Piperacillin and ceftazidime produce the strongest synergistic phage–antibiotic effect in Pseudomonas aeruginosa

Uchiyama, Jumpei; Shigehisa, Ryu; Nasukawa, Tadahiro; Mizukami, Keijiro; Takemura‐Uchiyama, Iyo; Ujihara, Takako; Murakami, Hironobu; Imanishi, Ichiro; Nishifuji, Koji; Sakaguchi, Masahiro; Matsuzaki, Shigenobu

doi:10.1007/s00705-018-3811-0

Cited by 64 publications

(60 citation statements)

References 31 publications

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“…In the last few years, studies involving the interaction of bacteriophages with various components have been frequently found in the literature. The majority of these studies are based on phage-antibiotic synergism and the elimination of biofilms (Chaudhry et al, 2017;Nouraldin et al, 2016) or bacteria such as Acinetobacter baumannii (Jansen et al, 2018), Money, 2017), Pseudomonas aeruginosa (Lin et al, 2018;Uchiyama et al, 2018), S. aureus (Jo, Kim, Ding, & Ahn, 2016). There are also studies examining the interaction of phages with different agents such as honey (Oliveira et al, 2017) or disinfectants (Agún et al, 2018).…”

Section: S Aureusmentioning

confidence: 99%

Investigation of different interactions between Staphylococcus aureus phages and pomegranate peel, grape seed, and black cumin extracts

Tayyarcan

Soykut

Yilmaz

et al. 2019

Journal of Food Safety

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Today, antibiotic resistance is one of the most crucial problems so that researchers have begun to search for alternatives to antibiotics. Among these alternatives, phage therapy and phytotherapy became prominent. The present study aims to put forward a different approach by combining these two methods. For this purpose, Staphylococcus aureus phages were isolated from commercial mixtures. After that, extraction of phenolic compounds from pomegranate peels (Ps), grape seeds (GSs), and black cumin (NS) was carried out and antimicrobial activities were determined. Phage‐phenolic interactions were investigated by examining the effect of phenolic extracts on phage plaque sizes and then on phage titer and bacteria count. As a result, it was found that only the NS extract had a positive effect on phage activity and increased the size of phage plaques. However, no synergistic effect was observed in experiments performed in liquid media. It was also found that P and GS extracts inhibited phage activity. Practical Applications The present study was focused on effects of extracts obtained from pomegranate peel, grape seed, and black cumin on Staphylococcus aureus phage activity. It is known that antibiotic resistance constitutes a major obstacle to the pathogen elimination. In this study, phage therapy and phytotherapy, which are prominent methods in pathogen elimination, have been combined and the effect of phenolic compounds isolated from natural sources on phage activity and bacteria count have been examined. Given the results of the current study, it has been demonstrated that the combined use of phages and antimicrobial compounds could be an important alternative to combating pathogens. It is thought that this combined method should be taken into consideration both in the practice of phage therapy on humans and animals, and in applications in the food industry.

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Section: S Aureusmentioning

confidence: 99%

Investigation of different interactions between Staphylococcus aureus phages and pomegranate peel, grape seed, and black cumin extracts

Tayyarcan

Soykut

Yilmaz

et al. 2019

Journal of Food Safety

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“…A synergistic effect was also observed when removing P. aeruginosa and S. aureus biofilms (12,13). The degree of synergy depended upon the specific antibiotic used (14).…”

