Cost-utility analysis of caspofungin and fluconazole for primary treatment of invasive candidiasis and candidemia in Ethiopia.

BACKGROUND: Invasive candidiasis and/or candidemia (IC/C) is a common fungal infection leading to significant health and economic losses worldwide. Caspofungin was shown to be more effective than fluconazole in treating inpatients with IC/C. However, cost-effectiveness of caspofungin for treating IC/C in Ethiopia remains unknown. We aimed to assess the cost-utility of caspofungin compared to fluconazole-initiated therapies as primary treatment of IC/C in Ethiopia. METHODS: A Markov cohort model was developed to compare the cost-utility of caspofungin versus fluconazole antifungal agents as first-line treatment for adult inpatients with IC/C from the Ethiopian health system perspective. Treatment outcome was categorized as either a clinical success or failure, with clinical failure being switched to a different antifungal medication. Liposomal amphotericin B (L-AmB) was used as a rescue agent for patients who had failed caspofungin treatment, while caspofungin or L-AmB were used for patients who had failed fluconazole treatment. Primary outcomes were expected quality-adjusted life years (QALYs), costs (US$2021), and the incremental cost-utility ratio (ICUR). These QALYs and costs were discounted at 3% annually. Cost data was obtained from Addis Ababa hospitals while locally unavailable data were derived from the literature. Cost-effectiveness was assessed against the recommended threshold of 50% of Ethiopia's gross domestic product/capita (i.e.,US$476). Deterministic and probabilistic sensitivity analyses were conducted to assess the robustness of the findings. RESULTS: In the base-case analysis, treatment of IC/C with caspofungin as first-line treatment resulted in better health outcomes (12.86 QALYs) but higher costs (US$7,714) compared to fluconazole-initiated treatment followed by caspofungin (12.30 QALYs; US$3,217) or L-AmB (10.92 QALYs; US$2,781) as second-line treatment. Caspofungin as primary treatment for IC/C was not cost-effective when compared to fluconazole-initiated therapies. Fluconazole-initiated treatment followed by caspofungin was cost-effective for the treatment of IC/C compared to fluconazole with L-AmB as second-line treatment, at US$316/QALY gained. Our findings were sensitive to medication costs, drug effectiveness, infection recurrence, and infection-related mortality rates. At a cost-effectiveness threshold of US$476/QALY, treating IC/C patient with fluconazole-initiated treatment followed by caspofungin was more likely to be cost-effective in 67.2% of simulations. CONCLUSION: Our study showed that the use of caspofungin as primary treatment for IC/C in Ethiopia was not cost-effective when compared with fluconazole-initiated treatment alternatives. The findings supported the use of fluconazole-initiated therapy with caspofungin as a second-line treatment for patients with IC/C in Ethiopia.

Pharmacokinetic modelling of caspofungin to develop an extended dosing regimen in paediatric patients.

BACKGROUND: Echinocandins are commonly used in treatment and prophylaxis of invasive fungal diseases. Intravenous daily dosing for prophylaxis in the outpatient setting can however become a hurdle for adequate compliance in the paediatric population. OBJECTIVES: Simulations were performed to assess extended twice-weekly dosing for antifungal prophylaxis using caspofungin. METHODS: A population pharmacokinetic model was developed based on previously published data from children aged 3 months to 17 years. Using the final model, Monte Carlo simulations were performed to assess the dose needed for adequate exposure in a twice-weekly setting. Mean weekly AUC0-24 h/MIC together with reported AUC0-24 h from previously reported paediatric trials were used to guide adequate exposure. RESULTS AND CONCLUSIONS: A two-compartment model with linear elimination and allometric scaling using fixed exponents was found most adequate to describe the given paediatric populations. Simulations showed that a 200 mg/m2 twice-weekly regimen with maximal 200 mg total dose should result in exposures matching registered daily dosing as well as commonly used pharmacokinetic/pharmacodynamic targets.

Pharmacokinetic/Pharmacodynamic Target Attainment of Different Antifungal Agents in De-escalation Treatment in Critically Ill Patients: a Step toward Dose Optimization Using Monte Carlo Simulation.

Differences in pharmacokinetics/pharmacodynamics (PK/PD) target attainment are rarely considered when antifungals are switched in critically ill patients. This study intends to explore whether the antifungal de-escalation treatment strategy and the new intermittent dosing strategy of echinocandins in critically ill patients are able to achieve the corresponding PK/PD targets. The published population PK models of antifungals in critically ill patients and a public data set from the MIMIC-III database (n = 662) were employed to evaluate PK/PD target attainment of different dosing regimens of antifungals. Cumulative fraction of response (CFR) was calculated for each dosing regimen. Most guideline-recommended dosing regimens of fluconazole and voriconazole could achieve target exposure as de-escalation treatment in critically ill patients. For initial echinocandin treatment, achievement of the target exposure decreased as body weight increased, and the intermittent dosing strategy had a slightly higher CFR value in most simulations compared to conventional dosing strategy. For Candida albicans and Candida glabrata infection, caspofungin at the lowest dose achieved a CFR of >90%, while micafungin or anidulafungin required almost the highest doses simulated in this study to achieve the same effect. None of the echinocandins other than 150 mg every 24 h (q24h) or 200 mg q48h of caspofungin achieved the target CFR for Candida parapsilosis infection. These findings support the guideline-recommended dose of triazoles for antifungal de-escalation treatment and confirm the insufficient dosage of echinocandins in critically ill patients, indicating that a dosing regimen based on body weight or intermittent dosing of echinocandins may be required.

Caspofungin Population Pharmacokinetic Analysis in Plasma and Peritoneal Fluid in Septic Patients with Intra-Abdominal Infections: A Prospective Cohort Study.

