In the first clinic session of my Infectious Diseases fellowship in July 2020, I met Mr. M - a 56-year-old man with disseminated cutaneous Mycobacterium chelonae infection. My clinic preceptor and longtime mentor, Dr. Francisco Marty, who tragically passed away in April 2021, filled our clinic with unique and puzzling cases from day 1 – “zebras” that continue to shape me as a physician even one year after his passing.  By the time we saw Mr. M, he had already been through a great deal. He was diagnosed with his infection 6 months prior and received treatment with a number of antimicrobials that was complicated by severe toxicities. This led to a period of single-drug therapy and subsequent acquisition of resistance to several first-line treatment options. At his initial visit, with worsening nodular lesions on the left arm, right leg, and peri-umbilical soft tissue, we were forced to be creative and employed antibiotic options that are rarely used in our clinical practice – tedizolid, omadacycline, and eventually clofazimine, and bedaquiline were chosen based on a small body of growing evidence for their utility in nontuberculous mycobacterial (NTM) infections.^1–8 Despite the use of these novel therapeutics, his lesions persisted and progressed, extending distally and proximally on the left arm, and eventually involving the left wrist with septic arthritis by December 2020. Furthermore, his skin biopsies continued to show abundant M. chelonae with advancing resistance to a number of antimicrobial agents on cultures.

One of the most important lessons that Dr. Marty taught me during our time together was to continually think of our practice in terms of possibilities rather than limitations. He would often respond to my anxious queries with one of his many mantras, “we don’t worry, we assess and plan, then reassess”. Renowned in our institution for his frequent pursuit of single patient emergency use of investigational drug (IND) applications for challenging cases, Dr. Marty was never one to concede when faced with a treatment failure. As our patient battled drug toxicities and refractory infection, we began to discuss one last option. 

Bacteriophages are viruses that infect bacteria, and were discovered independently more than one century ago by Frederick Twort, a British pathologist, and Félix d’Hérelle, a French-Canadian microbiologist.^9–11 Soon after the discovery of bacteriophages, explorations of their therapeutic use began. However due to mixed clinical results and the development and efficacy of antibiotics, interest in phage therapy declined.¹¹ Recently, with the rising threat of antimicrobial resistance, bacteriophages have reemerged as a promising therapeutic option.^12–14 While historically, phage therapy has most often been used in the treatment of multidrug-resistant gram-negative infections and infections related to biofilm formation including with Staphylococcus aureus, recent reports have suggested the utility of phage therapy for nontuberculous mycobacterial (NTM) infections.^15,16 Barriers to the expansion of phage therapy include the high specificity of phage activity that requires broad screening and limits large scale manufacturing, as well as limited evidence on optimal dose, route of administration, and pharmacokinetic properties of phages.^12,17 Heterogeneity of dosing and administration in published studies can make interpretation of results challenging and clinical trials are needed to better understand the benefits of this therapeutic approach. Finally, concerns around the potential of phages to contribute to antimicrobial resistance or virulence through lysogenic conversion have prompted recommendations for genomic sequencing of all phages to demonstrate the absence of identifiable antibiotic resistance elements and bacterial toxin genes prior to administration in humans.¹²

Bacteriophages are ubiquitous in the environment and unique programs such as the SEA-PHAGES (Science Education Alliance-Phage Hunters Advancing Genomics and Evolutionary Science) program have been created to advance phage science while promoting undergraduate education in microbiology and genomics and engaging students in authentic scientific research.^18,19 Through this program more than 20,000 novel phages have been isolated and added to a central phage database (https://phagesdb.org/).  Notably, when the students isolate a novel phage from soil or water samples in this program, they are able to choose the phage’s name.  This gives the students a sense of project ownership and a unique (and often amusing) way to identify their phage. You can peruse the names of phages isolated through this program at the website listed above.

