Comparison of the safety and cost-effectiveness of nebulized liposomal amphotericin B and amphotericin B deoxycholate for antifungal prophylaxis after lung transplantation.

INTRODUCTION: Fungal infection after lung transplantation can lead to poor clinical outcome, for which lung transplant recipients require prophylaxis. One of the antifungal agents used after lung transplantation is nebulized amphotericin B (AMB). Nebulized AMB causes adverse events such as dyspnea and airway irritation, and long-term use leads to high economic costs. So far, prophylactic regimens employing AMB deoxycholate (AMB-d) and liposomal AMB (L-AMB) have been developed. This study compared the efficacy, safety, and cost of AMB-d and L-AMB. PATIENTS AND METHODS: Patients who underwent lung transplantation at Kyoto University Hospital from January 2021 to May 2023 were included in this study. Thirty-three patients received nebulized AMB-d, whereas 29 received nebulized L-AMB. RESULTS: Both regimens maintained comparable prophylactic efficacy regarding the development of fungal infection in the AMB-d and L-AMB groups (3.0% vs. 3.4%, P = 0.877). Patients treated with nebulized L-AMB experienced fewer respiratory-related adverse reactions than those treated with nebulized AMB-d (6.9% vs. 30.3%, P < 0.05), leading to a longer treatment duration with L-AMB than with AMB-d. Additionally, the daily cost of administering L-AMB was lower than that of administering AMB-d (3609 Japanese yen vs. 1792.3 Japanese yen, P < 0.05). DISCUSSION: These results suggest that nebulized L-AMB is safer and more cost-effective than nebulized AMB-d, with comparable efficacy.

Superficial mycoses in Belgium: Burden, costs and antifungal drugs consumption.

BACKGROUND: Monitoring of superficial mycoses requires more attention due to their important incidence, health costs and antifungal drugs consumption. OBJECTIVES: The objectives were to estimate the burden of superficial mycoses in Belgium and to assess trends in associated antifungal consumption. METHODS: The burden of dermatophytoses (including onychomycosis), as well as skin and genital candidiasis, was estimated using disability-adjusted life years (DALY). Moreover, trends in systemic and topical antifungal consumption in ambulatory care were examined for the period 2010-2017, together with their associated costs. RESULTS: Due to their high incidence and long treatment duration, dermatophytoses represented the bulk of the burden, accounting for 92.2% of the total DALYs of superficial mycoses. Terbinafine was the most prescribed antifungal in terms of doses (35.4% of the total doses) while fluconazole was the most delivered drug in terms of packages (29.1% of the total packages). More than 70% of the prescriptions were made by general practitioners while consumption varied according to age and gender of the patients. A global 12% decrease in antifungal prescriptions was observed between 2011 and 2017. However, this reduction would result mainly from packaging changes and increased self-medication. A significant decrease in itraconazole treatments was notably compensated by an increased prescription of fluconazole packages. CONCLUSION: This study emphasises that dermatological presentations of superficial mycoses are the most important in terms of both burden and antifungal consumption in Belgium. Further reduction in antifungals use can be achieved by applying the adequate treatment after identification of the causative agent.

A population-based analysis of attributable hospitalisation costs of invasive fungal diseases in haematological malignancy patients using data linkage of state-wide registry and costing databases: 2009-2015.

