Cost-effectiveness of de-escalation from micafungin versus escalation from fluconazole for invasive candidiasis in China.

AIMS: Guidelines on treating invasive candidiasis recommend initial treatment with a broad-spectrum echinocandin (e.g. micafungin), then switching to fluconazole if isolates prove sensitive (de-escalation strategy). This study aimed to evaluate the cost-effectiveness of de-escalation from micafungin vs escalation from fluconazole from a Chinese public payers perspective. MATERIALS AND METHODS: Cost-effectiveness was estimated using a decision analytic model, in which patients begin treatment with fluconazole 400 mg/day (escalation) or micafungin 100 mg/day (de-escalation). From Day 3, when susceptibility results are available, patients are treated with either fluconazole (if isolates are fluconazole-sensitive/dose-dependent) or micafungin (if isolates are resistant). The total duration of (appropriate) treatment is 14 days. Model inputs are early (Day 3) and end-of-treatment mortality rates, treatment success rates, and health resource utilization. Model outputs are costs of health resource utilization over 42 days, incremental cost per life-year, and incremental cost per quality-adjusted life-year (QALY) over a lifetime horizon. RESULTS: In the base-case analysis, the de-escalation strategy was associated with longer survival and higher treatment success rates compared with escalation, at a lower overall cost (-¥1,154; -175 United States Dollars). Life-years and QALYs were also better with de-escalation. Thus, this strategy dominated the escalation strategy for all outcomes. In a probabilistic sensitivity analysis, 99% of 10,000 simulations were below the very cost-effective threshold (1 × gross domestic product). LIMITATIONS: The main limitation of the study was the lack of real-world input data for clinical outcomes on treatment with micafungin in China; data from other countries were included in the model. CONCLUSION: A de-escalation strategy is cost-saving from the Chinese public health payer perspective compared with escalation. It improves outcomes and reduces costs to the health system by reducing hospitalization, due to an increase in the proportion of patients receiving appropriate treatment.

Cost Effectiveness of Candida Polymerase Chain Reaction Detection and Empirical Antifungal Treatment among Patients with Suspected Fungal Peritonitis in the Intensive Care Unit.

BACKGROUND: Mortality from intra-abdominal candidiasis in intensive care units (ICUs) is high. It takes many days for peritoneal-fluid fungal culture to become positive, and the recommended empirical antifungal therapy involves excessive costs. Polymerase chain reaction (PCR) should produce results more rapidly than fungal culture. OBJECTIVES: To perform a cost-effectiveness analysis of the combination of several diagnostic and therapeutic strategies to manage Candida peritonitis in non-neutropenic adult patients in ICUs. METHODS: We constructed a decision tree model to evaluate the cost effectiveness. Cost and effectiveness were taken into account in a 1-year time horizon and from the French National Health Insurance perspective. Six strategies were compared: fluconazole or echinocandin as an empirical therapy, plus diagnosis by fungal culture or detection by PCR of all Candida species, or use of PCR to detect most fluconazole-resistant Candida species (i.e., Candida krusei and Candida glabrata). RESULTS: The use of fluconazole empirical treatment and PCR to detect all Candida species is more cost effective than using fluconazole empirical treatment without PCR (incremental cost-effectiveness ratio of €40,055/quality-adjusted life-year). Empirical treatment with echinocandin plus PCR to detect C. krusei and C. glabrata is the most effective strategy, but has an incremental cost-effectiveness ratio of €93,776/quality-adjusted life-year. If the cost of echinocandin decreases, then strategies involving PCR plus empirical echinocandin become more cost-effective. CONCLUSIONS: Detection by PCR of all Candida species and of most fluconazole-resistant Candida species could improve the cost-effectiveness of fluconazole and echinocandin given to non-neutropenic patients with suspected peritoneal candidiasis in ICUs.

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.

Population Pharmacokinetic Model and Pharmacokinetic Target Attainment of Micafungin in Intensive Care Unit Patients.

