July 7, 2025
Dr Tom Boyles, a senior researcher at CHRU co-authored this article which first appeared in Science Direct in July 2025
Tom Boyles, Asha C. Bowen, Rispah Chomba, Jeremy Nel, Joshua S. Davis, Steven Y.C. Tong*
Staphylococcus aureus bacteraemia (SAB) is associated with high mortality worldwide. Historically, randomized controlled trials (RCTs) of SAB have been limited in size and scope, and often failed to include diverse geographic populations. The Staphylococcus aureus Network Adaptive Platform (SNAP) trial addresses these limitations through an adaptive platform design that allows for ongoing comparisons of multiple interventions across global sites.
Despite the global burden of SAB being disproportionately higher in low and middle income countries (LMICs), participation of such sites in major trials remains rare. This underrepresentation threatens both the external validity of trial results and the equitable distribution of research benefits. The recently released WHO guidance on clinical trials provides a roadmap to inclusivity of these underrepresented groups and aligns with the goals of the SNAP trial. We present the experiences of the Clinical HIV Research Unit (CHRU), Johannesburg, South Africa---currently the only LMIC site involved in the SNAP trial.
CHRU is a division of the Wits Health Consortium, affiliated with the University of the Witwatersrand. The site recruits SAB patients admitted to Helen Joseph Hospital, a large tertiary public facility in Johannesburg. CHRU joined SNAP in February 2023 and enrollment commenced in August 2023 after obtaining full regulatory and ethics approvals. Operational activities were initially supported by two part-time staff: a medical doctor and a study coordinator. Blood cultures with confirmed S. aureus are identified by the hospital microbiology team and communicated via WhatsApp messaging to the operational team. Messages are encrypted and self-delete after 90 days. Gram stain results are released on the laboratory information system immediately but are only communicated by WhatsApp message once culture confirmed. SAB episodes are logged, and eligible patients are approached for consent and randomization. Reasons for non-randomization are documented in a locally approved database. Follow-up is continued for 90 days post-enrollment, either in person or by telephone, with mortality as the primary outcome.
Site operations were initially supported by ex-gratia payments from The Paterson Family Foundation: AUD$50,000 in 2023 and Australian National Health and Medical Research Council (NHMRC; Australia) AUD$50,000 in 2025. Approximately 90% of patients attending the hospital are Black African. The hospital does not serve a paediatric population although adolescents above 14 years can be admitted. Regulatory approvals have recently been received to recruit adolescents. No pregnant patients with SAB have been observed to date as the hospital does not serve pregnant women. Enrollment is limited to standard working hours.. While not quantified, supply chain issues have frequently led to stock-outs of blood culture media and antibiotic susceptibility disks, delaying pathogen identification beyond the 72-hour window allowed to complete randomization following index blood culture collection.
Between August 2023 and May 2025, the CHRU study team received 168 reports of SAB. Of these, 28 participants (17%) were successfully randomized, with a total of 44 randomisations across domains. Reasons for non-randomisation were staff unavailability at time of result 30 (18%), patient death prior to culture result 34 (20%), delays in result reporting >72 hours 40 (24%), lack of capacity to consent with no available surrogate decision maker 7(4%), paediatric 4 (2%), other reasons 25(15%).
Despite challenges, participant follow-up has been excellent, with 100% of 90-day mortality data collected and 11 protocol deviations observed. This demonstrates the feasibility of rigorous clinical trial operations in a resource-constrained setting, despite barriers to recruitment.
Based on the ex-gratia payments of AUD$ 100,000, we were able to pay for start-up costs and anticipate enrolling approximately 75 participants to the SNAP platform before funds are exhausted. In addition, we have enrolled 65 participants to the observational registry using the same funding mechanism and take part in activities such as membership of the Global Trial Steering Committee as the only site from an LMIC as well as organization of the local Trial Steering Committee and planning of sub-studies. This represents excellent cost effectiveness, particularly given that no staff members at CHRU receive alternative salary support. The funds include covering a 10% overhead fee to the university and the costs of drugs that are not considered standard of care (clindamycin for the adjunctive antibiotic domain and cefazolin for the methicillin-resistant S. aureus backbone antibiotic domain).
