The cost-utility analysis of antifungal prophylaxis for invasive fungal infections in acute myeloid leukaemia patients receiving chemotherapy: a study from a middle-income country.

BACKGROUND: Invasive fungal infections (IFIs) contribute to morbidity and mortality during acute myeloid leukaemia (AML) treatment. Without prophylaxis, IFI rate during AML treatment in Thailand is high and results in a high mortality rate and a prolonged hospital stay. AIM: To evaluate the cost-utility of antifungal therapy (AFT) prophylaxis during AML treatment. METHODS: We assessed the cost-utility of AFT available in Thailand, including posaconazole (solution), itraconazole (solution and capsule), and voriconazole. A hybrid model consisting of a decision tree and the Markov model was established. RESULTS: The costs to prevent overall IFI using any AFT were all lower than the treatment cost of a non-prophylaxis group, resulting in a saving of 808-1507 USD per patient. Prevention with voriconazole prophylaxis showed the highest quality-adjusted life years (QALYs = 3.51, incremental QALYs = 0.23), followed by posaconazole (QALYs = 3.46, incremental QALY = 0.18) and itraconazole solution (QALYs = 3.45, incremental QALYs = 0.17). Itraconazole capsule reduced QALY in the model. For invasive aspergillosis prevention, posaconazole and voriconazole both resulted in better QALYs and life year savings compared with no prophylaxis. However, posaconazole prophylaxis was the only cost-saving option (976 USD per patient). CONCLUSION: Posaconazole, itraconazole solution and voriconazole were all cost saving compared with no prophylaxis for overall IFI prophylaxis, with voriconazole being the most cost-effective option. Posaconazole and voriconazole were both cost effective for invasive aspergillosis prevention but only posaconazole was cost saving. A change in reimbursement policy for the use of AFT prophylaxis during intensive AML treatment could provide both clinical benefits to patients and substantial economic benefits to healthcare systems.

Incidence and Impact of Fungal Infections in Post-Transplantation Cyclophosphamide-Based Graft-versus-Host Disease Prophylaxis and Haploidentical Hematopoietic Cell Transplantation: A Center for International Blood and Marrow Transplant Research Analysis.

Fungal infection (FI) after allogeneic hematopoietic cell transplantation (HCT) is associated with increased morbidity and mortality. Neutropenia, HLA mismatch, graft-versus-host disease (GVHD), and viral infections are risk factors for FI. The objectives of this Center for International Blood and Marrow Transplant Research registry study were to compare the incidence and density of FI occurring within 180 days after HCT in matched sibling (Sib) transplants with either calcineurin inhibitor (CNI)-based or post-transplantation cyclophosphamide (PTCy)-based GVHD prophylaxis and related haploidentical transplants receiving PTCy, and to examine the impact of FI by day 180 on transplantation outcomes. METHODS: Patients who underwent their first HCT between 2012 and 2017 for acute myeloid leukemia, acute lymphoblastic leukemia, and myelodysplastic syndrome and received a related haploidentical transplant with PTCy (HaploCy; n = 757) or a Sib transplant with PTCy (SibCy; n = 403) or CNI (SibCNI; n = 1605) were analyzed. The incidence of FI by day 180 post-HCT was calculated as cumulative incidence with death as the competing risk. The associations of FI with overall survival, transplant-related mortality, chronic GVHD, and relapse at 2 years post-HCT were examined in Cox proportional hazards regression models. Factors significantly associated with the outcome variable at a 1% level were kept in the final model. RESULTS: By day 180 post-HCT, 56 (7%) HaploCy, 24 (6%), SibCy, and 59 (4%) SibCNI recipients developed ≥1 FI (P < .001). The cumulative incidence of yeast FI was 5.2% (99% confidence interval [CI], 3.3% to 7.3%) for HaploCy, 2.2% (99% CI, .7% to 4.5%) for SibCy, and 1.9% (99% CI, 1.1% to 2.9%) for SibCNI (P = .001), and that of mold FI was 2.9% (99% CI, 1.5% to 4.7%), 3.7% (99% CI, 91.7% to 6.6%), and 1.7% (99% CI, 1.0% to 2.6%), respectively (P = .040). FI was associated with an increased risk of death, with an adjusted hazard ratio (HR) of 4.06 (99% CI, 2.2 to 7.6) for HaploCy, 4.7 (99% CI, 2.0 to 11.0) for SibCy, and 3.4 (99% CI, 1.8 to 6.4) for SibCNI compared with SibCNI without FI (P < .0001 for all). Similar associations were noted for transplantation-related mortality. FI did not impact rates of relapse or chronic GVHD. CONCLUSIONS: Rates of FI by day 180 ranged between 1.9% and 5.2% for yeast FI and from 1.7% to 3.7% for mold FI across the 3 cohorts. The use of PTCy was associated with higher rates of yeast FI only in HaploHCT and with mold FI in both HaploHCT and SibHCT. The presence of FI by day 180 was associated with increased risk for overall mortality and transplant-related mortality at 2 years regardless of donor type or PTCy use. Although rates of FI were low with PTCy, FI is associated with an increased risk of death, underscoring the need for improved management strategies.

