Safety and Tolerability of Bacteriophage Therapy in Severe Staphylococcus aureus Infection

Abstract

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. AbstractImportance: 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 >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 bacteriophageattributable 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 welltolerated in critic...

Design and Preclinical Development of a Phage Product for the Treatment of Antibiotic-Resistant Staphylococcus aureus Infections

“…In vitro, mutual adaptation often leads to long-term maintenance of both phage and bacterial populations [49], but patterns of in vitro and in vivo mutation have been shown to differ [48]. The collective global experience treating single patients, including with AB-SA01 [50], strongly suggests that phage administration can lead to clinical resolution of infection, sometimes with confirmed pathogen eradication [51,52,53,54,55,56,57,58,59,60].…”

CRISPR-Cas9 modified bacteriophage for treatment of Staphylococcus aureus induced osteomyelitis and soft tissue infection

“…In April 2019, data from clinical trials were published from Sydney, Australia, where intravenous (IV) administration of phage was utilized for Staphylococcus infection treatment. Marked reduction of staphylococci with no adverse events were reported[14]. In the United States as of January 2019, IV administration of phage for ventricular assist device infection treatment received approval for phase I/II clinical trials[15].…”

Emerging Treatment Options for Infections by Multidrug-Resistant Gram-Positive Microorganisms

“…In addition, the role of AB-SA01 as an adjunct to surgical treatment in patients with a hip or knee prosthetic joint infection due to S. aureus will also be investigated [224]. An open-label, single-arm study has already evaluated the administration of AB-SA01 intravenously, as adjunctive treatment to antibiotics, in 13 critically ill patients with S. aureus bacteraemia (including six with endocarditis), in one centre in Australia [226]. No safety concerns were raised, and efficacy analyses showed a marked reduction in staphylococcal DNA in blood as well as decrease in inflammatory markers [226].…”