The epidemiology of invasive aspergillosis (IA) is evolving. To define the patient groups who will most likely benefit from primary or secondary Aspergillus prophylaxis, particularly those whose medical conditions and IA risk change over time, it is helpful to depict patient populations and their risk periods in a temporal visual model. The Sankey approach provides a dynamic figure to understand the risk of IA for various patient populations. While the figure depicted within this article is static, an internet-based version could provide pop-up highlights of any given flow's origin and destination nodes. A future version could highlight links to publications that support the color-coded incidence rates or other actionable items, such as bundles of applicable pharmacologic or non-pharmacologic interventions. The figure, as part of the upcoming Infectious Diseases Society of America's aspergillosis clinical practice guidelines, can guide decision-making in clinical settings.

The urgent cancer care (UCC) clinic at CancerCare Manitoba (CCMB) opened in 2013 to provide care to individuals diagnosed with cancer and serious blood disorders experiencing complications from the underlying disorder or its treatment. This study examined the impact of the UCC clinic on other health care utilization in Winnipeg, Manitoba, Canada. An interrupted time series study design was used to compare the rates of emergency department (ED) visits, primary care clinician (PCC) visits, and hospitalizations from 1 January 2010 to 31 December 2015. Rates of ED visits were also stratified by ED location, severity, and cancer type. We found a 6% (95% CI 1.00–1.13, p-value = 0.0389) increase in PCC visits, a 7% (95% CI 0.99–1.15, p-value = 0.0737) increase in hospitalizations, a 4% (95% CI 0.86–1.08, p-value = 0.5053) decrease in the rate of ED visits, and a 3% (95% CI 0.92–1.17, p-value = 0.5778) increase in the rate of ED visits during the UCC clinic hours after the UCC clinic opened. The implementation of the UCC clinic had minimal impact on health care utilization. Future work should examine the impact of the UCC clinic on other aspects of healthcare utilization (e.g., number of tests ordered and time spent waiting in CCMB’s main clinics) and patient quality of life and patient and health care provider experience.

The risks for invasive fungal infection (IFI) are enhanced by cytotoxic therapy-induced prolonged severe neutropenia, intestinal mucosal damage, and B- and T-cell immune suppression in patients receiving intensive therapy for acute myeloid leukemia (AML) or myelodyspla-sia(MDS)orhematopoieticstemcelltransplantation(HSCT).Mortality rates have remained unacceptably high in the range of one in four to one in five or higher for invasive candidiasis and invasive mold infection. There are four strategic approaches to IFI management for consid-eration: universal chemoprophylaxis to prevent IFI, diagnostics-driven preemptive therapy for early recognition and treatment of IFI, empirical therapy for suspected IFI based upon persistent or recrudescent neutropenic fever syndromes, and directed or targeted therapy for probable or proven IFI. Universal chemoprophylaxis has the potential to lower the risk of life-threatening IFI through prevention. Three classes of agents have been studied for universal chemopro-phylaxis,includingtopical,inhaled,andparenteralpolyenes,parenteral

BACKGROUND:Infectious disease physicians may be asked to evaluate and manage a variety of infections in immunocompromised hosts undergoing hematopoietic cell transplant (HCT) and cellular therapies. Over the last decade, several advances in cellular therapy have occurred, with implications for the types of infectious complications that may be seen.AIMS:The purpose of this review is to update the infectious disease physician on newer advances in HCT and cellular therapy, including haploidentical transplant, expanding indications for transplant in older individuals and children, and chimeric antigen receptor T-cells. We will review how these advances might influence infectious disease complications following HCT. We will also provide a perspective that infectious disease physicians can use to evaluate the degree of immune suppression in an individual patient to help determine the type of infections that may be encountered.

