A Review of Topical Phage Therapy for Chronically Infected Wounds and Preparations for a Randomized Adaptive Clinical Trial Evaluating Topical Phage Therapy in Chronically Infected Diabetic Foot Ulcers

Abstract

The advent and increasing prevalence of antimicrobial resistance commensurate with the absence of novel antibiotics on the horizon raises the specter of untreatable infections. Phages have been safely administered to thousands of patients exhibiting signals of efficacy in many experiencing infections refractory to antecedent antibiotics. Topical phage therapy may represent a convenient and efficacious treatment modality for chronic refractory infected cutaneous wounds spanning all classifications including venous stasis, burn-mediated, and diabetic ulcers. We will initially provide results from a systematic literature review of topical phage therapy used clinically in refractorily infected chronic wounds. We will then segue into a synopsis of the preparations for a forthcoming phase II a randomized placebo-controlled clinical trial assessing the therapeutic efficacy exploiting adjunctive personalized phage administration, delivered topically, intravenously (IV) and via a combination of both modalities (IV + topical) in the treatment of infected diabetic foot ulcers (perhaps the canonical paradigm representing complicated recalcitrant infected cutaneous wounds).

Keywords: and antibiotics; bacteriophage; infected ulcers; infected wounds; phage library; phage-antibiotic synergy; phage-phage synergy; topical; topical therapeutics; ulcers; wounds.

Figure 1

Flow chart depicting search methodology¹. (1). Report upon human trials (any age) assessing chronic recalcitrant wound infections conforming to any of the accepted search terms encompassing infected diabetic, venous stasis, decubitus (pressure ulcer), or burn associated wounds/ulcers. Accepted articles could additionally report agnostically upon any infected, purulent, or suppurative cutaneous wounds/ulcers. (2). Publication is in the English language between the years 1980–2020. (3). Report provides results from microbiological surveillance data and clinical wound healing efficacy. (4). Interventions reported must include the administration of topical phage: (a). concomitant antibiotics and alternative modes of phage delivery (oral and/or IV delivery) are acceptable; ((b). there were no constraints imposed upon the delivery vehicle, or administration regimen [dosing, or administration (frequency or duration)] ²Total exclusion criteria met eclipses 440 as many articles met multiple exclusion criteria.

Figure 2

Synopsis of trial preparations. 1. This is intended as a multi-site study. 2. Epidemiology: Acquire epidemiology of the circulating bacterial isolates (including incidence, and their virulence and antimicrobial susceptibility profiles) culpable in chronic diabetic ulcer infections at each site. Additionally, screen the PhageBankTM for phage targeting of a representative sampling of the circulating bacterial isolates at each site, and ensure >80% coverage prior to study initiation. Finally, confirm standard of care including antibiotic selection practices. 3. Demographics stratified by each participating site. 4. Site Staffing: Clinical Research Nurse, Research Associates, Research Physicians, Laboratory (including Microbiological) Support, Pharmacy Support, Data Management Support. 5. CRO: Clinical Research Organization. The contracted research organization (CRO) will be contracted by sponsor. The CRO will oversee study execution (provide oversight), and will perform (site initiation visits, surveillance clinical monitoring visits, confirmation of appropriate site staffing and support, liaison services between study sites and the sponsor, execution of study specific procedures (SSPs), and centralized data management). 6. SSPs: Study Specific Procedures. The SSPs will include (but is not limited to) procedures delineating (a). Staffing, ((b). Microbiological Sampling, (c). Phage Administration Procedures, (d). Storage, (e). Shipping, (f). Regulatory Communications, (g). Data Entry. 7. HRQT: Host Range Quick Test (see narrative). 8. PhageBankTM: Ensure >80% phage coverage targeting known circulating bacterial isolates culpable in diabetic foot ulcer (DFU) infections.

Figure 3

MCR-1 expressing E. coli strains were grown in TS broth (black). E. coli strains were grown with a MOI 10 of phage Ec2182201711φ1 (red), Ec2182201711φ2 (orange), Ec2182201711φ6 (yellow), Ec190520171φ7 (green), or a mixture of all phage together (blue).

Figure 4

MCR-1 expressing E. coli strains were grown in only TS broth (black), with ampicillin (32 µg/mL) (red), with their respective phage (green), and a combination of both ampicillin and their phage (blue). Panels are grown with E. coli 2182201711 and (A) Ec2182201711φ1, ((b) Ec2182201711φ2, (C) Ec2182201711φ6, or (D) E. coli 190520171 with Ec190520171φ7. The MIC for each isolate was 16 µg/mL to ampicillin.