BACKGROUND: Invasive fungal diseases (IFD) are associated with significant treatment-related costs in patients with haematological malignancies (HM). OBJECTIVES: The objectives of this study were to characterise the gross and attributable hospitalisation costs of a variety of IFD in patients with HM by linking state-wide hospital administrative and costing datasets. PATIENTS/METHODS: We linked the Victorian Admitted Episodes Dataset, Victorian Cancer Registry and the Victorian Cost Data Collection from 1 July 2009 to 30 June 2015. IFD cases and uninfected controls were matched 1:1 based on age within ten years, same underlying HM and length of stay prior to IFD diagnosis. The cost difference between surviving cases and controls, indexed to 2019 Australian dollars (AUD) calculated twelve months from IFD diagnosis, was determined using Poisson and negative binomial regression (NBR). RESULTS: From 334 matched pairs, the gross hospitalisation cost of cases was AUD$67 277 compared to AUD$51 158 among uninfected controls, associated with an excess median hospitalisation cost of AUD$16 119 (P < .001) attributable to IFD, approximating to USD$11 362 and €10 154 at purchasing power parity. Median attributable costs were highest for patients with invasive aspergillosis (AUD$55 642; P < .001) and mucormycosis (AUD$51 272; P = .043) followed by invasive candidiasis AUD$24 572 (P < .001). No change in median excess attributable costs was observed over the study period (P = .90) Analyses by NBR revealed a 1.36-fold increase (P < .001) in total hospitalisation costs among cases as compared to controls twelve months from IFD diagnosis. CONCLUSION: Invasive aspergillosis and mucormycosis have high attributable hospitalisation costs but the overall excess IFD cost of AUD$16 119 is modest, potentially reflecting missed or miscoded fungal episodes arguing for better quality surveillance data at hospital level.

Cost-Benefit and Cost-Utility Analysis of Amphotericin B Supplementation of Corneal Storage Media With Endothelial Keratoplasty-Prepared Tissue.

PURPOSE: To determine the cost-effectiveness of amphotericin B supplementation, we analyzed both current costs to treat postendothelial keratoplasty (EK) fungal infections and potential costs associated with amphotericin B supplementation. METHODS: We collected 19 US cases of post-EK fungal eye infections from the published literature and assessed the associated costs from the literature. A survey of surgeons was also conducted with questions regarding their experiences in managing these infections. RESULTS: We estimated that the costs to diagnose, manage, and treat post-EK fungal keratitis and post-EK fungal endophthalmitis are USD $21,113 and $34,850, respectively. The largest portion of the costs can be attributed to the need for additional surgical management, which is required in 79% of the cases. We estimated the total cost of amphotericin B supplementation to be $44.39 per graft with use of conventional amphotericin B and conservative assumptions regarding supplementation processes. Cost-effectiveness analysis demonstrated that amphotericin B supplementation is cost-effective at $100,000 per quality-adjusted life-year level only if amphotericin B supplementation can prevent more than 69.62% of post-EK fungal infections, assuming the incidence of post-EK fungal infection remains at the level it was between 2012 and 2017. CONCLUSIONS: We found that amphotericin B supplementation can be cost-effective under conservative assumptions if it is moderately effective in preventing post-EK fungal infections.

Estimation of Direct Healthcare Costs of Fungal Diseases in the United States.

BACKGROUND: Fungal diseases range from relatively-minor superficial and mucosal infections to severe, life-threatening systemic infections. Delayed diagnosis and treatment can lead to poor patient outcomes and high medical costs. The overall burden of fungal diseases in the United States is challenging to quantify, because they are likely substantially underdiagnosed. METHODS: To estimate the total, national, direct medical costs associated with fungal diseases from a healthcare payer perspective, we used insurance claims data from the Truven Health MarketScan 2014 Research Databases, combined with hospital discharge data from the 2014 Healthcare Cost and Utilization Project National Inpatient Sample and outpatient visit data from the 2005-2014 National Ambulatory Medical Care Survey and the National Hospital Ambulatory Medical Care Survey. All costs were adjusted to 2017 dollars. RESULTS: We estimate that fungal diseases cost more than $7.2 billion in 2017, including $4.5 billion from 75055 hospitalizations and $2.6 billion from 8993230 outpatient visits. Hospitalizations for Candida infections (n = 26735, total cost $1.4 billion) and Aspergillus infections (n = 14820, total cost $1.2 billion) accounted for the highest total hospitalization costs of any disease. Over half of outpatient visits were for dermatophyte infections (4981444 visits, total cost $802 million), and 3639037 visits occurred for non-invasive candidiasis (total cost $1.6 billion). CONCLUSIONS: Fungal diseases impose a considerable economic burden on the healthcare system. Our results likely underestimate their true costs, because they are underdiagnosed. More comprehensive estimates of the public health impact of these diseases are needed to improve their recognition, prevention, diagnosis, and treatment.

The socio-economic impact of multidrug-resistant nosocomial infections: a qualitative study.

