Abstract
Bacterial skin and soft tissue infections (SSTIs) represent a major public health challenge, contributing to 23% of skin diseases globally with approximately 98,500 deaths annually. Rising antimicrobial resistance (AMR), inconsistent treatment approaches, and limited therapeutic options pose significant challenges to the bacterial SSTI management in primary care, particularly in resource-limited settings. Chapter 1 explains the foundation for this thesis, emphasising the importance of public health management in SSTIs and the urgent need to address AMR. It outlines the primary research objectives, including a comprehensive investigation of SSTI epidemiology, an in-depth analysis of clinical management practices, and exploring novel antibacterial therapies. This thesis (1) investigates the epidemiology and risk factors associated with bacterial pathogens implicated in the SSTIs in primary care and community settings, (2) examines the practices, challenges, and facilitators in SSTI management in Australian primary care, and (3) explores novel topical antibacterials for impetigo.This introductory chapter lays the foundation for the multi-phase methodological approach employed in this thesis. Systematic reviews and meta-analyses provide the epidemiological foundation, identifying key pathogens and risk factors. Mixed-methods studies delve into clinical management practices, examining barriers and enablers to effective care. Narrative review combined with systematic reviews identify the potential agents with antibacterial properties to be tested in the laboratory. Laboratory experiments validate and extend these findings by evaluating novel antibacterial combinations, offering actionable insights for combating AMR. Together, these integrated methods form a unified conceptual framework, addressing the multifaceted issues related to SSTI management in primary care and community settings.
The research was structured into four sections as follows:
Section A: Epidemiology and Risk Factors (Chapter 2)
A systematic review and meta-analysis assessed data from over 63,000 records, identifying Staphylococcus aureus (pooled prevalence: 52%), methicillin-resistant S. aureus (MRSA, 17%), Gram-negative bacteria (19%), and Streptococcus pyogenes (6%) as the predominant pathogens causing SSTIs in primary care and community settings. In addition to prevalence, this analysis uncovered critical risk factors—such as younger age and the lowest economic status—that define which populations are most vulnerable for S. aureus and MRSA. High geographical variations were observed with causative pathogens, highlighting the possibility of mixed infections and the necessity for region-tailored management approaches. These findings provide the foundation for examining how current clinical management practices align with the epidemiological reality of SSTIs.
Section B: Management Practices in Australian Primary Care (Chapter 3)
A mixed-methods study explored practices, enablers and facilitators for SSTI management in Australian primary care. A survey of 51 clinicians and in-depth interviews with 16 participants revealed significant variability in SSTI management approaches which depended on practice settings. Clinicians practised variety of management approaches ranging from ‘watch-and-wait’, non-antibiotic management, topical antibiotics, oral antibiotics, and topical and oral adjuvant therapy. Quantitative data showed that while 73% to 84% of clinicians adhered to guidelines for antibiotic selection, adherence to recommended dosages and frequencies varied widely (26%–58%). The thematic analysis of qualitative interviews illuminated barriers such as diagnostic uncertainty and AMR, as well as enablers like multidisciplinary care and telehealth consultations. The mixed-methods approach provided a detailed understanding of challenges and potential solutions by linking these qualitative insights to quantitative adherence patterns.
Section C: Novel Antibacterials for Impetigo (Chapters 4–7)
The narrative review (Chapter 4) identifies manuka honey, manuka oil, medicinal cannabis, tea tree oil (TTO), and totarol as potential topical antibacterials with antistaphylococcal and antistreptococcal effects with other beneficial effects as topical antibacterials. This chapter describes the challenges in the treatment of impetigo and the importance of combination studies for antibacterial discovery.
Chapter 5 (Systematic Review, Published) evaluates the in vitro antibacterial effects of medicinal cannabis, which had high potential for synergy in combinations, against S. aureus and S. pyogenes. Cannabidiol (CBD), cannabichromene, cannabinol, cannabigerol (CBG), and Δ9-tetrahydrocannabinol (Δ9-THC) exhibited significant antimicrobial activity. In addition, cannabinoids, mainly CBD, exhibited synergistic effects in combination with other agents and antibiofilm effects. Therefore, cannabinoids have the potential to be developed as antibacterials against S. aureus and S. pyogenes including resistant strains.
Chapter 6 (Systematic Review, Published) assesses the wound-healing and antibacterial properties of medicinal cannabis in clinical and preclinical studies. CBD and tetrahydrocannabidiol exhibited antibacterial effects on murine models. Cannabinoid combinations exhibited promising wound healing effects with minor adverse effects in humans. Although high-quality studies are needed for a comprehensive understanding of the antibacterial and wound-healing potential of cannabinoids, high efficacy and lower side effects in current studies shed light on further experiments.
Building on these results, rigorous laboratory studies (Chapter 7) validated the efficacy of alternative therapies. These studies employed clinical laboratory-standard in vitro assays—such as minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC), checkerboard synergy testing, and time-kill assays—to evaluate topical antibacterials, including fusidic acid, hydrogen peroxide, manuka honey, manuka oil, mupirocin, TTO, totarol, and cannabinoids. Synergistic interactions between CBD and totarol (e.g., 0.5/2 mg/L) exhibited potent bactericidal effects, fully eliminating MRSA strains within two hours in the time-kill assay. Conversely, antagonistic effects between CBD and TTO highlighted the importance of selecting compatible agents in combination assays. These findings provide a robust foundation for preclinical and clinical evaluations of cannabinoid-based therapies.
Section D: Conclusion (Chapter 8)
This thesis integrates systematic reviews, meta-analyses, mixed-methods studies, and laboratory experiments into a cohesive conceptual framework that links epidemiological patterns, clinical management practices, and innovative therapeutic options. It bridges the gap between theoretical analysis and experimental validation by integrating comprehensive laboratory studies and explicitly linking them to the corresponding chapters of the thesis.
It highlights the global and regional burden of bacterial SSTIs, emphasising the need for geographically tailored treatment strategies. Younger age and the lowest economic status were risk factors for SSTIs associated with S. aureus including those caused by MRSA. Significant variations in SSTI management practices across Australia underscore the need for revised guidelines and enhanced clinician education. Concerns about AMR, treatment failure, and diagnostic uncertainty were the main barriers, while multidisciplinary care and telehealth consultations emerged as significant enablers to successful SSTI management in Australia. CBD/totarol combination demonstrated promising in vitro efficacy against drug-resistant S. aureus strains, suggesting potential for future therapeutic development.
This structured, evidence-based approach provides actionable insights for tackling AMR in SSTIs, improving management practices, and advancing the development of alternative antibacterial strategies. Ultimately, the framework contributes to reducing the burden of SSTIs and enhancing patient outcomes through informed global antimicrobial stewardship.
| Date of Award | 2025 |
|---|---|
| Original language | English |
| Supervisor | Mary BUSHELL (Supervisor), Jackson THOMAS (Supervisor), Indira SAMARAWICKREMA (Supervisor) & Wubshet TESFAYE (Supervisor) |
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