Sustained release of antibiotics from injectable and thermally responsive polypeptide depots (original) (raw)
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In vitro pharmacokinetics of antibiotic release from locally implantable materials
Journal of Orthopaedic Research, 1993
Local deposition of antibiotics has became increasingly popular in the management of open fractures or osteomyelitis, and several substances have been employed as the vehicle for delivery. Although the elution characteristics of some substances have been documented, a comparative study of the characteristics of the commonly used substances could establish the clinical indications for particular vehicles. Cylindrical pellets of uniform size (6 x 4 mm) were prepared from bone graft (BG), demineralized bone matrix (DBM), plaster of Paris (POP), or polymethylmethacrylate (PMMA), with 25 mg of tobramycidg of substance in each pellet. The pellets were suspended in phosphate buffered saline, and the antibiotic concentration in the buffer was determined at various time intervals by an enzyme immunoassay. BG and DBM eluted 70 and 45% of their antibiotic load by 24 h, and negligible amounts were detected at 1 week; POP released 17% of its load by 24 h, with trace amounts detected at 3 weeks; and PMMA eluted 7% at 24 h, with trace amounts detected for as long as 14 days. These findings suggest that the optimal vehicle for local deposition of antibiotic depends on the clinical setting. BG and DBM may be best employed when brief antibiotic coverage is required (as for acute contaminated open fractures), whereas POP and PMMA may be better suited for long-term coverage (such as for established osteomyelitis).
Newer methods of antimicrobial delivery for bone and joint infections
Instructional Course Lectures, 2003
The advantages of systemic therapy include the ability to deliver antibiotics to areas that cannot be reached with topical therapy, the choice of a large selection of agents directed against the pathogens encountered in orthopaedic infections, and arrest or eradication of infection in most cases (in conjunction with adequate débridement). Disadvantages include the potential for toxicity from systemic agents, difficulty in achieving high concentrations of antimicrobial agents at the site of infection, and problems with compliance. To combat these disadvantages, newer methods for the delivery of antimicrobial agents have been investigated. Some of these newer methods include new formulations of antimicrobial agents to decrease systemic toxicity and improved methods for delivering local antimicrobial therapy.
Biodegradable vs non-biodegradable antibiotic delivery devices in the treatment of osteomyelitis
Expert Opinion on Drug Delivery, 2013
Introduction: Chronic osteomyelitis, or bone infection, is a major worldwide cause of morbidity and mortality, as it is exceptionally hard to treat due to patient and pathogen-associated factors. Successful treatment requires surgical debridement together with long-term, high antibiotic concentrations that are best achieved by local delivery devices, either made of degradable or non-degradable materials. Areas covered: Non-degradable delivery devices are frequently constituted by polymethylmethacrylate-based carriers. Drawbacks are the need to remove the carrier (as the carrier itself may provide a substratum for bacterial colonization), inefficient release kinetics and incompatibility with certain antibiotics. These drawbacks have led to the quest for degradable alternatives, but also devices made of biodegradable calcium sulphate, collagen sponges, calcium phosphate or polylactic acids have their specific disadvantages. Expert opinion: Antibiotic treatment of osteomyelitis with the current degradable and non-degradable delivery devices is effective in the majority of cases. Degradable carriers have an advantage over non-degradable carriers that they do not require surgical removal. Synthetic poly(trimethylene carbonate) may be preferred in the future over currently approved lactic/ glycolic acids, because it does not yield acidic degradation products. Moreover, degradable poly(trimethylene carbonate) yields a zero-order release kinetics that may not stimulate development of antibiotic-resistant bacterial strains due to the absence of long-term, low-concentration tail-release.
Local Delivery of Antibiotics in the Surgical Treatment of Bone Infections
Thorough surgical debridement and intelligent use of antibiotics are key factors in the treatment of implant-associated bone infections and osteomyelitis. The local use of antibiotics is intended to achieve high concentrations of the antimicrobial agents in the wound for eradication of the bacteria or at least to reduce the bacterial load combined with low systemic concentrations to eliminate systemic side effects. Moreover, it enables access to necrotic and devascularized infected bone fragments in the wound which cannot be reached by intravenous therapy. The intention of this article is to review different antibiotics and carrier systems to provide a practical guideline for the intraoperative use of these agents for the surgeon. Gentamicin, tobra-mycin, and vancomycin are the most frequently used antibiotics in septic orthopedic surgery. However, only rifampicin offers the combination of antibiofilm activity and intracellular activity against Staphylococcus aureus, however, its use in combination with poly-methylmethacrylate (PMMA) is compromised due to the interference with PMMA polymerization. In general, there are resorbable and nonresorbable carriers which offer different antibiotic loading options. PMMA is the most common nonresorbable carrier for which commercial products, such as beads or antibiotic-loaded spacer cements are available. Different antibiotic loadings for handmade PMMA delivery systems have been described in the literature including antifungal agents. Resorbable carrier systems lead to a material-tissue interaction with subsequent degradation of the material and do not require removal by an additional surgical procedure. Collagen-based, calcium sulfate-based, and calcium phosphate-based materials are typical biodegradable carriers that can be used for the local delivery of antibiotics.
