Chitosan coating to enhance the therapeutic efficacy of calcium sulfate-based antibiotic therapy in the treatment of chronic osteomyelitis

Beenken, Karen E.; Smith, J. Keaton; Skinner, Robert A.; McLaren, Sandra G.; Bellamy, William; Gruenwald, Maike; Spencer, Horace J.; Jennings, Jessica Amber; Haggard, Warren O.; Smeltzer, Mark S.

doi:10.1177/0885328214535452

Cited by 47 publications

(47 citation statements)

References 68 publications

(87 reference statements)

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“…These factors emphasize the need to develop methods to enhance delivery of vancomycin to bone in the treatment of osteomyelitis. One way to accomplish this is to employ local antibiotic delivery, which while useful suffers from inherent limitations, not the least being the ability to gain direct access to the infection site (8)(9)(10)(11)(12)(13)(14)(15)(16). Thus, one of the major challenges to improve therapeutic outcomes for osteomyelitis patients is to develop methods for the systemic deliv-ery of vancomycin, and potentially other antibiotics, in sufficient concentrations to achieve the desired therapeutic effect.…”

mentioning

confidence: 99%

Novel Bone-Targeting Agent for Enhanced Delivery of Vancomycin to Bone

Albayati

Sunkara

Schmidt-Malan

et al. 2016

Antimicrob Agents Chemother

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hWe examined the pharmacokinetic properties of vancomycin conjugated to a bone-targeting agent (BT) with high affinity for hydroxyapatite after systemic intravenous administration. The results confirm enhanced persistence of BT-vancomycin in plasma and enhanced accumulation in bone relative to vancomycin. This suggests that BT-vancomycin may be a potential carrier for the systemic targeted delivery of vancomycin in the treatment of bone infections, potentially reducing the reliance on surgical debridement to achieve the desired therapeutic outcome. Osteomyelitis is defined as any inflammatory process in bone, the most common cause of which is infection. Although many bacterial pathogens have been associated with osteomyelitis, Staphylococcus aureus is the predominant cause and the pathogen responsible for the most serious forms of bone infection (1). Given the increasing prevalence of S. aureus strains resistant to methicillin (2), vancomycin remains the most commonly used antibiotic for the treatment of these infections (3). While true vancomycin resistance is rare, S. aureus strains with reduced susceptibility are common and often arise as a consequence of the prolonged periods of vancomycin therapy required to treat bone infections (1, 4). Vancomycin acts by inhibiting bacterial cell wall biosynthesis (5, 6) and is a large hydrophilic molecule that has limited penetration into bone and therefore low bone bioavailability when administered systemically (7). These factors emphasize the need to develop methods to enhance delivery of vancomycin to bone in the treatment of osteomyelitis. One way to accomplish this is to employ local antibiotic delivery, which while useful suffers from inherent limitations, not the least being the ability to gain direct access to the infection site (8-16). Thus, one of the major challenges to improve therapeutic outcomes for osteomyelitis patients is to develop methods for the systemic deliv-

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mentioning

confidence: 99%

Novel Bone-Targeting Agent for Enhanced Delivery of Vancomycin to Bone

Albayati

Sunkara

Schmidt-Malan

et al. 2016

Antimicrob Agents Chemother

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“…Diffusion and elution were not characterized over a 48-hour time course, but reduction in bacterial attachment confirmed release of active antibiotics observed in our in vitro studies. Future evaluations using coatings on orthopaedic implants in more complex models should follow our studies to confirm efficacy in clinically relevant orthopaedic applications [8,10,62].…”

Section: Discussionmentioning

confidence: 93%

“…Four replicates in each group were chosen for the elution and turbidity study based on activity and elution data from previous studies of calcium sulfate and chitosan-based drug delivery systems [8,50] Based on a power analysis using SigmaPlot (Systat Software, Inc, San Jose, CA, USA), it was determined that a number of 4 provides approximately 80% power to detect a difference in proportions of solutions with complete growth inhibition of 84% at a significance level of 5% and provides over 80% power to detect differences in concentration of 15 lg/mL or more in antibiotic concentration given the standard deviation of approximately 5 lg/mL. Three coupons in each group for the zone of inhibition study gives over 80% power to detect differences in clearing zones of 3 mm or more given the approximate SD of 0.9 mm.…”

Section: Discussionmentioning

confidence: 99%

“…Antiinfective biomaterials are increasingly used as an adjunctive strategy to prevent implanted biomaterial infections and to inhibit biofilm-forming microorganisms [13,27,44,49,55,63,64]. Commonly used local antibiotic delivery systems range from antibiotic-loaded bone cement to calcium-based drug delivery systems to sprinkling antibiotics within the wound site [8,24,40,42]. Recent developments have been focused on degradable and customizable local delivery strategies to ensure coverage of the wound, effective antibiotic elution, and minimization of secondary procedures [15,30,60].…”

Section: Introductionmentioning

confidence: 99%

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Novel Antibiotic-loaded Point-of-care Implant Coating Inhibits Biofilm

