Safety of bacteriophage therapy in severe Staphylococcus aureus infection

Abstract

In this single-arm non-comparative trial, 13 patients in an Australian hospital with severe Staphylococcus aureus infections were intravenously administered a good manufacturing practice-quality preparation of three Myoviridae bacteriophages (AB-SA01) as adjunctive therapy. AB-SA01 was intravenously administered twice daily for 14 d and the clinical, haematological and blood biochemical parameters of the recipients were monitored for 90 d. The primary outcome was the assessment of safety and tolerability (that is, pain and redness at the infusion site and systemic adverse reactions, such as fever, tachycardia, hypotension, diarrhoea or abdominal pain and the development of renal or hepatic dysfunction). No adverse reactions were reported, and our data indicate that AB-SA01 administered in this way is safe in severe S. aureus infections, including infective endocarditis and septic shock. Future controlled trials will be needed to determine the efficacy of AB-SA01 but no phage resistance evolved in vivo and the measurements of bacterial and phage kinetics in blood samples suggest that 12 h dosing of 109 plaque-forming units may be a rational basis for further studies. Trial Registration: Westmead Hospital Human Research Ethics Committee HREC/17/WMEAD/275; ClinicalTrials.gov: NCT03395769; Clinical Trials Notification (Australian Therapeutic Goods Association): CT-2018-CTN-02372-1.

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Fig. 1: Study outline from consent through to follow-up after 90 d.
Fig. 2: Monitoring over 28 d from the commencement of phage (AB-SA01) therapy.
Fig. 3: S. aureus blood cultures and bacterial DNA burden in the blood of patients with and without endocarditis.
Fig. 4: Phage titre in serum samples during bacteriophage therapy.
Fig. 5: Phage DNA load in serum samples during bacteriophage therapy.

Data availability

The AB-SA01 genomes have been published4 and are publicly available. Raw sequence reads are available on NCBI under the BioProject accession number PRJNA541589 and additional data is presented in the Supplementary section. Clinical data are subject to privacy constraints under Australian law and requests should be directed to the corresponding author.

Change history

  • 05 March 2020

    An amendment to this paper has been published and can be accessed via a link at the top of the paper.

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Acknowledgements

We thank J. Lai and L. Ma at the WIMR core facility, supported by the Westmead Research Hub, the Cancer Institute New South Wales, the National Health and Medical Research Council and the Ian Potter Foundation; the staff at the Pathogen Genomics Unit, Westmead Hospital and Ramaciotti Centre (UNSW) for their technical advice and sequencing support; A. Netluch and P. Fa for pharmacy support; S. Chan, K. Garnham, S. N. Hutabarat, C. Li, C. Robson, A. Ginn, B. Roychoudry, N. J. Rai as well as the staff at the NSW Pathology Microbiology laboratory, Westmead Hospital for their help with data and sample collection, S. Chan for performing the valve-replacement surgeries and B. Bowring for laboratory assistance. We thank staff at Ampliphi BioSciences Coporations (Sydney: S. Branston; San Diego: Z. Kovach, C.-L. Langlais Furr, F. Rosas, S. Lehman, I. Bilinsky and P. Grint) for provision of AB-SA01 and all related product information and certificates of analysis. This work was funded by the National Health and Medical Research Council (Australian Government) and by AmpliPhi Biosciences Corporation. Trial Registration: Westmead Hospital Human Research Ethics Committee HREC/17/WMEAD/275; ClinicalTrials.gov: NCT03395769. ABPH provided the investigational product AB-SA01 and partial financial support for the work carried out at WSLHD and WIMR to treat patients and for the analysis of samples, as investigator-led research sponsored and indemnified by the WSLHD. J.R.I., C.V. and N.B.Z. are supported by grant nos 1104232 and 1107322 from the Australian National Health and Medical Research Council.

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Contributions

J.R.I. conceived the project and devised the treatment protocol. S. Maddocks, R.C.Y.L. and J.H. were involved in the amendment of the protocol v.2.0 and v.3.0. S. Maddocks and J.H. created the case report forms. J.H. screened the patients. J.R.I., S. Maddocks, T.G. and I.S. consulted on the suitability of the patients. R.C. was consulted for the infective endocarditis patients and provided samples. J.R.I., R.C.Y.L. and A.P.F. designed the experiments. J.R.I., A.P.F., R.C.Y.L., J.H. and S. Maddocks wrote the paper. A.P.F., R.C.Y.L. and J.H. collected and processed the samples, and analysed the data. J.H. collected the patient data. A.P.F. conducted and analysed the phage susceptibility. A.P.F., R.C.Y.L. and J.R.I. analysed the bacterial- and phage-kinetics data. N.L.B.Z. analysed the isolate whole-genome sequencing data. R.C.Y.L. analysed the transcriptome data. S. Morales was involved in discussions of data and project planning. All members of WBTT participated in case finding and therapeutic management. AmpliPhi Biosciences collaborated in the design of the protocol and prepared essential supportive documents (including the Pharmacy Manual and AB-SA01 Product Information and certificates of analysis), participated in reviewing the patient narratives and produced AB-SA01 investigational phage product under GMP conditions.

Corresponding author

Correspondence to Jonathan R. Iredell.

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Competing interests

No personal financial interest was received by the listed authors or WBTT. A provisional patent has been filed in the United States, dated 4 October 2018. R.C.Y.L., J.R.I., A.P.F. and S. Morales are the inventors (attorney docket no. 054249-512; ‘Bacteriophage treatment and reduction of inflammatory response’). ABPH is the sole proprietary owner of AB-SA01. J.R.I. has previously acted as a clinical advisor to C3J Therapeutics. C3J Therapeutics and ABPH announced a merger on 4 January 2019 to become Armata Pharmaceuticals.

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Supplementary information

Supplementary Information

Supplementary Figs. 1 and 2 and Supplementary Tables 1 and 3.

Reporting Summary

Supplementary Table 2

Supplementary Data 2: patients’ S. aureus isolates metadata, sequence type and SNP relatedness.

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Petrovic Fabijan, A., Lin, R.C.Y., Ho, J. et al. Safety of bacteriophage therapy in severe Staphylococcus aureus infection. Nat Microbiol 5, 465–472 (2020). https://doi.org/10.1038/s41564-019-0634-z

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