Personalized Inhaled Bacteriophage Therapy Decreases Multidrug-Resistant<i>Pseudomonas aeruginosa</i>

Stanley, G.L.; Kortright, Kaitlyn E.; Modak, M.; Ott, Isabel M.; Sun, Ying; Würstle, Silvia; Grun, C.; Kazmierczak, Barbara I.; Rajagopalan, Govindarajan; Harris, Zachary M.; Britto, Clemente J.; Stewart, J R; Talwalkar, Jaideep S.; Appell, Casey; Chaudary, Nauman; Jagpal, Sugeet; Jain, Raksha; Kanu, Adaobi; Quon, Bradley S.; Reynolds, John M.; Nguyen, Quynh Anh Thi; Shabanova, Veronika; Turner, Paul; Koff, J.L.

doi:10.1101/2023.01.23.22283996

Cited by 11 publications

(14 citation statements)

References 36 publications

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“…To model phage therapy in the CF airways, we utilized a panel of P. aeruginosa phages that have been used therapeutically in pwCF under FDA emergency use authorization and in a clinical trial (NCT04684641) to treat chronic MDR P. aeruginosa infections (23). We complemented this panel with additional P. aeruginosa phages obtained from hospital wastewater that have lytic activity against various P. aeruginosa clinical isolates from pwCF that were isolated for use in therapeutic applications (24).…”

Section: Resultsmentioning

confidence: 99%

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Lytic bacteriophages interact with respiratory epithelial cells and induce the secretion of antiviral and proinflammatory cytokines

Zamora,

Reidy,

Armbruster

et al. 2024

Preprint

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Phage therapy is a therapeutic approach to treat multidrug resistant infections that employs lytic bacteriophages (phages) to eliminate bacteria. Despite the abundant evidence for its success as an antimicrobial in Eastern Europe, there is scarce data regarding its effects on the human host. Here, we aimed to understand how lytic phages interact with cells of the airway epithelium, the tissue site that is colonized by bacterial biofilms in numerous chronic respiratory disorders. We determined that interactions between phages and epithelial cells depend on specific phage properties as well as physiochemical features of the microenvironment. Although poor at internalizing phages, the airway epithelium responds to phage exposure by changing its transcriptional profile and secreting antiviral and proinflammatory cytokines that correlate with specific phage families. Overall, our findings indicate that mammalian responses to phages are heterogenous and could potentially alter the way that respiratory local defenses aid in bacterial clearance during phage therapy. Thus, besides phage receptor specificity in a particular bacterial isolate, the criteria to select lytic phages for therapy should be expanded to include mammalian cell responses.

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Section: Resultsmentioning

confidence: 99%

Section: Panel Of Therapeutic P Aeruginosa Lytic Bacteriophages Is Ge...mentioning

confidence: 99%

Lytic bacteriophages interact with respiratory epithelial cells and induce the secretion of antiviral and proinflammatory cytokines

Zamora,

Reidy,

Armbruster

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

“…aeruginosa phages that have been used therapeutically in pwCF under U.S. Food and Drug Administration (FDA) emergency use authorization and in a clinical trial (NCT04684641) to treat chronic MDR P . aeruginosa infections [ 23 ]. We complemented this panel with additional P .…”

Section: Resultsmentioning

confidence: 99%

Lytic bacteriophages induce the secretion of antiviral and proinflammatory cytokines from human respiratory epithelial cells

Zamora,

Reidy,

Armbruster

et al. 2024

PLoS Biol

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Phage therapy is a therapeutic approach to treat multidrug-resistant (MDR) infections that employs lytic bacteriophages (phages) to eliminate bacteria. Despite the abundant evidence for its success as an antimicrobial in Eastern Europe, there is scarce data regarding its effects on the human host. Here, we aimed to understand how lytic phages interact with cells of the airway epithelium, the tissue site that is colonized by bacterial biofilms in numerous chronic respiratory disorders. Using a panel of Pseudomonas aeruginosa phages and human airway epithelial cells (AECs) derived from a person with cystic fibrosis (CF), we determined that interactions between phages and epithelial cells depend on specific phage properties as well as physiochemical features of the microenvironment. Although poor at internalizing phages, the airway epithelium responds to phage exposure by changing its transcriptional profile and secreting antiviral and proinflammatory cytokines that correlate with specific phage families. Overall, our findings indicate that mammalian responses to phages are heterogenous and could potentially alter the way that respiratory local defenses aid in bacterial clearance during phage therapy. Thus, besides phage receptor specificity in a particular bacterial isolate, the criteria to select lytic phages for therapy should be expanded to include mammalian cell responses.

