Outcomes by Candida spp. in the ReSTORE Phase 3 trial of rezafungin versus caspofungin for candidemia and/or invasive candidiasis.

Rezafungin is a long-acting, intravenously administered echinocandin for the treatment of candidemia and invasive candidiasis (IC). Non-inferiority of rezafungin vs caspofungin for the treatment of adults with candidemia and/or IC was demonstrated in the Phase 3 ReSTORE study based on the primary endpoints of day 14 global cure and 30-day all-cause mortality. Here, an analysis of ReSTORE data evaluating efficacy outcomes by baseline Candida species is described. Susceptibility testing was performed for Candida species using the Clinical and Laboratory Standards Institute reference broth microdilution method. There were 93 patients in the modified intent-to-treat population who received rezafungin; 94 received caspofungin. Baseline Candida species distribution was similar in the two treatment groups; C. albicans (occurring in 41.9% and 42.6% of patients in the rezafungin and caspofungin groups, respectively), C. glabrata (25.8% and 26.6%), and C. tropicalis (21.5% and 18.1%) were the most common pathogens. Rates of global cure and mycological eradication at day 14 and day 30 all-cause mortality by Candida species were comparable in the rezafungin and caspofungin treatment groups and did not appear to be impacted by minimal inhibitory concentration (MIC) values for either rezafungin or caspofungin. Two patients had baseline isolates with non-susceptible MIC values (both in the rezafungin group: one non-susceptible to rezafungin and one to caspofungin, classified as intermediate); both were candidemia-only patients in whom rezafungin treatment was successful based on the day 30 all-cause mortality endpoint. This analysis of ReSTORE demonstrated the efficacy of rezafungin for candidemia and IC in patients infected with a variety of Candida species.

Characterizing patients with rare mucormycosis infections using real-world data.

BACKGROUND: Invasive mucormycosis (IM) is a rare and often life-threatening fungal infection, for which clinical and epidemiological understanding is lacking. Electronic health record (EHR) data can be utilized to elucidate large populations of patients with IM to address this unmet need. This study aimed to descriptively assess data on patients with IM using the Optum® EHR dataset. METHODS: US patient data from the Optum® deidentified EHR dataset (2007-2019) were analyzed to identify patients with IM. Patients with hematologic malignancies (HM), at high risk of IM, were selected and sorted by IM diagnosis (ICD9 117.7; ICD10 B46). Demographics, comorbidities/other diagnoses, and treatments were analyzed in patients with IM. RESULTS: In total, 1133 patients with HM and IM were identified. Most were between 40 and 64 years of age, Caucasian, and from the Midwest. Essential primary hypertension (50.31%) was the most common comorbidity. Of the 1133 patients, only 33.72% were prescribed an antifungal treatment. The most common antifungal treatments were fluconazole (24.27%) and posaconazole (16.33%), which may have been prophylactic, and any AmB (15.62%). CONCLUSIONS: A large population of patients with IM were identified, highlighting the potential of analyzing EHR data to investigate epidemiology, diagnosis, and the treatment of apparently rare diseases.

Efficacy of Voriconazole, Isavuconazole, Fluconazole, and Anidulafungin in the Treatment of Emerging Candida auris Using an Immunocompromised Murine Model of Disseminated Candidiasis.

Antifungal activity of anidulafungin, voriconazole, isavuconazole, and fluconazole in the treatment of Candida auris was determined in vitro and in vivo. MICs for anidulafungin, voriconazole, isavuconazole, fluconazole, and amphotericin B were 0.5, 1, >64, 0.25, and 4 µg/ml, respectively. Significant in vivo efficacy was observed in the anidulafungin- and voriconazole-treated groups in survival and reduction in kidney tissue fungal burden compared to that in the untreated group (P values of <0.001 and 0.044, respectively). Our data showed that anidulafungin and voriconazole had comparable efficacies against C. auris, whereas isavuconazole did not show significant in vivo activity.

Clinical experience with isavuconazole in healthy volunteers and patients with invasive aspergillosis in China, and the results from an exposure-response analysis.

