Summary: Infection in orthopaedic syok patients is a common duduk perkara associated with significant financial and psychosocial costs, and increased morbidity. This review outlines technologies to diagnose and prevent orthopaedic infection, examines implant-related infection and its management, and discusses the treatment of post-traumatic osteomyelitis. The gold standard for diagnosing infection has a number of disadvantages, and thus new technologies to diagnose infection are being explored, including multilocus polymerase chain reaction with electrospray ionization-mass spectrometry and optical imaging. Numerous strategies have been employed to prevent orthopaedic infection, including use of antibiotic-impregnated implant coatings and cement; however, further research is required to optimize these technologies. Biofilm formation on orthopaedic implants is attributed to the glycocalyx-mediated surface mode of bacterial growth and is usually treated through a secondary surgery involving irrigation, debridement and the appropriate use of antibiotics, or complete removal of the infected implant. Research into the treatment of post-traumatic osteomyelitis has focused on developing an optimal local antibiotic delivery vehicle, such as antibiotic-impregnated polymethylmethacrylate (PMMA) cement beads or bioabsorbable bone substitute (BBS) delivery systems. As these new technologies to diagnose, prevent and treat orthopaedic infection advance, the incidence of infection will decrease and patient care will be optimized.
INTRODUCTION
The incidence of infection in orthopaedic syok patients is high, ranging from 5% to 10% depending on the location and severity of the injury, and the type of fracture. Infection is associated with significant financial and psychosocial costs, and greater morbidity, and thus acquiring a thorough understanding of infection is warranted. This review will outline new technologies to diagnose and prevent orthopaedic infection, examine infection related to implants and how it can be managed, and finally it will discuss the treatment of post-traumatic osteomyelitis.
There is no standardized protocol for diagnosing infection, and as such diagnosis tends to be based upon clinical evaluation, laboratory examinations, imaging modalities, and intraoperative cultures. The gold standard for diagnosing infection has typically been cultivation and subsequent identification of a bacterial sample from the wound. However, this method is tissue-consumptive, is inaccurate in the assessment of the entire wound, introduces the potential for specimen contamination, and can take up to 3 days before useful information becomes available. As such, new diagnostic methods have been developed to increase specificity and sensitivity, and allow for determination of the spatial distribution of the bacteria.
Stucken et al conducted a retrospective review of 95 nonunions in 93 patients and found that preoperative serum tests, in particular the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels, were the best independent predictors of infection. On the other hand, nuclear imaging scans were the most expensive and least valuable tests for diagnosing infection, with a high level of specificity (92%) but low sensitivity (19%).
A new technology that is gaining traction is multilocus polymerase chain reaction with electrospray ionization-mass spectrometry (PCR/ESI-MS), which uses a single assay for the broad-range amplification and precise identification of many bacterial isolates, in much less time than traditional sequencing. This system amplifies most species within a sample and then meticulously determines the molecular mass of the PCR products, allowing for the unambiguous derivation of base compositions, which are in turn compared with a database for organism identification.
Bacterial imaging is a new technology, which could elucidate the spatial distribution of bacteria in an infection. Optical imaging of the bacteria in vivo is performed with either genetically modified bacteria encoded to emit photons, which are then quantified using a photon-counting camera or through use of a molecular probe with a fluorescent reporter group. Leevy et al used this second method to introduce a near-infrared (NIR) fluorescent probe into the bloodstream of mice that had been injected with Gram-positive Staphylococcus aureus, and significant accumulation at the site of the bacterial infection was noted after 18 hours. Through implementation of these new technologies in a clinical setting, there will be improved identification and localization of bacterial infections.
