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Diagnosis and Management of Chronic Infection

Forsberg, Jonathan Agner MD; Potter, Benjamin Kyle MD; Cierny, George III MD; Webb, Lawrence MD

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American Academy of Orthopaedic Surgeon: February 2011 - Volume 19 - Issue - p S8-S19
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Most commonly, the term chronic infection in combat-related extremity trauma connotes osteomyelitis. The cause is usually multifactorial but stems from the high-energy nature of the initial injury. Severe open fractures, with varying degrees of gross contamination and tenuous soft-tissue envelopes, are commonplace. Throughout the phases of treatment, considerable efforts are directed toward limb salvage or preservation of residual limb length. Despite the judicious use of internal and external fixation in these patients, the prevalence of osteomyelitis, chronic or otherwise, is relatively high compared with that in civilian trauma patients.1–3

Chronic infection negatively affects several aspects of recovery in this predominately young, active patient population. Severe open fractures, already predisposed to delayed union and nonunion in the absence of complication, become extremely difficult to treat, particularly in the presence of infected internal fixation.2,4 Weight-bearing restrictions affect ambulatory status, functional mobility, and independence. In addition, serial débridement procedures, prolonged hospitalization, and long-term antibiotic therapy are associated with considerable expense, delays in rehabilitation, and loss of productivity.5 Chronic osteomyelitis deserves many of the same clinical considerations as malignant tumors. For example, an accurate tissue (albeit microbiologic) diagnosis guides treatment;6,7 staging carries prognostic value8 and guides treatment;6 and the treatment often involves complete (ie, wide) excision of the involved bone,6,9 followed by complex bony and soft-tissue reconstruction.10


Diagnosing chronic osteomyelitis requires a thorough evaluation. A comprehensive physical examination is necessary to identify any systemic manifestations of infection, although these findings are rare. Focused physical examination of the extremities should also be performed, with an emphasis on the condition of the soft tissues overlying the area of interest. Neurologic and vascular function should be assessed and any deformities (including limb length discrepancies) noted. A thorough social, past medical, and surgical history should be taken to identify any comorbid conditions for the purpose of “describing the host”8 and assigning an accurate physiologic class (A through C).11

Imaging remains the cornerstone of the evaluation process.9 Radiographs provide useful information in terms of bone loss, deformity, and the type and number of implants. Cross-sectional imaging can help identify the presence of an abscess or sequestrum, as well as delineate the extent of medullary edema and, perhaps more importantly, the extent of cortical involvement. Contrast MRI studies should be obtained whenever possible, although these studies demonstrate signal degradation in the presence of internal and/or external fixation, particularly when intramedullary implants are present. For this reason, CT should be considered in this setting. Indium 111-labeled white blood cell scintigraphy is more specific than three-phase technetium-99m bone scan in identifying infection12 and thus is routinely used, not only to help diagnose and localize focal areas of osteomyelitis but also to evaluate response to treatment and, ultimately, the eradication of infection.

Laboratory evaluation, with the exception of microbiologic testing, is often nonspecific. Leukocyte count with differential is usually normal.7 The erythrocyte sedimentation rate, in contrast, is typically elevated but lacks specificity necessary to diagnose extremity infections. C-reactive protein, procalcitonin and other inflammatory cytokine levels are reliably elevated in the setting of acute, posttraumatic extremity infections13,14 but have not been fully evaluated in the setting of chronic osteomyelitis. Liver and kidney function as well as the patient's human immunodeficiency virus status should be assessed. An accurate microbiologic assessment should be performed in all cases and include tissue and fluid cultures for aerobic, anaerobic acid-fast bacilli, and fungal organisms. Gram stain results at the time of initial débridement/biopsy should also be recorded.


Chronic osteomyelitis is a biofilm infection caused by complex colonies of phenotypically diverse microor-ganisms propagating freely within a microbial-based, polysaccharide matrix that provides an immunity to host defenses and systemic concentrations of antimicrobial agents.15,16 Once the biofilm bacteria establish macromolecular attachments to exposed, nonviable surfaces within the wound (ie, tissue, implants, foreign bodies), there is no way to eradicate the disease shy of either killing the host or physically removing the inflammatory nidus, including the colony and all substrate attachments.17 Thorough surgical débridement, a competent host response, and pathogen-specific antimicrobial coverage are, therefore, the essential components of treatment protocols: the débridement removes the biofilm burden while antibiotics rid the host of residual bacterial phenotypes, leaving the host free to heal a live, clean, manageable wound.