BACKGROUND: Isavuconazole is a broad-spectrum triazole for the treatment of invasive fungal disease (IFD). OBJECTIVE: To investigate the clinical experience with isavuconazole in Chinese individuals. PATIENTS/METHODS: Participants were Chinese healthy volunteers from a Phase I pharmacokinetics (PK) and safety study of single/multiple doses of isavuconazole (n = 36) and Chinese patients from the global Phase III SECURE study that assessed safety and efficacy of isavuconazole vs voriconazole for IFD treatment (n = 26). RESULTS: No clinically relevant differences in PK were found between Chinese and Western participants, although exposure was increased in Chinese volunteers. Treatment-emergent adverse events (TEAEs) were reported in 75.0% of healthy volunteers, many of which were infusion-related. No serious AEs were reported. In SECURE, findings in Chinese patients (n = 26) were similar to the global population. For patients who received ≥1 dose of study drug, allcause mortality from first dose to Day 42 was 10.0% (1/10) with isavuconazole and 25.0% (4/16) with voriconazole (treatment difference [95% confidence interval, CI]: -15.0% [-43.2%, 13.2%]). Overall response at the end of treatment for patients with proven/probable IFD was 25.0% and 16.7% with isavuconazole and voriconazole, respectively (treatment difference [95% CI] -8.3% [-60.2%, 43.5%]). Isavuconazole was associated with lower incidence of hepatobiliary, eye, skin, subcutaneous tissue and psychiatric disorders compared with voriconazole and lower incidence of treatment-related TEAEs, serious TEAES or death overall. CONCLUSIONS: Although further research is required, this study demonstrated a favourable risk-benefit profile of isavuconazole in Chinese patients.

Evaluation of anidulafungin in the treatment of intra-abdominal candidiasis: a pooled analysis of patient-level data from 5 prospective studies.

The incidence of nosocomial invasive fungal infections involving Candida spp. has increased markedly in recent years in patients undergoing abdominal surgery. This post hoc analysis aimed to determine the efficacy and safety of anidulafungin treatment in patients with intra-abdominal candidiasis (IAC) from five prospective studies (one comparative and four open-label) of adult surgical patients with microbiologically confirmed Candida intra-abdominal infection. Patients received an intravenous (IV) loading dose of anidulafungin 200 mg, followed by a daily 100-mg maintenance dose. Per study protocols, some patients could be switched to an oral azole after ≥ 5 or ≥ 10 days of IV treatment. Antifungal treatment was maintained for ≥ 14 days after the last positive Candida culture and resolution of symptoms. The global response rate (GRR) at the end of IV treatment (EOIVT) was the primary endpoint. GRR at the end of therapy (EOT), all-cause mortality at days 14 and 28, and safety was also evaluated. Seventy-nine patients had IAC from peritoneal fluid or hepatobiliary tract. C. albicans (72.2%) and C. glabrata (32.9%) were the most common pathogens. Overall GRR was 73.4% and 67.1% at EOIVT and EOT, respectively. All-cause mortality was 17.7% at day 14 and 24.1% at day 28 in the modified intent-to-treat population. Anidulafungin was well tolerated in this population, with most adverse events mild or moderate in severity. In these patients with IAC, anidulafungin showed a GRR at EOIVT similar to the anidulafungin registrational trial, and the results of our analysis confirmed the known safety profile of anidulafungin. ClinicalTrials.gov registration number NCT00496197, registered July 3, 2007, https://clinicaltrials.gov/ct2/show/study/NCT00496197 ; ClinicalTrials.gov registration number NCT00548262, registered October 19, 2007, https://clinicaltrials.gov/ct2/show/record/NCT00548262 ; ClinicalTrials.gov registration number NCT00537329, registered September 25, 2007, https://clinicaltrials.gov/ct2/show/record/NCT00537329 ; ClinicalTrials.gov registration number NCT00689338, registered May 29, 2008, https://clinicaltrials.gov/ct2/show/study/NCT00689338 ; ClinicalTrials.gov registration number NCT00805740, registered November 26, 2008, https://clinicaltrials.gov/ct2/show/NCT00805740.

Utility of CT assessment in hematology patients with invasive aspergillosis: a post-hoc analysis of phase 3 data.

