Infectious Diseases - Research Publications

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    Cytomegalovirus DNAemia and disease: current-era epidemiology, clinical characteristics and outcomes in cancer patients other than allogeneic haemopoietic transplantation
    Tay, KH ; Slavin, MA ; Thursky, KA ; Coussement, J ; Worth, LJ ; Teh, BW ; Khot, A ; Tam, CS ; Yong, MK (WILEY, 2022-10)
    BACKGROUND: High-intensity chemotherapy and advances in novel immunotherapies have seen the emergence of cytomegalovirus (CMV) infections in cancer patients other than allogeneic haemopoietic cell transplantation (HCT). Aim To evaluate the epidemiology, clinical characteristics and outcomes of CMV infection in this population. METHODS: A retrospective review of cancer patients other than allogeneic HCT who had CMV DNAemia and/or disease from July 2013 till May 2020 at a quaternary cancer centre was performed. RESULTS: Of 11 485 cancer patients who underwent treatment during this period, 953 patients had CMV DNA testing performed and 238 of them had CMV DNAemia. After excluding patients with allogeneic HCT, 62 patients with CMV DNAemia were identified, of whom 10 had concurrent CMV disease. The most frequent underlying malignancies were B-cell lymphoproliferative disease (LPD) (31%; 19/62), T-cell LPD (21%; 13/62), chronic lymphocytic leukaemia (11%; 7/62) and multiple myeloma (10%; 6/62). Most patients had lymphopenia (77%; 48/62), multiple cancer therapies (63%; 39/62 received ≥2 previous therapies), co-infection (56%; 35/62 had ≥1 co-infection) and corticosteroid therapy (48%; 30/62) within 1 month before CMV diagnosis. CMV DNAemia and disease were observed in patients receiving novel immunotherapies, including bispecific antibody therapy, chimeric-antigen receptor T-cell therapy and immune checkpoint inhibitors. CONCLUSION: Patients with haematological malignancy, particularly B-cell LPD, T-cell LPD, chronic lymphocytic leukaemia and multiple myeloma, were frequently identified to have CMV DNAemia and disease. Lymphopenia, multiple cancer therapies, co-infection and recent receipt of systemic corticosteroids were also commonly observed. Future studies are necessary to determine optimal identification and management of CMV in these patients.
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    Auditing tools for antimicrobial prescribing in solid organ transplant recipients: The why, the how, and an assessment of current options
    So, M ; Nakamachi, Y ; Thursky, K (WILEY, 2022-10)
    BACKGROUND: Antimicrobial stewardship (AMS) aims to optimize antimicrobial use. Auditing and reporting of antimicrobial prescribing are essential. Auditing tools for solid organ transplant (SOT) patients should tailor to their needs. METHODS: We reviewed published data describing auditing tools in the general and SOT population. RESULTS: We focused on three internationally or nationally available auditing tools. The National Antimicrobial Prescribing Survey (NAPS) is web-based tool to report antimicrobial consumption and assess appropriateness using standardized definitions based on consensus guidelines. In the absence of guidelines, adjudication is based on AMS principles. An automated dashboard, analyses by indication or antimicrobial, and benchmarking reports are available. The National Healthcare Safety Network Antimicrobial Use/Resistance module was developed by the Centers for Disease Control and Prevention for hospitals to upload monthly data, which are standardized for benchmarking. It does not assess appropriateness or address SOT wards. The Global-Point Prevalence Survey from bioMérieux collects data on antimicrobial regimen, indication and microbial resistance. Variables unique to SOT include comorbidities and devices. Assessment of appropriateness is limited to guideline adherence, and benchmarking may require prearrangement with bioMérieux. Benchmarking requires prearrangement. Advances in electronic health record systems and clinical decision support tools can improve the efficiency of the auditing process. CONCLUSION: Each AMS auditing tool has unique features for SOT patients. Capturing immunosuppression, source control, organ dysfunction, donor-derived infection, serology, and colonization status will enhance their applicability.