Background The burden of mucormycosis has increased with the expansion of risk groups and improved diagnosis. Although diabetes mellitus has been the leading risk factor for mucormycosis globally, the emergence of risk groups such as hemato-oncology patients, allogeneic bone marrow transplantation and solid organ transplantation have shifted the epidemiology of mucormycosis. There is a paucity of literature describing the burden, clinical presentation, treatment and outcomes of mucormycosis in Canada. CANMUS (Canadian Mucormycosis Study)is a national registry with broad geographical representation ,that will assess the epidemiology and clinical outcomes of Canadian patients affected by mucormycosis. Here we assess the outcomes at 6 and 12 weeks of therapy and last clinical assessment. Methods This retrospective registry involving 15 centers across Canada, from 1/1/2009 to 1/31/2020 using pathology/microbiology records to identify proven cases of mucormycosis in patients ≥18 years of age. Patient medical record data were collected and reported in a web-based data management program (REDCap). Descriptive statistics analyzed both categorical and continuous data. Cox proportional hazards models were used to explore risk factors for 6 and 12-week survival. Logistical regression was employed to investigate factors associated with positive clinical outcomes (defined as partial or complete response versus stable disease or progression). Results Interim data was available on 108 patients. The mean age was 53 (range 20-91) and 55.6% were male patients. The leading diagnostic risk factor for mucormycosis was hematological malignancy (50.9%, of which AML comprised 54.5%) followed by diabetes mellitus (25%). The most common sites of infection were: pulmonary (42.6%) rhino-sinus and/or orbital and/or cerebral (22.2%) and cutaneous (18%). The distribution of pathogens was: Mucor spp. (45.2%), Rhizopus spp. (34.5%) and Lichtheimia spp. (10.7%). Clinical response (composite of complete and partial responses) at 6 and 12 weeks was 31% and 29%, respectively. Survival analyses will be presented using hazard ratios and confidence intervals (CI). Logistic regression of factors associated with a positive clinical response will also be presented. Conclusions The epidemiology of mucormycosis in Canada is evolving. Hematological malignancies rather than diabetes are the major predisposing risk factor for mucormycosis with Mucor spp. being the predominant pathogen. Despite modest advances in therapies, outcomes remain poor.

In 2013, CancerCare Manitoba (CCMB) launched an urgent cancer care clinic (UCC) to meet the needs of individuals diagnosed with cancer experiencing acute complications of cancer or its treatment. This retrospective cohort study compared the characteristics of individuals diagnosed with cancer that visited the UCC to those who visited an emergency department (ED) and determined predictors of use. Multivariable logistic mixed models were run to predict an individual’s likelihood of visiting the UCC or an ED. Scaled Brier scores were calculated to determine how greatly each predictor impacted UCC or ED use. We found that UCC visits increased up to 4 months after eligibility to visit and then decreased. ED visits were highest immediately after eligibility and then decreased. The median number of hours between triage and discharge was 2 h for UCC visits and 9 h for ED visits. Chemotherapy had the strongest association with UCC visits, whereas ED visits prior to diagnosis had the strongest association with ED visits. Variables related to socioeconomic status were less strongly associated with UCC or ED visits. Future studies would be beneficial to planning service delivery and improving clinical outcomes and patient satisfaction.

Background: We examined the patterns of hand hygiene compliance (HHC) among health care providers (HCP) as observed by trained nurse and patient auditors over time in an ambulatory care Canadian provincial cancer agency. Methods: Nurse and volunteer patient auditors completed separate standardized forms documenting hand cleansing opportunities during clinic visits. HHC rates were compared over time by HCP group and by specialty teams. Observations from 10 calendar quarters were analyzed from April 2015 to September 2019. Results: Nurse audit HHC rates ranged from 84% to 96%, encompassing 7,213 opportunities with no signifi-cant time-dependent trends by linear regression (R-2= 2.3E-005, P = .9895). The patient audit HHC rates ranged from 57% to 82%, encompassing 23,402 opportunities, were lower overall compared to the nurse audit (73.6% vs 89.2%, respectively, P < .0001), but displayed an increasing trend (R-2 = 0.5374, P = .0159) over the same 10 time periods. The relative risk ratio for the differences decreased over time (R-2= .5101, P = .0203). Patients acknowledged the importance of HHC and the audit process, but were reticent to remind HCP to comply. Conclusions: The nurse audit measuring HCP HHC before entering and after exiting patient examination rooms showed persistently high compliance over time whereas the patient-driven audit measuring HHC within the examination room increased over time suggesting a training effect upon practice. These measures appeared complementary. (C) 2020 Published by Elsevier Inc. on behalf of Association for Professionals in Infection Control and Epidemiology, Inc.