New and emerging options for management of invasive fungal diseases in paediatric patients.

Invasive fungal diseases (IFDs) play an important role in the supportive care of paediatric patients with acute leukaemia and those undergoing allogeneic haematopoietic cell transplantation, and they are associated with significantly decreased overall survival rates in affected individuals. Relative to adults, children and adolescents are distinct in terms of host biology, predisposing conditions, presentation and epidemiology of fungal diseases, and in the pharmacology of antifungal agents. The paediatric development of antifungal agents has moved forward in a coordinated manner, and major advances have been made regarding concepts and recommendations for the prevention and treatment of IFDs. However, antifungal therapy is increasingly complex, and a solid knowledge of the available options is needed more than ever for successful management. This narrative review provides a summary of the paediatric development of agents that have been recently approved (anidulafungin, posaconazole) or are in advanced stages of development (isavuconazole). It also reviews the emerging evidence for the efficacy of echinocandins for prophylaxis of invasive aspergillosis, presents new data on alternative dosing regimens of echinocandins and voriconazole, and provides a brief overview of new antifungal agents in clinical development that are expected to be developed for paediatric patients.

An analysis of the risk factors for invasive fungal infections in preterm infants and a discussion of prevention strategies.

BACKGROUND: Although the success rate of resuscitation in preterm infants is increasing, the long length of hospital stay in preterm infants and the need for more invasive operations, coupled with the widespread use of empirical antibiotics, have increased the prevalence of fungal infections in preterm infants in neonatal intensive care units (NICUs) year on year. OBJECTIVE: The present study aims to explore the risk factors of invasive fungal infections (IFI) in preterm infants and to identify some prevention strategies. METHODS: A total of 202 preterm infants with a gestational age of 26 weeks to 36+6 weeks and a birth weight of less than 2,000 g, admitted to our neonatal unit during the 5-year period from January 2014 to December 2018, were selected for the study. Among these preterm infants, six cases that developed fungal infections during hospitalization were enrolled as the study group, and the remaining 196 infants who did not develop fungal infections during hospitalization were the control group. The gestational age, length of hospital stay, duration of antibiotic therapy, duration of invasive mechanical ventilation, indwelling duration of the central venous catheter, and duration of intravenous nutrition of the two groups were compared and analyzed. RESULTS: There were statistically significant differences between the two groups in the gestational age, length of hospital stay, and duration of antibiotic therapy. CONCLUSION: A small gestational age, a lengthy hospital stay, and long-term use of broad-spectrum antibiotics are the high-risk factors for fungal infections in preterm infants. Medical and nursing measures to address the high-risk factors might reduce the incidence of fungal infections and improve the prognosis in preterm infants.

[From treatment to whole course management: envisioning comprehensive management of Talaromycosis marneffei].

Talaromycosis marneffei has been increasing in recent years. Our understanding of this disease has gradually deepened through extensive basic and clinical research, but there are still many limitations. In this article, by incorporating the latest research advancements, we discuss important issues in managing Talaromycosis marneffei trends, aiming to guide effective prevention and control of the disease, improving public health, and reducing the healthcare burden.

Vaccine development for pathogenic fungi: current status and future directions.

INTRODUCTION: Fungal infections are caused by a broad range of pathogenic fungi that are found worldwide with different geographic distributions, incidences, and mortality rates. Considering that there are relatively few approved medications available for combating fungal diseases and no vaccine formulation commercially available, multiple groups are searching for new antifungal drugs, examining drugs for repurposing and developing antifungal vaccines, in order to control deaths, sequels, and the spread of these complex infections. AREAS COVERED: This review provides a summary of advances in fungal vaccine studies and the different approaches under development, such as subunit vaccines, whole organism vaccines, and DNA vaccines, as well as studies that optimize the use of adjuvants. We conducted a literature search of the PubMed with terms: fungal vaccines and genus of fungal pathogens (Cryptococcus spp. Candida spp. Coccidioides spp. Aspergillus spp. Sporothrix spp. Histoplasma spp. Paracoccidioides spp. Pneumocystis spp. and the Mucorales order), a total of 177 articles were collected from database. EXPERT OPINION: Problems regarding the immune response development in an immunocompromised organism, the similarity between fungal and mammalian cells, and the lack of attention by health organizations to fungal infections are closely related to the fact that, at present, there are no fungal vaccines available for clinical use.