Multiple applications for sustained funding have been unsuccessful, despite demonstrable efficiency.
Whilst Africa has a strong track record in recruiting patients to trials, particularly of Tuberculosis and HIV, there's a scarcity of trials in inpatients, and even fewer in bloodstream infections. CHRU's experience in the SNAP trial provides critical insights into both the feasibility and value of including LMIC sites in global platform trials of bloodstream infections. The high disease burden, rapid enrollment potential, and cost-efficiency at CHRU reinforce the strategic and ethical imperative to broaden LMIC participation, to ensure generalizability of results to LMIC settings.
However, key structural barriers remain. Diagnostic delays due to supply chain inconsistencies compromise early intervention and randomisation opportunities. Staffing limitations, particularly outside regular hours, lead to missed enrollments and limit trial responsiveness.
High pre-diagnosis mortality (20% of SAB cases) at our site, compared to HIC averages (~5%) underscores the need for faster diagnostics and earlier triage in LMICs. Moreover, limited access to surrogate decision-makers presents ethical and logistical barriers in acutely ill populations. Opportunities to use telephonic consent from legally authorized representatives are being pursued.
The CHRU model also exemplifies the strengths of LMIC sites when adequately supported. Follow-up rates exceeded expectations, and the cost-effectiveness of trial operations presents a compelling case for investment. However, reliance on one-off grants threatens sustainability, particularly for long-duration trials like SNAP.
CHRU is slated to join three additional platform trials hosted by HIC institutions, investigating: Pneumocystis pneumonia, invasive streptococcal disease, and resistant Gram-negative bacteraemia. Each study includes dedicated funding for start-up and operational costs. Nonetheless, for long-term engagement in platform trials, a core funding model---complemented by targeted investments in laboratory and human resource capacity---is essential.
The inclusion of CHRU in the SNAP trial demonstrates that LMIC sites can contribute high-quality data in a cost-effective manner. To ensure sustained participation and enhance the generalisability of trial findings, global research consortia must move toward equitable funding models that include infrastructure and capacity building. Strengthening LMIC trial capacity is not only a matter of global equity---it is a strategic imperative for tackling infectious diseases that disproportionately affect the world's most vulnerable populations.
Acknowledgements
We thank The Paterson Family Foundation for the initial donation of AU$ 50,000. We thank the Australian National Health and Medical Research Council (NHMRC; Australia) for funding support and the microbiology team at Helen Joseph Hospital for their close collaboration. We also acknowledge the dedication of CHRU staff and the participants and families who made this research possible. There was no specific funding for this manuscript.
Conflict of interest disclosure
TB and RC declare no conflicts of interest related to this work. JD declares research grants from Australia's National Health and Medical Research Council supporting the SNAP trial including in South Africa. ST declares Australian National Health and Medical Research Council Grants; with payments to my institute. Australian Medical Research Futures FundGrants; with payments to my institute. UpToDate, royalties for editing articles on Staphylococcus aureus. AstraZeneca, payments claimed for sitting on advisory board for a clinical trial. JN declares Wellcome Trust grant for the RECOVERY trial. Payments from Novo Nordisk for a Study on AI in Anti-Microbial Resistance. A payment from Abbvie for a public lecture on HIV. AB declares NHMRC Investigator Grant (Leadership 1) 2025-29, GNT2032628 payment to The Kids Research Institute Australia, NHMRC Investigator Grant (Emerging Leadership 2), 2020-24 GNT1175509, payment to The Kids Research Institute Australia. Staphylococcus aureus Network Adaptive Platform trial in Paediatrics and Youth (SNAP-PY). NHMRC Clinical Trials and Cohort Studies Grant, 2022-27 GNT2014900, payment to The Kids Research Institute Australia. Chair, FOSUTI Trial Data Safety Monitoring Board. Chair, TIARA Trial, Data Safety Monitoring Board. Member, STAMPS (Phage) Trial Data Safety Monitoring Board. President & Board Member, World Society for Pediatric Infectious Diseases, travel reimbursement. Board Member, Riverview Church.
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