Production of Phage Therapeutics and Formulations: Innovative Approaches

Merabishvili, Maia; Pirnay, Jean-Paul; Vogele, Kilian; Malik, Danish J.

doi:10.1007/978-3-030-26736-0_1

Cited by 9 publications

(8 citation statements)

References 176 publications

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“…Methods that have been used for almost a century and have been considered “gold standards” for use since their discovery include storage in liquid formulations at 4 °C, lyophilization at 4 °C or room temperature, and freezing with glycerol at −80 °C [ 7 , 35 , 36 , 37 , 38 ]. A variety of pharmaceutical formulations can be used for the production of APIs and/or the final phage products, based on conventional and innovative platforms [ 39 , 40 ]. Following the Belgian “magistral preparation” pathway (compounding pharmacies in the US), the final phage products that will be used in patients are made by hospital pharmacists.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of the Stability of Bacteriophages in Different Solutions Suitable for the Production of Magistral Preparations in Belgium

Duyvejonck

Merabishvili

Vaneechoutte

et al. 2021

Viruses

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In Belgium, the incorporation of phages into magistral preparations for human application has been permitted since 2018. The stability of such preparations is of high importance to guarantee quality and efficacy throughout treatments. We evaluated the ability to preserve infectivity of four different phages active against three different bacterial species in five different buffer and infusion solutions commonly used in medicine and biotechnological manufacturing processes, at two different concentrations (9 and 7 log pfu/mL), stored at 4 °C. DPBS without Ca2+ and Mg2+ was found to be the best option, compared to the other solutions. Suspensions with phage concentrations of 7 log pfu/mL were unsuited as their activity dropped below the effective therapeutic dose (6–9 log pfu/mL), even after one week of storage at 4 °C. Strong variability between phages was observed, with Acinetobacter baumannii phage Acibel004 being stable in four out of five different solutions. We also studied the long term storage of lyophilized staphylococcal phage ISP, and found that the titer could be preserved during a period of almost 8 years when sucrose and trehalose were used as stabilizers. After rehydration of the lyophilized ISP phage in saline, the phage solutions remained stable at 4 °C during a period of 126 days.

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Section: Discussionmentioning

confidence: 99%

Evaluation of the Stability of Bacteriophages in Different Solutions Suitable for the Production of Magistral Preparations in Belgium

Duyvejonck

Merabishvili

Vaneechoutte

et al. 2021

Viruses

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“…Such crude preparations contain bacterial products, potentially including exotoxins, but also endotoxins such as LPS from the lysed cells. However, several processes have been developed to allow the LPS-free production of liquid phage preparations (32,33,34,35,36). Liquid formulations are technically easy to produce, and can generally be stored refrigerated for several years without a dramatic reduction in titre depending on the individual stability of the phage.…”

Section: Phage Delivery Systemsmentioning

confidence: 99%

“…These include the stability of phage preparations, target-site-specific delivery, as well as the antibody-mediated inactivation of phages and their clearance by the reticuloendothelial system of the recipient ( 26 – 28 ). To optimize the efficacy and delivery of phages, formulations for therapeutic phages are under constant development ( 29 – 31 ).…”

Section: Phage Delivery Systemsmentioning

confidence: 99%

Encapsulation and Delivery of Therapeutic Phages

Loh

Gondil

Manohar

et al. 2021

Appl Environ Microbiol

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Delivery of therapeutic compounds to the site of action is crucial. While many chemical substances such as beta-lactam antibiotics can reach therapeutic levels in most parts throughout the human body after administration, substances of higher molecular weight such as therapeutic proteins may not be able to reach the site of action (e.g. an infection), and are therefore ineffective. In the case of therapeutic phages, i.e. viruses that infect microbes that can be used to treat bacterial infections, this problem is exacerbated; not only are phages unable to penetrate tissues, but phage particles can be cleared by the immune system and phage proteins are rapidly degraded by enzymes or inactivated by the low pH in the stomach. Yet, the use of therapeutic phages is a highly promising strategy, in particular for infections caused by bacteria that exhibit multi-drug resistance. Clinicians increasingly encounter situations where no treatment options remain available for such infections, where antibiotic compounds are ineffective. While the number of drug-resistant pathogens continues to rise due to the overuse and misuse of antibiotics, no new compounds are becoming available as many pharmaceutical companies discontinue their search for chemical antimicrobials. In recent years, phage therapy has undergone massive innovation for the treatment of infections caused by pathogens resistant to conventional antibiotics. While most therapeutic applications of phages are well described in the literature, other aspects of phage therapy are less well documented. In this review, we focus on the issues that are critical for phage therapy to become a reliable standard therapy and describe methods for efficient and targeted delivery of phages, including their encapsulation.

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“…To be an appropriate candidate for phage therapy, a phage must be able to withstand different pH conditions and remain infectious for the moment of administration, while tolerating a large variation in pH and temperature during its application [51]. Tolerance to different environmental factors is also an important feature for potential therapeutic phages, as the production process of a number of pharmaceutical formulations implies wide range variability of such factors [61]. Phage PAK_P1, which is similar to the phages in our study, is well-known for its broad host range as well, including P. aeruginosa strains recovered from cystic fibrosis patients of primary and chronic colonization cases [49].…”

Section: Thermal and Ph Stabilitymentioning

confidence: 99%

Isolation and Characterization of Lytic Pseudomonas aeruginosa Bacteriophages Isolated from Sewage Samples from Tunisia

Akremi

Merabishvili

Jlidi

et al. 2022

Viruses

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Bacteriophages could be a useful adjunct to antibiotics for the treatment of multidrug-resistant Pseudomonas aeruginosa infections. In this study, lytic P. aeruginosa myoviruses PsCh, PsIn, Ps25, and Ps12on-D were isolated from Tunisian sewage samples. Phage Ps12on-D displayed an adsorption time of ~10 min, a short latency period (~10 min), and a large burst size (~115 PFU per infected cell) under standard growth conditions. All phages were active at broad temperature (4 °C to 50 °C) and pH (3.0 to 11.0) ranges and were able to lyse a wide variety of P. aeruginosa strains isolated from clinical and environmental samples worldwide. Illumina sequencing revealed double-stranded DNA genomes ranging from 87,887 and 92,710 bp with high sequence identity to Pseudomonas phage PAK_P1. All four phages based on sequence analysis were assigned to the Pakpunavirus genus. The presented characterization and preclinical assessment are part of an effort to establish phage therapy treatment as an alternative strategy for the management of multidrug-resistant P. aeruginosa infections in Tunisia.

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Production of Phage Therapeutics and Formulations: Innovative Approaches

Cited by 9 publications

References 176 publications

Evaluation of the Stability of Bacteriophages in Different Solutions Suitable for the Production of Magistral Preparations in Belgium

Evaluation of the Stability of Bacteriophages in Different Solutions Suitable for the Production of Magistral Preparations in Belgium

Encapsulation and Delivery of Therapeutic Phages

Isolation and Characterization of Lytic Pseudomonas aeruginosa Bacteriophages Isolated from Sewage Samples from Tunisia

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