When considering the use of bacteriophage therapy in a clinical setting, the first step is to identify a commercial or academic laboratory that can biomanufacture bacteriophages targeting the pathogen of interest. The bacterial isolate must then be sent to this laboratory in order to screen for therapeutic phages. The Hatfull laboratory at the University of Pittsburgh is a key academic laboratory that studies the molecular genetics of Mycobacteria and mycobacteriophages. They published the first reported case of a phage used for the treatment of a NTM infection and are actively collaborating with multiple centers to administer mycobacteriophages to patients in need.¹⁵ When we first contacted Dr. Hatfull and Dr. Dedrick about our refractory case, we were met with enthusiasm. The M. chelonae isolate was sent to them in early December 2020 for phage susceptibility testing. On January 28, 2021, we were notified that the isolate was susceptible and efficiently killed by one phage – Muddy. Muddy was originally isolated in Durban, South Africa in 2010, and was scraped from the underside a decomposing aubergine as described in its phage database entry (https://phagesdb.org/phages/Muddy/).

While phage therapy has frequently been administered in a “cocktail” containing multiple phages in order to broaden the spectrum of antibacterial activity and prevent the development of resistance, monotherapy is also used.¹² In this case, only a single phage was identified, precluding the use of a cocktail. As soon as we had this information, we sat down with Mr. M to outline the risks and potential benefits of this experimental therapy. We were very aware of the possibility of a poor clinical response as this would be the first case of a single mycobacteriophage in clinical use and the first case targeting the specific pathogen, M. chelonae. However, Mr. M had suffered frequent hospitalizations and severe side effects related to his antimicrobials over the previous year. Despite the risks of failure, he remained determined to seek any possible treatment that might improve his quality of life. With that in mind, we began the process to initiate a single patient IND.  

Life and science is filled with unforeseen obstacles, and when Dr. Marty died unexpectedly on April 8, 2021, I wondered if Mr. M would ever receive his phage therapy. But with my own redoubled dedication to complete this project in his memory, as well as the incredible mentorship of Dr. Daniel A. Solomon who stepped in as clinical principal investigator, and the unwavering support, guidance, and collaboration of Drs. Hatfull, Dedrick, and team, on May 28, 2021 we received the final regulatory approvals to proceed. Three weeks later we had finalized our clinical protocol and worked with pharmacists to integrate the protocol into the electronic medical record. On June 15, 2021, Mr. M was admitted to the hospital for initiation of intravenous phage therapy.

Phage therapy thus far has been shown to be safe with few adverse events reported, though robust data, in particular from randomized clinical trials remains limited. Mr. M tolerated his therapy well with only minor post-infusion side effects including flushing, chills, and nausea that abated after the first week. He has continued receiving Muddy for > 6 months in conjunction with an oral antibiotic regimen consisting of trimethoprim-sulfamethoxazole, bedaquiline, and omadacycline. His diffuse skin lesions have had an impressive response with decreased nodularity and erythema and repeat biopsies have shown no evidence of Mycobacteria for the first time since his initial presentation.

While mounting evidence suggests a potential clinical benefit of phage therapy, many questions remain. The impact of the host immune response via neutralizing antibodies or other immune mechanisms on the activity of phages is a key area for further investigation. Several case reports have now described conflicting outcomes in the face of neutralizing antibodies with one case that reported a clinical failure, while our patient has remained clinically stable without recrudescent infection despite the development of a robust anti-phage antibody response.

References:

1.     Ruth MM, Koeken VACM, Pennings LJ, et al. Is there a role for tedizolid in the treatment of non-tuberculous mycobacterial disease? J Antimicrob Chemother. 2020;75(3):609-617. doi:10.1093/jac/dkz511
2.     Tang YW, Cheng B, Yeoh SF, Lin RTP, Teo JWP. Tedizolid activity against clinical Mycobacterium abscessus complex isolates-an in vitro characterization study. Front Microbiol. 2018;9(SEP):2095. doi:10.3389/fmicb.2018.02095
3.     Pearson JC, Dionne B, Richterman A, et al. Omadacycline for the treatment of mycobacterium abscessus disease: A case series. Open Forum Infect Dis. 2020;7(10). doi:10.1093/ofid/ofaa415
4.     Morrisette T, Alosaimy S, Philley J V., et al. Preliminary, Real-world, Multicenter Experience with Omadacycline for Mycobacterium abscessus Infections. Open Forum Infect Dis. 2021;8(2). doi:10.1093/ofid/ofab002
5.     Brown-Elliott BA, Wallace RJ. In vitro susceptibility testing of omadacycline against nontuberculous mycobacteria. Antimicrob Agents Chemother. 2021;65(3). doi:10.1128/AAC.01947-20
6.     Vesenbeckh S, Schönfeld N, Roth A, et al. Bedaquiline as a potential agent in the treatment of Mycobacterium abscessus infections. Eur Respir J. 2017;49(5). doi:10.1183/13993003.00083-2017
7.     Yang B, Jhun BW, Moon SM, et al. Clofazimine-containing regimen for the treatment of mycobacterium abscessus lung disease. Antimicrob Agents Chemother. 2017;61(6). doi:10.1128/AAC.02052-16
8.     McGuffin SA, Pottinger PS, Harnisch JP. Clofazimine in Nontuberculous Mycobacterial Infections: A Growing Niche. Open Forum Infect Dis. 2017;4(3). doi:10.1093/ofid/ofx147
9.     Twort F. An investigation on the nature of ultra-microscopic viruses. Bacteriophage. 2011;1(3):127-129. doi:10.4161/bact.1.3.16737
10.     D’Herelle F. On an invisible microbe antagonistic toward dysenteric bacilli: brief note by Mr. F. D’Herelle, presented by Mr. Roux. 1917. Res Microbiol. 2007;158(7):553-554. doi:10.1016/J.RESMIC.2007.07.005
11.     Salmond GPC, Fineran PC. A century of the phage: Past, present and future. Nat Rev Microbiol. 2015;13(12):777-786. doi:10.1038/nrmicro3564
12.     Suh GA, Lodise TP, Tamma PD, et al. Considerations for the Use of Phage Therapy in Clinical Practice. Antimicrob Agents Chemother. 2022;66(3). doi:10.1128/aac.02071-21
13.     Levy SB, Bonnie M. Antibacterial resistance worldwide: Causes, challenges and responses. Nat Med. 2004;10(12S):S122-S129. doi:10.1038/nm1145
14.     Hatfull GF, Dedrick RM, Schooley RT. Phage Therapy for Antibiotic-Resistant Bacterial Infections. Annu Rev Med. 2022;73(1):197-211. doi:10.1146/annurev-med-080219-122208
15.     Dedrick RM, Guerrero-Bustamante CA, Garlena RA, et al. Engineered bacteriophages for treatment of a patient with a disseminated drug-resistant Mycobacterium abscessus. Nat Med. 2019;25(5):730-733. doi:10.1038/s41591-019-0437-z
16.     Dedrick RM, Freeman KG, Nguyen JA, et al. Potent antibody-mediated neutralization limits bacteriophage treatment of a pulmonary Mycobacterium abscessus infection. Nat Med. 2021;27(8):1357-1361. doi:10.1038/s41591-021-01403-9
17.     Pires DP, Costa AR, Pinto G, Meneses L, Azeredo J. Current challenges and future opportunities of phage therapy. FEMS Microbiol Rev. 2020;44(6):684-700. doi:10.1093/FEMSRE/FUAA017
18.     Hanauer DI, Graham MJ, Betancur L, et al. An inclusive Research Education Community (iREC): Impact of the SEA-PHAGES program on research outcomes and student learning. Proc Natl Acad Sci U S A. 2017;114(51):13531-13536. doi:10.1073/pnas.1718188115
19.     Hatfull GF. Innovations in Undergraduate Science Education: Going Viral. J Virol. 2015;89(16):8111-8113. doi:10.1128/jvi.03003-14

Image credit: https://phagesdb.org/phages/Muddy/