Salvage Bacteriophage Therapy for a Chronic MRSA Prosthetic Joint Infection

Doub, James B.; Ng, Vincent Y.; Johnson, Aaron J.; Slomka, Magdalena; Fackler, Joseph; Horne, Bri’Anna; Brownstein, Michael J.; Henry, Matthew; Malagón, Francisco; Biswas, Biswajit

doi:10.3390/antibiotics9050241

Cited by 66 publications

(98 citation statements)

References 14 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Critical appraisal highlighted various shortcomings in the quality of reporting but did not provide evidence of bias warranting exclusion (Supplementary File S3). A total of 17 eligible studies were identified for inclusion in this review [19,20,[23][24][25][26][27][32][33][34][35][36][37][38][39][40][41]. The data extracted from these studies is shown in Supplementary File S2.…”

Section: Resultsmentioning

confidence: 99%

“…Six of the nine articles that directly commented on safety or adverse effects reported no side-effects, with a seventh article highlighting that a patient's later myocardial infarction was not considered to be related to phage therapy [26]. Of the remaining two articles, Doub and colleagues suggested that their patient's pre-existing liver pathology explained their observation of non-life threatening reversible transaminitis in response to intravenous phage used at a titre of 2.7 × 10 9 plaque forming units (PFU)/mL [32]. This would be consistent with the absence of transaminitis among other patients treated with intravenous phage of a similar titre [27,36,56,57].…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

The Safety and Efficacy of Phage Therapy for Bone and Joint Infections: A Systematic Review

2020

View full text Add to dashboard Cite

Bacterial resistance to antibiotics has catalysed interest in alternative antimicrobial strategies. Bacteriophages (phages) are viruses of bacteria with a long history of successful therapeutic use. Phage therapy is a promising antibacterial strategy for infections with a biofilm component, including recalcitrant bone and joint infections, which have significant social, financial and human impacts. Here, we report a systematic review of the safety and efficacy of phage therapy for the treatment of bone and joint infections. Three electronic databases were systematically searched for articles that reported primary data about human phage therapy for bone and joint infections. Two authors independently assessed study eligibility and performed data extraction. Seventeen reports were eligible for inclusion in this review, representing the treatment of 277 patients. A cautionary, crude, efficacy estimate revealed that 93.1% (n = 258/277) achieved clinical resolution, 3.3% (n = 9/277) had improvement and 3.6% (n = 10/277) showed no improvement. Seven of the nine reports that directly commented on the safety of phage therapy did not express safety concerns. The adverse effects reported in the remaining two were not severe and were linked to the presence of contaminating endotoxins and pre-existing liver pathology in a patient treated with high-titre intravenous phage therapy. Three other reports, from 1940–1987, offered general comments on the safety of phage therapy and documented adverse effects consistent with endotoxin co-administration concomitant with the use of raw phage lysates. Together, the reports identified by this review suggest that appropriately purified phages represent a safe and highly efficacious treatment option for complex and intractable bone and joint infections.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The Safety and Efficacy of Phage Therapy for Bone and Joint Infections: A Systematic Review

2020

View full text Add to dashboard Cite

show abstract

“…While intravenous bacteriophage therapy has been used in the past with limited adverse events, recent compassionate use cases have shown two adverse events [ 38 , 39 ]. One occurred in the treatment of chronic pseudomonas left ventricular assist device (LVAD) infection in which no success occurred with low titers of intravenous bacteriophage therapy and subsequent bacteriophage therapy with high titers of 1 × 10 11 PFU induced fever, shortness of breath and wheezing [ 38 ]. These symptoms resolved with supportive medical care but continued with repeat dosing with the same titers.…”

Section: Parameters That Impact Treatment Protocolsmentioning

confidence: 99%

Bacteriophage Therapy for Clinical Biofilm Infections: Parameters That Influence Treatment Protocols and Current Treatment Approaches

Doub

2020

Antibiotics

Self Cite

View full text Add to dashboard Cite

Biofilm infections are extremely difficult to treat, which is secondary to the inability of conventional antibiotics to eradicate biofilms. Consequently, current definitive treatment of biofilm infections requires complete removal of the infected hardware. This causes significant morbidity and mortality to patients and therefore novel therapeutics are needed to cure these infections without removal of the infected hardware. Bacteriophages have intrinsic properties that could be advantageous in the treatment of clinical biofilm infections, but limited knowledge is known about the proper use of bacteriophage therapy in vivo. Currently titers and duration of bacteriophage therapy are the main parameters that are evaluated when devising bacteriophage protocols. Herein, several other important parameters are discussed which if standardized could allow for more effective and reproducible treatment protocols to be formulated. In addition, these parameters are correlated with the current clinical approaches being evaluated in the treatment of clinical biofilm infections.

show abstract

“…First, natural barriers such as cell layers and mucus can decrease accessibility of phages to sites of infection, thereby necessitating the administration of higher doses to achieve a favourable therapeutic effect. Second, phage clearance has been reported to occur rapidly; sometimes within just minutes to hours following parenteral administration in animal models and patients (14,(34)(35)(36)(37)(38)(39)(40). Phage clearance within the body is thought to be mediated by three main components: 1) Phagocytic cells (41), 2) The Mononuclear Phagocytic System (MPS;…”

Section: Introductionmentioning

confidence: 99%

“…During therapy, large quantities of phage monocultures or cocktails are administered to patients in order to maintain a killing titre to combat a bacterial infection. Once within the body, these phages can have very short half-lives and are actively removed or inactivated by the body (38)(39)(40)44). Following administration during phage therapy, epithelial and endothelial cell layers are amongst the first and most abundant phageeukaryote interactions.…”

Section: Introductionmentioning

confidence: 99%

Bacteriophage uptake by Eukaryotic cell layers represents a major sink for phages during therapy

Bichet

Chin

Richards

et al. 2020

Preprint

View full text Add to dashboard Cite

For over 100 years, bacteriophages have been known as viruses that infect bacteria. Yet it is becoming increasingly apparent that bacteriophages, or phages for short, have tropisms outside their bacterial hosts. During phage therapy, high doses of phages are directly administered and disseminated throughout the body, facilitating broad interactions with eukaryotic cells. Using live cell imaging across a range of cell lines we demonstrate that cell type plays a major role in phage internalisation and that smaller phages (< 100 nm) are internalised at higher rates. Uptake rates were validated under physiological shear stress conditions using a microfluidic device that mimics the shear stress to which endothelial cells are exposed to in the human body. Phages were found to rapidly adhere to eukaryotic cell layers, with adherent phages being subsequently internalised by macropinocytosis and functional phages accumulating and stably persisting intracellularly. Finally, we incorporate these results into an established pharmacokinetic model demonstrating the potential impact of phage accumulation by these cell layers, which represents a major sink for circulating phages in the body. Understanding these interactions will have important implications on innate immune responses, phage pharmacokinetics, and the efficacy of phage therapy.

show abstract

Salvage Bacteriophage Therapy for a Chronic MRSA Prosthetic Joint Infection

Cited by 66 publications

References 14 publications

The Safety and Efficacy of Phage Therapy for Bone and Joint Infections: A Systematic Review

The Safety and Efficacy of Phage Therapy for Bone and Joint Infections: A Systematic Review

Bacteriophage Therapy for Clinical Biofilm Infections: Parameters That Influence Treatment Protocols and Current Treatment Approaches

Bacteriophage uptake by Eukaryotic cell layers represents a major sink for phages during therapy

Contact Info

Product

Resources

About