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    Prevalence and predictors of poor outcome in children with febrile neutropaenia presenting to the emergency department
    Long, E ; Babl, FE ; Phillips, N ; Craig, S ; Zhang, M ; Kochar, A ; McCaskill, M ; Borland, ML ; Slavin, MA ; Phillips, R ; Lourenco, RDA ; Michinaud, F ; Thursky, KA ; Haeusler, G (WILEY, 2022-10)
    OBJECTIVE: Children with acquired neutropaenia due to cancer chemotherapy are at high risk of severe infection. The present study aims to describe the prevalence and predictors of poor outcomes in children with febrile neutropaenia (FN). METHODS: This is a multicentre, prospective observational study in tertiary Australian EDs. Cancer patients with FN were included. Fever was defined as a single temperature ≥38°C, and neutropaenia was defined as an absolute neutrophil count <1000/mm3 . The primary outcome was the ICU admission for organ support therapy (inotropic support, mechanical ventilation, renal replacement therapy, extracorporeal life support). Secondary outcomes were: ICU admission, ICU length of stay (LOS) ≥3 days, proven or probable bacterial infection, hospital LOS ≥7 days and 28-day mortality. Initial vital signs, biomarkers (including lactate) and clinical sepsis scores, including Systemic Inflammatory Response Syndrome, quick Sequential Organ Failure Assessment and quick Paediatric Logistic Organ Dysfunction-2 were evaluated as predictors of poor outcomes. RESULTS: Between December 2016 and January 2018, 2124 episodes of fever in children with cancer were screened, 547 episodes in 334 children met inclusion criteria. Four episodes resulted in ICU admission for organ support therapy, nine episodes required ICU admission, ICU LOS was ≥3 days in four, hospital LOS was ≥7 days in 153 and two patients died within 28 days. Vital signs, blood tests and clinical sepsis scores, including Systemic Inflammatory Response Syndrome, quick Sequential Organ Failure Assessment and quick Paediatric Logistic Organ Dysfunction-2, performed poorly as predictors of these outcomes (area under the receiver operating characteristic curve <0.6). CONCLUSIONS: Very few patients with FN required ICU-level care. Vital signs, biomarkers and clinical sepsis scores for the prediction of poor outcomes are of limited utility in children with FN.
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    [18F]FDG-PET-CT compared with CT for persistent or recurrent neutropenic fever in high-risk patients (PIPPIN): a multicentre, open-label, phase 3, randomised, controlled trial
    Douglas, A ; Thursky, K ; Spelman, T ; Szer, J ; Bajel, A ; Harrison, S ; Tio, SY ; Bupha-Intr, O ; Tew, M ; Worth, L ; Teh, B ; Chee, L ; Ng, A ; Carney, D ; Khot, A ; Haeusler, G ; Yong, M ; Trubiano, J ; Chen, S ; Hicks, R ; Ritchie, D ; Slavin, M (ELSEVIER SCI LTD, 2022-08)
    BACKGROUND: Management of neutropenic fever in high-risk haematology patients is challenging; there are often few localising clinical features, and diagnostic tests have poor sensitivity and specificity. We aimed to compare how [18F]flurodeoxyglucose ([18F]FDG)-PET-CT scans and conventional CT scans affected the guidance of antimicrobial management and the outcomes of patients with persistent or recurrent neutropenic fever. METHODS: We did a multicentre, open-label, phase 3, randomised, controlled trial in two tertiary referral hospitals in Australia. We recruited adults aged 18 years or older who were receiving conditioning chemotherapy for haematopoietic stem-cell transplantation or chemotherapy for acute leukaemia and had persistent (>72 h) or recurrent (new fever beyond 72 h of initial onset interspersed with >48 h defervescence) neutropenic fever. Exclusion criteria were pregnancy, allergy to iodinated contrast, or estimated glomerular filtration rate of less than 30 mL/min. Patients were randomly assigned by computer-generated randomisation chart (1:1) to [18F]FDG-PET-CT or conventional CT. Masking was not possible because of the nature of the investigation. Scans were done within 3 days of random assignment. The primary endpoint was a composite of starting, stopping, or changing the spectrum (broadening or narrowing) of antimicrobial therapy-referred to here as antimicrobial rationalisation-within 96 h of the assigned scan, analysed per protocol. This trial is registered with clinicaltrials.gov, NCT03429387, and is complete. FINDINGS: Between Jan 8, 2018, and July 23, 2020, we assessed 316 patients for eligibility. 