Current State of Compassionate Phage Therapy

McCallin, Shawna; Sacher, Jessica C; Zheng, Jan; Chan, Benjamin K

doi:10.3390/v11040343

Cited by 174 publications

(140 citation statements)

References 61 publications

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“…The adaptability and sheer number of phages imply that they are the largest repository of antibacterial information available to modern medicine. Furthermore, phages have been used to treat bacterial infections for decades in Eastern Europe, and recent compassionate care cases in the U.S. and U.K. has demonstrated clinical success (9,10). Phages are also specific for a given bacterial species (even strain), meaning off-target killing of "good" bacteria in our microbiome can be minimized.…”

Section: Five Years Later In 2019 the Centers For Disease Control Anmentioning

confidence: 99%

Phage-Antibiotic Synergy is Driven by a Unique Combination of Antibacterial Mechanism of Action and Stoichiometry

Liu

Green

Min

et al. 2020

Preprint

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The continued rise in antibiotic resistance is precipitating a medical crisis. Bacteriophage (phage) has been hailed as one possible therapeutic option to augment the efficacy of antibiotics.However, only a handful of studies have addressed the synergistic relationship between phage and antibiotics. Here, we report a comprehensive analysis of phage-antibiotic interaction that evaluates synergism, additivism, and antagonism for all classes of antibiotics across clinically achievable stoichiometries. We combined an optically-based real-time microtiter plate readout with a matrix-like heatmap of treatment potencies to measure phage and antibiotic synergy (PAS), a process we term synography. Phage-antibiotic synography was performed against a pandemic drug-resistant clonal group of E. coli (ExPEC) with antibiotic levels blanketing the minimum inhibitor concentration (MIC) across seven orders of viral titers. Our results suggest that, under certain conditions, phages provide an adjuvating effect by lowering the MIC for drugresistant strains. Furthermore, synergistic and antagonistic interactions are highly dependent on the mechanism of bacterial inhibition by the class of antibiotic paired to the phage, and when synergism is observed, it suppresses the emergence of resistant cells. Host conditions that simulate the infection environment, including serum and urine, suppress PAS in a bacterial growth-dependent manner. Lastly, phage burst size seems to be a significant driver of synergism.Collectively, this data suggests lytic phages can resuscitate an ineffective antibiotic for previously resistant bacteria, while also synergize with antibiotics in a class-dependent manner, processes that may be dampened by lower bacterial growth rates found in host environments. Significance StatementBacteriophage (phage) therapy is a promising approach to combat the rise of multi-drug resistant bacteria. Currently, the preferred clinical modality is to pair phage with an antibiotic, a practice thought to improve efficacy. However, antagonism between phage and antibiotics has been reported, the choice of phage and antibiotic is not often empirically determined, and the effect of the host factors on the effectiveness is unknown. Here, we interrogate phage-antibiotic interactions across antibiotics with different mechanisms of action. Our results suggest that phage can lower the working MIC for bacterial strains already resistant to the antibiotic, is dependent on the antibiotic class and stoichiometry of the pairing, and is dramatically influenced by the host microenvironment.

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Section: Five Years Later In 2019 the Centers For Disease Control Anmentioning

confidence: 99%

Phage-Antibiotic Synergy is Driven by a Unique Combination of Antibacterial Mechanism of Action and Stoichiometry

Liu

Green

Min

et al. 2020

Preprint

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“…These findings reinforce findings that phage and antibiotics can be used to treat a certain class of MDR P.a. pathogens in patients 11,37 . Model results also highlight the role of the immune response in realizing curative success -which will be relevant to expanding combination theory for a range of clinical applications.…”

Section: Discussionmentioning

confidence: 99%

Quantitative Models of Phage-Antibiotics Combination Therapy

Rodriguez-Gonzalez

Leung

Turner

et al. 2019

Preprint

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The spread of multi-drug resistant (MDR) bacteria is a global public health crisis. Bacteriophage therapy (or "phage therapy") constitutes a potential alternative approach to treat MDR infections. However, the effective use of phage therapy may be limited when phage-resistant bacterial mutants evolve and proliferate during treatment. Here, we develop a nonlinear population dynamics model of combination therapy that accounts for the system-level interactions between bacteria, phage and antibiotics for in-vivo application given an immune response against bacteria. We simulate the combination therapy model for two strains of Pseudomonas aeruginosa, one which is phage-sensitive (and antibiotic resistant) and one which is antibiotic-sensitive (and phage-resistant). We find that combination therapy outperforms either phage or antibiotic alone, and that therapeutic effectiveness is enhanced given interaction with innate immune responses. Notably, therapeutic success can be achieved even at sub-inhibitory concentrations of antibiotics, e.g., ciprofloxacin. These in-silico findings provide further support to the nascent application of combination therapy to treat MDR bacterial infections, while highlighting the role of innate immunity in shaping therapeutic outcomes.

