Safety and Tolerability of Bacteriophage Therapy in Severe Staphylococcus aureus Infection

Importance: The effect of IV administration of a bacteriophagecocktail 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 bacteriophagetherapy 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 hospitalwith 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 EthicsCommittee. Intervention: A GMP-quality preparation of three combined Myoviridae bacteriophageswith 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 bacteriophagekinetics 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: Bacteriophagetherapy was initiated 4-10 days after antibiotic commencement, at 109 plaque-forming units(PFU) twice daily. Infecting staphylococci were typical of common local subtypes. Initial input ratio of phages to bacteria in the bloodstream (MOIinput) was >100. Five of the thirteen patients died by D28 and a sixth patient suffered sudden cardiac death on D90. Bacteriophagetherapy 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 bacteriophageresistance was not observed. Population analysis revealed no significant effect of bacteriophagetherapy on the gut microflora. Conclusions and Relevance: Adjunctive bacteriophagetherapy 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 EthicsCommittee 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).