169 patients were excluded and 147 patients were randomly assigned to either [18F]FDG-PET-CT (n=73) or CT (n=74). Nine patients did not receive a scan per protocol, and two participants in each group were excluded for repeat entry into the study. 65 patients received [18F]FDG-PET-CT (38 [58%] male; 53 [82%] White) and 69 patients received CT (50 [72%] male; 58 [84%] White) per protocol. Median follow up was 6 months (IQR 6-6). Antimicrobial rationalisation occurred in 53 (82%) of 65 patients in the [18F]FDG-PET-CT group and 45 (65%) of 69 patients in the CT group (OR 2·36, 95% CI 1·06-5·24; p=0·033). The most frequent component of antimicrobial rationalisation was narrowing spectrum of therapy, in 28 (43%) of 65 patients in the [18F]FDG-PET-CT group compared with 17 (25%) of 69 patients in the CT group (OR 2·31, 95% CI 1·11-4·83; p=0·024). INTERPRETATION: [18F]FDG-PET-CT was associated with more frequent antimicrobial rationalisation than conventional CT. [18F]FDG-PET-CT can support decision making regarding antimicrobial cessation or de-escalation and should be considered in the management of patients with haematological diseases and persistent or recurrent high-risk neutropenic fever after chemotherapy or transplant conditioning. FUNDING: National Health and Medical Research Council Centre of Research Excellence (APP1116876), Melbourne Health foundation, Gilead Research Fellowship grants supported this study.
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    Opportunities for nurse involvement in surgical antimicrobial stewardship strategies: A qualitative study
    Ierano, C ; Rajkhowa, A ; Gotterson, F ; Marshall, C ; Peel, T ; Ayton, D ; Thursky, K (PERGAMON-ELSEVIER SCIENCE LTD, 2022-04)
    BACKGROUND: Multi-disciplinary antimicrobial stewardship teams are a common strategy employed to optimise antimicrobial prescribing. Nurses play a pivotal role in patient care and safety; however, their role and potential opportunities across surgical antimicrobial stewardship are not well-established. This study aims to highlight health professional perspectives of the nurse's role and relevant opportunities for nurses to engage in and lead surgical antimicrobial stewardship initiatives. METHODS: An exploratory, multi-site, collective qualitative case study. Transcribed audio-recordings of focus groups with health professionals underwent thematic analysis, with mapping to established frameworks. RESULTS: Four key themes were identified; surgical antimicrobial prophylaxis is not prioritised for quality improvement, but nurses perceive benefits from surgical antimicrobial prophylaxis education and training; professional hierarchy hinders nurse engagement and leadership in antimicrobial stewardship; nurses are consistently engaged with patient care throughout the surgical journey; and clarity of roles and accountability for surgical antimicrobial prophylaxis review and follow-up can bolster quality improvement initiatives. DISCUSSION: Many opportunities exist for nurse engagement in surgical antimicrobial stewardship. Identification of barriers and enablers support theoretically informed strategies i.e., education and guideline accessibility; multidisciplinary collaborations; executive support for nursing capacity building and the standardisation of surgical antimicrobial prophylaxis workflow and documentation. CONCLUSIONS: Nurses are critical to patient safety and to supporting antimicrobial stewardship, in the operating theatre, and throughout the patient's surgical journey. Applying theoretical frameworks to understand barriers and enablers to nurses' contribution to antimicrobial stewardship has given insights to inform interventions to support nurse engagement.  : Tweetable abstract: Nurses are critical for patient safety. Many opportunities exist to support them as surgical antimicrobial stewards.
