Advanced Drug Delivery Reviews 145 (2019) 18–39 Contents lists available at ScienceDirect Advanced Drug Delivery Reviews journal homepage: www.elsevier.com/locate/addr Use of phage therapy to treat long-standing, persistent, or chronic bacterial infections☆ Stephen T. Abedon Department of Microbiology, The Ohio State University, Mansfield, OH 44906 article info abstract Article history: Viruses of bacteria – known as bacteriophages or phages – have been used clinically as antibacterial agents for Received 1 January 2018 nearly 100 years. Often this phage therapy is of long-standing, persistent, or chronic bacterial infections, and Received in revised form 10 March 2018 this can be particularly so given prior but insufficiently effective infection treatment using standard antibiotics. Accepted 23 June 2018 Such infections, in turn, often have a biofilm component. Phages in modern medicine thus are envisaged to Available online 3 July 2018 serve especially as anti-biofilm/anti-persistent infection agents. Here I review the English-language literature Keywords: concerning in vivo experimental and clinical phage treatment of longer-lived bacterial infections. Overall, pub- Antibiotic resistance lished data appears to be supportive of a relatively high potential for phages to cure infections which are long Animal models standing and which otherwise have resisted treatment with antibieiotics. Bacteriophage © 2019 Elsevier B.V. All rights reserved. Bacteriophage therapy Biofilm Clinical treatment Contents 1. Introduction...............................................................19 2. Experimentaltreatmentoflong-standingbacterialinfections.........................................20 2.1. Judginginfectionsaspersistentorchronic...............................................20 2.1.1. Criterion0,infectionduration................................................20 2.1.2. Criterion1,infectionstasis.................................................20 2.1.3. Criterion2,treatmentequivalence..............................................21 2.1.4. Criteria3to5,furtherrobustness..............................................21 2.1.5. Criterion3,lackoftriviality.................................................22 2.1.6. Criterion 4, biofilmpresence.................................................22 2.1.7. Criterion5,antibiotictolerance...............................................22 2.1.8. Experimentalpersistentorchronicinfectioncriteria,conclusions................................22 2.2. Phagetreatmentofchronicorpersistentbacterialinfectionsinanimals.................................22 2.2.1. Abscesses.........................................................23 2.2.2. Chronicotitis.......................................................23 2.2.3. Chronicwoundinfection..................................................23 2.2.4. Cystic fibrosis.......................................................24 2.2.5. Mastitis..........................................................25 2.2.6. Osteomyelitis.......................................................25 2.2.7. Other...........................................................26 3. Treatmentofchronicorpersistentbacterialinfectionsintheclinic.......................................26 3.1. EatonandBayne-Jones'caveat(andsuggestion)............................................26 3.2. Abscesses.............................................................27 3.3. Bacterialprostatitis.........................................................30 3.4. Osteomyelitis...........................................................30 Abbreviations: MRSA, methicillin-resistant Staphylococcus aureus or multi-drug-resistant Staphylococcus aureus. ☆ This review is part of the Advanced Drug Delivery Reviews theme issue on “Virus-based biomaterials.” E-mail address: [email protected]. https://doi.org/10.1016/j.addr.2018.06.018 0169-409X/© 2019 Elsevier B.V. All rights reserved. S.T. Abedon / Advanced Drug Delivery Reviews 145 (2019) 18–39 19 3.5. Otitis............................................................... 30 3.6. Skinulcers............................................................ 31 3.6.1. Diabeticfootulcers.................................................... 31 3.6.2. Venouslegulcers..................................................... 31 3.6.3. Bedsores(a.k.a.,decubitusorpressureulcer)......................................... 32 3.7. Urinarytractinfections....................................................... 32 3.8. Other............................................................... 33 4. Recent treatment of a persistent Acinetobacter baumanni infection....................................... 33 4.1. Initialphagedosing........................................................ 33 4.2. Patientconditionfollowinginitialphagedosing............................................ 34 4.3. Phage resistance of two A. baumannii isolates............................................. 34 4.4. Late-stagephagedosing...................................................... 35 4.5. Evidence of phage therapy efficacy?................................................. 35 5. Persistent infection, immunodeficiency,andphagetherapy.......................................... 35 5.1. Immunityandphagetreatment................................................... 35 5.2. Immunodeficiencybeforeversusduringphagetreatment....................................... 36 5.3. Experimental exploration could be difficult.............................................. 36 5.4. Ofwhatpracticalutility?...................................................... 36 6. Conclusions............................................................... 36 Competinginterests.............................................................. 37 Fundingstatement............................................................... 37 References.................................................................. 37 1. Introduction Potentially addressing both issues is the use of bacteriophages as anti- biofilm/anti-bacterial infection agents. It is only relatively recently that the importance of biofilms in bacterial Phage therapy is bacteriophage use as antibacterial medicaments infections has come to be appreciated, e.g., Percival et al. [1, 2]. In part this [6, 23]. Alternatively, and more generally [24], is what can be described lag reflects that it is over only the past few decades that the very existence as a phage-mediated biocontrol of bacteria as found within environ- and importance of biofilms, in microbial ecology, has been recognized ments. As I and many others have discussed elsewhere, e.g., [25–28], [3–5]. Paralleling these trends, though generally only coincidentally, has an important utility of phage therapy, or biocontrol, is its relative safety. been a rebirth within Western medicine of an awareness of the potential As a consequence of the growing need for somewhat non-toxic antibac- for bacterial viruses (bacteriophages or phages) to serve as antibacterial terials, ones which are active even against pathogens which are other- agents [6, 7]. As part of that rebirth, phage interactions explicitly as anti- wise multiply antibiotic resistant, publications mentioning phage biofilm agents have been studied now for over 20 years—particularly therapy appear to be growing exponentially, doubling in number, ac- see Doolittle et al. [8] for an early example. Here I consider phage use as cording to Google Scholar, approximately every 4 years since 2003 [7]. antibacterial agents especially within the context of treatment of long- A growing literature furthermore considers the phage therapy or bio- standing, persistent, or chronic bacterial infections, infections which are control of bacterial biofilms [29, 30]. thought to typically possess a biofilm component [4, 9–15]. Included Notwithstanding this increasing knowledge base, the phage therapy among such infections which could be subject to phage treatment are of long-standing, persistent, or chronic infections is still poorly under- chronic otitis, chronic wound infections, lung infections associated with stood, especially mechanistically. Towards increasing that understand- cystic fibrosis, osteomyelitis, and chronic urinary tract infections, etc. ing we must consider a three-component, somewhat ecological Bacterial infections which are not acute in their duration at an abso- system consisting of phages (as the antibacterial), infecting bacteria lute minimum are ones which persist over long time frames. They often (often in a biofilm form), and the patient (providing biofilm substratum, involve, as well, chronic inflammatory responses along with interfer- nutrients, and immune responses). A thorough discussion of phage use ence with tissue healing—even when infecting bacteria are difficult to as anti-biofilm as well as anti-chronic/-persistent/-long-standing-bac- culture or relatively low in number. Persistence is a consequence of a terial-infection agents consequently could consider (i) the phage- body's immune system failing, on its own, to clear an infection. The ex- biofilm in vitro-treatment literature, (ii) the use of phages to treat istence of persistent bacterial infections in this modern era, however, long-standing or biofilm-associated bacterial infections experimentally typically also represents a failure of medical treatments to fully clear in- in vivo or in situ such as in terms of animal models, (iii) the use of fections. Thus, we usually have two general underlying bases of long- phages to treat long-standing bacterial infections in the clinic, (iv) lasting bacterial