Antimicrobial use and appropriateness in neutropenic fever: a study of the Hospital National Antimicrobial Prescribing Survey data.

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

The Who, What, When, and Where of Inpatient Direct Oral Penicillin Challenge-Implications for Health Services Implementation.

Inpatient direct oral challenge programs are increasingly deployed as part of antimicrobial stewardship initiatives to reduce the burden and impacts of penicillin allergy labels on antibiotic prescribing. Using data from a prospective, multicenter cohort inpatient penicillin allergy program, we identify the key targets for delabeling to aid health service implementation.

Consensus guidelines for the diagnosis and management of invasive aspergillosis, 2021.

Invasive aspergillosis (IA) in haematology/oncology patients presents as primary infection or breakthrough infection, which can become refractory to antifungal treatment and has a high associated mortality. Other emerging patient risk groups include patients in the intensive care setting with severe respiratory viral infections, including COVID-19. These guidelines present key diagnostic and treatment recommendations in light of advances in knowledge since the previous guidelines in 2014. Culture and histological-based methods remain central to the diagnosis of IA. There is increasing evidence for the utility of non-culture methods employing fungal biomarkers in pre-emptive screening for infection, as well as for IA diagnosis when used in combination. Although azole resistance appears to be uncommon in Australia, susceptibility testing of clinical Aspergillus fumigatus complex isolates is recommended. Voriconazole remains the preferred first-line antifungal agent for treating primary IA, including for extrapulmonary disease. Recommendations for paediatric treatment broadly follow those for adults. For breakthrough and refractory IA, a change in class of antifungal agent is strongly recommended, and agents under clinical trial may need to be considered. Newer immunological-based imaging modalities warrant further study, while surveillance for IA and antifungal resistance remain essential to informing the relevance of current treatment recommendations.

Epidemiology, treatment and outcomes of bloodstream infection due to vancomycin-resistant enterococci in cancer patients in a vanB endemic setting.

BACKGROUND: Vancomycin-resistant enterococcus (VRE) is an important cause of infection in immunocompromised populations. Few studies have described the characteristics of vanB VRE infection. We sought to describe the epidemiology, treatment and outcomes of VRE bloodstream infections (BSI) in a vanB predominant setting in malignant hematology and oncology patients. METHODS: A retrospective review was performed at two large Australian centres and spanning a 6-year period (2008-2014). Evaluable outcomes were intensive care admission (ICU) within 48 h of BSI, all-cause mortality (7 and 30 days) and length of admission. RESULTS: Overall, 106 BSI episodes were observed in 96 patients, predominantly Enterococcus faecium vanB (105/106, 99%). Antibiotics were administered for a median of 17 days prior to BSI, and 76/96 (79%) were neutropenic at BSI onset. Of patients screened before BSI onset, 49/72 (68%) were found to be colonised. Treatment included teicoplanin (59), linezolid (6), daptomycin (2) and sequential/multiple agents (21). Mortality at 30-days was 31%. On multivariable analysis, teicoplanin was not associated with mortality at 30 days. CONCLUSIONS: VRE BSI in a vanB endemic setting occurred in the context of substantive prior antibiotic use and was associated with high 30-day mortality. Targeted screening identified 68% to be colonised prior to BSI. Teicoplanin therapy was not associated with poorer outcomes and warrants further study for vanB VRE BSI in cancer populations.

The QuantiFERON Monitor® assay is predictive of infection post allogeneic hematopoietic cell transplantation.

INTRODUCTION: Following allogeneic hematopoietic stem cell transplantation (alloHCT), excessive immunosuppression can be complicated by infection, while inadequate immunosuppression can result in graft-vs-host disease (GVHD). An accurate method to assess overall immune status post HCT is lacking. The QuantiFERON Monitor® (QFM) assay measures interferon gamma (IFN-γ) release from whole blood following incubation with both innate (Toll-like receptor 7, TLR7) and adaptive (CD3 antibody) stimulants and may result in a more complete assessment of the immune system. METHODS: Whole blood samples were prospectively collected from alloHCT recipients at conditioning followed by days 10, 30, 60, 90, 120, and 180 post-transplant and assayed by the QFM test. IFN-γ levels were correlated to time post HCT and episodes of infection and GVHD. RESULTS: Forty patients were enrolled in the study (68% male; median age 47 years; 58% matched related donors, 42% unrelated; 33% myeloablative). Post-stimulation IFN-γ levels rose steadily over the first 180 days post transplantation. IFN-γ levels were significantly lower in those with active infection compared to those without during the neutropenic period (P < .001). The assay was predictive of CMV reactivation (VL > 1000 copies/mL) post alloHCT (P = .001). CONCLUSION: This is a promising assay to demonstrate immune recovery and predict risk of infection after alloHCT and may allow tailoring of immunosuppression, antimicrobial treatment, and prophylaxis.