OBJECTIVES: The aim of this study was to report the pharmacokinetics (PK) of caspofungin in plasma and peritoneal fluid and to identify optimal dosing strategies in septic patients with intra-abdominal infections. METHODS: Eleven patients with secondary peritonitis with septic shock received the standard dosing regimen of caspofungin. Total caspofungin plasma and peritoneal concentrations were subject to a population PK analysis using Pmetrics®. Monte Carlo simulations were performed considering the ratio of 24-h total drug exposure above the minimum inhibitory concentration (AUC24/MIC) in plasma and comparing simulated concentrations versus MIC in peritoneal fluid. RESULTS: Fat-free mass (FFM) was retained in the final model of caspofungin, reporting a total clearance (standard deviation) of 0.78 (0.17) L/h and a central volume of distribution of 9.36 (2.61) L. The peritoneal fluid/plasma ratio of caspofungin was 33% on the first day of therapy (AUC24 73.92 (21.93) and 26.03 (9.88) mg*h/L for plasma and peritoneal data, respectively). Dosing simulations supported the use of standard dosing regimens for patients with an FFM < 50 kg for the most susceptible candida species (C. albicans and C. glabrata). For higher FFM, a loading dose of 70 or 100 mg, with a maintenance dose of 70 mg, reached AUC24/MIC ratios for these species. CONCLUSIONS: There is moderate penetration of caspofungin into the peritoneal cavity (33%). For empirical treatment, a dose escalation of 100 mg loading dose on the first day is suggested for higher FFM to ensure adequate concentrations into the abdominal cavity for the most susceptible candida species.

Etest ECVs/ECOFFs for Detection of Resistance in Prevalent and Three Nonprevalent Candida spp. to Triazoles and Amphotericin B and Aspergillus spp. to Caspofungin: Further Assessment of Modal Variability.

Susceptibility testing is an important tool in the clinical setting; its utility is based on the availability of categorical endpoints, breakpoints (BPs), or epidemiological cutoff values (ECVs/ECOFFs). CLSI and EUCAST have developed antifungal susceptibility testing, BPs, and ECVs for some fungal species. Although the concentration gradient strip bioMérieux Etest is useful for routine testing in the clinical laboratory, ECVs are not available for all agent/species; the lack of clinical data precludes development of BPs. We reevaluated and consolidated Etest data points from three previous studies and included new data. We defined ECOFFinder Etest ECVs for three sets of species-agent combinations: fluconazole, posaconazole, and voriconazole and 9 Candida spp.; amphotericin B and 3 nonprevalent Candida spp.; and caspofungin and 4 Aspergillus spp. The total of Etest MICs from 23 laboratories (Europe, the Americas, and South Africa) included (antifungal agent dependent): 17,242 Candida albicans, 244 C. dubliniensis, 5,129 C. glabrata species complex (SC), 275 C. guilliermondii (Meyerozyma guilliermondii), 1,133 C. krusei (Pichia kudriavzevii), 933 C. kefyr (Kluyveromyces marxianus), 519 C. lusitaniae (Clavispora lusitaniae), 2,947 C. parapsilosis SC, 2,214 C. tropicalis, 3,212 Aspergillus fumigatus, 232 A. flavus, 181 A. niger, and 267 A. terreus SC isolates. Triazole MICs for 66 confirmed non-wild-type (non-WT) Candida isolates were available (ERG11 point mutations). Distributions fulfilling CLSI ECV criteria were pooled, and ECOFFinder Etest ECVs were established for triazoles (9 Candida spp.), amphotericin B (3 less-prevalent Candida spp.), and caspofungin (4 Aspergillus spp.). Etest fluconazole ECVs could be good detectors of Candida non-WT isolates (59/61 non-WT, 4 of 6 species).

Are we correctly treating invasive candidiasis under continuous renal replacement therapy with echinocandins? Preliminary in vitro assessment.

There is major concern regarding the pharmacokinetics of drugs under continuous renal replacement therapy (CRRT), including anti-infectious agents and more especially antifungal agents. From a regulatory viewpoint, only dialysis and filtration are considered meanwhile there is growing evidence that adsorption may also significantly alter the pharmacokinetics of anti-infectious agents. Adsorption results from a complex drug-filter interaction and might be considered an unexpected adverse effect induced by CRRT. Measurement of total plasma concentrations instead of the unbound, free, active concentrations in in vitro as well as in clinical studies hides this major adverse effect, which may jeopardise the therapeutic effect and even result in treatment failure. Noteworthy, minimal inhibitory concentrations (MIC) of anti-infectious agents are performed using solid and liquid medium without proteins testing only the antimicrobial activity of the free fraction of drugs. In a new in vitro model using crystalloid solution instead of blood, we report data supporting the assumption that the assessment of the disposition of the free fraction of caspofungin and micafungin unveils adverse effects of ST150® filter, which might eventually result in non-detectable drug concentrations and treatment failure. From a technical viewpoint, we conclude the measurement of the free fraction of drugs that largely bound to plasma proteins, including caspofungin and micafungin, should be considered instead of total plasma concentrations to assess all effects induced by filters used in CRRT.

