Paving the way for affordable and equitable liposomal amphotericin B access worldwide.

Amphotericin B has long been crucial for treating many serious infectious diseases, such as invasive fungal infections and visceral leishmaniasis, particularly for patients who are immunocompromised, including those with advanced HIV infection. The conventional amphotericin B deoxycholate formulation has largely been replaced in high-income countries with liposomal amphotericin B (LAmB), which has many advantages, including lower rates of adverse events, such as nephrotoxicity and anaemia. Despite an evident need for LAmB in low-income and middle-income countries, where mortality from invasive fungal infections is still substantial, many low-income and middle-income countries still often use the amphotericin B deoxycholate formulation because of a small number of generic formulations and the high price of the originator LAmB. The pricing of LAmB is also highly variable between countries. Overcoming supply barriers through the availability of additional quality-assured, generic formulations of LAmB at accessible prices would substantially facilitate equitable access and have a substantial effect on mortality attributable to deadly fungal infections.

Impact of new antifungal medications on onychomycosis prescriptions and costs in Japan: A nationwide claims database study.

Onychomycosis, a fungal nail infection, is a common dermatological condition in Japan, with a prevalence of approximately 5%-10%. Despite the introduction of new antifungal medications and updated treatment guidelines published in 2019, data on real-world prescription trends and the associated medical costs are limited. This study aimed to investigate the prescription patterns and medical costs of topical and oral antifungal medications for onychomycosis in Japan from fiscal years 2014 to 2021 using the National Database of Health Insurance Claims and Specific Health Checkups of Japan Open Data. We analyzed the annual prescription volumes and medical costs of four antifungal medications: efinaconazole, luliconazole, fosravuconazole, and terbinafine. The prescription volume of efinaconazole, a topical medication launched in 2014, rapidly increased and dominated the market share. Fosravuconazole, an oral medication introduced in 2018, showed an increasing trend, coinciding with a decline in efinaconazole prescriptions. Terbinafine, a well-established oral medication, experienced a substantial decrease in prescription volume. The sex- and age-adjusted prescription volume per 100 000 population was higher among older adults, particularly for efinaconazole. The total medical costs for onychomycosis treatment more than doubled in fiscal year 2015 compared with that for 2014, mainly driven by efinaconazole prescriptions, and exceeded 30 billion Japanese yen in fiscal years 2019-2021. The costs slightly decreased in fiscal years 2020 and 2021, possibly due to the introduction of fosravuconazole. The predominance of topical prescriptions, especially in older adults, raises concerns regarding adherence to the Japanese guidelines that recommend oral antifungals as the first-line treatment for onychomycosis. The substantial increase in medical costs also highlights the economic burden of onychomycosis and the need for cost-effective treatment strategies. This study provides valuable insights into the real-world prescription trends and medical costs of onychomycosis treatment in Japan, suggesting an opportunity to assess potential gaps between guideline recommendations and clinical practice.

Biomarker Driven Antifungal Stewardship (BioDriveAFS) in acute leukaemia-a multi-centre randomised controlled trial to assess clinical and cost effectiveness: a study protocol for a randomised controlled trial.

BACKGROUND: Acute leukaemias (AL) are life-threatening blood cancers that can be potentially cured with treatment involving myelosuppressive, multiagent, intensive chemotherapy (IC). However, such treatment is associated with a risk of serious infection, in particular invasive fungal infection (IFI) associated with prolonged neutropenia. Current practice guidelines recommend primary antifungal (AF) prophylaxis to be administered to high-risk patients to reduce IFI incidence. AFs are also used empirically to manage prolonged neutropenic fever. Current strategies lead to substantial overuse of AFs. Galactomannan (GM) and ß-D-glucan (BG) biomarkers are also used to diagnose IFI. Combining both biomarkers may enhance the predictability of IFI compared to administering each test alone. Currently, no large-scale randomised controlled trial (RCT) has directly compared a biomarker-based diagnostic screening strategy without AF prophylaxis to AF prophylaxis (without systematic biomarker testing). METHODS: BioDriveAFS is a multicentre, parallel, two-arm RCT of 404 participants from UK NHS Haematology departments. Participants will be allocated on a 1:1 basis to receive either a biomarker-based antifungal stewardship (AFS) strategy, or a prophylactic AF strategy, which includes existing standard of care (SoC). The co-primary outcomes will be AF exposure in the 12-month post randomisation and the patient-reported EQ-5D-5L measured at 12-month post randomisation. Secondary outcomes will include total AF exposure, probable/proven IFI, survival (all-cause mortality and IFI mortality), IFI treatment outcome, AF-associated adverse effects/events/complications, resource use, episodes of neutropenic fever requiring hospital admission or outpatient management, AF resistance in fungi (non-invasive and invasive) and a Desirability of Outcome Ranking. The trial will have an internal pilot phase during the first 9 months. A mixed methods process evaluation will be integrated in parallel to the internal pilot phase and full trial, aiming to robustly assess how the intervention is delivered. Cost-effectiveness analysis will also be performed. DISCUSSION: The BioDriveAFS trial aims to further the knowledge of strategies that will safely optimise AF use through comparison of the clinical and cost-effectiveness of a biomarker-led diagnostic strategy versus prophylactic AF to prevent and manage IFI within acute leukaemia. The evidence generated from the study will help inform global clinical practice and approaches within antifungal stewardship. TRIAL REGISTRATION: ISRCTN11633399. Registered 24/06/2022.

