A large animal model for a failed two-stage revision of intramedullary nail-related infection by methicillin-resistant Staphylococcus aureus

Abstract

The treatment of chronic orthopaedic device-associated infection (ODRI) often requires multiple surgeries and prolonged antibiotic therapy. Despite this extensive treatment protocol, the procedure is associated with significant failure rates. Currently, no large animal model is available that recapitulates a failed revision. Therefore, our aim was to establish a large animal model for failed treatment of an ODRI, in order to serve as a testbed for future interventional strategies.Adult Swiss Alpine sheep received an intramedullary nail in the tibia and a localised inoculum of either a methicillin-sensitive or methicillin-resistant Staphylococcus aureus (MSSA, MRSA respectively). After 8 weeks, when chronic infection had been established, the animals underwent a staged revision with debridement and temporary placement of an antibiotic-loaded cement spacer. Antibiotics were delivered systemically in a standard or pathogen-adapted manner.Debridement and implant exchange alone failed to treat the MSSA infection. Neither local therapy alone nor systemic therapy alone were effective in resolving infection with MSSA, but a combination of local and systemic therapy was effective against it. MRSA infection was not resolved by the combination of local and systemic antibiotics (standard or pathogen-adapted).A model for failed revision of MRSA infection is described despite the use of local and systemic antibiotics. Novel interventions may be assessed using this model, including antibiotic and non-antibiotic interventions.

Immunotherapy synergizes with debridement and antibiotic therapy in a murine 1‐stage exchange model of MRSA implant‐associated osteomyelitis

“…Although our findings support further development of anti‐Gmd immunotherapy as an adjuvant to vancomycin treatment of implant‐associated osteomyelitis, there are two notable limitations of our study. The first is that this is an initial proof of concept study that needs to be confirmed in other in vivo models, including large animal models that better reflect the clinical situation in terms of size and chronicity of infection . Secondly, we describe effects of a murine monoclonal antibody in mouse model, and it remains to be seen if a human anti‐Gmd antibody could have similar effects in animals and patients.…”

“…The first is that this is an initial proof of concept study that needs to be confirmed in other in vivo models, including large animal models that better reflect the clinical situation in terms of size and chronicity of infection. 50 Secondly, we describe effects of a murine monoclonal antibody in mouse model, and it remains to be seen if a human anti-Gmd antibody could have similar effects in animals and patients. Thus, additional research is needed to further assess this immunotherapy approach to prevent and treat S. aureus bone infections.…”

Single‐stage revision of MRSA orthopedic device‐related infection in sheep with an antibiotic‐loaded hydrogel

“…Thirteen skeletally mature Swiss alpine sheep were included in the study. A model of two‐stage revision for ODRI previously described was modified to a single‐stage revision, 26 which was performed in accordance with the current best practice for preclinical in vivo testing for ODRI (Figure 1). 27 Before inclusion, each sheep underwent a complete physical examination, including a complete blood count and radiographs.…”

“…The bacterial strain is a clinical isolate resistant to methicillin but sensitive to gentamicin (MIC 0.038 µg/ml), vancomycin (MIC 0.5 µg/ml), trimethoprim/sulfamethoxazole, and rifampin. The bacterial inoculum was prepared as previously described 26 . A 20 μl sample of the bacterial suspension was added to a collagen sponge to result in a target final inoculum of 2 × 10 7 CFU.…”

Recommendations for design and conduct of preclinical in vivo studies of orthopedic device‐related infection

“…A wide range of in vivo ODRI models are also available (reviewed in refs. ), ranging from the comparatively simple models amenable to most institutions and facilities, to the more complex models requiring more advanced expertise and facilities and finally the most complex models where the clinical condition is recapitulated to the closest extent possible . Figure outlines the types of animal models available, arranged according to complexity and appropriateness to different stages of product development.…”