Eficacia y seguridad de las terapias antifúngicas intravenosas para la aspergilosis invasiva, en pacientes adultos con nefrotoxicidad o intolerancia a la anfotericina B deoxicolato y enfermedad aguda o progresiva (segunda línea de tratamiento) / Efficacy and safety of intravenous antifungal therapies for invasive aspergillosis in adult patients with nephrotoxicity or intolerance to amphotericin B deoxycholate and acute or progressive disease (second-line treatment)

INTRODUCCIÓN: El presente dictamen preliminar expone la evaluación de la eficacia y seguridad de las terapias antifúngicas intravenosas para la aspergilosis invasiva, en pacientes adultos con nefrotoxicidad o intolerancia a la anfotericina B deoxicolato y enfermedad aguda o progresiva. La aspergilosis invasiva (AI) es una infección fúngica altamente letal en hospedadores inmunodeprimidos. Se estima que la tasa de mortalidad es de aproximadamente 30 a 80 %. La anfotericina B deoxicolato es el agente antifúngico (intravenoso) con mayor experiencia de uso para tratar la AI; sin embargo, se asocia con importantes toxicidades que limitan su uso, principalmente la nefrotoxicidad. En EsSalud, los pacientes con AI, nefrotoxicidad o intolerancia a anfotericina B deoxicolato y enfermedad aguda, disponen de caspofungina. Sin embargo, el IETSI recibió una solicitud de uso de isavuconazol intravenoso bajo la argumentación de que este fármaco representa la mejor opción terapéutica para este tipo de pacientes, basado en un mejor perfil de eficacia y seguridad. Considerando que, además del isavuconazol, existen otras alternativas antifúngicas intravenosas indicadas para este tipo de pacientes, algunas de las cuales tienen experiencia de uso en EsSalud, el equipo evaluador del IETSI optó por re-evaluar el problema de decisión y realizar una evaluación de múltiples tecnologías sanitarias con el fin de identificar la opción de tratamiento más efectiva, segura y costo-efectiva para la población de interés. METODOLOGÍA: Se realizó una búsqueda sistemática de literatura con el objetivo de identificar evidencia sobre la eficacia y seguridad de las terapias antifúngicas intravenosas para la aspergilosis invasiva, en pacientes adultos con nefrotoxicidad o intolerancia a la anfotericina B deoxicolato y enfermedad aguda o progresiva. Se utilizaron las bases de datos PubMed, Cochrane Library y LILACS, priorizándose la evidencia proveniente de ensayos clínicos controlados aleatorizados. Asimismo, se realizó una búsqueda dentro de bases de datos pertenecientes a grupos que realizan evaluación de tecnologías sanitarias (ETS) y guías de práctica clínica (GPC), incluyendo el Healthcare Improvement Scotland, el National Institute for Health and Care Excellence (NICE), la Canadian Agency for Drugs and Technologies in Health (CADTH), la Haute Autorité de Santé (HAS), el Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen (IQWiG), además de la Base Regional de Informes de Evaluación de Tecnologías en Salud de las Américas (BRISA) y páginas web de sociedades especializadas en aspergilosis como American Thoracic Society (ATS), Infectious Diseases Society of America (IDSA), European Society for Clinical Microbiology and Infectious Diseases (ESCMID) y European Conference on Infections in Leukaemia (ECIL). Se hizo una búsqueda adicional en la página web del Registro administrado por la Biblioteca Nacional de Medicina de los Estados Unidos (https://clinicaltrials.gov/) e International Clinical Trial Registry Platform (ICTRP) (https://apps.who.int/trialsearch/), para poder identificar ensayos clínicos en curso o que no hayan sido publicados para, de este modo, disminuir el riesgo de sesgo de publicación. Para que la búsqueda de información pueda ser empleada para responder a la pregunta PICO se utilizaron estrategias de búsqueda que incluyeron términos relacionados a la población de interés, la intervención, y el comparador. Se emplearon términos MeSH1 y términos libre junto con operadores booleanos acordes a cada una de las bases de datos elegidas para la búsqueda. Con la estrategia de búsqueda diseñada para PubMed, se generaron alertas diarias vía correo electrónico con el objetivo de identificar estudios publicados luego del 09 de octubre de 2020. La búsqueda bibliográfica se limitó a GPC, ETS, revisiones sistemáticas con meta-análisis, y ECA que hayan evaluado la pregunta PICO de interés del presente dictamen. Ante la ausencia de ECA, también se buscaron estudios observacionales comparativos. La búsqueda se limitó a estudios en inglés y español. Se excluyeron las series de casos, los reportes de casos, las cartas al editor, los comentarios, las editoriales, los resúmenes de congresos y los estudios in vitro. La selección de los estudios fue llevada a cabo en dos fases. La primera fase consistió en la revisión de los títulos o los resúmenes a través del aplicativo web Rayyan (https://rayyan.qcri.org), que permitió pre-seleccionar los estudios a incluir y/o los que requerían más información para decidir. En la segunda fase se aplicaron de nuevo los criterios de elegibilidad empleando el texto completo de los estudios que fueron pre-seleccionados. RESULTADOS: Se realizó una búsqueda de la literatura con respecto a la eficacia y seguridad de las terapias antifúngicas intravenosas para la aspergilosis invasiva, en pacientes adultos con nefrotoxicidad o intolerancia a la anfotericina B deoxicolato y enfermedad aguda o progresiva. A continuación, se describe la evidencia disponible según el orden jerárquico del nivel de evidencia o pirámide de Haynes 6S. CONCLUSIONES: El presente dictamen preliminar tuvo como objetivo evaluar la mejor evidencia sobre la eficacia y seguridad de las terapias antifúngicas intravenosas para la aspergilosis invasiva, en pacientes adultos con nefrotoxicidad o intolerancia a la anfotericina B deoxicolato y enfermedad aguda o progresiva (segunda línea de tratamiento). Las intervenciones de interés fueron el isavuconazol intravenoso, el voriconazol intravenoso y la L-AmB (intravenosa), y el comparador de interés fue la caspofungina. Los desenlaces de interés fueron la respuesta clínica, microbiológica y radiológica, la sobrevida global, la mortalidad, la calidad de vida y los eventos adversos. La evidencia disponible sobre la mejor alternativa antifúngica para pacientes con AI y nefrotoxicidad o intolerancia a anfotericina B deoxicolato (o tratamientos antifúngicos convencionales en general) es de baja calidad metodológica. La evidencia disponible sugiere, aunque con una gran incertidumbre, que los antifúngicos de interés para la presente evaluación (isavuconazol, voriconazol, L-AmB y caspofungina) tendrían similar eficacia, en términos de respuesta antifúngica, pero con diferentes perfiles de seguridad. De estos, caspofungina es el que tiene más evidencia en un contexto de intolerancia y sus estudios incluyen a la población de interés del presente dictamen preliminar. Caspofungina es mejor tolerado que otras clases de antifúngicos sistémicos, no habiéndose reportado eventos de nefrotoxicidad. En ese sentido, caspofungina sería el fármaco más adecuado para tratar a la población de interés del presente dictamen. De manera adicional, es importante resaltar que optar por el uso de caspofungina, en lugar de los otros antifúngicos evaluados, es una decisión con mejor perfil de costo-oportunidad; ya que este fármaco tiene los costos más asequibles a nivel institucional. Por lo expuesto, el IETSI no aprueba el uso de isavuconazol intravenoso, voriconazol intravenoso y L-AmB (intravenosa) en pacientes adultos con AI, nefrotoxicidad o intolerancia a la anfotericina B deoxicolato y enfermedad aguda o progresiva.