A cost-effectiveness analysis of the use of oral ibrexafungerp versus fluconazole for acute vulvovaginal candidiasis in the UK NHS primary care service.

BACKGROUND: Vulvovaginal Candidiasis (VVC) is a fungal infection causing inflammation of the vagina and/or the vulva. Symptoms include itching, irritation, and discharge. VVC presents commonly across primary care and, despite its mild symptoms, carries psychological burden and has a significant impact on women's quality of life. UK guidelines support treatment via oral or topical azole antifungal agents. Recent evidence attests to the superiority of novel non-azole antifungals. Thus, rigorous financial assessment of both antifungals is necessary for optimal VVC treatment allocation in UK primary care. AIM: To evaluate the cost-effectiveness of ibrexafungerp against the gold standard fluconazole as first-line treatment of VVC within the NHS. METHOD: A systematic review on the efficacy of ibrexafungerp and fluconazole in acute VVC was conducted. Cost-effectiveness analysis was initiated using health outcome data from the DOVE trial, a Phase 2 RCT. Costs in pound sterling were ascertained in monetary units, and effectiveness determined as reduced need for follow-up medication. RESULTS: An incremental cost-effectiveness ratio of £2185.74 was determined. This suggests oral ibrexafungerp being largely more costly yet slightly more effective than fluconazole, and thus has unfavourable net benefit. Two sensitivity analyses were conducted considering follow-up medication combination and market price, which provided confidence in the calculated cost-effectiveness ratio. CONCLUSION: This analysis highlights fluconazole's cost-effectiveness in current UK guidelines and favourability.

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.

Reimbursement of innovative pharmaceuticals in English and Spanish hospitals-The example of isavuconazole.

BACKGROUND: Kron et al (Mycoses, 64, 2021, 86) found cost savings for the use of the innovative pharmaceutical isavuconazole in the inpatient setting in Germany (Bismarck-based healthcare system). Little is known about the reimbursement of innovative pharmaceuticals in the inpatient setting of Beveridge-based healthcare systems. OBJECTIVES: The aim of this study was to evaluate the market access process and reimbursement of isavuconazole, exemplary for innovative pharmaceuticals, in England and Spain. PATIENTS/METHODS: Market access processes of both countries were described. Focussing on typical patient clusters for isavuconazole treatment, reimbursement data regarding inpatients with (i) allogeneic haematopoietic stem cell transplantation or (ii) acute myeloid leukaemia was considered. Data were publicly available and of high topicality (England 2020/2021, Spain 2018). Discounting and a currency conversion to Euro were applied. RESULTS: This study showed that market access processes of both countries are broadly similar. Further, full reimbursement of isavuconazole as an innovative pharmaceutical may lead to reduction in resource utilisation. Without medication costs, isavuconazole can thus result in cost savings for both patient clusters due to a reduction in length of stay. CONCLUSIONS: Expenses for innovative pharmaceuticals may be balanced or even lead to cost savings due to a reduction in length of stay. The latter contributes to a greater patient benefit. For both healthcare system, the analyses highlighted drugs' cost-effectiveness and assessing its added value into reimbursement decisions is highly relevant.

The cost-effectiveness of isavuconazole compared to voriconazole, the standard of care in the treatment of patients with invasive mould diseases, prior to differential pathogen diagnosis in Spain.