Implant infection after total joint replacement (TJR) is a common mode of failure. Numerous strategies have been employed to prevent implant infection, including implant surface fabrication and incorporation of antibiotics into the implant devices. Antibiotic-impregnated cement is commonly used to help prevent infections, but is limited to use with cemented implants or as a temporary spacer. One of the limitations of commonly used antibiotic-loaded implant coatings like hydroxyapatite (HA) is burst drug release because of the weak binding between loaded drugs and the HA surface. Recent developments in material science have shown that implants with biodegradable polymer coatings can be used as controllable means to deliver antibiotics in a sustained fashion, thereby minimizing any local or systemic toxicity associated with high fluctuating antibiotic concentrations. Song et al recently described the use of coaxial PCLCol/PVAHA nanofibers (NFs) as a nanofabricated implant coating. A sustained release (approximately 1 month) of doxycycline (Doxy) was observed when Doxy was doped in the PCLCol/PVAHA nanofibers. It was found that the Doxy-doped PCLCol/PVAHA nanofiber coated rods were sufficient to inhibit S. aureus infection and enhance osseointegration up to 8 weeks in a rat tibia implantation model. These results are promising, but require further validation in prospective clinical trials.
Another strategy is to coat intramedullary (IM) rods with antibiotic polymethylmethacrylate (PMMA) cement, which has the added benefit of increasing stability and may improve outcomes for infected nonunions of long bones. Yet the major problems with PMMA cement are burst drug release and low release capacity. Efforts have been made to enhance antibiotic elution from PMMA cement by incorporating silica or other fillers. However, the improvement in drug release was limited and was usually accompanied by a loss in mechanical strength, which is critical for weight-bearing bone cement. Song et al developed a calcium polyphosphate gel (CPP gel)-formulated PMMA cement, which significantly reduced the initial burst release and extended the release of loaded vancomycin and tobramycin up to 25 weeks. The improved antibiotic release was because of the strong ionic binding of the embedded drugs with the calcium polyphosphate gel, in addition to the greater hydrophilicity and porosity of the PMMA cement. Furthermore, incorporation of the calcium polyphosphate gel had no significant detrimental effects on the mechanical properties of the PMMA cement. More work is required to better understand infection as it pertains to indications, techniques, dosage, types of antibiotics, elution properties, and pharmacokinetics in the clinical setting. Further research into alternatives to PMMA for the delivery of antibiotics is critical for the improved prevention and treatment of orthopaedic infection.
A typical bacterial count for a fast flowing alpine stream at altitude is approximately 1-5 bacteria per cubic centimeter. However, for a square centimeter of the rock over which the stream flows, this count is 1 × 106 bacteria per cm2. This was the observation made by Bill Costerton, a young graduate student whose professional career was spent elucidating the phenomenon of bacterial adhesion. His ruthenium red electron microscopic techniques provided evidence for the ubiquitous bacterial glycocalyx and its role in enabling adhesive growth. His classic 1978 Scientific American article on “How Bacteria Stick” was read by orthopaedic surgeon Anthony Gristina who, years prior, had published an article on the facilitation of bacterial growth by vitallium wire in culture media. Following a telephone conversation and subsequent meeting, they embarked on a collaboration that resulted in numerous publications documenting the prevalence of the glycocalyceal mode of bacterial growth in a myriad of clinical settings, including orthopaedic implant infection and osteomyelitis. Gristina and Costerton frequently cited the work of Ronald Gibbons. This investigator detailed the relationship between Streptococcus salivarius and its enzymes, including glucosyltransferase, which polymerized glucose into long-chain carbohydrates called glucan. This molecule had a strong attachment to the enamel surface of the tooth. Over time, a syncytium of entrapped bacteria, built with a network of glucan fibres, firmly bound itself to the tooth surface. Within this syncytium, the acid products of bacterial metabolism were sequestered and acted to dissolve pits in the surface enamel of the tooth. These events elucidated the pathophysiology of dental caries and this syncytium or “plaque” was the first biofilm to be described in any detail.
