Amenable comorbidities are reversed and/or minimized (host optimization) before surgical intervention. Thereafter, soft tissues are resected to supple, well-perfused margins. Bone is tangentially excised until exposed surfaces bleed in a uniform, haversian (cortical) or sinusoidal (cancellous) pattern (ie, the paprika sign).40 All foreign bodies and surgical implants are removed, the wound is lavaged of debris, and the surgical field is prepared for closure (double setup).
Multiple tissue samples, not wound swabs, are collected from deep wound surfaces (eg, loculated fluids, reactive granulations, foreign bodies), and specimens are set up for culture and sensitivity testing for aerobic and anaerobic bacteria. When orthopaedic implants, foreign bodies, and/or sequestra are retrieved, quantitative cultures following sonication sequencing23 and/or quantitative polymerase chain reaction pyrosequencing24 are performed to identify the microbial populations within the biofilm colony. Frozensection biopsies confirm the presence of inflammation, validate the need for fungal and/or mycobacterial culture setups in the laboratory, and usually rule out the presence of pathologic states mimicking infection (eg, neoplasms, pseudotumors, autoimmune disorders, dysplasias).
Following débridement, each reconstruction must take into consideration (1) the advantages and disadvantages of attempting to supplement the existing soft-tissue envelope, (2) the mechanical integrity of the remaining bony segments, and (3) how best to manage residual dead space (Table 1: VI, A, 2; VI, B, 4;VIII, A, 3; and XI). Wound closure by any means is imperative when vital structures (eg, vessels, nerves, tendons) are exposed and/or when the reconstruction of choice (ie, surgical implants, allografts) requires a clean surgical field to succeed. Closure is safeguarded by the systemic administration of pathogen-specific antibiotics and the elimination of dead space by either the apposition of viable tissues (eg, soft-tissue transpositions and/or transfers; acute limb shortening) or the implantation of an antibiotic depot (eg, antibiotic beads, sponges, or spacers). In a closed wound, the high concentrations of antibiotics created by a space-filling, high-dose antibiotic depot will eliminate all remaining phenotypes from the biofilm colony. Furthermore, antibiotic-impregnated polymethylmethacrylate (PMMA) beads and/or spacers will maintain any workable dead space needed for future use (known as the spacer effect).41 Following wound healing and patient resuscitation, the depot is removed, the “space” reclaimed, and reconstruction performed as a clean surgical procedure.21,31 When flaps fail and/or circumstances preclude their use, bone transport,32–34 combined methods of limb shortening/lengthening,25 and negative pressure-assisted closures are valuable tools.42
A live, clean wound will heal by secondary intention and thereby circumvent the need for restoration of the soft-tissue envelope. For these reasons, open reconstruction techniques, such as open cancellous bone grafting,19 acute limb shortening,25 vascularized bone flaps, and open methods of bone transport,43 can be used, but they have several potential disadvantages. The components used in the reconstruction must also be live (Table 1: VI, A, 2 and XI); the open wound has a prolonged exposure to contamination and/or superinfection; external devices are the fixation of choice; and the surface area for bone grafting is limited. Nevertheless, despite these limitations, open techniques can be useful in carefully selected patients, particularly when a salvage solution is needed.