BACKGROUND: Pulmonary computed tomography (CT) scans are commonly used as part of the clinical criteria in diagnostic workup of invasive fungal diseases like invasive aspergillosis, and may identify radiographic abnormalities, such as halo signs or air-crescent signs. We assessed the diagnostic utility of CT assessment in patients with hematologic malignancies or those who had undergone allogeneic hematopoietic stem cell transplantation in whom invasive aspergillosis was suspected. METHODS: This post-hoc analysis assessed data from a prospective, multicenter, international trial of voriconazole (with and without anidulafungin) in patients with suspected invasive aspergillosis (IA; proven, probable, or possible, using 2008 European Organisation for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group criteria) [NCT00531479]. Eligible patients received at least one baseline lung CT scan. RESULTS: Of 395 patients included in this post-hoc analysis, 240 patients (60.8%) had 'confirmed' proven (9/240, 3.8%) or probable (231/240, 96.3%) invasive aspergillosis (cIA) and 155 patients (39.2%) had 'non-confirmed' invasive aspergillosis (all nIA; all possible IA (de Pauw et al., Clin Infect Dis 46:1813-21, 2008)). Mean age was 52.3 and 50.5 years, 56.3 and 60.0% of patients were male, and most patients were white (71.7 and 71.0%) in the cIA and nIA populations, respectively. Median baseline galactomannan was 1.4 (cIA) and 0.2 (nIA), mean Karnofsky score was 65.3 (cIA) and 66.8 (nIA), and mean baseline platelet count was 48.0 (cIA) and 314.1 (nIA). Pulmonary nodules (46.8% of all patients), bilateral lung lesions (37.5%), unilateral lung lesions (28.4%), and consolidation (24.8%) were the most common radiographic abnormalities. Ground-glass attenuation (cIA: 24.2%; nIA: 11.6%; P < 0.01) and pulmonary nodules (cIA: 52.5%; nIA: 38.1%; P < 0.01) were associated with cIA. Other chest CT scan abnormalities (including halo signs and air-crescent signs) at baseline in patients with hematologic malignancy or hematopoietic stem cell transplantation, and suspected IA, were not associated with cIA. CONCLUSIONS: These findings highlight the limitations in the sensitivity of chest CT scans for the diagnosis of IA, and reinforce the importance of incorporating other available clinical data to guide management decisions on individual patients, including whether empirical treatment is reasonable, pending full evaluation. TRIAL REGISTRATION: NCT00531479 (First posted on ClinicalTrials.gov on September 18, 2007).

Efficacy and safety of combination antifungal therapy in Korean haematological patients with invasive aspergillosis.

This randomised, double-blind, placebo-controlled trial assessed the efficacy, safety and tolerability of voriconazole+anidulafungin (combination) or voriconazole+placebo (monotherapy) for invasive aspergillosis (IA; NCT00531479). We present a post hoc analysis of Korean and non-Korean patients with IA (including baseline positive serum galactomannan [GM]). Immunocompromised patients ≥ 16 years with IA were randomised 1:1, combination or monotherapy, for ≥ 2 weeks' treatment. The primary endpoint was 6- and 12-week all-cause mortality (Korean modified intent-to-treat [mITT] population). Overall, 454 patients enrolled (Koreans: 56 [combination: 28, monotherapy: 28], non-Koreans: 398 [combination: 200, monotherapy: 198]). The mITT population comprised 40 Koreans (combination: 23; monotherapy: 17) and 237 non-Koreans (combination: 112; monotherapy: 125). Week 6 treatment difference in mortality rate between combination and monotherapy was -6.4% in non-Koreans. This reduction was more marked in Koreans (-22.4%). Week 12 difference in all-cause mortality between combination and monotherapy was -17.7% (Koreans) and -20.2% at Week 6 (Koreans; positive baseline GM). Week 6 mortality (Koreans [mITT]; baseline GM >0.5-2.0) was 0/13 (combination) and 2/6 (monotherapy). Serious adverse events were numerically higher for combination than monotherapy (Koreans: 57.1%, 46.4%; non-Koreans: 49.5%, 46.0%). In Koreans, combination therapy was associated with marginally better outcomes than monotherapy and more so than in non-Koreans.

