2020 John Charnley Award: The antimicrobial potential of bacteriophage-derived lysin in a murine debridement, antibiotics, and implant retention model of prosthetic joint infection

Sosa, Branden R.; Niu, Yingzhen; Turajane, Kathleen; Staats, Kevin; Suhardi, V; Carli, Alberto; Fischetti, Vincent A.; Bostrom, Mathias P.; Yang, Xu

doi:10.1302/0301-620x.102b7.bjj-2019-1590.r1

Cited by 40 publications

(41 citation statements)

References 36 publications

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“…Our study has several limitations. Although we have made every effort to develop a clinically relevant PJI model (28,29,63) and our findings are aligned with published studies of human PJI, (62,64) it will be important to compare our findings to human PJI in greater detail. To this effect, we have initiated a study of human PJI subjects that to date has confirmed low-level T-cell infiltration, but greater heterogeneity and variability in duration of infection before surgical intervention will necessitate a long enrollment period.…”

Section: Discussionsupporting

confidence: 72%

Immune Response to Persistent Staphyloccocus Aureus Periprosthetic Joint Infection in a Mouse Tibial Implant Model

Sokhi

Xia

Sosa

et al. 2020

Journal of Bone and Mineral Research

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Staphyloccocus aureus is one of the major pathogens in orthopedic periprosthetic joint infection (PJI), a devastating complication of total joint arthroplasty that often results in chronic and persistent infections that are refractory to antibiotics and require surgical interventions. Biofilm formation has been extensively investigated as a reason for persistent infection. The cellular composition, activation status, cytokine profile, and role of the immune response during persistent S. aureus PJI are incompletely understood. In this study, we used histology, multiparametric flow cytometry, and gene expression analysis to characterize the immune response in a clinically relevant orthopedic PJI model. We tested the hypothesis that persistent S. aureus infection induces feedback mechanisms that suppress immune cell activation, thereby affecting the course of infection. Surprisingly, persistent infection was characterized by strikingly high cytokine gene expression indicative of robust activation of multiple components of innate and adaptive immunity, along with ongoing severe neutrophil-dominated inflammation, in infected joint and bone tissues. Activation and expansion of draining lymph nodes and a bone marrow stress granulopoiesis reaction were also maintained during late phase infection. In parallel, feedback mechanisms involving T-cell inhibitory receptors and exhaustion markers, suppressive cytokines, and regulatory T cells were activated and associated with decreased T-cell proliferation and tissue infiltration during the persistent phase of infection. These results identify the cellular and molecular components of the mouse immune response to persistent S. aureus PJI and indicate that neutrophil infiltration, inflammatory cytokine responses, and ongoing lymph node and bone marrow reactions are insufficient to clear infection and that immune effector mechanisms are suppressed by feedback inhibitory pathways. These immune-suppressive mechanisms are associated with diminished T-cell proliferation and tissue infiltration and can be targeted as part of adjuvant immunotherapeutic strategies in combination with debridement of biofilm, antibiotics, and other therapeutic modalities to promote eradication of infection.

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Section: Discussionsupporting

confidence: 72%

Immune Response to Persistent Staphyloccocus Aureus Periprosthetic Joint Infection in a Mouse Tibial Implant Model

Sokhi

Xia

Sosa

et al. 2020

Journal of Bone and Mineral Research

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“…Bacteriophage therapy has generated interest for many decades, and recent studies have investigated it as an adjuvant in the treatment of osteomyelitis 174 . For example, in a murine model of implant-associated osteomyelitis, the use of a combination of systemic and locally applied bacteriophage-derived lysin (PlySs2), aimed at targeting both planktonic and biofilm-associated bacteria, improved S. aureus infection eradication after debridement and implant retention 175 . Phage therapy has been used for topical delivery in humans for indications such as diabetic toe ulcers and limited cases of other lower extremity osteomyelitis; however, these studies involved small patient numbers without control groups 133 .…”

