofungina , Modelos Animales de Enfermedad , Sinergismo Farmacológico , Quimioterapia Combinada , Femenino , Humanos , Aspergilosis Pulmonar Invasiva/complicaciones , Aspergilosis Pulmonar Invasiva/microbiología , Lactamas Macrocíclicas/toxicidad , Pruebas de Sensibilidad Microbiana , Neutropenia/complicaciones , RatasRESUMEN
Concerns with echinocandin use for infections caused by Candida parapsilosis complex species have driven the need for data to support echinocandin clinical efficacy in such patients. Data from six prospective studies were pooled to assess efficacy and safety of anidulafungin in patients with candidaemia caused by C. parapsilosis. Patient-level data were pooled from patients with microbiologically confirmed candidaemia due to C. parapsilosis treated with anidulafungin. Patients received a 200 mg intravenous (IV) loading dose of anidulafungin (day 1) and 100 mg daily thereafter. IV treatment could be switched to oral azole therapy after ≥5 or ≥10 days. Primary endpoint was global response at end of IV therapy (EOIVT). Seventy patients had candidaemia caused by C. parapsilosis. Global response was 77.1% (95% CI: 67.3, 87.0) at EOIVT and 70.0% (95% CI: 59.3, 80.7) at end of treatment. Three of 55 isolates (with MICs available) were resistant to anidulafungin (MIC ≥8 mg/L). All-cause mortality was 5.7% (n=4/70) by day 14 and 14.3% (n=10/70) by day 28. IV anidulafungin was effective for the treatment of C. parapsilosis candidaemia in this population, consistent with efficacy previously demonstrated for other Candida species. (ClinicalTrials.gov identifiers: NCT00496197, NCT00548262, NCT00537329, NCT00689338, NCT00806351, NCT00805740).
Asunto(s)
Antifúngicos/uso terapéutico , Candida parapsilosis/efectos de los fármacos , Candidemia/tratamiento farmacológico , Equinocandinas/uso terapéutico , Administración Intravenosa , Adulto , Anidulafungina , Antifúngicos/administración & dosificación , Antifúngicos/efectos adversos , Azoles/farmacología , Azoles/uso terapéutico , Candidemia/microbiología , Candidiasis Invasiva/tratamiento farmacológico , Ensayos Clínicos como Asunto , Equinocandinas/administración & dosificación , Equinocandinas/efectos adversos , Femenino , Fluconazol/farmacología , Fluconazol/uso terapéutico , Humanos , Masculino , Pruebas de Sensibilidad Microbiana , Persona de Mediana Edad , Estudios Prospectivos , Resultado del TratamientoRESUMEN
BACKGROUND: Whether echinocandins could be used to treat candidemia of a urinary tract source (CUTS) is unknown. We aimed to provide current epidemiological information of CUTS and to compare echinocandin to fluconazole treatment on CUTS outcomes. METHODS: A multicenter study of adult patients with candidemia was conducted in 9 hospitals. CUTS was defined as a candidemia with concomitant candiduria by the same organism associated with significant urological comorbidity. The primary outcome assessed was clinical failure (defined by 7-day mortality or persistent candidemia) in patients treated with either an echinocandin or fluconazole. A propensity score was calculated and then entered into a regression model. RESULTS: Of 2176 episodes of candidemia, 128 were CUTS (5.88%). Most CUTS cases were caused by Candida albicans (52.7%), followed by Candida glabrata (25.6%) and Candida tropicalis (16.3%). Clinical failure occurred in 7 patients (20%) treated with an echinocandin and in 15 (17.1%) treated with fluconazole (P = .730). Acute renal failure (adjusted odds ratio [AOR], 3.01; 95% confidence interval [CI], 1.01-8.91; P = .047) was the only independent factor associated with clinical failure, whereas early urinary tract drainage procedures (surgical, percutaneous, or endoscopic) were identified as protective (AOR, 0.08; 95% CI, .02-.31; P < .001). Neither univariate nor multivariate analysis showed that echinocandin therapy altered the risk of clinical failure. CONCLUSIONS: Initial echinocandin therapy was not associated with clinical failure in patients with CUTS. Notably, acute renal failure predicted worse outcomes and performing an early urologic procedure was a protective measure.
