Simulated large joint fluid model for evaluating intra-articular antibiotic delivery systems: initial evaluation using antibiotic-loaded calcium sulfate beads.

Introduction: Local antimicrobial delivery via calcium sulfate (CaSO 4 ) beads is used as an adjunctive treatment for periprosthetic joint infection. There is limited clinical information describing the performance of antimicrobial-loaded CaSO 4 (ALCS) in large-scale applications. We developed a simulated large joint model to study properties of eluting ALCS. Methods: The in vitro testing platform was an adapted standardized model for tribological testing of prosthetic total hips and total knees (ASTM F732). The model was 70 mL total fluid volume, 25 % bovine serum, and 75 % phosphate-buffered saline, using ISO standard 14242-1 for human synovial fluid simulation. Four brands of CaSO 4 were evaluated. Each 10 mL of CaSO 4 was loaded with 1.2 grams (g) of tobramycin and 1 g of vancomycin powders. A 35 mL bead volume, equaling 175 beads, of each product was placed in incubated flasks. The test period was 6 weeks with scheduled interval fluid exchanges. Fluid samples were tested for antibiotic and calcium concentrations and pH. Results: Antibiotic elution showed an initial burst on Day 1, followed by a logarithmic reduction over 1 week. Tobramycin fully eluted within 2.5 weeks. Vancomycin showed sustained release over 6 weeks. Calcium ion concentrations were high, with gradual decrease after 3 weeks. All four CaSO 4 products were inherently acidic. Fluid became more acidic with the addition of antibiotics primarily driven by vancomycin. Discussion: Clinicians should be cognizant of tobramycin elution burst with ALCS in large loads. The main driver of acidic pH levels was vancomycin. We propose that joint complications may result from lowered fluid acidity, and we suggest clinical study of synovial pH.

Locally Delivered Nonsteroidal Antiinflammatory Drug: A Potential Option for Heterotopic Ossification Prevention.

Oral nonsteroidal antiinflammatory drugs (NSAIDs) are prescribed for heterotopic ossification prophylaxis following at-risk injuries and procedures. We hypothesized that NSAIDs may be delivered locally in a wound for heterotopic ossification prophylaxis. In in vitro work, we cultured osteoblasts with three commercially available NSAIDs and then measured cell viability and DNA content. Indomethacin caused a 50% decrease in DNA at the lowest dose (0.0001 mM) and the most potent decrease in cell viability (<10% of control at 0.0005 mM). Ketorolac and ibuprofen required 10 times the dose to achieve a comparable decrease (<20% of control at 0.005 mM). In an animal study, 20 rats per treatment group received a full-thickness wound dressed with either saline-moistened gauze, saline-moistened chitosan sponge, or chitosan sponge loaded with indomethacin. After 28 days, we examined the tissue for healing. Wounds exposed to indomethacin loaded sponges demonstrated fewer inflammatory cells. All 20 rats in the indomethacin group had complete epithelial coverage at 28 days. Eighteen (90%) wounds in the saline-chitosan group and 11 (55%) wounds in the saline-gauze group were healed. Locally delivered NSAIDs may be useful for heterotopic ossification prophylaxis due to effects on osteoblast viability and lack of negative effects on wound healing.

Local antibiotic delivery using tailorable chitosan sponges: the future of infection control?