Purpose To provide an updated joint ASCO/Infectious Diseases Society of American (IDSA) guideline on outpatient management of fever and neutropenia in patients with cancer. Methods ASCO and IDSA convened an Update Expert Panel and conducted a systematic review of relevant studies. The guideline recommendations were based on the review of evidence by the Expert Panel. Results Six new or updated meta-analyses and six new primary studies were added to the updated systematic review. Recommendation Clinical judgment is recommended when determining which patients are candidates for outpatient management, using clinical criteria or a validated tool such as the Multinational Association of Support Care in Cancer risk index. In addition, psychosocial and logistic considerations are outlined within the guideline. The panel continued to endorse consensus recommendations from the previous version of this guideline that patients with febrile neutropenia receive initial doses of empirical antibacterial therapy within 1 hour of triage and be monitored for ≥ 4 hours before discharge. An oral fluoroquinolone plus amoxicillin/clavulanate (or clindamycin, if penicillin allergic) is recommended as empirical outpatient therapy, unless fluoroquinolone prophylaxis was used before fever developed. Patients who do not defervesce after 2 to 3 days of an initial, empirical, broad-spectrum antibiotic regimen should be re-evaluated and considered as candidates for inpatient treatment. Additional information is available at www.asco.org/supportive-care-guidelines and www.asco.org/guidelineswiki .

The purpose of this study was to determine whether fungicidal versus fungistatic pharmacotherapy of invasive candidiasis/candidemia yields superior outcomes. Data sources included MEDLINE (1966–June 2017), EMBASE (1980–June 2017), PubMed (1966–June 2017), Global Health-Ovid (inception to June 2017), LILACS Virtual Health Library (inception to June 2017) and the Cochrane Central Register of Controlled Trials (to 2nd quarter 2017). The ClinicalTrial.gov database, the SCOPUS database, SIGLE (System for Information on Grey Literature) and Google Scholar were also utilised to search for relevant studies. Randomised studies of any pharmacotherapy of invasive candidiasis including candidemia using a fungicidal (amphotericin B or echinocandin compound) versus a fungistatic (triazole) compound in adolescent or adult non-neutropenic patients. Eight studies met the inclusion criteria. Pooled odds ratios demonstrated an advantage of fungicidal therapy with respect to early therapeutic success (OR 1.61, 95% CI 1.27–2.03, p < 0.0001, I2 = 0%) and persistence or recurrence of infection (OR 0.51, 95% CI 0.35–0.74, p = 0.0005, I2 = 0%) but no advantage for late survival (OR 0.97, 95% CI 0.77–1.21, p = 0.77, I2 = 0%). Fungicidal therapy of invasive candidiasis and candidemia is associated with a higher probability of early therapeutic success and decreased probability of persistent or recurrent infection. However, there is no improvement in survival.

A patient-driven hand hygiene compliance audit strategy was piloted in a Canadian provincial cancer agency during routine provision of cancer outpatient care by health care providers (physicians, nurses, and health care aides) under conditions where the deployment of an independent external auditor was not feasible. The results of the audit suggest the feasibility of this approach as a routine institutional performance metric.

SummaryPatients undergoing allogeneic haematopoietic stem cell transplantation (alloHSCT) are at risk of developing invasive fungal infections (IFIs). Even with introduction of oral triazole antifungal agents (fluconazole, itraconazole, posaconazole and voriconazole) IFI‐associated morbidity and mortality rates and economic burden remain high. Despite their proven efficacy, it is currently unknown which is the most cost‐effective antifungal prophylaxis (AFP) agent. To determine the costs and outcomes associated with AFP, a decision‐analytic model was used to simulate treatment in a hypothetical cohort of 1000 patients undergoing alloHSCT from the perspective of the Spanish National Health System. Generic itraconazole was the least costly AFP (€162) relative to fluconazole (€500), posaconazole oral suspension (€8628) or voriconazole (€6850). Compared with posaconazole, voriconazole was associated with the lowest number of breakthrough IFIs (36 vs 60); thus, the model predicted fewer deaths from breakthrough IFI for voriconazole (24) than posaconazole (33), and the lowest predicted costs associated with other licensed antifungal treatment and IFI treatment in a cohort of 1000. Voriconazole resulted in cost savings of €4707 per patient compared with posaconazole. Itraconazole demonstrated a high probability of being cost‐effective. As primary AFP in alloHSCT patients 180 days posttransplant, voriconazole was more likely to be cost‐effective than posaconazole regarding cost per additional IFI and additional death avoided.

