Therapeutics and delivery vehicles for local treatment of osteomyelitis

Abstract

Osteomyelitis, or the infection of the bone, presents a major complication in orthopedics and may lead to prolonged hospital visits, implant failure, and in more extreme cases, amputation of affected limbs. Typical treatment for this disease involves surgical debridement followed by long‐term, systemic antibiotic administration, which contributes to the development of antibiotic‐resistant bacteria and has limited ability to eradicate challenging biofilm‐forming pathogens including Staphylococcus aureus—the most common cause of osteomyelitis. Local delivery of high doses of antibiotics via traditional bone cement can reduce systemic side effects of an antibiotic. Nonetheless, growing concerns over burst release (then subtherapeutic dose) of antibiotics, along with microbial colonization of the nondegradable cement biomaterial, further exacerbate antibiotic resistance and highlight the need to engineer alternative antimicrobial therapeutics and local delivery vehicles with increased efficacy against, in particular, biofilm‐forming, antibiotic‐resistant bacteria. Furthermore, limited guidance exists regarding both standardized formulation protocols and validated assays to predict efficacy of a therapeutic against multiple strains of bacteria. Ideally, antimicrobial strategies would be highly specific while exhibiting a broad spectrum of bactericidal activity. With a focus on S. aureus infection, this review addresses the efficacy of novel therapeutics and local delivery vehicles, as alternatives to the traditional antibiotic regimens. The aim of this review is to discuss these components with regards to long bone osteomyelitis and to encourage positive directions for future research efforts.

Silver ion‐doped calcium phosphate‐based bone‐graft substitute eliminates chronic osteomyelitis: An experimental study in animals

“…Acute osteomyelitis can generally be cleared with antibiotics if treated in a timely manner. Chronic osteomyelitis represents a progressive inflammatory process resulting in bone destruction and sequestrum formation 1 . The incidence of chronic osteomyelitis is increasing because of higher frequency of disorders that lead to infection, such as obesity, diabetes mellitus, malignancy, immune defiencies, trauma, and orthopedic surgeries.…”

“…Local delivery of high doses of antibiotics via traditional bone cement can reduce systemic side effects of an antibiotic 12,13 . Nonetheless, disadvantages such as growing concerns over burst release (then subtherapeutic dose) of antibiotics, microbial colonization of the nondegradable cement biomaterial which further exacerbate antibiotic resistance led to the search for degradable alternatives 1,14 . The potential of antibiotic‐eluting, biodegradable, calcium‐based scafolds in chronic osteomyelitis has been long recognized 15 .…”

“…Silver is a good option for a metal‐based therapeutic. As an ionic form, it has exhibited cytocompatibility, efficacy against planktonic and sessile bacteria, and bactericidal activity against methicillin‐susceptible Staphylococcus aureus and methicillin‐resistant Staphylococcus aureus (MRSA) strains 1 . The clinical incidence of silver resistant bacteria remains low because silver, unlike common antibiotics, activates multiple mechanisms and hits different targets within the bacterial cells 18 .…”

Diflunisal‐loaded poly(propylene sulfide) nanoparticles decrease S. aureus‐mediated bone destruction during osteomyelitis

“…Although nanoparticle accumulation has not been extensively studied in the context of osteomyelitis, effective treatment of bone infection with systemically administered nanoparticles has been reported 23,26 . Delivery of antimicrobial compounds using locally administered nanoparticles has also been investigated both in vitro 14,38 and in vivo, 39–41 but systemic delivery of nanoparticles capable of carrying hydrophobic drugs is under‐investigated in osteomyelitis. Delivery of diflunisal using nanoparticles may provide effective therapy and limit potential complications associated with avascular local delivery devices.…”

“…Although nanoparticle accumulation has not been extensively studied in the context of osteomyelitis, effective treatment of bone infection with systemically administered nanoparticles has been reported. 23,26 Delivery of antimicrobial compounds using locally administered nanoparticles has also been investigated both in vitro 14,38 and in vivo, [39][40][41] Compared to free-drug administration via intravenous or oral delivery routes, synthetic nanoparticles offer the potential to accumulate and release loaded compounds at target sites. [14][15][16][17][18] As described by the EPR effect, both tumors and inflammation result in enhanced vascular permeability allowing for extravasation of nanoparticles.…”