Inherent to the aforementioned concepts was the recognition that medical therapy alone was minimally effective at resolving implant related infection. The foreign body effect, which was so elegantly and simply elucidated in the experiments of Elek and Conen now could be attributed to the glycocalyx-mediated surface mode of bacterial growth, where white cell engulfment and antibiotic effectiveness were compromised. The treatment classification devised by Cierny et al recognized the limitations of traditional medical treatment and was based on staging and surgical resection with reconstruction of the resulting bone and soft tissue defect (analogous to that utilized for tumor resections).
Hudson et al illustrated the ability of Staphylococcus to reside intracellularly in an osteoblast. Ellington et al showed that when killed, these cells could relinquish their Staphylococci to the surrounding tissue, making them free to grow and divide again, and thereby providing an explanation for clinical quiescence/osteomyelitic indolence. Subsequent work by Gonsoves et al demonstrated that the use of poly(lactic-co-glyc0l1c acid) (PLGA)-based nanoparticle carrier molecules complexed to the antibiotic nafcillin was effective in allowing access to the intracellular space, whereas nafcillin alone was not. The authors published experimental evidence supportive of this therapeutic approach in the osteoblast with internalized Staphylococci.
The phenomenon of quorum sensing was first described by Nealson and Hastings when recounting the commensal relationship between Vibrio fischeri and the Hawaiian Bobtail squid in 1979. Bonnie Bassler has furthermore shown that the principle of quorum sensing holds promise for therapeutics. Her team of researchers illustrated the use of analogues to bacterial sensor molecules in a rat model. Interestingly, this strategy did not entail the killing of bacteria, but rather a “behavior modification,” which brought about the switching off of microbial virulence, making this line of research very promising.
Three factors have increased the frequency and severity of hardware-related infections in the modern orthopaedic practice. First, the virulence of the bacterial landscape has significantly changed, to the point where methicillin-resistant S. aureus (MRSA), vancomycin-resistant Enterococcus (VRE), and extended-spectrum beta-lactamase (ESBL) organisms are now commonplace. Secondly, the age and associated comorbidities of the fracture population has also increased significantly, including diabetes, morbid obesity, immunosuppression, kidney disease and other chronic medical conditions. Third, as implants and techniques improve, a greater number of fractures are treated operatively. An increasing number of hardware-related infections are therefore encountered, especially in revision practices. Fortunately, there is also increasing information on optimizing the management, eradicating (or controlling) infection, and promoting union in these patients.
Treatment starts with a thorough assessment of the factors that have been shown to affect prognosis and guide treatment. The type and sensitivity of the infecting organism (preferably obtained from deep or intraoperative cultures) is important. Puig-Verdié et al demonstrated that sonication of an orthopaedic implant removed for infection increased the sensitivity of cultures from 67% to 90%. This will guide antibiotic treatment and even surgical tactics as it is easier to retain an implant infected with a single low-grade organism than one afflicted with highly virulent (ie, MRSA) or multiple organisms. Secondly, the stability of the implanted hardware is critical. Berkes et al examined 121 cases of infection following fracture fixation and showed that if the implant was stable, it could be salvaged 71% of the time with irrigation, debridement, and appropriate antibiotics, such that union was obtained with the implant remaining in situ. Unstable or loose fixation must be removed and stability provided in another fashion (ie, external fixation). Third, the soft-tissue envelope must be evaluated as healthy coverage is a critical aspect of infection control and is often a problem, especially after radical debridement of the tibia.
The health of the patient (or “host”) should also be evaluated. Often, there are remediable factors that can be corrected prior to surgical intervention. For example, surgical failure rates are higher in diabetic patients with poor glycemic control, and smokers fare worse in most reviews of fracture treatment. In a randomized clinical trial, Lindström et al34 showed that a preoperative smoking cessation course for orthopaedic patients who smoked reduced postoperative complications from 41% to 21%, a relative risk reduction of 49%. Thus, there is evidence that optimizing the “host health” prior to intervention can improve results.