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confidence: 94%

Phage-Antibiotic Synergy via Delayed Lysis

Kim

Hwang

et al. 2018

Appl Environ Microbiol

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When phages infect bacteria cultured in the presence of sublethal doses of antibiotics, the sizes of the phage plaques are significantly increased. This phenomenon is known as phage-antibiotic synergy (PAS). In this study, the observation of PAS was extended to a wide variety of bacterium-phage pairs using different classes of antibiotics. PAS was shown in both Gram-positive and Gram-negative bacteria. Cells stressed with β-lactam antibiotics filamented or swelled extensively, resulting in an increase in phage production. PAS was also sometimes observed in the presence of other classes of antibiotics with or without bacterial filamentation. The addition of antibiotics induced expression in various bacteria, but a deletion mutant strain of also showed filamentation and PAS in the presence of quinolone antibiotics. The phage adsorption efficiency did not change in the presence of the antibiotics when the cell surfaces were enlarged as they filamented. Increases in the production of phage DNA and mRNAs encoding phage proteins were observed in these cells, with only a limited increase in protein production. The data suggest that PAS is the product of a prolonged period of particle assembly due to delayed lysis. The increase in the cell surface area far exceeded the increase in phage holin production in the filamented host cells, leading to a relatively limited availability of intracellular holins for aggregating and forming holes in the host membrane. Reactive oxygen species (ROS) stress also led to an increased production of phages, while heat stress resulted in only a limited increase in phage production. Phage-antibiotic synergy (PAS) has been reported for a decade, but the underlying mechanism has never been vigorously investigated. This study shows the presence of PAS from a variety of phage-bacterium-antibiotic pairings. We show that increased phage production resulted directly from a lysis delay caused by the relative shortage of holin in filamented bacterial hosts in the presence of sublethal concentrations of stress-inducing substances, such as antibiotics and reactive oxygen species (ROS).

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“…In contrast to previous studies, the Transwell filter assay allowed us to investigate phage/bacteria/host interactions for up to 72 h. While phage or ciprofloxacin alone could not prevent bacterial regrowth after 24 h, a combined two-phage cocktail/ciprofloxacin treatment decreased P. aeruginosa counts by 6-logs at 72 h. Synergistic effects of antibiotic/phage combinations have been reported against P. aeruginosa during short (24 h) and long-term (7 days) exposures, including quinolones, beta-lactams and aminoglycosides (Knezevic et al, 2013;. However, synergy seems to be phage-dependent (Uchiyama et al, 2018), and influenced by the order of phage/antibiotic administration (Chaudhry et al, 2017). Phage/antibiotic synergism is not restricted to P. aeruginosa but has been reported in other bacterial species (Zhang and Buckling, 2012;.…”

Section: Discussionmentioning

confidence: 99%

Combined Bacteriophage and Antibiotic Treatment Prevents Pseudomonas aeruginosa Infection of Wild Type and cftr- Epithelial Cells

et al. 2020

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With the increase of infections due to multidrug resistant bacterial pathogens and the shortage of antimicrobial molecules with novel targets, interest in bacteriophages as a therapeutic option has regained much attraction. Before the launch of future clinical trials, in vitro studies are required to better evaluate the efficacies and potential pitfalls of such therapies. Here we studied in an ex vivo human airway epithelial cell line model the efficacy of phage and ciprofloxacin alone and in combination to treat infection by Pseudomonas aeruginosa. The Calu-3 cell line and the isogenic CFTR knock down cell line (cftr-) infected apically with P. aeruginosa strain PAO1 showed a progressive reduction in transepithelial resistance during 24 h. Administration at 6 h p.i. of single phage, phage cocktails or ciprofloxacin alone prevented epithelial layer destruction at 24 h p.i. Bacterial regrowth, due to phage resistant mutants harboring mutations in LPS synthesis genes, occurred thereafter both in vitro and ex vivo. However, coadministration of two phages combined with ciprofloxacin efficiently prevented PAO1 regrowth and maintained epithelial cell integrity at 72 p.i. The phage/ciprofloxacin treatment did not induce an inflammatory response in the tested cell lines as determined by nanoString R gene expression analysis. We conclude that combination of phage and ciprofloxacin efficiently protects wild type and cftr-epithelial cells from infection by P. aeruginosa and emergence of phage resistant mutants without inducing an inflammatory response. Hence, phage-antibiotic combination should be a safe and promising anti-Pseudomonas therapy for future clinical trials potentially including cystic fibrosis patients.

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Piperacillin and ceftazidime produce the strongest synergistic phage–antibiotic effect in Pseudomonas aeruginosa

Cited by 64 publications

References 31 publications

Investigation of different interactions between Staphylococcus aureus phages and pomegranate peel, grape seed, and black cumin extracts

Investigation of different interactions between Staphylococcus aureus phages and pomegranate peel, grape seed, and black cumin extracts

Phage-Antibiotic Synergy via Delayed Lysis

Combined Bacteriophage and Antibiotic Treatment Prevents Pseudomonas aeruginosa Infection of Wild Type and cftr- Epithelial Cells

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