Retrospective cohort study comparing the risk of severe hepatotoxicity in hospitalized patients treated with echinocandins for invasive candidiasis in the presence of confounding by indication.

BACKGROUND: To compare the risk of severe hepatotoxicity with anidulafungin versus caspofungin and micafungin in hospitalized adults. METHODS: This retrospective cohort study combined data from two large US- based hospital electronic medical record databases. Severe hepatotoxicity was a Grade ≥ 3 liver function test (LFT) post-echinocandin initiation. Adjusted incidence rate ratios (IRRs) were estimated for anidulafungin versus caspofungin and micafungin, overall and in patients with normal baseline LFT (Grade 0). RESULTS: Treatments included anidulafungin (n = 1700), caspofungin (n = 4431), or micafungin (n = 6547). The proportions with LFT Grade ≥ 3 pre-echinocandin initiation were: anidulafungin 40.4% versus caspofungin 25.9% (p <  0.001) and micafungin 25.6% (p <  0.001). Rates of severe underlying diseases or comorbidities were: critical care admissions: 75.3% versus 52.6 and 48.6%; and organ failures: 69.4% versus 46.7 and 51.5%. Adjusted IRRs of severe hepatotoxicity for anidulafungin versus caspofungin and micafungin were 1.43 (p = 0.002) and 1.19 (p = 0.183) overall, and 0.88 (P = 0.773) and 0.97 (P = 0.945) for normal baseline LFT, respectively. CONCLUSIONS: Accounting for confounders, severe hepatotoxicity risk was not significantly different across echinocandins in this real-world head-to-head study. Anidulafungin was used more frequently in patients with more comorbidities. Those with normal baseline LFT (least susceptible to confounding by indication), showed no elevated hepatotoxicity risk for anidulafungin.

Efficacy of anidulafungin in 539 patients with invasive candidiasis: a patient-level pooled analysis of six clinical trials.

Objectives: To evaluate the efficacy of anidulafungin for the treatment of candidaemia and invasive candidiasis in a large dataset, including patients with deep-seated tissue candidiasis, neutropenia and infection due to non- albicans Candida species. Methods: Data were pooled from six prospective, multicentre, multinational studies: four open-label, non-comparative studies of anidulafungin and two double-blind, double-dummy, randomized studies of anidulafungin versus caspofungin (clinical trial registrations: NCT00496197, NCT00548262, NCT00537329, NCT00689338, NCT00806351 and NCT00805740; ClinicalTrials.gov). In all studies, patients with culture-confirmed invasive candidiasis received a single intravenous (iv) loading dose of anidulafungin 200 mg on day 1, followed by 100 mg once-daily. Switch to oral fluconazole or voriconazole was permitted after 5-10 days of iv treatment in all studies except one. Antifungal treatment (iv plus oral therapy if applicable) was maintained for ≥14 days after the last positive Candida culture. The primary endpoint was successful global response at end of iv therapy (EOivT) in the modified ITT (mITT) population. Results: In total, 539 patients were included (mITT population). The most common baseline Candida species were Candida albicans (47.9%), Candida glabrata (21.0%), Candida tropicalis (13.7%), Candida parapsilosis (13.2%) and Candida krusei (3.5%). Median duration of anidulafungin iv treatment was 10.0 days. The global response success rate at EOivT was 76.4% (95% CI 72.9%-80.0%). All-cause mortality was 13.0% on day 14 and 19.1% on day 28. Adverse events (AEs) were consistent with the known AE profile for anidulafungin. Conclusions: These data demonstrate that anidulafungin is effective for treatment of candidaemia and invasive candidiasis in a broad patient population.

Anidulafungin for the treatment of candidaemia caused by Candida parapsilosis: Analysis of pooled data from six prospective clinical studies.