Local depot delivery of antibiotics to infected wounds has become a critical component of musculoskeletal infection management in the last two decades. By this method, one can achieve local antibiotic concentrations several-fold greater than both bacterial minimum inhibitory concentrations and the levels safely attainable with systemic administration, with negligible systemic toxicity. The elution rates and ultimate local concentrations of antibiotics are dependent on the delivery vehicle, surface area of the delivery vehicle, type and concentration of antibiotics, fluid presence and fluid turnover rate, time in vivo, and permanence or bioabsorbable nature of the vehicle.44 Antibiotic-impregnated PMMA is versatile and can be used to make spacers for prosthetic joint resections or segmental bone defects and beads to increase surface area and resultant elution rate of antibiotics, as well as to coat intramedullary implants when needed to simultaneously treat osteomyelitis and bony instability. These techniques have been widely adopted and have proven utility in the management of a variety of deep, fracture- and implant-related infections.44–46 Sustained supratherapeutic local antimicrobial concentrations exceeding 6 weeks in duration are routinely achievable with these delivery methods.47 The so-called membrane technique of PMMA spacer placement, followed by subsequent spacer removal and bone grafting, has demonstrated both good clinical success and the bioactivity of the biologic and osteoinductive layer that forms around such spacers.46
More recently, several bioabsorbable delivery vehicles have become available with favorable elution characteristics and putatively similar efficacy. These delivery vehicles have the added benefits of obviating the need for removal and, in many cases, of being osteoconductive and/or osteoinductive.26,48,49 Direct and minimal carrier application of local antibiotics is now being investigated via several modalities, although the duration of effect persistence will ostensibly be decreased.50–54 Local adjuvants therefore represent an increasingly critical component of the physician's armamentarium in the fight against chronic musculoskeletal infections. As increasingly biocompatible and bioabsorbable technologies continue to develop and greater supporting evidence becomes available, a shift away from PMMAbased therapy appears both inevitable and advisable in the absence of planned secondary procedures for reinstrumentation, bone grafting, or soft-tissue reconstruction. As infection eradication rates improve, additional focus may be warranted in assessing and minimizing local tissue toxicity because of supratherapeutic antibiotic concentrations in search of the optimal balance between infection eradication and osseous union or soft-tissue healing.55,56
There is now evidence that local depot antibiotic delivery has equivalent or better efficacy with regard to infection prevention or eradication than does systemic therapy.57 However, the efficacy of combining these antibiotic treatment modalities appears to be additive, if not synergistic;45 particularly in the setting of chronic infection, primary treatment success rates are not yet high enough, and long-term recidivism is too frequent, to routinely eschew systemic in favor of local therapy. A general guideline for the duration of systemic antimicrobial therapy is 6 weeks for most patients, with extension to 3 months for patients with retained infected implants,58 although extended suppressive therapy to fracture union, followed by subsequent implant removal, has been advocated.59
High-volume, low-pressure irrigation remains a critical component of the débridement process. Intermediate- and high-pressure lavage systems are readily available and widely used, but they decrease wound bioburden and contamination at the expense of host tissue damage, which may be responsible for the reported bacterial rebound phenomenon observed following their use.60 The addition of detergents, antiseptics, or antimicrobials to irrigant solutions has not consistently been demonstrated to improve outcomes.61
Negative-pressure wound therapy with reticulated open-cell foam dressings (NPWT/ROCF) is an important wound adjunct that increases patient comfort and care convenience while improving local circulation, accelerating granulation tissue formation, and increasing edema clearance, but it only variably affects bacterial bioburden and may be more effective at preventing than treating infections.62 Silver nanoparticulate-impregnated ROCF and infusion of antiseptics have recently become commonplace supplements to NPWT, but to date, clinical evidence of efficacy is limited.
Part of the reason for the current difficulty with antibiotic resistance is attributable to our misunderstanding of what an antibiotic is and what it imposes on the bacterial genome. This is exemplified by the declaration credited to the surgeon general William Stewart in 1967: “The time has come to close the book on infectious diseases. We have basically wiped out infection in the United States.”63 Antibiotics came to be (and, at the time of this writing, continue to be) used as a feed additive in subtherapeutic doses in the dairy and livestock industries. In fact, 70% of all antibiotics used in the United States are administered in this fashion.64 What has been little appreciated is the resilience and adaptability of the bacterial genome, which were, from an evolutionary viewpoint, minimally thwarted by the widespread use of antibiotics. Currently, penicillin is as effective against acute hematogenous osteomyelitis as is a placebo, whereas, shortly after its introduction in World War II, penicillin was nearly 100% curative of this disease.65 As Nobel laureate Christian de Duve points out, “Given an adequate supply of nutrients, a single bacterial cell can generate 280,000 billion individuals (‘generations’) in a single day.”66 This rapid duplication and exchange of bacterial genetic material represents a continuous probing of the environment by the bacterial genome for selective advantage by spontaneous mutations. In 70 years, penicillin has gone from wonder drug to placebo. The message is clear: indiscriminate use of antibiotics facilitates the emergence of resistance.