Access, knowledge and experience with fluorodeoxyglucose positron emission tomography/computed tomography in infection management: a survey of Australia and New Zealand infectious diseases physicians and microbiologists.

BACKGROUND: Despite fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) being funded only for staging and restaging of some malignancies in Australia, there is evidence of benefit of FDG-PET/CT for infection indications such as pyrexia of unknown origin (PUO), prolonged neutropenic fever (NF) and prosthetic device infection. AIM: To evaluate the current knowledge, utilisation of and gaps in access to FDG-PET/CT for infectious indications by Australasian infectious diseases (ID) physicians and microbiologists. METHODS: An online survey was administered to ID and microbiology doctors practising in adult medicine in Australia and New Zealand through two established email networks. Using targeted questions and case-based examples, multiple themes were explored, including access to FDG-PET/CT, use and perceived benefit of FDG-PET/CT in diagnosis and monitoring of non-malignant conditions such as NF and PUO, and barriers to clinical use of FDG-PET/CT. RESULTS: A response was received from 120 participants across all states and territories. Onsite and offsite FDG-PET/CT access was 63% and 31% respectively. Eighty-six percent reported using FDG-PET/CT for one or more infection indications and all had found it clinically useful, with common indications being PUO, prosthetic device infections and use in the immunocompromised host for prolonged NF and invasive fungal infection. Thirty-eight percent reported barriers in accessing FDG-PET/CT for infection indications and 76% would utilise FDG-PET/CT more frequently if funding existed for infection indications. CONCLUSION: Access to FDG-PET/CT in Australia and New Zealand is modest and is limited by lack of reimbursement for infection indications. There is discrepancy between recognised ID indications for FDG-PET/CT and funded indications.

PCR-based tests for the early diagnosis of sepsis. Where do we stand?

PURPOSE OF REVIEW: Bloodstream infections are a major cause of hospital and ICU admission with high morbidity and mortality; however, early and targeted antimicrobial therapy reduces mortality in high-risk patients. This article focuses on the diagnosis of bloodstream infections by PCR-based approaches at an early stage to enable prompt treatment and prevent organ dysfunction. RECENT FINDINGS: PCR systems offering highly multiplexed targeting of bacterial and/or fungal pathogens (in whole blood) offer the best opportunity for clinical impact, as informed decisions can be made within 4-8 h of the blood draw. Although more rapid, these systems are typically associated with lower sensitivity and specificity than postculture detection methods which rely on microbial growth. Additionally, unlike postculture methods, detection directly from blood is not prone to misleading results because of concurrent (or previous) therapy, which limit clinical relevance. SUMMARY: Rapid and accurate identification of the cause of sepsis is essential in improving patient outcomes. Early identification of these pathogens by nucleic acid detection assays directly from blood samples remains key to achieving this, particularly if taken at the time of presentation. Selection of the most suitable PCR system is typically influenced by local epidemiology and by the resources of the testing laboratory.

Outbreaks of Fungal Infections in Hospitals: Epidemiology, Detection, and Management.

Nosocomial clusters of fungal infections, whilst uncommon, cannot be predicted and are associated with significant morbidity and mortality. Here, we review reports of nosocomial outbreaks of invasive fungal disease to glean insight into their epidemiology, risks for infection, methods employed in outbreak detection including genomic testing to confirm the outbreak, and approaches to clinical and infection control management. Both yeasts and filamentous fungi cause outbreaks, with each having general and specific risks. The early detection and confirmation of the outbreak are essential for diagnosis, treatment of affected patients, and termination of the outbreak. Environmental sampling, including the air in mould outbreaks, for the pathogen may be indicated. The genetic analysis of epidemiologically linked isolates is strongly recommended through a sufficiently discriminatory approach such as whole genome sequencing or a method that is acceptably discriminatory for that pathogen. An analysis of both linked isolates and epidemiologically unrelated strains is required to enable genetic similarity comparisons. The management of the outbreak encompasses input from a multi-disciplinary team with epidemiological investigation and infection control measures, including screening for additional cases, patient cohorting, and strict hygiene and cleaning procedures. Automated methods for fungal infection surveillance would greatly aid earlier outbreak detection and should be a focus of research.

