Treatment of experimental osteomyelitis caused by methicillin-resistant Staphylococcus aureus with a biodegradable system of lactic acid polymer releasing pefloxacin

The concept of local antibiotic delivery via biodegradable bone defect fillers with multifunctional properties for the treatment of bone infections is highly appealing. Fillers can be used to obliterate surgical dead space and to provide targeted local bactericidal concentrations in tissue for extended periods. Eventually, the osteoconductive component of the filler could guide the healing of the bone defect. The present experimental study was carried out to test this concept in a localized Staphylococcus aureus osteomyelitis model in the rabbit (n ‫؍‬ 31). A metaphyseal defect of the tibia was filled with a block of bone cement, followed by insertion of a bacterial inoculum. After removal of the bone cement and surgical debridement at 2 weeks, the defect was filled with a ciprofloxacin-containing (7.6% ؎ 0.1%, by weight) composite (treated-infection group) or with a composite without antibiotic (sham-treated group). Both a positive control group (untreated-infection group) and a negative control group were also produced.

Section: Discussionmentioning

confidence: 99%

Efficacy of Ciprofloxacin-Releasing Bioabsorbable Osteoconductive Bone Defect Filler for Treatment of Experimental Osteomyelitis Due to Staphylococcus aureus

Koort

Mäkinen

Suokas

et al. 2005

“…After overnight growth, an inoculum of 2 ϫ 10 8 CFU/ml was prepared and applied for bacterial challenge. The polymer was prepared as described previously (8) by direct polymerization of lactic acid, with tin(II) octoate used as the catalyst. Ciprofloxacin (Bayer, Leverkusen, Germany) was incorporated at a 1:10 ratio.…”

Section: Methodsmentioning

confidence: 99%

“…They consisted of polymethylmethacrylate beads that release gentamicin locally. The main problem, however, with antibiotic-impregnated bone cement was the need for surgical removal upon the completion of drug release (8). To alleviate this difficulty, biodegradable materials were developed as antibiotic carriers.…”

mentioning

confidence: 99%

“…Intermediate-molecular-weight (26,000) polymers demonstrated better properties, releasing ciprofloxacin for almost 100 days and at levels higher than the levels released from low-and high-molecular-mass polymers. The successful management of experimental osteomyelitis caused by methicillin-resistant Staphylococcus aureus was achieved by the local application of a PLA that releases pefloxacin (8).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Local Treatment of Experimental Pseudomonas aeruginosa Osteomyelitis with a Biodegradable Dilactide Polymer Releasing Ciprofloxacin

Kanellakopoulou

Thivaios

Kolia

et al. 2008

A biodegradable system of poly-D,L-dilactide releasing ciprofloxacin was assessed in a Pseudomonas aeruginosa osteomyelitis model after inoculation of the test pathogen into the left tibia of 76 New Zealand White rabbits; 31 were controls (group A), and 45 were implanted with the polymer at the infection site (group B). The rabbits were killed on a weekly basis, and cancellous bone was harvested for histopathology and for estimation of bacterial growth and the concentrations of ciprofloxacin. Tibial X ray was performed immediately before the animals were killed. The total number of fistulas with purulent discharge that developed after inoculation of the pathogen was counted, and fistulas with purulent discharge were found in 16 animals in group A (51.6%) and 3 animals in group B (6.7%) (P < 0.0001). The animals in group A had a profound loss of body weight compared to the animals in group B. The main radiological finding was the presence of sequestra in 25 animals (80.6%) in group A and 6 animals in group B (13.3%) (P < 0.0001). The bacterial load in group B was significantly reduced compared to that in group A, possibly due to the prolonged local antibiotic release at concentrations exceeding even 80 times the MIC for the test pathogen. The histology of animals killed after week 49 revealed a mild inflammatory reaction accompanied by diffuse fibrosis and new bone formation in group A animals and the presence of small polymer particles in group B animals. It is concluded that the system described achieved eradication of the pathogen, accompanied by clinical and radiologically confirmed benefits, so this treatment may be a candidate for the management of difficult orthopedic infections.

“…Carriers for local delivery of antimicrobials have been developed, attempting to provide locally high concentrations of antibiotics (5). Some newly developed biodegradable carriers have been shown to be very potent for the eradication of experimental osteomyelitis (6,7). The semihydrate form of calcium sulfate (CaSO 4 ), commonly known as plaster of Paris, may be applied as a biodegradable system for local drug delivery.…”

mentioning

confidence: 99%

In Vitro Elution of Daptomycin by a Synthetic Crystallic Semihydrate Form of Calcium Sulfate, Stimulan

Kanellakopoulou¹,

Panagopoulos²,

Giannitsioti³

et al. 2009

A synthetic crystallic semihydrate form of calcium sulfate, Stimulan, was evaluated as a biodegradable carrier for the daily in vitro elution of daptomycin. Daptomycin and Stimulan were admixed at a ratio of 95:5. Elution lasted for 28 days. Eluted concentrations peaked on days 1 and 11, when the mean values were 1,320.1 and 949.2 g/ml, respectively. The lowest eluted concentration was detected on day 28. These results support the application of the system described in experimental models of osteomyelitis.Chronic osteomyelitis is an infection difficult to treat due both to multidrug resistance of common pathogens and to poor penetration of antibiotics into bone (16). Carriers for local delivery of antimicrobials have been developed, attempting to provide locally high concentrations of antibiotics (5). Some newly developed biodegradable carriers have been shown to be very potent for the eradication of experimental osteomyelitis (6, 7). The semihydrate form of calcium sulfate (CaSO 4 ), commonly known as plaster of Paris, may be applied as a biodegradable system for local drug delivery. It has been used for decades to fill bone cavities resulting from disease, trauma, or surgery (11). It was recently shown to be potent in vitro for the release of vancomycin, teicoplanin, gentamicin, and clindamycin (15). The antimicrobial applied in such an elution system should be active against the most commonly involved pathogens of chronic bone infections, namely, methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-resistant coagulase-negative staphylococci (CoNS) (5). Daptomycin, which is a novel lipopeptide antimicrobial with excellent in vitro activity against these isolates (4), may be a candidate for application in a system for local drug delivery.Stimulan (Biocomposites, Keele Science Park, Staffordshire, United Kingdom) is a synthetic biocompatible bone graft material made of calcium sulfate. It is completely reabsorbed and replaced with new bone. It is synthesized at 100% purity with no traces of potentially toxic impurities that have been associated with naturally occurring mineral sources of calcium sulfate. It has been recently shown by our group that moxifloxacin and fusidic acid may be eluted at high concentrations in vitro by using Stimulan as a carrier (11). The purpose of the present study was to develop an in vitro system for daptomycin elution by using Stimulan as a delivery system. Stimulan was mixed with daptomycin (Novartis, Basel, Switzerland) at a ratio 95:5 to a total weight of 3 g. This was put into sterile vials (160 by 100 mm) and left at room temperature for 15 to 30 min for solidification. Five similar vials were prepared. One milliliter of Mueller-Hinton broth (Trec Diagnostic Systems, West Sussex, United Kingdom) was added over the free surface of each mixture and replaced every 24 h. The vials were incubated at 37°C. On each consecutive day, the eluent was removed, transferred to a sterile plastic tube, and replaced with 1 ml of broth. That procedure was repeated until the optical...