Environmental monitoring for filamentous fungal pathogens in hematopoietic cell transplant units.

The incidence of invasive fungal disease (IFD) is on the rise due to increasing numbers of highly immunocompromized patients. Nosocomial IFD remains common despite our better understanding of its risk factors and pathophysiology. High-efficiency particulate air filtration with or without laminar air flow, frequent air exchanges, a positive pressure care environment, and environmental hygiene, amongst other measures, have been shown to reduce the mould burden in the patient environment. Environmental monitoring for moulds in areas where high-risk patients are cared for, such as hematopoietic cell transplant units, has been considered an adjunct to other routine environmental precautions. As a collaborative effort between authors affiliated to the Infection Prevention and Control Working Group and the Fungal Infection Working Group of the International Society of Antimicrobial Chemotherapy (ISAC), we reviewed the English language literature and international guidance to describe the evidence behind the need for environmental monitoring for filamentous fungi as a quality assurance approach with an emphasis on required additional precautions during periods of construction. Many different clinical sampling approaches have been described for air, water, and surface sampling with significant variation in laboratory methodologies between reports. Importantly, there are no agreed-upon thresholds that correlate with an increase in the clinical risk of mould infections. We highlight important areas for future research to assure a safe environment for highly immunocompromized patients.

Mould infections have a high mortality in high-risk patients. Ventilation engineering significantly reduces the risk of acquiring such infections. Environmental sampling for moulds is carried out in many centers in addition to standard precautions. We review the literature on this subject.

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).

Antifungal prophylaxis and pre-emptive therapy: When and how?

The growing pool of critically ill or immunocompromised patients leads to a constant increase of life-threatening invasive infections by fungi such as Aspergillus spp., Candida spp. and Pneumocystis jirovecii. In response to this, prophylactic and pre-emptive antifungal treatment strategies have been developed and implemented for high-risk patient populations. The benefit by risk reduction needs to be carefully weighed against potential harm caused by prolonged exposure against antifungal agents. This includes adverse effects and development of resistance as well as costs for the healthcare system. In this review, we summarise evidence and discuss advantages and downsides of antifungal prophylaxis and pre-emptive treatment in the setting of malignancies such as acute leukaemia, haematopoietic stem cell transplantation, CAR-T cell therapy, and solid organ transplant. We also address preventive strategies in patients after abdominal surgery and with viral pneumonia as well as individuals with inherited immunodeficiencies. Notable progress has been made in haematology research, where strong recommendations regarding antifungal prophylaxis and pre-emptive treatment are backed by data from randomized controlled trials, whereas other critical areas still lack high-quality evidence. In these areas, paucity of definitive data translates into centre-specific strategies that are based on interpretation of available data, local expertise, and epidemiology. The development of novel immunomodulating anticancer drugs, high-end intensive care treatment and the development of new antifungals with new modes of action, adverse effects and routes of administration will have implications on future prophylactic and pre-emptive approaches.

The efficacy and safety of fluconazole in preventing invasive fungal infection in very low birth weight infants: a systematic review and meta-analysis.

This meta-analysis aimed to assess the efficacy and safety of fluconazole for the prevention of invasive fungal infections (IFI) in very low birth weight infants (VLBWI) and to provide a basis for the clinical use. A detailed search of Pubmed, Embase, Cochrane Library and other databases was performed to carefully screen eligible randomized controlled clinical studies to assess the safety and efficacy of fluconazole in very low birth weight infants in terms of the incidence of invasive fungal infections, fungal colonization rate, and mortality. Our research indicated that the application of fluconazole did not result in intolerable adverse reactions in patients. Fluconazole is effective in preventing invasive fungal infections in very low birth weight infants without serious adverse effects. The dose and frequency of fluconazole in very low birth weight infants still needs to be evaluated in consequent studies.

FUNGAL METABOLITES PROVIDE PRE-EXPOSURE PROTECTION BUT NO POSTEXPOSURE BENEFIT OR HARM AGAINST BATRACHOCHYTRIUM DENDROBATIDIS.