To compound matters, the development of new antibiotics by the pharmaceutical industry has been slow. No fundamentally new class of antibiotics has been brought to market since the 1970s. Thus, clinicians need to be resourceful in the use of the tools available. Buchholz and Engelbrecht67 as well as Klemm27 were early proponents of local antibiotic elution from impregnated PMMA. Theoretically, when the local antibiotic concentration is kept high (ie, levels well above minimal bacterial concentration levels of relevant pathogens), bacterial growth can be eliminated; low systemic concentrations associated with this strategy minimize the likelihood of adverse systemic effects.28 The concept has been successfully employed and incorporated in several treatment regimens.68 One problem is the permanence of methylmethacrylate as a carrier. Frequently, this warrants additional surgery for removal. Hence, the use of a resorbable carrier has appeal. Recent clinical reports of calcium sulfate, polylactic acid, and calcium phosphate, as well as other bioabsorbable “carrier” materials,69–72 are encouraging but limited. One study involved the use of tobramycin with calcium sulfate carrier pellets in 25 patients with chronic osteomyelitis following débridement, with eradication reported in 92%.26 A second study on the use of either vancomycin or tobramycin in calcium sulfate carrier pellets in six patients with chronic osteomyelitis following débridement showed no infection and progressive bony healing in five of the six at a mean follow-up of 28 months.73
Another aspect of musculoskeletal infection that has prompted research includes bacterial adhesion. This feature is thought to be pivotal to the chronicity of osteomyelitis as well as the “foreign body effect.” Elek and Conen74 elegantly demonstrated a 10,000-fold enhancement of the “minimal pustule forming dose” of staphylococcus in human skin by the presence of a single silk suture. Gibbons and Socransky75 elucidated the complex affinity of Streptococcus mutans for the enamel of the human tooth by identifying specific enzymes that break down sucrose and polymerize the component glucose into insoluble glucan. The specific affinity of glucan for the enamel of the tooth provides the “glue” that binds that surface to bacterial microcolonies (ie, plaque) acting as a syncytium. Bacterial metabolism generates the acid responsible for enamel dissolution and formation of dental caries. By understanding the complex relationships between glucan, the bacteria, plaque formation, and acid generation, the pathophysiology of dental caries and gum disease was elucidated, and appropriate therapies were designed to greatly lower their incidence and severity. Paralleling these insights, Gristina and Costerton76 and others28 have shown the role of the glycocalyx and biofilm in adhesion to dead bone and implants and its pivotal role in the production of and persistence of musculoskeletal infection.
One of the major obstacles to basic research in this area is the fact that standard bacterial culture (eg, Columbia blood agar plate) selects for bacteria devoid of glycocalyceal coats. The free-floating, “naked” bacteria seen in pure laboratory cultures are not the same as their glycocalyceal-coated cousins adhering to bone or implant in an area of osteomyelitic focus. Hence, new bacterial culture techniques that select for and preserve the glycocalyx and, therefore, the bacteria in their adherent mode, need to be developed, standardized, and used as a system for assessing the effectiveness of therapeutic agents.77
New concepts of bacterial syncytia and quorum sensing may help provide a way of averting the elaboration of virulent factors characteristic of fulminance.78 That is, by preventing the ability of resident bacteria to “sense a quorum,” it may be possible to keep the resident bacteria in their peaceful commensal state and thereby avoid the confrontation with host white cells and the elaboration of tissue-destructive lysosomal enzymes and free radicals, which characterize a full-blown local tissue infection. Investigation of quorumsensing signal molecules or their receptors, and understanding their interactions, may provide novel strategies for treatment and prevention. 78,79 The development of appropriate models to enable standardization and assessment of these parameters is in its infancy.80
Other aspects of microbial pathophysiology that provide potentially fertile areas for research are bacterial viruses, or bacteriophages. One of the largest centers investigating this approach is the Eliava Institute of Bacteriophage, Microbiology and Virology in Tbilisi, Georgia. Currently, treatment using bacteriophages is not approved in countries other than Georgia. The FDA obstacles against the use of the methodology are significant. Although employing bacteriophages is theoretically appealing, the level of evidence for efficacious treatment of chronic infection using this approach has been low. One compelling and potentially promising line of inquiry is the multidisci-plinary approach combining phage research with nanotechnology.85 Phage is species- and strain-specific; tying that specificity to a drug is appealing and at least theoretically offers the potential for a unique class of therapeutic drugs.
Understanding the fundamental aspects of the pathophysiology of microbial musculoskeletal infection is necessary for the development of efficacious treatment strategies. Despite new and exciting lines of inquiry, it is still very early in this process.
The treatment of chronic, posttraumatic osteomyelitis in the extremity is challenging and often requires a commitment by both the patient and the treating surgeon toward complete (ie, wide) resection of the involved bone. Reconstruction can be safely performed by a variety of methods; however, proper staging and patient selection remain critical to a successful outcome. Consensus regarding the use of depot-delivered antibiotics, as well as the timing and duration of systemic antibiotics, is lacking and deserving of further study.
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