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Understanding and Treating Chronic Osteomyelitis
History
Osteomyelitis can occur for a variety of reasons and is often a result of open fractures. Therefore it is quite obvious that osteomyelitis has accompanied humankind and also animals over thousands or even millions of years. The most likely oldest evidence of osteomyelitis was found in a 250- to 290-million-year-old infected spinal fracture of a dimetrodon Permian reptile. Also, an approximately 500,000-year-old skeleton of a Java man (Homo erectus) shows possible signs of an infected nonunion. The Edwin Smith Papyrus (3000–2500 BC) is often cited as the earliest written evidence of bone diseases, including descriptions of bone infection.
In ancient times, Hippocrates (460–370 BC) described the link between open fractures and necrosis of the bone. The Romans also contributed to a deeper understanding and treatment of osteomyelitis; Celsus, for example, recommended débridement and the importance of preserving vital bone tissue. He emphasized that débridement should continue until bleeding bone is encountered. Today, this has been coined by the late George Cierny as the “paprika sign” and remains an important hallmark in the current surgical débridement procedure.
The history of posttraumatic osteomyelitis has always been associated with combat injuries. The invention of firearms led to a tremendous increase in open wounds and fractures, which often had to undergo amputation procedures, as described by Baron Jean Larrey (1766–1842), a military surgeon in Napoleon's army. He is said to have performed more than 200 amputations on soldiers at the “Bataille de la Moskova” on August 26, 1812, during Napoleon's invasion in Russia.
Key discoveries in bacteriology and antisepsis by Louis Pasteur (1822–1895), Robert Koch (1843–1910), and Joseph Lister (1827–1912) significantly improved the understanding of the pathophysiology of bacterial infections, including osteomyelitis. Ignaz Semmelweis (1818–1865) of Budapest, described as the “saviour of mothers,” discovered the link between hand disinfection and the incidence of puerperal fever. He found that the simple act of a physician washing one's hands dramatically reduced the incidence of such infections. His observations were later confirmed by Louis Pasteur, who identified microbes in puerperal fever but also in furuncles and osteomyelitis. Joseph Lister described his aseptic technique for surgery using carbolic acid, which led to the term “Lister's dressing,” and also discussed its application to open fractures.
Sir Alexander Ogston (1844–1929), a professor of surgery in Aberdeen, described osteomyelitis as a “boil of the bone marrow” and identified microorganisms in acute abscesses. He was the first to name these bacteria staphylococci at the suggestion of Geddes, a Greek professor in Aberdeen, because the bacteria were growing in masses like bunches of grapes.
Key work on the management of osteomyelitis in the early 20th century was done by the American surgeon Hiram Winnett Orr (1877–1956), with detailed descriptions of surgical protocols, postoperative management, and outcomes. In his protocol, all necrotic bone was to be removed with “saucerisation” of the resulting cavity, followed by immobilization of the limb in a neutral position.
The discovery of penicillin by Sir Alexander Fleming (1881–1955) in 1928 revolutionized the whole field of medicine, including the treatment and outcome of osteomyelitis. One of the first reports on the new “wonder drug” in osteomyelitis from the Royal Hospital of Sick Children in Glasgow in 1948 showed a tremendous decrease in mortality when penicillin was used in the treatment of hematogenous osteomyelitis. He also observed radiographical restoration of more normal bone with the induction of this treatment.
Advancing internal fixation techniques were also accompanied by the complication of osteomyelitis, which was named “postoperative osteomyelitis.” The Austrian Lorenz Böhler (1855–1973), one of the founders of modern orthopaedic trauma surgery, said in 1930: “The most dangerous innovation in treatment of fresh fractures is the fundamental operative approach, especially when practiced by novices, without the appropriate indication and with insufficient asepsis and inadequate materials.” He relied on Robert Koch's recommendation to use safer and more reliable sterilization techniques with the use of heat and steam compared with disinfection with acid.
After World War II, improved surgical principles and techniques combined with proper dead-space management by the introduction of local and free muscle grafts helped to improve blood supply and outcome in patients with chronic osteomyelitis. Another important evolution was made in the field of local delivery of antibiotics by poly-methyl-methacrylate (PMMA) to achieve high local concentrations in the bone and reduce systemic concentrations and systemic complications, such as nephro- and ototoxicity by aminoglycosides. The key discovery for this was made by Hans-Wilhelm Buchholz for periprosthetic joint infections (PJIs) and reported in 1970. Sir John Charnley doubted this concept and replied in a letter to Buchholz: “My dear Buchholz, nothing leaks out of stone.” However, Wahlig and Dingeldein could clearly demonstrate the favorable release kinetics from different antibiotics out of PMMA, which paved the way for the invention of PMMA-gentamicin beads by Klaus Klemm (1932–2000) by enhancing the release of antibiotics through a higher surface area of the PMMA carrier in small beads and proved successful for the treatment of osteomyelitis.
