Abstract Importance The effect of IV administration of a bacteriophage cocktail produced under GMP conditions on patients with severe S. aureus infection, including complicated bacteraemia, endocarditis and septic shock, is unknown. Objective To assess safety and tolerability of adjunctive bacteriophage therapy in patients with severe S. aureus infections. Design, Setting, Participants Observational, open-label clinical trial of thirteen critically-ill patients admitted to a tertiary-referral hospital with S. aureus bacteraemia (including infective endocarditis, n=6) were assessed by the treating clinician and two consulting infectious diseases physicians to independently verify that routine medical and surgical therapy was optimal and that a poor outcome remained likely. Compassionate access to therapy was approved by both US and Australian regulators and by the Westmead Hospital Human Research Ethics Committee. Intervention A GMP-quality preparation of three combined Myoviridae bacteriophages with specific activity against S. aureus (AB-SA01), was administered intravenously in conjunction with optimal antibiotic therapy. Main Outcome and Measurements Physiological, haematological and biochemical markers of infection, bacterial and bacteriophage kinetics in blood, development of resistance to bacteriophages, and mortality at 28 (D28) and 90 (D90) days were measured. Main outcomes were safety and tolerability. Results Bacteriophage therapy was initiated 4-10 days after antibiotic commencement, at 10 9 plaque-forming units (PFU) twice daily. Infecting staphylococci were typical of common local subtypes. Initial input ratio of phages to bacteria in the bloodstream (MOI input ) was &gt;100. Five of the thirteen patients died by D28 and a sixth patient suffered sudden cardiac death on D90. Bacteriophage therapy coincided with a marked reduction in staphylococcal bacterial DNA in the blood and in sepsis-associated inflammatory responses in almost all cases. No bacteriophage-attributable adverse events were identified. Development of bacteriophage resistance was not observed. Population analysis revealed no significant effect of bacteriophage therapy on the gut microflora. Conclusions and Relevance Adjunctive bacteriophage therapy appears to be safe and well-tolerated in critically ill patients with severe S. aureus infection. Two weeks of twice daily intravenous administration may be a suitable protocol. Controlled trials are needed. Trial Registration Westmead Hospital Human Research Ethics Committee approval July 11, 2017; ClinicalTrials.gov Identifier: NCT03395769 , AB-SA01-EAP01 (January 10, 2018); Clinical Trials Notification (Australian Therapeutic Goods Association): CT-2018-CTN-02372-1 (July 23, 2018). Key Points Question Is intravenous (IV) administration of investigational bacteriophage (phage) therapy safe and well-tolerated in patients with severe Staphylococcus aureus infection? Findings Thirteen patients with severe S. aureus infections received AB-SA01, a bacteriophage product prepared according to Good Manufacturing Practices (GMP), as adjunctive therapy to antibiotics. AB-SA01 was well-tolerated with no adverse events identified. Bacterial burden and inflammatory responses were reduced and no phage-resistant staphylococci were isolated during or after therapy. Meaning Our results will inform future randomised controlled trials assessing the antibacterial and anti-inflammatory potential of bacteriophages in the treatment of severe S. aureus infection.

Safety and Tolerability of Bacteriophage Therapy in Severe Staphylococcus aureus Infection

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