BACKGROUND: Invasive mould diseases are associated with high morbidity, mortality and economic impact. Its treatment is often started prior to differential pathogen diagnosis. Isavuconazole is approved for treatment of invasive aspergillosis (IA) and invasive mucormycosis (IM) when amphotericin-B is not indicated. OBJECTIVES: To estimate the cost-effectiveness of isavuconazole vs voriconazole for the treatment of adult patients with possible IA prior to differential pathogen diagnosis, in Spain. METHODS: A decision tree analysis was performed using the Spanish Healthcare System perspective. Among all patients with possible IA, it was considered that 7.81% actually had IM. Costs for laboratory analysis, management of adverse events, hospitalisation and drugs per patient, deaths and long-term effects in life years (LYs) and quality-adjusted LYs (QALYs) were considered. Efficacy data were obtained from clinical trials and utilities from the literature. Deterministic and probabilistic sensitivity analyses (PSA) were conducted. RESULTS: In patients with possible IA and when compared to voricanozole, isavuconazole showed an incremental cost of 4758.53€, besides an incremental effectiveness of +0.49 LYs and +0.41 QALYs per patient. The Incremental Cost Effectiveness Ratio was 9622.52€ per LY gained and 11,734.79€ per QALY gained. The higher cost of isavuconazole was due to drug acquisition. Main parameters influencing results were mortality, treatment duration and hospitalisation days. The PSA results showed that isavuconazole has a probability of being cost-effective of 67.34%, being dominant in 24.00% of cases. CONCLUSIONS: Isavuconazole is a cost-effective treatment compared to voriconazole for patients with possible IA for a willingness to pay threshold of 25,000€ per additional QALY.

Oral versus intra-vaginal imidazole and triazole anti-fungal treatment of uncomplicated vulvovaginal candidiasis (thrush).

BACKGROUND: Anti-fungals are available for oral and intra-vaginal treatment of uncomplicated vulvovaginal candidiasis. OBJECTIVES: The primary objective of this review is to assess the relative effectiveness (clinical cure) of oral versus intra-vaginal anti-fungals for the treatment of uncomplicated vulvovaginal candidiasis. Secondary objectives include the assessment of the relative effectiveness in terms of mycological cure, in addition to safety, side effects, treatment preference, time to first relief of symptoms, and costs. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, and two trials registers on 29 August 2019 together with reference checking and citation searching. SELECTION CRITERIA: We included randomised controlled trials published in any language comparing at least one oral anti-fungal with one intra-vaginal anti-fungal in women (aged 16 years or over) with a mycological diagnosis (positive culture, microscopy for yeast, or both) of uncomplicated vulvovaginal candidiasis. We excluded trials if they solely involved participants who were HIV positive, immunocompromised, pregnant, breast feeding or diabetic. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures as recommended by Cochrane. MAIN RESULTS: This review includes 26 trials (5007 participants). Eight anti-fungals are represented. All but three trials included participants with acute vulvovaginal candidiasis. Trials were conducted in Europe: UK (3), Croatia (2). Finland (2), the Netherlands (2), Germany (1), Italy (1), Sweden (1) and one trial across multiple European countries, USA (7) Thailand (2), Iran (2), Japan (1) and Africa (Nigeria) (1). The duration of follow-up varied between trials. The overall risk of bias of the included trials was high. There was probably little or no difference shown between oral and intra-vaginal anti-fungal treatment for clinical cure at short-term follow-up (OR 1.14, 95% CI 0.91 to 1.43; 13 trials; 1859 participants; moderate-certainty evidence) and long-term follow-up (OR 1.07, 95% CI 0.77 to 1.50; 9 trials; 1042 participants; moderate-certainty evidence). The evidence suggests that if the rate of clinical cure at short-term follow-up with intra-vaginal treatment is 77%, the rate with oral treatment would be between 75% and 83%; if the rate of clinical cure at long term follow-up with intra-vaginal treatment is 84%, the rate with oral treatment would be between 80% and 89%. Oral treatment probably improves mycological cure over intra-vaginal treatment at short term (OR 1.24, 95% CI 1.03 to 1.50: 19 trials; 3057 participants; moderate-certainty evidence) and long-term follow-up (OR 1.29, 95% CI 1.05 to 1.60; 13 trials; 1661 participants; moderate-certainty evidence). The evidence suggests that if the rate of mycological cure at short-term follow-up with intra-vaginal treatment is 80%, the rate with oral treatment would be between 80% and 85%; if the rate of mycological cure at long-term follow-up with intra-vaginal treatment is 66%, the rate with oral treatment would be between 67% and 76%. In terms of patient safety, there is a low risk of participants withdrawing from the studies due to adverse drug effects for either treatment (23 trials; 4637 participants; high-certainty evidence). Due to the low certainty of evidence, it is undetermined whether oral treatments reduced the number of side effects compared with intra-vaginal treatments (OR 1.04, 95% CI 0.84 to 1.29; 16 trials; 3155 participants; low-certainty evidence). The evidence suggests that if the rate of side effects with intra-vaginal treatment is 12%, the rate with oral treatment would be between 10% and 15%. We noted that the type of side effects differed, with intra-vaginal treatments being more often associated with local reactions, and oral treatments being more often associated with systemic effects including gastro-intestinal symptoms and headaches. Oral treatment appeared to be the favoured treatment preference over intra-vaginal treatment or no preference (12 trials; 2206 participants), however the data were poorly reported and the certainty of the evidence was low. There was little or no difference in time to first relief of symptoms between oral and intra-vaginal treatments: four trials favoured the oral treatment, four favoured intra-vaginal, one study reported no difference and one was unclear. The measurements varied between the 10 trials (1910 participants) and the certainty of the evidence was low. Costs were not reported in any of the trials. AUTHORS' CONCLUSIONS: Oral anti-fungal treatment probably improves short- and long-term mycological cure over intra-vaginal treatment for uncomplicated vaginal candidiasis. Oral treatment was the favoured treatment preference by participants, though the certainty of this evidence is low. The decision to prescribe or recommend an anti-fungal for oral or intra-vaginal administration should take into consideration safety in terms of withdrawals and side effects, as well as cost and treatment preference. Unless there is a previous history of adverse reaction to one route of administration or contraindications, women who are purchasing their own treatment should be given full information about the characteristics and costs of treatment to make their own decision. If health services are paying the treatment cost, decision-makers should consider whether the higher cost of some oral anti-fungals is worth the gain in convenience, if this is the patient's preference.