Jennings

Carpenter

Troxel

et al. 2015

Clinical Orthopaedics &Amp; Related Research

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Background Orthopaedic biomaterials are susceptible to biofilm formation. A novel lipid-based material has been developed that may be loaded with antibiotics and applied as an implant coating at point of care. However, this material has not been evaluated for antibiotic elution, biofilm inhibition, or in vivo efficacy.Questions/purposes (1) Do antibiotic-loaded coatings inhibit biofilm formation? (2) Is the coating effective in preventing biofilm in vivo? Methods Purified phosphatidylcholine was mixed with 25% amikacin or vancomycin or a combination of 12.5% of both. A 7-day elution study for coated titanium and stainless steel coupons was followed by turbidity and zone of inhibition assays against Staphylococcus aureus and Pseudomonas aeruginosa. Coupons were inoculated with bacteria and incubated 24 hours (N = 4 for each test group). Microscopic images of biofilm were obtained. After washing and vortexing, attached bacteria were counted. A mouse biofilm model was modified to include coated and uncoated stainless steel wires inserted into the lumens of catheters inoculated with a mixture of S aureus or P aeruginosa. Colony-forming unit counts (N = 10) and scanning electron microscopy imaging of implants were used to determine antimicrobial activity. Results Active antibiotics with colony inhibition effects were eluted for up to 6 days. Antibiotic-loaded coatings inhibited biofilm formation on in vitro coupons (log-fold reductions of 4.3 ± 0.4 in S aureus and 3.1 ± 0 for P aeruginosa in phosphatidylcholine-only coatings, 5.6 ± 0 for S aureus and 3.1 ± 0 for P aeruginosa for combinationloaded coatings, 5.5 ± 0.3 for S aureus in vancomycinloaded coatings, and 3.1 ± 0 for P aeruginosa for amikacinloaded coatings (p \ 0.001 for all comparisons of antibiotic-loaded coatings against uncoated controls for both bacterial strains, p \ 0.001 for comparison of antibioticloaded coatings against phosphatidylcholine only for S aureus, p = 0.54 for comparison of vancomycin versus combination coating in S aureus, P = 0.99 for comparison of antibiotic-and unloaded phosphatidylcholine coatings in P aeruginosa). Similarly, antibiotic-loaded coatings reduced attachment of bacteria to wires in vivo (log-fold

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“…In fact, it is not clear if the concentrations used in our study can be achieved at the site of infection when antibiotics are administered systemically. However, antibiotics are also often administered locally using some form of matrix-based delivery system, particularly in orthopedic medicine (11,(23)(24)(25). We also recently described a novel nanocage-based system for the targeted local delivery of daptomycin (26).…”

Section: Figmentioning

confidence: 99%

Evaluation of Antibiotics Active against Methicillin-Resistant Staphylococcus aureus Based on Activity in an Established Biofilm

Meeker

Beenken

Mills

et al. 2016

Antimicrob Agents Chemother

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We used in vitro and in vivo models of catheter-associated biofilm formation to compare the relative activity of antibiotics effective against methicillin-resistant Staphylococcus aureus (MRSA) in the specific context of an established biofilm. The results demonstrated that, under in vitro conditions, daptomycin and ceftaroline exhibited comparable activity relative to each other and greater activity than vancomycin, telavancin, oritavancin, dalbavancin, or tigecycline. This was true when assessed using established biofilms formed by the USA300 methicillin-resistant strain LAC and the USA200 methicillin-sensitive strain UAMS-1. Oxacillin exhibited greater activity against UAMS-1 than LAC, as would be expected, since LAC is an MRSA strain. However, the activity of oxacillin was less than that of daptomycin and ceftaroline even against UAMS-1. Among the lipoglycopeptides, telavancin exhibited the greatest overall activity. Specifically, telavancin exhibited greater activity than oritavancin or dalbavancin when tested against biofilms formed by LAC and was the only lipoglycopeptide capable of reducing the number of viable bacteria below the limit of detection. With biofilms formed by UAMS-1, telavancin and dalbavancin exhibited comparable activity relative to each other and greater activity than oritavancin. Importantly, ceftaroline was the only antibiotic that exhibited greater activity than vancomycin when tested in vivo in a murine model of catheter-associated biofilm formation. These results emphasize the need to consider antibiotics other than vancomycin, most notably, ceftaroline, for the treatment of biofilm-associated S. aureus infections, including by the matrix-based antibiotic delivery methods often employed for local antibiotic delivery in the treatment of these infections.

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Chitosan coating to enhance the therapeutic efficacy of calcium sulfate-based antibiotic therapy in the treatment of chronic osteomyelitis

Cited by 47 publications

References 68 publications

Novel Bone-Targeting Agent for Enhanced Delivery of Vancomycin to Bone

Novel Bone-Targeting Agent for Enhanced Delivery of Vancomycin to Bone

Novel Antibiotic-loaded Point-of-care Implant Coating Inhibits Biofilm

Evaluation of Antibiotics Active against Methicillin-Resistant Staphylococcus aureus Based on Activity in an Established Biofilm

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