Clearly, osteomyelitis is not a new ailment. It has been in existence since the start of mammalian history. Its treatment has been poor at best until the recent era. Clearly, certain hallmarks of treatment have evolved over the past 250 years that have helped form a foundation for our current treatment. These are further addressed throughout this chapter.
Epidemiology
According to Lew and Waldvogel, chronic, nonhematogenously spread infection occurs secondary to a contiguous focus infection after trauma, from inoculation after surgical intervention, from infection secondary to vascular insufficiency, or due to skin breakdown with wound creation due to peripheral neuropathy. Hematogenous spread can occur due to a host of reasons.
Epidemiology of Hematogenous Osteomyelitis
The epidemiology of hematogenous osteomyelitis still differs between developed and third-world countries. Chronic hematogenous osteomyelitis is seen less frequently in industrialized countries. Previous studies from Norway between 1965 and 1994 and Lithuania reported an annual incidence of hematogenous osteomyelitis of approximately 10 to 14 cases per 100,000 children compared with approximately 43 cases for Maori children. A recent comprehensive work on the epidemiology of osteomyelitis in the United States in a population-based historical cohort study from 1969 to 2009 carried out in Olmsted, Minnesota, showed an incidence of 8 to 10 cases of osteomyelitis per 100,000 person-years in children.
The same publication revealed an overall age and sex-adjusted independent annual incidence of osteomyelitis of 21.8 cases per 100,000 person-years, including hematogenous-related, diabetes mellitus–related, contiguous, and iatrogenic causes. Interestingly, the incidence of osteomyelitis increased over this 40-year period from 11.4 cases per 100,000 person-years in the period from 1969 to 1979 to 24.4 cases per 100,000 person-years in the period from 2000 to 2009. The incidence tripled among individuals older than 60 years, which is mainly attributable to diabetes-related osteomyelitis, with an increase from 2.3 cases per 100,000 person-years in the period from 1969 to 1979 to 7.6 cases per 100,000 person-years in the period from 2000 to 2009.
Epidemiology of Osteomyelitis Secondary to Vascular Insufficiency and Systemic Disorders
Diabetic patients suffer from peripheral neuropathy with loss of protective sensation combined with microvascular disease and elevated blood sugar levels compromising local and systemic host infection response systems. A lifetime risk of foot ulcers of approximately 25%, with the risk of spreading to the underlying bone, is mainly responsible for the high incidence of chronic osteomyelitis in diabetic patients.
Further systemic risk factors for osteomyelitis in adults include peripheral vascular disease, pressure ulcers, and surgical interventions, as well as age due to the immunocompromised nature of aging. Immunocompromised patients after organ transplantation, hemodialysis, and chemotherapy and patients with polymorphonuclear leukocytes have also been found to be at an elevated risk for osteomyelitis. Furthermore, intravenous (IV) drug abuse is a significant risk factor for osteomyelitis.
Epidemiology of Posttraumatic and Postoperative Osteomyelitis
Besides systemic risk fractures, open fractures with bacterial contamination of the soft tissue and bone are at increased risk for the development of osteomyelitis. Ramón Gustilo was one of the pioneers to scientifically assess the association between the severity of tissue trauma and development of osteomyelitis. In one of his review articles, deep infection rates in the setting of open fractures were found to be anywhere from 2% to 50%. Based on his observational studies, he proposed, together with Anderson, a new classification system for open fractures depending on the severity of the soft tissue lesion. This Gustilo-Anderson classification has been widely accepted and adopted and uses three general types of injuries with a subclassification of type III lesions and allows for an estimation of posttraumatic osteomyelitis risk depending on the type of injury. Types I and II open fractures are associated with around a 2% risk of infection as compared with 10% to 50% in type III injuries. In addition, type IIIC fractures with neurovascular lesions to the leg have a significantly greater risk of infection compared with types IIIA and IIIB. Court-Brown confirmed these findings also for tibia shaft fractures treated by intramedullary nailing in a review article, with infection rates of 0% to 3.2% in injuries with mild soft tissue lesions (closed, Gustilo-Anderson types I and II injuries) compared with 17.5% to 23.1% in Gustilo-Anderson type IIIB injuries with severe soft tissue injuries. The burden of disease of infected tibia fractures for the United States was recently estimated by Alt ( Table 25.1 ), with approximately 1620 infections and financial costs of approximately $83.3 million per year. We feel this is probably underestimated due to the fact that many patients with posttraumatic chronic osteomyelitis are forced to simply live with the disease because reasonable treatment options are often not offered.