Section: Synovial Fluidmentioning

confidence: 99%

Skeletal infections: microbial pathogenesis, immunity and clinical management

et al. 2022

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Osteomyelitis is an infection of bone that can result from contiguous spread from surrounding tissue, direct bone trauma due to surgery or injury, or haematogenous spread from systemic bacteraemia. It remains a significant health-care burden with a prevalence of ~22 cases per 100,000 person-years in the United States, and its incidence has been rising over time, especially in the elderly and individuals with diabetes 1 . Although it is a heterogeneous disease, subset classifications include implant-associated osteomyelitis (including peri-prosthetic joint infection (PJI) and instrumented spinal infections), fracture-related infection, acute haematogenous osteomyelitis, diabetic foot infection, septic arthritis and native spinal osteomyelitis.Crucial to expanding our understanding of osteomyelitis and advancing treatment algorithms has been the application of animal models, which illustrate the interaction between the pathogen and cells of both the immune and skeletal systems in a manner that in vitro models cannot yet replicate. Animal models are available to study virtually all aspects of skeletal infection, and typically involve inoculation of bacteria at the time of implant placement (Fig. 1). They can vary in complexity from simple models where metal implants are placed under the skin (for example, tissue cage 2 ) or into cortical bone (for example, metal wire 3 ) versus more complex models that mimic functional orthopaedic devices 4 . Additionally, approaches have been developed to induce non-implant infections by haematogenous inoculation into the tail vein 5 , direct inoculation into vertebral bodies or intervertebral discs 6 to induce vertebral osteomyelitis, or inoculation into the foot pad of diabetic obese rodents to induce diabetic foot infection 7 .As disease pathogenesis differs across different infection classes, so does microbial aetiology. Many different microorganisms have been implicated in skeletal infection, and the most common, along with their incidence and tropism, are shown in Table 1. In general, Staphylococcus aureus and coagulase-negative staphylococci (CoNS), such as Staphylococcus epidermidis and Staphylococcus lugdunensis, are responsible for up to two-thirds of all skeletal infections, with S. aureus being the most prevalent single pathogen. Additionally, antimicrobial resistance remains a challenge in osteomyelitis treatment with up to 50% of cases of S. aureus osteomyelitis caused by methicillin-resistant S. aureus (MRSA) strains 8 . Other less commonly identified pathogens include Enterococcus spp., Pseudomonas aeruginosa, Escherichia coli and Cutibacterium acnes (Table 1). Most cases of osteomyelitis are monomicrobial; however,

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“…One possible way to circumvent this would be to apply enzybiotics systemically, although this faces its own hurdles. A recent study using the PlySs2 endolysin against an in vivo model of prosthetic joint infection found little significant reduction in CFU numbers in the infected bone following intraperitoneal injection of the lysin, demonstrating that systemic administration does not necessarily ameliorate bone treatment [57]. Systemic lysin administration has always faced the hurdle of rapid renal clearance.…”

Section: Discussionmentioning

confidence: 99%

“…A recent study revealed the effectiveness of lysostaphin application via a hydrogel to prevent the onset of S. aureus ODRI [56]. In a separate study, the application of the endolysin PlySs2 was effective in combination with vancomycin in treating an in vivo model of staphylococcal prosthetic joint infection [57]. We, therefore, set out to explore whether an enzybiotic combination specifically tailored for its efficacy in vivo could be effective in treating established ODRI.…”

Section: Introductionmentioning

confidence: 99%

An Enzybiotic Regimen for the Treatment of Methicillin-Resistant Staphylococcus aureus Orthopaedic Device-Related Infection

et al. 2021

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Orthopaedic device-related infection (ODRI) presents a significant challenge to the field of orthopaedic and trauma surgery. Despite extensive treatment involving surgical debridement and prolonged antibiotic therapy, outcomes remain poor. This is largely due to the unique abilities of Staphylococcus aureus, the most common causative agent of ODRI, to establish and protect itself within the host by forming biofilms on implanted devices and staphylococcal abscess communities (SACs). There is a need for novel antimicrobials that can readily target such features. Enzybiotics are a class of antimicrobial enzymes derived from bacteria and bacteriophages, which function by enzymatically degrading bacterial polymers essential to bacterial survival or biofilm formation. Here, we apply an enzybiotic-based combination regimen to a set of in vitro models as well as in a murine ODRI model to evaluate their usefulness in eradicating established S. aureus infection, compared to classical antibiotics. We show that two chimeric endolysins previously selected for their functional efficacy in human serum in combination with a polysaccharide depolymerase reduce bacterial CFU numbers 10,000-fold in a peg model and in an implant model of biofilm. The enzyme combination also completely eradicates S. aureus in a SAC in vitro model where classical antibiotics are ineffective. In an in vivo ODRI model in mice, the antibiofilm effects of this enzyme regimen are further enhanced when combined with a classical gentamicin/vancomycin treatment. In a mouse model of methicillin-resistant S. aureus (MRSA) ODRI following a fracture repair, a combined local enzybiotic/antibiotic treatment regimen showed a significant CFU reduction in the device and the surrounding soft tissue, as well as significant prevention of weight loss. These outcomes were superior to treatment with antibiotics alone. Overall, this study demonstrates that the addition of enzybiotics, which are distinguished by their extremely rapid killing efficacy and antibiofilm activities, can enhance the treatment of severe MRSA ODRI.

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2020 John Charnley Award: The antimicrobial potential of bacteriophage-derived lysin in a murine debridement, antibiotics, and implant retention model of prosthetic joint infection

Cited by 40 publications

References 36 publications

Immune Response to Persistent Staphyloccocus Aureus Periprosthetic Joint Infection in a Mouse Tibial Implant Model

Immune Response to Persistent Staphyloccocus Aureus Periprosthetic Joint Infection in a Mouse Tibial Implant Model

Skeletal infections: microbial pathogenesis, immunity and clinical management

An Enzybiotic Regimen for the Treatment of Methicillin-Resistant Staphylococcus aureus Orthopaedic Device-Related Infection

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