Bacteriophages in the treatment of chronic rhinosinusitis resistant to therapy
The journal Antibiotics published a review devoted to the prospects and challenges of using bacteriophages in patients with treatment-resistant chronic rhinosinusitis. Specifically, the review presents the results of preclinical and clinical studies in this area.
Chronic rhinosinusitis is a common condition affecting one in ten Europeans. For some patients, chronic rhinosinusitis is resistant to both medical and surgical treatment, significantly worsening their physical, social, and emotional well-being and increasing the burden on the healthcare system. Biofilms and disruption of the microbial ecology of the upper respiratory tract mucosa due to the active growth of Staphylococcus aureus and Pseudomonas aeruginosa play a significant role in the pathogenesis of treatment-resistant chronic sinusitis.
In a review published in the journal Antibiotics*, Belgian researchers summarized the results of preclinical and clinical studies on the effectiveness of phage preparations, including bacteriophage enzymes, both in vitro —in the destruction of bacteria isolated from patients with chronic rhinosinusitis—and in vivo —in animal models or in the treatment of such patients.
Table 1. In vitro studies of the efficacy of phages or phage enzymes against bacteria isolated from patients with therapy-resistant chronic rhinosinusitis
|
Author (year) |
Strains seen from the mucous membrane of the nasal sinuses |
Number of patients |
Phages |
Sensitivity to phages |
Efficiency |
|
Drilling A. et al. (2014) |
S. aureus |
66 |
CT-SA cocktail |
94% 90% |
Reduction in biofilm mass: 80% after application of CT-SA |
|
Drilling A. et al. (2016) |
S. aureus |
Didn't determine |
P128, a phage enzyme that hydrolyzes the bacterial cell wall |
Didn't determine |
Biofilm mass reduction: 95.5% |
|
Fong S. et al. (2017) |
P. aeruginosa |
47 |
Pa193, single drug |
73% |
Significant reduction in biofilm mass after application of CT-PA, Pa222 and Pa223 |
|
Drilling A. et al. (2017) |
S. aureus |
61 |
P68, single-drug |
74% |
Didn't determine |
|
Bachert C. et al. (2018) |
S. aureus |
9 |
ISP, monodrug |
Didn't determine |
Reduction in IL-5 levels after 24 and 72 hours, no significant differences compared to antibiotics |
|
Zhang G. et al. (2018) |
S. aureus |
65 |
Sa83, single drug |
69% |
Didn't determine |
|
Szaleniec J. et al. (2019) |
S. aureus, S. epidermidis, P. aeruginosa, H. influenza |
50 |
Phage from the Biophage Pharma collection |
80% |
Didn't determine |
|
Ooi M. et al. (2019) |
S. aureus |
15 |
AB-SA01, cocktail |
80% |
Didn't determine |
Table 2. Studies of the safety and efficacy of phages or phage enzymes in the treatment of chronic rhinosinusitis in animal models
|
Author (year) |
Pathogen |
Animal and method of administration |
Number of animals in the experiment |
Phage/drug |
Safety |
Efficiency |
|
Fenton M. et al. (2010) |
S. aureus |
Mouse, intranasal instillation |
14 |
Phage lysin CHAPk from phage K |
Didn't determine |
A 2-order reduction in the number of S. aureus cells 1 hour after instillation |
|
Drilling A. et al. (2014) |
S. aureus |
Sheep, irrigation of the frontal sinuses through mini-trephination |
27 |
CT-SA |
There are no histological changes in the mucous membrane of the frontal sinuses. |
Significant reduction in biofilm mass |
|
Drilling A. et al. (2017) |
S. aureus |
Sheep, irrigation of the frontal sinuses through mini-trephination |
21 |
NOV012 |
There are no histological changes in the mucous membrane of the frontal sinuses. |
Didn't determine |
|
Fong S. et al. (2019) |
P. aeruginosa |
Sheep, irrigation of the frontal sinuses through mini-trephination |
32 |
CT-PA |
There are no histological changes in the mucous membrane of the frontal sinuses. |
Significant reduction in biofilm mass |