OBJECTIVES: Local antibiotic delivery is a viable and attractive option for preventing infection. Unfortunately, the current options are limited and often necessitate surgical removal. This study evaluates the ability of a biodegradable and biocompatible chitosan sponge to minimize infection by delivering local antibiotics within the wound. METHODS: A complex musculoskeletal wound was created on the hindlimb of goats and contaminated with Pseudomonas aeruginosa (lux) or Staphylococcus aureus (lux) bacteria. These bacteria are genetically engineered to emit photons, allowing for quantification with a photon-counting camera system. The wounds were closed and similarly débrided and irrigated with 9 L normal saline using bulb-syringe irrigation 6 hours after inoculation. Goats were assigned to different treatment groups: a control group with no adjunctive treatment and an experimental group using a chitosan sponge loaded with either amikacin (for wounds contaminated with P. aeruginosa) or vancomycin (for wounds contaminated with S. aureus). The wounds were closed after the procedure and evaluated 48 hours after initial contamination. Serum levels of the antibiotics were also measured at 6, 12, 24, 36, and 42 hours after treatment was initiated. RESULTS: The wounds treated with the antibiotic-loaded chitosan sponge had significantly less bacteria than the untreated wounds (P < 0.05). The highest serum levels were 6 hours after treatment but remained less than 15% of target serum levels for systemic treatment. At study end point, all sponges were between 60% and 100% degraded. CONCLUSIONS: The chitosan sponges are effective delivering the antibiotic and reducing the bacteria within the wounds.

Chitosan sponges to locally deliver amikacin and vancomycin: a pilot in vitro evaluation.

BACKGROUND: Open orthopaedic wounds are ideal sites for infection. Preventing infection in these wounds is critical for reducing patient morbidity and mortality, controlling antimicrobial resistance and lowering the cost of treatment. Localized drug delivery has the potential to overcome the challenges associated with traditional systemic dosing. A degradable, biocompatible polymer sponge (chitosan) that can be loaded with clinician-selected antibiotics at the point of care would provide the patient and clinician with a desirable, adjunctive preventive modality. QUESTIONS/PURPOSES: We asked (1) if an adaptable, porous chitosan matrix could absorb and elute antibiotics for 72 hours for potential use as an adjunctive therapy to débridement and lavage; and (2) if the sponges could elute levels of antibiotic that would inhibit growth of Staphylococcus aureus and Pseudomonas aeruginosa? METHODS: We fabricated a degradable chitosan sponge that can be loaded with antibiotics during a 60-second hydration in drug-containing solution. In vitro evaluation determined amikacin and vancomycin release from chitosan sponges at six time points. Activity tests were used to assess the release of inhibitory levels of amikacin and vancomycin. RESULTS: Amikacin concentration was 881.5 microg/mL after 1 hour with a gradual decline to 13.9 microg/mL after 72 hours. Vancomycin concentration was 1007.4 microg/mL after 1 hour with a decrease to 48.1 microg/mL after 72 hours. Zone of inhibition tests were used to verify inhibitory levels of drug release from chitosan sponges. A turbidity assay testing activity of released amikacin and vancomycin indicated inhibitory levels of elution from the chitosan sponge. CLINICAL RELEVANCE: Chitosan sponges may provide a potential local drug delivery device for preventing musculoskeletal infections.

Chitosan films: a potential local drug delivery system for antibiotics.

Local antibiotic delivery is an emerging area of study designed to provide alternative methods of treatment to clinicians for compromised wound sites where avascular zones can prevent the delivery of antibiotics to the infected tissue. Antibiotic-loaded bone cement is the gold standard for drug-eluting local delivery devices but is not ideal because it requires a removal surgery. Chitosan is a biocompatible, biodegradable polymer that has been used in several different drug delivery applications. We evaluated chitosan as a potential localized drug delivery device. We specifically determined if chitosan could elute antibiotics in an active form that would be efficacious in inhibiting S. aureus growth. Elution of amikacin was 24.67 +/- 2.35 microg/mL (85.68%) after 1 hour with a final cumulative release of 27.31 +/- 2.86 microg/mL (96.23%) after 72 hours. Elution of daptomycin was 10.17 +/- 3.83 microg/mL after 1 hour (31.61% release) and 28.72 +/- 6.80 microg/mL after 72 hours (88.55%). The data from the elution study suggested effective release of amikacin and daptomycin. The activity studies indicated the eluants inhibited the growth of S. aureus. Incorporating antibiotics in chitosan could provide alternative methods of treating musculoskeletal infections.