Clinical Experience of Personalized Phage Therapy Against Carbapenem-Resistant Acinetobacter baumannii Lung Infection in a Patient With Chronic Obstructive Pulmonary Disease

Tan, Xin; Chen, Huaisheng; Zhang, Min; Zhao, Ying; Jiang, Yichun; Liu, Xueyan; Huang, Wei; Ma, Yingfei

doi:10.3389/fcimb.2021.631585

Cited by 61 publications

(38 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Single intratracheal phage administration has successfully improved mortality in murine PsA mediated pneumonia models [ 13 , 15 , 16 ]. Additionally, our one-time IMIT administration conforms to recent literature seeking efficacy via similar dosing frequency in other pathogens including Acinetobacter baumanii (AB) [ 26 , 27 , 28 ].…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Successful Intratracheal Treatment of Phage and Antibiotic Combination Therapy of a Multi-Drug Resistant Pseudomonas aeruginosa Murine Model

et al. 2021

View full text Add to dashboard Cite

Background: Pseudomonas aeruginosa (PsA) is a common etiology of bacteria-mediated lower respiratory tract infections, including pneumonia, hospital acquired pneumonia (HAP), and ventilator-associated pneumonia (VAP). Given the paucity of novel antibiotics in our foreseeable pipeline, developing novel non-antibiotic antimicrobial therapies saliently targeting drug resistant PsA isolates remains a priority. Lytic bacteriophages (or phages) have come under scrutiny as a potential antimicrobial for refractory bacterial infections. We evaluated intratracheally and intraperitoneally (IP) administered phage therapy (with/without meropenem) in an acute immunocompromised mouse model of multi-drug resistant (MDR) PsA pulmonary infection. The MDR P. aeruginosa respiratory disease model used in these studies was developed to investigate novel therapies that might have efficacy as either monotherapies or as combination therapy with meropenem. Methods: We utilized eight-week-old, 18 g BALB/cJ female mice and an MDR strain of PsA (UNC-D). Mice were immunosuppressed with cyclophosphamide. We employed a three-phage cocktail targeting PsA (PaAH2ΦP (103), PaBAP5Φ2 (130), and PaΦ (134)), confirmed to exhibit in vitro suppression of the infecting isolate out to 45 h. Suppression was confirmed with phages acting in isolation and in combination with meropenem. Results: IP administration of phage did not protect mice from death. A one-time delivery of phage directly to the lungs via a single intubation-mediated, intratracheal (IMIT) instillation protected mice from lethal infection. Protection was observed despite delaying therapy out to 6 h. Finally, we observed that, by slowing the progression of infection by treatment with a sub-efficacious dose of meropenem, we could protect the mice from lethal infection via IP phage administration coupled to meropenem, observing partial additive effects of phage–antibiotic combination therapy. Conclusions: A personalized phage cocktail administered via IMIT exhibits high therapeutic efficacy, despite delayed treatment of 6 h in a lethal MDR PsA pneumonia model. IP phage alone did not forestall mortality, but exhibited efficacy when combined with meropenem and IMIT-administered phage. These additive effects of combined IP phage and meropenem confirm that phage may indeed reach the lung bed via the systemic circulation and protect mice if the infection is not too acute. Therefore, adjunctive phage therapy with concerted attention to identifying optimal phage targeting of the infecting isolate in vitro may exhibit transformative potential for combating the specter of MDR bacterial infections. Phage should serve as an integral component of a four-pronged approach coupled with antibiotics, source control, and immune optimization.

show abstract

Section: Discussionmentioning

confidence: 99%

“…In this investigation, a single intratracheal dose of phage cocktail targeting the AB isolate proved efficacious in reducing the pulmonary bacterial burden. A clinical case study exhibited efficacy in multiple (16 days) intratracheal dosing of targeted phage against an AB mediated pneumonia [ 28 ].…”

Section: Discussionmentioning

confidence: 99%

Successful Intratracheal Treatment of Phage and Antibiotic Combination Therapy of a Multi-Drug Resistant Pseudomonas aeruginosa Murine Model

et al. 2021

View full text Add to dashboard Cite

show abstract

“…Several in vivo studies have recently shown that bacteriophages—i.e., viruses that specifically infect bacteria without damaging eukaryotic cells—might represent a potential alternative to antibiotics for the treatment of A. baumannii infections [ 197 , 198 ]. Phages and phage-associated enzymes have been extensively studied as strategies for biofilm prevention and eradication.…”