Concerns with echinocandin use for infections caused by Candida parapsilosis complex species have driven the need for data to support echinocandin clinical efficacy in such patients. Data from six prospective studies were pooled to assess efficacy and safety of anidulafungin in patients with candidaemia caused by C. parapsilosis. Patient-level data were pooled from patients with microbiologically confirmed candidaemia due to C. parapsilosis treated with anidulafungin. Patients received a 200 mg intravenous (IV) loading dose of anidulafungin (day 1) and 100 mg daily thereafter. IV treatment could be switched to oral azole therapy after ≥5 or ≥10 days. Primary endpoint was global response at end of IV therapy (EOIVT). Seventy patients had candidaemia caused by C. parapsilosis. Global response was 77.1% (95% CI: 67.3, 87.0) at EOIVT and 70.0% (95% CI: 59.3, 80.7) at end of treatment. Three of 55 isolates (with MICs available) were resistant to anidulafungin (MIC ≥8 mg/L). All-cause mortality was 5.7% (n=4/70) by day 14 and 14.3% (n=10/70) by day 28. IV anidulafungin was effective for the treatment of C. parapsilosis candidaemia in this population, consistent with efficacy previously demonstrated for other Candida species. (ClinicalTrials.gov identifiers: NCT00496197, NCT00548262, NCT00537329, NCT00689338, NCT00806351, NCT00805740).

Healthcare Resource Utilization and Discharge Readiness in Adult Hospitalized Patients With Candidemia or Invasive Candidiasis Who Received an Echinocandin: An Analysis of United States Hospitals.

Background: Scant real-world outcomes data are available among hospitalized patients with candidemia (C) or invasive candidiasis without candidemia (IC) who were treated with an echinocandin and few have assessed if there is an opportunity to accelerate the transition of their care to the outpatient setting. This study described the outcomes associated with echinocandin therapy for C/IC and determined the proportion of patients on an echinocandin at hospital discharge (HD) who were potentially eligible for an earlier HD. Methods: A retrospective, multicenter observational study was performed using the PINC AI Healthcare Database (January 2016-April 2019) of hospitalized adult patients with C/IC who received ≥3 days of an echinocandin. Outcomes included post-index culture hospital costs and discharge location. Patients were considered potentially dischargeable earlier than actual HD day if they met the following 3 criteria prior to their actual HD day: resided on a non-intensive care unit hospital ward until HD, received any oral medications, and had no diagnostic/therapeutic interventions. Results: A total of 1865 patients met study criteria. Mean (standard deviation) post-index culture hospital costs for patients with C and IC were 50 196 (64 630) US dollars and 61 551 (73 080) US dollars, respectively. Of the 1008 patients on an echinocandin near HD and discharged alive, 432 (42.9%) were potentially dischargeable prior to their actual hospital day. Most patients (35.8%) were discharged to a long-term care facility. Conclusions: The findings suggest that a high proportion of hospitalized C/IC patients receiving an echinocandin near the time of HD were potentially dischargeable earlier. Like all studies of this nature, the findings need to be prospectively validated.

Efficacy and safety of rezafungin and caspofungin in candidaemia and invasive candidiasis: pooled data from two prospective randomised controlled trials.

BACKGROUND: Rezafungin, a new US Food and Drug Administration-approved, long-acting echinocandin to treat candidaemia and invasive candidiasis, was efficacious with a similar safety profile to caspofungin in clinical trials. We conducted pooled analyses of the phase 2 STRIVE and phase 3 ReSTORE rezafungin trials. METHODS: ReSTORE was a multicentre, double-blind, double-dummy, randomised phase 3 trial conducted at 66 tertiary care centres in 15 countries. STRIVE was a multicentre, double-blind, double-dummy, randomised phase 2 trial conducted at 44 centres in 10 countries. Adults (≥18 years) with candidaemia or invasive candidiasis were treated with once-a-week intravenous rezafungin (400 mg and 200 mg) or once-a-day intravenous caspofungin (70 mg and 50 mg). Efficacy was evaluated in a pooled modified intent-to-treat (mITT) population. Primary efficacy endpoint was day 30 all-cause mortality (tested for non-inferiority with a pre-specified margin of 20%). Secondary efficacy endpoint was mycological response. Safety was also evaluated. The STRIVE and ReSTORE trials are registered with ClinicalTrials.gov, NCT02734862 and NCT03667690, and both studies are complete. FINDINGS: ReSTORE was conducted from Oct 12, 2018, to Oct 11, 2021, and STRIVE from July 26, 2016, to April 18, 2019. The mITT population, pooling the data from the two trials, comprised 139 patients for rezafungin and 155 patients for caspofungin. Day 30 all-cause mortality rates were comparable between groups (19% [26 of 139] for the rezafungin group and 19% [30 of 155] for the caspofungin group) and the upper bound of the 95% CI for the weighted treatment difference was below 10% (-1·5% [95% CI -10·7 to 7·7]). Mycological eradication occurred by day 5 in 102 (73%) of 139 rezafungin patients and 100 (65%) of 155 caspofungin patients (weighted treatment difference 10·0% [95% CI -0·3 to 20·4]). Safety profiles were similar across groups. INTERPRETATION: Rezafungin was non-inferior to caspofungin for all-cause mortality, with a potential early treatment benefit, possibly reflecting rezafungin's front-loaded dosing regimen. These findings are of clinical importance in fighting active and aggressive infections and reducing the morbidity and mortality caused by candidaemia and invasive candidiasis. FUNDING: Melinta Therapeutics and Cidara Therapeutics.