OBJECTIVE: To study the pharmacokinetics of micafungin in intensive care patients and assess pharmacokinetic (PK) target attainment for various dosing strategies. METHODS: Micafungin PK data from 20 intensive care unit patients were available. A population-PK model was developed. Various dosing regimens were simulated: licensed regimens (I) 100 mg daily; (II) 100 mg daily with 200 mg from day 5; and adapted regimens 200 mg on day 1 followed by (III) 100 mg daily; (IV) 150 mg daily; and (V) 200 mg daily. Target attainment based on a clinical PK target for Candida as well as non-Candida parapsilosis infections was assessed for relevant minimum inhibitory concentrations [MICs] (Clinical and Laboratory Standards Institute). Parameter uncertainty was taken into account in simulations. RESULTS: A two-compartment model best fitted the data. Clearance was 1.10 (root square error 8%) L/h and V 1 and V 2 were 17.6 (root square error 14%) and 3.63 (root square error 8%) L, respectively. Median area under the concentration-time curve over 24 h (interquartile range) on day 14 for regimens I-V were 91 (67-122), 183 (135-244), 91 (67-122), 137 (101-183) and 183 (135-244) mg h/L, respectively, for a typical patient of 70 kg. For the MIC/area under the concentration-time curve >3000 target (all Candida spp.), PK target attainment was >91% on day 14 (MIC 0.016 mg/L epidemiological cut-off) for all of the dosing regimens but decreased to (I) 44%, (II) 91%, (III) 44%, (IV) 78% and (V) 91% for MIC 0.032 mg/L. For the MIC/area under the concentration-time curve >5000 target (non-C. parapsilosis spp.), PK target attainment varied between 62 and 96% on day 14 for MIC 0.016. CONCLUSIONS: The licensed micafungin maintenance dose results in adequate exposure based on our simulations with a clinical PK target for Candida infections but only 62% of patients reach the target for non-C. parapsilosis. In the case of pathogens with an attenuated micafungin MIC, patients may benefit from dose escalation to 200 mg daily. This encourages future study.

Population pharmacokinetics of micafungin in ICU patients with sepsis and mechanical ventilation.

OBJECTIVES: To identify the factors associated with the interindividual pharmacokinetic (PK) variability of micafungin and to evaluate the probability of reaching the previously determined PK/pharmacodynamic efficacy thresholds (AUC/MIC >5000 for non-parapsilosis Candida sp. and ≥285 for Candida parapsilosis) with the recommended 100 mg daily dose in ICU patients with sepsis and mechanical ventilation. METHODS: One hundred patients were included and 436 concentrations were available for PK analysis performed with NONMEM software. PTA was determined by Monte Carlo simulations. RESULTS: Micafungin obeyed a two-compartment model with first-order elimination from the central compartment. Mean parameter estimates (percentage interindividual variability) were 1.34 L/h (34%) for clearance (CL), 11.80 L (38%) and 7.68 L (39%) for central (Vc) and peripheral (Vp) distribution volumes, respectively, and 4.67 L/h (37%) for distribution clearance. CL, Vc and Vp increased by 14% when the albumin level was ≤25 g/L and CL decreased by 25% when SOFA score was ≥10. Body weight was related to CL, Vc and Vp by allometric models. PTA was ≥90% in Candida albicans and Candida glabrata infections, except when the MIC was ≥0.015 mg/L, and ranged between 0% and 40% for C. parapsilosis infections with MIC ≥0.5 mg/L. CONCLUSIONS: A possible increase in the dose should be evaluated for infections due to C. parapsilosis and for infections due to C. albicans and C. glabrata with MICs ≥0.015 mg/L.