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    A Novel GPPAS Model: Guiding the Implementation of Antimicrobial Stewardship in Primary Care Utilising Collaboration between General Practitioners and Community Pharmacists
    Saha, SK ; Thursky, K ; Kong, DCM ; Mazza, D (MDPI, 2022-09)
    Interprofessional collaboration between general practitioners (GPs) and community pharmacists (CPs) is central to implement antimicrobial stewardship (AMS) programmes in primary care. This study aimed to design a GP/pharmacist antimicrobial stewardship (GPPAS) model for primary care in Australia. An exploratory study design was followed that included seven studies conducted from 2017 to 2021 for the development of the GPPAS model. We generated secondary and primary evidence through a systematic review, a scoping review, a rapid review, nationwide surveys of Australian GPs and CPs including qualitative components, and a pilot study of a GPPAS submodel. All study evidence was synthesised, reviewed, merged, and triangulated to design the prototype GPPAS model using a Systems Engineering Initiative for Patient Safety theoretical framework. The secondary evidence provided effective GPPAS interventions, and the primary evidence identified GP/CP interprofessional issues, challenges, and future needs for implementing GPPAS interventions. The framework of the GPPAS model informed five GPPAS implementation submodels to foster implementation of AMS education program, antimicrobial audits, diagnostic stewardship, delayed prescribing, and routine review of antimicrobial prescriptions, through improved GP-CP collaboration. The GPPAS model could be used globally as a guide for GPs and CPs to collaboratively optimise antimicrobial use in primary care. Implementation studies on the GPPAS model and submodels are required to integrate the GPPAS model into GP/pharmacist interprofessional care models in Australia for improving AMS in routine primary care.
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    Prophylactic Antimicrobial Prescribing in Australian Residential Aged-Care Facilities: Improvement is Required
    Bennett, N ; Malloy, MJ ; James, R ; Fang, X ; Thursky, K ; Worth, LJ (SPRINGERNATURE, 2022-12)
    BACKGROUND AND OBJECTIVE: Inappropriate antimicrobial use can lead to adverse consequences, including antimicrobial resistance. The objective of our study was to describe patterns of prophylactic antimicrobial prescribing in Australian residential aged-care facilities and thereby provide insight into antimicrobial stewardship strategies that might be required. METHODS: Annual point prevalence data submitted by participating residential aged-care facilities as part of the Aged Care National Antimicrobial Prescribing Survey between 2016 and 2020 were extracted. All antimicrobials except anti-virals were counted; methenamine hippurate was classified as an antibacterial agent. RESULTS: The overall prevalence of residents prescribed one or more prophylactic antimicrobial on the survey day was 3.7% (n = 4643, 95% confidence interval 3.6-3.8). Of all prescribed antimicrobials (n = 15,831), 27.1% (n = 4871) were for prophylactic use. Of these prophylactic antimicrobials, 87.8% were anti-bacterials and 11.4% antifungals; most frequently, cefalexin (28.7%), methenamine hippurate (20.1%) and clotrimazole (8.8%). When compared with prescribing of all antimicrobial agents, prophylactic antimicrobials were less commonly prescribed for pro re nata administration (7.0% vs 20.3%) and more commonly prescribed greater than 6 months (52.9% vs 34.1%). The indication and review or stop date was less frequently documented (67.5% vs 73.8% and 20.9% vs 40.7%, respectively). The most common body system for which a prophylactic antimicrobial was prescribed was the urinary tract (54.3%). Of all urinary tract indications (n = 2575), about two thirds (n = 1681, 65.3%) were for cystitis and 10.6% were for asymptomatic bacteriuria. CONCLUSIONS: Our results clearly identified immediate antimicrobial stewardship strategies that aim to improve prophylactic antimicrobial prescribing in Australian residential-aged care facilities are required.