Table 3. Overview of clinical studies on the safety and efficacy of phages or phage enzymes in the treatment of therapy-resistant chronic rhinosinusitis
|
Author (year) |
Type of study |
Number of patients |
Pathogen |
Therapy regimen |
Phages |
Safety |
Efficiency |
|
Mills E. et al. |
Observational |
Therapy-resistant HR (n = 60) |
S. aureus |
Nebulizer (nasal douche) |
Phage lysate A-1 and B-7 |
There are no reports of side effects. |
Clinical improvement: |
|
Weber-Dabrowska et al. (2000) |
Observational |
Purulent sinusitis (n = 46) |
S. aureus , E. coli, Klebsiella, Proteus, P. aeruginosa , etc. |
Drops orally or intranasally |
Specific phages from the collection |
Didn't determine |
Clinical improvement: |
|
McCallin S. et al. (2018) |
Observational |
Healthy carriers (n = 21) |
S. aureus |
Oral (n = 10) or nasal (n = 11) administration |
Antistaphylococcal phage monodrug (n = 21), Pyophage cocktail |
Nasal administration: No adverse effects reported. Oral administration: Mild adverse effects (vomiting, bowel upset, mild abdominal pain, low-grade fever) reported in 4 participants. No changes in blood counts. |
Didn't determine |
|
Kryukov A. et al. (2019) |
Randomized controlled |
Acute sinusitis |
S. pneumoniae , S. aureus, H. influenza, hemolytic treptococcus, etc. |
Perioperative irrigation followed by oral administration (n = 38); second-generation cephalosporins (n = 20) |
Polyvalent Pyophagus |
There are no reports of side effects. |
Clinical improvement: there are no significant differences between the phage and antibiotic therapy groups after 10 days of treatment |
|
Ooi M. et al. (2019) |
Observational |
Therapy-resistant HR (n = 9) |
S. aureus |
Intranasal high-volume irrigation |
AB-SA01, cocktail |
Mild side effects (diarrhea, nosebleeds, nasopharyngeal pain, cough) were reported in 3 participants. No changes in vital signs or blood counts were observed. |
Improvement of Lund-Kennedy scores in all patients. Reduction of arterial load: 100%. |
|
Lusiak M. et al. (2020) |
Observational |
Therapy-resistant HR (n = 25) |
S. aureus , P. aeruginosa, Klebsiellapneumoniae, E. coli , etc. |
Nasal administration (n = 4) or nasal + oral administration (n = 21) |
Specific phage from the collection |
Didn't determine |
Clinical response: |
The authors note the need for further, larger-scale clinical trials of phage therapy for treatment-resistant chronic rhinosinusitis. At the same time, they point to regulatory issues hindering such research, specifically the limited use of phages in Western Europe and the United States as a "last resort" therapy, that is, in cases where all other treatments have proven ineffective.
In 2019, Belgium authorized the use of custom-made phage preparations for the treatment of difficult-to-treat bacterial infections. Special multidisciplinary committees have been established at Belgian medical institutions to determine which patients can benefit from phage therapy. For each case, an active phage is identified and administered according to standard protocols.
In conclusion, the authors note that bacterial strains isolated from patients with treatment-resistant chronic sinusitis are, in most cases, sensitive to bacteriophages, regardless of their antibiotic susceptibility. Furthermore, phages are capable of reducing the biofilm mass produced by S. aureus and P. aeruginosa in patients with chronic rhinosinusitis. Both systemic and intranasal administration of phages is generally safe and does not cause serious side effects. Therefore, high-level clinical trials are needed.
All literary sources mentioned above are included in the review’s bibliography*.
* Uyttebroek S, Onsea J, Metsemakers WJ, Dupont L et al. The Potential Role of Bacteriophages in the Treatment of Recalcitrant Chronic Rhinosinusitis. Antibiotics 2021, 10 675. https://doi.org/10.3390/antibiotics1006067