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“…Recently, Chan et al . showed that, by applying personalized phage therapy, they could decrease virulence and effectively re-sensitize P. aeruginosa strains against multiple antibiotics ( 81 ). By twisting evolution in their favor, they could improve antibiotic treatment and therapeutic outcome further underlining the importance of a phage-antibiotic combination therapy, especially in a patient-tailored approach.…”

Section: Discussionmentioning

confidence: 99%

Exploiting phage-antibiotic synergies to disrupt Pseudomonas aeruginosa PAO1 biofilms in the context of orthopedic infections

De Soir,

Parée,

Kamarudin

et al. 2024

Microbiol Spectr

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In recent years, bacteriophages (or phages) have reentered the spotlight as alternative or adjuvant therapeutic agents to antibiotics. Their efficacy in more recalcitrant forms of infections like biofilms, frequently encountered in the orthopedic setting, remains less characterized. The present study aimed at evaluating the activity of phage-antibiotic combinations against Pseudomonas aeruginosa biofilms. A large collection of phages was de novo isolated from a wide variety of environmental sources. Three phages with a large host range against a.o. clinical orthopedic isolates, PSP2 ( Yuavirus ), PSP3 ( Pbunavirus ), and PSP30 ( Bruynoghevirus ), were selected for phage-antibiotic synergy assays on mature P. aeruginosa PAO1 biofilms. Phages were combined with ciprofloxacin, meropenem, and ceftazidime, all used as standard of care in bone-related infections. Significant reductions in both cell counts and biomass were observed for all phage-antibiotic combinations. The highest reduction in viable cell counts was observed for PSP3 and PSP2 in combination with ceftazidime [4.58 and 4.30 log 10 Colony Forming Units (CFU)/well], followed by all phage combinations with ciprofloxacin (up to 3.56 log 10 CFU/well). The highest reduction in biomass was obtained by combining PSP3 with ciprofloxacin (29.8%). Metabolic assays confirmed these findings with reductions in biofilm respiratory rate of up to 65%. Scanning electron microscopy imaging of PAO1 biofilms grown on titanium coupons and treated by ciprofloxacin and PSP30 confirmed the efficacy of the combined treatment with PSP30 and ciprofloxacin. This study highlights the synergetic effects of phage-antibiotic combinations on P. aeruginosa biofilms, thereby offering a promising approach to combat biofilm-associated infections. IMPORTANCE Biofilm-related infections are among the most difficult-to-treat infections in all fields of medicine due to their antibiotic tolerance and persistent character. In the field of orthopedics, these biofilms often lead to therapeutic failure of medical implantable devices and urgently need novel treatment strategies. This forthcoming article aims to explore the dynamic interplay between newly isolated bacteriophages and routinely used antibiotics and clearly indicates synergetic patterns when used as a dual treatment modality. Biofilms were drastically more reduced when both active agents were combined, thereby providing additional evidence that phage-antibiotic combinations lead to synergism and could potentially improve clinical outcome for affected patients.

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Personalized Inhaled Bacteriophage Therapy Decreases Multidrug-ResistantPseudomonas aeruginosa

Cited by 11 publications

References 36 publications

Lytic bacteriophages interact with respiratory epithelial cells and induce the secretion of antiviral and proinflammatory cytokines

Lytic bacteriophages interact with respiratory epithelial cells and induce the secretion of antiviral and proinflammatory cytokines

Lytic bacteriophages induce the secretion of antiviral and proinflammatory cytokines from human respiratory epithelial cells

Exploiting phage-antibiotic synergies to disrupt Pseudomonas aeruginosa PAO1 biofilms in the context of orthopedic infections

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