Evaluating the cost-effectiveness of [18F]FDG-PET/CT for investigation of persistent or recurrent neutropenic fever in high-risk haematology patients.

BACKGROUND: A recent randomised trial demonstrated [18F]fluorodeoxyglucose positron-emission tomography in combination with low-dose CT (FDG-PET/CT), compared to standard of care computed tomography (CT) imaging, positively impacted antimicrobial management and outcomes of acute leukaemia and haematopoietic stem cell transplant recipients with persistent and recurrent neutropenic fever. We conducted an economic evaluation from a healthcare perspective alongside the clinical trial. METHODS: Unit costs in Australian dollars were applied to all resources used (antimicrobials, diagnostic tests, ICU and hospital bed days). Effectiveness was measured as number of patients with antimicrobial rationalisation, 6-month mortality and quality-adjusted life years (QALYs) derived from patient-reported trial-based health-related quality-of-life. Generalised linear models were used to analyse costs and outcomes. Incremental cost-effectiveness ratios (ICERs) for all outcomes and net monetary benefit (NMB) for QALYs were calculated. We performed bootstrapping with 1000 replications using the recycled predictions method. RESULTS: The adjusted healthcare costs were lower for FDG-PET/CT (mean $49,563; 95%CI 36,867, 65,133) compared to CT (mean $57,574; 95% CI 44,837, 73,347). The difference in QALYs between the two groups was small (0.001; 95% CI -0.001, 0.004). When simulated 1000 times, FDG-PET/CT was the dominant strategy as it was cheaper with better outcomes than the standard CT group in 74% of simulations. The estimated NMBs at willingness-to-pay thresholds of $50,000 and $100,000 per QALY were positive, thus FDG-PET/CT remained cost-effective at these thresholds. CONCLUSIONS: FDG-PET/CT is cost effective when compared to CT for investigation of persistent/recurrent neutropenic fever in high-risk patients, providing further support for incorporation of FDG-PET/CT into clinical guidelines and funding. TRIAL REGISTRATION: This trial is registered with ClinicalTrials.gov, NCT03429387.

Quality of inpatient antimicrobial use in hematology and oncology patients.

OBJECTIVES: To compare antimicrobial prescribing practices in Australian hematology and oncology patients to noncancer acute inpatients and to identify targets for stewardship interventions. DESIGN: Retrospective comparative analysis of a national prospectively collected database. METHODS: Using data from the 2014-2018 annual Australian point-prevalence surveys of antimicrobial prescribing in hospitalized patients (ie, Hospital National Antimicrobial Prescribing Survey called Hospital NAPS), the most frequently used antimicrobials, their appropriateness, and guideline concordance were compared among hematology/bone marrow transplant (hemBMT), oncology, and noncancer inpatients in the setting of treatment of neutropenic fever and antibacterial and antifungal prophylaxis. RESULTS: In 454 facilities, 94,226 antibiotic prescriptions for 62,607 adult inpatients (2,230 hemBMT, 1,824 oncology, and 58,553 noncancer) were analyzed. Appropriateness was high for neutropenic fever management across groups (83.4%-90.4%); however, hemBMT patients had high rates of carbapenem use (111 of 746 prescriptions, 14.9%), and 20.2% of these prescriptions were deemed inappropriate. Logistic regression demonstrated that hemBMT patients were more likely to receive appropriate antifungal prophylaxis compared to oncology and noncancer patients (adjusted OR, 5.3; P < .001 for hemBMT compared to noncancer patients). Oncology had a low rate of antifungal prophylaxis guideline compliance (67.2%), and incorrect dosage and frequency were key factors. Compared to oncology patients, hemBMT patients were more likely to receive appropriate nonsurgical antibacterial prophylaxis (aOR, 8.4; 95% CI, 5.3-13.3; P < .001). HemBMT patients were also more likely to receive appropriate nonsurgical antibacterial prophylaxis compared to noncancer patients (OR, 3.1; 95% CI, 1.9-5.0; P < .001). However, in the Australian context, the hemBMT group had higher than expected use of fluoroquinolone prophylaxis (66 of 831 prescriptions, 8%). CONCLUSIONS: This study demonstrates why separate analysis of hemBMT and oncology populations is necessary to identify specific opportunities for quality improvement in each patient group.