Eficacia y seguridad del uso de anidulafungina en pacientes no neutropénicos con candidemia y respuesta inadecuada o reaccion adversa a fluconazol / Efficacy and safety of the use of anidulafungin in non-neutropenic patients with candidemia and inadequate response or adverse reaction to fluconazole

INTRODUCCIÓN: Antecedentes: El presente dictamen expone la evaluación de tecnología de la eficacia y seguridad del uso Anidulafungina en pacientes no neutropénicos con candidemia y respuesta inadecuada o reacción adversa a fluconazol. Aspectos Generales: La candidiasis sistémica es una patología con alta morbilidad y mortalidad (1). La colonización por candida spp. se desarrolla en hasta el 80 % de los pacientes críticos que permanecen más de una semana en cuidados intensivos, mientras que la candidiasis invasiva se documenta en sólo un 5 a un 10% de ellos. El tiempo de diagnóstico puede ser afectado por la complejidad que representa en sus criterios, causando retrasos en el inicio del tratamiento adecuado, haciendo que las candidemia y las candidiasis invasivas tengan peores pronósticos que otras infecciones de reconocimiento más sencillo. Tecnologia Sanitaria de Interés: La anidulafungina es una equinocandina semisintética, un lipopéptido obtenido a partir de un producto de fermentación de Aspergillus nidulans. Este producto farmacéutico actúa inhibiendo selectivamente la 1,3-3-D glucanosintetasa, enzima presente en las células fúngicas, pero no en las células de mamíferos. Como resultado no se forma 1,3-13- D glucano, el cual es esencial en la pared celular fúngica. La anidulafungina ha demostrado actividad fungicida frente a candida spp. y actividad frente a Aspergillus fumigatus; la actividad in vitro de anidulafungina frente a las especies de candida spp. no es homogénea. En concreto, la concentración mínima inhibitoria de la anidulafungina en el caso de la C. parapsilosis es superior a la observadas en otras especies de candida spp. METODOLOGIA: Estrategia de Búsqueda: Se realizó una estrategia de búsqueda sistemática de la evidencia científica con respecto a la eficacia y seguridad de Anidulafungina en pacientes adultos no neutropénicos con candidemia que son intolerantes o resistentes a fluconazol. Para la búsqueda primaria se revisó la información disponible por entes reguladoras y normativas como la Food and Drug Administration (FDA), la Agencia Europea de Medicamentos (EMA), y la Dirección General de Medicamentos y Drogas (DIGEMID). Posteriormente se buscaron Guías de Práctica Clínica a través de los metabuscadores: Translating Research into Practice (TRIPDATABASE), National Library of Medicine (Pubmed-Medline), The National Guideline Clearinghouse (NGC), UpToDate y Health Systems Evidence (HSE). Finalmente, se realizó una búsqueda dentro de la información generada por grupos internacionales que realizan revisiones sistemáticas, evaluación de tecnologías sanitarias y guías de práctica clínica, tales como The Cochrane Library, The National Institute for Health and Care Excellence (NICE), The Canadian Agency for Drugs and Technologies in Health (CADTH), The Scottish Medicines Consortium (SMC), que a su vez fue complementada con una búsqueda en ww.clinicaltrials.gov , para identificar estudios primarios en elaboración o que no hayan sido publicados aún. RESULTADOS: Sinopsis de la Evidencia: Se realizó búsqueda bibliográfica y de evidencia científica que sustente el uso de Anidulafungina en pacientes adultos no neutropénicos con candidemia que son intolerantes o resistentes a fluconazol según la pregunta PICO establecida. En relación a los estudios encontrados para la población de interés descrita en la pregunta PICO no se encontraron estudios que comparen directamente mediante un ensayo clínico las equinocandinas (anidulafungina, caspofungina y micafungina) en pacientes con candidemia o infecciones sistémicas por candida spp. Se encontraron 2 revisiones sistemáticas con evidencia indirecta. Además, se encontró un ensayo clínico de evidencia indirecta que puede ser usada para responder la pregunta PICO, que compara Anidulafungina con Fluconazol en pacientes con candidiasis invasiva. CONCLUSIONES: El Instituto de Evaluación de Tecnologías en Salud e Investigación (IETSI) aprueba el uso de anidulafungina según el esquema planteado en la pregunta PICO para pacientes no neutropénicos con candidemia y respuesta inadecuada o reacción adversa a fluconazol.

Dose optimization of voriconazole/anidulafungin combination against Aspergillus fumigatus using an in vitro pharmacokinetic/pharmacodynamic model and response surface analysis: clinical implications for azole-resistant aspergillosis.

