Assessment of micafungin dosage regimens against Candida spp. in pediatric patients undergoing hematopoietic stem cell transplantation: a pharmacokinetic/pharmacodynamic analysis using Monte Carlo simulation.

The objective of this study was to evaluate the efficacy of various micafungin dosing regimens against Candida spp. in pediatric patients undergoing hematopoietic stem cell transplantation (HSCT). Monte Carlo simulations were conducted using pharmacokinetic (PK) parameters and pharmacodynamic (PD) data to determine the probabilities of target attainment and cumulative fractions of response in terms of area under the concentration curve/minimum inhibition concentration targets of micafungin. Current standard clinical micafungin dosing regimens of 1 and 2 mg/kg/day were appropriate for the prevention and treatment of Candida glabrata infection in pediatric patients undergoing HSCT, respectively. Moreover, the high-dose prophylactic dosage (2 mg/kg/day) and therapeutic dosage (4 mg/kg/day) should be the preferred option to optimize efficacy against Candida albicans. However, none of the simulated regimens was effective against Candida parapsilosis in pediatric HSCT patients. These PK/PD-based simulations rationalize and optimize the micafungin dosing regimens against Candida spp. in pediatric patients undergoing HSCT.

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/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.

Post-Prescription Audit Plus Beta-D-Glucan Assessment Decrease Echinocandin Use in People with Suspected Invasive Candidiasis.

Background and Objectives: Overtreatment with antifungal drugs is often observed. Antifungal stewardship (AFS) focuses on optimizing the treatment for invasive fungal diseases. The objective of the present study was to evaluate the utility of a post-prescription audit plus beta-D-glucan (BDG) assessment on reducing echinocandin use in persons with suspected invasive candidiasis. Materials and Methods: This is a prospective, pre-post quasi-experimental study of people starting echinocandins for suspected invasive candidiasis. The intervention of the study included review of each echinocandin prescription and discontinuation of treatment if a very low probability of fungal disease or a negative BDG value were found. Pre-intervention data were compared with the intervention phase. The primary outcome of the study was the duration of echinocandin therapy. Secondary outcomes were length of hospital stay and mortality. Results: Ninety-two echinocandin prescriptions were reviewed, 49 (53.3%) in the pre-intervention phase and 43 (46.7%) in the intervention phase. Discontinuation of antifungal therapy was possible in 21 of the 43 patients in the intervention phase (48.8%). The duration of echinocandin therapy was 7.4 (SD 4.7) in the pre-intervention phase, 4.1 days (SD 2.9) in persons undergoing the intervention, and 8.6 (SD 7.3) in persons in whom the intervention was not feasible (p at ANOVA = 0.016). Length of stay and mortality did not differ between pre-intervention and intervention phases. Conclusions: An intervention based on pre-prescription restriction and post-prescription audit when combined with BDG measurement is effective in optimizing antifungal therapy by significantly reducing excessive treatment duration.

Resistance to echinocandin antifungal agents in the United Kingdom in clinical isolates of Candida glabrata: Fifteen years of interpretation and assessment.

Candidemia is widely reported as the fourth most common form of bloodstream infection worldwide. Reports of breakthrough cases of candidemia are increasing, especially in the context of a move away from azole antifungals as prophylactic or first line treatment toward the use of echinocandin agents. The global evaluation of echinocandin antifungal susceptibility since 2003 has included switches in testing methodologies and the move to a sentinel echinocandin approach for classification reporting. This study compiles previously unpublished data from echinocandin susceptibility testing of UK clinical isolates of C. glabrata received at the Public Health England Mycology Reference Laboratory from 2003 to 2016 and reevaluates the prevalence of resistance in light of currently accepted testing protocols. From 2015 onward, FKS gene mutation detection using a novel Pyrosequencing® assay was assessed as a predictor of echinocandin resistance alongside conventional susceptibility testing. Overall, our data show that echinocandin resistance in UK isolates of C. glabrata is a rare phenomenon and prevalence has not appreciably increased in the last 14 years. The pyrosequencing assay was able to successfully detect hot spot mutations in FKS1 and FKS2, although not all isolates that exhibited phenotypic resistance demonstrated detectable hot spot mutations. We propose that a rapid genomic based detection method for FKS mutations, as part of a multifactorial approach to susceptibility testing, could help provide accurate and timely management decisions especially in regions where echinocandin resistance has been reported to be emerging in this important pathogen.