Published in 1985, the Cierny-Mader classification of adult osteomyelitis11 is the first system to articulate treatment with the natural history of the disease.6,18 In this system, the biofilm nidus is characterized by one of four anatomic types whose complexity and associated risk for treatment failure escalate numerically (Figure 1). In type I, medullary osteomyelitis (Figure 2), the nidus is endosteal whereas, in type II, superficial osteomyelitis (Figure 3), it is confined to an outer surface of bone that remains exposed, usually unprotected by a refractory, soft-tissue deficit. Localized osteomyelitis, type III, is a well-marginated sequestration of an attached or floating fragment of bone (Figure 4), often combining the features of both types I and II osteomyelitis. In localized osteomyelitis, the entire nidus can be excised with a wide margin without causing the osseous segment to become unstable. In type IV lesions, diffuse osteomyelitis, the process is permeative and involves a segment of bone and/or an entire joint (Figure 5), and it often exhibits characteristics of types I, II and III. Type IV lesions are mechanically unstable either before and/or after a complete and thorough débridement.

Figure 1
Figure 1:
A graphic depiction of the four anatomic types of osteomyelitis, matched with their respective treatment formats and components of their reconstruction. (Adapted from Cierny G III: Chronic osteomyelitis: Results of treatment. Instr Course Lect 1990;39:495–508.)
Figure 2
Figure 2:
Type I osteomyelitis of the distal femur. A, Clinical photograph demonstrating draining fistula (arrow) at the medial knee in a man with an open fracture. He had undergone intramedullary fixation of the femur more than 20 years previously. B, Lateral radiograph demonstrating the healed fracture (white arrow) and possible sequestra distally (black arrows). C, Axial T1-weighted postcontrast magnetic resonance image of the distal femur. The solid arrow indicates the medial sinus. The dashed arrow indicates the medullary nidus.
Figure 3
Figure 3:
Type II osteomyelitis of the distal femur. A, Clinical photograph showing two sinus tracts (black arrows) at the lateral knee, near the tip of a partially failed free flap (white arrow), 2 years after resection and postoperative radiation done for liposarcoma. B, AP radiograph with periosteal new bone formation seen along the lateral femur (arrow). C, A T1-weighted magnetic resonance image depicting no involvement of the medullary contents (arrow), consistent with superficial (type II) osteomyelitis.
Figure 4
Figure 4:
Type III osteomyelitis of the distal tibia. A, Scar contracture, soft-tissue loss, and a draining sinus (arrow) in the distal leg of a 39-year-old diabetic who sustained an open tibial fracture 13 years before presentation. B, AP radiograph demonstrating healed fractures, a distal cortical defect (white arrow), and medullary sequestration proximally (black arrow). C, An inversion recovery magnetic resonance scan depicting the cloaca (white arrow), a medullary nidus (dashed arrow), and a cortical sequestrum (asterisk).
Figure 5
Figure 5:
Type IV osteomyelitis of the distal femur, knee joint, and proximal tibia. A and B, Two different patients, who each presented with a soft-tissue deficit (white arrows) at the knee and/or proximal leg associated with an underlying, diffuse osteomyelitis. C, AP radiograph illustrating deformity with nonunion of a tibial plateau fracture, antibiotic beads (black arrow), and clinician markings at the sites of intended resection (white arrows). D, Lateral radiograph of the second patient showing air within the joint (white arrow) containing a well-fixed, long-stemmed revision total knee prosthesis.