Impact of Loading Dose of Caspofungin in Pharmacokinetic-Pharmacodynamic Target Attainment for Severe Candidiasis Infections in Patients in Intensive Care Units: the CASPOLOAD Study.

This study evaluated the impact of a high loading dose of caspofungin (CAS) on the pharmacokinetics of CAS and the pharmacokinetic-pharmacodynamic (PK-PD) target attainment in patients in intensive care units (ICU). ICU patients requiring CAS treatment were prospectively included to receive a 140-mg loading dose of CAS. Plasma CAS concentrations (0, 2, 3, 5, 7, and 24 h postinfusion) were determined to develop a two-compartmental population PK model. A Monte Carlo simulation was performed and the probabilities of target attainment (PTAs) were computed using previously published MICs. PK-PD targets were ratios of area under the concentration-time curve from 0 to 24 h (AUC0-24h) divided by the MIC (AUC0-24h/MIC) of 250, 450, and 865 and maximal concentration (Cmax) divided by the MIC (Cmax/MIC) of 5, 10, 15, and 20. Among 13 included patients, CAS clearance was 0.98 ± 0.13 liters/h and distribution volumes were V1 = 9.0 ± 1.2 liters and V2 = 11.9 ± 2.9 liters. Observed and simulated CAS AUC0-24h were 79.1 (IQR 55.2; 108.4) and 81.3 (IQR 63.8; 102.3) mg · h/liter during the first 24 h of therapy, which is comparable to values usually observed in ICU patients at day 3 or later. PTAs were >90% for MICs of 0.19 and 0.5 mg/liter, considering AUC/MIC = 250 and Cmax/MIC = 10 as PK-PD targets, respectively. Thus, a high loading dose of CAS (140 mg) increased CAS exposure in the first 24 h of therapy, allowing early achievement of PK-PD targets for most Candida strains. Such a strategy seems to improve treatment efficacy, though further studies are needed to assess the impact on clinical outcomes. (This study has been registered at ClinicalTrials.gov under identifier NCT02413892.).

Caspofungin Weight-Based Dosing Supported by a Population Pharmacokinetic Model in Critically Ill Patients.

The objective of this study was to develop a population pharmacokinetic model and to determine a dosing regimen for caspofungin in critically ill patients. Nine blood samples were drawn per dosing occasion. Fifteen patients with (suspected) invasive candidiasis had one dosing occasion and five had two dosing occasions, measured on day 3 (±1) of treatment. Pmetrics was used for population pharmacokinetic modeling and probability of target attainment (PTA). A target 24-h area under the concentration-time curve (AUC) value of 98 mg·h/liter was used as an efficacy parameter. Secondarily, the AUC/MIC targets of 450, 865, and 1,185 were used to calculate PTAs for Candida glabrata, C. albicans, and C. parapsilosis, respectively. The final 2-compartment model included weight as a covariate on volume of distribution (V). The mean V of the central compartment was 7.71 (standard deviation [SD], 2.70) liters/kg of body weight, the mean elimination constant (Ke ) was 0.09 (SD, 0.04) h-1, the rate constant for the caspofungin distribution from the central to the peripheral compartment was 0.44 (SD, 0.39) h-1, and the rate constant for the caspofungin distribution from the peripheral to the central compartment was 0.46 (SD, 0.35) h-1 A loading dose of 2 mg/kg on the first day, followed by 1.25 mg/kg as a maintenance dose, was chosen. With this dose, 98% of the patients were expected to reach the AUC target on the first day and 100% of the patients on the third day. The registered caspofungin dose might not be suitable for critically ill patients who were all overweight (≥120 kg), over 80% of median weight (78 kg), and around 25% of lower weight (≤50 kg). A weight-based dose regimen might be appropriate for achieving adequate exposure of caspofungin in intensive care unit patients.

Caspofungin PK in critically ill patients after the first and fourth doses: suggestions for therapeutic drug monitoring?