Educational ICU Antimicrobial Stewardship model: the daily activities of the AMS team over a 10-month period.

The emergence of antibiotic resistance as a consequence of inappropriate use results in higher mortality rates and has become a major public health challenge worldwide. Antimicrobial stewardship programs (ASPs) aim to ensure proper use of antimicrobials and reduce health care costs. We assessed the impact of using a behavioral approach during a persuasive ASP on antibiotic appropriateness, consumption and costs. We conducted a prospective interventional cohort before-and-after study in the intensive care unit (ICU) of a 554-bed, university teaching hospital in Terni, Italy, 14 of which are located in the ICU. We describe a 10-month persuasive ASP intervention model used in a referral ICU with daily rounds. The aim of the study was to improve medication appropriateness through educational action and reduce the consumption of carbapenems and echinocandins by conducting post-prescription reviews, prescribing reviews and holding daily discussions with the ICU team. We analyzed the prescribing appropriateness of the ICU team in accordance with the decisions made by the Antimicrobial Stewardship (AMS) team to improve the quality of antibiotic prescribing during the first five months and the last five months of the surveillance period. The results were expressed as the defined daily dose (DDD) per 100 occupied bed-days and costs. The data were compared with those previously obtained during the pre-educational period (the year before ASP implementation). Comparisons were made between the decisions taken to improve antimicrobial treatments administered during the first half of the surveillance period (March-July) and those administered during the second half (August-December). In all, 116 decisions were made from March to July while only 65 were made from August to December (p-value 0.00001). A significant reduction was observed in the consumption of carbapenems and echinocandins (11.15% and 25.62%, respectively). Total antibiotic cost savings amounted to 57,541.16 euros. The persuasive ASP strategy positively influenced the prescribing behavior of physicians, thus improving the appropriateness of antibiotic therapy and reducing antimicrobial consumption.

Population pharmacokinetics/pharmacodynamics of micafungin against Candida species in obese, critically ill, and morbidly obese critically ill patients.

BACKGROUND: Dosing in obese critically ill patients is challenging due to pathophysiological changes derived from obesity and/or critical illness, and it remains fully unexplored. This study estimated the micafungin probability of reaching adequate 24-h area under the curve (AUC0-24h)/minimum inhibitory concentration (MIC) values against Candida spp. for an obese/nonobese, critically ill/noncritically ill, large population. METHODS: Blood samples for pharmacokinetic analyses were collected from 10 critically ill nonobese patients, 10 noncritically ill obese patients, and 11 critically ill morbidly obese patients under empirical/directed micafungin treatment. Patients received once daily 100-150 mg micafungin at the discretion of the treating physician following the prescribing information and hospital guidelines. Total micafungin concentrations were determined by high-performance liquid chromatography (HPLC). Monte-Carlo simulations were performed and the probability of target attainment (PTA) was calculated using the AUC0-24/MIC cut-offs 285 (C. parapsilosis), 3000 (all Candida spp.), and 5000 (nonparapsilosis Candida spp.). Intravenous once-daily 100-mg, 150-mg, and 200-mg doses were simulated at different body weights (45, 80, 115, 150, and 185 kg) and age (30, 50, 70 and 90 years old). PTAs ≥ 90% were considered optimal. Fractional target attainment (FTA) was calculated using published MIC distributions. A dosing regimen was considered successful if the FTA was ≥ 90%. RESULTS: Overall, 100 mg of micafungin was once-daily administered for nonobese and obese patients with body mass index (BMI) ≤ 45 kg/m2 and 150 mg for morbidly obese patients with BMI > 45 kg/m2 (except two noncritically ill obese patients with BMI ~ 35 kg/m2 receiving 150 mg, and one critically ill patient with BMI > 45 kg/m2 receiving 100 mg). Micafungin concentrations in plasma were best described using a two-compartment model. Weight and age (but not severity score) were significant covariates and improved the model. FTAs > 90% were obtained against C. albicans with the 200 mg/24 h dose for all body weights (up to 185 kg), and with the 150 mg/24 h for body weights < 115 kg, and against C. glabrata with the 200 mg/24 h dose for body weights < 115 kg. CONCLUSION: The lack of adequacy for the 100 mg/24 h dose suggested the need to increase the dose to 150 mg/24 h for C. albicans infections. Further pharmacokinetic/pharmacodynamic studies should address optimization of micafungin dosing for nonalbicans Candida infections.

