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Background Many patients with hematological malignancy develop fever after chemotherapy/conditioning but before chemotherapy-induced neutropenia (preneutropenic fever [PNF]). The proportion of PNF with an infectious etiology is not well established. Methods We conducted a single-center, prospective observational substudy of PNF (neutrophils >0.5 cells/μL, ≥38.0°C) in adults receiving acute myeloid leukemia (AML) chemotherapy, or allogeneic hematopoietic cell transplant (allo-HCT) conditioning enrolled in a neutropenic fever randomized controlled trial between 1 January and 31 October 2018. Eligible patients had anticipated neutropenia ≥10 days and exclusions included concurrent infection and/or neutropenia prior to chemotherapy or conditioning. PNF rates and infections encountered were described. Associations between noninfectious etiologies and fever were explored. Antimicrobial therapy prescription across preneutropenic and neutropenic periods was examined. Results Of 62 consecutive patients included (43 allo-HCT, 19 AML), 27 had PNF (44%) and 5 (19%) had an infective cause. Among allo-HCT, PNF occurred in 14 of 17 (82%) who received thymoglobulin; only 1 of 14 (7%) had infection. During AML chemotherapy, 18 of 19 received cytarabine, of which 8 of 18 (44%) had PNF and 3 of 8 (38%) had infection. Most patients with PNF had antimicrobial therapy continued into the neutropenic period (19/27 [70%]). Those with PNF were more likely to be escalated to broader antimicrobial therapy at onset/during neutropenic fever (5/24 [21%] vs 2/30 [7%]). Conclusions Rates of PNF were high, and documented infection low, leading to prolonged and escalating antimicrobial therapy. In the absence of infection, early cessation of empiric therapy after PNF is recommended as an important stewardship intervention. [ABSTRACT FROM AUTHOR]

The article explores the need for updated and standardized definitions for assessing treatment response in clinical trials for invasive fungal diseases (IFD). The current definitions, established in 2008, may not accurately capture the complexities of evaluating antifungal efficacy in patients with mold disease. This could potentially impact the evaluation and approval of new antifungal agents. The article presents arguments for and against updating the definitions, emphasizing the importance of clear and non-subjective criteria for standardized assessment in clinical trials. The article also discusses the limitations of the current definitions and proposes potential improvements, such as incorporating new assessment methods and considering diverse patient populations. [Extracted from the article]

This case involves a 53‐year‐old female with concurrent acute myeloid leukemia (AML) and multiple myeloma. She underwent cytarabine and daunorubicin (7+3) induction chemotherapy followed by cytarabine (HiDAC) consolidation, with an early AML relapse requiring azacitidine and venetoclax therapy. She achieved complete remission and incomplete count recovery. Following fludarabine, melphalan, and thymoglobulin induction chemotherapy, she underwent an allogeneic stem cell transplant with failure to engraft, requiring autologous stem cell rescue, buffy coat, and granulocyte transfusions, eventually presenting with a diffuse skin rash consistent with Steven‐Johnson syndrome and toxic epidermal necrolysis, persistent neutropenic fevers and positive blood cultures. [ABSTRACT FROM AUTHOR]

Cryptococcus is an opportunistic fungal pathogen that can cause disseminated infection with predominant central nervous system involvement in patients with compromised immunity. Biologics are increasingly used in the treatment of neoplasms and autoimmune/inflammatory conditions and the prevention of transplant rejection, which may affect human defense mechanisms against cryptococcosis. In this review, we comprehensively investigate the association between cryptococcosis and various biologics, highlighting their risks of infection, clinical manifestations, and clinical outcomes. Clinicians should remain vigilant for the risk of cryptococcosis in patients receiving biologics that affect the Th1/macrophage activation pathways, such as tumor necrosis factor α antagonists, Bruton tyrosine kinase inhibitors, fingolimod, JAK/STAT inhibitors (Janus kinase/signal transducer and activator of transcription), and monoclonal antibody against CD52. Other risk factors—such as age, underlying condition, and concurrent immunosuppressants, especially corticosteroids—should also be taken into account during risk stratification. [ABSTRACT FROM AUTHOR]

