Experimental phage therapy against lethal lung-derived septicemia caused by Staphylococcus aureus in mice

Takemura‐Uchiyama, Iyo; Uchiyama, Jumpei; Osanai, Makoto; Morimoto, Norihito; Asagiri, Tadashi; Ujihara, Takako; Daibata, Masanori; Sugiura, Tetsuro; Matsuzaki, Shigenobu

doi:10.1016/j.micinf.2014.02.011

Cited by 72 publications

(58 citation statements)

References 22 publications

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“…For instance, with regard to the latter point: All but one of the animal studies involved only a single phage dosing and most 23,[54][55][56][57][58][59]62 involved topical phage application into the lungs. Exceptional were the mouse studies by Chhibber et al, 60 Semler et al, 62 and Singla et al 61 which also tested intraperitoneal phage application.…”

Section: Resultsmentioning

confidence: 99%

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Phage therapy of pulmonary infections

Abedon

2015

Bacteriophage

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Section: Resultsmentioning

confidence: 99%

“…Takemura-Uchiyama et al 23 describe the phage treatment of a lung-derived septicemia following intranasal inoculation of cyclophosphamide-treated mice with S. aureus. Phage application of 10 10 plaque-forming units was intraperitoneal, 6-h post bacterial challenge, and resulted in nearly 70% mouse survival vs. 10% with mock treatment.…”

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confidence: 99%

Phage therapy of pulmonary infections

Abedon

2015

Bacteriophage

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“…Indeed, human trials with phages against a number of infections have confirmed their safety and shown that phage therapy can provide good results for untreatable chronic infections (12,13). Specifically, recent results showed the efficacy of phages in animal models, such as S. aureus septicemia in mice (14) and in silkworms (15). The safety and efficacy of phage products for removal of this bacterium in a sinusitis sheep model have also been proven (16).…”

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confidence: 97%

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

Gutiérrez

Vandenheuvel

Martínez

et al. 2015

Appl Environ Microbiol

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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“…Today, we are globally threatened by antibiotic-resistant bacteria, and phage therapy is being reassessed as a new strategy for treatment of infectious disease (13,17). Indeed, researchers have reported the efficacy of phage therapy for experimental bacterial disease (18)(19)(20)(21)(22). Examples include applications for use of the phages ListShield (Intralytix, Inc., Baltimore, MD) for Listeria monocytogenes and EcoShield (Intralytix) for Escherichia coli O157:H7 to protect against foodborne disease (23,24).…”

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Phage Therapy Is Effective in a Mouse Model of Bacterial Equine Keratitis

Furusawa

Iwano

Hiyashimizu

et al. 2016

Appl Environ Microbiol

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Bacterial keratitis of the horse is mainly caused by staphylococci, streptococci, and pseudomonads. Of these bacteria, Pseudomonas aeruginosa sometimes causes rapid corneal corruption and, in some cases, blindness. Antimicrobial resistance can make treatment very difficult. Therefore, new strategies to control bacterial infection are required. A bacteriophage (phage) is a virus that specifically infects and kills bacteria. Since phage often can lyse antibiotic-resistant bacteria because the killing mechanism is different, we examined the use of phage to treat horse bacterial keratitis. We isolated Myoviridae or Podoviridae phages, which together have a broad host range. They adsorb efficiently to host bacteria; more than 80% of the ⌽R18 phage were adsorbed to host cells after 30 s. In our keratitis mouse model, the administration of phage within 3 h also could kill bacteria and suppress keratitis. A phage multiplicity of infection of 100 times the host bacterial number could kill host bacteria effectively. A cocktail of two phages suppressed bacteria in the keratitis model mouse. These data demonstrated that the phages in this study could completely prevent the keratitis caused by P. aeruginosa in a keratitis mouse model. Furthermore, these results suggest that phage may be a more effective prophylaxis for horse keratitis than the current preventive use of antibiotics. Such treatment may reduce the use of antibiotics and therefore antibiotic resistance. Further studies are required to assess phage therapy as a candidate for treatment of horse keratitis. IMPORTANCEAntibiotic-resistant bacteria are emerging all over the world. Bacteriophages have great potential for resolution of this problem. A bacteriophage, or phage, is a virus that infects bacteria specifically. As a novel therapeutic strategy against racehorse keratitis caused by Pseudomonas aeruginosa, we propose the application of phages for treatment. Phages isolated in this work had in vitro effectiveness for a broad range of P. aeruginosa strains. Indeed, a great reduction of bacterial proliferation was shown in phage therapy for mouse models of P. aeruginosa keratitis. Therefore, to reduce antibiotic usage, phage therapy should be investigated and developed further.

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Experimental phage therapy against lethal lung-derived septicemia caused by Staphylococcus aureus in mice

Cited by 72 publications

References 22 publications

Phage therapy of pulmonary infections

Phage therapy of pulmonary infections

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

Phage Therapy Is Effective in a Mouse Model of Bacterial Equine Keratitis

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