Disease control tools are needed to mitigate the effect of the fungal pathogen Batrachochytrium dendrobatidis (Bd) on amphibian biodiversity loss. In previous experiments, Bd metabolites (i.e., noninfectious chemicals released by Bd) have been shown to induce partial resistance to Bd when administered before live pathogen exposure and therefore have potential as an intervention strategy to curb Bd outbreaks. In the wild, however, amphibians inhabiting Bd-endemic ecosystems may have already been exposed to or infected with Bd before metabolite administration. It is therefore critical to evaluate the efficacy and safety of Bd metabolites applied postexposure to live Bd. We tested whether Bd metabolites administered postexposure would induce resistance, exacerbate infections, or have no effect. The results confirmed that Bd metabolites applied before pathogen exposure significantly reduced infection intensity, but Bd metabolites applied after pathogen exposure neither protected against nor exacerbated infections. These results reveal the importance of timing the application of Bd metabolites early in the transmission season for Bd-endemic ecosystems and emphasize that Bd metabolites prophylaxis may be a useful tool in captive reintroduction campaigns where Bd threatens the success of re-establishing endangered amphibian populations.

Fungal infections in pediatric patients with acute myeloid leukemia in a tertiary hospital.

Introduction: Acute leukemia accounts for more than 30% of all pediatric cancer cases, and of these, 15-20% are acute myeloid leukemia (AML). Children who super from AML are more likely to develop infections due to the humoral and cellular immune deficits generated by the disease and its treatment. The incidence of fungal infections is underestimated; reports show that up to 75% of fungal infections go undiagnosed until autopsy. In only 30 years, the incidence of invasive candidiasis has increased by 40-fold. Thus, the high morbidity and mortality associated with fungal infections in hematological patients make it necessary to adopt preventive measures. Methods: This work aimed to retrospectively identify pediatric patients with acute myeloid leukemia and invasive fungal diseases (IFDs) in a Latin American tertiary care hospital. A retrospective analysis of 36 clinical records of pediatric patients diagnosed with AML from 2007 to 2017 was carried out. Results: One hundred and twenty-nine hospitalizations were associated with infectious events. Thirteen patients in our study presented 15 infectious events associated with IFDs (11.6%). Two patients died because of complications related to IFDs (15.3%). The most frequent IFD type was aspergillosis, which was observed in 7 cases, followed by Candidemia, which was observed in 4 cases. The most frequent clinical manifestations were fever and respiratory distress. Discussion: Mortality due to IFD can be prevented with effective pharmacotherapy. An appropriate antifungal prophylaxis strategy still needs to be developed through larger prospective studies in Latin America.

Progress of polymer-based strategies in fungal disease management: Designed for different roles.

Fungal diseases have posed a great challenge to global health, but have fewer solutions compared to bacterial and viral infections. Development and application of new treatment modalities for fungi are limited by their inherent essential properties as eukaryotes. The microorganism identification and drug sensitivity analyze are limited by their proliferation rates. Moreover, there are currently no vaccines for prevention. Polymer science and related interdisciplinary technologies have revolutionized the field of fungal disease management. To date, numerous advanced polymer-based systems have been developed for management of fungal diseases, including prevention, diagnosis, treatment and monitoring. In this review, we provide an overview of current needs and advances in polymer-based strategies against fungal diseases. We high light various treatment modalities. Delivery systems of antifungal drugs, systems based on polymers' innate antifungal activities, and photodynamic therapies each follow their own mechanisms and unique design clues. We also discuss various prevention strategies including immunization and antifungal medical devices, and further describe point-of-care testing platforms as futuristic diagnostic and monitoring tools. The broad application of polymer-based strategies for both public and personal health management is prospected and integrated systems have become a promising direction. However, there is a gap between experimental studies and clinical translation. In future, well-designed in vivo trials should be conducted to reveal the underlying mechanisms and explore the efficacy as well as biosafety of polymer-based products.

Enhancement of herbicolin A production by integrated fermentation optimization and strain engineering in Pantoea agglomerans ZJU23.

BACKGROUND: The lipopeptide herbicolin A (HA) secreted by the biocontrol agent Pantoea agglomerans ZJU23 is a promising antifungal drug to combat fungal pathogens by targeting lipid rafts, both in agricultural and clinical settings. Improvement of HA production would be of great significance in promoting its commercialization. This study aims to enhance the HA production in ZJU23 by combining fermentation optimization and strain engineering. RESULTS: Based on the results in the single-factor experiments, corn steep liquor, temperature and initial pH were identified as the significant affecting factors by the Plackett-Burman design. The fermentation medium and conditions were further optimized using the Box-Behnken response surface method, and the HA production of the wild type strain ZJU23 was improved from ~ 87 mg/mL in King's B medium to ~ 211 mg/mL in HA induction (HAI) medium. A transposon library was constructed in ZJU23 to screen for mutants with higher HA production, and two transcriptional repressors for HA biosynthesis, LrhA and PurR, were identified. Disruption of the LrhA gene led to increased mRNA expression of HA biosynthetic genes, and subsequently improved about twofold HA production. Finally, the HA production reached ~ 471 mg/mL in the ΔLrhA mutant under optimized fermentation conditions, which is about 5.4 times higher than before (~ 87 mg/mL). The bacterial suspension of the ΔLrhA mutant fermented in HAI medium significantly enhanced its biocontrol efficacy against gray mold disease and Fusarium crown rot of wheat, showing equivalent control efficacies as the chemical fungicides used in this study. Furthermore, HA was effective against fungicide resistant Botrytis cinerea. Increased HA production substantially improved the control efficacy against gray mold disease caused by a pyrimethanil resistant strain. CONCLUSIONS: This study reveals that the transcriptional repressor LrhA negatively regulates HA biosynthesis and the defined HAI medium is suitable for HA production. These findings provide an extended basis for large-scale production of HA and promote biofungicide development based on ZJU23 and HA in the future.