Asunto(s)
Antifúngicos/uso terapéutico , Candidemia/tratamiento farmacológico , Equinocandinas/uso terapéutico , Fluconazol/uso terapéutico , Infecciones Urinarias/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Antifúngicos/administración & dosificación , Candida albicans/efectos de los fármacos , Candida albicans/aislamiento & purificación , Candida glabrata/efectos de los fármacos , Candida glabrata/aislamiento & purificación , Candidemia/microbiología , Candidemia/mortalidad , Estudios de Cohortes , Comorbilidad , Equinocandinas/administración & dosificación , Femenino , Fluconazol/administración & dosificación , Humanos , Masculino , Pruebas de Sensibilidad Microbiana , Persona de Mediana Edad , Análisis Multivariante , Puntaje de Propensión , Insuficiencia Renal/microbiología , Resultado del Tratamiento , Infecciones Urinarias/microbiologíaRESUMEN
OBJECTIVES: The aim of the present study was to evaluate the effects of delayed antifungal therapy on the outcome of invasive aspergillosis due to Aspergillus fumigatus in experimental models of infection. METHODS: A clinical isolate of A. fumigatus susceptible to amphotericin B (MIC 0.5 mg/L) and micafungin [minimum effective concentration (MEC) 0.03 mg/L] was used in all experiments. Two models of infection were investigated in immunosuppressed mice: disseminated infection and pulmonary infection. Twenty-four hours (early therapy) and 48 h (delayed therapy) post-infection, the mice were given vehicle, liposomal amphotericin B, micafungin or liposomal amphotericin B plus micafungin (combination). Drug efficacy was assessed by either survival or tissue burden experiments. RESULTS: In disseminated infection, any drug regimen given early significantly prolonged survival. When therapy was delayed, only micafungin and the combination were effective. In pulmonary infection, although there was a trend towards a prolongation of survival of mice treated early with liposomal amphotericin B, only the combination was effective. Similarly, when therapy was delayed, only the combination was effective. In disseminated infection, any drug regimen given early was effective at reducing the cfu in kidney tissue. In pulmonary infection, only liposomal amphotericin B and the combination given early were effective at reducing the cfu in lung tissue. Conversely, when therapy was delayed, no regimen was effective at reducing the tissue burden, regardless of the type of infection. CONCLUSIONS: Our data indicate that delayed initiation of antifungal therapy is deleterious in experimental models of invasive aspergillosis. A combination regimen seems to have some advantages over a single-drug approach when the therapy is started late.
Asunto(s)
Antifúngicos/administración & dosificación , Aspergilosis Pulmonar Invasiva/tratamiento farmacológico , Factores de Tiempo , Anfotericina B/administración & dosificación , Anfotericina B/farmacología , Animales , Antifúngicos/farmacología , Aspergillus fumigatus/efectos de los fármacos , Recuento de Colonia Microbiana , Modelos Animales de Enfermedad , Quimioterapia Combinada , Equinocandinas/administración & dosificación , Equinocandinas/farmacología , Femenino , Lipopéptidos/administración & dosificación , Lipopéptidos/farmacología , Pulmón/microbiología , Micafungina , Ratones , Pruebas de Sensibilidad Microbiana , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
Prolonged empiric and etiotropic therapy of multidrug-resistant or pan-resistant bacterial flora in different gestation age newborns has led to the growth of resistant fungalflora in intencive care units (ICU). According to risk factors and rating scales every child of ICU undergoing the abdominal cavity surgery is threatened the development of a fungal infection and requires antifungal therapy appointment or causal prophylactic. In recent years, before the advent of medications of the group of echinocandins, therapy of invasive fungal infections has been a challenge. Currently alternative drug to diflucane in neonates and infants is micafungine (mycamine) in the dose of 2-8 mg/kg/day, depending on the signs of infestation and severity of the condition.
