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      1. Author :
        Penn-Barwell, J. G.; Murray, C. K.; Wenke, J. C.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2012
      5. Publication :
        J Bone Joint Surg Br
      6. Products :
      7. Volume :
        94
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Xen36, Xen 36, Staphylococcus aureus Xen36, IVIS
      12. Abstract :
        Most animal studies indicate that early irrigation and debridement reduce infection after an open fracture. Unfortunately, these studies often do not involve antibiotics. Clinical studies indicate that the timing of initial debridement does not affect the rate of infection but these studies are observational and fraught with confounding variables. The purpose of this study was to control these variables using an animal model incorporating systemic antibiotics and surgical treatment. We used a rat femur model with a defect which was contaminated with Staphylococcus aureus and treated with a three-day course of systemic cefazolin (5 mg/kg 12-hourly) and debridement and irrigation, both of which were initiated independently at two, six and 24 hour time points. After 14 days the bone and hardware were harvested for separate microbiological analysis. No animal that received antibiotics and surgery two hours after injury had detectable bacteria. When antibiotics were started at two hours, a delay in surgical treatment from two to six hours significantly increased the development of infection (p = 0.047). However, delaying surgery to 24 hours increase the rate of infection, but not significantly (p = 0.054). The timing of antibiotics had a more significant effect on the proportion of positive samples than earlier surgery. Delaying antibiotics to six or 24 hours had a profoundly detrimental effect on the infection rate regardless of the timing of surgery. These findings are consistent with the concept that bacteria progress from a vulnerable planktonic form to a treatment-resistant biofilm.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/22219257
      14. Call Number :
        PKI @ kd.modi @ 10
      15. Serial :
        10404
      1. Author :
        van Staden, A. D.; Brand, A. M.; Dicks, L. M.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2012
      5. Publication :
        J Appl Microbiol
      6. Products :
      7. Volume :
        N/A
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Xen36, Xen 36, Staphylococcus aureus Xen36, IVIS
      12. Abstract :
        Aims: To determine if nisin F-loaded self-setting brushite cement could control the growth of Staphylococcus aureus in vivo. Methods and Results: Brushite cement was prepared by mixing equimolar concentrations of beta-tricalcium phosphate and monocalcium phosphate monohydrate. Nisin F was added at 5.0%, 2.5% and 1.0% (w/w) and the cement moulded into cylinders. In vitro antibacterial activity was determined using a delayed agar diffusion assay. Release of nisin F from the cement was determined using BCA protein assays. Based on scanning electron microscopy and X-ray diffraction analysis, nisin F did not cause significant changes in cement structure or chemistry. Cement containing 5.0% (w/w) nisin F yielded the most promising in vitro results. Nisin F-loaded cement was implanted into a subcutaneous pocket on the back of mice and then infected with S. aureus Xen 36. Infection was monitored for 7 days, using an in vivo imaging system. Nisin F prevented S. aureus infection for 7 days and no viable cells were isolated from the implants. Conclusions: Nisin F-loaded brushite cement successfully prevented in vivo growth of S. aureus. Significance and Impact of the Study: Nisin F incorporated into bone cement may be used to control S. aureus infection in vivo. (c) 2012The Authors Journal of Applied Microbiology (c) 2012 The Society for Applied Microbiology.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/22268790
      14. Call Number :
        PKI @ kd.modi @ 11
      15. Serial :
        10402
      1. Author :
        Ketonis, C.; Barr, S.; Shapiro, I. M.; Parvizi, J.; Adams, C. S.; Hickok, N. J.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2011
      5. Publication :
        Bone
      6. Products :
      7. Volume :
        48
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Xen36, Xen 36, Staphylococcus aureus Xen36, IVIS, Adsorption/drug effects; Anti-Bacterial Agents/chemistry/*pharmacology; Biological Markers/metabolism; *Bone Transplantation; Cell Differentiation/drug effects; Cell Shape/drug effects; Cells, Cultured; Colony Count, Microbial; Drug Stability; Fetus/cytology; Fluorescence; Gene Expression Profiling; Humans; Microbial Sensitivity Tests; Osteoblasts/cytology/drug effects/metabolism; Phenotype; Time Factors; Transplantation, Homologous; Vancomycin/chemistry/*pharmacology
      12. Abstract :
