Quantitative mouse model of implant‐associated osteomyelitis and the kinetics of microbial growth, osteolysis, and humoral immunity

Li, Dan; Gromov, Kirill; Søballe, Kjeld; Puzas, J. Edward; O’Keefe, Regis J.; Awad, Hani A.; Drissi, Hicham; Schwarz, Edward M.

doi:10.1002/jor.20452

Cited by 140 publications

(178 citation statements)

References 27 publications

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“…Furthermore, we show that Ti pins in synovial fluid that contains CFZ due to preoperative prophylaxis can be colonized by added S. aureus at clinically significant numbers. In the presence of metal implants, it is now known that both in vitro (24,25) and in vivo, as few as 100 CFU of S. aureus are sufficient to establish infection (26). Accompanying this diminished level of efficacy of antibiotics in synovial fluid, our in vitro findings show that in general, up to 90% of bacteria survive, suggesting that preoperative prophylaxis may be ineffective in the synovial fluid environment.…”

Section: Discussionmentioning

confidence: 71%

Staphylococcal Persistence Due to Biofilm Formation in Synovial Fluid Containing Prophylactic Cefazolin

Dastgheyb

Hammoud

Ketonis

et al. 2015

Antimicrob Agents Chemother

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Antibiotic prophylaxis is standard for patients undergoing surgical procedures, yet despite the wide use of antibiotics, breakthrough infections still occur. In the setting of total joint arthroplasty, such infections can be devastating. Recent findings have shown that synovial fluid causes marked staphylococcal aggregation, which can confer antibiotic insensitivity. We therefore asked in this study whether clinical samples of synovial fluid that contain preoperative prophylactic antibiotics can successfully eradicate a bacterial challenge by pertinent bacterial species. This study demonstrates that preoperative prophylaxis with cefazolin results in high antibiotic levels. Furthermore, we show that even with antibiotic concentrations that far exceed the expected bactericidal levels, Staphylococcus aureus bacteria added to the synovial fluid samples are not eradicated and are able to colonize model implant surfaces, i.e., titanium pins. Based on these studies, we suggest that current prophylactic antibiotic choices, despite high penetration into the synovial fluid, may need to be reexamined.I nfection remains a major concern with orthopedic procedures, although infection rates are generally Ͻ1% (1). Because of the high prophylactic antibiotic levels within synovial fluid, the use of minimally invasive techniques, and short surgical times, infection rates remain low. However, with increasing numbers of total knee arthroplasties, infections are projected to exceed 60,000 to 70,000 cases in the United States by 2020 (2, 3). When hardware, such as a prosthesis, is present, infection is recalcitrant to antibiotic treatment. Once established, infection can cause prolonged disability, multiple operations, and increased health care costs (3, 4). According to the WHO, patients with a surgical site infection have twice the mortality rate, are twice as likely to spend time in an intensive care unit, and are five times more likely to be readmitted to the hospital than uninfected patients (5).To avoid the establishment of infection, antibiotic prophylaxis has become the standard of care (6, 7). For orthopedic procedures, cefazolin (CFZ), which is bactericidal for staphylococci, streptococci, and Escherichia coli (8, 9), is commonly used in the absence of a penicillin allergy (10). Alternative prophylactic antibiotics include fusidic acid, cloxacillin (11), cefixime (12), vancomycin, and gentamicin (13). Interestingly, synovial fluid has been suggested to possess antibacterial properties (14-16) that are attributed to hyaluronic acid within the synovial fluid (17), the induction of bactericidal/permeability-increasing protein (15), or unknown compounds, including antimicrobial peptides, within the synovial fluid (14). We recently reported that this ostensible decrease in bacterial numbers, which is perceived to be an "antibacterial" effect, is actually due to the clumping of bacteria within synovial fluid, which masks the true microbial load levels (18).The recognition of this behavior also helps to elucidate the difficulties ...

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Section: Discussionmentioning

confidence: 71%

Staphylococcal Persistence Due to Biofilm Formation in Synovial Fluid Containing Prophylactic Cefazolin

Dastgheyb

Hammoud

Ketonis

et al. 2015

Antimicrob Agents Chemother

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“…Animal sera were obtained from Balb/c or C57BL/6 mice (Jackson Laboratory, Bar Harbor, ME, USA). Six-to-eight-week-old female mice were inoculated once (Day 0) or twice (Days 0 and 28) by transtibial pin surgery [26] with a vehicle (Tryptic Soy Broth, Recombinant Antigens of S aureus S aureus antigens were selected by the following criteria: (1) expression by the majority of clinical S aureus isolates; (2) high sequence conservation among strains; (3) display on the cell wall or secretion; and (4) function essential for the growth and survival of S aureus in vivo. Using these criteria, 14 S aureus antigens were chosen ( Table 2).…”

Section: Animal Seramentioning

confidence: 99%

A Diagnostic Serum Antibody Test for Patients With Staphylococcus aureus Osteomyelitis