BACKGROUND: Combination therapy of voriconazole with an echinocandin is often employed in order to increase the efficacy of voriconazole monotherapy. METHODS: Four clinical Aspergillus fumigatus isolates with different in vitro susceptibilities to voriconazole (MIC 0.125-2 mg/L) and anidulafungin (MEC 0.008-0.016 mg/L) were tested in an in vitro pharmacokinetic/pharmacodynamic model simulating human serum concentrations of standard dosages of voriconazole and anidulafungin. Fungal growth was assessed using galactomannan production and quantitative PCR. Drug concentrations were determined with bioassays. Pharmacodynamic interactions were assessed using Bliss independence analysis (BI) and Loewe additivity-based canonical mixture response-surface non-linear regression analysis (LA). Probability of target attainment (PTA) was estimated with Monte Carlo analysis for different doses of anidulafungin (25, 50 and 100 mg) and azole resistance rates (5%-25%). RESULTS: Synergy [BI 51% (8%-80%), LA 0.63 (0.38-0.79)] was found at low anidulafungin (fCmax/MEC <10) and voriconazole (fAUC/MIC <10) exposures, whereas antagonism [BI 12% (5%-18%, LA 1.12 (1.04-4.6)] was found at higher drug exposures. The largest increase in PTA was found with 25 mg of anidulafungin and voriconazole MIC distributions with high (>10%) resistance rates. PTAs for isolates with voriconazole MICs of 1, 2 and 4 mg/L was 78%, 12% and 0% with voriconazole monotherapy and 96%-100%, 68%-82% and 9%-20% with combination therapy, respectively. Optimal activity was associated with a voriconazole tCmin/MIC ratio of 1.5 for monotherapy and 0.75 for combination therapy. CONCLUSIONS: The present study indicated that the combination of voriconazole with low-dose anidulafungin may increase the efficacy and reduce the cost and potential toxicity of antifungal therapy, particularly against azole-resistant A. fumigatus isolates and in patients with subtherapeutic serum levels. This hypothesis warrants further in vivo verification.

Pharmacokinetic/pharmacodynamic adequacy of echinocandins against Candida spp. in intensive care unit patients and general patient populations.

This study evaluated whether contemporary echinocandin regimens achieved pharmacokinetic/pharmacodynamic targets in ICU patients and general patient populations (GPPs) and assessed caspofungin (CAS) regimens in hepatic impairment (HI) patients. A Monte Carlo simulation was performed using previously published data. Recommended dosing regimens of echinocandins in ICU patients, GPPs and healthy volunteers were evaluated: 70mg loading dose then 50mg maintenance dose (70/50mg) for CAS; 100mg q24h for micafungin (MCF); and 200/100mg for anidulafungin (ANF). Moreover, CAS 70mg and 100mg q24h in GPPs, and CAS 70/50mg and 70/35mg in mild and moderate HI patients, respectively, were evaluated. Cumulative fraction of response (CFR) was calculated for each dosing regimen. For Candida albicans, CFRs for the recommended doses of CAS, MCF and ANF were 95.8%, 13.5% and 50.5% in ICU patients and 96.3%, 42.4% and 61.6% in GPPs, respectively; for Candida glabrata, CFRs were 99.4%, 90.6% and 44.6% in ICU patients and 99.5%, 97.1% and 59.8% in GPPs. For Candida parapsilosis, CFRs of echinocandins for standard regimens were <70%; only CAS 100mg q24h achieved the target CFR. CAS 70/50mg and 70/35mg in mild and moderate HI patients were appropriate. Considerable interindividual variability was observed. For C. albicans and C. glabrata, CAS is good choice both for ICU and other patient populations, but for C. parapsilosis an increased dose should be considered. For MCF and ANF, administering higher doses with longer dosing intervals achieves better target attainment and should be investigated in clinical trials.

Dose Reduction of Caspofungin in Intensive Care Unit Patients with Child Pugh B Will Result in Suboptimal Exposure.

