Patterns and Drivers of Antifungal Prescribing in Acute Leukemia: A Retrospective Cohort Study.

Background: Patients with hematological malignancy are at high risk of invasive fungal infections (IFIs). Diagnosis is challenging, which can lead to overtreatment. Reducing exposure to inappropriate antifungal prescribing is likely to improve patient safety, but modifying prescribing behavior is difficult. We aimed to describe patterns and drivers of therapeutic antifungal prescribing in a large tertiary hemato-oncology center in the United Kingdom. Methods: We studied adults receiving treatment for acute leukemia at our center between 1 April 2019 and 14 October 2022. We developed a reproducible method to analyze routinely collected data on antifungal therapy episodes in a widely used electronic health record system. We report antifungal use in days of therapy stratified by level of diagnostic confidence, as defined by consensus diagnostic guidelines (European Organisation for Research and Treatment of Cancer/Mycoses Study Group). Results: Two hundred ninety-eight patients were included in the analysis; 21.7% of inpatient antifungal use occurred in cases of proven/probable IFI. Substantial antifungal use occurred in the absence of strong evidence of infection in patients receiving high-intensity first-line chemotherapy or approaching death (81.0% and 77.9%, respectively). Approximately 33% of high-resolution computed tomography (HRCT) reports were indeterminate for IFI. Indeterminate reports were around 8 times more likely to be followed by a new antifungal therapy episode than a negative report. Conclusions: Antifungal stewardship remains challenging in the absence of reliable diagnostics, particularly in more unwell patients. The proportion of antifungal therapy given for proven/probable infection is a new metric that will likely be useful to target antifungal stewardship programs. The thoracic HRCT report is an important contributor to diagnostic uncertainty.

A Case for Regularly Obtaining Nutrition History: Food for Thought.

This Teachable Moment discusses providing patients with an opportunity to initiate dietary change before prescribing statin therapy for even severely high low-density lipoprotein cholesterol levels.

High pretreatment disease burden as a risk factor for infectious complications following CD19 chimeric antigen receptor T-cell therapy for large B-cell lymphoma.

Infection has emerged as the chief cause of non-relapse mortality (NRM) post CD19-targeting chimeric antigen receptor T-cell therapy (CAR-T) therapy. Even though up to 50% of patients may remain infection-free, many suffer multiple severe, life-threatening, or fatal infectious events. The primary aim of this study was to explore severe and life-threatening infections post licensed CAR-T therapy in large B-cell lymphoma, with a focus on the role of disease burden and disease sites in assessing individual risk. We sought to understand the cohort of patients who experience ≥2 infections and those at the highest risk of infectious NRM. Our analysis identifies a higher disease burden after bridging therapy as associated with infection events. Those developing ≥2 infections emerged as a uniquely high-risk cohort, particularly if the second (or beyond) infection occurred during an episode of immune effector cell-associated neurotoxicity syndrome (ICANS) or while on steroids and/or anakinra for ICANS. Herein, we also describe the first reported cases of "CAR-T cold sepsis," a phenomenon characterized by the lack of an appreciable systemic inflammatory response at the time of detection of infection. We propose a risk-based strategy to encourage heightened clinician awareness of cold sepsis, with a view to reducing NRM.

Mucormycosis after CD19 chimeric antigen receptor T-cell therapy: results of a US Food and Drug Administration adverse events reporting system analysis and a review of the literature.

Chimeric antigen receptor (CAR) T-cell therapy leads to durable remissions in relapsed B-cell cancers, but treatment-associated immunocompromise leads to a substantial morbidity and mortality risk from atypical infection. Mucormycosis is an aggressive and invasive fungal infection with a mortality risk of 40-80% in patients with haematological malignancies. In this Grand Round, we report a case of mucormycosis in a 54-year-old patient undergoing CAR T-cell therapy who reached complete clinical control of Mucorales with combined aggressive surgical debridement, antifungal pharmacotherapy, and reversal of underlying risk factors, but with substantial morbidity from extensive oro-facial surgery affecting the patient's speech and swallowing. For broader context, we present our case alongside an US Food and Drugs Administration adverse events reporting database analysis and a review of the literature to fully evaluate the clinical burden of mucormycosis in patients treated with CAR T-cell therapy. We discuss epidemiology, clinical features, diagnostic tools, and current frameworks for treatment and prophylaxis. We did this analysis to promote increased vigilance for mucormycosis among physicians specialising in CAR T-cell therapy and microbiologists and to illustrate the importance of early initiation of therapy to effectively manage this condition. Mucormycosis prevention and early diagnosis, through targeted surveillance and mould prevention in patients at highest risk and Mucorales-specific screening assays, is likely to be key to improving outcomes in patients treated with CAR T-cell therapy.

