Case Reports

. 2021 Apr 14;9(1):92.

doi: 10.1186/s40168-021-01026-9.

Assessment of the microbiome during bacteriophage therapy in combination with systemic antibiotics to treat a case of staphylococcal device infection

Andre Mu^{1

2}, Daniel McDonald³, Alan K Jarmusch^{4

5}, Cameron Martino^{3

6

7}, Caitriona Brennan³, Mackenzie Bryant³, Gregory C Humphrey³, Julia Toronczak³, Tara Schwartz³, Dominic Nguyen³, Gail Ackermann³, Anthony D'Onofrio⁸, Steffanie A Strathdee⁹, Robert T Schooley⁹, Pieter C Dorrestein^{3

4

5

7}, Rob Knight^{10

11

12

13}, Saima Aslam⁹

Affiliations

¹ Doherty Applied Microbial Genomics, Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Australia.
² Microbiological Diagnostic Unit Public Health Laboratory, Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Australia.
³ Department of Pediatrics, University of California San Diego, La Jolla, CA, USA.
⁴ Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, USA.
⁵ Collaborative Mass Spectrometry Innovation Center, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, USA.
⁶ Bioinformatics and Systems Biology Program, University of San Diego, La Jolla, USA.
⁷ Center for Microbiome Innovation, University of California San Diego, La Jolla, CA, USA.
⁸ Antimicrobial Discovery Center, Department of Biology, Northeastern University, Boston, USA.
⁹ Division of Infectious Diseases and Global Public Health, Department of Medicine, University of California San Diego, La Jolla, USA.
¹⁰ Department of Pediatrics, University of California San Diego, La Jolla, CA, USA. robknight@ucsd.edu.
¹¹ Center for Microbiome Innovation, University of California San Diego, La Jolla, CA, USA. robknight@ucsd.edu.
¹² Department of Bioengineering, University of California San Diego, La Jolla, CA, USA. robknight@ucsd.edu.
¹³ Department of Computer Sciences and Engineering, University of California San Diego, La Jolla, CA, USA. robknight@ucsd.edu.

PMID: 33853672
PMCID: PMC8048313
DOI: 10.1186/s40168-021-01026-9

Case Reports

Assessment of the microbiome during bacteriophage therapy in combination with systemic antibiotics to treat a case of staphylococcal device infection

Andre Mu et al. Microbiome. 2021.

. 2021 Apr 14;9(1):92.

doi: 10.1186/s40168-021-01026-9.

Authors

Affiliations

¹ Doherty Applied Microbial Genomics, Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Australia.
² Microbiological Diagnostic Unit Public Health Laboratory, Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Australia.
³ Department of Pediatrics, University of California San Diego, La Jolla, CA, USA.
⁴ Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, USA.
⁵ Collaborative Mass Spectrometry Innovation Center, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, USA.
⁶ Bioinformatics and Systems Biology Program, University of San Diego, La Jolla, USA.
⁷ Center for Microbiome Innovation, University of California San Diego, La Jolla, CA, USA.
⁸ Antimicrobial Discovery Center, Department of Biology, Northeastern University, Boston, USA.
⁹ Division of Infectious Diseases and Global Public Health, Department of Medicine, University of California San Diego, La Jolla, USA.
¹⁰ Department of Pediatrics, University of California San Diego, La Jolla, CA, USA. robknight@ucsd.edu.
¹¹ Center for Microbiome Innovation, University of California San Diego, La Jolla, CA, USA. robknight@ucsd.edu.
¹² Department of Bioengineering, University of California San Diego, La Jolla, CA, USA. robknight@ucsd.edu.
¹³ Department of Computer Sciences and Engineering, University of California San Diego, La Jolla, CA, USA. robknight@ucsd.edu.

PMID: 33853672
PMCID: PMC8048313
DOI: 10.1186/s40168-021-01026-9

Abstract

Background: Infectious bacterial diseases exhibiting increasing resistance to antibiotics are a serious global health issue. Bacteriophage therapy is an anti-microbial alternative to treat patients with serious bacterial infections. However, the impacts to the host microbiome in response to clinical use of phage therapy are not well understood.

Results: Our paper demonstrates a largely unchanged microbiota profile during 4 weeks of phage therapy when added to systemic antibiotics in a single patient with Staphylococcus aureus device infection. Metabolomic analyses suggest potential indirect cascading ecological impacts to the host (skin) microbiome. We did not detect genomes of the three phages used to treat the patient in metagenomic samples taken from saliva, stool, and skin; however, phages were detected using endpoint-PCR in patient serum.