Dr. Cierny or an immediate family member has stock or stock options held in Royer Biomedical and serves as a board member, owner, officer, or committee member of the Limb Lengthening and Reconstruction Society and the Musculoskeletal Infection Society. Dr. Webb or an immediate family member is a member of a speakers' bureau or has made paid presentations on behalf of the Musculoskeletal Transplant Foundation; serves as a paid consultant to Zimmer; has received nonincome support (such as equipment or services), commercially derived honoraria, or other non-research-related funding (such as paid travel) from Synthes, Smith & Nephew, Stryker, and Kinetic Concepts; and serves as a board member, owner, officer, or committee member of the Orthopaedic Trauma Association Southeastern Fracture Consortium. Neither of the following authors or any immediate family member has received anything of value from or owns stock in a commercial company or institution related directly or indirectly to the subject of this article: Dr. Forsberg and Dr. Potter.

Examples for each anatomic type include the following: type I, hematogenous osteomyelitis, or an infected fracture-union following medullary stabilization; type II, full-thickness wounds resulting from pressure or venous stasis ulcers, an infected fracture-union with a soft-tissue deficit, or nonhealing Papineau grafts;19 type III, infected fracture-union with butterflyfragment sequestration or previous plate fixation; and type IV, periprosthetic infections, chronic septic arthritis, or infected nonunions.

In this same system, the patienthost is stratified with regard to his or her physiologic capacity to detour infection, withstand treatment, and/or benefit from cure. A hosts are healthy patients; B hosts are patients who possess comorbidities known to have a detrimental effect on wound healing. The effect can be local (BL), systemic (BS), or combined (BL/S), depending on the circulatory, hematopoietic, metabolic, immunologic, and nutritional status of the patient. Finally, a C host is a patient, compromised or otherwise healthy, who qualifies only for palliative, not curative, treatment (eg, patients who derive no quality-of-life improvement with cure, the morbidity of treatment is excessive, the prognosis is poor, and/or the patient's cooperation is lacking). By combining the anatomic type with the host classification, a clinical stage is designated. For example, a diabetic patient (BS/L host) with an infected nonunion of the distal tibia (type IV osteomyelitis) is designated as a stage IV BS/L osteomyelitis.

Deriving an accurate clinical stage is important for many reasons. It aids in planning the course of treatment, identifies progressive stages of the disease,6 and serves as a prognostic indicator.18 In addition, determination of an accurate clinical stage guides the nature of the surgical procedure20 and is reproducible, so it can be used to compare outcomes in patient and treatment cohorts.8,21


Clinical staging begins with a review of the patient's medical and surgical history and ends with assignment of the treatment format (Table 1). To justify the morbidity and risk of limb salvage, the expected outcome must offer a distinct advantage over amputation or observation alone. If treatment for cure is contraindicated or deemed to be excessive, the patient is classified as a C host, and he or she is offered palliation (eg, incision/drainage, oral antibiotics, ambulatory aides, pain medication). Amputation is indicated when limb salvage and palliation are neither safe nor feasible.

Table 1
Table 1:
Treatment of Adult Chronic Osteomyelitisa
Table 1
Table 1:

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.

Depot and Systemic Delivery of Antibiotics

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.

Future Directions

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 insights into musculoskeletal infection include those of Hudson et al,81 who demonstrated the intracellular presence of staphylococci in osteoblasts. Later work demonstrated that the intracellular staphylococci were potentially viable and “reinfective,” given their “passage” through their host osteoblast.82 Additionally, it was shown that antibiotic “pressure” caused an adaptive change in intracellular staphylococci—that is, the elaboration of an extracellular capsule.83 Pillai et al84 have used nanotechnologic methodologies to couple the antibiotic nafcillin to poly(lactic-co-glycolic acid) and thereby facilitate its ability to penetrate the cell membrane of the osteoblast. Using this Trojan horse strategy, they have reported clearance of intracellular staphylococci.

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.


