Successful adjunctive use of bacteriophage therapy for treatment of multidrug-resistant Pseudomonas aeruginosa infection in a cystic fibrosis patient

Law, Nancy; Logan, Cathy; Yung, Gordon; Furr, C.; Lehman, Susan M.; Morales, Sandra; Rosas, F.; Gaidamaka, A.; Bilinsky, Igor P; Grint, P.; Schooley, Robert T.; Aslam, Saima

doi:10.1007/s15010-019-01319-0

Cited by 175 publications

(123 citation statements)

References 6 publications

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“…show a synergistic effect of phage and antibiotic, and rather gave evidence for an additive response. Our results nevertheless support the basic findings of other studies showing improved treatment outcomes with phage for a range of in vivo systems ranging from C elegans (15) to mammals including humans (7,11,(36)(37)(38)(39). Our work is the first to our knowledge to show a reduction in resistance in any in vivo system.…”

Section: Discussionsupporting

confidence: 90%

Phage steering of antibiotic-resistance evolution in the bacterial pathogen Pseudomonas aeruginosa

Gurney

Pradier

Griffin

et al. 2019

Preprint

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Antimicrobial resistance is a growing global concern and has spurred increasing efforts to find alternative therapeutics. Bacteriophage therapy has seen near constant use in eastern Europe since its discovery over a century ago. One promising approach is to use phages that not only reduce bacterial pathogen loads, but also select for phage resistance mechanisms that trade-off with antibiotic resistance -so called 'phage steering'. Recent work has shown that phage OMKO1 can interact with efflux pumps and in so doing select for both phage resistance and antibiotic sensitivity. We tested the robustness of this approach to three different antibiotics in vitro and one in vivo. We show that in vitro OMKO1 can reduce antibiotic resistance either in the absence or the presence of antibiotics. Our in vivo experiment showed that phage increased the survival times of wax moth larvae and increased bacterial sensitivity to erythromycin, both in the absence and presence of the antibiotic. We discuss the implications of our findings for future research on this promising therapeutic approach using OMKO1.

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Section: Discussionsupporting

confidence: 90%

Phage steering of antibiotic-resistance evolution in the bacterial pathogen Pseudomonas aeruginosa

Gurney

Pradier

Griffin

et al. 2019

Preprint

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“…Historically, however, phage therapy has often been a response to failures of antibiotic treatment [3,6]. More recently, there also have been several case studies involving both phage therapy following antibiotic failures and continued antibiotic treatment even after phage therapy has begun [10,12,13,[15][16][17]. Therefore, it would seem that the time has come for more rigorous scrutiny of phage activity as may or may not be present given antibiotic co-treatments of especially still antibiotic-susceptible bacteria.…”

Section: General Conclusionmentioning

confidence: 99%

“…Phages have been employed clinically to treat bacterial infections for roughly one-hundred years [1,2], and many of these efforts seem to have been successful, e.g., such as in terms of treatment of chronic infections [3,4], wound infections [4][5][6], or lung-associated infections [7][8][9][10]. This 'phage therapy' furthermore has been proven to be efficacious in at least one modern efficacy (phase I/II) clinical trial [11], and recently there have been several well publicized phage therapy case-study successes [12][13][14]; see also [4,9,10,[15][16][17]. Phages also can be effective against bacterial biofilms, e.g., [18][19][20][21], as well as against persister cells [22,23], though phages do not necessarily actively kill bacteria while these cells are still in the low-growth persister state [24].…”

Section: Introductionmentioning

confidence: 99%

Phage-Antibiotic Combination Treatments: Antagonistic Impacts of Antibiotics on the Pharmacodynamics of Phage Therapy?

Abedon

2019

Antibiotics

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Bacteria can evolve resistance to antibiotics. Even without changing genetically, bacteria also can display tolerance to antibiotic treatments. Many antibiotics are also broadly acting, as can result in excessive modifications of body microbiomes. Particularly for antibiotics of last resort or in treating extremely ill patients, antibiotics furthermore can display excessive toxicities. Antibiotics nevertheless remain the standard of care for bacterial infections, and rightly so given their long track records of both antibacterial efficacy and infrequency of severe side effects. Antibiotics do not successfully cure all treated bacterial infections, however, thereby providing a utility to alternative antibacterial approaches. One such approach is the use of bacteriophages, the viruses of bacteria. This nearly 100-year-old bactericidal, anti-infection technology can be effective against antibiotic-resistant or -tolerant bacteria, including bacterial biofilms and persister cells. Ideally phages could be used in combination with standard antibiotics while retaining their anti-bacterial pharmacodynamic activity, this despite antibiotics interfering with aspects of bacterial metabolism that are also required for full phage infection activity. Here I examine the literature of pre-clinical phage-antibiotic combination treatments, with emphasis on antibiotic-susceptible bacterial targets. I review evidence of antibiotic interference with phage infection activity along with its converse: phage antibacterial functioning despite antibiotic presence.

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“…In recent years some Western European countries have begun approved therapeutic use (Belgium, France), while in the United States a number of entities are developing phage therapeutics to bring them into clinical use but these are yet to be approved by the US Food and Drug Administration. Meanwhile, recent FDA-approved "expanded access" experimental phage treatments in cases in the United States [28][29][30][31][32][33] have alerted the news media and public to the safety and potential of phage therapeutics, sparked excitement about phage therapy, and begun to shift the landscape so that more physicians are open to the use of phage treatments in combination with standard of care antibiotics.…”

Section: A Brief History Of Bacteriophage Therapymentioning

confidence: 99%

“…Phages infect their specific bacterial hosts and in the lytic (or virulent) lifestyle highjack the machinery of the host cell to replicate and ultimately destroy the host, thus simultaneously producing progeny and killing the host. Phages are the most abundant biological entities on earth, with greater than 10 30 individual virions estimated to be on the planet [7], and a well-described diversity that is still being discovered [8,9]. This vast abundance and diversity of phages in nature provides a ready resource to mine for the selection of phages for a variety of purposes, including not only anti-bacterial therapy but also decontamination, infection control, detection, diagnosis, etc.…”

Section: Introductionmentioning

confidence: 99%

Bacteriophage Therapy: Developments and Directions

Nikolich

Filippov

2020

Antibiotics

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In an era of proliferating multidrug resistant bacterial infections that are exhausting the capacity of existing chemical antibiotics and in which the development of new antibiotics is significantly rarer, Western medicine must seek additional therapeutic options that can be employed to treat these infections. Among the potential antibacterial solutions are bacteriophage therapeutics, which possess very different properties from broad spectrum antibiotics that are currently the standard of care, and which can be used in combination with them and often provide synergies. In this review we summarize the state of the development of bacteriophage therapeutics and discuss potential paths to the implementation of phage therapies in contemporary medicine, focused on fixed phage cocktail therapeutics since these are likely to be the first bacteriophage products licensed for broad use in Western countries.

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Successful adjunctive use of bacteriophage therapy for treatment of multidrug-resistant Pseudomonas aeruginosa infection in a cystic fibrosis patient

Cited by 175 publications

References 6 publications

Phage steering of antibiotic-resistance evolution in the bacterial pathogen Pseudomonas aeruginosa

Phage steering of antibiotic-resistance evolution in the bacterial pathogen Pseudomonas aeruginosa

Phage-Antibiotic Combination Treatments: Antagonistic Impacts of Antibiotics on the Pharmacodynamics of Phage Therapy?

Bacteriophage Therapy: Developments and Directions

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