Antifungal susceptibility profiles for fungal isolates from corneas and contact lenses in the United Kingdom.

OBJECTIVE: To report the identification and results of susceptibility testing for fungal isolates from the cornea or contact lens care systems. MATERIALS AND METHODS: In this retrospective epidemiological study, we searched the results of fungal cultures from cornea or contact lens systems referred for identification and susceptibility testing to the United Kingdom National Mycology Reference Laboratory between October 2016 and March 2022. For each fungal isolate, we recorded the genus and species of the fungus and the minimum inhibitory concentration (MIC) to six antifungal agents available to treat corneal infection (amphotericin, econazole, itraconazole, natamycin, posaconazole, and voriconazole). RESULTS: There were 600 isolates from 585 patients, comprising 374 (62%) from corneal samples and 226 from contact lenses and care systems, of which 414 (69%) isolates were moulds (filamentous fungi) and 186 (31%) were yeasts. The most frequent moulds isolated were Fusarium spp (234 isolates, 39%) and Aspergillus spp (62, 10%). The most frequent yeasts isolated were Candida spp (112, 19%), predominantly Candida parapsilosis (65, 11%) and Candida albicans (33, 6%), with 35 isolates (6%) of Meyerozyma guilliermondii. In vitro susceptibility was greatest for natamycin (347 moulds tested, mode 4 mg/L, range 0.25-64 mg/L; 98 yeasts tested, mode 4 mg/L, range 0.5-32 mg/L), with susceptibility for 94% for moulds and 99% yeasts. Of the 16 isolates interpreted as highly resistant to natamycin (MIC ≥16 mg/L), 13 were Aspergillus flavus complex. CONCLUSIONS: In vitro susceptibility supports the use of natamycin for the empiric treatment of fungal keratitis in the UK.

Challenges in the Management of Invasive Fungal Infections in the Middle East: Expert Opinion to Optimize Management Using a Multidisciplinary Approach.

Invasive fungal infection (IFI) is a significant global healthcare concern among critically ill and immunocompromised patients. In Middle Eastern countries, IFI has been steadily increasing among hospitalized patients in the past two decades. Diagnosis of IFI at an early stage is crucial for efficient management. Invasive fungal infection management is complex and requires the involvement of physicians from different specialties. There are several challenges associated with IFI management in the countries in the Middle East. This review aims to understand the key challenges associated with IFI management in the Middle East, encompassing epidemiology, diagnosis, therapeutic options, and optimizing a multidisciplinary approach. In addition, this review aims to incorporate expert opinions from multidisciplinary fields for optimizing IFI management in different Middle Eastern countries by addressing key decision points throughout the patient's journey. Lack of epidemiological data on fungal infections, slow and poorly sensitive conventional culture-based diagnostic tests, limited availability of biomarker testing, lack of awareness of clinical symptoms of the disease, limited knowledge on fungal infections, lack of local practice guidelines, and complicated disease management are the major challenges associated with IFI diagnosis and management in the Middle Eastern countries. Implementation of a multidisciplinary approach, antifungal stewardship, improved knowledge of fungal infections, the use of rapid diagnostic tests, and enhanced epidemiological research are warranted to lower the IFI burden in the Middle East.

Purpura fulminans secondary to Capnocytophaga canimorsus bacteraemia following a dog bite: A case report and review of literature.