1. Pollak AN, Jones AL, Castillo RC, Bosse MJ, MacKenzie EJ; LEAP Study Group: The relationship between time to surgical debridement and incidence of infection after open high-energy lower extremity trauma. J Bone Joint Surg Am 2010; 92(1):7-15.
2. Shawen SB, Keeling JJ, Branstetter J, Kirk KL, Ficke JR: The mangled foot and leg: salvage versus amputation. Foot Ankle Clin 2010;15(1):63-75.
3. Mody RM, Zapor M, Hartzell JD, et al: Infectious complications of damage control orthopedics in war trauma. J Trauma 2009;67(4):758-761.
4. McGuigan FX, Forsberg JA, Andersen RC: Foot and ankle reconstruction after blast injuries. Foot Ankle Clin 2006; 11(1):165-182, x.
5. Masini BD, Waterman SM, Wenke JC, Owens BD, Hsu JR, Ficke JR: Resource utilization and disability outcome assessment of combat casualties from Operation Iraqi Freedom and Operation Enduring Freedom. J Orthop Trauma 2009;23(4):261-266.
6. Cierny G III: Chronic osteomyelitis: results of treatment. Instr Course Lect 1990;39:495-508.
7. Trampuz A, Zimmerli W: Diagnosis and treatment of implant-associated septic arthritis and osteomyelitis. Curr Infect Dis Rep 2008;10(5):394-403.
8. Bowen TR, Widmaier JC: Host classification predicts infection after open fracture. Clin Orthop Relat Res 2005;433:205-211.
9. Calhoun JH, Manring MM: Adult osteomyelitis. Infect Dis Clin North Am 2005;19(4):765-786.
10. Cierny G III, Zorn KE, Nahai F: Bony reconstruction in the lower extremity. Clin Plast Surg 1992;19(4):905-916.
11. Cierny G III, Mader JT, Penninck JJ: A clinical staging system for adult osteomyelitis. Contemp Orthop 1985; 10(5):17-37.
12. Sayle BA, Fawcett HD, Wilkey DJ, Cierny G III, Mader JT: Indium-111 chloride imaging in chronic osteomyelitis. J Nucl Med 1985;26(3): 225-229.
13. Forsberg JA, Elster EA, Andersen RC, et al: Correlation of procalcitonin and cytokine expression with dehiscence of wartime extremity wounds. J Bone Joint Surg Am 2008;90(3):580-588.
14. Neumaier M, Scherer MA: C-reactive protein levels for early detection of postoperative infection after fracture surgery in 787 patients. Acta Orthop 2008;79(3):428-432.
15. Gristina AG: Biomaterial-centered infection: Microbial adhesion versus tissue integration. Science 1987; 237(4822):1588-1595.
16. Hall-Stoodley L, Costerton JW, Stoodley P: Bacterial biofilms: from the natural environment to infectious diseases. Nat Rev Microbiol 2004;2(2):95-108.
17. Ehrlich GD, Hu FZ, Post JC: Role for biofilms in infectious disease, in Ghannoum MA, ed: Microbial Biofilms. Washington DC: ASM Press, 2004:332-358.
18. Cierny G III, DiPasquale D: Treatment of chronic infection, in Extremity War Injuries: State of the Art and Future Directions. J Am Acad Orthop Surg 2006;14(10):S105-S110.
19. Papineau LJ: Osteocutaneous resectionreconstruction in diaphyseal osteomyelitis. Clin Orthop Relat Res 1974;101:306.
20. Cierny G III: The classification and treatment of adult osteomyelitis, in Evarts CM, ed: Surgery of the Musculoskeletal System, ed 2. Philadelphia, PA: WB Saunders, 1990.
21. Cierny G III, DiPasquale D: Periprosthetic total joint infections: Staging, treatment, and outcomes. Clin Orthop Relat Res 2002;23-28.
22. Rao N, Cannella B, Crossett LS, Yates AJ Jr, McGough R III: A preoperative decolonization protocol for Staphylococcus aureus prevents orthopaedic infections. Clin Orthop Relat Res 2008;466(6):1343-1348.
23. Wolcott RD, Dowd SE: A rapid molecular method for characterising bacterial bioburden in chronic wounds. J Wound Care 2008;17(12):513-516.
24. Edwards RA, Rodriguez-Brito B, Wegley L, et al: Using pyrosequencing to shed light on deep mine microbial ecology. BMC Genomics 2006;7:57.