Background Neutropenic sepsis frequently requires admission to an intensive care unit (ICU). Differences between subgroups of patients with neutropenic sepsis are not well characterized. Aims To investigate clinical outcomes among patients with neutropenic sepsis and hematological malignancy, metastatic solid cancer, or no cancer diagnosis. Methods Retrospective cohort study of all patients admitted to ICU in Australia or New Zealand between January 2000 and December 2022 with a primary admission diagnosis of sepsis and total white cell count <1.0 × 109 cells/L. Results We identified 8617 ICU admissions with neutropenic sepsis (hematological malignancy n = 4660; metastatic solid cancer n = 1034; no cancer n = 2800). Patients with hematological malignancy were younger (median, 61.5 years) with low rates of chronic comorbidities (4.7%) and were usually admitted to ICU from the ward (67.4%). Mechanical ventilation rates were 20.2% and in-hospital mortality was 30.6%. Patients with metastatic solid cancers were older (median, 66.3 years), with higher rates of chronic comorbidities (9.9%), and were usually admitted to the ICU from the emergency department (50.8%). Mechanical ventilation rates were 16.9% and in-hospital mortality was 42.4%. Patients with no documented cancer had highest rates of mechanical ventilation (41.7%) and mortality (46.3%). Neutropenia was independently associated with mortality among patients with solid cancers or no cancer but did not confer increased risk among patients with hematological malignancy (odds ratio, 0.98; 95% confidence interval,.90–1.06; P =.60). Conclusions Patients with neutropenic sepsis and hematological malignancy, metastatic solid cancer, or no cancer diagnosis constitute 3 distinct clinical groups. Management approaches should be tailored accordingly. [ABSTRACT FROM AUTHOR]

Background: Investigation of infection risk with subcutaneous versus intravenous trastuzumab and rituximab administration in an individual patient data (IPD) and published data meta-analysis of randomised controlled trials (RCTs). Methods: Databases were searched to September 2021. Primary outcomes were serious and high-grade infection. Relative-risk (RR) and 95% confidence intervals (95%CI) were calculated using random-effects models. Results: IPD meta-analysis (6 RCTs, 2971 participants, 2320 infections) demonstrated higher infection incidence with subcutaneous versus intravenous administration, without reaching statistical significance (serious: 12.2% versus 9.3%, RR 1.28, 95%CI 0.93to1.77, P = 0.13; high-grade: 12.2% versus 9.9%, RR 1.32, 95%CI 0.98to1.77, P = 0.07). With exclusion of an outlying study in post-hoc analysis, increased risks were statistically significant (serious: 13.1% versus 8.4%, RR 1.53, 95%CI 1.14to2.06, P = 0.01; high-grade: 13.2% versus 9.3%, RR 1.56, 95%CI 1.16to2.11, P < 0.01). Published data meta-analysis (8 RCTs, 3745 participants, 648 infections) demonstrated higher incidence of serious (HR 1.31, 95%CI 1.02to1.68, P = 0.04) and high-grade (HR 1.52, 95%CI 1.17to1.98, P < 0.01) infection with subcutaneous versus intravenous administration. Conclusions: Results suggest increased infection risk with subcutaneous versus intravenous administration, although IPD findings are sensitive to exclusion of one trial with inconsistent results and identified risk-of-bias. Ongoing trials may confirm findings. Clinical surveillance should be considered when switching to subcutaneous administration. PROSPERO registration CRD42020221866/CRD42020125376. [ABSTRACT FROM AUTHOR]

Background: Sepsis occurs in 12–27% of patients with haematological malignancy within a year of diagnosis. Sepsis mortality has improved in non-cancer patients in the last two decades, but longitudinal trends in patients with haematological malignancy are not well characterised. We aimed to compare outcomes, including temporal changes, in patients with and without a haematological malignancy admitted to ICU with a primary diagnosis of sepsis in Australia and New Zealand over the past two decades. Methods: We performed a retrospective cohort study of 282,627 patients with a primary intensive care unit (ICU) admission diagnosis of sepsis including 17,313 patients with haematological malignancy, admitted to 216 intensive care units (ICUs) in Australia or New Zealand between January 2000 and December 2022. Annual crude and adjusted in-hospital mortality were reported. Risk factors for in-hospital mortality were determined using a mixed methods logistic regression model and were used to calculate annual changes in mortality. Results: In-hospital sepsis mortality decreased in patients with haematological malignancy, from 55.6% (95% CI 46.5–64.6%) in 2000 to 23.1% (95% CI 20.8–25.5%) in 2021. In patients without haematological malignancy mortality decreased from 33.1% (95% CI 31.3–35.1%) to 14.4% (95% CI 13.8–14.8%). This decrease remained significant after adjusting for mortality predictors including age, SOFA score and comorbidities, as estimated by adjusted annual odds of in-hospital death. The reduction in odds of death was of greater magnitude in patients with haematological malignancy than those without (OR 0.954, 95% CI 0.947–0.961 vs. OR 0.968, 95% CI 0.966–0.971, p < 0.001). However, absolute risk of in-hospital mortality remained higher in patients with haematological malignancy. Older age, higher SOFA score, presence of comorbidities, and mechanical ventilation were associated with increased mortality. Leukopenia (white cell count < 1.0 × 109 cells/L) was not associated with increased mortality in patients with haematological malignancy (p = 0.60). Conclusions: Sepsis mortality has improved in patients with haematological malignancy admitted to ICU. However, mortality remains higher in patients with haematological malignancy than those without. Key points: Among patients with haematological malignancy and sepsis admitted to intensive care, mortality has fallen by over 50% in the last two decades. Improvements are independent of organ failure, neutropenia, and age; however, mortality remains higher than for patients with no malignancy. [ABSTRACT FROM AUTHOR]

