Early clinical experience of bacteriophage therapy in 3 lung transplant recipients

Abstract

Bacteriophage therapy (BT) employs bacteriophages to treat pathogenic bacteria and is an emerging strategy against multidrug-resistant (MDR) infections. Experience in solid organ transplant is limited. We describe BT in three lung transplant recipients (LTR) with life-threatening MDR infections caused by Pseudomonas aeruginosa (n=2) and Burkholderia dolosa (n=1). For each patient, lytic bacteriophages were selected against their bacterial isolates. BT was administered for variable durations under emergency Investigational New Drug applications and with patient informed consent. Safety was assessed using clinical/laboratory parameters and observed clinical improvements described as appropriate. All patients received concurrent antibiotics. Two ventilator-dependent LTR with large airway complications and refractory MDR P. aeruginosa pneumonia received BT. Both responded clinically and were discharged from the hospital off ventilator support. A third patient had recurrent B. dolosa infection following transplant. Following BT initiation, consolidative opacities improved and ventilator weaning was begun. However, infection relapsed on BT and the patient expired. No BT-related adverse events were identified in the three cases. BT was well tolerated and associated with clinical improvement in LTRs with MDR bacterial infection not responsive to antibiotics alone. BT may be a viable adjunct to antibiotics for patients with MDR infections.

Phage-Antibiotic Combination Treatments: Antagonistic Impacts of Antibiotics on the Pharmacodynamics of Phage Therapy?

“…9 Section 3.3.2, phages tested individually: ϕR, λ, T2, T4, or T5. 10 Section 3.3.3, antibiotics tested individually: chloramphenicol, ciprofloxacin, or tetracycline.…”

“…Historically, however, phage therapy has often been a response to failures of antibiotic treatment [3,6]. More recently, there also have been several case studies involving both phage therapy following antibiotic failures and continued antibiotic treatment even after phage therapy has begun [10,12,13,[15][16][17]. Therefore, it would seem that the time has come for more rigorous scrutiny of phage activity as may or may not be present given antibiotic co-treatments of especially still antibiotic-susceptible bacteria.…”

“…Phages have been employed clinically to treat bacterial infections for roughly one-hundred years [1,2], and many of these efforts seem to have been successful, e.g., such as in terms of treatment of chronic infections [3,4], wound infections [4][5][6], or lung-associated infections [7][8][9][10]. This 'phage therapy' furthermore has been proven to be efficacious in at least one modern efficacy (phase I/II) clinical trial [11], and recently there have been several well publicized phage therapy case-study successes [12][13][14]; see also [4,9,10,[15][16][17]. Phages also can be effective against bacterial biofilms, e.g., [18][19][20][21], as well as against persister cells [22,23], though phages do not necessarily actively kill bacteria while these cells are still in the low-growth persister state [24].…”

Phage-Antibiotic Synergy is Driven by a Unique Combination of Antibacterial Mechanism of Action and Stoichiometry

“…Finally, there may be antagonism whereby the molecular action of one of the agents somehow interferes with the action of the other. In reported cases of phage therapy in the U.S., the choice of antibiotic was often made on the bases of antibiogram data and the medical condition of the patients (14).…”

Bacteriophage Therapy: Developments and Directions

“…In recent years some Western European countries have begun approved therapeutic use (Belgium, France), while in the United States a number of entities are developing phage therapeutics to bring them into clinical use but these are yet to be approved by the US Food and Drug Administration. Meanwhile, recent FDA-approved "expanded access" experimental phage treatments in cases in the United States [28][29][30][31][32][33] have alerted the news media and public to the safety and potential of phage therapeutics, sparked excitement about phage therapy, and begun to shift the landscape so that more physicians are open to the use of phage treatments in combination with standard of care antibiotics.…”