Validation of the Antifungal National Antimicrobial Prescribing Survey (AF-NAPS) quality assessment tool.

BACKGROUND: The Antifungal National Antimicrobial Prescribing Survey (AF-NAPS) was developed to undertake streamlined quality audits of antifungal prescribing. The validity and reliability of such tools is not characterized. OBJECTIVES: To assess the validity and reliability of the AF-NAPS quality assessment tool. METHODS: Case vignettes describing antifungal prescribing were prepared. A steering group was assembled to determine gold-standard classifications for appropriateness and guideline compliance. Infectious diseases physicians, antimicrobial stewardship (AMS) and specialist pharmacists undertook a survey to classify appropriateness and guideline compliance of prescriptions utilizing the AF-NAPS tool. Validity was measured as accuracy, sensitivity and specificity compared with gold standard. Inter-rater reliability was measured using Fleiss' kappa statistics. Assessors' responses and comments were thematically analysed to determine reasons for incorrect classification. RESULTS: Twenty-eight clinicians assessed 59 antifungal prescriptions. Overall accuracy of appropriateness assessment was 77.0% (sensitivity 85.3%, specificity 68.0%). Highest accuracy was seen amongst specialist (81%) and AMS pharmacists (79%). Prescriptions with lowest accuracy were in the haematology setting (69%), use of echinocandins (73%), mould-active azoles (75%) and for prophylaxis (71%). Inter-rater reliability was fair overall (0.3906), with moderate reliability amongst specialist pharmacists (0.5304). Barriers to accurate classification were incorrect use of the appropriateness matrix, knowledge gaps and lack of guidelines for some indications. CONCLUSIONS: The AF-NAPS is a valid tool, assisting assessors to correctly classify appropriate prescriptions more accurately than inappropriate prescriptions. Specialist and AMS pharmacists had similar performance, providing confidence that both can undertake AF-NAPS audits to a high standard. Identified reasons for incorrect classification will be targeted in the online tool and educational materials.

Establishing essential metrics for antifungal stewardship in hospitals: the results of an international Delphi survey.

BACKGROUND: Guidance on assessment of the quantity and appropriateness of antifungal prescribing is required to assist hospitals to interpret data effectively and structure quality improvement programmes. OBJECTIVES: To achieve expert consensus on a core set of antifungal stewardship (AFS) metrics and to determine their feasibility for implementation. METHODS: A literature review was undertaken to develop a list of candidate metrics. International experts were invited to participate in sequential web-based surveys to evaluate the importance and feasibility of metrics in the area of AFS using Delphi methodology. Three surveys were completed. Consensus was predefined as ≥80% agreement on the importance of each metric. RESULTS: Eighty-two experts consented to participate from 17 different countries. Response rate for each survey was >80%. The panel included adult and paediatric physicians, microbiologists and pharmacists with diverse content expertise. Consensus was achieved for 38 metrics considered important to routinely include in AFS programmes, and related to antifungal consumption (n = 5), quality of antifungal prescribing and management of invasive fungal infection (IFI) (n = 24), and clinical outcomes (n = 9). Twenty-one consensus metrics were considered to have moderate to high feasibility for routine collection. CONCLUSIONS: The identified core AFS metrics will provide a framework to comprehensively assess the quantity and quality of antifungal prescribing within hospitals to develop quality improvement programmes aimed at improving IFI prevention, management and patient-centred outcomes. A standardized approach will support collaboration and benchmarking to monitor the efficacy of current prophylaxis and treatment guidelines, and will provide important feedback to guideline developers.

Epidemiology and risks for infection following cytoreductive surgery and hyperthermic intra-peritoneal chemotherapy.

BACKGROUND: CRS-HIPEC is associated with improved cancer survival but an increased risk of infection. METHODS: Consecutive patients undergoing CRS-HIPEC between January 2016 and May 2018 were retrospectively reviewed. Malignancy type, comorbidities, perioperative risk factors and infectious complications were captured, using standardised definitions. Association between risk factors and infection outcomes was evaluated by logistic regression modelling. RESULTS: One-hundred patients underwent CRS-HIPEC, predominantly for colorectal cancer and pseudomyxoma peritonei. Overall, 43 (43.0%) experienced an infectious complication, including infections at surgical site (27), respiratory tract (9), urinary tract (11), Clostridium difficile (2) and post-operative sepsis (15). In most, infection onset was within 7 days post-operatively. Median length of hospitalisation was 19 days for patients with infection, compared to 8 days for those without (p = 0.000). There were no deaths at 60 days. Of variables potentially associated with surgical site infection, small bowel resection (OR 4.01, 95% confidence interval [CI] 1.53-10.83; p = 0.005) and number of resected viscera (OR 1.41, 95% CI 1.00-1.98; p = 0.048) were significantly associated with infection. CONCLUSIONS: We demonstrate a significant burden of early infective complications in patients undergoing CRS-HIPEC. Higher-risk subgroups, including those with small bowel resection and increased number of resected viscera, may benefit from enhanced monitoring.

FDG PET/CT imaging in detecting and guiding management of invasive fungal infections: a retrospective comparison to conventional CT imaging.

PURPOSE: Invasive fungal infections (IFIs) are common in immunocompromised patients. While early diagnosis can reduce otherwise high morbidity and mortality, conventional CT has suboptimal sensitivity and specificity. Small studies have suggested that the use of FDG PET/CT may improve the ability to detect IFI. The objective of this study was to describe the proven and probable IFIs detected on FDG PET/CT at our centre and compare the performance with that of CT for localization of infection, dissemination and response to therapy. METHODS: FDG PET/CT reports for adults investigated at Peter MacCallum Cancer Centre were searched using keywords suggestive of fungal infection. Chart review was performed to describe the risk factors, type and location of IFIs, indication for FDG PET/CT, and comparison with CT for the detection of infection, and its dissemination and response to treatment. RESULTS: Between 2007 and 2017, 45 patients had 48 proven/probable IFIs diagnosed prior to or following FDG PET/CT. Overall 96% had a known malignancy with 78% being haematological. FDG PET/CT located clinically occult infection or dissemination to another organ in 40% and 38% of IFI patients, respectively. Of 40 patients who had both FDG PET/CT and CT, sites of IFI dissemination were detected in 35% and 5%, respectively (p < 0.001). Of 18 patents who had both FDG PET/CT and CT follow-up imaging, there were discordant findings between the two imaging modalities in 11 (61%), in whom normalization of FDG avidity of a lesion suggested resolution of active infection despite a residual lesion on CT. CONCLUSION: FDG PET/CT was able to localize clinically occult infection and dissemination and was particularly helpful in demonstrating response to antifungal therapy.

Candidaemia and a risk predictive model for overall mortality: a prospective multicentre study.

BACKGROUND: Candidaemia is associated with high mortality. Variables associated with mortality have been published previously, but not developed into a risk predictive model for mortality. We sought to describe the current epidemiology of candidaemia in Australia, analyse predictors of 30-day all-cause mortality, and develop and validate a mortality risk predictive model. METHODS: Adults with candidaemia were studied prospectively over 12 months at eight institutions. Clinical and laboratory variables at time of blood culture-positivity were subject to multivariate analysis for association with 30-day all-cause mortality. A predictive score for mortality was examined by area under receiver operator characteristic curves and a historical data set was used for validation. RESULTS: The median age of 133 patients with candidaemia was 62 years; 76 (57%) were male and 57 (43%) were female. Co-morbidities included underlying haematologic malignancy (n = 20; 15%), and solid organ malignancy in (n = 25; 19%); 55 (41%) were in an intensive care unit (ICU). Non-albicans Candida spp. accounted for 61% of cases (81/133). All-cause 30-day mortality was 31%. A gastrointestinal or unknown source was associated with higher overall mortality than an intravascular or urologic source (p < 0.01). A risk predictive score based on age > 65 years, ICU admission, chronic organ dysfunction, preceding surgery within 30 days, haematological malignancy, source of candidaemia and antibiotic therapy for ≥10 days stratified patients into < 20% or ≥ 20% predicted mortality. The model retained accuracy when validated against a historical dataset (n = 741). CONCLUSIONS: Mortality in patients with candidaemia remains high. A simple mortality risk predictive score stratifying patients with candidaemia into < 20% and ≥ 20% 30-day mortality is presented. This model uses information available at time of candidaemia diagnosis is easy to incorporate into decision support systems. Further validation of this model is warranted.

Is a biomarker-based diagnostic strategy for invasive aspergillosis cost effective in high-risk haematology patients?

Empirical antifungal therapy is frequently used in hematology patients at high risk of invasive aspergillosis (IA), with substantial cost and toxicity. Biomarkers for IA aim for earlier and more accurate diagnosis and targeted treatment. However, data on the cost-effectiveness of a biomarker-based diagnostic strategy (BDS) are limited. We evaluated the cost effectiveness of BDS using results from a randomized controlled trial (RCT) and individual patient costing data. Data inputs derived from a published RCT were used to construct a decision-analytic model to compare BDS (Aspergillus galactomannan and PCR on blood) with standard diagnostic strategy (SDS) of culture and histology in terms of total costs, length of stay, IA incidence, mortality, and years of life saved. Costs were estimated for each patient using hospital costing data to day 180 and follow-up for survival was modeled to five years using a Gompertz survival model. Treatment costs were determined for 137 adults undergoing allogeneic hematopoietic stem cell transplant or receiving chemotherapy for acute leukemia in four Australian centers (2005-2009). Median total costs at 180 days were similar between groups (US$78,774 for SDS [IQR US$50,808-123,476] and US$81,279 for BDS [IQR US$59,221-123,242], P = .49). All-cause mortality was 14.7% (10/68) for SDS and 10.1% (7/69) for BDS, (P = .573). The costs per life-year saved were US$325,448, US$81,966, and US$3,670 at 180 days, one year and five years, respectively. BDS is not cost-sparing but is cost-effective if a survival benefit is maintained over several years. An individualized institutional approach to diagnostic strategies may maximize utility and cost-effectiveness.

New developments and directions in the clinical application of the echinocandins.

The echinocandins-caspofungin, anidulafungin and micafungin-are semi-synthetic cyclic hexapeptide antimicrobial agents with modified N-linked acyl lipid side chains which anchor the compounds to the phospholipid bilayer of the fungal cell membrane, thereby inhibiting synthesis of fungal cell wall glucan. Over the last 10 years, echinocandins have become the first-line antifungal treatment of candidaemia and other forms of invasive candidiasis (IC). Echinocandins are generally well tolerated, but their use is limited by their requirement for daily intravenous dosing, lack of oral formulation and limited spectrum. In critically ill patients, it is also recognised that achievement of their pharmacokinetic/pharmacodynamic targets shows large inter-individual variability. As a drug class, they are safe to use and are associated with few adverse reactions and few drug-drug interactions of significance. Recent discovery of their ability to prevent and treat Candida biofilm formation particularly in the presence of invasive medical devices and also their ability to penetrate into mucosal surfaces such as vulvovaginal candidiasis has opened up new opportunities for research into their drug delivery. New dosing intervals are being explored to allow less frequent intravenous dosing in the ambulatory setting, and a new long-acting echinocandin, CD101, is being developed for weekly and topical administration.

Antimicrobial allergy 'labels' drive inappropriate antimicrobial prescribing: lessons for stewardship.

BACKGROUND: The presence of antimicrobial allergy designations ('labels') often substantially reduces prescribing options for affected patients, but the frequency, accuracy and impacts of such labels are unknown. METHODS: The National Antimicrobial Prescribing Survey (NAPS) is an annual de-identified point prevalence audit of Australian inpatient antimicrobial prescribing using standardized definitions of guideline compliance, appropriateness and indications. Data were extracted for 2 years (2013-14) and compared for patients with an antimicrobial allergy label (AAL) and with no AAL (NAAL). RESULTS: Among 21 031 patients receiving antimicrobials (33 421 prescriptions), an AAL was recorded in 18%, with inappropriate antimicrobial use significantly higher in the AAL group versus the NAAL group (OR 1.12, 95% CI 1.05-1.22, P < 0.002). Patterns of antimicrobial use were significantly influenced by AAL, with lower ß-lactam use (AAL versus NAAL; OR 0.47, 95% CI 0.43-0.50, P < 0.001) and higher quinolone (OR 2.07, 95% CI 1.83-2.34, P < 0.0001), glycopeptide (OR 1.59, 95% CI 1.38-1.83, P < 0.0001) and carbapenem (OR 1.74, 95% CI 1.43-2.13, P < 0.0001) use. In particular, among immunocompromised patients, AAL was associated with increased rates of inappropriate antimicrobial use (OR 1.68, 95% CI 1.21-2.30, P = 0.003), as well as increased use of quinolones (OR 1.88, 95% CI 1.16-3.03, P = 0.02) and glycopeptides (OR 1.82, 95% CI 1.17-2.84, P = 0.01). CONCLUSIONS: AALs are common and appear to be associated with higher rates of inappropriate prescribing and increased use of broad-spectrum antimicrobials. Improved accuracy in defining AALs is likely to be important for effective antimicrobial stewardship (AMS), with efforts to 'de-label' inappropriate AAL patients a worthwhile feature of future AMS initiatives.

