Feasibility of spray drying bacteriophages into respirable powders to combat pulmonary bacterial infections

Vandenheuvel, Dieter; Singh, Abhishek; Vandersteegen, Katrien; Klumpp, Jochen; Lavigne, Rob; Mooter, Guy Van den

doi:10.1016/j.ejpb.2012.12.022

Cited by 111 publications

(106 citation statements)

References 40 publications

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“…From the perspective of feasibility for therapeutic application, we determined that the stabilities of phages phiIPLA-RODI and phiIPLA-C1C at various pHs and temperatures were very similar to those described for related phages, such as MSA6 (49) and Romulus and Remus (28), and therefore that these phages are suitable for design of different pharmaceutical formulations by lyophilization (50), spray drying (51), and aerosolization (52). Bioinformatic analysis of the phiIPLA-RODI and phiIPLA-C1C genomes showed the typical characteristics of the "Twort-like viruses" (Spounavirinae subfamily): strictly virulent, with large genomes (127 to 140 kb) containing LTRs, genes grouped into modules that are not clearly separated, a few genes encoding tRNAs, and the presence of group I introns (42).…”

Section: Discussionmentioning

confidence: 99%

Two Phages, phiIPLA-RODI and phiIPLA-C1C, Lyse Mono- and Dual-Species Staphylococcal Biofilms

Gutiérrez

Vandenheuvel

Martínez

et al. 2015

Appl Environ Microbiol

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131

133

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Phage therapy is a promising option for fighting against staphylococcal infections. Two lytic phages, vB_SauM_phiIPLA-RODI (phiIPLA-RODI) and vB_SepM_phiIPLA-C1C (phiIPLA-C1C), belonging to the Myoviridae family and exhibiting wide host ranges, were characterized in this study. The complete genome sequences comprised 142,348 bp and 140,961 bp and contained 213 and 203 open reading frames, respectively. The gene organization was typical of Spounavirinae members, with long direct terminal repeats (LTRs), genes grouped into modules not clearly separated from each other, and several group I introns. In addition, four genes encoding tRNAs were identified in phiIPLA-RODI. Comparative DNA sequence analysis showed high similarities with two phages, GH15 and 676Z, belonging to the Twort-like virus genus (nucleotide identities of >84%); for phiIPLA-C1C, a high similarity with phage phiIBB-SEP1 was observed (identity of 80%). Challenge assays of phages phiIPLA-RODI and phiIPLA-C1C against planktonic staphylococcal cells confirmed their lytic ability, as they were able to remove 5 log units in 8 h. Exposure of biofilms to phages phiIPLA-RODI and phiIPLA-C1C reduced the amount of adhered bacteria to about 2 log units in both monospecies and dual-species biofilms, but phiIPLA-RODI turned out to be as effective as the mixture of both phages. Moreover, the frequencies of bacteriophage-insensitive mutants (BIMs) of Staphylococcus aureus and S. epidermidis with resistance to phiIPLA-RODI and phiIPLA-C1C were low, at 4.05 ؋ 10 ؊7 ؎ 2.34 ؋ 10 ؊9 and 1.1 ؋ 10 ؊7 ؎ 2.08 ؋ 10 ؊9 , respectively. Overall, a generally reduced fitness in the absence of phages was observed for BIMs, which showed a restored phage-sensitive phenotype in a few generations. These results confirm that lytic bacteriophages can be efficient biofilm-disrupting agents, supporting their potential as antimicrobials against staphylococcal infections.T wo staphylococcal species, Staphylococcus aureus and Staphylococcus epidermidis, are the main causes of nosocomial infections due to their ability to adhere to, colonize, and develop biofilms in medical devices and human organs (1). Staphylococcal biofilms are complex structures in which bacterial cells are surrounded by an extracellular material (polysaccharides, teichoic acids, proteins, and extracellular DNA) which confers protection against antibacterial drugs and the host immune system. In addition, growth of bacteria in a biofilm facilitates the development of antibiotic-resistant organisms (2). S. epidermidis is one of the most abundant species in the human skin microbiota, from which it easily reaches catheters, heart valves, and contact lenses. Despite being regarded as an innocuous bacterium, it is now accepted as an opportunistic pathogen and one of the most common causes of bacteremia in immunocompromised patients (3), preterm infants (4), and biofilm-related infections (5). In addition, resistance to methicillin due to the presence of the mecA gene is widely spread in hospital isolates (6). Similarly, virule...