Trends of Antifungal Use Based on Sales Data in Japan from 2006 to 2015.

The detailed epidemiology of invasive mycoses and superficial mycoses has not been clarified in Japan. In addition, treatment options have increased because of novel antifungals and/or guidelines for fungal infection. In the present study, we aimed to clarify the trends of antifungal use in Japan from 2006 to 2015 based on sales data to serve as an alternative indicator of fungal infection trends. We found that the total antifungal use decreased over time (r = -0.057, Pfor trend < 0.0001). Oral and parenteral use significantly decreased by 44.1% (r = -0.056, Pfor trend < 0.0001) and 27.1% (r = -0.0012, Pfor trend = 0.00061), respectively. The trend of antifungal use for superficial mycoses significantly decreased by 49.8% (r = -0.061, Pfor trend < 0.0001). However, the trend of antifungal use for invasive mycoses was significantly increased by 19.9% (r = 0.0032, Pfor trend = 0.00045). In Japan, the increase in the number of immunocompromised patients might be associated with the increase in the frequency of antifungal use for invasive mycoses. This is the first study to clarify the trends of antifungal use in Japan. Further research is needed to establish a continuous surveillance system to compare fungal infections between Japan and the world.

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.

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

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

The cost-effectiveness of isavuconazole compared to the standard of care in the treatment of patients with invasive fungal infection prior to differential pathogen diagnosis in the United Kingdom.

Aims: To estimate the cost-effectiveness of isavuconazole compared with the standard of care, voriconazole, for the treatment of patients with invasive fungal infection disease when differential diagnosis of the causative pathogen has not yet been achieved at treatment initiation.Materials and methods: The economic model was developed from the perspective of the UK National Health Service (NHS) and used a decision-tree approach to reflect real-world treatment of patients with invasive fungal infection (IFI) prior to differential pathogen diagnosis. It was assumed that 7.8% of patients with IFI prior to differential pathogen diagnosis at treatment initiation actually had mucormycosis, and confirmation of pathogen identification was achieved for 50% of all patients during treatment. To extrapolate to a lifetime horizon, the model considered expected survival based on the patients' underlying condition. The model estimated the incremental costs (costs of drugs, laboratory analysis, hospitalization, and management of adverse events) and clinical outcomes (life-years (LYs) and quality-adjusted life-years (QALYs)) of first-line treatment with isavuconazole compared with voriconazole. The robustness of the results was assessed by conducting deterministic and probabilistic sensitivity analyses.Results: Isavuconazole delivered 0.48 more LYs and 0.39 more QALYs per patient at an incremental cost of £3,228, compared with voriconazole in the treatment of patients with IFI prior to differential pathogen diagnosis. This equates to an incremental cost-effectiveness ratio (ICER) of £8,242 per additional QALY gained and £6,759 per LY gained. These results were driven by a lack of efficacy of voriconazole in mucormycosis. Results were most sensitive to the mortality of IA patients and treatment durations.Conclusions: At a willingness to pay (WTP) threshold of £30,000 per additional QALY, the use of isavuconazole for the treatment of patients with IFI prior to differential pathogen diagnosis in the UK can be considered a cost-effective allocation of healthcare resources compared with voriconazole.