Introduction: Infection due to Capnocytophaga canimorsus may result in a wide variety of clinical presentations. We present a case of life-threatening Capnocytophaga canimorsus infection with evolution of ecchymosis to purpura fulminans. Case description: We present a case of a 43-year-old male with a history of excessive alcohol consumption who presented with features of sepsis following a dog bite. This was associated with a striking, widespread purpuric rash. A causative pathogen, C. canimorsus was identified through blood culture and 16S RNA sequencing. His initially purpuric rash underwent bullous transformation and was diagnosed clinically as purpura fulminans, confirmed on skin biopsy. He made a full recovery with prompt antimicrobial therapy, initially with co-amoxiclav but escalated to clindamycin and meropenem due to clinical deterioration and concerns of beta-lactamase resistance. Discussion: ß-Lactamase producing Capnocytophaga strains are of increasing concern. This particular concern is reflected in our case as 5 days into treatment with ß-lactamase inhibitor combination therapy the patients clinical condition deteriorated but demonstrably improved on switching to a carbapenem.The development of biopsy proven purpura fulminans in this immunocompetent case is a rare severe manifestation of the previously reported manifestation of disseminated intravascular coagulation (DIC) in Capnocytophaga bacteraemia. The case reported describes characteristics common with other DIC presentations such as the presence of clinical risk factors (history of excessive alcohol consumption) and symmetrical involvement. However, an unusual feature in that initial purpuric lesions were followed by the development of a bullous appearance and peripheral necrotic features concerning for purpura fulminans and confirmed with skin biopsy.

T2Candida assay: diagnostic performance and impact on antifungal prescribing.

Objectives: To assess the performance of T2Candida for the diagnosis of invasive candidiasis (IC) against gold standards of candidaemia or consensus IC definitions, and to evaluate the impact of T2Candida on antifungal drug prescribing. Methods: A retrospective review was undertaken of all T2Candida (T2MR technology, T2 Biosystems) performed from October 2020 to February 2022. T2Candida performance was evaluated against confirmed candidaemia or against proven/probable IC within 48 hours of T2Candida, and its impact on antifungal drug prescriptions. Results: T2Candida was performed in 61 patients, with 6 (9.8%) positive results. Diagnostic performance of T2Candida against candidaemia had a specificity of 85.7% and negative predictive value (NPV) of 96.8%. When comparing T2Candida results with consensus definitions of IC, the specificity and NPV of T2Candida was respectively 90% (54/60) and 98.2% (54/55) for proven IC, and 91.4% (53/58) and 96.4% (53/55) for proven/probable IC. Antifungals were initiated in three of six patients (50%) with a positive T2Candida result. Thirty-three patients were receiving empirical antifungals at the time of T2Candida testing, and a negative result prompted cessation of antifungals in 11 (33%) patients, compared with 6 (25%) antifungal prescriptions stopped following negative beta-d-glucan (BDG) testing in a control population (n = 24). Conclusions: T2Candida shows high specificity and NPV compared with evidence of Candida bloodstream infection or consensus definitions for invasive Candida infection, and may play an adjunctive role as a stewardship tool to limit unnecessary antifungal prescriptions.

Presacral malakoplakia presenting as foot drop: a case report.

BACKGROUND: Malakoplakia is a rare condition characterized by inflammatory masses with specific histological characteristics. These soft tissue masses can mimic tumors and tend to develop in association with chronic or recurrent infections, typically of the urinary tract. A specific defect in innate immunity has been described. In the absence of randomized controlled trials, management is based on an understanding of the biology and on case reports. CASE PRESENTATION: Here we describe a case of presacral malakoplakia in a British Indian woman in her late 30s, presenting with complex unilateral foot drop. Four years earlier, she had suffered a protracted episode of intrapelvic sepsis following a caesarean delivery. Resection of her presacral soft tissue mass was not possible. She received empiric antibiotics, a cholinergic agonist, and ascorbic acid. She responded well to medical management both when first treated and following a recurrence of symptoms after completing an initial 8 months of therapy. Whole exome sequencing of the patient and her parents was undertaken but no clear causal variant was identified. CONCLUSIONS: Malakoplakia is uncommon but the diagnosis should be considered where soft tissue masses develop at the site of chronic or recurrent infections. Obtaining tissue for histological examination is key to making the diagnosis. This case suggests that surgical resection is not always needed to achieve a good clinical and radiological outcome.