Table 25.1
Estimated Number and Costs of Infected Tibia Fractures Per Year for the United States
From Alt V. Antimicrobial coated implants in trauma and orthopaedics—a clinical review and risk-benefit analysis. Injury . 2017;48:599–607.
| Estimated Number of Closed and Open Tibia Shaft Fractures a | Infection Rate b | Estimated Number Infected Tibia Fractures | Costs c | |
|---|---|---|---|---|
| Closed | 46,000 | 2% | 920 | $47.2 M |
| Open | 8000 | 8.8% | 700 | $36.1 M |
| Total | 54,000 | 1620 | $83.3 M |
a US population of 318 million, incidence for tibial shaft fractures of 17/100,000 and distribution of 85% of closed vs. 15% of open fractures (Weiss et al., 2008).
Pressure ulcers, mainly in bedridden patients, with contiguous spread to the bone are mainly responsible for osteomyelitis of the pelvis and of the calcaneus. This is frequently the case in people suffering from paraplegia and quadriplegia. In most cases, polymicrobial infections with different organisms from the external environment can be found.
Chronic osteomyelitis is not only a consequence of certain predisposing factors but is also associated with an increased risk of the patient developing other morbid conditions and even an increased chance of death. Chronic inflammation in the body has been directly related to a higher incidence of cardiac disease.
Patients with chronic osteomyelitis and chronic draining sinuses carry a low risk of malignant changes of the sinus tract epithelium in 0.2% to 1.6% of cases, with squamous cell carcinoma being the most common form of malignant transformation, which should be suspected in patients with the triad of elevated symptoms, foul discharge, and hemorrhage. Chronic osteomyelitis in the elderly was also shown to be associated with a significantly higher mortality risk compared with controls without chronic osteomyelitis, with an incidence ratio of 2.29 (2.01 to 2.59) compared with 1.89 (1.66 to 2.15) after adjusting for age, gender, comorbidities, and monthly income.
Furthermore, the psychosocial and economic consequences of long-term disability have a significant negative impact on the quality of life of patients suffering from chronic osteomyelitis, including separation from family, loss of job, and so forth, and these often represent the greatest toll on the patient and greatest economic burden to society. It should thus be quite apparent that the cost to society of chronic osteomyelitis represents a real health and social burden.
Pathogenesis
Causative Organisms
According to our best current knowledge, the leading cause of osteomyelitis is bacterial infection. Hematogenous osteomyelitis is typically monomicrobial in most cases, whereas in posttraumatic osteomyelitis after open fracture and exposure to water, soil, foreign bodies, and skin flora, polymicrobial infection is likely.
By far, gram-positive aerobe (89%) pathogens are the most frequent cause of bone infection, followed by gram-negative aerobes (45%) and anaerobes (16%). Staphylococcus aureus is the predominant cause of osteomyelitis in the adult population. Between 38% and 67% of chronic osteomyelitis is reported to be caused by S. aureus . About 33% to 55% of all S. aureus osteomyelitis cases can be traced back to methicillin-resistant S. aureus (MRSA) strains. However, the trend toward increasing rates of MRSA infections, in general, has recently reversed, probably due to widely defined preventive initiatives. Other important microbes implicated in causing osteomyelitis seen commonly in clinical practice include Streptococcus spp., Bacteroides spp., coagulase-negative Staphylococcus spp., Corynebacteria spp., Klebsiella spp., Bacillus spp., Enterococcus faecalis, Propionibacterium acnes, and the very important pathogen Pseudomonas aeruginosa . Pseudomonas is most commonly seen in injuries of the foot and lower leg. In its chronic biofilm state, Pseudomonas hides perfectly in the body, with its biofilm biosphere often living in harmonious existence with its host. Differences in the prevalence of certain organisms may depend on the anatomical location of osteomyelitis, the route of infection, host factors, and the regional origin of the outlined cases. However, we have seen many cases of certain microbes described as having a prevalence in one part of the body (e.g., Propionibacterium around the apocrine glands between the neck and breast line) that cause pathogenic osteomyelitis in a far distant location of the body (e.g., tibial osteomyelitis; see Fig. 25.4 ).