25. Sales de Gauzy J, Vidal H, Cahuzac JP: Primary shortening followed by callus distraction for the treatment of a posttraumatic bone defect: Case report. J Trauma 1993;34(3):461-463.
26. McKee MD, Wild LM, Schemitsch EH, Waddell JP: The use of an antibiotic-impregnated, osteoconductive, bioabsorbable bone substitute in the treatment of infected long bone defects: Early results of a prospective trial. J Orthop Trauma 2002;16(9):622-627.
27. Klemm KW: Antibiotic bead chains. Clin Orthop Relat Res 1993;295:63-76.
28. Wahlig H, Dingeldein E, Bergmann R, Reuss K: The release of gentamicin from polymethylmethacrylate beads: An experimental and pharmacokinetic study. J Bone Joint Surg Br 1978;60(2):270-275.
29. Adams K, Couch L, Cierny G, Calhoun J, Mader JT: In vitro and in vivo evaluation of antibiotic diffusion from antibiotic-impregnated polymethylmethacrylate beads. Clin Orthop Relat Res 1992;278:244-252.
30. Walenkamp GHIM: Gentamicin-PMMA Beads: A Clinical, Pharmacokinetic, and Toxicological Study. Darmstadt, FR Germany, E Merck, 1983, pp 19-22.
    31. Cierny G III: Managing the débridement defect, in Coombs R, Fitzgerald R, eds: Infection in the Orthopaedic Patient. London, UK: Butterworth Publishers, 1988:123-131.
    32. Cattaneo R, Catagni M, Johnson EE: The treatment of infected nonunions and segmental defects of the tibia by the methods of Ilizarov. Clin Orthop Relat Res 1992;280:143-152.
    33. Green SA: Skeletal defects: A comparison of bone grafting and bone transport for segmental skeletal defects. Clin Orthop Relat Res 1994;301:111-117.
    34. Ilizarov GA, Lediaev VI: Replacement of defects of long tubular bones by means of one of their fragments. Vestn Khir Im I I Grek 1969;102(6):77-84.
    35. Ilizarov GA, Ledyaev VI: The replacement of long tubular bone defects by lengthening distraction osteotomy of one of the fragments. 1969. Clin Orthop Relat Res 1992;280:7-10.
    36. Cierney G III, DiPasquale D: Adult osteomyelitis, in Cierny G III, McLaren AC, Wongworawat MD, eds: Orthopaedic Knowledge Update: Musculoskeletal Infection. Rosemont IL: American Academy of Orthopaedic Surgeons, 2009:135-155.
      37. Madanagopal SG, Seligson D, Roberts CS: The antibiotic cement nail for infection after tibial nailing. Orthopedics 2004;27(7):709-712.
      38. Younger AS, Duncan CP, Masri BA: Treatment of infection associated with segmental bone loss in the proximal part of the femur in two stages with use of an antibiotic-loaded interval prosthesis. J Bone Joint Surg Am 1998;80(1):60-69.
      39. Nelson CL: The current status of material used for depot delivery of drugs. Clin Orthop Relat Res 2004;427(427): 72-78.
      40. Sachs BL, Shaffer JW: A staged Papineau protocol for chronic osteomyelitis. Clin Orthop Relat Res 1984;184:256-263.
      41. Volz RG, Kloss J, Peltier LF: The use of methylmethacrylate as a temporary spacer following en bloc resection of the distal femur. Clin Orthop Relat Res 1980;147:185-187.
      42. Webb LX: New techniques in wound management: vacuum-assisted wound closure. J Am Acad Orthop Surg 2002; 10(5):303-311.
      43. Cierney G III, DiPasquale D: Limb lengthening for bone loss due to infection, in Handy RC, ed: Management of Limb-length Discrepancies. Rosemont, IL: American Academy of Orthopaedic Surgeons, forthcoming.
      44. Zalavras CG, Patzakis MJ, Holtom P: Local antibiotic therapy in the treatment of open fractures and osteomyelitis. Clin Orthop Relat Res 2004;427:86-93.
      45. Ostermann PA, Seligson D, Henry SL: Local antibiotic therapy for severe open fractures: A review of 1085 consecutive cases. J Bone Joint Surg Br 1995;77(1): 93-97.