The burden of healthcare-associated infections (HCAIs) has traditionally been measured using clinical and economic outcomes. We conducted semi-structured interviews with 18 patients or their caregivers affected by HCAI caused by multidrug-resistant organisms to better understand the human impact of HCAI. Most patients had misconceptions about HCAI and antimicrobial resistance, leading to strong negative feelings towards HCAIs despite positive views of their healthcare providers. Communication issues across power imbalances need to be addressed to help deal with trauma of HCAIs. A holistic approach to HCAIs incorporating patient perspectives will likely help guide policymakers developing solutions to improve patient outcomes.

Cost-effectiveness of posaconazole in private and public Brazilian hospitals.

BACKGROUND: Posaconazole is used for the prophylaxis of invasive fungal disease (IFD). Previous studies have shown it to be cost-effective compared to fluconazole/itraconazole. However, posaconazole has never been economically evaluated in developing countries. AIMS: The aim of the present study was to perform a cost-effectiveness analysis of posaconazole compared to fluconazole in public (SUS) and private hospitals (PHS) in Brazil. METHODS: A cost-effectiveness simulation was conducted on the basis of a pivotal study on the use of posaconazole in acute myeloid leukemia (AML) patients, adjusting the costs to Brazilian data. RESULTS: A pharmacoeconomic analysis was performed on a hypothetical sample of 100 patients in each drug group. The total cost of posaconazole use alone was USD$ 220,656.31, whereas that for fluconazole was USD$ 83,875.00. Our results showed that patients with IFD remain hospitalized for an additional 12 days, at an average cost of USD$ 850.85 per patient per day. The total money spent by PHS for 100 patients for 100 days was USD$ 342,318.00 for the posaconazole group and USD$ 302,039.00 for the fluconazole group. An analysis of sensitivity (10%) revealed no intergroup difference. CONCLUSIONS: In Brazil posaconazole is cost-effective, and should be considered for the prophylaxis of patients with AMD/myelodysplasia (AML/MDS) undergoing chemotherapy.

An investigation of operative outcomes: Pediatric invasive fungal sinusitis.

OBJECTIVES/HYPOTHESIS: Invasive fungal sinusitis is an uncommon entity among children. Early recognition is crucial for facilitating successful treatment with minimal morbidity. The goal of this analysis was to identify patient characteristics associated with high-risk surgical disease through a population-based examination into this rare and deadly disease process. METHODS: A retrospective chart review of the 2009 and 2012 Kids' Inpatient Database (KID) was conducted. A series of queries (Fungal infection→immunocompromised diagnosis→sinus procedure) identified 102 patients with likely invasive fungal sinusitis. Outcomes included: species, invasive extension, death, and other clinical characteristics. RESULTS: Patients with leukemia/lymphoma constituted 90.2% of individuals evaluated in this analysis. Nearly a quarter of pediatric patients receiving surgical treatment for invasive fungal sinusitis died during their hospital stay -24.9%. Aspergillus was the most commonly recorded mycotic species. Average hospital stay was 59.3 days, and associated hospital costs averaged $746,299 per stay. Patients 0-5 years old were more likely to have orbital involvement -56.3%. Brain extension was noted in 33.7% of this cohort as well. Mucormycosis was an independent predictor of death (p = 0.03), with an odds ratio of 3.835. CONCLUSION: To the best of our knowledge, this is the largest pediatric cohort with invasive fungal sinusitis in the literature. Patient demographics, cytology, and disease extension offer predictive information regarding patient outcomes for invasive fungal sinusitis. A high clinical suspicion and early treatment may decrease the lengthy and costly hospitalizations in this population.

Estimating the burden of invasive and serious fungal disease in the United Kingdom.