Incidence of breakthrough fungal infections on isavuconazole prophylaxis compared to posaconazole and voriconazole.

BACKGROUND: Invasive fungal infections (IFIs) are a common infectious complication during the treatment of acute myeloid leukemia (AML), high-risk myelodysplastic syndrome (MDS) or post hematopoietic cell transplantation (HCT). For these patients, the National Comprehensive Cancer Network recommends posaconazole or voriconazole for IFI prophylaxis. In clinical practice, however, there has been increased use of isavuconazole due to favorable pharmacokinetic and pharmacodynamic parameters despite limited data for this indication. The comparative prophylactic efficacy of antifungals in this patient population has not been reported, and an analysis is warranted. METHODS: This retrospective, matched cohort, single-center study, included AML, MDS, or HCT patients who began treatment or underwent transplant between January 1, 2015 and July 31, 2021. Isavuconazole patients were matched 1:2 with patients receiving posaconazole or voriconazole prophylaxis. RESULTS: A total of 126 patients were included, 42 received isavuconazole, 81 received posaconazole, and three received voriconazole. The majority of patients were male receiving secondary IFI prophylaxis while receiving steroids for treatment of GVHD. The incidence of possible, probable or proven IFI was 16.7% in the isavuconazole group compared to 10.7% in the posaconazole and voriconazole group (OR 1.28, 95% CI -0.9-1.4; p = .67). Hepatotoxicity occurred in 16 total patients, 14 receiving posaconazole and two receiving isavuconazole. CONCLUSION: Patients who received isavuconazole prophylaxis during AML induction therapy or post-HCT experienced a similar incidence of breakthrough fungal infections compared to those who received posaconazole or voriconazole. These results suggest no difference in antifungal prophylactic efficacy; however larger prospective comparative studies are needed.

Vincristine Side Effects With Concomitant Fluconazole Use During Induction Chemotherapy in Pediatric Acute Lymphoblastic Leukemia.

As a mainstay of treatment for acute lymphoblastic leukemia (ALL), vincristine's side effect profile is well known. Parallel administration of the antifungal fluconazole has been shown to interfere with the metabolism of vincristine, potentially resulting in increased side effects. We conducted a retrospective chart review to determine whether concomitant administration of vincristine and fluconazole during pediatric ALL induction therapy impacted the frequency of vincristine side effects, namely, hyponatremia and peripheral neuropathy. We also evaluated whether the incidence of opportunistic fungal infections was impacted by fluconazole prophylaxis. Medical charts of all pediatric ALL patients treated with induction chemotherapy at Children's Hospital and Medical Center in Omaha, NE, from 2013 to 2021 were retrospectively reviewed. Fluconazole prophylaxis did not significantly impact the rate of fungal infections. We found no correlation between fluconazole use and increased incidence of hyponatremia or peripheral neuropathy, which supports the safety of fungal prophylaxis with fluconazole during pediatric ALL induction therapy.

Utility of deceased donor cultures in solid organ transplantation in preventing donor-derived bacterial and fungal infectious diseases transmission.

Deceased donor and organ perfusion fluid cultures are obtained in order to inform recipient antimicrobial management and therefore reduce the risk of donor-derived bacterial and fungal infections. However, important heterogeneity exists in laboratory practice across organ procurement organizations and clinical management of culture results across transplant centers. While not standardized, the clinical approach to donors with positive bacterial and/or fungal cultures should be informed by the risk of donor-derived infection (DDI) and the consequence of organ non-utilization and account for potential unintended effects of antimicrobial use in the recipient. In this review, we summarize the literature on bacterial and fungal DDIs, describe the significance of positive cultures by anatomic site, and summarize current guidance on the management of positive cultures from donors or preservation fluids.