Asunto(s)
Antifúngicos/uso terapéutico , Candidiasis/prevención & control , Anomalías Congénitas/cirugía , Equinocandinas/uso terapéutico , Lipopéptidos/uso terapéutico , Antibacterianos/administración & dosificación , Antibacterianos/uso terapéutico , Antifúngicos/administración & dosificación , Infecciones Bacterianas/tratamiento farmacológico , Infecciones Bacterianas/microbiología , Candida/efectos de los fármacos , Candida/aislamiento & purificación , Candidiasis/microbiología , Candidiasis/mortalidad , Anomalías Congénitas/mortalidad , Equinocandinas/administración & dosificación , Humanos , Lactante , Recién Nacido , Lipopéptidos/administración & dosificación , Micafungina , Pruebas de Sensibilidad Microbiana , Resultado del TratamientoRESUMEN
Candida kefyr is an emerging pathogen able to cause disseminated infection, especially in immunocompromised patients. Although guidelines for the treatment of invasive candidiasis have been published, no specific recommendations against C. kefyr are available. We determine the in vitro killing activity of amphotericin B (AMB), fluconazole (FLC) and caspofungin (CFG) as well as their efficacy in a murine model of systemic infection by two C. kefyr strains. Time-kill curves of AMB, FLC and CFG were determined in final volumes of 10 ml containing the assayed drugs ranged from 0.03 to 32 µg ml-1 at different time points and efficacy of the drugs was evaluated in a systemic model of candidiasis, conducted in immunosuppressed mice, through survival, (1â3)-ß-D-glucan levels in serum and fungal load in kidneys. AMB and CFG showed fungicidal and FLC fungistatic activity against both isolates. The three drugs were able to reduce fungal burden in kidneys and (1â3)-ß-D-glucan concentration in serum of infected mice, with CFG showing the highest efficacy, followed by FLC. In conclusion, CFG showed efficacy over AMB and FLC against the systemic candidiasis by C. kefyr. The established epidemiological cut-off for anidulafungin seems the best indicator of outcome for echinocandins.
Asunto(s)
Anfotericina B/administración & dosificación , Antifúngicos/administración & dosificación , Candida/efectos de los fármacos , Candidiasis Invasiva/tratamiento farmacológico , Equinocandinas/administración & dosificación , Fluconazol/administración & dosificación , Lipopéptidos/administración & dosificación , Anfotericina B/farmacología , Animales , Antifúngicos/farmacología , Caspofungina , Recuento de Colonia Microbiana , Modelos Animales de Enfermedad , Equinocandinas/farmacología , Fluconazol/farmacología , Riñón/microbiología , Lipopéptidos/farmacología , Masculino , Ratones , Pruebas de Sensibilidad Microbiana , Viabilidad Microbiana/efectos de los fármacos , Proteoglicanos , Análisis de Supervivencia , Resultado del Tratamiento , beta-Glucanos/sangreRESUMEN
Treatment of Candida glabrata cystitis remains a therapeutic challenge, and an antifungal combination using flucytosine is one option. We describe two patients with refractory C. glabrata cystitis who failed flucytosine combined with caspofungin with early-acquired high-level resistance to flucytosine due to nonsense mutations in the FUR1 gene. Rapidly acquired flucytosine resistance with microbiological failure should discourage combination of caspofungin and flucytosine during urinary candidiasis.
Asunto(s)
Antifúngicos/administración & dosificación , Candida glabrata/efectos de los fármacos , Candidiasis/tratamiento farmacológico , Cistitis/tratamiento farmacológico , Farmacorresistencia Fúngica/efectos de los fármacos , Equinocandinas/administración & dosificación , Flucitosina/administración & dosificación , Lipopéptidos/administración & dosificación , Anciano , Secuencia de Bases , Candida glabrata/genética , Candida glabrata/aislamiento & purificación , Candida glabrata/metabolismo , Candidiasis/microbiología , Candidiasis/patología , Caspofungina , Codón sin Sentido , Cistitis/microbiología , Cistitis/patología , Farmacorresistencia Fúngica/genética , Quimioterapia Combinada , Femenino , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Expresión Génica , Humanos , Masculino , Datos de Secuencia Molecular , Proteínas de Transporte de Nucleobases/genética , Proteínas de Transporte de Nucleobases/metabolismo , Insuficiencia del Tratamiento , Vejiga Urinaria/microbiología , Vejiga Urinaria/patologíaRESUMEN
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 , ConejosRESUMEN
OBJECTIVE: The objective of this study was to evaluate the efficacy of combinations of nystatin-intralipid, found previously to be more active than nystatin, with antifungals of different mode of activity, against Aspergillus terreus. METHODS: Antifungal activity of combinations of nystatin-intralipid with voriconazole, caspofungin, terbinafine or 5-fluorocytosine were evaluated by the checkerboard and disk diffusion methods. The results were compared to those obtained with nystatin. RESULTS: The combination of nystatin-intralipid with caspofungin exhibited better antifungal activity than each drug alone and resulted in a synergistic interaction in three out of six tested strains of A. terreus. No such effect was obtained with Nystatin and caspofungin. Nystatin-intralipid or nystatin with voriconazole yielded indifferent interactions. When nystatin-intralipid was combined with terbinafine, a strong antagonism was produced in all six A. terreus strains. This effect was observed both by checkerboard and disk diffusion methods. In contrast no interaction or only slight antagonism was observed in the combination of nystatin with terbinafine. Disk diffusion method revealed similar inhibition zones when disks impregnated with 5-fluorocytosine were placed on plain, nystatin-intralipid or nystatin containing agar plates. CONCLUSIONS: Among four tested combinations, only combination of nytatin-intralipid with caspofungin, a representative of the echinocandin class of antifungals, resulted in synergistic interaction. Antagonism obtained by combining nystatin-intralipid with terbinafine can be explained by existence of hydrophobic interaction between these two compounds interfering with their antifungal action. The fact that nystatin-intralipid and nystatin interact differently with other antifungals, may indicate differences in their mechanisms of activity.