BACKGROUND AND OBJECTIVES: Caspofungin is an echinocandin antifungal agent used as first-line therapy for the treatment of invasive candidiasis. The maintenance dose is adapted to body weight (BW) or liver function (Child-Pugh score B or C). We aimed to study the pharmacokinetics of caspofungin and assess pharmacokinetic target attainment for various dosing strategies. METHODS: Caspofungin pharmacokinetic data from 21 intensive care unit (ICU) patients was available. A population pharmacokinetic model was developed. Various dosing regimens (loading dose/maintenance dose) were simulated: licensed regimens (I) 70/50 mg (for BW <80 kg) or 70/70 mg (for BW >80 kg); and (II) 70/35 mg (for Child-Pugh score B); and adapted regimens (III) 100/50 mg (for Child-Pugh score B); (IV) 100/70 mg; and (V) 100/100 mg. Target attainment based on a preclinical pharmacokinetic target for Candida albicans was assessed for relevant minimal inhibitory concentrations (MICs). RESULTS: A two-compartment model best fitted the data. Clearance was 0.55 L/h and the apparent volumes of distribution in the central and peripheral compartments were 8.9 and 5.0 L, respectively. The median area under the plasma concentration-time curve from time zero to 24 h on day 14 for regimens I-V were 105, 65, 93, 130, and 186 mg·h/L, respectively. Pharmacokinetic target attainment was 100 % (MIC 0.03 µg/mL) irrespective of dosing regimen but decreased to (I) 47 %, (II) 14 %, (III) 36 %, (IV) 69 %, and (V) 94 % for MIC 0.125 µg/mL. CONCLUSION: The caspofungin maintenance dose should not be reduced in non-cirrhotic ICU patients based on the Child-Pugh score if this classification is driven by hypoalbuminemia as it results in significantly lower exposure. A higher maintenance dose of 70 mg in ICU patients results in target attainment of >90 % of the ICU patients with species with an MIC of up to 0.125 µg/mL.

Economic evaluation of a preemptive treatment strategy for invasive fungal infection in neutropenic patients with hematological diseases.

We compared the expected medical costs of empirical and preemptive treatment strategies for invasive fungal infection in neutropenic patients with hematological diseases. Based on the results of two clinical trials with different backgrounds reported by Oshima et al. [J Antimicrob Chemother 60(2):350-355; Oshima study] and Cordonnier et al. [Clin Infect Dis 48(8):1042-1051; PREVERT study], we developed a decision tree model that represented the outcomes of empirical and preemptive treatment strategies, and estimated the expected medical costs of medications and examinations in the two strategies. We assumed that micafungin was started in the empirical group at 5 days after fever had developed, while voriconazole was started in the preemptive group only when certain criteria, such as positive test results of imaging studies and/or serum markers, were fulfilled. When we used an incidence of positive test results of 6.7 % based on the Oshima study, the expected medical costs of the empirical and preemptive groups were 288,198 and 150,280 yen, respectively. Even in the case of the PREVERT study, in which the incidence of positive test results was 32.9 %, the expected medical costs in the empirical and preemptive groups were 291,871 and 284,944 yen, respectively. A sensitivity analysis indicated that the expected medical costs in the preemptive group would exceed those in the empirical group when the incidence of positive test results in the former was over 34.4 %. These results suggest that a preemptive treatment strategy can be expected to reduce medical costs compared with empirical therapy in most clinical settings.

A cost and resource utilization analysis of micafungin bridging for hemato-oncological high-risk patients undergoing allogeneic stem cell transplantation.