Background: Antifungal prophylaxis is a promising strategy for reducing invasive fungal infections (IFIs) in allogeneic hematopoietic cell transplant (alloHCT) recipients, but the optimum prophylactic agent is unknown. We used mixed treatment comparison (MTC) meta-analysis to compare clinical trials examining the use of oral antifungals for prophylaxis in alloHCT recipients, with the goal of informing medical decision-making.Methods: Randomized controlled trials (RCTs) of fluconazole, itraconazole, posaconazole, and voriconazole for primary antifungal prophylaxis were identified through a systematic literature review. Outcomes of interest (incidence of IFI/invasive aspergillosis/invasive candidiasis, all-cause mortality, and use of other antifungals) were extracted from eligible RCTs and incorporated into a Bayesian hierarchical random-effects MTC.Results: Five eligible RCTs, randomizing 2147 patients in total, were included. Relative to fluconazole, prophylaxis with itraconazole (odds ratio [OR]: 0.52; interquartile range [IQR]: 0.35-0.76), posaconazole (OR: 0.56; IQR: 0.32-0.99), and voriconazole (OR: 0.46; IQR: 0.28-0.73) reduced incidence of overall proven/probable IFI. Posaconazole (OR: 0.31; IQR: 0.17-0.58) and voriconazole (OR: 0.33; IQR: 0.17-0.58) prophylaxis reduced proven/ probable invasive aspergillosis more than itraconazole (OR: 0.68; IQR: 0.42-1.12). All-cause mortality was similar across all mould-active agents.Conclusion: As expected, mould-active azoles prevented IFIs, particularly invasive aspergillosis, more effectively than fluconazole in alloHCT recipients. The paucity of comparative efficacy data suggests that other factors such as long-term tolerability, availability of intravenous formulations, local IFI epidemiology, and drug costs may need to form the basis for selection among the mould-active azoles.

Purpose: Patients with persistent or recurrent neutropenic fevers at risk of invasive fungal disease (IFD) are treated empirically with antifungal therapy (AFT). Early treatment using a diagnostic-driven (DD) strategy may reduce clinical and economic burdens. We compared costs and outcomes of both strategies from a UK perspective.Methods: An empirical strategy with conventional amphotericin B deoxycholate (C-AmB), liposomal amphotericin B (L-AmB), or caspofungin was compared with a DD strategy (initiated based on positive ELISA results for galactomannan antigen) and/or positive results for Aspergillus species on polymerase chain reaction assay) using C-AmB, voriconazole, or L-AmB in a decision-analytic model. Rates of IFD incidence, overall mortality, and IFD-related mortality in adults expected to be neutropenic for days were obtained. The empirical strategy was assumed to identify 30% of IFD and targeted AFT to improve survival by a hazard ratio of 0.589. AFT-specific adverse events were obtained from a summary of product characteristics. Resource use was obtained, and costs were estimated by using standard UK costing sources. All costs are presented in 2012 British pounds sterling.Findings: Total costs were 32% lower for the DD strategy (1561.29) pound versus the empirical strategy (2301.93) pound due to a reduced incidence of adverse events and decreased use of AFT. Administration of AFT was reduced by 41% (DD strategy, 74 of 1000; empirical strategy, 125 of 1000), with similar survival rates.Implications: This study suggests that a DD strategy is likely to be cost-saving versus empirical treatment for immunocompromised patients with persistent or recurrent neutropenic fevers. (C) 2015 The Authors. Published by Elsevier HS Journals, Inc.

