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Hydrogel delivery of lysostaphin eliminates orthopedic implant infection by Staphylococcus aureus and supports fracture healing.

ABSTRACT: Orthopedic implant infections are a significant clinical problem, with current therapies limited to surgical debridement and systemic antibiotic regimens. Lysostaphin is a bacteriolytic enzyme with high antistaphylococcal activity. We engineered a lysostaphin-delivering injectable PEG hydrogel to treat Staphylococcus aureus infections in bone fractures. The injectable hydrogel formulation adheres to exposed tissue and fracture surfaces, ensuring efficient, local delivery of lysostaphin. Lysostaphin encapsulation within this synthetic hydrogel maintained enzyme stability and activity. Lysostaphin-delivering hydrogels exhibited enhanced antibiofilm activity compared with soluble lysostaphin. Lysostaphin-delivering hydrogels eradicated S. aureus infection and outperformed prophylactic antibiotic and soluble lysostaphin therapy in a murine model of femur fracture. Analysis of the local inflammatory response to infections treated with lysostaphin-delivering hydrogels revealed indistinguishable differences in cytokine secretion profiles compared with uninfected fractures, demonstrating clearance of bacteria and associated inflammation. Importantly, infected fractures treated with lysostaphin-delivering hydrogels fully healed by 5 wk with bone formation and mechanical properties equivalent to those of uninfected fractures, whereas fractures treated without the hydrogel carrier were equivalent to untreated infections. Finally, lysostaphin-delivering hydrogels eliminate methicillin-resistant S. aureus infections, supporting this therapy as an alternative to antibiotics. These results indicate that lysostaphin-delivering hydrogels effectively eliminate orthopedic S. aureus infections while simultaneously supporting fracture repair.

SUBMITTER: Johnson CT

PROVIDER: S-EPMC5984524 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Hydrogel delivery of lysostaphin eliminates orthopedic implant infection by <i>Staphylococcus aureus</i> and supports fracture healing.

Johnson Christopher T CT Wroe James A JA Agarwal Rachit R Martin Karen E KE Guldberg Robert E RE Donlan Rodney M RM Westblade Lars F LF García Andrés J AJ

Proceedings of the National Academy of Sciences of the United States of America 20180514 22

Orthopedic implant infections are a significant clinical problem, with current therapies limited to surgical debridement and systemic antibiotic regimens. Lysostaphin is a bacteriolytic enzyme with high antistaphylococcal activity. We engineered a lysostaphin-delivering injectable PEG hydrogel to treat <i>Staphylococcus aureus</i> infections in bone fractures. The injectable hydrogel formulation adheres to exposed tissue and fracture surfaces, ensuring efficient, local delivery of lysostaphin. L ...[more]

PMID: 29760099

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Project description:BACKGROUND:This study assessed incidence, risk factors, and outcomes of Staphylococcus aureus infections (SAI) following endoprosthetic hip or knee, or spine surgeries. METHODS:Adult patients with at least one of the selected surgeries from 2012 to 2015 captured in a German sickness fund database were included. SAI were identified using S. aureus-specific ICD-10 codes. Patients with certain prior surgeries and infections were excluded. Cumulative incidence and incidence density of post-surgical SAI were assessed. Risk factors, mortality, healthcare resource utilization and direct costs were compared between SAI and non-SAI groups using multivariable analyses over the 1 year follow-up. RESULTS:Overall, 74,327 patients who underwent a knee (28.6%), hip (39.6%), or spine surgery (31.8%) were included. The majority were female (61.58%), with a mean age of 69.59 years and a mean Charlson Comorbidity Index (CCI) of 2.3. Overall, 1.92% of observed patients (20.20 SAI per 1000 person-years (PY)) experienced a SAI within 1 year of index hospitalization. Knee surgeries were associated with lower SAI risk compared with hip surgeries (Hazard Ratio (HR) = 0.8; p = 0.024), whereas spine surgeries did not differ significantly from hip surgeries. Compared with non-SAI group, the SAI group had on average 4.4 times the number of hospitalizations (3.1 vs. 0.7) and 7.7 times the number of hospital days (53.5 vs. 6.9) excluding the index hospitalization (p < 0.001). One year post-orthopedic mortality was 22.38% in the SAI and 5.31% in the non-SAI group (p < 0.001). The total medical costs were significantly higher in the SAI group compared to non-SAI group (42,834€ vs. 13,781€; p < 0.001). Adjusting for confounders, the SAI group had nearly 2 times the all-cause direct healthcare costs (exp(b) = 1.9; p < 0.001); and 1.72 times higher risk of death (HR = 1.72; p < 0.001). CONCLUSIONS:SAI risk after orthopedic surgeries persists and is associated with significant economic burden and risk of mortality. Hence, risk reduction and prevention methods are of utmost importance.

Dataset Information

Hydrogel delivery of lysostaphin eliminates orthopedic implant infection by Staphylococcus aureus and supports fracture healing.

Publications

Hydrogel delivery of lysostaphin eliminates orthopedic implant infection by <i>Staphylococcus aureus</i> and supports fracture healing.

Similar Datasets

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