Post-hoc analysis of the safety and efficacy of isavuconazole in older patients with invasive fungal disease from the VITAL and SECURE studies.

Isavuconazole is a triazole with broad-spectrum antifungal activity. In this post-hoc analysis of two prospective clinical trials (VITAL and SECURE), the safety and efficacy of isavuconazole in patients aged ≥ 65 years with invasive fungal diseases were evaluated. Patients were divided into two subgroups (≥ 65 and < 65 years). Adverse events (AEs); all-cause mortality; and overall, clinical, mycological, and radiological response were assessed. A total of 155 patients ≥ 65 years were enrolled in both trials. Most patients reported AEs. In the isavuconazole arm of both studies, serious AEs (SAEs) were greater in patients ≥ 65 versus < 65 years: 76.7% versus 56.9% (VITAL); 61.9% versus 49.0% (SECURE). In SECURE, SAE rates were similar in the ≥ 65 years subgroup of both treatment arms (61.9% vs 58.1%), while in the < 65 years subgroup the SAE rate was lower in the isavuconazole arm (49.0% vs 57.4%). In VITAL, all-cause mortality through day 42 (30.0% vs 13.8%) was higher, and overall response at end of treatment (27.6% vs 46.8%) was lower in patients ≥ 65 years versus < 65 years. In SECURE, all-cause mortality was similar between both subgroups, and isavuconazole (20.6% vs 17.9%) and voriconazole (22.6% vs 19.4%) treatment arms. The overall response was lower in the ≥ 65 years than the < 65 years subgroup in the isavuconazole (23.7% vs 39.0%) and voriconazole (32.0% vs 37.5%) arms. The safety and efficacy of isavuconazole were better in patients < 65 versus ≥ 65 years, and the safety profile was more favorable than that of voriconazole in both subgroups.Clinicaltrials.gov identifier NCT00634049 and NCT00412893.

A plain language summary on preventing fungal infections with isavuconazole in people with blood-related conditions.

WHAT IS THIS SUMMARY ABOUT?: People with blood-related conditions have a higher chance of getting invasive fungal infections (IFIs). IFIs are severe fungal infections that can lead to death. Only a few medications, known as antifungals, exist that can be used to prevent IFIs, and sometimes they can cause very bad side effects. Isavuconazole is an antifungal which has been approved to treat IFIs, but it has not been approved to prevent IFIs. In this study, we reviewed published studies that looked at how well isavuconazole prevented IFIs in people who have a higher chance of getting IFIs. WHAT WERE THE RESULTS?: This review showed that isavuconazole could be effective at preventing IFIs in people with blood-related conditions, as well as being a safe medication. WHAT DO THE RESULTS OF THE STUDY MEAN?: Isavuconazole can prevent IFIs in people who have a higher chance of getting IFIs. Guidelines should consider that patients need new antifungals to prevent IFIs, and more research needs to be done to see which medicines work best, and which have fewer side effects. Clinical Trial Registration: Please note that 7 studies included in this review were planned studies (1 prospective, 6 retrospective), 2 were real- world studies, 1 of which was registered as a clinical trial NCT03019939 (ClinicalTrials.gov).

Study of an antifungal medicine isavuconazole used in treatment of mold infections in China: A plain language summary.