Background Neutropenic fever (NF) is a common complication in patients receiving chemotherapy. Judicious antimicrobial use is paramount to minimize morbidity and mortality and to avoid antimicrobial-related harms. Objectives To use an Australian national dataset of antimicrobial prescriptions for the treatment of NF to describe antimicrobial use, prescription guideline compliance and appropriateness; and to compare these findings across different healthcare settings and patient demographics. We also aimed to identify trends and practice changes over time. Methods Data were extracted from the Hospital National Antimicrobial Prescribing Survey (Hospital NAPS) database from August 2013 to May 2022. Antimicrobial prescriptions with a NF indication were analysed for antimicrobial use, guideline compliance and appropriateness according to the Hospital NAPS methodology. Demographic factors, hospital classifications and disease characteristics were compared. Results A total of 2887 (n = 2441 adults, n = 441 paediatric) NF prescriptions from 254 health facilities were included. Piperacillin-tazobactam was the most prescribed antimicrobial. Overall, 87.4% of prescriptions were appropriate. Piperacillin-tazobactam and cefepime had the highest appropriateness though incorrect piperacillin-tazobactam dosing was observed. Lower appropriateness was identified for meropenem, vancomycin, and gentamicin prescribing particularly in the private hospital and paediatric cohorts. The most common reasons for inappropriate prescribing were spectrum too broad, incorrect dosing or frequency, and incorrect duration. Conclusions This study provides insights into antimicrobial prescribing practices for NF in Australia. We have identified three key areas for improvement: piperacillin-tazobactam dosing, paediatric NF prescribing and private hospital NF prescribing. Findings from this study will inform the updated Australian and New Zealand consensus guidelines for the management of neutropenic fever in patients with cancer. [ABSTRACT FROM AUTHOR]

Background Little is known about the short- and long-term healthcare costs of invasive Scedosporium/Lomentospora prolificans infections, particularly in patient groups without haematological malignancy. This study investigated excess index hospitalization costs and cumulative costs of these infections. The predictors of excess cost and length of stay (LOS) of index hospitalization were determined. These estimates serve as valuable inputs for cost-effectiveness models of novel antifungal agents. Methods A retrospective case-control study was conducted at six Australian hospitals. Cases of proven/probable invasive Scedosporium/L. prolificans infections between 2011 and 2021 (n = 34) were matched with controls (n = 66) by predefined criteria. Cost data were retrieved from activity-based costing systems and analysis was performed from the Australian public hospital perspective. All costs were presented in 2022 Australian dollars (AUD). Median regression analysis was used to adjust excess costs of index hospitalization whereas cumulative costs up to 1.5 years follow-up were estimated using interval-partitioned survival probabilities. Results Invasive Scedosporium/L. prolificans infections were independently associated with an adjusted median excess cost of AUD36 422 (P = 0.003) and LOS of 16.27 days (P < 0.001) during index hospitalization. Inpatient stay was the major cost driver (42.7%), followed by pharmacy cost, of which antifungal agents comprised 23.8% of the total cost. Allogeneic haematopoietic stem cell transplant increased the excess cost (P = 0.013) and prolonged LOS (P < 0.001) whereas inpatient death within ≤28 days reduced both cost (P = 0.001) and LOS (P < 0.001). The median cumulative cost increased substantially to AUD203 292 over 1.5 years in cases with Scedosporium/L. prolificans infections. Conclusions The economic burden associated with invasive Scedosporium/L. prolificans infections is substantial. [ABSTRACT FROM AUTHOR]

