The Safety and Toxicity of Phage Therapy: a Review of Animal and Clinical Studies

viruses Review The Safety and Toxicity of Phage Therapy: A Review of Animal and Clinical Studies Dan Liu 1,2,† , Jonas D. Van Belleghem 2,† , Christiaan R. de Vries 2 , Elizabeth Burgener 3, Qingquan Chen 2, Robert Manasherob 4, Jenny R. Aronson 2, Derek F. Amanatullah 4, Pranita D. Tamma 5 and Gina A. Suh 6,* 1 Department of Burn, School of Medicine, Shanghai Jiao Tong University, Shanghai 200025, China; [email protected] 2 Division of Infectious Diseases and Geographic Medicine, Department of Medicine, School of Medicine, Stanford University, Stanford, CA 94305, USA; [email protected] (J.D.V.B.); [email protected] (C.R.d.V.); [email protected] (Q.C.); [email protected] (J.R.A.) 3 Center for Excellence in Pulmonary Biology, Department of Pediatrics, Stanford University, Stanford, CA 94305, USA; [email protected] 4 Department of Orthopaedic Surgery, School of Medicine, Stanford University, Stanford, CA 94305, USA; [email protected] (R.M.); [email protected] (D.F.A.) 5 Division of Pediatric Infectious Diseases, Department of Pediatrics, School of Medicine, Johns Hopkins University, Baltimore, MD 21287, USA; [email protected] 6 Division of Infectious Diseases, Department of Medicine, Mayo Clinic, Rochester, MN 55905, USA * Correspondence: [email protected] † Theses authors contributed equally to this work. Citation: Liu, D.; Van Belleghem, Abstract: Increasing rates of infection by antibiotic resistant bacteria have led to a resurgence of J.D.; de Vries, C.R.; Burgener, E.; Chen, interest in bacteriophage (phage) therapy. Several phage therapy studies in animals and humans have Q.; Manasherob, R.; Aronson, J.R.; been completed over the last two decades. We conducted a systematic review of safety and toxicity Amanatullah, D.F.; Tamma, P.D.; Suh, data associated with phage therapy in both animals and humans reported in English language G.A. The Safety and Toxicity of Phage publications from 2008–2021. Overall, 69 publications met our eligibility criteria including 20 animal Therapy: A Review of Animal and Clinical Studies. Viruses 2021, 13, 1268. studies, 35 clinical case reports or case series, and 14 clinical trials. After summarizing safety and https://doi.org/10.3390/v13071268 toxicity data from these publications, we discuss potential approaches to optimize safety and toxicity monitoring with the therapeutic use of phage moving forward. In our systematic review of the Academic Editors: literature, we found some adverse events associated with phage therapy, but serious events were Ryszard Mi˛edzybrodzki, extremely rare. Comprehensive and standardized reporting of potential toxicities associated with Nina Chanishvili, Nina V. Tikunova, phage therapy has generally been lacking in the published literature. Structured safety and tolerability Jean-Paul Pirnay, Petar Knezevic and endpoints are necessary when phages are administered as anti-infective therapeutics. Shawna McCallin Keywords: phage therapy; clinical trials; animal models; safety and toxicity; immune activation Received: 10 May 2021 Accepted: 23 June 2021 Published: 29 June 2021 1. Introduction Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in Antibiotic resistance remains an ongoing global threat. The failure to implement published maps and institutional affil- widespread stewardship over these precious resources, the resulting spread of antibiotic iations. resistance, and an under-resourced antibiotic pipeline portend the coming of a “post- antibiotic era” [1]. Lytic bacteriophages (phages) have been known to be a potential antibacterial agent for over a century since their first formal discovery and application as a treatment against human bacterial infections in the 1920s. Though subsequent success of antibiotics had quelled investigations into phage as potential anti-infectives, increasing Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. antibiotic resistance has hastened the reemergence of interest in phage therapy [2–4]. This article is an open access article Despite attractive advantages, including widespread prevalence, activity against distributed under the terms and multidrug-resistant (MDR) bacteria, high specificity, and activity against biofilms [5,6], conditions of the Creative Commons phage therapy is still not considered a mainstream treatment due to several obstacles. Attribution (CC BY) license (https:// First, the lack of reliable data regarding its safety and efficacy in clinical settings [7–9]. creativecommons.org/licenses/by/ Second, appropriate regulatory guidelines specific to phage therapeutics have not been de- 4.0/). veloped [10,11]. Finally, the pharmaceutical and biotech industries have not yet developed Viruses 2021, 13, 1268. https://doi.org/10.3390/v13071268 