Section: Prevention and Treatment Strategies Against A Baumannii Biofilmmentioning

confidence: 99%

Gram-Negative Bacteria Holding Together in a Biofilm: The Acinetobacter baumannii Way

et al. 2021

View full text Add to dashboard Cite

Bacterial biofilms are a serious public-health problem worldwide. In recent years, the rates of antibiotic-resistant Gram-negative bacteria associated with biofilm-forming activity have increased worrisomely, particularly among healthcare-associated pathogens. Acinetobacter baumannii is a critically opportunistic pathogen, due to the high rates of antibiotic resistant strains causing healthcare-acquired infections (HAIs). The clinical isolates of A. baumannii can form biofilms on both biotic and abiotic surfaces; hospital settings and medical devices are the ideal environments for A. baumannii biofilms, thereby representing the main source of patient infections. However, the paucity of therapeutic options poses major concerns for human health infections caused by A. baumannii strains. The increasing number of multidrug-resistant A. baumannii biofilm-forming isolates in association with the limited number of biofilm-eradicating treatments intensify the need for effective antibiofilm approaches. This review discusses the mechanisms used by this opportunistic pathogen to form biofilms, describes their clinical impact, and summarizes the current and emerging treatment options available, both to prevent their formation and to disrupt preformed A. baumannii biofilms.

show abstract

“…As a consequence, there can be no means of knowing how long initial phage doses are retained, whether phage numbers decline over time, or instead whether phage numbers increase in the course of phage in situ propagation ( Figure 3 ). In clinical settings, declines in concentrations of antibacterials found in association with targeted bacteria would suggest a need for drug re-application, and in clinical practice phages often are delivered not as only a single dose per treatment [ 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 ]. Thus, measuring phage titers over time, minimally such as at time zero in combination with end-point determinations, can be relevant to translating phage treatments of biofilm from in vitro or in vivo experimentation to clinical settings, or otherwise toward better appreciation of the ecology of phage-biofilm interactions.…”

Section: Improving Phage-biofilm In Vitro Experimentationmentioning

confidence: 99%

Improving Phage-Biofilm In Vitro Experimentation

Abedon

Danis-Wlodarczyk

Wozniak

et al. 2021

Viruses

View full text Add to dashboard Cite

Bacteriophages or phages, the viruses of bacteria, are abundant components of most ecosystems, including those where bacteria predominantly occupy biofilm niches. Understanding the phage impact on bacterial biofilms therefore can be crucial toward understanding both phage and bacterial ecology. Here, we take a critical look at the study of bacteriophage interactions with bacterial biofilms as carried out in vitro, since these studies serve as bases of our ecological and therapeutic understanding of phage impacts on biofilms. We suggest that phage-biofilm in vitro experiments often may be improved in terms of both design and interpretation. Specific issues discussed include (a) not distinguishing control of new biofilm growth from removal of existing biofilm, (b) inadequate descriptions of phage titers, (c) artificially small overlying fluid volumes, (d) limited explorations of treatment dosing and duration, (e) only end-point rather than kinetic analyses, (f) importance of distinguishing phage enzymatic from phage bacteriolytic anti-biofilm activities, (g) limitations of biofilm biomass determinations, (h) free-phage interference with viable-count determinations, and (i) importance of experimental conditions. Toward bettering understanding of the ecology of bacteriophage-biofilm interactions, and of phage-mediated biofilm disruption, we discuss here these various issues as well as provide tips toward improving experiments and their reporting.

show abstract

Clinical Experience of Personalized Phage Therapy Against Carbapenem-Resistant Acinetobacter baumannii Lung Infection in a Patient With Chronic Obstructive Pulmonary Disease

Cited by 61 publications

References 26 publications

Successful Intratracheal Treatment of Phage and Antibiotic Combination Therapy of a Multi-Drug Resistant Pseudomonas aeruginosa Murine Model

Successful Intratracheal Treatment of Phage and Antibiotic Combination Therapy of a Multi-Drug Resistant Pseudomonas aeruginosa Murine Model

Gram-Negative Bacteria Holding Together in a Biofilm: The Acinetobacter baumannii Way

Improving Phage-Biofilm In Vitro Experimentation

Contact Info

Product

Resources

About