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Original Investigation
June 20, 2019

Safety and Tolerability of Bacteriophage Therapy for Chronic Rhinosinusitis Due to Staphylococcus aureus

Author Affiliations
  • 1Department of Otolaryngology–Head and Neck Surgery, Basil Hetzel Institute for Translational Health Research, The University of Adelaide, Adelaide, Australia
  • 2AmpliPhi Australia, Pty Ltd, Sydney, Australia
  • 3Department of Otolaryngology–Head and Neck Surgery, Hospital Español de México, Facultad Mexicana de Medicina Universidad La Salle, Mexico City, Mexico
JAMA Otolaryngol Head Neck Surg. 2019;145(8):723-729. doi:10.1001/jamaoto.2019.1191
Key Points

Question  What are the systematic safety and efficacy data necessary to incorporate bacteriophage therapy as a clinical alternative to antibiotics?

Findings  This first-in-humans, phase 1 trial aimed to investigate the safety, tolerability, and preliminary efficacy of the ascending dose intranasal phage cocktail AB-SA01 in 9 patients with recalcitrant chronic rhinosinusitis positive for Staphylococcus aureus. Intranasal AB-SA01 was safe and well tolerated to doses of 3 × 109 plaque-forming units for 14 days, and 2 of 9 patients had eradication of infection.

Meaning  Intranasal irrigation with phage cocktail AB-SA01 is safe and well tolerated at the highest study dose with promising preliminary efficacy results and could be a potential alternative to antibiotics for patients with chronic rhinosinusitis due to S aureus.

Abstract

Importance  Staphylococcus aureus infections are associated with recalcitrant chronic rhinosinusitis (CRS). The emerging threat of multidrug-resistant S aureus infections has revived interest in bacteriophage (phage) therapy.

Objective  To investigate the safety, tolerability, and preliminary efficacy of ascending multiple intranasal doses of investigational phage cocktail AB-SA01 in patients with recalcitrant CRS due to S aureus.

Design, Setting, and Participants  This phase 1, first-in-humans, open-label clinical trial of multiple ascending doses was conducted at a single tertiary referral center from December 1, 2015, through September 30, 2016, with follow-up completed on December 31, 2016. Patients with recalcitrant CRS (aged 18-70 years) in whom surgical and medical treatment had failed and who had positive S aureus cultures sensitive to AB-SA01 were recruited. Findings were analyzed from February 2 through August 31, 2017.

Interventions  Three patient cohorts (3 patients/cohort) received serial doses of twice-daily intranasal irrigations with AB-SA01 at a concentration of 3 × 108 plaque-forming units (PFU) for 7 days (cohort 1), 3 × 108 PFU for 14 days (cohort 2), and 3 × 109 PFU for 14 days (cohort 3).

Main Outcomes and Measures  The primary study outcome was the safety and tolerability of intranasal AB-SA01. Safety observations included vital signs, physical examinations, clinical laboratory test results, and adverse events. The secondary outcome was preliminary efficacy assessed by comparing pretreatment and posttreatment microbiology results, disease-relevant endoscopic Lund-Kennedy Scores, and symptom scores using a visual analog scale and Sino-Nasal Outcome Test–22.

Results  All 9 participants (4 men and 5 women; median age, 45 years [interquartile range, 41.0-71.5 years]) completed the trial. Intranasal phage treatment was well tolerated, with no serious adverse events or deaths reported in any of the 3 cohorts. No change in vital signs occurred before and 0.5 and 2.0 hours after administration of AB-SA01 and at the exit visit. No changes in biochemistry were found except for 1 participant in cohort 3 who showed a decrease in blood bicarbonate levels on exit visit, with normal results of physical examination and vital signs. All biochemistry values were normalized 8 days later. No changes in temperature were recorded before, during, or after treatment. Six adverse effects were reported in 6 participants; all were classified as mild treatment-emergent adverse effects and resolved by the end of the study. Preliminary efficacy results indicated favorable outcomes across all cohorts, with 2 of 9 patients showing clinical and microbiological evidence of eradication of infection.

Conclusions and Relevance  Intranasal irrigation with AB-SA01 of doses to 3 × 109 PFU for 14 days was safe and well tolerated, with promising preliminary efficacy observations. Phage therapy could be an alternative to antibiotics for patients with CRS.

Trial Registration  http://anzctr.org.au identifier: ACTRN12616000002482

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