      46. Pelissier P, Masquelet AC, Bareille R, Pelissier SM, Amedee J: Induced membranes secrete growth factors including vascular and osteoinductive factors and could stimulate bone regeneration. J Orthop Res 2004;22(1): 73-79.
      47. Bertazzoni Minelli E, Caveiari C, Benini A: Release of antibiotics from polymethylmethacrylate cement. J Chemother 2002;14(5):492-500.
      48. Beardmore AA, Brooks DE, Wenke JC, Thomas DB: Effectiveness of local antibiotic delivery with an osteoinductive and osteoconductive bone-graft substitute. J Bone Joint Surg Am 2005; 87(1):107-112.
      49. Shirtliff ME, Calhoun JH, Mader JT: Experimental osteomyelitis treatment with antibiotic-impregnated hydroxyapatite. Clin Orthop Relat Res 2002;401:239-247.
      50. Cavanaugh DL, Berry J, Yarboro SR, Dahners LE: Better prophylaxis against surgical site infection with local as well as systemic antibiotics: An in vivo study. J Bone Joint Surg Am 2009;91(8):1907-1912.
      51. Mader JT, Stevens CM, Stevens JH, Ruble R, Lathrop JT, Calhoun JH: Treatment of experimental osteomyelitis with a fibrin sealant antibiotic implant. Clin Orthop Relat Res 2002;403:58-72.
      52. Mendel V, Simanowski HJ, Scholz HC, Heymann H: Therapy with gentamicin-PMMA beads, gentamicin-collagen sponge, and cefazolin for experimental osteomyelitis due to Staphylococcus aureus in rats. Arch Orthop Trauma Surg 2005;125(6):363-368.
      53. Orhan Z, Cevher E, Yildiz A, Ahiskali R, Sensoy D, Mülazimoĝlu L: Biodegradable microspherical implants containing teicoplanin for the treatment of methicillin-resistant Staphylococcus aureus osteomyelitis. Arch Orthop Trauma Surg 2009;May 12:[Epub ahead of print].
      54. Teupe C, Meffert R, Winckler S, Ritzerfeld W, Törmälä P, Brug E: Ciprofloxacin-impregnated poly-l-lactic acid drug carrier: New aspects of a resorbable drug delivery system in local antimicrobial treatment of bone infections. Arch Orthop Trauma Surg 1992;112(1):33-35.
      55. Edin ML, Miclau T, Lester GE, Lindsey RW, Dahners LE: Effect of cefazolin and vancomycin on osteoblasts in vitro. Clin Orthop Relat Res 1996;333:245-251.
      56. Isefuku S, Joyner CJ, Simpson AH: Gentamicin may have an adverse effect on osteogenesis. J Orthop Trauma 2003; 17(3):212-216.
      57. Moehring HD, Gravel C, Chapman MW, Olson SA: Comparison of antibiotic beads and intravenous antibiotics in open fractures. Clin Orthop Relat Res 2000;372:254-261.
      58. Trebse R, Pisot V, Trampuz A: Treatment of infected retained implants. J Bone Joint Surg Br 2005;87(2):249-256.
      59. Dunbar RP Jr: Treatment of infection after fracture fixation: Opinion. Retain stable implant and suppress infection until union. J Orthop Trauma 2007; 21(7):503-505.
      60. Owens BD, White DW, Wenke JC: Comparison of irrigation solutions and devices in a contaminated musculoskeletal wound survival model. J Bone Joint Surg Am 2009;91(1):92-98.
      61. Anglen JO: Comparison of soap and antibiotic solutions for irrigation of lower-limb open fracture wounds: A prospective, randomized study. J Bone Joint Surg Am 2005;87(7):1415-1422.
      62. Webb LX, Pape HC: Current thought regarding the mechanism of action of negative pressure wound therapy with reticulated open cell foam. J Orthop Trauma 2008;22(10 suppl):S135-S137.
      63. Gorbach SL, Bartlett JG, Blacklow NR: Infectious Diseases, ed 3. Philadelphia, PA, Lippincott Williams & Wilkins, 2004.
      64. Mellon M, Benbrook C, Benbrook KL: Hogging It: Estimates of Antimicrobial Abuse in Livestock. Cambridge, MA: Union of Concerned Scientists, 2001.