Journal of Orthopaedic Research, 1993
Acute and chronic osteomyelitis can be difficult to treat by conventional means. Current methods of treatment involve the use of systemic antibiotics, the local implantation of non-degradable drug carriers, and surgical dkbridement. Each method has specific drawbacks. We report on the use of a new controlled release system utilizing gentamicin and bioerodible, biocompatible polymers (polyanhydrides) designed for drug delivery applications for the treatment of clinical osteomyelitis. We compared this system's ability to reduce bacterial levels in infected bone with that of conventional non-degradable delivery systems based on polymethylmethacrylate (PMMA) and gentamicin. Polyanhydride copolymers of bis-carboxyphenoxypropane and sebacic acid P loaded with gentamicin sulfate and PMMA/gentamicin matrices were implanted in the long bones of Sprague-Dawley rats infected with a strain of Staphylococcus aureus. After 3 weeks of implantation, the polymeric delivery devices were removed and quantitative cultures were used to determine bacterial levels in bone. The polyanhydride/gentamicin matrices demonstrated significant degradation over the 3 week implantation period. Levels of bacteria, measured in colony forming units, were significantly lower in bone implanted with the polyanhydride/gentamicin release system than in long bones of control animals without an implant (p < 0.01), of animals with a polyanhydride polymer implant alone (p < 0.01), and of animals with a PMMAigentamicin implant (p = 0.03). Bioerodible polyanhydrides show promise as a new treatment modality for infections in bone. Osteomyelitis, in both its acute and chronic forms, remains difficult to treat (29). In acute osteomyelitis, a rapidly progressing infection of bone takes place,
Journal of Biomedical Materials Research Part A, 2006
The use of local antibiotics from a biodegradable implant is appealing concept for treatment of chronic osteomyelitis. Our aim was to develop a new drug delivery system based on controlled ciprofloxacin release from poly(d/l-lactide). Cylindrical composite pellets (1.0 ϫ 0.9 mm) were manufactured from bioabsorbable poly(d/l-lactide) matrix and ciprofloxacin (7.4 wt %). In vitro studies were carried out to delineate the release profile of the antibiotic and to verify its antimicrobial activity by means of MIC testing. A long-term study in rabbits was performed to validate the release of ciprofloxacin from the composite in vivo. Therapeutic level of ciprofloxacin (Ͼ2 g/mL) was maintained between 60 and 300 days and the concentration remained below the potentially detrimental level of 20 g/mL in vitro. The released ciprofloxacin had retained its antimicrobial properties against common pathogens. In an exploratory long-term in vivo study with three rabbits, cip-rofloxacin could not be detected from the serum after moderate filling (160 mg) of the tibia (follow-up 168 days), whereas after high dosing (a total dose of 1000 mg in both tibias) ciprofloxacin was found temporarily at low serum concentrations (14-34 ng/mL) during the follow-up of 300 days. The bone concentrations of ciprofloxacin could be measured in all samples at 168 and 300 days. The tested copolylactide matrix seems to be a promising option in selection of resorbable carriers for sustained release of antibiotics, but the composite needs modifications to promote ciprofloxacin release during the first 60 days of implantation.
Evaluating antibiotic release profiles as a function of polymer coating formulation - biomed 2011
Biomedical sciences instrumentation, 2011
To address persistent 1-3% infection rates associated with orthopedic implant surgeries, the next generation of bone graft filler materials will no longer pharmacologically silent being endowed as a local drug delivery vehicle to maintain locally high levels of antibiotic. Bone allograft material, used as a structural support to fill the avascular spaces in bone defects, revision surgeries, and traumatic injury, can be used as a drug depot to provide effective antibiotic delivery over the orthopedically relevant six-to-eight week time period. Passive antibiotic coatings, applied in the surgical theater, are quickly depleted from the site, inadvertently promoting the development of drug-resistance. Alternatively, many promising controlled-delivery strategies provide an initial burst release of antibiotic within 24 to 72 hours; however, this remains inadequate to combat the onslaught of ubiquitous pathogens that can persist only to reemerge once drug concentrations fall below the mini...
Journal of Pharmaceutical Innovation, 2015
Purpose Antibiotic-loaded polymethylmethacrylate has been conventionally used for osteomyelitis treatment, but it requires a second operation for removal. This study aimed to develop and examine the properties of a novel vancomycin-loaded composite fabricated from biodegradable poly(ε-caprolactone)/ poly(hydroxybutyrate-co-hydroxyvalerate)/biphasic calcium phosphate (PCL/PHBV/BCP) for chronic methicillin-resistant Staphylococcus aureus (MRSA) osteomyelitis. Materials and methods The drug-loaded composite was developed using a solvent casting method and fabricated into four formulations: FV1, FV2, FV3, and FV4. The physicochemical characteristics and osteoblast biocompatibility were evaluated. In addition, the drug-release profile and anti-MRSA activity were examined. Results Vancomycin conserved its antibiotic property and did not form any interactions with the raw materials. A loading efficiency of more than 80 % was achieved with all formulations. FV2, FV3, and FV4 demonstrated cumulative release of more than 90 % over a couple of months. The bactericidal property was assessed to confirm the efficacy of the released vancomycin, and all composites showed antibacterial effects over 28 days. The release kinetics were best-fitted with the Korsmeyer-Peppas model, and Fickian diffusion was the main transport mechanism. A cytotoxicity test was also performed, and all formulations showed more than 80 % osteoblast viability. Conclusions All of the present in vitro results indicated the effectiveness of the new materials as local vancomycin carriers. In vivo animal models should be evaluated to confirm the efficacy for use in humans in the future.
European Journal of Pharmaceutics and Biopharmaceutics, 2015
A new device for local delivery of antibiotics is presented, with potential use as a drug-eluting fixation pin for orthopedic applications. The implant consists of a stainless steel hollow tubular reservoir packed with the desired antibiotic. Release takes place through several orifices previously drilled in the reservoir wall, a process that does not compromise the mechanical properties required for the implant. Depending on the antibiotic chosen and the number of orifices, the release profile can be tailored from a rapid release of the load (ca. 20 h) to a combination of rapid initial release and slower, sustained release for a longer period of time (ca. 200 h). An excellent bactericidal action is obtained, with 4-log reductions achieved in as little as 2 h, and total bacterial eradication in 8 h using 6-pinholed implants filled with cefazolin.