We describe caspofungin pharmacokinetics (PK) after the first and fourth doses in 20 critically ill septic patients. Monte Carlo simulation was used to analyze the probability of target attainment (PTA) (AUC/MIC > 865) for Candida spp. Caspofungin concentrations were analyzed by HPLC in plasma and urine. A great variability in PK parameters was observed after both doses. Patients were divided in two groups according to their AUC values (AUC ≤ 75 mg h/L cut-off). In the low-AUC group Cmax, Cmin and AUC were lower, while Vd and Cl were higher than in the high-AUC group (p < 0.05, both at day 1 and 4). The mean 24-h urinary recovery of the drug was 8 ± 6.3% (day1) and 9.8 ± 6.3 (day4). Monte Carlo simulation analysis (0.03-1 mg/L MIC-range) showed that PTA was guaranteed only for MICs ≤ 0.03 mg/L in the low-AUC group, and for MICs ≤ 0.06 mg/L in the high-AUC group. No group had a PTA ≥ 90% for 0.125 mg/L MIC (the epidemiological cut-off). Mortality was higher in low-AUC group (p < 0.01). In our 'real-world' population, no clinical data can predict which patient will have lower, suboptimal caspofungin exposure, therefore we suggest TDM to optimize caspofungin therapy and reduce the risk of selecting resistances (CEAVC, 32366/2015; OSS.15.114, NCT03798600).

Cost-Effectiveness of Antifungal Supplementation of Corneal Cold Storage Media.

PURPOSE: To evaluate the cost-effectiveness of supplementing hypothermic cold storage media (CSM) with antifungal therapy. DESIGN: Cost-effectiveness analysis (CEA). PARTICIPANT: Base case of a patient with Fuch's endothelial dystrophy undergoing a first eye keratoplasty. METHODS: Cost-effective analysis of the base case with corneal tissue stored in CSM or CSM supplemented with antifungal therapy over a 16-year time horizon. Multiple clinical scenarios were considered, including endothelial keratoplasty (EK) and penetrating keratoplasty (PK); amphotericin B, voriconazole, caspofungin, and combination therapy; and third-party payer and societal perspectives. The incidences were derived from PubMed literature searches and average wholesale prices of medications; all costs were discounted 3% per annum and adjusted for inflation to 2019 US dollars. MAIN OUTCOME MEASURES: Incremental cost-effectiveness ratios (ICERs). RESULTS: In the reference case, a corneal endothelial graft stored in amphotericin B-supplemented CSM was the most cost-effective approach from a third-party payer and societal perspective. Probability sensitivity analysis (PSA) of the societal model for the EK was robust, with 93.5% being below an arbitrary willingness-to-pay threshold (WTP) of $20 000 per fungal infection averted. Voriconazole, caspofungin, and combination antifungals were less cost-effective than amphotericin B. The main factors influencing the CEA were the incidences of postkeratoplasty fungal infections, potential increases in graft failures, and antifungal costs. For grafts intended for PKs, antifungal supplementation was less cost-effective than for EKs. CONCLUSIONS: Antifungal supplementation with amphotericin B for EK grafts was the most cost-effective approach of the studied antifungals; however, the CEA was sensitive to potential changes in graft failure rates, underlining the importance of long-term safety studies. For full-thickness corneal grafts, antifungal supplementation was less cost-effective.

Eficacia y seguridad de anidulafungina en pacientes adultos postrasplante hepático que requieren tratamiento dirigido o anticipado contra candidiasis / Efficacy and safety of anidulafungin in adult patients after liver transplantation who require targeted or anticipated treatment against candidiasis