      65. Altemeier WA, Wadsworth CL: An evaluation of penicillin therapy in acute hematogenous osteomyelitis. J Bone Joint Surg Am 1948;30(3):657-673.
      66. Cierney G III: A Guided Tour of the Living Cell. Scientific American Library Series, vol 1. New York, NY: W. H. Freeman, Scientific American Books, 1984.
      67. Buchholz HW, Engelbrecht H: Depot effects of various antibiotics mixed with Palacos resins [German]. Chirurg 1970; 41(11):511-515.
      68. Hsieh PH, Chen LH, Chen CH, Lee MS, Yang WE, Shih CH: Two-stage revision hip arthroplasty for infection with a custom-made, antibiotic-loaded, cement prosthesis as an interim spacer. J Trauma 2004;56(6):1247-1252.
      69. Branstetter JG, Jackson SR, Haggard WO, Richelsoph KC, Wenke JC: Locally administered antibiotics in wounds in a limb. J Bone Joint Surg Br 2009;91(8): 1106-1109.
      70. Garvin K, Feschuk C: Polylactidepolyglycolide antibiotic implants. Clin Orthop Relat Res 2005;437:105-110.
      71. Nelson CL, McLaren SG, Skinner RA, Smeltzer MS, Thomas JR, Olsen KM: The treatment of experimental osteomyelitis by surgical débridement and the implantation of calcium sulfate tobramycin pellets. J Orthop Res 2002; 20(4):643-647.
      72. Noel SP, Courtney HS, Bumgardner JD, Haggard WO: Chitosan sponges to locally deliver amikacin and vancomycin: A pilot in vitro evaluation. Clin Orthop Relat Res 2010;468(8):2074-2080.
      73. Gitelis S, Brebach GT: The treatment of chronic osteomyelitis with a biodegradable antibiotic-impregnated implant. J Orthop Surg (Hong Kong) 2002;10(1):53-60.
      74. Elek SD, Conen PE: The virulence of Staphylococcus pyogenes for man: A study of the problems of wound infection. Br J Exp Pathol 1957;38(6): 573-586.
      75. Gibbons RJ, Socransky SS: Intracellular polysaccharide storage by organisms in dental plaques: Its relation to dental caries and microbial ecology of the oral cavity. Arch Oral Biol 1962;7:73-79.
      76. Gristina AG, Costerton JW: Bacterial adherence to biomaterials and tissue: The significance of its role in clinical sepsis. J Bone Joint Surg Am 1985;67(2): 264-273.
      77. Brown MR, Costerton JW, Gilbert P: Extrapolating to bacterial life outside the test tube. J Antimicrob Chemother 1991; 27(5):565-567.
      78. Miller MB, Bassler BL: Quorum sensing in bacteria. Annu Rev Microbiol 2001; 55:165-199.
      79. Huber B, Eberl L, Feucht W, Polster J: Influence of polyphenols on bacterial biofilm formation and quorum-sensing. Z Naturforsch C 2003;58(11-12):879-884.
      80. Danino T, Mondragón-Palomino O, Tsimring L, Hasty J: A synchronized quorum of genetic clocks. Nature 2010; 463(7279):326-330.
      81. Hudson MC, Ramp WK, Nicholson NC, Williams AS, Nousiainen MT: Internalization of Staphylococcus aureus by cultured osteoblasts. Microb Pathog 1995;19(6):409-419.
      82. Ellington JK, Harris M, Webb L, et al: Intracellular Staphylococcus aureus: A mechanism for the indolence of osteomyelitis. J Bone Joint Surg Br 2003; 85(6):918-921.
      83. Ellington JK, Harris M, Hudson MC, Vishin S, Webb LX, Sherertz R: Intracellular Staphylococcus aureus and antibiotic resistance: Implications for treatment of staphylococcal osteomyelitis. J Orthop Res 2006;24(1): 87-93.
      84. Pillai RR, Somayaji SN, Rabinovich M, Hudson MC, Gonsalves KE: Nafcillinloaded PLGA nanoparticles for treatment of osteomyelitis. Biomed Mater 2008;3(3):034114.
      85. Petty NK, Evans TJ, Fineran PC, Salmond GP: Biotechnological exploitation of bacteriophage research. Trends Biotechnol 2007;25(1):7-15.
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