        Bacterial contamination of bone allograft is a significant complication of orthopedic surgery. To address this issue, we have engineered a method for covalently modifying bone allograft tissue with the antibiotic vancomycin. The goal of this investigation was to compare the biocidal properties of this new allograft material with those of vancomycin physisorbed onto graft material. The duration of antibiotic release from the vancomycin-modified allograft matrix was determined, and no elution was observed. In contrast, the adsorbed antibiotic showed a peak elution at 24h that then decreased over several days. We next used an Staphylococcus aureus disk diffusion assay to measure the activity of the eluted vancomycin. Again we found that no active antibiotic was eluted from the covalently modified allograft. Similarly, when the vancomycin-modified allograft morsel was used in the assay, no measurable elution was observed; amounts of antibiotic released from the adsorbed samples inhibited S. aureus growth for 4-7 days. Probably the most telling property of the allograft was that after 2 weeks, the tethered allograft was able to resist bacterial colonization. Unlike the elution system in which vancomycin was depleted over the course of days-weeks, the antibiotic on the allograft was stably bound even after 300 days, while its biocidal activity remained undiminished for 60 days. This finding was in stark contrast to the antibiotic impregnated allograft, which was readily colonized by bacteria. Finally we chose to evaluate three indicators of cell function: expression of a key transcription factor, expression of selected transcripts, and assessment of cell morphology. Since the tethered antibiotic appeared to have little or no effect on any of these activities, it was concluded that the stable, tethered antibiotic prevented bacterial infection while not modifying bone cell function.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/21035576
      14. Call Number :
        PKI @ kd.modi @ 7
      15. Serial :
        10407
      1. Author :
        Bernthal, N. M.; Pribaz, J. R.; Stavrakis, A. I.; Billi, F.; Cho, J. S.; Ramos, R. I.; Francis, K. P.; Iwakura, Y.; Miller, L. S.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2011
      5. Publication :
        J Orthop Res
      6. Products :
      7. Volume :
        29
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Xen36, Xen 36, Staphylococcus aureus Xen36, IVIS, Animals; Arthroplasty; Biofilms/growth & development; Bone Wires/microbiology; Interleukin-1beta/*metabolism; Male; Mice; Mice, Congenic; Mice, Inbred C57BL; Myeloid Differentiation Factor 88/metabolism; Neutrophil Infiltration; Prosthesis-Related Infections/*immunology/metabolism; Staphylococcal Infections/*immunology/metabolism; Staphylococcus aureus; Toll-Like Receptor 2/*metabolism
      12. Abstract :
        MyD88 is an adapter molecule that is used by both IL-1R and TLR family members to initiate downstream signaling and promote immune responses. Given that IL-1beta is induced after Staphylococcus aureus infections and TLR2 is activated by S. aureus lipopeptides, we hypothesized that IL-1beta and TLR2 contribute to MyD88-dependent protective immune responses against post-arthroplasty S. aureus infections. To test this hypothesis, we used a mouse model of a post-arthroplasty S. aureus infection to compare the bacterial burden, biofilm formation and neutrophil recruitment in IL-1beta-deficient, TLR2-deficient and wild-type (wt) mice. By using in vivo bioluminescence imaging, we found that the bacterial burden in IL-1beta-deficient mice was 26-fold higher at 1 day after infection and remained 3- to 10-fold greater than wt mice through day 42. In contrast, the bacterial burden in TLR2-deficient mice did not differ from wt mice. In addition, implants harvested from IL-1beta-deficient mice had more biofilm formation and 14-fold higher adherent bacteria compared with those from wt mice. Finally, IL-1beta-deficient mice had approximately 50% decreased neutrophil recruitment to the infected postoperative joints than wt mice. Taken together, these findings suggest a mechanism by which IL-1beta induces neutrophil recruitment to help control the bacterial burden and the ensuing biofilm formation in a post-surgical joint.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/21445990
      14. Call Number :
        PKI @ kd.modi @ 5
      15. Serial :
        10411
      1. Author :
        Brand, A. M.; de Kwaadsteniet, M.; Dicks, L. M.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2010
      5. Publication :
        Lett Appl Microbiol
      6. Products :
      7. Volume :
        51
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Xen36, Xen 36, Staphylococcus aureus Xen36, IVIS, Animals; Mice; Mice, Inbred C57BL; Microbial Sensitivity Tests; Nisin/*pharmacology; Peritoneal Cavity/*microbiology; Staphylococcal Infections/*prevention & control; Staphylococcus aureus/*drug effects/growth & development
      12. Abstract :