Social Mycology: Using Social Media Networks in the Management of Aspergillosis and Other Mycoses.

Online social media networks are an integral part of modern life. Microblogging sites such as Twitter have hundreds of millions of active users globally and have been enthusiastically adopted by many in the medical profession. For advancing a relatively neglected field such as fungal infection, this can be especially advantageous. Education, research networking, case discussions and public and patient engagement can all be greatly enhanced through the use of social media networks. This review highlights the ways in which this can work successfully in the case of aspergillosis and fungal infection in general, as well as highlighting the dangers and pitfalls of social media medicine.

Antimicrobial resistance in topical treatments for microbial keratitis: protocol for a systematic review and meta-analysis.

INTRODUCTION: There is evidence for increased resistance against the antimicrobials used to treat keratitis. This review aims to provide global and regional prevalence estimates of antimicrobial resistance in corneal isolates and the range of minimum inhibitory concentrations (MIC) with their associated resistance breakpoints. METHODS AND ANALYSIS: We report this protocol following Preferred Reporting Items for Systematic Review and Meta-Analyses Protocols guidelines. We will conduct an electronic bibliographic search in MEDLINE, EMBASE, Web of Science and the Cochrane Library. Eligible studies will report in any language data for the resistance or MIC for antimicrobials against bacterial, fungal or amoebic organisms isolated from suspected microbial keratitis. Studies that only report on viral keratitis will not be included. There will be no time restrictions on the date of publication. Screening for eligible studies, assessment of risk of bias and data extraction will be conducted by two reviewers independently, using predefined inclusion criteria and prepiloted data extraction forms. We will resolve disagreements between the reviewers by discussion and, if required, a third (senior) reviewer will arbitrate. We will assess the risk of bias using a tool validated in prevalence studies. The certainty of the evidence will be assessed using the Grades of Recommendation, Assessment, Development and Evaluation approach. Pooled proportion estimates will be calculated using a random-effects model. Heterogeneity will be assessed using the I2 statistic. We will explore differences between Global Burden of Disease regions and temporal trends. ETHICS APPROVAL AND DISSEMINATION: Ethics approval is not required as this is a protocol for a systematic review of published data. The findings of this review will be published in an open-access, peer-reviewed journal. PROSPERO REGISTRATION NUMBER: CRD42023331126.

Diagnosis of invasive respiratory mycoses in the immunocompromised host.

PURPOSE OF REVIEW: The burden of invasive fungal infection is increasing worldwide, largely due to a growing population at-risk. Most serious human fungal pathogens enter the host via the respiratory tract. Early identification and treatment of invasive fungal respiratory infections (IFRIs) in the immunocompromised host saves lives. However, their accurate diagnosis is a difficult challenge for clinicians and mortality remains high. RECENT FINDINGS: This article reviews IFRIs, focussing on host susceptibility factors, clinical presentation, and mycological diagnosis. Several new diagnostic tools are coming of age including molecular diagnostics and point-of-care antigen tests. As diagnosis of IFRI relies heavily on invasive procedures like bronchoalveolar lavage and lung biopsy, several novel noninvasive diagnostic techniques are in development, such as metagenomics, 'volatilomics' and advanced imaging technologies. SUMMARY: Where IFRI cannot be proven, clinicians must employ a 'weights-of-evidence' approach to evaluate host factors, clinical and mycological data. Implementation studies are needed to understand how new diagnostic tools can be best applied within clinical pathways. Differentiating invasive infection from colonization and identifying antifungal resistance remain key challenges. As our diagnostic arsenal expands, centralized clinical mycology laboratories and efforts to ensure access to new diagnostics in low-resource settings will become increasingly important.

Primary Prevention Management of Elevated Lipoprotein(a).

A male individual in his 40s with a strong family history of atherosclerotic cardiovascular disease including premature cardiovascular events in multiple family members presents to your clinic to establish care for cardiovascular risk stratification. What would you do next?