INTRODUCCIÓN: El presente dictamen expone la evaluación de tecnología de la eficacia y seguridad de anidulafungina, en comparación con caspofungina, para el tratamiento dirigido o tratamiento anticipado (TD/TA) de candidiasis invasiva y/o candidemia en pacientes adultos posterior a trasplante hepático (PTH). La candidiasis invasiva/candidemia (IC/C) es la infección por hongos más común en los pacientes hospitalizados, y es la cuarta infección hematógena más frecuente en los pacientes de cuidados intensivos (UCI). Esta tiene una alta mortalidad (alrededor del 70 %) en pacientes postrasplante hepático (PTH). Además, una gran cantidad de pacientes PTH (alrededor del 30 %) pueden cursar con disfunción temprana del injerto (DTI), la cual consiste en el aumento de las enzimas hepáticas y la alteración de las pruebas de coagulación durante los primeros siete días PTH. La DTI está asociada a un mayor riesgo de pérdida del injerto, de mortalidad y de prolongación de la estancia hospitalaria. TECNOLOGÍA SANITARIA DE INTERÉS: Anidulafungina. La anidulafungina es una equinocandina semisintética en forma de lipopéptido obtenido a partir de la fermentación del hongo Aspergillus nidulans. Este medicamento actúa inhibiendo de forma no competitiva la enzima 1,3-beta-D-glucano sintetasa, parte de la armazón de la pared celular de los hongos. La anidulafungina tiene acción contra las especies de Candida, incluyendo aquellas resistentes a los azoles, así como contra especies de Aspergillus y Pneumocystis jiroveci. Asimismo, a pesar que la anidulafungina tiene acción contra la C. albicans, C. glabrata, C. krusei y C. tropicalis, la anidulafungina es relativamente inactiva contra C. parapsilosis y C. guilliermondii. De esta manera, la resistencia de las especies de Candida a las equinocandinas es muy rara, y está reportada principalmente la resistencia a caspofungina. METODOLOGÍA: Se llevó a cabo una búsqueda bibliográfica exhaustiva y jerárquica de la literatura con respecto a la eficacia y seguridad de anidulafungina para pacientes PTH que requieren TD/TA de IC/C; comparado con caspofungina. La búsqueda se inició revisando la información sobre el uso del medicamento de acuerdo con entidades reguladoras como la FDA, la EMA, y la DIGEMID en el Perú. En cuanto a los estudios de eficacia y seguridad, se realizó una búsqueda sistemática en las principales bases de datos, tales como MEDLINE vía PubMed, Cochrane Library y en el metabuscador de medicina basada en evidencia Turning Research Into Practice (TRIP). Asimismo, se realizó una búsqueda manual en las páginas web de grupos dedicados a la investigación y educación en salud que elaboran guías de práctica clínica: National Institute for Health and Care Excellence (NICE), Canadian Agency for Drugs and Technologies in Health (CADTH), Scottish Medicines Consortium (SMC), Haute Authorité de Santé (HAS) y la Institute for Clinical and Economic Review (ICER) y el Ministerio de Salud del Perú y (MINSA). Además, se realizó una búsqueda de las guías de las principales sociedades o instituciones especializadas en infectología, tales como Infectious Diseases Society of America (IDSA), European Society of Clinical Microbiology and Infectious Diseases (ESCMID), Australasian Society for Infectious Diseases (ASID) y la British Societyfor Medical Mycology (BSMM). Adicionalmente, se buscaron ensayos clínicos en desarrollo o que no hayan sido publicados aún en la página web www.clinicaltrials.gov que contengan estudios acerca de la tecnología evaluada, y así disminuir el sesgo de publicación. Finalmente, se consideró extraer información con una estrategia de "bola de nieve" mediante la revisión de las listas de referencias de las revisiones sistemáticas, estudios primarios y revisiones narrativas seleccionadas que sean relevantes para responder a la pregunta PICO. RESULTADOS: En la búsqueda bibliográfica no se identificaron ensayos clínicos aleatorizados que hayan comparado anidulafungina con caspofungina en la población de pacientes PTH con necesidad de TD/TA de IC/C, ni en pacientes con IC/C en general. Por ello, se extendieron los criterios de búsqueda, y se encontró un ECA fase III (Winston et al., 2014) que comparó anidulafungina y fluconazol como profilaxis, y dos ensayos clínicos (Sganga et al., 2012 y Fortun et al., 2009) de un solo brazo que estudiaron anidulafungina y caspofungina en pacientes PTH, respectivamente. Estos tres ensayos, ayudaron a responder de manera indirecta a la pregunta PICO de interés del presente dictamen. Por otro lado, no se encontraron guías de práctica clínica (GPC) ni evaluaciones de tecnología sanitaria (ETS) que hagan referencia específicamente a la población PTH. CONCLUSIONES: El presente dictamen preliminar expone la ETS de la eficacia y seguridad de anidulafungina, frente a caspofungina, para el TD/TA de IC/C en pacientes PTH. - La IC/C es la cuarta infección hematógena más frecuente en los pacientes de UCI, con una mortalidad de alrededor del 70 % en pacientes PTH. Por otro lado, los pacientes PTH que presentan DTI tienen un mayor riesgo de rechazo del injerto, mortalidad, y mayor tiempo hospitalario, que aquellos que no lo presentan. En el Petitorio Farmacológico de EsSalud se cuenta con caspofungina para el TD/TA de IC/C en pacientes PTH, en la misma línea que las GPC internacionales, las cuales recomiendan a las equinocandinas como la primera línea de tratamiento de las IC/C en aquellos pacientes críticos con alto riesgo de resistencia a azoles. Los especialistas de Trasplante Hepático de EsSalud plantearon que, en vista que caspofungina tiene metabolismo hepático, puede producir hepatotoxicidad, lo que pone en riesgo al injerto y puede ocasionar interacciones medicamentosas. Por ello, propusieron a anidulafungina como medicamento para el TD/TA de IC/C en pacientes PTH, ya que sufre degradación enzimática en el plasma, evitando el metabolismo hepático, y reduciendo así la carga funcional del injerto trasplantado. La búsqueda bibliográfica identificó un ECA fase III y dos ensayos clínicos de un solo brazo de etiqueta abierta que sirvieron de evidencia indirecta para responder la pregunta PICO. Sin embargo, estos estudios presentaron una serie de limitaciones, debido principalmente a los diseños de un solo brazo, muestras no aleatorizadas, tamaños de muestra pequeños, y reportes incompletos de EA. Asimismo, los estudios incluidos no evaluaron de forma comparativa a anidulafungina y caspofungina, por lo que, los resultados obtenidos en todos ellos fueron exploratorios. De esta manera, se desconoce el beneficio clínico neto de anidulafungina sobre caspofungina, en la población de la pregunta PICO. Sin embargo, los resultados mostraron un aumento considerable de hepatotoxicidad con caspofungina en los pacientes PTH. No obstante, la escasa evidencia a la fecha y las diferencias en el metabolismo de ambas equinocandinas, sugiere que anidulafungina sería menos hepatotóxico que caspofungina y, podría entonces, implicar una menor carga funcional para el hígado recientemente trasplantado, reduciendo el riesgo de presentar DTI en los pacientes PTH. En línea con ello, los expertos indican que la reducción del riesgo de hepatotoxicidad implicaría reducir el riesgo de pérdida del injerto, de muerte, y de prolongación de la estancia hospitalaria. Esto se suma a la plausibilidad biológica de que el uso de anidulafungina implicaría un menor riesgo de hepatotoxicidad al degradarse en el plasma y no presentar metabolismo hepático como caspofungina. El Instituto de Evaluaciones de Tecnologías en Salud e Investigación - IETSI, aprueba el uso de anidulafungina para el TD/TA de la IC/C en pacientes PTH, según lo establecido en el Anexo N° 1. La vigencia del presente dictamen preliminar es de un año a partir de la fecha de publicación. Así, la continuación de dicha aprobación estará sujeta a la evaluación de los resultados obtenidos y de nueva evidencia que pueda surgir en el tiempo.

Whole-body physiology-based pharmacokinetics of caspofungin for general patients, intensive care unit patients and hepatic insufficiency patients.