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    Ophthalmic Antimicrobial Prescribing in Australian Healthcare Facilities
    Fang, X ; Bennett, N ; Ierano, C ; James, R ; Thursky, K (MDPI, 2022-05)
    The National Antimicrobial Prescribing Survey (NAPS) is a web-based, standardized tool, widely adopted in Australian healthcare facilities to assess the reasons for, the quantity of, and the quality of antimicrobial prescribing. It consists of multiple modules tailored towards the needs of a variety of healthcare facilities. Data regarding ophthalmological antimicrobial use from Hospital NAPS, Surgical NAPS, and Aged Care NAPS were analysed. In Hospital NAPS, the most common reasons for inappropriate prescribing were incorrect dose or frequency and incorrect duration. Prolonged duration was also common in Aged Care prescribing: about one quarter of all antimicrobials had been prescribed for greater than 6 months. All three modules found chloramphenicol to be the most prescribed antimicrobial with a high rate of inappropriate prescribing, usually for conjunctivitis.
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    Blood transcriptomics identifies immune signatures indicative of infectious complications in childhood cancer patients with febrile neutropenia
    Haeusler, GM ; Garnham, AL ; Li-Wai-Suen, CS ; Clark, JE ; Babl, FE ; Allaway, Z ; Slavin, MA ; Mechinaud, F ; Smyth, GK ; Phillips, B ; Thursky, KA ; Pellegrini, M ; Doerflinger, M (WILEY, 2022)
    OBJECTIVES: Febrile neutropenia (FN) is a major cause of treatment disruption and unplanned hospitalization in childhood cancer patients. This study investigated the transcriptome of peripheral blood mononuclear cells (PBMCs) in children with cancer and FN to identify potential predictors of serious infection. METHODS: Whole-genome transcriptional profiling was conducted on PBMCs collected during episodes of FN in children with cancer at presentation to the hospital (Day 1; n = 73) and within 8-24 h (Day 2; n = 28) after admission. Differentially expressed genes as well as gene pathways that correlated with clinical outcomes were defined for different infectious outcomes. RESULTS: Global differences in gene expression associated with specific immune responses in children with FN and documented infection, compared to episodes without documented infection, were identified at admission. These differences resolved over the subsequent 8-24 h. Distinct gene signatures specific for bacteraemia were identified both at admission and on Day 2. Differences in gene signatures between episodes with bacteraemia and episodes with bacterial infection, viral infection and clinically defined infection were also observed. Only subtle differences in gene expression profiles between non-bloodstream bacterial and viral infections were identified. CONCLUSION: Blood transcriptome immune profiling analysis during FN episodes may inform monitoring and aid in defining adequate treatment for different infectious aetiologies in children with cancer.
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    The feasibility and generalizability of assessing the appropriateness of antimicrobial prescribing in hospitals: a review of the Australian National Antimicrobial Prescribing Survey
    James, R ; Nakamachi, Y ; Morris, A ; So, M ; Ponnampalavanar, SSLS ; Chuki, P ; Loong, LS ; Lai, PSM ; Chen, C ; Ingram, R ; Rajkhowa, A ; Buising, K ; Thursky, K (OXFORD UNIV PRESS, 2021-12-22)
    The National Antimicrobial Prescribing Survey (NAPS) is a web-based qualitative auditing platform that provides a standardized and validated tool to assist hospitals in assessing the appropriateness of antimicrobial prescribing practices. Since its release in 2013, the NAPS has been adopted by all hospital types within Australia, including public and private facilities, and supports them in meeting the national standards for accreditation. Hospitals can generate real-time reports to assist with local antimicrobial stewardship (AMS) activities and interventions. De-identified aggregate data from the NAPS are also submitted to the Antimicrobial Use and Resistance in Australia surveillance system, for national reporting purposes, and to strengthen national AMS strategies. With the successful implementation of the programme within Australia, the NAPS has now been adopted by countries with both well-resourced and resource-limited healthcare systems. We provide here a narrative review describing the experience of users utilizing the NAPS programme in Canada, Malaysia and Bhutan. We highlight the key barriers and facilitators to implementation and demonstrate that the NAPS methodology is feasible, generalizable and translatable to various settings and able to assist in initiatives to optimize the use of antimicrobials.