Asunto(s)
Antifúngicos/farmacología , Aspergillus/efectos de los fármacos , Nistatina/farmacología , Fosfolípidos/farmacología , Aceite de Soja/farmacología , Antifúngicos/administración & dosificación , Aspergillus/crecimiento & desarrollo , Caspofungina , Combinación de Medicamentos , Equinocandinas/administración & dosificación , Equinocandinas/farmacología , Emulsiones/administración & dosificación , Emulsiones/farmacología , Flucitosina/administración & dosificación , Flucitosina/farmacología , Humanos , Lipopéptidos , Pruebas de Sensibilidad Microbiana/métodos , Naftalenos/administración & dosificación , Naftalenos/farmacología , Nistatina/administración & dosificación , Fosfolípidos/administración & dosificación , Aceite de Soja/administración & dosificación , Terbinafina , Voriconazol/administración & dosificación , Voriconazol/farmacologíaRESUMEN
This study evaluated the in vitro and in vivo activity of micafungin alone and in combination with the iron chelator deferasirox against Pythium insidiosum. Micafungin showed a poor in vitro activity when it was used alone, but synergistic interactions were observed for 88.2% of the strains when the drug was combined with deferasirox. Smaller lesions were observed in infected rabbits receiving the combination therapy, although it favored disease dissemination to the lungs. The present results show that micafungin alone is ineffective against P. insidiosum, and the combination micafungin-deferasirox might have deleterious effects for the host.
Asunto(s)
Benzoatos/administración & dosificación , Equinocandinas/administración & dosificación , Lipopéptidos/administración & dosificación , Pitiosis/tratamiento farmacológico , Pythium/efectos de los fármacos , Triazoles/administración & dosificación , Animales , Antifúngicos/administración & dosificación , Deferasirox , Modelos Animales de Enfermedad , Quimioterapia Combinada , Femenino , Enfermedades de los Caballos/tratamiento farmacológico , Enfermedades de los Caballos/microbiología , Caballos , Micafungina , Pruebas de Sensibilidad Microbiana , Pitiosis/microbiología , Pythium/crecimiento & desarrollo , ConejosRESUMEN
Pathogenic yeast forms are commonly associated with invasive fungal disease in the immunocompromised host, including patients with haematological malignancies and patients of haemopoietic stem cell transplants. Yeasts include the Candida spp., Cryptococcus spp., Pneumocystis jirovecii and some lesser-known pathogens. Candida species remain the most common cause of invasive yeast infections (and the most common human pathogenic fungi). These guidelines present evidence-based recommendations for the antifungal management of established, invasive yeast infections in adult and paediatric patients in the haematology/oncology setting. Consideration is also given to the critically ill patient in intensive care units, including the neonatal intensive care unit. Evidence for 'pre-emptive' or 'diagnostic-driven antifungal therapy' is also discussed. For the purposes of this paper, invasive yeast diseases are categorised under the headings of invasive candidiasis, cryptococcosis and uncommon yeast infections. Specific recommendations for the management of Pneumocystis jirovecii are presented in an accompanying article (see consensus guidelines by Cooley et al. appearing elsewhere in this supplement).