https://www.mdpi.com/journal/viruses Viruses 2021, 13, x FOR PEER REVIEW 2 of 20 Viruses 2021, 13, 1268 Second, appropriate regulatory guidelines specific to phage therapeutics have not2 of 20been developed [10,11]. Finally, the pharmaceutical and biotech industries have not yet developed economical and scalable production processes for widespread adoption of phage economicaltherapy. While and scalablemuch progress production has processesbeen made, for many widespread questions adoption remain of phage[2,12–14], therapy. such as Whilethe safety much and progress toxicity has of been phage made, preparations. many questions remain [2,12–14], such as the safety and toxicityTo ensure of phage confidence preparations. in the use of phages as anti-infectives, it is critical that basic safetyTo issues ensure of confidence phage therapy in the are use established of phages as [8,15,16]. anti-infectives, Here, we it isfocus critical on thatthe safety basic of safetyphage issues therapy of phagein clinical therapy trials, are case established reports, and [8,15 in,16 vivo]. Here, animal we model focus on studiessince the safety of2008. phageWe review therapy the in current clinical safety trials, assessments case reports, in and phagein vivo therapyanimal research model studiessince and reported 2008. safety Weissues. review We the found current that safety there assessmentswere gaps and in phagea lack therapyof systematic research and and detailed reported descriptions safety issues.regarding We foundsafety thatissues. there However, were gaps there and were a lack no of major systematic adverse and events detailed reported. descriptions We then regardingdiscuss the safety potential issues. safety However, issues there of phage were notherapy, major including adverse events the effects reported. of phage We then on the discusshuman the body, potential human safety flora, issues immune of phage system, therapy, and the including release theof endotoxin effects of phage caused on by the lysis humanof the body,bacteria. human Furthermore, flora, immune bacterial system, andresidues the release in phage of endotoxin preparations caused and by lysis possible of the bacteria. Furthermore, bacterial residues in phage preparations and possible chemical chemical components in the purification process can influence the safety of phage thera- components in the purification process can influence the safety of phage therapy. Finally, py. Finally, we discuss the challenges and opportunities to optimize methods of phage we discuss the challenges and opportunities to optimize methods of phage therapy safety therapy safety monitoring and quality control to enhance implementationstrategies. monitoring and quality control to enhance implementationstrategies. ThereThere is is significant significant contribution contribution to to this this literature literature from from Europe Europe with with 30% 30% (6/20) (6/20) of of animalanimal studies, studies, 43% 43% (15/35) (15/35) of of case case reports, reports, and and 50% 50% (7/14) (7/14) of of clinical clinical trials trials published published out out ofof Europe. Europe. 2.2. MaterialsMaterials and and Methods Methods InIn this this section, section, we we focus focus on the on safety the safety of phage of therapyphage therapy through through a review ofa review both clinical of both trialsclinical and trialsin vivo andanimal in vivo studies. animal We studies. have limitedWe have these limited efforts these to reports efforts publishedto reports inpub- Englishlished in language English journals language between journals 1 January between 2008 1 January and 28 March 2008 2021and 28 available March on2021 PubMed. available Weon excludedPubMed. theWe following:excluded the (1) following: non-vertebrate (1) non-vertebrate animal studies, animal (2) reports studies, of phage(2) reports use of otherphage than use for other anti-infective than for purposes,anti-infective (3) phage purposes, lysin investigations,(3) phage lysin and investigations, (4) investigations and (4) intoinvestigations non-lytic phage. into Wenon-lytic identified phage. 20 animal We studies, identified 35 case 20 reports/series, animal studies, and 1435 clinical case re- trialsports/series, that met and our 14 eligibility clinical criteriatrials that (Figure met1 our). eligibility criteria (Figure 1). FigureFigure 1. 1.Search Search strategy. strategy. The search terms “phage therapy” or “bacteriophage therapy” were used in PubMed. The study types were defined as “Clinical Trials”, “Case Reports” and “Animal Studies”, Viruses 2021, 13, 1268 3 of 20 respectively. The total of 14 clinical trials, 35 case reports, and 20 animal studies were included and discussed in this review. 3. Results 3.1. Animal Studies Of

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