Nishitani

Beck

Rosenberg

et al. 2015

Clinical Orthopaedics &Amp; Related Research

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Background Because immunity against Staphylococcus aureus has not been fully elucidated, there is no diagnostic test to gauge how robust a patient's host response is likely to be. Therefore, we aimed to develop a test for specific antibodies in serum with diagnostic and prognostic potential. Questions/Purposes We describe the development and validation of a multiplex immunoassay for characterizing a patient's immune response against 14 known S aureus antigens, which we then used to answer four questions: (1) Do certain antigens predominate in the immune response against S aureus? (2) Is there a predominant pattern of antigens recognized by patients and mice with infections? (3) Is the immunoglobulin G (IgG) response to any single antigen a useful predictor of ongoing S aureus infection? (4) Does measurement of the combined response against all 14 antigens provide a better predictor of ongoing infection? Methods A case-control study was performed. Sera were collected from 35 consecutive patients with S aureus culture-confirmed (methicillin-sensitive S aureus or methicillin-resistant S aureus) musculoskeletal infections The institution of one or more of the authors (EMS, SLK, JLD, CAB) has received, during the study period, funding from the National Institutes of Health, NIAMS (Bethesda, MD, USA) and (EMS, SLK, JLD) the AOTrauma Clinical Priority Program (Davos, Switzerland). One of the authors certifies that he (JLD) or she or a member of his or her immediate family, has received or may receive payments or benefits, during the study period, an amount of USD 10,000 to 100,000 from Telephus Medical LLC (San Diego, CA, USA) and an amount of less than USD 10,000 from Calorics Pharmaceuticals (Waltham, MA, USA). One of the authors certifies that he (EMS) or she or a member of his or her immediate family, has received or may receive payments or benefits, during the study period, an amount of USD 10,000 to 100,000 from Telephus Medical LLC (San Diego, CA, USA). One of the authors certifies that he (SLK) or she or a member of his or her immediate family, has received or may receive payments or benefits, during the study period, an amount of less than USD 10,000 from Surgical Excellence Healthcare Quality Consulting, and an amount of USD 10,000 to 100,000 from Sage Publications (Thousand Oaks, CA, USA) One of the authors certifies that he (CAB) or she or a member of his or her immediate family, has received or may receive payments or benefits, during the study period, an amount of USD 10,000 to 100,000 from the FDA (Silver Spring, MD, USA), and an amount of USD 10,000 to 100,000 from Boston Scientific (Marlborough, MA, USA), an amount of USD 10,000 to 100,000 from Lundbeck Inc (Deerfield, IL, USA), an amount of USD 10,000 to 100,000 from Patient-Centered Outcomes Research Institute (PCORI, Washington, DC, USA), and an amount of less than USD 10,000 from Auspex Pharmaceuticals (La Jolla, CA, USA). All ICMJE Conflict of Interest Forms for authors and Clinical Orthopaedics and Related Research 1 editors and board mem...

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“…Infected orthopedic implants were generated and placed as we have previously described (26). In short, a flat (cross-section, 0.2 by 0.5 mm), stainless steel surgical wire was cut to a 4-mm length and bent at 1 mm to form an L-shaped pin.…”

Section: Animalsmentioning

confidence: 99%

A Humoral Immune Defect Distinguishes the Response to Staphylococcus aureus Infections in Mice with Obesity and Type 2 Diabetes from That in Mice with Type 1 Diabetes

et al. 2015

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Obesity and diabetes are among the greatest risk factors for infection following total joint arthroplasty. However, the underlying mechanism of susceptibility is unclear. We compared orthopedic implant-associated Staphylococcus aureus infections in type 1 (T1D) versus type 2 (T2D) diabetic mouse models and in patients with S. aureus infections, focusing on the adaptive immune response. Mice were fed a high-fat diet to initiate obesity and T2D. T1D was initiated with streptozotocin. Mice were then given a trans-tibial implant that was precoated with bioluminescent Xen36 S. aureus. Although both mouse models of diabetes demonstrated worse infection severity than controls, infection in T2D mice was more severe, as indicated by increases in bioluminescence, S. aureus CFU in tissue, and death within the first 7 days. Furthermore, T2D mice had an impaired humoral immune response at day 14 with reduced total IgG, decreased S. aureus-specific IgG, and increased IgM. These changes were not present in T1D mice. Similarly, T2D patients and obese nondiabetics with active S. aureus infections had a blunted IgG response to S. aureus. In conclusion, we report the first evidence of a humoral immune deficit, possibly due to an immunoglobulin class switch defect, in obesity and T2D during exacerbated S. aureus infection which may contribute to the increased infection risk following arthroplasty in patients with T2D and obesity.

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Quantitative mouse model of implant‐associated osteomyelitis and the kinetics of microbial growth, osteolysis, and humoral immunity

Cited by 140 publications

References 27 publications

Staphylococcal Persistence Due to Biofilm Formation in Synovial Fluid Containing Prophylactic Cefazolin

Staphylococcal Persistence Due to Biofilm Formation in Synovial Fluid Containing Prophylactic Cefazolin

A Diagnostic Serum Antibody Test for Patients With Staphylococcus aureus Osteomyelitis

A Humoral Immune Defect Distinguishes the Response to Staphylococcus aureus Infections in Mice with Obesity and Type 2 Diabetes from That in Mice with Type 1 Diabetes

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