A systematic review of animal models for Staphylococcus aureus osteomyelitis

Reizner, W; Hunter, Joshua G.; O’Malley, Natasha T.; Southgate, R D; Schwarz, E M; Kates, Stephen L.

doi:10.22203/ecm.v027a15

Cited by 112 publications

(113 citation statements)

References 131 publications

(107 reference statements)

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“…In a recent review on S. aureus osteomyelitis and animal models published, the authors clearly showed the limitations of various animal models concerning the transfer from animal data to the clinical situation (Reizner et al, 2014). We think that choosing a certain material instead of another will not solely solve the problem of implant-associated infections alone but might be one step in reducing the number of infections.…”

Section: Discussion With Reviewersmentioning

confidence: 99%

Influence of physico-chemical material characteristics on staphylococcal biofilm formation – A qualitative and quantitative in vitro analysis of five different calcium phosphate bone grafts

Clauss

U²,

Bétrisey³

et al. 2014

eCM

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Various compositions of synthetic calcium phosphates (CaP) have been proposed and their use has considerably increased over the past decades. Besides differences in physicochemical properties, resorption and osseointegration, artificial CaP bone graft might differ in their resistance against biofilm formation. We investigated standardised cylinders of 5 different CaP bone grafts (cyclOS, chronOS (both β-TCP (tricalcium phosphate)), dicalcium phosphate (DCP), calcium-deficient hydroxyapatite (CDHA) and α-TCP). Various physico-chemical characterisations e.g., geometrical density, porosity, and specific surface area were investigated. Biofilm formation was carried out in tryptic soy broth (TSB) and human serum (SE) using Staphylococcus aureus (ATCC 29213) and S. epidermidis RP62A (ATCC 35984). The amount of biofilm was analysed by an established protocol using sonication and microcalorimetry. Physico-chemical characterisation showed marked differences concerning macro-and micropore size, specific surface area and porosity accessible to bacteria between the 5 scaffolds. Biofilm formation was found on all scaffolds and was comparable for α-TCP, chronOS, CDHA and DCP at corresponding time points when the scaffolds were incubated with the same germ and/or growth media, but much lower for cyclOS. This is peculiar because cyclOS had an intermediate porosity, mean pore size, specific surface area, and porosity accessible to bacteria. Our results suggest that biofilm formation is not influenced by a single physico-chemical parameter alone but is a multi-step process influenced by several factors in parallel. Transfer from in vitro data to clinical situations is difficult; thus, advocating the use of cyclOS scaffolds over the four other CaP bone grafts in clinical situations with a high risk of infection cannot be clearly supported based on our data.

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Section: Discussion With Reviewersmentioning

confidence: 99%

Influence of physico-chemical material characteristics on staphylococcal biofilm formation – A qualitative and quantitative in vitro analysis of five different calcium phosphate bone grafts

Clauss

U²,

Bétrisey³

et al. 2014

eCM

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“…The ideal small animal model to study post-infection treatments would utilize a fixation device that maintains stability after infection establishment and can readily accommodate an antibiotic-laden biomaterial spacer in a bone defect following extensive debridement. The limited in vivo evaluation of novel antibiotic spacers and dual-purpose (infection management and bone regeneration) scaffolds may be attributable to the unavailability of such an animal model [11, 12]. …”

Section: Introductionmentioning

confidence: 99%

A novel murine model of established Staphylococcal bone infection in the presence of a fracture fixation plate to study therapies utilizing antibiotic-laden spacers after revision surgery

Inzana

Schwarz

Kates

et al. 2015

Bone

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Mice are the small animal model of choice in biomedical research due to the low cost and availability of genetically engineered lines. However, the devices utilized in current mouse models of implant-associated bone infection have been limited to intramedullary or trans-cortical pins, which are not amenable to treatments involving extensive debridement of a full-thickness bone loss and placement of a segmental antibiotic spacer. To overcome these limitations, we developed a clinically faithful model that utilizes a locking fracture fixation plate to enable debridement of an infected segmental bone defect (full-thickness osteotomy) during a revision surgery, and investigated the therapeutic effects of placing an antibiotic-laden spacer in the segmental bone defect. To first determine the ideal time point for revision following infection, a 0.7 mm osteotomy in the femoral mid-shaft was stabilized with a radiolucent PEEK fixation plate. The defect was inoculated with bioluminescent Staphylococcus aureus, and the infection was monitored over 14 days by bioluminescent imaging (BLI). Osteolysis and reactive bone formation were assessed by X-ray and micro-computed tomography (micro-CT). The active bacterial infection peaked by 5 days post-inoculation, however the stability of the implant fixation became compromised by 10–14 days post-inoculation due to osteolysis around the screws. Thus, day 7 was defined as the ideal time point to perform the revision surgery. During the revision surgery, the infected tissue was debrided and the osteotomy was widened to 3 mm to place a poly-methyl methacrylate spacer, with or without vancomycin. Half of the groups also received systemic vancomycin for the remaining 21 days of the study. The viable bacteria remaining at the end of the study were measured using colony forming unit assays. Volumetric bone changes (osteolysis and reactive bone formation) were directly measured using micro-CT image analysis. Mice that were treated with local or systemic vancomycin did not display gross pathology at the end of the study. While localized vancomycin delivery alone tended to decrease the bacterial burden and osteolysis, these effects were only significant when combined with systemic antibiotic therapy. This novel mouse model replicates key features of implant-associated osteomyelitis that make treatment extremely difficult, such as biofilm formation and osteolysis, and imitates the clinical practice of placing an antibiotic-laden spacer after infected tissue debridement. In addition, the model demonstrates the limitations of current PMMA spacers and could be an invaluable tool for evaluating alternative antimicrobial treatments for implant-associated bone infection.

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“…The range of diseases caused by S. aureus is represented by the diversity of animal model systems currently being studied (28,29). In terms of S. aureus biofilm infection, some models utilize a large infectious inoculum or introduce implants that are precoated with bacteria (30)(31)(32)(33)(34)(35)(36).…”

mentioning

confidence: 99%

Infectious Dose Dictates the Host Response during Staphylococcus aureus Orthopedic-Implant Biofilm Infection

Vidlak

Kielian

2016

Infect Immun

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Staphylococcus aureus is a leading cause of prosthetic joint infections (PJIs) that are typified by biofilm formation. Given the diversity of S. aureus strains and their propensity to cause community-or hospital-acquired infections, we investigated whether the immune response and biofilm growth during PJI were conserved among distinct S. aureus clinical isolates. Three S. aureus strains representing USA200 (UAMS-1), USA300 (LAC), and USA400 (MW2) lineages were equally effective at biofilm formation in a mouse model of PJI and elicited similar leukocyte infiltrates and cytokine/chemokine profiles. Another factor that may influence the course of PJI is infectious dose. In particular, higher bacterial inocula could accelerate biofilm formation and alter the immune response, making it difficult to discern underlying pathophysiological mechanisms. To address this issue, we compared the effects of two bacterial doses (10 3 or 10 5 CFU) on inflammatory responses in interleukin-12p40 (IL-12p40) knockout mice that were previously shown to have reduced myeloid-derived suppressor cell recruitment concomitant with bacterial clearance after low-dose challenge (10 3 CFU). Increasing the infectious dose of LAC to 10 5 CFU negated these differences in IL-12p40 knockout animals, demonstrating the importance of bacterial inoculum on infection outcome. Collectively, these observations highlight the importance of considering infectious dose when assessing immune responsiveness, whereas biofilm formation during PJI is conserved among clinical isolates commonly used in mouse S. aureus infection models.

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A systematic review of animal models for Staphylococcus aureus osteomyelitis

Cited by 112 publications

References 131 publications

Influence of physico-chemical material characteristics on staphylococcal biofilm formation – A qualitative and quantitative in vitro analysis of five different calcium phosphate bone grafts

Influence of physico-chemical material characteristics on staphylococcal biofilm formation – A qualitative and quantitative in vitro analysis of five different calcium phosphate bone grafts

A novel murine model of established Staphylococcal bone infection in the presence of a fracture fixation plate to study therapies utilizing antibiotic-laden spacers after revision surgery

Infectious Dose Dictates the Host Response during Staphylococcus aureus Orthopedic-Implant Biofilm Infection

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