Anita J. Campbell

Objective: As antimicrobial resistance (AMR) continues to threaten global public health, bacteriophage therapy products (BTPs) offer a promising alternative to conventional antimicrobials. However, translation into routine clinical practice requires best practice standards for manufacturing and quality control to ensure the consistent safety, quality, and reliability of personalised BTPs produced for individual patients or small cohorts. Design: A modified Delphi methodology was used to develop consensus statements, engaging experts from Australia’s National Bacteriophage Therapy Regulatory Working Group across the fields of clinical microbiology, phage biology, good manufacturing practice (GMP), regulatory science, and government. The process comprised three iterative phases: (1) structured statement development, (2) an anonymous REDCap survey, and (3) a hybrid consensus meeting. The strength of evidence and recommendations was assessed using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) framework. Results: Consensus was reached on 35 statements to provide best practice manufacture and quality control guidance for BTPs. These statements address requirements for phage identification and characterisation; define the point at which GMP-aligned processes commence for ubiquitous phages; outline quality control expectations for phage active pharmaceutical ingredient (pAPI) production and maintenance of BTP and host cell repositories. Additional guidance covers quality management systems, including documentation, traceability, and governance. Conclusion: These consensus statements provide comprehensive best practice recommendations for the manufacture and quality control of BTPs in Australia. By promoting consistent, safe, and quality-assured approaches to personalised BTPs, they aim to facilitate clinical implementation while remaining aligned with existing international pharmacopoeial standards and regulatory frameworks. Significance of this study: What is already known on this subject?: Bacteriophage Therapy Products (BTPs) have re-emerged as a potential solution to antimicrobial resistance (AMR), supported by growing clinical evidence and global research activity. Data available to the regulatory working party includes more than 70 high-risk patients treated with dozens of different bacteriophages under a national open-label protocol (unpubl.). Published guidance from the European Pharmacopoeia, European Medicines Agency (EMA), UK Medicines & Healthcare products Regulatory Agency (MHRA), and World Health Oragnization (WHO) exists, yet no practical standards for personalised BTP manufacture have been established. What are the new findings?: Recommendations have been made to define minimum quality and manufacturing stasndards for the safe, consistent production of BTPs. This is the first expert endorsed, risk-based framework to support the translation of personliased BTPs into routine clinical practice, cobering manufacture, repository management, quality control and supply. How might it impact on clinical practice in the foreseeable future?: These consensus statements, developed by Australia’s National Bacteriophage Therapy Regulatory Working Group, can assist researchers, clinicians and regulatory authorities to develop BTP production protocols.

Lay Summary: The Staphylococcus aureus Network Adaptive Platform trial is a whole-of-life infectious disease trial. Recently, results for the methicillin-susceptible Staphylococcus aureus domain in adults showed cefazolin is non-inferior to (flu)cloxacillin for S. aureus bacteremia. The trial continues in children. Here the investigators outline why.

Background: Vancomycin is first‐line treatment for methicillin‐resistant Staphylococcus aureus (MRSA) infections. However, despite guideline recommendations, there is no evidence that targeting vancomycin trough concentrations of ≥15 mg/L in children confers clinical benefit and is associated with vancomycin‐associated nephrotoxicity (VAN). Aim: This study aimed to evaluate the impact of a vancomycin safety bundle on VAN and vancomycin utilisation in hospitalised paediatric inpatients. Method: A pre–post‐intervention study was conducted in a tertiary paediatric hospital comparing January–December 2018 (pre‐intervention) to May 2019–April 2020 (post‐intervention). Hospitalised children, aged 30 days to Ethical considerations in quality assistance and evaluation activities . Results: A total of 314 vancomycin prescriptions were analysed ( n = 204 pre‐intervention; n = 110 post‐intervention). Post‐intervention, VAN incidence decreased almost twofold from 0.46 to 0.25 episodes per 1000 patient bed days (p ≤ 0.01), and vancomycin prescription days decreased by 19%. Total hospital drug costs for vancomycin decreased by AUD $16 033. Overall, and for paediatric invasive MRSA, no significant difference in clinical outcomes or 30‐day mortality was observed between study periods. Conclusion: This study demonstrated the implementation of a vancomycin safety bundle significantly reduced paediatric VAN and vancomycin utilisation without compromising clinical outcomes. These data support antimicrobial stewardship interventions to improve medication safety for children.

Background: Staphylococcus aureus bacteremia (SAB) is the most common cause of childhood sepsis contributing to pediatric intensive care unit admission. The cost of adult SAB hospitalization is well described globally, but limited costing information is available for children. To bridge this knowledge gap, we investigated the cost of hospitalization in children with SAB in Australia. Methods: An economic analysis of hospitalization costs involving children aged ≤18 years with SAB admitted to Perth Children’s Hospital (PCH) between January 2017 and December 2018 was completed. Children were identified from the Invasive Staphylococcus aureus Infections and Hospitalisations (ISAIAH) cohort, a prospective multicenter study of pediatric SAB in Australia and New Zealand. The primary measure was mean hospitalization cost of community-onset SAB, overall and stratified by key variables, with 95% CIs calculated by bootstrapping. Results: There were 61 patients with SAB admitted to PCH. Fifty-six patients had community-onset SAB. The mean hospitalization cost per patient with community-onset SAB was A$53 037 [95% CI $44 623-$61 452]. The annual total cost was A$1 485 058. Hospital-onset SAB costs were significantly higher than community-onset SAB costs, and there was no difference in hospitalization costs by antibiotic susceptibility profile for community-onset SAB. The total cost of pediatric hospitalization for community-onset SAB within the ISAIAH cohort was estimated to be over A$9 million. Conclusion: This study provides the first in-depth analysis of the cost of hospitalization for SAB in children. This study suggests that the economic burden of SAB in children is substantial, and prevention and treatment strategies should remain focused on S. aureus as a whole.

Background: There is growing evidence to support partial oral antibiotic treatment of severe infections such as Staphylococcus aureus bacteremia, but clinical practice is slow to adopt this paradigm. We know little about how patients with severe infection experience and perceive intravenous and oral antibiotics in terms of quality of life and clinical effectiveness. We performed a qualitative study to elicit patients’ views on treatment with intravenous and oral antibiotics, aiming to provide insights that could inform collaborative treatment decision-making. Methods: We conducted semi-structured interviews with participants in the Staphylococcus aureus Network Adaptive Platform trial pharmacological sub-study PR-O-SNAP by telephone, in person, or via video conferencing. Interviews were recorded, transcribed and coded, and used to analyze and identify themes. Interviews occurred in 2 phases between November 2024 and January 2025, with interim analysis to refine interview questions between each phase. Results: We interviewed 17 patients who had received sequential intravenous then oral antibiotics for treatment of Staphylococcus aureus bacteremia. Overall, most participants preferred oral antibiotics for their convenience, which enabled improved mobility and independence, despite a perception that oral regimens were more complex and likely to cause side effects, and that intravenous antibiotics were more effective. Conclusions: Choosing a route of antibiotic administration for treatment of severe infection is a nuanced decision which should incorporate not just a patient's clinical status but also their preferences and personal context. Patient convenience and functional goals should be considered in treatment discussions between clinicians and patients.

Tuberculosis (TB) is caused by Mycobacterium tuberculosis (Mtb) and is a leading cause of death. BCG is the only licensed TB vaccine. Preclinical studies have shown that in adults, intravenous administration of BCG improves protection against TB. We hypothesize that intradermal administration of BCG to the human newborn leads to low-grade BCG bacteremia and that this systemic dissemination improves protection against Mtb infection. This hypothesis is based on supporting observations including animal and human studies. It is a testable hypothesis and offers to deliver immediately actionable insight to advance the global efforts against TB.

