Bacteriophages as Adjuvant to Antibiotics for the Treatment of Periprosthetic Joint Infection Caused by Multidrug-Resistant Pseudomonas aeruginosa

Tkhilaishvili, Tamta; Winkler, Tobias; Müller, Michael; Perka, Carsten; Trampuž, Andrej

doi:10.1128/aac.00924-19

Cited by 119 publications

(90 citation statements)

References 23 publications

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“…To this research team's knowledge, this is the first case of bacteriophage therapy being used successfully as an adjuvant therapy to cure a chronic MRSA PJI. Two other successful bacteriophage treatments of MSSA and Pseudomonas PJIs have been reported [10,11]. Unique to our case is that no chronic suppression antibiotics were used.…”

Section: Discussionmentioning

confidence: 70%

“…Given the ability of bacteriophages to self-replicate, perhaps only a few days of bacteriophage therapy are required as an adjunct to surgical debridement. Clinical trials are needed to determine adequate duration of bacteriophage therapy in this setting [10,11].…”

Section: Discussionmentioning

confidence: 99%

“…To date, all PJI patients who were successfully treated with bacteriophages required surgical debridement [10,11]. This surgery allows for manual scrubbing of biofilm, ensures that the prosthesis is salvable, and allows instilment of bacteriophages directly to the biofilm.…”

Section: Discussionmentioning

confidence: 99%

“…This surgery allows for manual scrubbing of biofilm, ensures that the prosthesis is salvable, and allows instilment of bacteriophages directly to the biofilm. Local dosing of bacteriophages may be vital to clear biofilm infections, but limited data beyond case reports is available [10][11][12]. No adverse events occurred with repeated IA doses, which may be due to limited systemic absorption.…”

Section: Discussionmentioning

confidence: 99%

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Salvage Bacteriophage Therapy for a Chronic MRSA Prosthetic Joint Infection

Doub

Johnson

et al. 2020

Antibiotics

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Section: Discussionmentioning

confidence: 70%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Salvage Bacteriophage Therapy for a Chronic MRSA Prosthetic Joint Infection

Doub

Johnson

et al. 2020

Antibiotics

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“…However, the recent awareness of antagonism has propelled some in vitro assessment of phageantibiotic action prior to treatment to select for synergistic combinations, a personalized approach that has led to satisfactory therapeutic outcomes (15,16). Several phage-antibiotic combinations have been investigated in vitro and in vivo in multiple bacterial species (17,18) but there have been mixed results with combinatorial treatment (13,19,20).…”

Section: Five Years Later In 2019 the Centers For Disease Control Anmentioning

confidence: 99%

Phage-Antibiotic Synergy is Driven by a Unique Combination of Antibacterial Mechanism of Action and Stoichiometry

Liu

Green

Min

et al. 2020

Preprint

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The continued rise in antibiotic resistance is precipitating a medical crisis. Bacteriophage (phage) has been hailed as one possible therapeutic option to augment the efficacy of antibiotics.However, only a handful of studies have addressed the synergistic relationship between phage and antibiotics. Here, we report a comprehensive analysis of phage-antibiotic interaction that evaluates synergism, additivism, and antagonism for all classes of antibiotics across clinically achievable stoichiometries. We combined an optically-based real-time microtiter plate readout with a matrix-like heatmap of treatment potencies to measure phage and antibiotic synergy (PAS), a process we term synography. Phage-antibiotic synography was performed against a pandemic drug-resistant clonal group of E. coli (ExPEC) with antibiotic levels blanketing the minimum inhibitor concentration (MIC) across seven orders of viral titers. Our results suggest that, under certain conditions, phages provide an adjuvating effect by lowering the MIC for drugresistant strains. Furthermore, synergistic and antagonistic interactions are highly dependent on the mechanism of bacterial inhibition by the class of antibiotic paired to the phage, and when synergism is observed, it suppresses the emergence of resistant cells. Host conditions that simulate the infection environment, including serum and urine, suppress PAS in a bacterial growth-dependent manner. Lastly, phage burst size seems to be a significant driver of synergism.Collectively, this data suggests lytic phages can resuscitate an ineffective antibiotic for previously resistant bacteria, while also synergize with antibiotics in a class-dependent manner, processes that may be dampened by lower bacterial growth rates found in host environments. Significance StatementBacteriophage (phage) therapy is a promising approach to combat the rise of multi-drug resistant bacteria. Currently, the preferred clinical modality is to pair phage with an antibiotic, a practice thought to improve efficacy. However, antagonism between phage and antibiotics has been reported, the choice of phage and antibiotic is not often empirically determined, and the effect of the host factors on the effectiveness is unknown. Here, we interrogate phage-antibiotic interactions across antibiotics with different mechanisms of action. Our results suggest that phage can lower the working MIC for bacterial strains already resistant to the antibiotic, is dependent on the antibiotic class and stoichiometry of the pairing, and is dramatically influenced by the host microenvironment.

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Introduction

Zimmerli¹

2021

Bone and Joint Infections

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Bacteriophages as Adjuvant to Antibiotics for the Treatment of Periprosthetic Joint Infection Caused by Multidrug-Resistant Pseudomonas aeruginosa

Cited by 119 publications

References 23 publications

Salvage Bacteriophage Therapy for a Chronic MRSA Prosthetic Joint Infection

Salvage Bacteriophage Therapy for a Chronic MRSA Prosthetic Joint Infection

Phage-Antibiotic Synergy is Driven by a Unique Combination of Antibacterial Mechanism of Action and Stoichiometry

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