Putting CYP2C19 genotyping to the test: utility of pharmacogenomic evaluation in a voriconazole-treated haematology cohort.

OBJECTIVES: The clinical utility of pharmacogenomic testing in haematology patients with invasive fungal disease (IFD) receiving azole therapy has not been defined. We report our experience with CYP2C19 testing in haematological patients requiring voriconazole therapy for IFD. METHODS: As a single-centre pilot study, 19 consecutive patients with a haematological malignancy undergoing active chemotherapy with a possible, probable or proven IFD requiring voriconazole therapy underwent CYP2C19 testing from 2013 to 2014. Baseline patient demographics, concurrent medications, voriconazole levels and IFD history were captured. RESULTS: The median voriconazole levels for intermediate metabolizer (IM) (CYP2C19*2 or 3/*1 or 17), extensive metabolizer (EM) (CYP2C19*1/*1) and heterozygote ultrarapid metabolizer (HUM)/ultrarapid metabolizer (UM) (UM, CYP2C19*17/*17; HUM, CYP2C19*1/*17) patients were 5.23, 3.3 and 1.25 mg/L, respectively. Time to therapeutic voriconazole levels was longest in the IM group, whilst voriconazole levels <1 mg/L were only seen in UM, HUM and EM phenotypes. The highest rates of clinical toxicity were seen in the IM group (3/5, 60%). CONCLUSIONS: Voriconazole exposure and toxicity was highest for IM and lowest for HUM/UM phenotypes. Time to therapeutic voriconazole level was longest in IM, whilst refractory subtherapeutic levels requiring CYP2C19 inhibition were only seen in the EM, HUM and UM phenotypes. CYP2C19 genotyping may predict those likely to have supratherapeutic or subtherapeutic levels and/or toxicity. Prospective evaluation of clinical pathways incorporating genotyping and voriconazole dose-titrating algorithms is required.

Introduction to the updated Australian and New Zealand consensus guidelines for the use of antifungal agents in the haematology/oncology setting, 2014.

This article introduces the second revision of the Australian and New Zealand consensus guidelines for the use of antifungal agents in the haematology/oncology setting. The current update occurs within the context of a growing population at risk of invasive fungal disease, improved understanding of risk factors, availability of new diagnostic tests, a much-expanded evidence base and changing clinical paradigms. Here, we provide an overview of the history and purpose of the guidelines, including changes in scope since the last clinical update was published in 2008. The process for development, and for enabling review of draft recommendations by end-users and other relevant stakeholders, is described. The approach to assigning levels of evidence and grades of recommendation is also provided, along with a comparison to international grading systems.

Consensus guidelines for the treatment of yeast infections in the haematology, oncology and intensive care setting, 2014.

Pathogenic yeast forms are commonly associated with invasive fungal disease in the immunocompromised host, including patients with haematological malignancies and patients of haemopoietic stem cell transplants. Yeasts include the Candida spp., Cryptococcus spp., Pneumocystis jirovecii and some lesser-known pathogens. Candida species remain the most common cause of invasive yeast infections (and the most common human pathogenic fungi). These guidelines present evidence-based recommendations for the antifungal management of established, invasive yeast infections in adult and paediatric patients in the haematology/oncology setting. Consideration is also given to the critically ill patient in intensive care units, including the neonatal intensive care unit. Evidence for 'pre-emptive' or 'diagnostic-driven antifungal therapy' is also discussed. For the purposes of this paper, invasive yeast diseases are categorised under the headings of invasive candidiasis, cryptococcosis and uncommon yeast infections. Specific recommendations for the management of Pneumocystis jirovecii are presented in an accompanying article (see consensus guidelines by Cooley et al. appearing elsewhere in this supplement).