BACKGROUND: The burden of fungal disease in the UK is unknown. Only limited data are systematically collected. We have estimated the annual burden of invasive and serious fungal disease. METHODS: We used several estimation approaches. We searched and assessed published estimates of incidence, prevalence or burden of specific conditions in various high risk groups. Studies with adequate internal and external validity allowed extrapolation to estimate current UK burden. For conditions without adequate published estimates, we sought expert advice. RESULTS: The UK population in 2011 was 63,182,000 with 18% aged under 15 and 16% over 65. The following annual burden estimates were calculated: invasive candidiasis 5142; Candida peritonitis complicating chronic ambulatory peritoneal dialysis 88; Pneumocystis pneumonia 207-587 cases, invasive aspergillosis (IA), excluding critical care patients 2901-2912, and IA in critical care patients 387-1345 patients, <100 cryptococcal meningitis cases. We estimated 178,000 (50,000-250,000) allergic bronchopulmonary aspergillosis cases in people with asthma, and 873 adults and 278 children with cystic fibrosis. Chronic pulmonary aspergillosis is estimated to affect 3600 patients, based on burden estimates post tuberculosis and in sarcoidosis. CONCLUSIONS: Uncertainty is intrinsic to most burden estimates due to diagnostic limitations, lack of national surveillance systems, few published studies and methodological limitations. The largest uncertainty surrounds IA in critical care patients. Further research is needed to produce a more robust estimate of total burden.

Healthcare costs of urinary tract infections and genital mycotic infections among patients with type 2 diabetes mellitus initiated on canagliflozin: a retrospective cohort study.

OBJECTIVE: To assess the economic impact of urinary tract infections (UTIs) and genital mycotic infections (GMIs) among patients with type 2 diabetes mellitus (T2DM) initiated on canagliflozin. METHODS: Administrative claims data from April 2013 through June 2014 MarketScan® databases were extracted. Adults with ≥1 claim for canagliflozin, T2DM diagnosis, and ≥90 days enrollment before and after canagliflozin initiation were propensity score matched to controls with T2DM initiated on other anti-hyperglycemic agents (AHAs). UTI and GMI healthcare costs were evaluated 90-days post-index and reported as cohort means. RESULTS: Rates of UTI claims 90 days post-index were similar in patients receiving canagliflozin for T2DM (n = 31,257) and matched controls (2.7% vs 2.8%, p = .677). More canagliflozin than control patients had GMI claims (1.2% vs 0.6%, p < .001) and antifungal utilization (5.3% vs 2.6%, p < .001). Mean post-index costs to treat UTIs were lower but not significantly different for canagliflozin patients vs matched controls ($27.61 vs $37.33, p = .150). GMI treatment costs were higher for the canagliflozin cohort ($3.68 vs $2.44, p = .041). Combined costs to treat either UTI and/or GMI averaged $31.29 per patient for the canagliflozin cohort v $39.77 for controls (p = .211). Rates and costs of UTIs and GMIs were higher for females than males, but the canagliflozin vs control trends observed for the overall sample were similar for both sexes. There were no significant cost differences between the canagliflozin and control cohorts among patients aged 18-64. Among patients aged 65 and above, GMI treatment costs were not significantly different, but costs to treat UTIs and either UTI and/or GMI were significantly lower for canagliflozin patients vs controls. CONCLUSIONS: In a real-world setting, the costs to payers of treating UTIs and GMIs are generally similar for patients with T2DM initiated on canagliflozin vs other AHAs.

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.

Hospital resource use of patients receiving isavuconazole vs voriconazole for invasive mold infections in the phase III SECURE trial.

OBJECTIVE: In the phase III SECURE trial, isavuconazole was non-inferior to voriconazole for all-cause mortality for the primary treatment of invasive mold disease (IMD) caused by Aspergillus spp. and other filamentous fungi. This analysis assessed whether hospital resource utilization was different between patients treated with isavuconazole vs voriconazole in SECURE. METHODS: The analysis population comprised adults with proven/probable/possible IMD enrolled in SECURE. The primary endpoint was hospital length of stay (LOS) in the overall trial population. Patients were also stratified by estimated glomerular filtration rate-modification of diet in renal disease category (< 60 mL/min/1.73 m(2) [moderate-to-severe impairment] and ≥60 mL/min/1.73 m(2) [mild or no impairment]), body mass index (BMI; <25, ≥25-<30, and ≥30 kg/m(2)), and age (≤45, >45-≤65, and >65 years). RESULTS: Data from 516 patients (258 per arm) were evaluated. Overall, median LOS was not statistically significantly different between the isavuconazole (15.0 days) and voriconazole (16.0 days; p = 0.607) arms. Median LOS was statistically significantly shorter in patients with moderate-to-severe renal impairment treated with isavuconazole (9.0 days) vs voriconazole (19.0 days; hazard ratio [HR]: 3.44; 95% confidence interval [CI] = 1.51-7.83). Median LOS was shorter, but not significantly, in patients with a BMI ≥30 kg/m(2) (isavuconazole 13.5 days vs voriconazole 22 days; HR = 1.57; 95% CI = 0.70-3.52) or aged >65 years (isavuconazole 15.0 days vs voriconazole 20.0 days; HR = 1.37; 95% CI = 0.87-2.16). LIMITATIONS: As the patient subgroups analyzed were small, sub-group findings should be interpreted with caution in light of the lack of statistical significance for each sub-group-by-treatment interaction. CONCLUSIONS: Isavuconazole may reduce hospital LOS in certain subgroups of patients with IMD, especially those with moderate-to-severe renal impairment.

