Use of Autologous Bacteriotherapy to Treat Staphylococcus aureus in Patients With Atopic Dermatitis: A Randomized Double-blind Clinical Trial

Abstract

Importance: Atopic dermatitis (AD) can be negatively affected by Staphylococcus aureus. The skin microbiome of AD is deficient in coagulase-negative Staphylococcus (CoNS) that can kill S aureus.

Objective: To evaluate if the antimicrobial-producing CoNS (CoNS-AM+) of a patient with AD can be autologously reintroduced to the same patient to inhibit survival of S aureus and improve clinical outcomes.

Design, setting, and participants: This double-blind, vehicle-controlled, single-center randomized clinical trial of 11 adult patients with moderate to severe AD who were randomized to receive either an autologous CoNS-AM+ (n = 5) or the vehicle (n = 6) was conducted between April 2016 and May 2018. The data were analyzed from May 2018 to July 2019.

Interventions: Autologous CoNS-AM+ was isolated from swabs that were obtained from the nonlesional skin of each patient with AD, expanded by culture, and then reapplied topically to the forearms at a concentration of 107 colony-forming units/g.

Main outcomes and measures: The primary end point of this study was to assess S aureus abundance after 1 week of application of autologous CoNS-AM+ on patients with AD by culture-based and DNA-based methods. The secondary end points were to assess the safety and clinical outcomes.

Results: Eleven patients (4 men [36.4%] and 7 women [63/6%]) were recruited based on the inclusion criteria. There were no serious adverse events in groups treated with autologous CoNS-AM+ or the vehicle. Staphylococcus aureus colonization on lesional skin at the end of treatment on patients who were treated with autologous CoNS-AM+ (mean of log10 ratio to baseline, -1.702; 95% CI, -2.882 to -0.523) was reduced by 99.2% compared with vehicle treatment (mean of log10 ratio to baseline, 0.671; 95% CI, -0.289 to 1.613; P = .01) and persisted for 4 days after treatment (CoNS-AM+: mean of log10 ratio to baseline, -1.752; 95% CI, -3.051 to -0.453; vehicle: mean of log10 ratio to baseline, -0.003; 95% CI, -1.083 to 1.076; P = .03). Importantly, local Eczema Area And Severity Index scores that were assessed at day 11 on patients who received CoNS-AM+ (mean of percentage change, -48.45; 95% CI, -84.34 to -12.55) were significantly improved compared with vehicle treatment (mean of percentage change, -4.52; 95% CI, -36.25 to 27.22; P = .04).

Conclusions and relevance: The data from this randomized clinical trial suggest that bacteriotherapy with an autologous strain of skin commensal bacteria can safely decrease S aureus colonization and improve disease severity. Although larger studies will be needed, this personalized approach for S aureus reduction may provide an alternative treatment for patients with AD beyond antibiotics, immunosuppression, and immunomodulation.

Trial registration: ClinicalTrials.gov Identifier: NCT03158012.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Nakatsuji reported a patent for a bacteriotherapy for atopic dermatitis from the University of California, San Diego. Dr Gallo reported grants from the National Institutes of Health (NIH) during the conduct of the study in addition to a pending patent; being a cofounder, scientific advisor, consultant, and holding equity in MatriSys Biosciences and receiving consulting fees and holding equity in Sente Inc outside of the submitted work. Dr Shafiq reported grants from the National Institute of Allergy and Infectious Diseases during the conduct of the study. No other disclosures were reported.

Figures

Figure 1.. CONSORT Flow Diagram of Participant Recruitment

CoNS-AM+ indicates coagulase-negative Staphylococcus.

Figure 2.. One-Week Treatment With Autologous Antimicrobial-Producing Coagulase-Negative Staphylococcus (CoNS-AM+) Decreases Proportion of Staphylococcus aureus in the Microbial Community Without Leading to Excess Bacteria Accumulation on the Skin Surface

Effect of topical application of CoNS-AM+ or vehicle on the abundance (A) and proportion (B) of total 16S ribosomal RNA (rRNA) gene on the surface of lesional skin of patients with atopic dermatitis (AD). Data represent the mean (SEM) from each arm of individual patients. Data were compared with a 2-tailed parametric unpaired t test. The following CoNS-AM+ was transplanted to each patient: patient 1, Staphylococcus epidermidis-N009-G7; patient 2, Staphylococcus epiermidis-N018-F3; patient 3, Staphylococcus warneri-N025-G2; patient 4, Staphylococcus hominis-N005-E10; and patient 5, Staphylococcus capitis-N030-H8 (eFigure 1B in Supplement 2); spp indicates species. Relative abundance of CoNS (C) and S aureus 16S rRNA genes (D) determined from panel B. Data represent mean (SEM). Data were compared with a 2-tailed parametric paired (between points within the same group) or unpaired (between different treatment groups) t test. E, Dissimilarity in the microbial proportion calculated based on the Jaccard distance of the data from panel B. The P value was calculated by a 2-tailed parametric paired (baseline [BL] vs day 7 within the same patient’s group) or unpaired (BL data between different treatment group) t test.

Figure 3.. One-Week Treatment With Autologous Antimicrobial-Producing Coagulase-Negative Staphylococcus (CoNS-AM+) Inhibited Staphylococcus aureus Survival and Improved Local Disease Severity in Adult Patients With Atopic Dermatitis (AD)

Effect of twice-a-day topical application of CoNS-AM+ or vehicle on S aureus survival on the lesional skin of patients with AD (A) and local inflammation (B). S aureus survival was evaluated by counting colony forming units (CFUs) on an S aureus-selective agar plate. Data represent the mean (SEM) from each arm as the ratio to baseline (BL; day 0 point). Local inflammation was evaluated by calculating the local Eczema Area and Severity Index (EASI) score on the entire arm. Data represent mean (SEM). P values were calculated with a 2-tailed parametric unpaired t test.