Phage therapy of pulmonary infections

Abstract

It is generally agreed that a bacteriophage-associated phenomenon was first unambiguously observed one-hundred years ago with the findings of Twort in 1915. This was independently followed by complementary observations by d'Hérelle in 1917. D'Hérelle's appreciation of the bacteriophage phenomenon appears to have directly led to the development of phages as antibacterial agents within a variety of contexts, including medical and agricultural. Phage use to combat nuisance bacteria appears to be especially useful where targets are sufficiently problematic, suitably bactericidal phages exist, and alternative approaches are lacking in effectiveness, availability, safety, or cost effectiveness, etc. Phage development as antibacterial agents has been strongest particularly when antibiotics have been less available or useful, e.g., such as in the treatment of chronic infections by antibiotic-resistant bacteria. One relatively under-explored or at least not highly reported use of phages as therapeutic agents has been to combat bacterial infections of the lungs and associated tissues. These infections are diverse in terms of their etiologies, manifestations, and also in terms of potential strategies of phage delivery. Here I review the literature considering the phage therapy of pulmonary and pulmonary-related infections, with emphasis on reports of clinical treatment along with experimental treatment of pulmonary infections using animal models.

Keywords: lung infection; phage therapy; pharmacology; pleural infection; pulmonary infection.

Figure 1.

Pharmacokinetics of different phage application strategies. Inefficiencies of phage movement from one body compartment to another can serve to limit the potential for phages to effect an inundative therapy. Both parenteral and per os dosing result initially in systemic circulation. This absorption is expected to be more efficient given application into the body via parenteral dosing, that is, there is an expectation of less phage loss with parenteral application in comparison to oral delivery. With per os dosing, by contrast, phages must first survive and then move out the gastrointestinal tract, both of which are not straightforward processes. Per os in the hands of different researchers also does not appear to consistently occur with phages, so possesses some controversy. Topical application by contrast avoids losses associated with absorption and distribution, increasing the potential for local achievement of inundative phage densities. Direct injection of phages into sites of bacterial infection (not shown) similarly avoids issues of adsorption and distribution though is more invasive than topical application.

Figure 2.

Results of lung treatment by Meladze et al. as translated and summarized by Chanishvili. Numbers found along the x axis correspond to (1) “Acute lung abscess” (24 and 17 cases for the phage therapy experimental group and the control group, respectively), (2) “Bronchoextatic [sic] disease” (27 and 13), (3) “Chronic festering bronchitis” (29 and 13), (4) “Chronic lung abscess” (51 and 40), (5) “Chronic pneumonia” (56 and 20), (6) “Pleural empyema” (22 and 8), and (7) “Suppurating lung cyst” (11 and 9). The top panel shows phage treatment (both with and without antibiotic treatment) and the bottom antibiotic therapy only. In the key, “++++” corresponds to “Stable remission”, “++” to “Comparative remission”, and “0=neg” to “Consequences, lethal outcome”.

Figure 3.

Summary of lung treatment of Staphylococcus aureus provided by Chanishvili (p. 176). Numbers found along the x axis correspond to (1) “Acute lung abscess” (9, 11, and 9 cases for IVSP, IVSP + ABP, and ABP, respectively), (2) “Bronchiectasis” (9, 10, 9), (3) “Chronic bronchitis” (8, 8, 7), (4) “Chronic lung abscess” (20, 20, 18), and (5) “Chronic pneumonia” (14, 12, 12). The top panel shows phage therapy only (IVSP), the middle combination of phage and antibiotic therapy (IVSP + ABP), and the bottom antibiotic therapy only (ABP). Phage application appears to have been intravenous. In the key, “++++” corresponds to “Complete cure”, “++” to “Improvement”, and “0=neg” to “No effect”.

Figure 4.

Summary of lung-treatment results provided by Ślopek et al. Numbers found along the x axis correspond to (1) “Inflammation of the upper and lower respiratory tract” (74 cases), (2) “Pneumonia, pneumonia abscedens, bronchopneumonia” (57 cases), (3) “Suppurative pneumonia, empyema with thoracic fistula” (27 cases), and (4) “Pleuritis with fistula” (22 cases). “++++” means “outstanding effect manifesting by a complete recovery,” “+++” means “elimination of suppurative process and healing of the local wounds,” “++” means “marked improvement with a tendency to healing of the local lesions with negative results of bacteriological control,” “+=neg” means only “transient improvement,” and “0=neg” means “no effect.” The authors suggest that (p. 570), “While evaluating the final results, it should be taken into consideration that in 518 cases, i.e., in 94.2% the treatment preceding phage therapy failed, among others, due to resistance of bacteria to antibiotics and chemotherapeutics used.”

Figure 5.

Summary of lung-treatment results provided by Weber-Dabrowska et al. Numbers found along the x axis correspond to (1) “Mucopurulent chronic bronchitis, laryngitis, rhinitis” (271 cases), (2) “Bronchopneumonia, Empyema” (57 cases), (3) “Pleuritis with fistula” (49 cases). “++++” means “Full recovery and complete elimination of bacteria”, “++” means “marked improvement” or “Improvement, bacteria still detectable”, and “0=neg” means “no effect.” These results cover years post those considered by Ślopek et al.