BACKGROUND: Intravenous bridging strategies increase exposure of antifungal prophylaxis in high-risk hematological patients. The cost-effectiveness of such strategies has not been analyzed. METHODS: A recent study compared the impact of oral posaconazole (POS) and oral posaconazole with intravenous micafungin bridging (POS-MIC) as prophylactic antifungal regimens in patients undergoing allogeneic stem cell transplantation (aSCT). Based on data from the Cologne Cohort of Neutropenic Patients (CoCoNut), a health economic evaluation of direct treatment costs was performed to analyze the economic impact of micafungin bridging. Analysis was undertaken based on current guidelines for the German societal perspective with an annual discount rate of 5%, whereby indirect costs were disregarded due to the severity of the underlying disease. Sensitivity analysis of cost calculation with different discount rates was performed to improve robustness of our health economic evaluation. RESULTS: A retrospective case-control analysis of patients undergoing aSCT between 05/2006 and 07/2011 was performed; 106 patients each in the POS and POS-MIC group were included. In the POS and POS-MIC group, mean costs per patient for the treatment on bone marrow transplant ward were €27,228 (95% CI: €24,932-€29,525) vs. €27,894 (95% CI: €26,414-€29,375; P = 0.629), for diagnostic measures €2124 (95% CI: €1823-€2425) vs. €1269 (95% CI: €1168-€1370; P ≤ 0.001), for laboratory findings €10,612 (95% CI: €9681-€11,544) vs. €8836 (95% CI: €8198-€9475; P = 0.002), and for overall antifungal treatment €6105 (95% CI: €4703-€7508) vs. €6943 (95% CI: €5393-€8493; P = 0.428), resulting in mean overall costs per patient of €60,304 (95% CI: €53,969-€66,639) vs. €58,089 (95% CI: €51,736-64,442; P = 0.625). CONCLUSIONS: Our health economic evaluation shows micafungin bridging in aSCT patients did not result in excess cost. Higher acquisition costs of antifungal prophylaxis were balanced by a reduced incidence of possible IFD and lower costs for empirical, preemptive, and targeted antifungal therapy as well as lower costs for diagnostic measures and laboratory tests in the micafungin bridging group.

Antifungal step-down therapy based on hospital intravenous to oral switch policy and susceptibility testing in adult patients with candidaemia: a single centre experience.

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.

De-escalation from micafungin is a cost-effective alternative to traditional escalation from fluconazole in the treatment of patients with systemic Candida infections.

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.

Non-clinical safety assessment and toxicokinetics of voriconazole and anidulafungin in the juvenile rat: a combination study design in support of a Paediatric Investigation Plan.

Anidulafungin and voriconazole are potent antifungal agents that may provide a powerful therapeutic option over current therapies when coadministered. A non-clinical combination toxicity study was required as part of the voriconazole Paediatric Investigation Plan. Rats received anidulafungin or voriconazole alone or in combination once daily from postnatal day (PND) 21-56 with a recovery period to PND 84. Doses used were based upon the approximate adult rat no observed adverse-effect level (NOAEL). Transient and reversible reductions in bodyweight, haematology, serum chemistry, liver weight and minimal liver changes were associated with anidulafungin. Voriconazole caused an increase in gamma-glutamyltransferase in female rats only. No increased toxicity was observed with the combination. Toxicokinetics were determined using a validated dual-analyte bioanalytical method. Systemic exposure at juvenile rat NOAELs was comparable to that found with adult rats in previous studies. There were no drug-drug interactions affecting exposure of either drug. Juvenile rats were not more sensitive to each drug dosed alone compared with adult rat data on the single drugs. No novel, additive or synergistic toxicities were noted with the combination in juvenile rats. This study will support future studies of the combination of voriconazole and anidulafungin in children with invasive fungal infection.

[Cost analysis of 3 candins in the treatment of invasive candidiasis in adult non-neutropaenic patients in Spain]. / Análisis de costes de tres candinas en el tratamiento de la candidiasis invasora en pacientes adultos no neutropénicos en España.