Network Meta-analysis and Pharmacoeconomic Evaluation of Fluconazole, Itraconazole, Posaconazole, and Voriconazole in Invasive Fungal Infection Prophylaxis.

Invasive fungal infections (IFIs) are associated with high mortality rates and large economic burdens. Triazole prophylaxis is used for at-risk patients with hematological malignancies or stem cell transplants. We evaluated both the efficacy and the cost-effectiveness of triazole prophylaxis. A network meta-analysis (NMA) of randomized controlled trials (RCTs) evaluating fluconazole, itraconazole capsule and solution, posaconazole, and voriconazole was conducted. The outcomes of interest included the incidences of IFIs and deaths. This was coupled with a cost-effectiveness analysis from patient perspective over a lifetime horizon. Probabilities of transitions between health states were derived from the NMA. Resource use and costs were obtained from the Singapore health care institution. Data on 5,505 participants in 21 RCTs were included. Other than itraconazole capsule, all triazole antifungals were effective in reducing IFIs. Posaconazole was better than fluconazole (odds ratio [OR], 0.35 [95% confidence interval [CI], 0.16 to 0.73]) and itraconazole capsule (OR, 0.25 [95% CI, 0.06 to 0.97]), but not voriconazole (OR, 1.31 [95% CI, 0.43 to 4.01]), in preventing IFIs. Posaconazole significantly reduced all-cause deaths, compared to placebo, fluconazole, and itraconazole solution (OR, 0.49 to 0.54 [95% CI, 0.28 to 0.88]). The incremental cost-effectiveness ratio for itraconazole solution was lower than that for posaconazole (Singapore dollars [SGD] 12,546 versus SGD 26,817 per IFI avoided and SGD 5,844 versus SGD 12,423 per LY saved) for transplant patients. For leukemia patients, itraconazole solution was the dominant strategy. Voriconazole was dominated by posaconazole. All triazole antifungals except itraconazole capsule were effective in preventing IFIs. Posaconazole was more efficacious in reducing IFIs and all-cause deaths than were fluconazole and itraconazole. Both itraconazole solution and posaconazole were cost-effective in the Singapore health care setting.

Analysis of the efficiency and costs of antifungal prophylaxis and mycological diagnostics in patients undergoing allogeneic haematopoietic cell transplantation: "real life" evaluation.

Antifungal prophylaxis/therapy (AP/AT) raises the cost of allogeneic haematopoietic cell transplantation (alloHCT). Its efficacy, different approaches for AP/AT, diagnostic measures and cost-effectiveness must still be evaluated. In 2010, we conducted a prospective study with 106 consecutive patients receiving an alloHCT analysing AP/AT, choice and costs of diagnostics applied including CT scans, galactomannan (Gal) and ß-D-glucan (ß-D) testing. Antifungal prophylaxis in 91 patients consisted of fluconazole (FLU) or L-AMB (AmBisome™ 1 or 3 mg/kg/day b.w.), and antifungal therapy had to be initiated in 38 % of the FLU/L-AMB-1-mg patients but in none with L-AMB 3 mg. Empirical AT consisted of L-AMB 1 mg/kg (n = 12) and preemptive AT of L-AMB 3 mg/kg (n = 17) and proved very efficacious with no further antifungal drug escalation in 89.6 %. Mean costs of diagnostic measures were 402 €/alloHCT; however, only 22 % of the CT scans, 4 % of ß-D and 3 % of galactomannan testing were positive. We detected one proven, 17 probable and 14 possible fungal infections. Due to the German diagnosis-related group system with additional compensation, all our AP/AT strategies were adequately reimbursed. While clinical symptoms and CT scans are the most commonly used, inexpensive decision-making tools for starting AT, the expensive laboratory diagnostic procedures are ineffective; we have therefore discontinued regular GAL/ß-D testing and changed our AP in patients at risk.