WHAT IS THIS SUMMARY ABOUT?: Molds are types of fungus that can cause sickness and death. Mold infections are increasing in China. Until 2022, medicines that can effectively treat all mold infections were still lacking in China. This summary of a study originally published in the journal Infection and Drug Resistance. The study took place in China and tested a medicine called isavuconazole on mold samples to check if isavuconazole can be used to treat mold infections. Isavuconazole became available in China in January 2022 as a capsule (a hard gel-covered pill filled with a dose of medicine) and in June 2022 as an injection or a shot. WHAT WERE THE RESULTS?: Isavuconazole stopped the growth of most molds. Other medicines were needed at higher amounts to stop the growth of molds. WHAT DO THE RESULTS OF THE STUDY MEAN?: Isavuconazole is another option to treat mold infections in China.

Tissue distribution of anidulafungin in neonatal rats.

Anidulafungin, an echinocandin, is currently approved for treatment of fungal infections in adults. There is a high unmet medical need for treatment of fungal infections in neonatal patients, who may be at higher risk of infections involving bone, brain, and heart tissues. This in vivo preclinical study investigated anidulafungin distribution in plasma, bone, brain, and heart tissues in neonatal rats. Postnatal day (PND) 4 and PND 8 Fischer (F344/DuCrl) rats were dosed subcutaneously once with anidulafungin (10 mg/kg) or once daily for 5 days (PND 4-8). Plasma and tissue samples were collected and anidulafungin levels were measured by liquid chromatography-tandem mass spectrometry. The mean plasma Cmax and AUC0-24 values were consistent with single-dose plasma pharmacokinetics (dose normalized) reported previously for adult rats. Observed bone concentrations were similar to plasma concentrations regardless of dosing duration, with bone-to-plasma concentration ratios of approximately 1.0. Heart concentrations were higher than plasma, with heart to plasma concentration ratios of 1.3- to 1.8-fold. Brain concentrations were low after single dose, with brain-to-plasma concentration ratio of approximately 0.23, but increased to approximately 0.71 after 5 days of dosing. Tissue concentrations were nearly identical after single-dose administration in both PND 4 and PND 8 animals, indicating that anidulafungin does not appear to differentially distribute in this period in neonatal rats. In conclusion, anidulafungin distributes to bone, brain, and heart tissues of neonatal rats; such results are supportive of further investigation of efficacy against infections involving bone, brain, and heart tissues.

Risk factors in people with mold infections that have spread to different parts of the body: a plain language summary.

WHAT IS THIS SUMMARY ABOUT?: This is a summary of a study originally published in ClinicoEconomics and Outcomes Research. Mold infections spread from one to other parts of the body and can infect other body parts. We need to understand what makes people more likely to get this type of mold infection (called invasive mold infection). This summary may help doctors to understand the risks that can relate to invasive mold infections. WHAT WERE THE RESULTS?: The main risks in people with invasive aspergillosis (shortened to IA) and invasive mucormycosis (shortened to IM) were: ○diabetes (high blood sugar and associated conditions), ○lung disease (such as tuberculosis, chronic obstructive pulmonary disorder), ○blood-related cancers (such as leukemia, lymphoma), and ○solid organ transplant (removing an organ from one person and placing in another person). WHAT DO THE RESULTS OF THE STUDY MEAN?: People with the risks listed above may be more likely to get invasive mold infections. People with these risks should talk to their doctor about invasive mold infections. Being aware of these risks may help doctors to be aware of which people are at risk of invasive mold infections.

Plain language summary: use of isavuconazole in Chinese patients with an invasive fungal disease.

WHAT IS THIS SUMMARY ABOUT?: Invasive aspergillosis (also known as IA) is a type of fungal infection, caused by a species of fungus called Aspergillus, that can be life threatening. Isavuconazole and voriconazole belong to a group of antifungal drugs called triazoles that are recommended for treating IA. In the USA and in Europe, isavuconazole is approved for treating patients with IA. In China, isavuconazole was recently being reviewed for approval for treating patients with IA. This study looked at whether isavuconazole works in the same way in healthy Chinese people as it does in healthy Western people. It also looked to see how well isavuconazole works and how many side effects it has compared with voriconazole in Chinese patients with IA. WHAT WERE THE RESULTS?: The results of this study showed that healthy Chinese people's bodies processed isavuconazole the same way as healthy Western people's bodies. The amount of drug in people's bodies did not change how well the drug worked or how many side effects there were. Isavuconazole worked as well as and had a similar number of side effects as voriconazole in treating Chinese patients with IA. WHAT DO THE RESULTS OF THE STUDY MEAN?: These findings show that isavuconazole may be a suitable treatment for Chinese patients with IA using the same dose that is used in Western patients.