Asunto(s)
Antifúngicos/administración & dosificación , Fiebre de Origen Desconocido/microbiología , Huésped Inmunocomprometido/inmunología , Infecciones Oportunistas/inmunología , Infecciones Oportunistas/microbiología , Adolescente , Adulto , Candidiasis Invasiva/inmunología , Candidiasis Invasiva/prevención & control , Niño , Preescolar , Consenso , Enfermedad Crítica , Criptococosis/inmunología , Criptococosis/prevención & control , Esquema de Medicación , Equinocandinas/administración & dosificación , Medicina Basada en la Evidencia , Fiebre de Origen Desconocido/inmunología , Fluconazol/administración & dosificación , Humanos , Lactante , Unidades de Cuidados Intensivos , Pruebas de Sensibilidad Microbiana , Datos de Secuencia Molecular , Infecciones Oportunistas/prevención & control , Infecciones por Pneumocystis/inmunología , Infecciones por Pneumocystis/prevención & control , Pneumocystis carinii , Guías de Práctica Clínica como AsuntoRESUMEN
OBJECTIVES: Scedosporium infections are associated with high therapeutic failure rates. Combination therapy may be an alternative approach to improve outcome. The in vitro and in vivo efficacy of micafungin plus posaconazole or plus voriconazole was investigated herein. METHODS: Scedosporium boydii (nâ=â17) and Scedosporium apiospermum (nâ=â26) were tested using the chequerboard method according to CLSI M38-A2 guidelines and the fractional inhibitory concentration index (FICI) was evaluated. In vivo outcome of micafungin plus posaconazole or micafungin plus voriconazole against two isolates of each of the mentioned species was evaluated in a well-established, immunocompromised, haematogenous murine model of systemic scedosporiosis. Survival and tissue burden in kidneys and brain were investigated. RESULTS: The FICI category of 'no interaction' was most frequent, while 'synergism' or 'antagonism' was rarely observed. FICI failed to predict the in vivo outcome of both combinatorial treatment strategies. In vivo outcome was strain-dependent rather than species-dependent, even though effects on fungal tissue burden were more pronounced for S. boydii. Both combinations improved survival significantly when compared with untreated controls and micafungin monotherapy. Voriconazole and posaconazole did not differ in their efficacy and micafungin failed to be effective. Combinations were by trend better than voriconazole and posaconazole as single therapy, but statistically significant differences were lacking. CONCLUSIONS: No benefit of the azole/echinocandin combination was found when compared with voriconazole and posaconazole monotherapies. FICI failed to predict the outcome of in vivo drug combinations in the murine study.
Asunto(s)
Antifúngicos/administración & dosificación , Equinocandinas/administración & dosificación , Lipopéptidos/administración & dosificación , Micosis/tratamiento farmacológico , Scedosporium/efectos de los fármacos , Triazoles/administración & dosificación , Animales , Quimioterapia Combinada , Masculino , Micafungina , Ratones , Pruebas de Sensibilidad Microbiana/métodos , Micosis/mortalidad , Distribución Aleatoria , Scedosporium/aislamiento & purificaciónRESUMEN
Neonatal Candida infections are the leading cause of invasive fungal infections that might cause severe morbidity or mortality in a large majority of those affected. Although Candida albicans has been the most common species, Candida parapsilosis is increasingly being recognized as an important cause of invasive candidiasis in neonates. Among the Candida species, C. parapsilosis has been commonly isolated and shown to be less susceptible in vitro to echinocandins than other Candida species. We report an infant who had refractory C. parapsilosis septicemia cured with caspofungin.