        AIMS: To determine the ability of nisin F to control systematic infection caused by Staphylococcus aureus, using C57BL/6 mice as a model. METHODS AND RESULTS: Twelve mice were intraperitoneally injected with 1 x 10(8) viable cells of Staph. aureus Xen 36 containing the modified Photorhabdus luminescence luxABCDE operon on plasmid pAUL-A Tn4001. After 4 h, six mice were intraperitoneally injected with 640 arbitrary units (AU) nisin F, and six were injected with sterile saline. Six mice, not infected with Staph. aureus, were treated with nisin F, and six not infected were left untreated. The viability of Staph. aureus Xen 36 was monitored over 48 h by recording photon emission levels. Nisin F suppressed Staph. aureus for 15 min in vivo. No abnormalities were recorded in blood analyses and internal organs of mice treated with nisin F. CONCLUSIONS: Nisin F suppressed the growth of Staph. aureus in the peritoneal cavity for at least 15 min. Re-emergence of Staph. aureus bioluminescence over the next 44 h suggests that nisin F was inactivated, most probably by proteolytic enzymes. SIGNIFICANCE AND IMPACT OF THE STUDY: A single dosage of nisin F administered in the peritoneal cavity controlled the growth of Staph. aureus for at least 15 min in vivo.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/21029139
      14. Call Number :
        PKI @ kd.modi @ 2
      15. Serial :
        10410
      1. Author :
        Ketonis, C.; Barr, S.; Adams, C. S.; Shapiro, I. M.; Parvizi, J.; Hickok, N. J.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2011
      5. Publication :
        Antimicrob Agents Chemother
      6. Products :
      7. Volume :
        55
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Xen36, Xen 36, Staphylococcus aureus Xen36, IVIS, Anti-Bacterial Agents/chemistry/*pharmacology; Bacterial Adhesion/drug effects; Biofilms/drug effects/growth & development; *Bone Transplantation; Bone and Bones/*chemistry/*microbiology; Cell Adhesion/drug effects; Cell Line; Colony Count, Microbial; Humans; Microscopy, Confocal; Osteoblasts/cytology; Staphylococcus aureus/drug effects/*growth & development/physiology; Vancomycin/chemistry/*pharmacology
      12. Abstract :
        Infection is an important medical problem associated with the use of bone allografts. To retard bacterial colonization, we have recently reported on the modification of bone allografts with the antibiotic vancomycin (VAN). In this report, we examine the ability of this antibiotic-modified allograft to resist bacterial colonization and biofilm formation. When antibiotic was coupled to the allograft, a uniform distribution of the antibiotic was apparent. Following challenges with Staphylococcus aureus for 6 h, the covalently bonded VAN decreased colonization as a function of inoculum, ranging from 0.8 to 2.0 log(10) CFU. Furthermore, the VAN-modified surface resisted biofilm formation, even in topographical niches that provide a protected environment for bacterial adhesion. Attachment of the antibiotic to the allograft surface was robust, and the bonded VAN was stable whether incubated in aqueous media or in air, maintaining levels of 75 to 100% of initial levels over 60 days. While the VAN-modified allograft inhibited the Gram-positive S. aureus colonization, in keeping with VAN's spectrum of activity, the VAN-modified allograft was readily colonized by the Gram-negative Escherichia coli. Finally, initial toxicity measures indicated that the VAN-modified allograft did not influence osteoblast colonization or viability. Since the covalently tethered antibiotic is stable, is active, retains its specificity, and does not exhibit toxicity, it is concluded that this modified allograft holds great promise for decreasing bone graft-associated infections.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/21098245
      14. Call Number :
        PKI @ kd.modi @ 8
      15. Serial :
        10408
      1. Author :
        Fink, D.; Romanowski, K.; Valuckaite, V.; Babrowski, T.; Kim, M.; Matthews, J. B.; Liu, D.; Zaborina, O.; Alverdy, J. C.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2011
      5. Publication :
        J Trauma
      6. Products :
      7. Volume :
        71
      8. Issue :
        N/A
      9. Page Numbers :
        1575-82
      10. Research Area :
        N/A
      11. Keywords :
        Xen41, Xen 41, Pseudomonas aeruginosa Xen41, IVIS
      12. Abstract :
        BACKGROUND: : Experimental models of intestinal ischemia-reperfusion (IIR) injury are invariably performed in mice harboring their normal commensal flora, even though multiple IIR events occur in humans during prolonged intensive care confinement when they are colonized by a highly pathogenic hospital flora. The aims of this study were to determine whether the presence of the human pathogen Pseudomonas aeruginosa in the distal intestine potentiates the lethality of mice exposed to IIR and to determine what role any in vivo virulence activation plays in the observed mortality. METHODS: : Seven- to 9-week-old C57/BL6 mice were exposed to 15 minutes of superior mesenteric artery occlusion (SMAO) followed by direct intestinal inoculation of 1.0 x 10 colony-forming unit of P. aeruginosa PAO1 into the ileum and observed for mortality. Reiterative studies were performed in separate groups of mice to evaluate both the migration/dissemination pattern and in vivo virulence activation of intestinally inoculated strains using live photon camera imaging of both a constitutive bioluminescent P. aeruginosa PAO1 derivative XEN41 and an inducible reporter derivative of PAO1, the PAO1/lecA:luxCDABE that conditionally expresses the quorum sensing-dependent epithelial disrupting virulence protein PA 1 Lectin (PA-IL). RESULTS: : Mice exposed to 15 minutes of SMAO and reperfusion with intestinal inoculation of P. aeruginosa had a significantly increased mortality rate (p < 0.001) of 100% compared with <10% for sham-operated mice intestinally inoculated with P. aeruginosa without SMAO and IIR alone (<50%). Migration/dissemination patterns of P. aeruginosa in mice subjected to IIR demonstrated proximal migration of distally injected strains and translocation to mesenteric lymph nodes, liver, spleen, lung, and kidney. A key role for in vivo virulence expression of the barrier disrupting adhesin PA-IL during IIR was established since its expression was enhanced during IR and mutant strains lacking PA-IL displayed attenuated mortality. CONCLUSIONS: : The presence of intestinal P. aeruginosa potentiates the lethal effect of IIR in mice in part due to in vivo virulence activation of its epithelial barrier disrupting protein PA-IL.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/22002612
      14. Call Number :
        PKI @ kd.modi @ 1
      15. Serial :
        10423
      1. Author :
        Hamrahi, V.; Hamblin, M. R.; Jung, W.; Benjamin, J. B.; Paul, K. W.; Fischman, A. J.; Tompkins, R. G.; Carter, E. A.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2012
      5. Publication :
        Interdiscip Perspect Infect Dis
      6. Products :
      7. Volume :
        2012
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Xen44, Xen 44, Proteus mirabilis, bioluminescence imaging
      12. Abstract :
        Sepsis remains the major cause of death in patients with major burn injuries. In the present investigation we evaluated the interaction between burn injuries of varying severity and preexisting distant infection. We used Gram-negative bacteria (Pseudomonas aeruginosa and Proteus mirabilis) that were genetically engineered to be bioluminescent, which allowed for noninvasive, sequential optical imaging of the extent and severity of the infection. The bioluminescent bacteria migrated from subcutaneous abscesses in the leg to distant burn wounds on the back depending on the severity of the burn injury, and this migration led to increased mortality of the mice. Treatment with ciprofloxacin, injected either in the leg with the bacterial infection or into the burn eschar, prevented this colonization of the wound and decreased mortality. The present data suggest that burn wounds can readily become colonized by infections distant from the wound itself.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/22899912
      14. Call Number :
        PKI @ kd.modi @ 2
      15. Serial :
        10562
      1. Author :
        Lu, Z.; Dai, T.; Huang, L.; Kurup, D. B.; Tegos, G. P.; Jahnke, A.; Wharton, T.; Hamblin, M. R.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2010
      5. Publication :
        Nanomedicine (Lond)
      6. Products :
      7. Volume :
        5
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Xen44, Xen 44, Proteus mirabilis, bioluminescence imaging, Animals; Fullerenes/*chemistry; Male; Mice; Mice, Inbred BALB C; Photochemotherapy/*methods; Photosensitizing Agents/*chemistry; Pseudomonas Infections/*drug therapy; Pseudomonas aeruginosa/drug effects; Wound Infection/*drug therapy
      12. Abstract :
        AIMS: Fullerenes are under intensive study for potential biomedical applications. We have previously reported that a C60 fullerene functionalized with three dimethylpyrrolidinium groups (BF6) is a highly active broad-spectrum antimicrobial photosensitizer in vitro when combined with white-light illumination. We asked whether this high degree of in vitro activity would translate into an in vivo therapeutic effect in two potentially lethal mouse models of infected wounds. MATERIALS & METHODS: We used stable bioluminescent bacteria and a low light imaging system to follow the progress of the infection noninvasively in real time. An excisional wound on the mouse back was contaminated with one of two bioluminescent Gram-negative species, Proteus mirabilis (2.5 x 10(7) cells) and Pseudomonas aeruginosa (5 x 10(6) cells). A solution of BF6 was placed into the wound followed by delivery of up to 180 J/cm(2) of broadband white light (400-700 nm). RESULTS: In both cases there was a light-dose-dependent reduction of bioluminescence from the wound not observed in control groups (light alone or BF6 alone). Fullerene-mediated photodynamic therapy of mice infected with P. mirabilis led to 82% survival compared with 8% survival without treatment (p < 0.001). Photodynamic therapy of mice infected with highly virulent P. aeruginosa did not lead to survival, but when photodynamic therapy was combined with a suboptimal dose of the antibiotic tobramycin (6 mg/kg for 1 day) there was a synergistic therapeutic effect with a survival of 60% compared with a survival of 20% with tobramycin alone (p < 0.01). CONCLUSION: These data suggest that cationic fullerenes have clinical potential as an antimicrobial photosensitizer for superficial infections where red light is not needed to penetrate tissue.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/21143031
      14. Call Number :
        PKI @ kd.modi @ 1
      15. Serial :
        10563