The burden of serious human fungal infections in Brazil.

In Brazil, human fungal infections are prevalent, however, these conditions are not officially reportable diseases. To estimate the burden of serious fungal diseases in 1 year in Brazil, based on available data and published literature. Historical official data from fungal diseases were collected from Brazilian Unified Health System Informatics Department (DATASUS). For fungal diseases for which no official data were available, assumptions of frequencies were made by estimating based on published literature. The incidence (/1000) of hospital admissions for coccidioidomycosis was 7.12; for histoplasmosis, 2.19; and for paracoccidioidomycosis, 7.99. The estimated number of cryptococcal meningoencephalitis cases was 6832. Also, there were 4115 cases of Pneumocystis pneumonia in AIDS patients per year, 1 010 465 aspergillosis and 2 981 416 cases of serious Candida infections, including invasive and non-invasive diseases. In this study, we demonstrate that more than 3.8 million individuals in Brazil may be suffering from serious fungal infections, mostly patients with malignant cancers, transplant recipients, asthma, previous tuberculosis, HIV infection and those living in endemic areas for truly pathogenic fungi. The scientific community and the governmental agencies should work in close collaboration in order to reduce the burden of such complex, difficult-to-diagnose and hard to treat diseases.

Meta-Analysis and Cost Comparison of Empirical versus Pre-Emptive Antifungal Strategies in Hematologic Malignancy Patients with High-Risk Febrile Neutropenia.

BACKGROUND: Invasive fungal disease (IFD) causes significant morbidity and mortality in hematologic malignancy patients with high-risk febrile neutropenia (FN). These patients therefore often receive empirical antifungal therapy. Diagnostic test-guided pre-emptive antifungal therapy has been evaluated as an alternative treatment strategy in these patients. METHODS: We conducted an electronic search for literature comparing empirical versus pre-emptive antifungal strategies in FN among adult hematologic malignancy patients. We systematically reviewed 9 studies, including randomized-controlled trials, cohort studies, and feasibility studies. Random and fixed-effect models were used to generate pooled relative risk estimates of IFD detection, IFD-related mortality, overall mortality, and rates and duration of antifungal therapy. Heterogeneity was measured via Cochran's Q test, I2 statistic, and between study τ2. Incorporating these parameters and direct costs of drugs and diagnostic testing, we constructed a comparative costing model for the two strategies. We conducted probabilistic sensitivity analysis on pooled estimates and one-way sensitivity analyses on other key parameters with uncertain estimates. RESULTS: Nine published studies met inclusion criteria. Compared to empirical antifungal therapy, pre-emptive strategies were associated with significantly lower antifungal exposure (RR 0.48, 95% CI 0.27-0.85) and duration without an increase in IFD-related mortality (RR 0.82, 95% CI 0.36-1.87) or overall mortality (RR 0.95, 95% CI 0.46-1.99). The pre-emptive strategy cost $324 less (95% credible interval -$291.88 to $418.65 pre-emptive compared to empirical) than the empirical approach per FN episode. However, the cost difference was influenced by relatively small changes in costs of antifungal therapy and diagnostic testing. CONCLUSIONS: Compared to empirical antifungal therapy, pre-emptive antifungal therapy in patients with high-risk FN may decrease antifungal use without increasing mortality. We demonstrate a state of economic equipoise between empirical and diagnostic-directed pre-emptive antifungal treatment strategies, influenced by small changes in cost of antifungal therapy and diagnostic testing, in the current literature. This work emphasizes the need for optimization of existing fungal diagnostic strategies, development of more efficient diagnostic strategies, and less toxic and more cost-effective antifungals.