A carrier that might solve this problem is bone itself.
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The concept of impregnating bone with antibiotics is not a new idea. De Grood was the first to report on mixing penicillin with cancellous bone when filling bone defects in . Two patients were successfully treated for residual cavities due to osteomyelitis.
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Although this idea seemed promising, it was not until the mid 80's that further reports have been presented at different scientific meetings . Since then,. Despite the increasing popularity of this treatment option, generalized conclusions still cannot be drawn from the existing literature due to differences of bone and antibiotics used, impregnation method and dose, laboratory circumstances, or clinical indications. Hence, the aim of the present work was to review the literature regarding this topic and shed some light onto the choice of bone and antibiotics, manufacturing details, and clinical experience.
A systematic literature search was carried out through Medline until Only articles about orthopaedic and trauma surgery were evaluated except for those deriving from other surgical facilities but providing new information to this topic. From the initially retrieved studies, a further search was made throughout the bibliography of the identified publications for inclusion of as many studies as possible. Only English publications were included into the review process. Reviews and case reports were excluded from the study unless they provided new information which was not reported in the other identified publications.
A total of 35 studies could be identified . Based on the experience gained from aseptic surgery, the great majority of the studies report on the use of cancellous bone grafts Table 1. Due to the known osteoconductive properties, cancellous bone carries a lower, theoretical risk of sequester formation compared with cortical bone which is of great importance in the treatment of bone infections. Depending on the surgical indication itself, infection localization, size of bone defect, and presence of an internal bone bank, either autologous or allogenous bone graft might be used.
Generally, there are three types of bone allograft available: i fresh or fresh-frozen, ii freeze-dried, and iii demineralised freeze-dried. Despite the wide use of all bone graft types, to the best of our knowledge, there exists no information whether there is a difference regarding the pharmacokinetic properties among the groups. Moreover, it is unclear whether the manual fragmentation of the graft before or after the impregnation process might also have a theoretical impact on the pharmacokinetic properties of AIBGs.
Knowledge about the pharmacokinetic properties of bone itself but also about the possible influence of the incorporated antibiotics on the physical properties of the bone is an essential premise before clinical use of antibiotic-loaded. Theoretically, all antibiotics might be appropriate for bone impregnation as long as they are eluted to sufficient amounts.
In contrast to acrylic bone cement, where the polymerization heat might lead to an inactivation of the incorporated agents , the physical properties of the antibiotics are not influenced by the impregnation process at the site of AIBGs. Although no specific guidelines exist, the drug choice should be generally made in accordance with the sensitivity profile of the causative pathogen organism if preoperatively known. Otherwise, a calculated local antibiotic therapy should be applied, which should be effective against frequent pathogen organisms in orthopaedic surgery e.
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Literature data report mostly on monoantibiotic-loading. More detailed information about this topic is discussed later in the paper. Regarding the impregnation process, several methods are described in the literature Table 1. Some authors incorporate the antibiotics by manual mixing, whereas others place the bone grafts into antibiotic-containing solutions for various time periods.
In some cases, the harvested bone graft has been specially prepared before antibiotic impregnation . Which of the methods leads to the highest antibiotic impregnation remains, however, unknown.
Beside the aforementioned methods, single reports have indicated that iontophoresis might also be a novel method for incorporating antibiotics into bone [17, 24, 27]. Under experimental conditions, high levels of gentamicin and flucloxacillin could be initially released, whereas sufficient amounts could be eluted for a period of up to two weeks and the antibiotics have remained biologically active .
Some authors define the impregnation amount per femoral head or grams of bone, whereas others determine this according to the bone volume Table 1. This makes a comparison of the literature extremely difficult. Intraoperatively, harvested bone may greatly vary with regard to weight or cannot be compared with a femoral head depending on the harvesting area e. Therefore, for future studies it might be advisable to define the antibiotic amounts in accordance to the volume of bone used which is easier to determine intraoperatively than the weight. Knowledge about the elution kinetics of AIBG's is an indispensable premise for the successful planning and treatment ofbone and joint infections.
Numerous publications provide information about this topic, mostly consisting of in vitro and animal studies. For other local antibiotic-impregnated carriers, such as bone cement, gentamicin is regarded to be the antibiotic with the best pharmacokinetic properties . However, in case of AIBG's, other antibiotics have been proven to be superior.