OBJECTIVE: To estimate the cost of 3 candins (anidulafungin, caspofungin and micafungin) in the treatment of adult non-neutropaenic patients with invasive candidiasis (IC) in a Spanish hospital pharmacy setting. METHODS: The overall cost impact was evaluated by varying the percentage dosage required of each candin in different possible scenarios. The prices (in euros) for each presentation were obtained from the Drug Catalogue (in August 2010). Only drug purchase costs were considered. The results are expressed as total cost for each of the 3 candins. RESULTS: The cost per episode (14 days) of anidulafungin was constant at €5400 per patient. The cost of caspofungin varied from €4281 to €7991, depending on patient weight and liver dysfunction. The cost of micafungin varied from €6000 (100mg/day) to €9000 (when increasing the dose due to inadequate response). Based on a hypothetic cohort of 100 patients with IC, the total cost of anidulafungin treatment would be €540,000, for caspofungin it would be €631,459, and for micafungin it would be €632,998, depending on any dose adjustment required. CONCLUSION: Patients treated with anidulafungin did not require dose adjustment, unlike those treated with caspofungin or micafungin. The use of anidulafungin is a cost-saving treatment for adult non-neutropaenic patients with IC, which would result in better control of the Spanish pharmacy budget.

[Echinocandins: searching for differences. The example of their use in patients requiring continuous renal replacement therapy]. / Equinocandinas: buscando diferencias. El ejemplo de su uso en pacientes sometidos a técnicas continuas de reemplazamiento renal.

The echinocandins have a growing role in the treatment of fungal infections because of their novel mechanism of action. This is reflected in recently published management guidelines, but available in vitro data, animal studies, and clinical studies do not clearly differentiate the three agents in class. Comparative clinical efficacy among agents within the class, pharmacokinetic profiles in special populations, pharmacoeconomics justifications, and place in therapy have been largely unanswered. They share many common properties but marketing strategies of drug manufacturers are engaged in product differentiation. Although exist similarities in the pharmacokinetic (PK) profiles of the echinocandins, limited data have been published regarding their pharmacokinetics in continuous renal replacement therapy (CRRT) patients. The pharmacokinetics of drug removal in critically ill patients receiving CRRT is very complex, with multiple variables affecting clearance. This review outlines the basic principles that determine whether a dose adjustment is required. Two studies with data on PK parameters of micafungin and anidulafungin in CRRT patients have been published and are compared following that basic principles in the review.

Antifungal management and resource use in patients with acute myeloid leukaemia after chemotherapy--retrospective analysis of changes over 3 yr in a German hospital.

OBJECTIVES: To describe changes in costs of managing hospitalised patients with acute myeloid leukaemia (AML) after chemotherapy in Germany over 3 yr, with a special focus on prophylaxis and treatment patterns as well as resource use related to invasive fungal infections (IFI). METHODS: The study was conducted as a retrospective, single-centre chart review in patients with AML hospitalised for chemotherapy, neutropenia and infections after myelosuppressive chemotherapy from January 2004 to December 2006 in Germany. The following resource utilisation data were collected: inpatient stay, mechanical ventilation, parenteral feeding, diagnostics, systemic antifungal medication and cost-intensive concomitant medication. Direct medical costs were calculated from hospital provider perspective. RESULTS: A total of 471 episodes in 212 patients were included in the analysis. Occurrence of IFI decreased from 5.9% in 2004 to 1.9% in 2006. Mean (± standard deviation) hospital stay decreased from 28.7 ± 17.9 d in 2004 to 22.4 ± 11.8 d in 2006. From 2004 to 2006, the use of a single antifungal drug increased from 30.4% to 46.9%, whereas the use of multiple antifungal drugs decreased from 24.4% to 13.1%. The use of liposomal amphotericin B declined between 2004 and 2006 (21.4% vs. 3.8%) and caspofungin between 2005 and 2006 (19.3% vs. 8.1%). Total costs per episode declined from €19051 ± 19024 in 2004 to €13531 ± 9260 in 2006; major reductions were observed in the use of antimycotics and blood products as well as length of hospital stay. CONCLUSION: Analysis of real-life data from one single centre in Germany demonstrated a change in antifungal management of patients with AML between 2004/2005 and 2006, accompanied by a decline in total costs.

Anidulafungin for neonatal hematogenous Candida meningoencephalitis: identification of candidate regimens for humans using a translational pharmacological approach.