Overcoming the Resistance Hurdle: Pharmacokinetic-Pharmacodynamic Target Attainment Analyses for Rezafungin (CD101) against Candida albicans and Candida glabrata.

Rezafungin (CD101) is a novel echinocandin antifungal agent with activity against Aspergillus and Candida species, including azole- and echinocandin-resistant isolates. The objective of these analyses was to conduct pharmacokinetic (PK)-pharmacodynamic (PD) target attainment analyses to evaluate single and once-weekly rezafungin dosing to provide dose selection support for future clinical studies. Using a previously developed rezafungin population PK model, Monte Carlo simulations were conducted utilizing the following three intravenous rezafungin regimens: (i) a single 400 mg dose, (ii) 400 mg for week 1 followed by 200 mg weekly for 5 weeks, and (iii) 400 mg weekly for 6 weeks. Percent probabilities of achieving the nonclinical PK-PD targets associated with net fungal stasis and 1-log10 CFU reductions from baseline for Candida albicans and Candida glabrata were calculated for each rezafungin regimen. At the MIC90 for C. albicans and C. glabrata, a single 400 mg dose of rezafungin achieved probabilities of PK-PD target attainment of ≥90% through week 3 of therapy for all PK-PD targets evaluated. When evaluating the multiple-dose (i.e., weekly) regimens under these conditions, percent probabilities of PK-PD target attainment of 100% were achieved through week 6. Moreover, high (>90%) probabilities of PK-PD target attainment were achieved through week 6 following administration of the weekly regimens at or above the MIC100 values for C. albicans and C. glabrata based on contemporary in vitro surveillance data. These analyses support the use of single and once-weekly rezafungin regimens for the treatment of patients with candidemia and/or candidiasis due to C. albicans or C. glabrata.

Rezafungin (CD101), a next-generation echinocandin: A systematic literature review and assessment of possible place in therapy.

OBJECTIVES: Rezafungin (CD101) is a novel echinocandin currently under development. The purpose of this study was to perform a systematic literature review of published evidence on rezafungin and an antimicrobial stewardship audit of real-world use of echinocandins to determine areas of unmet medical needs and potential places in therapy for rezafungin. METHODS: The systematic literature review identified 8 peer-reviewed manuscripts and 19 separate abstracts. A stewardship audit was performed on hospitalised patients receiving echinocandins to better understand potential future areas of use for rezafungin. RESULTS: Rezafungin is a cyclic hexapeptide with a lipophilic tail derived from anidulafungin, with a choline moiety at the C5 ornithine position resulting in increased in vitro and in vivo stability compared with other echinocandins. Microbiological data showed similar susceptibility and resistance development between rezafungin and other echinocandins. Rezafungin has a long half-life (80h) and a favourable safety profile that allows for high doses (up to 400mg) given once weekly. A phase 2 study is ongoing. The antimicrobial stewardship audit of echinocandin identified several areas of possible use for rezafungin, including patients receiving daily echinocandins for >7 days, patients who remained in the hospital to complete a full course of daily echinocandin therapy, and patients who required an echinocandin scheduled via an infusion clinic after discharge. CONCLUSION: Rezafungin is a novel echinocandin currently in phase 2 studies, differentiated by a long half-life that allows once-weekly dosing and a safety profile that allows higher doses. Several potential areas of use for rezafungin were identified.

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.

Cost-effectiveness analysis of anidulafungin vs fluconazole for the treatment of invasive candidiasis (IC) in Turkey.