Staphylococci are ubiquitous organisms and elements of the natural skin flora. Trauma with disruption of the skin envelope enables inoculation of soft and bony tissue. Because S. aureus is by far the most common bacteria causing osteomyelitis, staphylococcal virulence factors besides biofilm itself have been intensively addressed in clinical and experimental research. First, adhesion factors expressed by S. aureus, such as fibronectin-binding proteins and collagen-binding proteins, facilitate attachment to wounded tissue after inoculation has taken place. In the case of implantation of biomaterials or orthopaedic implants, extracellular matrix and plasma proteins (fibronectin, collagen, vitronectin, fibrinogen, laminin, thrombospondin, bone sialoprotein, elastin or von Willebrand factor) rapidly cover foreign surfaces. Colonization of foreign surfaces by adhesion factors against the host-derived protein layer, which covers the orthopaedic devices, can be regarded as the first step in biofilm formation. For the development of biofilms, intercellular adhesins are expressed, which enable the formation of cellular clusters. Second, factors that promote evasion from host defenses are relevant. S. aureus protein A (SpA) is a surface protein that binds to the Fc region of immunoglobulin G (IgG), which prevents the Fc regions of IgG from binding to the Fc receptors of phagocytes. Besides this antiphagocytic effects of SpA, binding to tumor necrosis factor receptor-1, which is expressed on pre-osteoblastic cells, was shown to induce apoptosis and bone loss. In addition, SpA binding to osteoblasts was demonstrated to induce expression of receptor activator of nuclear factor kappa B ligand (RANKL) and secretion of proinflammatory cytokines, leading to stimulation of osteoclastogenesis and bone resorption. Third, the ability to gain intracellular access to host cells is an important virulence factor. Both S. aureus and Staphylococcus epidermidis have been shown to invade osteoblasts. Surface proteins, such as fibronectin-binding protein, allow staphylococci to complex with osteoblastic integrins, which leads to consecutive internalization. Thus intracellular staphylococci are protected from host immunity and antibiotics. Finally, destructive capacities characterize staphylococcal virulence. Exotoxins attack host cells, and enzymes such as hydrolases degrade the extracellular matrix. This promotes bacterial invasion and tissue penetration.
Small colony variants (SCVs) were first described in 1910. According to their name, the most obvious feature is that they form colonies that are nearly one-tenth the size of colonies created by wild-type bacteria. Intracellular survival as well as the growth of S. aureus in eukaryotic cells, such as osteoblasts, has been elucidated ( Fig. 25.1 ).
The intracellular invasion of the microbes enables them to avoid host innate and noninnate defense mechanisms such as host antibody and phagocytic response. In doing so, they are hidden from all body defense mechanisms because they are no longer recognized as being foreign. Because nearly all antibiotics, except rifampin, used in clinical practice do not cross the eukaryotic cell membrane, they have no effect on the SCVs because the host cells’ envelope shields the SCVs from such exposure. The SCVs then go into a reduced metabolic state once they are intracellular. In essence, they behave like the sessile phase of growth in a biofilm. With their reduced metabolic rate and greatly reduced generational cycle, reduced alpha-toxin production by these microbes has also been confirmed. Essentially, the SCVs are trying to effectively coexist with the host cell they have invaded because it is to their benefit to peacefully coexist with their new host cell biosphere.
SCVs have been shown in a wide range of bacterial genera and species, including S. aureus, S. epidermidis, Staphylococcus capitis, P. aeruginosa, Burkholderia cepacia, Salmonella serovars, Vibrio cholerae, Shigella spp., Brucella melitensis, Escherichia coli, Lactobacillus acidophilus, Serratia marcescens, and Neisseria gonorrhoeae . Besides osteomyelitis, SCVs can be evidenced in abscesses, soft tissue, the respiratory tract, and blood. Recrudescent or persistent infections have been associated with the occurrence of SCVs. In addition to their phenotype and reduced growth rate and metabolic characteristics, these SCVs do not produce virulence factors, which stimulate cytokine release and immune response. Different mechanisms, such as low ATP levels, defective catalase activity, and depressed electron transport activity, are responsible for decreased aminoglycoside uptake to the cell and may account for antibiotic resistance. The comparable slow growth, with its reduced cell-wall division in SCVs, is a reason for the ineffectiveness of antibiotics that act on the cell wall. The pathophysiologic significance became obvious after minimum inhibitory concentrations of aminoglycosides were found to be up to 16 times higher for SCVs compared with normal colony types.
One must note, though, that the clinical relevance of intracellular persistence of S. aureus as SCVs has yet to be determined, and no true disease recurrence has been confirmed due to these intracellular SCVs. However, the sessile phase of existence and intracellular hiding with similar reduced growth and metabolic characteristics both clearly represent defenses by the microbes that overwhelm our current host defense mechanisms and therapeutic modalities in fighting them.
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