Calcium Phosphate Spacers for the Local Delivery of Sitafloxacin and Rifampin to Treat Orthopedic Infections: Efficacy and Proof of Concept in a Mouse Model of Single-Stage Revision of Device-Associated Osteomyelitis

Abstract

Osteomyelitis is a chronic bone infection that is often treated with adjuvant antibiotic-impregnated poly(methyl methacrylate) (PMMA) cement spacers in multi-staged revisions. However, failure rates remain substantial due to recurrence of infection, which is attributed to the poor performance of the PMMA cement as a drug release device. Hence, the objective of this study was to design and evaluate a bioresorbable calcium phosphate scaffold (CaPS) for sustained antimicrobial drug release and investigate its efficacy in a murine model of femoral implant-associated osteomyelitis. Incorporating rifampin and sitafloxacin, which are effective against bacterial phenotypes responsible for bacterial persistence, into 3D-printed CaPS coated with poly(lactic co-glycolic) acid, achieved controlled release for up to two weeks. Implantation into the murine infection model resulted in decreased bacterial colonization rates at 3- and 10-weeks post-revision for the 3D printed CaPS in comparison to gentamicin-laden PMMA. Furthermore, a significant increase in bone formation was observed for 3D printed CaPS incorporated with rifampin at 3 and 10 weeks. The results of this study demonstrate that osteoconductive 3D printed CaPS incorporated with antimicrobials demonstrate more efficacious bacterial colonization outcomes and bone growth in a single-stage revision in comparison to gentamicin-laden PMMA requiring a two-stage revision.

Therapeutics and delivery vehicles for local treatment of osteomyelitis

“…In the past, these cements were largely nondegradable which impeded bone healing and necessitated additional surgeries. Recent modifications of bone cement have improved degradation rates and enabled them to serve as local drug carriers for antibiotics such as teicoplanin, 105 vancomycin, 113,114 gentamicin, 115,116 and doxycycline, 117 along with antimicrobial peptides, 60,64 and other multifactor therapies. [118][119][120][121] Nonetheless, empirical use of high-dose, antibiotic-loaded bone cement (ALBC) typically elicits a burst release (then subtherapeutic dose), contributing to antibiotic resistance.…”

“…[118][119][120][121] Nonetheless, empirical use of high-dose, antibiotic-loaded bone cement (ALBC) typically elicits a burst release (then subtherapeutic dose), contributing to antibiotic resistance. 122 For enhanced antimicrobial properties and extended duration of drug elution, new formulations of bone cements are being engineered including core materials of calcium sulfate, 120 calcium phosphate, 115,118 PMMA, 113 and even bioactive glasses. 119,121 PMMA has been the most commonly utilized and modified bone cement.…”

Developments in Antibiotic-Eluting Scaffolds for the Treatment of Osteomyelitis

“…Antibiotic-eluting scaffolds can be produced using this method if a thermostable drug such as tobramycin is used [43]. Many of these materials have been shown to be efficacious in both in vitro and in vivo models of osteomyelitis [43,44]. In the latter study, 3D-printed resorbable calcium phosphate scaffolds containing sitafloxacin and rifampin outperformed gentamicin-laden PMMA when bacterial colonization outcomes and bone growth were assessed [44].…”

“…Many of these materials have been shown to be efficacious in both in vitro and in vivo models of osteomyelitis [43,44]. In the latter study, 3D-printed resorbable calcium phosphate scaffolds containing sitafloxacin and rifampin outperformed gentamicin-laden PMMA when bacterial colonization outcomes and bone growth were assessed [44]. Another benefit of 3D-printing is that it allows for the fabrication of patient-specific designs which completely fill the bone void.…”

Evolving concepts in bone infection: redefining “biofilm”, “acute vs. chronic osteomyelitis”, “the immune proteome” and “local antibiotic therapy”

“…In a follow-up study, 3D-printed calcium phosphate scaffolds (CaPS) with incorporated sitafloxacin and rifampin were implemented into this single-stage revision mouse model of femoral implant-associated osteomyelitis. 266 A dual coating of PLGA enhanced the mechanical strength and elution kinetics of the scaffolds. Drug-release kinetics exhibited a biphasic release in which an initial burst release was observed within the first 48 h followed by sustained zero-order release, which maintained the local concentration at ~ 900× the minimum inhibitory concentration of each drug.…”