Anidulafungin has been shown to be non-inferior to, and possibly more efficacious, than fluconazole in treating patients with invasive candidiasis (IC). This study aimed to determine the cost-effectiveness of anidulafungin vs fluconazole for treatment of IC in the Turkish setting. A decision analytic model was constructed to depict downstream economic consequences of using anidulafungin or fluconazole for treatment of IC in the Turkish hospitals. Transition probabilities (ie treatment success, observed or indeterminate treatment failures) were obtained from a published randomised clinical trial. Cost inputs were from the latest Turkish resources. Data not available in the literature were estimated by expert panels. Sensitivity analyses were performed to assess the robustness of the model outcome. While anidulafungin [TL 17 171 (USD 4589)] incurred a higher total cost than fluconazole [TL 8233 (USD 2200) per treated patient, treatment with anidulafungin was estimated to save an additional 0.58 life-years, with an incremental cost-effectiveness ratio of TL 15 410 (USD 4118) per life-years saved. Drug acquisition cost and hospitalisation were the main cost drivers for anidulafungin and fluconazole arms respectively. The model findings were robust over a wide range of input variables except for anidulafungin drug cost. Anidulafungin appears to be a cost-effective therapy in treating IC from the Turkish hospital perspective.

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.

Epidemiology and cost implications of candidemia, a 6-year analysis from a developing country.

Surveillance of candidemia is essential to monitor trends in species distribution and change in the incidence and antifungal resistance. In this study, we aimed to investigate prevalence, resistance rates, antifungal utilization and costs. A 6-year retrospective analysis of the data belonging to patients with candidemia hospitalized between 2010 and 2016 was performed. The annual usage of fluconazole and caspofungin and the usage of these antifungals in different units were described in defined daily doses (DDD) per 1000 patient days. In total, 351 patients of candidemia were included. Median age of the patients was 45 (0-88) and 55.1% of them were male. Overall, 48.1% of the candidemia episodes (169/351) were due to C. albicans, followed by C. parapsilosis (25.1%), C. glabrata (11.7%). Length of hospital stay was longer with a median of 20 days among patients with non-albicans candidemia. Presence of a central venous catheter was found to be an associated risk for candidemia caused by non-albicans strains. Annual incidence of candidemia increased from 0.10 to 0.30 cases/1000 patient days. Antifungal use was increased over years correlated with the cost paid for it. The policy against candidemia should be specified by each institution with respect to candidemia prevalence, resistance rates, antifungal use and costs.

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.

Utilidad de anfotericina B y caspofungina en micosis invasivas / Utility of amphotericin B and caspofungin in invasive fungal infections