Hematogenous Candida meningoencephalitis (HCME) is a serious infection in premature neonates. Anidulafungin is an echinocandin antifungal agent with potent activity against Candida spp., but its efficacy and optimal regimens for human neonates with HCME are not known. A well-validated rabbit model of HCME was used to define pharmacokinetic-pharmacodynamic (PK-PD) relationships of anidulafungin. A mathematical model was fitted to the entire data set. The experimental data were bridged to humans. A population PK model was fitted to the data from human neonates receiving anidulafungin receiving a loading dose of 3 mg/kg, followed by 1.5 mg/kg/day. Monte Carlo simulations were performed to identify candidate anidulafungin regimens for humans. All untreated rabbits succumbed by ≤96 h postinoculation. The PK of anidulafungin was linear with dose-dependent penetration into the cerebrum. Anidulafungin exerted a rapid antifungal effect that was apparent in the first dosing interval. Near-maximal antifungal activity was observed with dosages of 10 to 20 mg/kg/day. The bridging studies suggested that the current regimen of first 3 mg/kg, followed by 1.5 mg/kg/day, is suboptimal. Higher dosages were associated with progressively greater antifungal effect. Anidulafungin is effective for the treatment of experimental HCME. Higher dosages than those currently used for clinical care are required for maximal antifungal effect.

Economic evaluation of caspofungin versus liposomal amphotericin B for empirical antifungal therapy in patients with persistent fever and neutropenia in Sweden.

OBJECTIVE: To evaluate the cost-effectiveness of caspofungin versus liposomal amphotericin B (L-AmB) for empirical antifungal therapy in patients with persistent fever and neutropenia in Sweden. METHODS: With a decision-analytic model, the expected direct costs, life-years lost and quality adjusted life-years lost were estimated for an average patient in Sweden. Efficacy/tolerability data were obtained from analysis of a randomized, double-blind multinational trial. Life expectancy, medical resource use and unit costs data were gathered from the literature and expert opinion. Probabilistic sensitivity analysis was used to evaluate the impact of uncertainty in data on outcomes. RESULTS: The direct cost with caspofungin amounted to 233,851 SEK (95% uncertainty interval 225,091-242,210) and with L-AmB to 271,921 SEK (262,935-281,363), a difference of 38,070 SEK (31,745-44,811) favouring caspofungin. Treatment with caspofungin resulted in 0.25 (0.01-0.55) quality-adjusted life-years (QALYs) saved in comparison to L-AmB. Given the uncertainty in the estimates there is a >95% probability that caspofungin is economically dominant over L-AmB, i.e. cost-saving and QALY-saving. CONCLUSION: Given the underlying assumptions and data used, caspofungin is expected to be cost-effective with at least comparable outcomes compared to L-AmB for the empirical treatment of patients with suspected fungal infections in Sweden.

Hospital costs and outcomes among intravenous antifungal therapies for patients with invasive aspergillosis in the United States.

This study determined the economic burden of aspergillosis-related hospitalisations in the United States during years when new antifungal treatments were introduced. A retrospective observational cohort study from the hospital perspective was conducted using national administrative data from the Premier Perspective™ Database. Patients (n=1603) coded for infection caused by Aspergillus species during 1835 admissions who received at least 3 days of intravenous antifungal therapy between 2000 and 2006 were included. All costs were inflated to $US 2006. Length of stay, hospital costs and mortality were compared after stratification by initial antifungal therapy. Median hospital costs were $ 52,803 (25,929-100,730) and did not differ by year over the study period. Intravenous antifungals accounted for 7.2% (range: 0.78-15.9%) of the cost of aspergillosis-related hospitalisation. Crude mortality was 36.7% and was the lowest in the last 2 years of the study (2005, 2006). Although antifungal utilisation changed over the course of the study, initial antifungal choice was not independently associated with crude mortality. In contrast, initial therapy with intravenous voriconazole was associated with reduced total hospitalisation costs and length of hospital stay. Treatment with amphotericin B lipid complex or caspofungin was also independently associated with a reduced length of hospital stay. In this large US study, mortality and costs for aspergillosis-related hospitalisations were considerable, but antifungals accounted for a small percentage of total costs associated with treatment and did not independently affect in-hospital crude mortality. Only initial treatment with intravenous voriconazole was associated with reduced total hospitalisation costs.