Caspofungin is an echinocandin antifungal agent licensed as a first-line therapy for invasive candidiasis in patients with moderate to severe illness or recent exposure to azoles. In this study we developed a whole-body physiology-based pharmacokinetics (WB-PBPK) model to predict the pharmacokinetics (PK) of caspofungin, and combined with Monte Carlo simulation (MCS) to optimize clinical dosage regimens of caspofungin in different kinds of patients. A WB-PBPK model of caspofungin was built and validated with raw data from 4 previous trials of general patients, intensive care unit (ICU) patients with Child-Pugh B, ICU patients on continuous renal replacement therapy, mild and moderate hepatic insuffciency (HI) patients. MCS was used to optimize clinical dosage regimens of caspofungin in these patients. A cumulative fraction of response (CFR) value of ≥90% was considered to be the minimum for achieving optimal empirical therapy. The simulated results of the WB-PBPK model were in good agreement with observed values of all trials. For general and ICU patients with caspofungin 70/50 mg, AUC and Cmax were decreased with the increase of body weight (BW) and showed great variation. MCS showed all general patients achieved CFR≥90% regardless of BW. But not all ICU patients with higher BW (≥70 kg) could achieve CFR≥90%. Compared with standard dosage regimens in general patients, caspofungin 70/35 mg in ICU patients with Child-Pugh B achieved significantly decreased AUC and Cmax, but obtained similar AUC and Cmax in moderate HI patients with Child-Pugh B. The WB-PBPK model of caspofungin is able to predict PK of all populations correctly. The combined WB-PBPK model with MCS can successfully optimize clinical dosage regimens of caspofungin in all patient populations.

Caspofungin dosage adjustments are not required for patients with Child-Pugh B or C cirrhosis.

Background: Controversies remain over caspofungin dosage adjustments in cirrhosis, particularly Child-Pugh (CP) B or C. The product information for of caspofungin recommends a maintenance dose reduction from 50 to 35 mg for patients with CP-B cirrhosis. Objectives: To quantify the impact of cirrhosis and the severity of hepatic impairment on the pharmacokinetics (PK) of caspofungin. Patients and methods: We performed PK studies of a single 70 mg dose of caspofungin in patients with decompensated CP-B (n = 10) or CP-C (n = 10) cirrhosis and of multiple doses in 21 non-cirrhotic ICU patients with hypoalbuminaemia. A Monte Carlo simulation was performed to investigate the impact of a maintenance dose reduction from 50 to 35 mg on the steady-state area under the 24 h concentration-time curve. Results: We observed a marginal reduction of caspofungin clearance in a PK study in patients with decompensated CP-B or CP-C cirrhosis. Dose reduction to 35 mg in cirrhotic patients resulted in lower drug exposure than with the approved dose in non-cirrhotic patients. Conclusions: In contrast to the product information, we recommend giving the full dose of caspofungin regardless of the presence and severity of cirrhosis to avoid a subtherapeutic exposure.

Pharmacoeconomic evaluation of micafungin versus caspofungin as definitive therapy for candidaemia and invasive candidiasis (IC) in Turkey.

Micafungin was shown to be as efficacious as caspofungin in treating patients with candidaemia and invasive candidiasis (IC). However, it remains unknown if micafungin or caspofungin is a cost-effective definitive therapy for candidaemia and IC in Turkey. The present study aimed to determine the economic impact of using micafungin versus caspofungin for treatment of candidaemia and IC in the Turkish setting. A decision analytic model was constructed and was populated with data (i.e. transition probabilities, duration of initial antifungal treatment, reasons for treatment failure, percentage of patients who stepped down to oral fluconazole, and duration on oral fluconazole) obtained from a published randomised clinical trial. Cost inputs were derived from the latest Turkish resources while data that were not readily available in the literature were estimated by expert panels. One-way sensitivity analyses, threshold analyses, scenario analyses and probabilistic sensitivity analyses were conducted. Caspofungin (€2693) incurred a lower total cost than micafungin (€4422), with a net cost saving of €1729 per treated patient. Drug acquisition cost was the main cost driver for both study arms. The model outcome was robust over wide variations (of ±100.0% from the base case value) for all input parameters except for micafungin drug cost and the duration of initial treatment with micafungin. Caspofungin appears to be a cost-saving option in treating candidaemia and IC from the Turkish hospital perspective.

Choosing Optimal Antifungal Agents To Prevent Fungal Infections in Nonneutropenic Critically Ill Patients: Trial Sequential Analysis, Network Meta-analysis, and Pharmacoeconomic Analysis.

The use of antifungal interventions in critically ill patients prior to invasive fungal infection (IFI) being microbiologically confirmed and the preferred drug are still controversial. A systematic literature search was performed to identify randomized controlled trials (RCTs) that compared untargeted antifungal treatments applied to nonneutropenic critically ill patients. The primary outcomes were all-cause mortality and proven IFI rates. A random-effects model was used with trial sequential analyses (TSA), a network meta-analysis (NMA) was conducted to obtain indirect evidence, and a cost-effectiveness analysis using a decision-analytic model was completed from the patient perspective over a lifetime horizon. In total, 19 RCTs involving 2,556 patients (7 interventions) were included. Untargeted antifungal treatment did not significantly decrease the incidence of all-cause mortality (odds ratio [OR] = 0.89, 95% confidence interval [95%CI] = 0.70 to 1.14), but it did reduce the incidence of proven IFI (OR = 0.45, 95%CI = 0.29 to 0.71) relative to placebo/no intervention. The TSA showed that there was sufficient evidence supporting these findings. In the NMA, the only significant difference found for both primary outcomes was between fluconazole and placebo/no intervention in preventing proven IFI (OR = 0.35, 95%CI = 0.19 to 0.65). Based on drug and hospital costs in China, the incremental cost-effectiveness ratios per life-year saved for fluconazole, caspofungin, and micafungin relative to placebo/no intervention corresponded to US$889, US$9,994, and US$10,351, respectively. Untargeted antifungal treatment significantly reduced proven IFI rates in nonneutropenic critically ill patients but with no mortality benefits relative to placebo/no intervention. Among the well-tolerated antifungals, fluconazole remains the only one that is effective for IFI prevention and significantly cheaper than echinocandins.