Background: Rising proportions of antimicrobial resistance (AMR) have been observed in both Staphylococcus aureus and Enterococcus spp. isolates. Methods: The Australian Group on Antimicrobial Resistance surveillance program captures clinical and microbiological data of isolates detected in blood cultures across Australia. EUCAST 2022 was used for interpretation and the AMR package in R for data analysis. Results: There were 2091 bloodstream infections (BSIs) with S. aureus and 534 enterococcal BSI episodes in children 50% of enterococcal BSIs were in children <12 months old. Fifteen percent of S. aureus isolates were methicillin-resistant. Overall, 85.3% of S. aureus were resistant to penicillin, 12.5% resistant to erythromycin, 10.3% to clindamycin, and 4.7% to ciprofloxacin. Resistance to penicillin decreased over time, while clindamycin resistance increased. Resistance in Enterococcus spp. was almost entirely observed in Enterococcus faecium; only 1 Enterococcus faecalis isolate was ampicillin-resistant, and no E. faecalis isolates were vancomycin or teicoplanin-resistant. Seventy-three percent of E. faecium were resistant to ampicillin, 25.5% to vancomycin (VREfm), and 8.8% to teicoplanin. Conclusions: Significant shifts in the epidemiology and resistance profiles of S. aureus and Enterococcus spp. BSIs in Australian children were observed, making clear the importance of age-stratified reporting in AMR data.

Gram-negative bloodstream infections are associated with significant morbidity and mortality in children. Increasing antimicrobial resistance (AMR) is reported globally, yet efforts to track pediatric AMR at a national level over time are lacking. The Australian Group on Antimicrobial Resistance (AGAR) surveillance program captures clinical and microbiological data of isolates detected in blood cultures across Australia. EUCAST 2022 was used for MIC interpretation and the AMR package in R for data analysis. Over a nine-year period, there were 3,145 bloodstream infections with 3,266 gram-negative isolates reported in hospitalized children aged p: 0.001). Escherichia coli (44.5%) and Klebsiella pneumoniae complex (12.6%) were the two most frequently reported organisms. Overall resistance in Enterobacterales to gentamicin/tobramycin was 11.6%, to ceftazidime/ceftriaxone was 12.9%, and 13.2% to ciprofloxacin. Resistance increased over time. Of 201 Pseudomonas aeruginosa isolates reported, 19.7% were resistant to piperacillin-tazobactam, 13.1% resistant to cefepime/ceftazidime and 9.8% to ciprofloxacin. Of 108 Acinetobacter spp. isolates, one was resistant to meropenem, and two were resistant to ciprofloxacin. Resistance did not increase over time. AMR in gram-negative organisms causing bloodstream infections in Australian children is increasing which should be considered when updating guidelines and empiric treatment regimens. Ongoing pediatric-specific national surveillance with pediatric reporting must remain a priority to strengthen antimicrobial stewardship and infection control programs.

International consensus definitions for invasive aspergillosis (IA) in research are rigorous, yet clinically significant cases are often excluded from clinical studies for not meeting proven/probable IA case definitions. To better understand reasons for the failure to meet criteria for proven/probable infection, we herein review 47 such cases for their clinical and microbiological characteristics and outcomes. Data on 47 cases that did not meet consensus IA definitions but were deemed significant were derived from a retrospective, observational, multicenter survey of 382 presumed IA cases across Australasia, of which findings of 221 proven/probable infections were recently published. The clinical, microbiological, and radiologic characteristics of these cases were analyzed. Mortality outcomes were compared with those of 221 proven/probable cases. Of 47 cases studied, 15 lacked classical host factors; 22 exhibited only a single positive Aspergillus polymerase chain reaction result; 7 lacked typical IA radiologic findings on chest computed tomography; and 3 had borderline galactomannan optical density indices (Aspergillus polymerase chain reaction result and those without host factors, are needed to determine if future consensus definitions may benefit from modifications.