INTRODUCCIÓN: Las infecciones constituyen una complicación frecuente en los pacientes inmunocomprometidos y provocan un aumento considerable de los costos debido a hospitalizaciones y tratamientos específicos. Si bien las infecciones bacterianas son las que ocurren más frecuentemente en éste grupo de pacientes, las infecciones fúngicas representan una causa importante de morbimortalidad. Clásicamente, los hongos causantes de las principales infecciones micóticas se dividen en las categorías de levaduras (incluyendo Candida spp, Cryptococcus spp, Trichosporon spp), filamentos o mohos (incluyendo Aspergillus spp, Fusarium spp, los agentes causantes de la mucormicosis y los dermatofitos), y hongos dimórficos (incluyendo las micosis endémicas debido a Histoplasma capsulatum, Coccidioides immitis, Blastomyces dermatitidis, entre otros). DEFINICIONES: -Tratamiento profiláctico o profilaxis: se refiere al uso de un tratamiento antimicrobiano (antibiótico, antifúngico, etc) en forma preventiva; -Tratamiento empírico: uso de agentes antimicrobianos (antibiótico, antifúngico, etc.) antes de determinar la causa de un problema (ej. Fiebre); -Tratamiento antifúngico empírico: se refiere al inicio del uso de un agente antimicótico ante la primera evidencia de posible infección fúngica que usualmente suele ser la persistencia de fiebre de 4 o más días de duración luego de haber iniciado tratamiento antibiótico empírico; -Tratamiento anticipado o de anticipación (Preemptive treatment): se refiere al inicio de un tratamiento más dirigido, en lugar de utilizar uno de amplio espectro. Está indicado sólo en aquellos pacientes con indicios sugestivos de una infección fúngica determinada en base a estudios de laboratorio (Ej.: Antígeno aspergilar galactomanano) o de imágenes como TAC de tórax; -Neutropenia: recuento absoluto de neutrófilos (RAN) <500 células/mm3; -Neutropenia profunda: recuento absoluto de neutrófilos ≤100 células/ mm3; -Neutropenia prolongada: neutropenia de duración ≥7 días - Infección fúngica invasora (según Consenso EORTC/MSG19): Infección probada: Tinción y/o cultivo que demuestre levaduras u hongo filamentoso en sangre o muestra clínica de cavidad estéril o estudio histológico con evidencia de invasión fúngica. Infección probable: Factores del huésped más criterios clínicos y criterios micológicos. Infección posible: Factores del huésped más criterios clínicos sin criterios micológicos. CATEGORIZACIÓN DE PACIENTES NEUTROPÉNICOS FEBRILES EN ALTO Y BAJO RIESGO DE INFECCIONES SEVERAS: En las últimas décadas se han publicado numerosos trabajos que intentan identificar pacientes neutropénicos febriles (NF) de bajo riesgo, pasibles de recibir una terapia menos agresiva, incluyendo el manejo ambulatorio y el tratamiento oral. La mayoría de los expertos coincide en considerar pacientes de ALTO RIESGO a aquellos en los cuales la expectativa de prolongación de la neutropenia es mayor de 7 días. (> 7 días de duración) o profunda, clínicamente inestables (dolor no controlado, alteración del sensorio, hipotensión), con comorbilidades significativas (cáncer en progresión, EPOC, performance status pobre, edad avanzada), aquellos con tipos especiales de cáncer como leucemia aguda o síndromes linfoproliferativos o que recibirán un esquema quimioterápico intenso (para leucemia o trasplante hematopoyético). La Sociedad Argentina de Infectología (SADI) recomienda el uso del Score de la MASCC para identificar el riesgo de los pacientes en desarrollar infecciones severas. Según este score, los pacientes se clasifican en: Bajo Riesgo: pacientes con score MASCC ≥ de 21 puntos. Según el modelo de la MASCC, este grupo de pacientes tiene un riesgo de complicaciones menor del 5% y menos del 1% de riesgo de mortalidad. Algunos pacientes seleccionados de este grupo podrían recibir tratamiento ambulatorio y/o por vía oral. La IDSA (Sociedad Americana de enfermedades Infecciosas) considera dentro de este grupo de pacientes, a aquellos en los cuales se prevee una neutropenia de <7 días de duración, sin comorbilidades activas, clínicamente estables y sin alteración de la función renal ni hepática. Alto Riesgo: pacientes con score MASCC <21 puntos. La IDSA considera dentro de este grupo a pacientes con: -Neutropenia profunda (RAN <100 cél/ml) o prolongada anticipada (duración prevista >7 días); -Presencia de comorbilidades incluyendo: - Inestabilidad hemodinámica, -Mucositis oral o intestinal, -Síntomas gastrointestinales como dolor abdominal, náuseas y vómitos, -Cambios del sensorio o alteraciones neurológicas, -Infección de catéter vascular, -Nuevos infiltrados pulmonares, hipoxemia o EPOC de base; -Evidencia de insuficiencia hepática o renal. ANFOTERICINA B Y CASPOFUNGINA: ANFOTERICINA B: La anfotericina B es un antifúngico de amplio espectro producido por Streptomyces nodosus. Tiene muy buena actividad in vitro contra la mayoría de Candida spp., Aspergillus spp. y otros hongos filamentosos. Se acepta que las anfotericinas asociadas a lípidos tienen el mismo espectro in vitro que la anfotericina B6. CASPOFUNGINA: La caspofungina es un agente antifúngico de la familia de las equinocandinas, que posee un claro espectro de acción, frente a Candida spp. y Aspergillus spp. Actúa inhibiendo la síntesis de (1,3) D-glucano que un componente de la pared celular del hongo y que, al no estar presente en la pared de las células de los mamíferos, explicaría la escasa incidencia de efectos adversos. La caspofungina ha mostrado ser efectiva en la candidiasis esofágica y candidiasis invasiva, como tratamiento de la aspergilosis y como tratamiento empírico de pacientes adultos con neutropenia y fiebre. Es importante destacar que presenta poco potencial de resistencia. Su aparente baja toxicidad y falta de interacciones convierten la caspofungina en una alternativa útil para la profilaxis y el tratamiento de infecciones fúngicas. TRATAMIENTO EMPÍRICO: La anfotericina B desoxicolato (AMB-d) ha sido durante muchos años el antifúngico de elección; sin embargo, su nefrotoxicidad y las reacciones relacionadas con su infusión han motivado la realización de estudios con nuevas alternativas de drogas antimicóticas como formulaciones lipídicas de anfotericina B (liposomal y complejo lipídico), itraconazol, fluconazol, voriconazol y caspofungina. TRATAMIENTO ANTIFÚNGICO ANTICIPADO O DE ANTICIPACIÓN: El tratamiento anticipado es una alternativa al tratamiento empírico sólo en aquellos pacientes neutropénicos de alto riesgo en quienes hay evidencia de una infección micótica específica a través de pruebas de detección temprana validadas, como la detección de antígenos o ADN específicos o la TAC de alta resolución con patrón altamente sugestivo de infección micótica. La presencia de macronódulos con o sin halo periférico en TAC de tórax de alta resolución es un signo temprano muy típico de aspergilosis pulmonar en particular en pacientes neutropénicos. Otros signos más tardíos incluyen la presencia de múltiples nódulos, lesiones periféricas y/o cavitadas. El inicio de tratamiento anticipado para aspergilosis en pacientes neutropénicos con signo del halo ha demostrado mejorar la sobrevida en forma estadísticamente significativa. Se han desarrollado dos test serológicos para diagnóstico temprano de infección micótica: la prueba b (1-3)-D-glucano (actualmente no disponible en Hospitales de CABA) y la prueba de galactomananos. Estas pruebas no se recomiendan en pacientes de bajo riesgo y un resultado negativo no descarta la infección micótica invasiva.