Consensus guidelines for implementation of quality processes to prevent invasive fungal disease and enhanced surveillance measures during hospital building works, 2014.

Healthcare-associated fungal outbreaks impose a substantial economic burden on the health system and typically result in high patient morbidity and mortality, particularly in the immunocompromised host. As the population at risk of invasive fungal infection continues to grow due to the increased burden of cancer and related factors, the need for hospitals to employ preventative measures has become increasingly important. These guidelines outline the standard quality processes hospitals need to accommodate into everyday practice and at times of healthcare-associated outbreak, including the role of antifungal stewardship programmes and best practice environmental sampling. Specific recommendations are also provided to help guide the planning and implementation of quality processes and enhanced surveillance before, during and after high-risk activities, such as hospital building works. Areas in which information is still lacking and further research is required are also highlighted.

Survey of antifungal prophylaxis and fungal diagnostic tests employed in malignant haematology and haemopoietic stem cell transplantation (HSCT) in Australia and New Zealand.

This article reports the findings of a survey developed to assess the current use of antifungal prophylaxis among haematology and infectious disease clinicians across Australia and New Zealand, and their alignment with existing consensus guidelines for the use of antifungal agents in the haematology/oncology setting (published 2008). Surveyed clinicians largely followed the current recommendations for prophylaxis in the setting of induction chemotherapy for acute myeloid leukaemia, as well as autologous and low-risk allogeneic haemopoietic stem cell transplantation (HSCT). In keeping with guideline recommendations, posaconazole was the agent used by most centres for high-risk allogeneic HSCT. However, its routine continuation for 75-100 days post-transplantation without de-escalation suggested use beyond those indications described in the 2008 guidelines, namely pre-engraftment neutropenia and graft-versus-host disease. Variations in practice were observed in other settings, such as acute lymphoblastic leukaemia and myelodysplastic syndrome, reflecting the general lack of evidence for antifungal prophylaxis in these patient populations and changing perceptions of risk. With regard to the availability of testing in cases of suspected breakthrough IFD, 40% of centres did not have access to investigative bronchoscopy within 48 h of referral, and results of Aspergillus galactomannan (GM), fungal polymerase chain reaction and therapeutic drug monitoring (TDM) were not available within 48 h in 83%, 90% and 85% of centres respectively. The survey's findings will influence the recommendations provided in the updated 2014 consensus guidelines for the use of antifungal agents in the haematology/oncology setting.

Consensus guidelines for antifungal prophylaxis in haematological malignancy and haemopoietic stem cell transplantation, 2014.

There is a strong argument for the use of antifungal prophylaxis in high-risk patients given the significant mortality associated with invasive fungal disease, the late identification of these infections, and the availability of safe and well-tolerated prophylactic medications. Clinical decisions about which patients should receive prophylaxis and choice of antifungal agent should be guided by risk stratification, knowledge of local fungal epidemiology, the efficacy and tolerability profile of available agents, and estimates such as number needed to treat and number needed to harm. There have been substantial changes in practice since the 2008 guidelines were published. These include the availability of new medications and/or formulations, and a focus on refining and simplifying patient risk stratification. Used in context, these guidelines aim to assist clinicians in providing optimal preventive care to this vulnerable patient demographic.

Hampered by historical paradigms--echinocandins and the treatment of Candida endocarditis.

Infective endocarditis due to Candida sp. has a high mortality rate. Traditionally, management involves early surgery and prolonged amphotericin ± flucytosine. We report a case of Candida parapsilosis bileaflet mitral valve endocarditis cured with anidulafungin and fluconazole, and review the role of echinocandins in the management of Candida endocarditis.

Disseminated Scedosporium prolificans infection in an 'extensive metaboliser': navigating the minefield of drug interactions and pharmacogenomics.

We report a case of non-fatal disseminated Scedosporium prolificans infection, including central nervous system disease and endophthalmitis, in a relapsed acute myeloid leukaemia patient with extensive CYP2C19 metabolism. Successful treatment required aggressive surgical debridement, three times daily voriconazole dosing and cimetidine CYP2C19 inhibition. In addition, the unique use of miltefosine was employed due to azole-chemotherapeutic drug interactions. Prolonged survival following disseminated S. prolificans, adjunctive miltefosine and augmentation of voriconazole exposure with cimetidine CYP2C19 inhibition has not been reported.