Pharmacoeconomic analysis of antifungal therapy for primary treatment of invasive candidiasis caused by Candida albicans and non-albicans Candida species.

BACKGROUND: Cost-effectiveness studies of echinocandins for the treatment of invasive candidiasis, including candidemia, are rare in Asia. No study has determined whether echinocandins are cost-effective for both Candida albicans and non-albicans Candida species. There have been no economic evaluations that compare non-echinocandins with the three available echinocandins. This study was aimed to assess the cost-effectiveness of individual echinocandins, namely caspofungin, micafungin, and anidulafungin, versus non-echinocandins for C. albicans and non-albicans Candida species, respectively. METHODS: A decision tree model was constructed to assess the cost-effectiveness of echinocandins and non-echinocandins for invasive candidiasis. The probability of treatment success, mortality rate, and adverse drug events were extracted from published clinical trials. The cost variables (i.e., drug acquisition) were based on Taiwan's healthcare system from the perspective of a medical payer. One-way sensitivity analyses and probability sensitivity analyses were conducted. RESULTS: For treating invasive candidiasis (all species), as compared to fluconazole, micafungin and caspofungin are dominated (less effective, more expensive), whereas anidulafungin is cost-effective (more effective, more expensive), costing US$3666.09 for each life-year gained, which was below the implicit threshold of the incremental cost-effectiveness ratio in Taiwan. For C. albicans, echinocandins are cost-saving as compared to non-echinocandins. For non-albicans Candida species, echinocandins are cost-effective as compared to non-echinocandins, costing US$652 for each life-year gained. The results were robust over a wide range of sensitivity analyses and were most sensitive to the clinical efficacy of antifungal treatment. CONCLUSIONS: Echinocandins, especially anidulafungin, appear to be cost-effective for invasive candidiasis caused by C. albicans and non-albicans Candida species in Taiwan.

Assessment of high-priced systemic antifungal prescriptions.

OBJECTIVES: To assess compliance with international guidelines for costly antifungal prescriptions and to compare these results with a first study performed in 2007. METHODS: Retrospective study including all costly antifungal prescriptions made in surgical and medical intensive care units and in a hepatobiliary, pancreatic, and digestive surgery unit. Prescriptions were assessed in terms of indication, dosage, and antifungal de-escalation. RESULTS: Seventy-four treatments were analyzed. Treatments were prescribed for prophylactic (1%), empirical (22%), pre-emptive (16%), or targeted therapy (61%). Caspofungin accounted for 68% of prescriptions, followed by voriconazole (20%) and liposomal amphotericin B (12%). Indication was appropriate in 91%, debatable in 1%, and inappropriate in 8%. Dosage was appropriate in 69%, debatable in 8%, and inappropriate in 23%. Prescriptions were inappropriate for the following reasons: lack of dosage adjustment in light of the hepatic function (10 cases), underdosage or excessive dosage by>25% of the recommended dose in seven cases. De-escalation to fluconazole was implemented in 40% of patients presenting with a fluconazole-susceptible candidiasis. CONCLUSION: The overall incidence of appropriate use was higher in 2012 compared with 2007 (62% and 37% respectively, P=0.004). Nevertheless, costly antifungal prescriptions need to be optimized in particular for empirical therapy, dosage adjustment, and potential de-escalation to fluconazole.

Assessment and Optimizations of Candida albicans In Vitro Biofilm Assays.

Candida albicans biofilms have a significant medical impact due to their rapid growth on implanted medical devices, their resistance to antifungal drugs, and their ability to seed disseminated infections. Biofilm assays performed in vitro allow for rapid, high-throughput screening of gene deletion libraries or antifungal compounds and typically serve as precursors to in vivo studies. Here, we compile and discuss the protocols for several recently published C. albicansin vitro biofilm assays. We also describe improved versions of these protocols as well as novel in vitro assays. Finally, we consider some of the advantages and disadvantages of these different types of assays.

Use of intravoxel incoherent motion diffusion-weighted MR imaging for assessment of treatment response to invasive fungal infection in the lung.

OBJECTIVES: The purpose of this study was to determine whether intravoxel incoherent motion (IVIM) -derived parameters and apparent diffusion coefficient (ADC) could act as imaging biomarkers for predicting antifungal treatment response. METHODS: Forty-six consecutive patients (mean age, 33.9 ± 13.0 y) with newly diagnosed invasive fungal infection (IFI) in the lung according to EORTC/MSG criteria were prospectively enrolled. All patients underwent diffusion-weighted magnetic resonance (MR) imaging at 3.0 T using 11 b values (0-1000 sec/mm2). ADC, pseudodiffusion coffiecient D*, perfusion fraction f, and the diffusion coefficient D were compared between patients with favourable (n=32) and unfavourable response (n=14). RESULTS: f values were significantly lower in the unfavourable response group (12.6%±4.4%) than in the favourable response group (30.2%±8.6%) (Z=4.989, P<0.001). However, the ADC, D, and D* were not significantly different between the two groups (P>0.05). Receiver operating characteristic curve analyses showed f to be a significant predictor for differentiation, with a sensitivity of 93.8% and a specificity of 92.9%. CONCLUSIONS: IVIM-MRI is potentially useful in the prediction of antifungal treatment response to patients with IFI in the lung. Our results indicate that a low perfusion fraction f may be a noninvasive imaging biomarker for unfavourable response. KEY POINTS: • Recognition of IFI indicating clinical outcome is important for treatment decision-making. • IVIM can reflect diffusion and perfusion information of IFI lesions separately. • Perfusion characteristics of IFI lesions could help differentiate treatment response. • An initial low f may predict unfavourable response in IFI.