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In an in vitro study, Winkler and colleagues could demonstrate that vancomycin is significantly better eluted from cancellous bone in comparison with tobramycin . Table 1: Literature review about antibiotic-impregnated bone grafts with specific attention on types of bone graft, antibiotics, and impregnation details. Allende et al. Michalak et al. Winkler et al. Wits0 et al. Kanellakopoulou et al.
While allografts impregnated with fusidic acid could release high concentrations for the first 20 days, those loaded with teicoplanin showed low concentrations after the first 4 days. The antibiotic concentrations eluted from antibiotic-impregnated bone grafts vastly exceed those from other local antibiotic-loaded carriers [11, 21, 34, 36]. The release of tobramycin was significantly lower than that of vancomycin. Buttaro et al. For the same surgical indication, Winkler et al.
Although high local concentrations are eligible for a successful eradication of the infection, it should be born mind that these concentrations might be associated with an accompanying toxic effect on cells. High concentrations of vancomycin have been reported to substantially reduce osteoblast replication and even cause cell death [42, 43]. In case of a biantibiotic combination, a synergistic effect has been described between aminoglycosides and glycopep-tides when eluted from acrylic bone cement . This effect might appear for a single or both antibiotic groups depending on the antibiotic ratio .
To our knowledge, there exists only a single study which tried to investigate this effect at the site of AIBGs. Whether this effect might vary depending on the antibiotic ratio of these agents or also counts for other antibiotic groups remains unclear. Rhyu et al. The authors could demonstrate a significant difference regarding the amount of the antibiotic uptake between demineralized and undem-ineralized bone for the former.
Moreover, the addition of blood significantly slowed down the antibiotic elution over the first 7 days in vitro. During a bone-grafting operation, there is usually a delay between procurement of the graft and its implantation. The delay might range from a few minutes to several hours.
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This raises several practical questions concerning the harmful effects of delay on eventual osteogenesis: for how long a graft can be left without being damaged, the optimal environment for the graft, and the deleterious effects of antibiotics on the graft and graft bed. Gray and Elves tried to answer these questions in a rat study . The authors could demonstrate that the uptake of the used antibiotics had significant differences depending on the medium used as well as the storage period.
Moreover, the use of any of the antibiotic preparations led to a highly significant drop in the relative index of osteogenesis compared with that of untreated controls. Similar findings could be shown in the histological examination ofthese grafts, indicating a decrease in the osteogenesis rate; however, this effect was antibiotic dose-dependent. On the contrary, Petri could not determine any statistical difference of the osteogenic activity between antibiotic-supplemented bone grafts and their controls in a pig model .
In this study, demineralized bone had a higher antibiotic uptake than the mineralized allografts in both the control the antibiotic-loaded group. Furthermore, demineralized grafts stimulated more bone growth than the mineralized allografts in the antibiotic-loaded group. In a dog model, Lindsey and colleagues could not observe any histological, microradiographical, or biomechanical statistical differences after implantation of tobramycin-loaded bone grafts compared with a control group .
Serum tobramycin levels at 24 and 48 h were found to be below. Similar to that, Buttaro et al. Compared with a control group where bone allografts without antibiotics have been used, the authors could not determine any statistical differences between both groups regarding the radiographical bone healing, the rate of graft incorporation, or other similar histopathological or immunohistochemical parameters. On the contrary, tetracycline deposited locally was shown by Gudmundson to markedly inhibit bone graft incorporation . In clinical practise, AIBGs might be used in the prophylaxis as well as in the treatment of bone and joint infections Table 2.
The prophylactic use of antibiotic-loaded bone grafts for prevention of wound infections after orthopaedic surgery has been only sparsely discussed in the literature. To our knowledge, there exist only two studies which tried to investigate this prophylactic effect on the postoperative infection rate. Khoo et al. There were no early infections, whereas two late infections were presumed to be hematogenous at a mean followup of 51 months. Regarding the therapeutic use of AIBGs, some very encouraging results have been recently published about vancomycin-loaded bone grafts in the treatment of late infections after total hip replacement.
In their latest report, Winkler et al. After a two-stage revision in 29 cases, Buttaro et al. The success of their treatment led them to make the proposal that vancomycin-impregnated bone might also be used as antibiotic prophylaxis in patients undergoing revision THA for aseptic loosening. Similar favourable results have also been reported by English and colleagues after the use of vancomycin-, gentamicin-, or flucloxacillin-loaded bone grafts .
In another work by Buttaro et al. Both patients suffered from periprosthetic fractures that had to be revised.