FDG-PET/CT in managing infection in patients with hematological malignancy: clinician knowledge and experience in Australia.

PET/CT is useful for investigation of neutropenic fever (NF) and potential invasive fungal infection (IFI) in those with hematological malignancies (HM). An online survey evaluating the utility and current practices regarding PET/CT scanning for investigation of NF was distributed to infectious diseases (ID) clinicians and hematologists via email lists hosted by key professional bodies. One-hundred and forty-five clinicians responded (120 ID; 25 hematologists). Access to PET/CT was fair but timeliness of investigation was limited (within 3 days in 35% and 46% of ID and hematology respondents, respectively). Among those with experience with PET/CT for infection (n = 109), 40% had utilized PET/CT for prolonged NF and 20% for diagnosing IFI. The majority of respondents indicated the desire to utilize PET/CT more frequently for infection indications. There is a strong desire among surveyed Australian clinicians to use PET/CT for prolonged NF and potential IFI. However, access to PET/CT is a current barrier to uptake.

Utilizing genomic analyses to investigate the first outbreak of vanA vancomycin-resistant Enterococcus in Australia with emergence of daptomycin non-susceptibility.

INTRODUCTION: The majority of vancomycin-resistant Enterococcus faecium (VREfm) in Australia is of the vanB genotype. An outbreak of vanA VREfm emerged in our haematology/oncology unit between November 2014 and May 2015. The first case of daptomycin non-susceptible E. faecium (DNSEfm) detected was a patient with vanA VREfm bacteraemia who showed clinical failure of daptomycin therapy, prompting microbiologic testing confirming daptomycin non-susceptibility. OBJECTIVES: To describe the patient profiles, antibiotic susceptibility and genetic relatedness of vanA VREfm isolates in the outbreak. METHODS: Chart review of vanA VREfm colonized and infected patients was undertaken to describe the demographics, clinical features and outcomes of therapy. Whole genome sequencing of vanA VREfm isolates involved in the outbreak was conducted to assess clonality. RESULTS: In total, 29 samples from 24 patients tested positive for vanA VREfm (21 screening swabs and 8 clinical isolates). Five isolates were DNSEfm (four patients colonized, one patient with bacteraemia), with only one patient exposed to daptomycin previously. In silico multi-locus sequence typing of the isolates identified 25/26 as ST203, and 1/26 as ST796. Comparative genomic analysis revealed limited core genome diversity amongst the ST203 isolates, consistent with an outbreak of a single clone of vanA VREfm. CONCLUSIONS: Here we describe an outbreak of vanA VREfm in a haematology/oncology unit. Genomic analysis supports transmission of an ST203 vanA VRE clone within this unit. Daptomycin non-susceptibility in 5/24 patients left linezolid as the only treatment option. Daptomycin susceptibility cannot be assumed in vanA VREfm isolates and confirmatory testing is recommended.

Risk factors and prophylaxis against invasive fungal disease for haematology and stem cell transplant recipients: an evolving field.

INTRODUCTION: Due to increasing intensity and complexity of therapies and longer survivorship, many patients with haematologic malignancy (HM) are at risk of invasive fungal disease (IFD). Mortality from IFD is high and treatment of an episode of IFD results in an excess length of hospital stay and costs and delays delivery of curative therapy of the underlying haematologic condition. Therefore, prevention and early recognition and treatment of IFD are crucial. Areas covered: Risk factors particular to certain HMs and haematopoietic stem cell transplantation, as well as those risk factors universal to all HM groups are examined. Expert commentary: Risk stratification identifies those patients who would benefit most from mould active versus yeast active prophylaxis and those who can be safely managed with monitoring and clinically driven interventions for IFD. This approach aids in antifungal stewardship.