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Section: Discussionmentioning

confidence: 99%

Two Phages, phiIPLA-RODI and phiIPLA-C1C, Lyse Mono- and Dual-Species Staphylococcal Biofilms

Gutiérrez

Vandenheuvel

Martínez

et al. 2015

Appl Environ Microbiol

Self Cite

131

133

View full text Add to dashboard Cite

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“…The concentrations were determined based on other studies on phage or protein stabilisation in dry powder formulations [23, 24, 26, 28]. Phage viability was tested using plaque assay.…”

Section: Methodsmentioning

confidence: 99%

“…Several studies have shown processing liquid phage formulation into dry powders using lyophilisation [23], spray drying [24–26] and spray-freeze drying [25]. Vandenheuvel and colleagues [26] produced highly stable spray dried anti-Pseudomonal Podoviridae phage powders using trehalose as an excipient with less than 1 log 10 unit reduction in phage titre. On the other hand, powders containing anti- Staphylococcal phage from Myoviridae family resulted in 2.5 log 10 loss.…”

Section: Introductionmentioning

confidence: 99%

Production of highly stable spray dried phage formulations for treatment of Pseudomonas aeruginosa lung infection

Chang

Wong

Mathai

et al. 2017

European Journal of Pharmaceutics and Biopharmaceutics

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The potential of bacteriophage therapy for the treatment of pulmonary infections caused by antibiotic-resistant bacteria has been well recognised. The purpose of this study was to investigate the effect of excipients on stabilisation and aerosolisation of spray dried powders of morphologically different phages – PEV podovirus and PEV myovirus. Seven anti-pseudomonal phages were screened against 90 clinical strains of bacterial hosts and three of the phages were selected for formulation study based on the host range. Design of experiments was utilised to assess the effect of different excipients on the stabilisation and aerosolisation of spray dried phages. Both podovirus and myovirus phages were stable in spray dried formulations containing trehalose or lactose and leucine as excipients with less than 1-log10 titre reduction during spray drying, with lactose providing superior phage protection over trehalose. Furthermore, the spray dried phage formulations dispersed in an Osmohaler at 85 L/min produced a high fine particle fraction of over 50 %. The results showed that the phages in this study can form respirable dry powder phage formulations using the same excipient composition. Spray dried various types of lytic phages hold significant potential for the treatment of pulmonary infections.

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“…Although the use of icosahedral viruses remains highly promising, attention has more recently shifted towards the use of bacteriophages for the detection and treatment of bacterial infections (Carson et al, 2010;Chibeu et al, 2012;Hodgson, 2013;Mendes et al, 2013;Seth et al, 2013;Takemura-Uchiyama et al, 2013;Vandenheuvel et al, 2013;Yilmaz et al, 2013). Bacteriophages have been used in the past in Eastern Europe and the former Soviet Union to treat bacterial infections; however, it is only over the past two decades, with the rising problem of antibiotic-resistant infections, that their potential use has re-emerged worldwide (Kaur et al, 2012).…”

Section: Bacterial Infectionsmentioning

confidence: 99%

Using viruses as nanomedicines

Kan-Davelaar

Hest

Cornelissen

et al. 2014

British J Pharmacology

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The field of nanomedicine involves the design and fabrication of novel nanocarriers for the intracellular delivery of therapeutic cargo or for use in molecular diagnostics. Although traditionally recognized for their ability to invade and infect host cells, viruses and bacteriophages have been engineered over the past decade as highly promising molecular platforms for the targeted delivery and treatment of many human diseases. Inherently biodegradable, the outer capsids of viruses are composed entirely of protein building blocks, which can be genetically or chemically engineered with molecular imaging reagents, targeting ligands and therapeutic molecules. While there are several examples of viruses as in vitro molecular cargo carriers, their potential for applications in nanomedicine has only recently emerged. Here we highlight recent developments towards the design and engineering of viruses for the treatment of cancer, bacterial infections and immune system-related diseases. LINKED ARTICLESThis article is part of a themed section on Nanomedicine. To view the other articles in this section visit http://dx

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Feasibility of spray drying bacteriophages into respirable powders to combat pulmonary bacterial infections

Cited by 111 publications

References 40 publications

Two Phages, phiIPLA-RODI and phiIPLA-C1C, Lyse Mono- and Dual-Species Staphylococcal Biofilms

Two Phages, phiIPLA-RODI and phiIPLA-C1C, Lyse Mono- and Dual-Species Staphylococcal Biofilms

Production of highly stable spray dried phage formulations for treatment of Pseudomonas aeruginosa lung infection

Using viruses as nanomedicines

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