Conclusion: Results from our proof-of-principal study supports the use of bacteriophages as a microbiome-sparing approach to treat bacterial infections. Video abstract.

Keywords: Bacteriophages; Metabolomics; Microbiome; Phage therapy; Staphylococcus aureus.

PubMed Disclaimer

Conflict of interest statement

The authors have no conflicts of interest to declare.

Figures

**Fig. 1**
Microbiota analysis of a patient undergoing adjunctive phage therapy, and analysis of patient samples with respect to intensive care unit (ICU) patients, a subset of the American Gut Project (AGP) population that have taken antibiotics within the past week, and a subset of the AGP population who have not taken antibiotics in the past year. a Patient microbiota profile. A principal coordinate plot of unweighted UniFrac distances of skin (forehead, blue; nares, green; axilla, red;), oral (mouth, orange), and fecal (stool, purple) samples from phage patient. b Comparison of alpha diversity across sample type. Shannon’s diversity for skin (forehead, nares, axilla), oral (mouth), and fecal (stool) samples from phage patient. Boxplots are showing the quartiles (25^th and 75^th percentiles) on the box, and ± 1.5 interquartile ranges for the whiskers. P-values of pairwise Kruskal-Wallis testing are shown for fecal samples compared to other sample types on the figure. A complete list of p-values for pairwise comparisons of each sample type is provided in supplementary file. c Comparative microbiota analyses. A principal coordinate plot of unweighted UniFrac distances of phage patient (orange) skin (ring), oral (diamond), and fecal (sphere) samples in the context of ICU (green) and AGP (purple or yellow) samples. The sample type is denoted by shape, while sample cohort is denoted by the different colors, within the plot

**Fig. 2**
Pairwise distance plots from baseline (pre-treatment) for skin (axilla) microbiome and metabolome samples. a Pairwise distances from baseline pre-treatment sample as calculated by a mixed-effects model. The only sample type with significance during phage-treatment is the skin (axilla) microbiome (P<0.001). Significance was evaluated by a linear mixed effect model and error bars represent standard error from the mean. b Heatmap. Presence of antimicrobial resistance genes and/or its homologs detected in metagenomic samples. Present is defined as 90% gene coverage and 90% nucleotide identity; homolog is defined as 70% gene coverage and 70% nucleotide identity. ^{^}Sample time point, and sample type. ^#Qiita study ID followed by Qiita sample ID. This ID can be used to search https://qiita.ucsd.edu/ for the primary derived data and associated metadata

See this image and copyright information in PMC

References

1. Giulieri SG, Holmes NE, Stinear TP, Howden BP. Use of bacterial whole-genome sequencing to understand and improve the management of invasive Staphylococcus aureus infections. Expert Rev Anti Infect Ther. 2016;14(11):1023–1036. doi: 10.1080/14787210.2016.1233815. - DOI - PubMed
1. World Health Organization. Antimicrobial Resistance: Global Report on Surveillance 2014. http://www.who.int/drugresistance/documents/surveillancereport/en/ Accessed on 22 July 2019
1. Schooley RT, Biswas B, Gill JJ, et al. Development and use of personalized bacteriophage-based therapeutic cocktails to treat a patient with a disseminated resistant Acinetobacter baumannii infection. Antimicrob. Agents Chemother. 2017;61(10):e00954–e00917. doi: 10.1128/AAC.00954-17. - DOI - PMC - PubMed
1. Aslam S, Lampley E, Wooten D, et al. Lessons learned from the first 10 consecutive cases of intravenous bacteriophage therapy to treat multidrug-resistant bacterial infections at a single center in the United States. Open Forum Infect Dis. 2020;7(9):ofaa389. doi: 10.1093/ofid/ofaa389. - DOI - PMC - PubMed
1. Segall AM, Roach DR, Strathdee SA. Stronger together? Perspectives on phage-antibiotic synergy in clinical applications of phage therapy. Curr Opin Microbiol. 2019;51:46–50. doi: 10.1016/j.mib.2019.03.005. - DOI - PubMed

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Assessment of the microbiome during bacteriophage therapy in combination with systemic antibiotics to treat a case of staphylococcal device infection

Affiliations

Assessment of the microbiome during bacteriophage therapy in combination with systemic antibiotics to treat a case of staphylococcal device infection

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Substances

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical