Hyperbaric oxygen therapy in a mouse model of implant‐associated osteomyelitis

Shandley, Sabrina; Matthews, Krista Prato; Cox, Jennifer H.; Romano, Desiree R; Abplanalp, Allison; Kalns, John

doi:10.1002/jor.21522

Cited by 20 publications

(16 citation statements)

References 26 publications

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“…Previously, mouse models of implant-associated osteomyelitis have been limited to intramedullary [9, 20, 24] or trans-cortical pins [17, 25]. These models are beneficial for studying the general etiology of osteomyelitis and biofilm formation [24] or systemic treatment strategies such as various antibiotic regimens [20] and immunization [26].…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…For example, Shandley et al used an experimental model similar to ours to test the effect of HBOT (80 min of 100% O 2 at 240 kPa) on bacterial growth in implant-associated OM. The bacterial load (CFU/tibia) of MRSA in infected tibias was significantly higher in HBOT-treated animals, and the authors concluded that HBOT accelerates the growth of S. aureus [20]. It could be hypothesized that HBOT could oxygenate hypoxic biofilms and boost bacterial metabolism, which should lead to higher CFU counts in tibias from animals treated with HBOT compared with no HBOT.…”

Section: Discussionmentioning

confidence: 99%

“…However, a more recent study demonstrated that HBOT could stimulate bacterial growth and thereby accelerate the infection. This was shown by Shandley et al who used a model of implant-associated OM to test the effect of HBOT (100% O 2 at 240 kPa for 80 min) [20]. They found that the bacterial load of Methicillin-resistant Staphylococcus aureus (MRSA) in infected tibias was significantly higher in HBOT-treated animals compared to untreated animals, concluding that HBOT accelerates the growth of S. aureus [20].…”

Section: Introductionmentioning

confidence: 94%

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Hyperbaric Oxygen Therapy is Ineffective as an Adjuvant to Daptomycin with Rifampicin Treatment in a Murine Model of Staphylococcus aureus in Implant-Associated Osteomyelitis

et al. 2017

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Implant-associated infections caused by bacterial biofilms are difficult to treat. Surgical intervention is often necessary to cure the patient, as the antibiotic recalcitrance of biofilms renders them untreatable with conventional antibiotics. Intermittent hyperbaric oxygen treatment (HBOT) has been proposed as an adjuvant to conventional antibiotic treatment and it has been speculated that combining HBOT with antibiotics could improve treatment outcomes for biofilm infections. In this study we addressed whether HBOT could improve treatment outcomes of daptomycin and rifampicin combination therapy. The effect of HBOT on the treatment outcomes of daptomycin and rifampicin against implant-associated osteomyelitis was quantified in a murine model. In total, 80 mice were randomized into two groups receiving antibiotics, either alone or in combination with daily intermittent HBOT (304 kPa for 60 min) following injection of antibiotics. Treatment was initiated 11 days after animals were infected with Staphylococcus aureus and treatment duration was 14 days. We found that HBOT did not improve the cure rate and did not reduce the bacterial load on the implant surface or in the surrounding tissue. Cure rates of daptomycin + rifampicin were 40% in infected tibias and 75% for implants while cure rates for HBOT-daptomycin + rifampicin were 50% and 85%, respectively, which were not significantly higher (Fisher’s exact test). While it is encouraging that the combination of daptomycin and rifampicin is very effective, our study demonstrates that this efficacy cannot be improved by adjuvant HBOT.

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“…In the case of osteomyelitis with MRSA infection for example, the effect of HBO is attributed to increased availability of oxygen used by neutrophils for killing microorganisms through oxidative burst [28]. …”

Section: Introductionmentioning

confidence: 99%

The bactericidal effect of 470-nm light and hyperbaric oxygen on methicillin-resistant Staphylococcus aureus (MRSA)

et al. 2015

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It has been shown that, in vitro, hyperbaric oxygen (HBO) suppresses 28% bacterial growth, while 470 nm blue light alone suppresses up to 92% methicillin resistant Staphylococcus aureus (MRSA) in one application in vitro. Therefore, we determined if combined 470 nm light (55 J/cm2) and HBO will yield 100% bacterial suppression in experimental simulation of mild, moderate or severe MRSA infection. We cultured MRSA at 3×106, 5×106, 7×106, 8×106 or 12×106 CFU/ml and treated each concentration in four groups as follows: (1) Control (no treatment) (2) photo-irradiation only, (3) photo-irradiation then HBO, (4) HBO only, and (5) HBO then photo-irradiation. Bacteria colonies were then quantified. The results showed that at each bacterial concentration, HBO alone was significantly less effective in suppressing MRSA than photo-irradiation or combined HBO and photo-irradiation (p<0.0001). Similarly, at no bacterial concentration did combined HBO and 470 nm light treatment yield a statistically better result than 470 nm light alone (p > 0.05), neither did HBO treatment either before or after irradiation make a difference. Furthermore, at no bacterial concentration was 100% MRSA suppression achieved. Indeed, the maximum bacterial suppression attained was in the mild infection model (3×106 CFU/ml), with blue light producing 97.3±0.2% suppression and HBO +55 J/cm2 yielding 97.5±2.5% suppression. We conclude that: (1) HBO and 470 nm light individually suppress MRSA growth; (2) 470nm blue light is more effective in suppressing MRSA than HBO; and (3) HBO did not act synergistically to heighten the bactericidal effect of 470 nm light.

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Hyperbaric oxygen therapy in a mouse model of implant‐associated osteomyelitis

Cited by 20 publications

References 26 publications

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

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

Hyperbaric Oxygen Therapy is Ineffective as an Adjuvant to Daptomycin with Rifampicin Treatment in a Murine Model of Staphylococcus aureus in Implant-Associated Osteomyelitis

The bactericidal effect of 470-nm light and hyperbaric oxygen on methicillin-resistant Staphylococcus aureus (MRSA)

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