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“…While researchers have discussed the idea of compassionate phage therapy (14), few trials have occurred either in Europe or the US. In the US, phage therapy has mostly occurred for unmet medical needs, as experimental therapies when all other treatment options have been exhausted (https://www.sciencemag.org/news/2019/05/viruses-genetically-engineered-kill-bacteria-rescuegirl-antibiotic-resistant-infection), as phage are able to eliminate bacteria in a manner independent of the MDR phenotype (59,64).…”

Section: During Bouts Of Acute Diarrhea Protective Microbiome Membersmentioning

confidence: 99%

“…Three patients enrolled in the study experienced full resolution of symptoms as determined by both the study physicians and self-reporting. Though there are significant hurdles for developing mechanisms for FDA approval of the clinical use of bacteriophage (13,14), the results of these studies strongly suggest that the efficacy of phage therapeutics is not the limiting factor in making such applications available.…”

Section: Introductionmentioning

confidence: 99%

MyoviridaePhagePDXKills EnteroaggregativeEscherichia coliwithout Human Microbiome Dysbiosis

Cepko

Garling

Dinsdale

et al. 2018

Preprint

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Escherichia virus, microbiome, dysbiosis antibiotic alternatives. AbstractPurpose. To identify therapeutic a bacteriophage that kills diarrheagenic enteroaggregative Escherichia coli (EAEC) while leaving the human microbiome intact.Methodology. Phages from wastewater in Portland, OR, were screened for bacteriolytic activity using an overlay assay, and isolated in a sequential procedure to enrich for the recognition of core bacterial antigens. Electron microscopy and genome sequencing were performed to classify the isolated phage, and the host range was determined by spot tests and plaque assays. One-step growth curves and time-kill assays were conducted to characterize the life cycle of the phage, and to interrogate the multiplicity of infection (MOI) necessary for killing. A mouse model of infection was used to determine whether the phage could be used therapeutically against EAEC in vivo. Anaerobic culture in the presence of human fecal bacteria determined whether the phage could kill EAEC in vitro, and to assess whether the microbiome had been altered.Results. The isolated phage, termed Escherichia virus PDX, is a member of the strictly lytic Myoviridae family of viruses. Phage PDX killed EAEC isolate EN1E-0227, a case-associated isolate from a child in rural Tennessee, in a dose-dependent manner, and also formed plaques on case-associated clinical EAEC isolates from Columbian children suffering from diarrhea. A single dose of PDX, at a MOI of 100, one day post infection, reduced the population of recovered EAEC isolate EN1E-0227 bacteria in fecal pellets in a mouse model of colonization, over a fiveday period. Phage PDX also killed EAEC EN1E-0227 when cultured anaerobically in vitro in the presence of human fecal bacteria. While the addition of EAEC EN1E-0227 reduced the adiversity of the human microbiota, that of the cultures with either feces alone, feces with EAEC and PDX, or with just the PDX phage were not different statistically, as measured by Chao1 and Shannon diversity indices. Additionally, b-diversity and differential abundance analyses show that conditions with PDX added were not different from feces alone, but all groups were significantly different from feces + EAEC.Conclusions. The strictly bacteriolytic, Myoviridae Escherichia virus PDX killed EAEC isolate EN1E-0227 bacteria both in vivo and in vitro, while simultaneously not altering the diversity of normal human microbiota in anaerobic culture. Thus, the PDX phage could be part of an effective therapeutic intervention for children in developing countries who suffer from acute, or persistent EAEC-mediated diarrhea, and to help reduce the serious effects of environmental enteropathy. Because the emerging pathogen EAEC is now the second leading cause of traveler's diarrhea, PDX could also provide therapeutic relief for these individuals, particularly in light of the growing crisis of antibiotic resistances.

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Current State of Compassionate Phage Therapy

Cited by 174 publications

References 61 publications

Phage-Antibiotic Synergy is Driven by a Unique Combination of Antibacterial Mechanism of Action and Stoichiometry

Phage-Antibiotic Synergy is Driven by a Unique Combination of Antibacterial Mechanism of Action and Stoichiometry

Quantitative Models of Phage-Antibiotics Combination Therapy

MyoviridaePhagePDXKills EnteroaggregativeEscherichia coliwithout Human Microbiome Dysbiosis

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