Fungal Lanosterol 14α-demethylase: A target for next-generation antifungal design.

The cytochrome P450 enzyme lanosterol 14α-demethylase (LDM) is the target of the azole antifungals used widely in medicine and agriculture as prophylaxis or treatments of infections or diseases caused by fungal pathogens. These drugs and agrochemicals contain an imidazole, triazole or tetrazole substituent, with one of the nitrogens in the azole ring coordinating as the sixth axial ligand to the LDM heme iron. Structural studies show that this membrane bound enzyme contains a relatively rigid ligand binding pocket comprised of a deeply buried heme-containing active site together with a substrate entry channel and putative product exit channel that reach to the membrane. Within the ligand binding pocket the azole antifungals have additional affinity determining interactions with hydrophobic side-chains, the polypeptide backbone and via water-mediated hydrogen bond networks. This review will describe the tools that can be used to identify and characterise the next generation of antifungals targeting LDM, with the goal of obtaining highly potent broad-spectrum fungicides that will be able to avoid target and drug efflux mediated antifungal resistance.

Cost-effectiveness of selective digestive decontamination (SDD) versus selective oropharyngeal decontamination (SOD) in intensive care units with low levels of antimicrobial resistance: an individual patient data meta-analysis.

OBJECTIVE: To determine the cost-effectiveness of selective digestive decontamination (SDD) as compared to selective oropharyngeal decontamination (SOD) in intensive care units (ICUs) with low levels of antimicrobial resistance. DESIGN: Post-hoc analysis of a previously performed individual patient data meta-analysis of two cluster-randomised cross-over trials. SETTING: 24 ICUs in the Netherlands. PARTICIPANTS: 12 952 ICU patients who were treated with ≥1 dose of SDD (n=6720) or SOD (n=6232). INTERVENTIONS: SDD versus SOD. PRIMARY AND SECONDARY OUTCOME MEASURES: The incremental cost-effectiveness ratio (ICER; ie, costs to prevent one in-hospital death) was calculated by comparing differences in direct healthcare costs and in-hospital mortality of patients treated with SDD versus SOD. A willingness-to-pay curve was plotted to reflect the probability of cost-effectiveness of SDD for a range of different values of maximum costs per prevented in-hospital death. RESULTS: The ICER resulting from the fixed-effect meta-analysis, adjusted for clustering and differences in baseline characteristics, showed that SDD significantly reduced in-hospital mortality (adjusted absolute risk reduction 0.0195, 95% CI 0.0050 to 0.0338) with no difference in costs (adjusted cost difference €62 in favour of SDD, 95% CI -€1079 to €935). Thus, SDD yielded significantly lower in-hospital mortality and comparable costs as compared with SOD. At a willingness-to-pay value of €33 633 per one prevented in-hospital death, SDD had a probability of 90.0% to be cost-effective as compared with SOD. CONCLUSION: In Dutch ICUs, SDD has a very high probability of cost-effectiveness as compared to SOD. These data support the implementation of SDD in settings with low levels of antimicrobial resistance.

Scalable and cost-effective tosylation-mediated synthesis of antifungal and fungal diagnostic 6″-Modified amphiphilic kanamycins.

Amphiphilic kanamycins bearing hydrophobic modifications at the 6″ position have attracted interest due to remarkable antibacterial-to-antifungal switches in bioactivity. In this report, we investigate a hurdle that hinders practical applications of these amphiphilic kanamycins: a cost-effective synthesis that allows the incorporation of various connecting functionalities to which the hydrophobic moieties are connected to the kanamycin core. A cost-effective tosylation enables various modifications at the 6″ position, which is scalable to a 90-g scale. The connecting functionalities, such as amine and thiol, were not the dominant factor for biological activity. Instead, the linear chain length played the decisive role. Amphiphilic kanamycin attached with tetradecyl (C14) or hexadecyl (C16) showed strong antifungal and modest antibacterial activities than with shorter chains (C6-C10). However, increases in chain length were closely correlated with an increase in HeLa cell toxicity. Thus, a compromise between the antimicrobial activities and cytotoxicities, for optimal efficacy of amphiphilic kanamycins may contain chain lengths between C8 and C12. Finally, the described synthetic protocol also allows the preparation of a fluorescent amphiphilic kanamycin selective toward fungi.