Outcomes of Antiviral Retreatment for Immunocompromised Hosts With Prolonged Severe Acute Respiratory Syndrome Coronavirus 2 Polymerase Chain Reaction Positivity: A Multicenter Australian Retrospective Case Series.

Outcomes are presented for a multisite retrospective case series, describing a contemporary cohort of 22 immunocompromised patients with persistent coronavirus disease 2019 (COVID-19) polymerase chain reaction positivity who were retreated with antiviral therapy. For those with data available 14 and 30 days after commencement of antiviral therapy, 41% (9 of 22) and 68% (15 of 22), respectively, cleared COVID-19.

Hepatitis B serological changes following allogeneic bone marrow transplantation.

Hepatitis B (HBV) reverse seroconversion (RS) in immunocompromised patients with serological evidence of past HBV infection (hepatitis B surface antigen [sAg] negative, core antibody [cAb] positive) has been reported with increasing frequency following allogeneic hematopoietic stem cell transplant (allo-HSCT). We performed a retrospective review of serial HBV serological testing in patients who had undergone allo-HSCT at our center between 2000 and 2006. We identified 12 patients with serological evidence of past HBV, including 1 case of RS. Although 7 of these 12 patients had no changes in serological markers detected after transplantation, 5 of them had declining levels of hepatitis B surface antibodies [sAb], with 2 to < 10 IU/mL. The remaining 4 patients with past HBV had loss of antiHBcAb. An additional 14 patients developed isolated antiHBcAb post allo-HSCT in the setting of receiving HBV screened (HBsAg, antiHBcAb) negative donor stem cells. Monitoring of HBV serological markers (including antiHBsAb) and HBV DNA levels pre allo-HSCT in recipients and donors, and post allo-SCT in recipients, would allow early detection and treatment of RS and identify new acquisition of HBV.

A messenger at the door: cytomegalovirus retinitis in myeloma patients with progressive disease.

Cytomegalovirus (CMV) retinitis is an uncommon manifestation of CMV disease and is a marker of severe and profound immunosuppression in human immunodeficiency virus-positive patients. Here, we describe 2 cases of CMV retinitis in myeloma patients with progressive disease, following autologous stem cell transplantation and immunomodulatory therapy for myeloma. To our knowledge, this is the first report of CMV retinitis in this patient population. This report illustrates the need for close monitoring of relapsed and refractory myeloma patients for new presentations of opportunistic infections secondary to severe immunosuppression.

Preemptive treatment with voriconazole in lung transplant recipients.

BACKGROUND: Invasive fungal infection (IFI) is associated with high mortality in lung transplant (LTx) recipients. Data for voriconazole use in preemptive treatment remain scant. METHOD: A single-center, retrospective cohort study was conducted to investigate the efficacy and safety of voriconazole preemptive treatment for post-LTx colonization. RESULTS: We reviewed 62 adult LTx patients, who received their first course of voriconazole prophylaxis (i.e., as preemptive treatment) between July 2003 and June 2010. Outcomes were determined at 6 and 12 months after commencing therapy. Aspergillus fumigatus (75.8%) was the most common colonizing isolate. Median duration of voriconazole prophylaxis was 85 days. At 6 months, 1 LTx patient (1.6%) had IFI, 47 (75.8%) cleared their colonizing isolate, 3 (4.8%) had persistent colonization, 7 (11.3%) had recurrent colonization, 1 (1.6%) had new colonization, 2 (3.2%) had aspergilloma, and 1 (1.6%) was clinically unstable with no culture results. Sixteen (25.8%) had died by 12 months. Ten (16.1%) had likely drug-related hepatotoxicity. LTx patients with diabetes mellitus within 30 days before commencing prophylaxis were at higher risk of recurrent Aspergillus colonization at 6 months (P = 0.030). Chronic rejection within 30 days before prophylaxis was associated with 12-month mortality (P = 0.007). CONCLUSIONS: Voriconazole preemptive treatment resulted in low incidence of IFI and IFI-related mortality.