Dataset Information

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

ABSTRACT: Methicillin-resistant Staphylococcus aureus (MRSA) reinfection following revision surgery remains a major orthopaedic problem. Toward the development of immunotherapy with anti-glucosaminidase monoclonal antibodies (anti-Gmd), we aimed to: (i) develop a murine 1-stage exchange model of bioluminescent MRSA (USA300LAC::lux) contaminated femoral implants; and (ii) utilize this model to demonstrate the synergistic effects of combination vancomycin and anti-Gmd therapy on reinfection and bone healing. Following an infection surgery, the original plate and two screws were removed on day 7, and exchanged with sterile implants. Mice were randomized to five groups: (i) no infection control; (ii) infected placebo; (iii) anti-Gmd; (iv) vancomycin; and (v) combination therapy. Bioluminescent imaging (BLI) was performed on days 0, 1, 3, 5, 7, 8, 10, 12, and 14. Mice were euthanized on day 14 (day 7 post-revision), and efficacy was assessed via colony forming units (CFU) on explanted hardware, micro-CT, and histology. As monotherapies, anti-Gmd inhibited Staphylococcus abscess communities, and vancomycin reduced CFU on the implants. However, only combination therapy prevented increased BLI post-revision surgery, with a significant 6.5-fold reduction on day 10 (p?

SUBMITTER: Yokogawa N

PROVIDER: S-EPMC6541030 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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

Yokogawa Noriaki N Ishikawa Masahiro M Nishitani Kohei K Beck Christopher A CA Tsuchiya Hiroyuki H Mesfin Addisu A Kates Stephen L SL Daiss John L JL Xie Chao C Schwarz Edward M EM

Journal of orthopaedic research : official publication of the Orthopaedic Research Society 20180205 6

Methicillin-resistant Staphylococcus aureus (MRSA) reinfection following revision surgery remains a major orthopaedic problem. Toward the development of immunotherapy with anti-glucosaminidase monoclonal antibodies (anti-Gmd), we aimed to: (i) develop a murine 1-stage exchange model of bioluminescent MRSA (USA300LAC::lux) contaminated femoral implants; and (ii) utilize this model to demonstrate the synergistic effects of combination vancomycin and anti-Gmd therapy on reinfection and bone healing ...[more]

PMID: 29405452

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Project description:Methicillin-resistant Staphylococcus aureus (MRSA) is a major threat to human health, as the US mortality rate outweighs those from HIV, tuberculosis, and viral hepatitis combined. In the wake of the COVID-19 pandemic, antibiotic resistant bacterial infections acquired during hospital stays have increased. Instead of designing and deploying new antibiotics which MRSA would quickly develop resistance to, adjuvants are a key strategy to combatting these bacteria. We have evaluated several small molecule adjuvants that have strong potentiation with β-lactam antibiotics and have now investigated at the molecular level how the lead adjuvant exerts its effects. We hypothesized that the expression levels of key resistance genes would decrease once cotreated with a β-lactam antibiotic (oxacillin) and the adjuvant (compound 8). Furthermore, bioinformatic analyses would reveal biochemical pathways enriched in differentially expressed genes. RNA-seq analysis showed 176 and 233 genes significantly up and downregulated, respectively, upon cotreatment with oxacillin and compound 8. We identified four subclusters of genes that were regulated in similar patterns in response to drug treatment. Many of these genes displayed a similar pattern of expression where they were unaffected by compound 8 treatment alone, upregulated upon antibiotic challenge, and downregulated again upon cotreatment. GO categories that were significantly enriched among downregulated genes involved carbohydrate utilization and/or transport. Most of the biochemical pathways enriched with significantly downregulated genes involved carbohydrate utilization, such as the citric acid cycle (p=6.4x10-6) and the phosphotransferase system (p=1.8x10-5). The most populated pathway was S. aureus infection (p=3.0x10-3). Creating a network of affected gene products helped uncover potential master regulators for further investigation. This study revealed a dramatic impact of our lead adjuvant on the transcriptome that is consistent with a pleiotropic effect. These results point to this adjuvant as having potential broad therapeutic use in combatting MRSA infections.

Project description:Background: Debridement, antibiotics and implant retention (DAIR) is a valuable option for treating early and acute periprosthetic joint infection (PJI). The inflammation caused by the infection and the surgical intervention during DAIR may influence the long-term stability of the implant. In this study, we analyzed the sequelae of DAIR on implant survival in hip PJI after cure of infection. Methods: Total hip arthroplasties (THAs) from our database implanted between 1992 and 2016 were included in a retrospective double-cohort study. THAs were exposed (DAIR cohort) or not exposed to DAIR (control cohort). The control cohort comprised patients matched 3:1 to the DAIR cohort. The outcome was implant failure over time. It was evaluated for (i) revision for any reason, (ii) aseptic loosening of any component, and (iii) radiographic evidence of loosening. Results: 57 THAs (56 patients) were included in the DAIR cohort and 170 THAs (168 patients) in the control cohort. The mean follow-up periods in the DAIR and control cohorts were 6.1 and 7.8 years, respectively. During follow-up, 20 (36%) patients in the DAIR cohort and 54 (32%) in the control cohort died after a mean of 4.1 and 7.2 years, respectively. Revision for any reason was performed in 9 (16%) THAs in the DAIR cohort and in 10 (6%) THAs (p=0.03) in the control cohort, and revision for aseptic loosening of any component in 5 (9%) and 8 (5%) THAs (p=0.32), respectively. Radiological analysis included 56 THAs in the DAIR cohort and 168 THAs in the control cohort. Two (4%) stems and 2 (4%) cups in the DAIR cohort and 7 (4%) and 1 (0.6%) in the control cohort, respectively, demonstrated radiological signs of failure (p=1). Conclusions: THAs exposed to DAIR were revised for any reason more frequently than were THAs in the control cohort. The difference was mainly caused by septic failures. After cure of PJI, the difference in revisions for aseptic loosening was not significant. There was no significant difference in radiographic evidence of loosening of any component between cohorts. These data suggest that cured hip PJI previously exposed to DAIR do not fail more frequently for aseptic reasons than do THAs not exposed to DAIR.

Dataset Information

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

Publications

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

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