Gabrielle M. Haeusler

Background: Antimicrobials are frequently prescribed to neonates who require hospital care, but the influences on clinical decision-making and practice variation in this process are ill-understood. We performed a cross-sectional survey of practitioners who prescribe antimicrobials in 3 Australian neonatal units. Methods: During two 5-day data capture periods per center, 56 practitioners reported their general confidence in antimicrobial decision-making for neonates. Then, 4 questionnaires evaluated diagnostic certainty and influences on antimicrobial decision-making for 68 antimicrobial courses and 11 infection evaluations where antimicrobials were not prescribed. Results: Self-reported guideline use at antimicrobial commencement was high (26/31, 84%). Clinical risk factors, clinical signs and laboratory tests contributed variably to decisions to start and cease antimicrobials. Consultation with a colleague contributed to 14/31 (45%) decisions to commence antimicrobials and 13/34 (38%) decisions to cease them. The most frequent responses to questions regarding the likelihood of infection and the possibility of an alternative diagnosis were "some possibility" and "some likelihood." Team concordance in responses ranged from 14% to 50%. While practitioners in roles that denoted more clinical experience had greater general confidence in antimicrobial decision-making, this difference was not observed in real-world clinical situations where infection was not microbiologically confirmed. Conclusions: Clinical, laboratory, practitioner, team and center-based factors each influence antimicrobial prescribing decisions. Clinical uncertainty and differing guidelines likely contribute to practice variation. Future work to inform stewardship efforts should include improved guideline consistency, roles of diagnostic aids and a better understanding of the medicocultural contributors to neonatal antimicrobial prescribing.

Background: Pulmonary complications due to infection contribute significantly to post-haematopoietic stem cell transplant (HCT) morbidity and mortality. Standard microbiological investigations, when performed on bronchoalveolar lavage (BAL) fluid, can take days to weeks to confirm a diagnosis. We aimed to determine the diagnostic performance of the BioFire FilmArray pneumonia panel plus (FA-PP), a multiplex polymerase chain reaction (PCR) panel that detects 18 bacterial and nine viral targets, when applied to BAL obtained by flexible bronchoscopy, in children undergoing HCT. Methods: We performed a single-centre prospective observational study in children undergoing allogeneic HCT, who underwent BAL pre- and post-HCT. To determine the diagnostic performance of the FA-PP, we measured the positive and negative concordance, sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV), compared with standard microbiological investigations, which was considered the gold standard. The clinical impact of the FA-PP was also qualitatively measured. Results: This study enrolled 16 children who had 31 BAL samples collected, both pre- and post-HCT. In total, there were seven patients who underwent eight BALs while symptomatic, and 50% (4/8) of these results were concordant between FA-PP and standard microbiological investigations. In the 13 patients who had 23 BALs collected while asymptomatic, 78% (18/23) of these results were concordant. In the cohort as a whole, sensitivity, specificity, PPV and NPV were 100%, 78%, 54% and 100%, respectively. In 50% (4/8) of patients who underwent a BAL while symptomatic, the FA-PP resulted in a hypothetical or actual clinical change, compared to 22% (5/23) of patients who underwent an asymptomatic BAL. Conclusions: In conclusion, we report the first prospective evaluation of the diagnostic performance of the FA-PP in BAL, in a high-risk paediatric HCT cohort. We demonstrate that the FA-PP is a potentially useful adjunct to traditional standard microbiological investigations that can provide clinically impactful diagnostic information.

Objective: Cytomegalovirus (CMV) infection is associated with severe clinical disease and high morbidity in immunocompromised hosts. Letermovir and maribavir, are two recently developed antiviral drugs used in the prevention and treatment of resistant and refractory CMV. Following the publication of landmark randomized trials and increased use, both clinical trial data and real-world experience has reported the development of antiviral drug resistance. The aim of this review was to comprehensively review the published literature on letermovir and maribavir drug resistance and to describe the clinical scenarios in which they may emerge. Results: For letermovir, the most frequently detected resistance mutations occur in the UL56 gene (C325Y/W/F) and confer total resistance. Maribavir resistance mutations most often occur in the UL97 gene and resistance-associated variants (RAVs) T409M, H411Y, C480F have all been detected. The clinical context in which letermovir and maribavir resistance occurs include high viral loads at initiation, intensified immunosuppression, subtherapeutic drug exposure because of poor adherence, drug interactions, and inadequate central nervous system (CNS) penetration. Emergence of resistance mutations generally occurs within the first 3 months of initiation. Conclusions: The detection of letermovir and maribavir resistance mutations highlights an ongoing clinical challenge in the management of CMV.