Asunto(s)
Antifúngicos/uso terapéutico , Candida/efectos de los fármacos , Candidiasis/tratamiento farmacológico , Farmacorresistencia Fúngica , Equinocandinas/uso terapéutico , Enfermedades del Prematuro/tratamiento farmacológico , Antifúngicos/administración & dosificación , Candida/clasificación , Candida/aislamiento & purificación , Candidiasis/congénito , Candidiasis/microbiología , Caspofungina , Equinocandinas/administración & dosificación , Femenino , Humanos , Recién Nacido , Recien Nacido Prematuro , Enfermedades del Prematuro/microbiología , Lipopéptidos , Pruebas de Sensibilidad Microbiana , Resultado del TratamientoRESUMEN
AIMS: Echinocandins are recommended for the treatment of candidaemia in moderately severe to severely ill patients. Step-down or de-escalation from echinocandin to fluconazole is advised in patients who are clinically stable but data in relation to step-down therapy are sparse. Using our hospital intravenous to oral switch therapy (IVOST) policy to guide antifungal de-escalation in patients with candidaemia, we aimed to determine what proportion of patients are de-escalated to fluconazole, the timescale to step-down, associated reduction in consumption of echinocandins and antifungal cost savings. METHODOLOGY: Patients with candidaemia were followed from April 2011 to March 2013. RESULTS: A total of 37 episodes of candidaemia were documented during the study period. Twenty-seven patients were commenced on an echinocandin or voriconazole and 19 (70.3%) were de-escalated to fluconazole based on the IVOST policy. The mean and median number of days to de-escalation of therapy was 4.6 and 5 days, respectively. One patient whose therapy was de-escalated relapsed. The overall 30 day crude mortality was 37.1%. The step-down approach led to significant saving in antifungal drug cost of £1133.88 per candidaemic episode and £2208.08 per de-escalation. CONCLUSION: Implementation of IVOST policy led to streamlining of antifungal therapy.
Asunto(s)
Antifúngicos/administración & dosificación , Candidemia/tratamiento farmacológico , Administración Oral , Anciano , Antibacterianos/administración & dosificación , Antibacterianos/economía , Antifúngicos/economía , Candidemia/economía , Esquema de Medicación , Costos de los Medicamentos , Equinocandinas/administración & dosificación , Equinocandinas/economía , Femenino , Fluconazol/administración & dosificación , Fluconazol/economía , Hospitalización , Humanos , Infusiones Intravenosas , Masculino , Pruebas de Sensibilidad Microbiana , Política Organizacional , Recurrencia , Resultado del Tratamiento , Voriconazol/administración & dosificación , Voriconazol/economíaRESUMEN
BACKGROUND: Systemic Candida infections (SCI) occur predominantly in intensive care unit patients and are a common cause of morbidity and mortality. Recently, changes in Candida epidemiology with an increasing prevalence of SCI caused by Candida non-albicans species have been reported. Resistance to fluconazole and azoles in general is not uncommon for non-albicans species. Despite guidelines recommending initial treatment with broad-spectrum antifungals such as echinocandins with subsequent switch to fluconazole if isolates are sensitive (de-escalation strategy), fluconazole is still the preferred first-line antifungal (escalation) in many clinical practice settings. After diagnosis of the pathogen, the initial therapy with fluconazole is switched to a broad-spectrum antifungal if a non-albicans is identified. METHODS: The cost-effectiveness of initial treatment with micafungin (de-escalation) vs fluconazole (escalation) in patients with SCI was estimated using decision analysis based on clinical and microbiological data from pertinent studies. The model horizon was 42 days, and was extrapolated to cover a lifetime horizon. All costs were analyzed from the UK NHS perspective. Several assumptions were taken to address uncertainties; the limitations of these assumptions are discussed in the article. RESULTS: In patients with fluconazole-resistant isolates, initial treatment with micafungin avoids 30% more deaths and successfully treats 23% more patients than initial treatment with fluconazole, with cost savings of £1621 per treated patient. In the overall SCI population, de-escalation results in 1.2% fewer deaths at a marginal cost of £740 per patient. Over a lifetime horizon, the incremental cost-effectiveness of de-escalation vs escalation was £15,522 per life-year and £25,673 per QALY. CONCLUSIONS: De-escalation from micafungin may improve clinical outcomes and overall survival, particularly among patients with fluconazole-resistant Candida strains. De-escalation from initial treatment with micafungin is a cost-effective alternative to escalation from a UK NHS perspective, with a differential cost per QALY below the 'willingness-to-pay' threshold of £30,000.