Finally, adherence to evidence-based principles can make a difference to patients. Copley et al showed that application of evidence-based clinical guidelines at their institution improved the care of children with osteomyelitis through quicker diagnosis, more appropriate antibiotics, shorter admission times, and a lower readmission rate following their implementation. Hardware-related infection is a difficult clinical problem; the practicing orthopaedic surgeon needs to use high-quality evidence to optimize treatment for their patients.
Osteomyelitis is characterized by infection of the bone and marrow, and most commonly occurs secondary to a contiguous focus of infection; namely after trauma, reconstructive bone surgery, or insertion of an implant. Osteomyelitis is difficult to treat, as in its chronic form it causes devascularization of the periosteal and endosteal arterial systems, resulting in necrosis of the bone and limiting the amount of antibiotic that can be delivered systemically. Development of a biofilm is another defining feature of chronic osteomyelitis as it increases the resistance of bacterial organisms to conventional systemic antibiotic therapy and contributes to the recurrent nature of osteomyelitis. An integrated therapeutic treatment approach is therefore required, which includes surgical debridement of all nonviable and infected tissues followed by antimicrobial therapy, the gold standard for which includes local antibiotic delivery and subsequent systemic antibiotic therapy.
There has been a great deal of research into developing an optimal local antibiotic delivery system that would provide a concentration of antibiotic at the site of infection that is sufficient to overcome remaining pathogens, while reducing the risk of systemic toxicity. Antibiotic-impregnated PMMA cement beads are used most commonly to fill the dead space resulting from debridement.6 However, there are a number of disadvantages to this system, including inefficient release of antibiotic and thus a potential to act as a foreign body for bacterial colonization as levels of eluted antibiotic fall, and the need for a revision surgery to remove the PMMA beads. Beenken et al incorporated xylitol into daptomycin-impregnated PMMA to increase the porosity of PMMA and enhance its elution profile. It was found that 3 weeks after placement in vivo, therapeutically relevant levels of daptomycin were still recoverable from the xylitol-daptomycin treatment group, while not from PMMA beads containing daptomycin alone, which confirms that incorporation of xylitol is able to prolong the release of antibiotic thereby enhancing the elution profile of PMMA. However, use of PMMA as an antibiotic delivery system still has the drawback of necessitating a secondary surgery, and as such there is growing interest in developing a biodegradable delivery system.
Jia et al explored using borate glass combined with chitosan as a local antibiotic delivery vehicle as borate glass is a bone substitute material that rapidly converts to HA and has osteoconductive capabilities, while chitosan is a natural-based polymer that can be used for the controlled release of drugs. Following impregnation with teicoplanin, this composite was implanted into a rabbit model for osteomyelitis. At 3 months, this composite was found to yield significantly lower radiological and histological scores when compared with rabbits treated with either additive alone, and the pellets were seen to completely convert to HA. In a randomized trial by McKee et al, a bioabsorbable bone substitute (BBS) delivery vehicle that included tobramycin-impregnated medical-grade alpha-hemihydrate calcium sulfate resulted in the eradication of infection in 86% of patients; a value equivalent to that achieved when using antibiotic-impregnated PMMA beads.40 The bioabsorbable bone substitute system furthermore underwent complete pellet resorption in an average of 8 weeks with new bone growth exhibited, indicating osteoconductive capabilities, and resulting in a decreased rate of secondary surgical procedures and their associated complications.
Orthopaedic infection is a costly condition for which there is minimal research progress and few innovations that change clinical practice and outcomes. Antibiotic-loaded implant coatings and local antibiotic delivery systems have been explored as means to prevent and treat infection; however, further research is required to optimize these systems. If infection is indeed suspected, then it can be diagnosed through a number of promising new technologies, such as PCR/ESI-MS and bacterial imaging. Following confirmation of infection, treatment may include a secondary surgery and use of appropriate antibiotics. With the improvement of these technologies to diagnose, prevent and treat orthopaedic infection, the incidence of infection will decrease and patient care will be optimized.
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*Source : Journal of Orthopaedic Trauma: Volume 29
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