The article discusses the need for a standardized approach to reporting infection events in immunocompromised patients. The authors highlight the limitations in current reporting practices and emphasize the importance of accurate and comprehensive reporting in clinical trials and observational studies. They introduce a basic core reporting dataset called "SCORE," which consists of five components that describe an infection event. The authors also provide guidance on additional details that should be included in different types of studies. They recommend the use of a ready-built data collection instrument and established definitions for pathogens and infectious syndromes. The article concludes by emphasizing the importance of adopting the proposed reporting dataset to improve research collaboration and advance research in immunocompromised patients. [Extracted from the article]

This article, published in the Journal of Antimicrobial Chemotherapy, discusses the importance of rapidly determining the cause of an infection and the susceptibility of the pathogen to antibiotics in order to initiate effective therapy. The authors present their experiences with different diagnostic laboratory methods and the challenges of translating test results into improved clinical outcomes. Topics covered include the validation of a short-incubation method for identifying bacteria from blood culture, the potential of VITEK® REVEALTM for generating rapid antimicrobial susceptibility test results, and the communication of test results to clinical personnel. The article aims to provide a valuable resource for improving laboratory support for infected patients and antimicrobial stewardship practice. The supplement was financially supported by bioMérieux. [Extracted from the article]

Background Methods Results Conclusion The purpose of this study was to understand how transplant infectious disease (TID) physicians assess a potential donor with known or suspected infection and describe posttransplant management.We designed a survey of 10 organ offer scenarios and asked questions pertaining to organ acceptability for transplantation and management posttransplant. The survey was distributed to TID clinicians via transplant society listservs and email. Responses were recorded in REDCap, and descriptive statistics were employed.One hundred thirteen infectious disease physicians responded to the survey, of whom 85 completed all cases. Respondents were generally in agreement regarding organ acceptability, although some divergence was seen when evaluating lungs from donors with influenza, tuberculosis, or multidrug‐resistant Acinetobacter infection. Posttransplant management showed more variation. Areas of optimization were identified: (1) Further understanding of where risk‐mitigation strategies within the donor offer process may improve donor acceptability and therefore organ utilization; (2) importance of recipient considerations in assessing degree of infectious risk; and (3) gaps in evidenced‐based data regarding optimal posttransplant management of recipients.Evaluation of donor offers by TID clinicians is a complex process. Although the survey does not itself serve to make recommendations regarding best practices, it highlights areas where generation of data to inform acceptance and management practices may allow for improved organ utilization and recipient management. [ABSTRACT FROM AUTHOR]

Introduction: The rising prevalence of difficult-to-treat, deep-seated invasive fungal diseases (IFD) has led to high mortality. Currently available antifungal treatments, administered predominantly orally or intravenously, may not sufficiently penetrate certain body sites, and/or are associated with systemic toxicity. Little is known about how to position alternative administration approaches such as inhalational and direct drug delivery routes., Areas Covered: This review provides an updated overview of unconventional drug delivery strategies for managing IFD, focusing on inhalational (to target the lungs) and direct delivery methods to the central nervous system, bone/joint, and eyes. Novel compounds (e.g. opelconazole) and existing antifungals with innovative drug delivery systems currently undergoing clinical trials and/or used off-label in the clinical setting are discussed., Expert Opinion: For both inhalational agents and direct delivery approaches, there are similar challenges that include the absence of: approved formulations for specific administration routes, delivery vehicles that are simple and safe to use whilst maintaining potency and efficiency of delivery, animal models suitable for investigating pharmacokinetic/pharmacodynamic profiles of inhaled antifungals, and consensus on the composite endpoints and intervals for of follow-up in clinical trials. To meet these challenges, cooperation of all stakeholders in drug development and regulation is required.