Micafungin versus anidulafungin in critically ill patients with invasive candidiasis: a retrospective study.

BACKGROUND: In critically ill patients the incidence of invasive fungal infections caused by Candida spp. has increased remarkably. Echinocandins are recommended as initial treatment for invasive fungal infections. The safety and efficacy of micafungin compared to caspofungin is similar, but no comparison is made between anidulafungin and micafungin concerning safety and efficacy. We therefore performed a retrospective study to assess these aspects in critically ill patients with invasive candidiasis. METHODS: All patients in the intensive care unit (ICU) with invasive candidiasis, who were only treated with anidulafungin or micafungin, between January 2012 and December 2014 were retrospectively included. Baseline demographic characteristics, infection characteristics and patient courses were assessed. RESULTS: A total of 63 patients received either anidulafungin (n = 30) or micafungin (n = 33) at the discretion of the attending intensivist. Baseline characteristics were comparable between the two groups, suggesting similar risk for developing invasive candidiasis. Patients with invasive candidiasis and liver failure were more often treated with anidulafungin than micafungin. Response rates were similar for both groups. No difference was observed in 28-day mortality, but 90-day mortality was higher in patients on anidulafungin. Multivariable cox regression analysis showed that age and serum bilirubin were the best parameters for the prediction of 90-day mortality, whereas APACHE II, Candida score and antifungal therapy did not contribute (P > 0.05). None of the patients developed impaired liver function related to antifungal use and no differences were seen in prothrombin time, serum transaminases and bilirubin levels between the groups, after exclusion of patients with liver injury or failure. CONCLUSION: Micafungin can be safely and effectively used in critically ill patients with invasive candidiasis. The observed increased 90-day mortality with anidulafungin can be explained by intensivists unnecessarily avoiding micafungin in patients with liver injury and failure.

Cost-effectiveness of caspofungin versus liposomal amphotericin B in the treatment of systemic fungal infections: a systematic review of economic analyses.

INTRODUCTION: The treatment of fungal infections in severely ill patients is a clinical and economic challenge worldwide. Liposomal amphotericin B and caspofungin are highly effective antifungal drugs; however, they are very expensive and health systems must select the drug that results in the best clinical outcomes and is economically feasible. AREAS COVERED: A systematic search was conducted in PubMed, Scopus, Web of Science, Cochrane Library, Health Economic Evaluation Database, and Centre for Review and Dissemination to find complete economic evaluations that directly compared the two treatment strategies. Expert commentary: Because of the high cost, patients in developing countries experience difficulty accessing highly effective treatments. These data can subsidize a decision for an effective antifungal treatment with reduced costs from all perspectives.

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.