Early clinical experience of bacteriophage therapy in 3 lung transplant recipients

Abstract

Bacteriophage therapy (BT) uses 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 3 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 died. No BT-related adverse events were identified in the 3 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.

Keywords: antibiotic drug resistance; antibiotic: antibacterial; clinical research/practice; infection and infectious agents - bacterial; infectious disease; lung disease: infectious; lung transplantation/pulmonology; translational research/science.

Figure 1

Detection of active bacteriophages in respiratory samples during use of AB-PA01 for Patient One. Collected BAL samples were serially diluted in phage buffer and the phage titer of AB-PA01 assessed in triplicate using the double agar overlay method with nutrient broth-based liquid and agar media Bacteriophage was absent in BAL prior BT (day 1 ) and were measured at high concentrations during therapy (days 4–29).

Figure 2

Effects of Navy phage cocktails 1 and 2 on Patient One’s P. aeruginosa isolates. P. aeruginosa isolates (10⁴ CFU/ml) were inoculated with bacteriophage cocktail individually and in combination in a 96-well microtiter plate containing tryptic soy media in 1% (vol/vol) tetrazolium dye and incubated at 37°C in a Biolog® machine for 24 hours to evaluate bacteriophage killing activities. Bacterial respiration reduced the tetrazolium dye which changed the color of the media to purple. This change of color was recorded by a camera and depicted as relative units of bacterial growth. (A) The graphs depict the growth of P. aeruginosa day 29 isolate in presence of individual bacteriophages (Paϕ1, PaSKWϕ17, PaSKWϕ22, PaATFϕ1 and PaATFϕ3) along with Navy phage cocktails 1 and 2. (B) The graphs depict the growth of P. aeruginosa isolate on Day 95 in presence of individual Navy phages (Paϕ1, PaSKWϕ17, PaSKWϕ22, PaATFϕ1 and PaATFϕ3) along with Navy phage cocktails 1 and 2.