Asunto(s)
Antifúngicos/economía , Antifúngicos/uso terapéutico , Candidiasis/tratamiento farmacológico , Equinocandinas/economía , Equinocandinas/uso terapéutico , Lipopéptidos/economía , Lipopéptidos/uso terapéutico , Antifúngicos/administración & dosificación , Candidiasis/economía , Candidiasis/mortalidad , Análisis Costo-Beneficio , Técnicas de Apoyo para la Decisión , Equinocandinas/administración & dosificación , Fluconazol/economía , Fluconazol/uso terapéutico , Servicios de Salud/economía , Servicios de Salud/estadística & datos numéricos , Humanos , Esperanza de Vida , Lipopéptidos/administración & dosificación , Micafungina , Pruebas de Sensibilidad Microbiana , Años de Vida Ajustados por Calidad de VidaRESUMEN
Mutations in Candida glabrata FKS genes, which encode the echinocandin target enzyme, are independent risk factors for treatment failures during invasive candidiasis. We retrospectively compared the ability of caspofungin susceptibility testing methods to identify C. glabrata FKS mutant isolates and predict outcomes among patients at our center. Eight percent (10/120) of sterile-site C. glabrata isolates harbored FKS1 (n = 3) or FKS2 (n = 7) mutations, including 32% (10/32) recovered from patients with prior echinocandin exposure. Median echinocandin exposures for mutant and nonmutant isolates were 55 (range, 7 to 188) and 13 (3 to 84) days, respectively (P = 0.004). Sensitivity and specificity of the CLSI caspofungin resistance breakpoint MIC (>0.12 µg/ml by broth microdilution using RPMI medium [BMD-RPMI]) were 90% (9/10) and 3% (3/110), respectively, for identifying FKS mutants. Sensitivity and specificity of receiver-operator characteristic (ROC) curve-derived breakpoints by BMD-RPMI, BMD-antibiotic medium 3, Etest, and YeastOne ranged from 70 to 100% and 89 to 95%, respectively; susceptibility rates varied from 83 to 90%. The 14-day echinocandin treatment success rate was 67% (44/66); failure was more likely with prior echinocandin exposure (P = 0.002) or infection with an FKS mutant (P = 0.0001) or echinocandin-resistant isolates by BMD-AM3, Etest, and YeastOne (P ≤ 0.03). The failure rate among patients with prior exposure and infection with a resistant isolate was 91% (10/11); it was 22% (12/55) among others (P < 0.0001). In conclusion, ROC-derived caspofungin MIC breakpoints by several methods were sensitive and specific for identifying C. glabrata FKS mutant isolates. Mutations were seen exclusively among patients with prior echinocandin exposure. A paradigm that considers prior echinocandin exposure and caspofungin MICs accurately classified treatment outcomes for C. glabrata invasive candidiasis.
Asunto(s)
Candida glabrata/efectos de los fármacos , Candidiasis Invasiva/tratamiento farmacológico , Farmacorresistencia Fúngica , Equinocandinas/administración & dosificación , Equinocandinas/farmacología , Antifúngicos/administración & dosificación , Antifúngicos/farmacología , Candida glabrata/genética , Candida glabrata/aislamiento & purificación , Candidiasis Invasiva/microbiología , Caspofungina , Humanos , Lipopéptidos , Pruebas de Sensibilidad Microbiana , Mutación , Valor Predictivo de las Pruebas , Curva ROC , Estudios Retrospectivos , Sensibilidad y Especificidad , Resultado del TratamientoRESUMEN
BACKGROUND: Pediatric patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) often receive intravenous liposomal amphotericin B (L-AmB) as antifungal prophylaxis. There are no guidelines for antifungal prophylaxis in children in this situation. Caspofungin (CAS), a broad-spectrum echinocandin, could be an effective alternative with lower nephrotoxicity than L-AmB. METHODS: We retrospectively analyzed the safety, feasibility, and efficacy of CAS in our center, and compared the results with L-AmB as antifungal monoprophylaxis in pediatric patients undergoing HSCT. 60 pediatric patients received L-AmB (1 or 3 mg/kg bw/day) and another 60 patients received CAS (50 mg/m2/day) as antifungal monoprophylaxis starting on day one after HSCT. The median ages of patients receiving L-AmB and CAS were 7.5 years and 9.5 years, respectively. RESULTS: No proven breakthrough fungal infection occurred in either group during the median treatment period of 23 days in the L-AmB group and 24 days in the CAS group. One patient receiving CAS developed probable invasive aspergillosis. During L-AmB treatment, potassium levels significantly decreased below normal values. Patients treated with L-AmB had more drug-related side effects and an increased need for oral supplementation with potassium, sodium bicarbonate and calcium upon discharge as compared with the CAS group. CAS was well-tolerated and safe in this cohort of immunocompromised pediatric patients, who underwent high-dose chemotherapy and HSCT. CONCLUSION: Prophylactic CAS and L-AmB showed similar efficacy in this biggest cohort of pediatric patients after allogeneic HSCT reported, so far. A prospective randomized trial in children is warranted to allow for standardized guidelines.