Background: Invasive fungal disease (IFD) is a significant complication for children receiving treatment for leukaemia, contributing to morbidity and mortality. Recent regional paediatric epidemiological IFD data are lacking. Additionally uncertainty remains regarding the optimal prophylactic approach in this context., Methods: In a multi-centre Australian cohort study of children diagnosed with de novo acute leukaemia between 1st January 2017 and 30th June 2020, we characterised antifungal prophylaxis prescribing and IFD prevalence. Impact of antifungal prophylaxis was assessed using Kaplan Meier curves and Cox-proportional hazards regression adjusting for known IFD risk factors., Findings: A total of 434 children were included (47.2% female; median age 5.0 years, median follow-up 240 days). This cohort included 351 children with ALL (214 high-risk [HR-ALL]; 137 standard-risk [SR-ALL]), and 73 with AML. The prevalence of proven/probable IFD was 6.8% for AML, 14.0% for HR-ALL and 4.4% for SR-ALL. A mould was implicated as the causative pathogen in almost two thirds of cases. Antifungal prophylaxis was prescribed in 98.7% of chemotherapy cycles for AML, 56.7% for HR-ALL and 14.9% for SR-ALL. A mould-active agent was used in 77.4% of AML cycles and 21.2% of HR-ALL cycles. Mould-active prophylaxis was associated with a lower risk of IFD overall and increased IFD-free survival in AML., Interpretation: These data demonstrate the persistent high regional burden of IFD in children with HR-ALL, and the potential for mould-active prophylaxis to ameliorate this. Strategies to increase uptake of appropriate prophylaxis are required in this cohort., Funding: This study was supported by a Perth Children's Hospital Foundation grant (PCHF9973)., Competing Interests: All authors declare no conflicts of interest associated with this publication. MS has received honoraria from Gilead and F2G, outside of this work and participates on a Data Safety and Monitoring Board for Basilea, Pfizer, Roche and Merck. All other authors declare no competing interests., (Crown Copyright © 2024 Published by Elsevier Ltd.)

Introduction: The human gut microbiota has the potential to modulate the outcomes of several human diseases. This effect is likely to be mediated through interaction with the host immune system. This protocol details the establishment of a biorepository of clinically annotated samples, which we will use to explore correlations between the gut microbiota and the immune system of immune-compromised patients. We aim to identify microbiome-related risk factors for adverse outcomes., Methods and Analyses: This is a protocol for the development of a biorepository of clinically annotated samples collected prospectively across three centres in Melbourne, Australia. Participants will be recruited across the following clinical streams: (1) acute leukaemia and allogeneic stem cell transplant; (2) end-stage liver disease and liver transplant; (3) patients receiving any cancer immunotherapies (eg, chimeric antigen receptor therapy); (4) deceased organ donors and (5) healthy adult controls. Participants will be asked to provide paired peripheral blood and microbiota samples (stool and saliva) at either (1) single time point for healthy controls and deceased organ donors or (2) longitudinally over multiple prespecified or event-driven time points for the remaining cohorts. Sampling of fluid from bronchoalveolar lavage and colonoscopy or biopsy of tissues undertaken during routine care will also be performed., Ethics and Dissemination: Ethical approval has been obtained from the relevant local ethics committee (The Royal Melbourne Hospital Human Research Ethics Committee). The results of this study will be disseminated by various scientific platforms including social media, international presentations and publication in peer-reviewed journals., Trial Registration Number: ACTRN12623001105639. Date registered 20 October 2023., Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at http://www.icmje.org/disclosure-of-interest/ and declare: OS had financial support in the form of a postdoctoral scholarship from the National Health and Medical Research Council (NHMRC) for the submitted work (#1191571). MS is supported by NHMRC Leadership Investigator Grant (#1173791). KAM is on the advisory board for and holds equity in Postbiotics Plus Research, and she also reports consulting fees from Crestone and Incyte. All authors have no financial relationships with any organisations that might have an interest in the submitted work in the previous 3 years; no other relationships or activities that could appear to have influenced the submitted work. KAM reports that she holds equity and is ok the advisory board for Postbiotics Plus, and consults for Crestone., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Purpose of Review: Given the high mortality and morbidity associated with invasive fungal diseases (IFDs), the use of combination antifungal therapies is often considered despite the dearth of data. This review aims to summarize the current state of literature of combination antifungal therapies, discussing the potential roles of newer antifungal combinations and key considerations for their clinical use., Recent Findings: In infections other than cryptococcal meningitis or in the setting of empirical treatment for suspected azole-resistant Aspergillus infections, the utility of the combination antifungal approaches remains controversial given the paucity of well designed randomized controlled trials. Data on potential combined antifungal treatments have been primarily limited to in-vitro studies, animal models, case reports and/or observational studies. With availability of novel antifungal agents (e.g. ibrexafungerp, fosmanogepix), combination therapy to treat mould infections should be re-visited. A phase 2 clinical trial of ibrexafungerp combined with voriconazole to treat invasive pulmonary aspergillosis is on-going., Summary: There is a need to investigate the use of combination antifungal agents. This includes delineating the indication of these combined antifungal therapies and determining how to use them most appropriately in the clinical setting., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)