Background: Posaconazole is used to prevent and treat invasive fungal infections (IFIs) in immunocompromised children, including those undergoing cancer treatment or HSCT. Despite differences in pharmacokinetics and IFI epidemiology between children and adults, therapeutic targets established in adult studies are often applied to children. Objective: This systematic review evaluated the correlation between serum posaconazole concentrations and clinical outcomes of IFI prophylaxis and treatment in children with malignancies or HSCT recipients. Methods: Four databases (Cochrane, Embase, MEDLINE and PubMed) were searched for studies involving children (≤18 years old) receiving cancer treatment or HSCT that reported posaconazole serum concentrations and treatment outcomes. Animal studies, those primarily in adult (>18 years old) populations, non-malignant conditions (excluding HSCT), case reports, letters, editorials, conference abstracts and narrative reviews were excluded. Bias was assessed using the Newcastle-Ottawa scale. Results: Nineteen studies were included: 12 reported outcomes of posaconazole prophylaxis; two of treatment; and five of both. For prophylaxis, breakthrough IFIs occurred in 1%-12% of children. All but one occurred with serum concentrations of ≤0.7 mg/L. For treatment, no clear association was observed between a trough concentration of >1.0 mg/L and treatment efficacy, with poor outcomes reported for serum concentrations ranging between 0.2 and 4.8 mg/L. Overall, quality of evidence was poor (medium to high risk of bias for 18 papers, low risk for 1 paper) and there was variation in IFI definitions across studies. Conclusions: This review supports current recommendations for posaconazole prophylaxis in paediatric oncology and HSCT recipients. The absence of a clear correlation found between serum trough concentrations and treatment efficacy highlights the need for further studies to determine optimal therapeutic targets for treatment.

Food restrictions during periods of neutropenia have been widely used in oncology settings to prevent infections. As there is a lack of clearly demonstrated effectiveness, this strategy is being increasingly questioned. A multi-national panel of 23 individuals was convened to develop a clinical practice guideline (CPG) on the use of food restrictions to prevent infections in paediatric patients with cancer and haematopoietic cell transplantation (HCT) recipients. It included representation from persons with lived experience and physicians, dieticians, nurses, pharmacists and guideline methodologists working in paediatric oncology/HCT or infectious diseases. Panel members (female n = 15; 65%) were from North America (12, 52%), Europe (8, 35%), South America (2, 9%) and Australia (1, 4%). The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to formulate the CPG recommendations based on a systematic review of randomised controlled trials (RCTs). MEDLINE, MEDLINE in-Process and Embase databases were searched from January 1, 1980, to May 7, 2024, with a broad strategy which combined subject headings and text words relating to neutropenia, infection and diet. The systematic review, which provided the evidence base for the CPG recommendations, identified 4312 unique citations, of which 52 were retrieved for full-text evaluation. Eight RCTs met the eligibility criteria and informed panel deliberations. Although there was clinical heterogeneity in the food restrictions evaluated, data were consistent in suggesting that food restrictions lack clinically significant benefit in preventing infections. The panel made two conditional recommendations against the use of food restrictions in a) paediatric patients with cancer receiving chemotherapy and b) in the setting of allogeneic and autologous HCT. The panel developed a good practice statement to emphasise the importance of health care organisations and families adhering to local food safety practices. This CPG provides the first evidence-based recommendations on use of food restrictions to prevent infections in children and adolescents undergoing chemotherapy and paediatric haematopoietic cell transplant recipients. This CPG was funded and developed through the POGO Guidelines Program.