BACKGROUND:Isavuconazole is a novel triazole with broad-spectrum antifungal activity. The SECURE trial assessed efficacy and safety of isavuconazole versus voriconazole in patients with invasive mould disease. METHODS:This was a phase 3, double-blind, global multicentre, comparative-group study. Patients with suspected invasive mould disease were randomised in a 1:1 ratio using an interactive voice-web response system, stratified by geographical region, allogeneic haemopoietic stem cell transplantation, and active malignant disease at baseline, to receive isavuconazonium sulfate 372 mg (prodrug; equivalent to 200 mg isavuconazole; intravenously three times a day on days 1 and 2, then either intravenously or orally once daily) or voriconazole (6 mg/kg intravenously twice daily on day 1, 4 mg/kg intravenously twice daily on day 2, then intravenously 4 mg/kg twice daily or orally 200 mg twice daily from day 3 onwards). We tested non-inferiority of the primary efficacy endpoint of all-cause mortality from first dose of study drug to day 42 in patients who received at least one dose of the study drug (intention-to-treat [ITT] population) using a 10% non-inferiority margin. Safety was assessed in patients who received the first dose of study drug. This study is registered with ClinicalTrials.gov, number NCT00412893. FINDINGS:527 adult patients were randomly assigned (258 received study medication per group) between March 7, 2007, and March 28, 2013. All-cause mortality from first dose of study drug to day 42 for the ITT population was 19% with isavuconazole (48 patients) and 20% with voriconazole (52 patients), with an adjusted treatment difference of -1·0% (95% CI -7·8 to 5·7). Because the upper bound of the 95% CI (5·7%) did not exceed 10%, non-inferiority was shown. Most patients (247 [96%] receiving isavuconazole and 255 [98%] receiving voriconazole) had treatment-emergent adverse events (p=0·122); the most common were gastrointestinal disorders (174 [68%] vs 180 [69%]) and infections and infestations (152 [59%] vs 158 [61%]). Proportions of patients with treatment-emergent adverse events by system organ class were similar overall. However, isavuconazole-treated patients had a lower frequency of hepatobiliary disorders (23 [9%] vs 42 [16%]; p=0·016), eye disorders (39 [15%] vs 69 [27%]; p=0·002), and skin or subcutaneous tissue disorders (86 [33%] vs 110 [42%]; p=0·037). Drug-related adverse events were reported in 109 (42%) patients receiving isavuconazole and 155 (60%) receiving voriconazole (p<0·001). INTERPRETATION:Isavuconazole was non-inferior to voriconazole for the primary treatment of suspected invasive mould disease. Isavuconazole was well tolerated compared with voriconazole, with fewer study-drug-related adverse events. Our results support the use of isavuconazole for the primary treatment of patients with invasive mould disease. FUNDING:Astellas Pharma Global Development, Basilea Pharmaceutica International.

Invasive fungal infections cause significant morbidity and mortality in patients with concomitant underlying immunosuppressive diseases. The recent addition of new triazoles to the antifungal armamentarium has allowed for extended-spectrum activity and flexibility of administration. Over the years, clinical use has raised concerns about the degree of drug exposure following standard approved drug dosing, questioning the need for therapeutic drug monitoring (TDM). Accordingly, the present guidelines focus on TDM of triazole antifungal agents. A review of the rationale for triazole TDM, the targeted patient populations and available laboratory methods, as well as practical recommendations based on current evidence from an extended literature review are provided in the present document.

PURPOSE:To provide guidelines on antimicrobial prophylaxis for adult neutropenic oncology outpatients and on selection and treatment as outpatients of those with fever and neutropenia. METHODS:A literature search identified relevant studies published in English. Primary outcomes included: development of fever and/or infections in afebrile neutropenic outpatients and recovery without complications and overall mortality in febrile neutropenic outpatients. Secondary outcomes included: in afebrile neutropenic outpatients, infection-related mortality; in outpatients with fever and neutropenia, defervescence without regimen change, time to defervescence, infectious complications, and recurrent fever; and in both groups, hospital admissions, duration, and adverse effects of antimicrobials. An Expert Panel developed guidelines based on extracted data and informal consensus. RESULTS:Forty-seven articles from 43 studies met selection criteria. RECOMMENDATIONS:Antibacterial and antifungal prophylaxis are only recommended for patients expected to have < 100 neutrophils/μL for > 7 days, unless other factors increase risks for complications or mortality to similar levels. Inpatient treatment is standard to manage febrile neutropenic episodes, although carefully selected patients may be managed as outpatients after systematic assessment beginning with a validated risk index (eg, Multinational Association for Supportive Care in Cancer [MASCC] score or Talcott's rules). Patients with MASCC scores ≥ 21 or in Talcott group 4, and without other risk factors, can be managed safely as outpatients. Febrile neutropenic patients should receive initial doses of empirical antibacterial therapy within an hour of triage and should either be monitored for at least 4 hours to determine suitability for outpatient management or be admitted to the hospital. An oral fluoroquinolone plus amoxicillin/clavulanate (or plus clindamycin if penicillin allergic) is recommended as empiric therapy, unless fluoroquinolone prophylaxis was used before fever developed.