Effectiveness and safety of isavuconazole prophylaxis for invasive fungal infections in the haematologic setting.

OBJECTIVES: Patients with haematologic malignancies are at high risk of developing invasive fungal infections (IFIs). Current guidelines recommend the use of azoles for IFI prophylaxis; however, in many clinical situations, antifungal prophylaxis is used off-label. We conducted a systematic literature review to provide haematologists with the available evidence on the effectiveness and safety of isavuconazole in IFI prophylaxis in interventional and real-world, observational studies. METHODS: Embase, MEDLINE and Cochrane Library databases, and relevant conference proceedings and clinical trial registries, were searched for studies on the effectiveness and safety of isavuconazole prophylaxis in adults at high risk of IFIs. Studies were assessed for inclusion and risk of bias. RESULTS: Nine studies were eligible for inclusion in the review, eight of which were in haematologic populations (patients undergoing haematopoietic stem cell transplantation or with acute myeloid leukaemia or myelodysplastic syndromes; n = 5) or included haematologic populations (n = 3). Evidence from these studies suggests isavuconazole is effective for IFI prophylaxis in the haematologic setting. However, the studies frequently lacked safety data, most were based on small patient populations from single centres and risk of bias could not be assessed for five studies. DISCUSSION: These findings provide evidence for isavuconazole as an alternative azole for prophylaxis in high-risk populations. Limitations include lack of applicability of risk of bias assessment tools, level of filtering applied in the search strategy and focus on English-language publications. CONCLUSION: Isavuconazole may be an effective azole for IFI prophylaxis in high-risk haematologic populations, although further studies are needed.

In vitro Activity of Isavuconazole and Comparators Against Clinical Isolates of Molds from a Multicenter Study in China.

Purpose: Monitoring antifungal susceptibility patterns for new or established antifungals is imperative. Antifungal resistance is frequent in molds, frequently leading to invasive mold infections (IMIs) in immunocompromised patients with high morbidity and mortality. Limited availability of effective antifungals for treatment of IMIs in China is an enormous challenge. The purpose of this study was to monitor in vitro antifungal resistance profiles of mold isolates from China, with a particular focus on evaluating in vitro isavuconazole (ISA) activity against these isolates, contributing to the treatment guidance in clinics. Methods: We evaluated the in vitro activity of ISA and its comparators (voriconazole [VOR] and amphotericin B [AMB]) against 131 clinical isolates of Aspergillus spp. (n = 105) and Mucorales order (n = 26) collected between 2017 and 2020 from China. Results: ISA and VOR exhibited similar in vitro activity against Aspergillus spp., with minimum inhibitory concentration (MIC)50 of 1 µg/mL and MIC90 of 2 µg/mL, respectively. Overall, AMB was less active than azoles against Aspergillus spp. (MIC50: 4 µg/mL, MIC90: 8 µg/mL). Against the Mucorales order, ISA demonstrated MIC50 of 0.5 µg/mL and MIC90 of 1 µg/mL; however, one strain each of Mucor circinelloides and Syncephalastrum racemosum were resistant to ISA (MICs: >8 µg/mL). VOR exhibited little or no activity (MIC50: 8 µg/mL, MIC90: >8 µg/mL) against the Mucorales order, whereas AMB had MIC50 and MIC90 of 1 µg/mL. Conclusion: This was the first multicenter, in vitro study conducted in China and demonstrated the excellent activities of ISA against most species of the Mucorales order. MIC indicated an advantage over currently available azole antifungals, positioning ISA as a potential alternative to VOR for clinical management of IMIs. As with other antimicrobials, clinicians should employ stewardship and best practices in relation to potential resistance to new azole antifungals.