Description of the condition
Chronic osteomyelitis is a long-lasting infection of the bone and bone marrow, caused by pyogenic bacteria, mycobacteria or fungi, which can progress to bone necrosis and sequestrum formation. Usually long-lasting symptoms are vague and can include chronic pain, chills and low grade fever. Physical examination can reveal erythema, or swelling, sometimes in association with a draining sinus tract.
Osteomyelitis can be classified as either exogenous or hematogenous, based on its pathogenesis. Exogenous osteomyelitis results from a direct inoculation of bacteria into the bone at the time of trauma, during surgical reduction and internal fixation of fractures, or from an adjacent focus of infection (e.g. decubitus ulcer, soft tissue trauma) (Cunha 2002; Lew 2004; Mader 1997a; Mader 1999a; Mader 1999b; Waldvogel 1970; Walenkamp 1997). Thus, exogenous osteomyelitis includes post-traumatic and post-operative osteomyelitis, as well as osteomyelitis that is secondary to a contiguous focus (adjacent areas that are in contact) of infection or associated with peripheral vascular disease. In hematogenous osteomyelitis, blood-borne bacteria reach bone from a remote portal of entry. This type is predominantly encountered in paediatric populations.
Regardless of the route of access, the microorganism (for example Staphylococcus aureus) adheres to fibronectin receptors or other membrane proteins of the bone marrow to establish an infection. Subsequently, biofilm development occurs whereby bacteria are covered by a layer of fibrinogen (slimy coat) and protected from host defence mechanism and antibiotics. The local inflammation elicited by the bacteria or by trauma contributes to destruction of bone trabeculae and bone matrix. The devitalised bone and tissue provide an inert matrix upon which microorganisms thrive. This biofilm can act as a barrier that retards the penetration of nutrients and antimicrobial agents, and together with impaired vascularisation, favours infection persistence. In the biofilm, the bacteria hide intracellularly and achieve a slow metabolic rate. The metabolically-inactive bacteria are largely insensitive to antibiotics. Fragments of dead bone (sequestra) or metal implants can perpetuate the infection by exposing sites to which pathogenic bacteria can bind (Ciampolini 2000; Gristina 1990; Haas 1996; Lew 2004; Mader 1997a; Waldvogel 1970; Walter 2012).
Another classification of osteomyelitis is based on the anatomical stage of disease and is related to prognosis: medullary (confined to medullary cavity), superficial (involves just cortical bone), localised (involves both the cortical and medullary bone, but not the entire bone diameter) or diffuse (involves the entire thickness of the bone). Under this classification system, patients are classified as A, B or C according to the presence and severity of underlying diseases (Cierny 1985; Cierny 2003).
All aetiological classes of osteomyelitis may progress to a chronic process and it is not possible to define a time threshold after which an acute infection becomes chronic. The infection can persist intermittently for years with frequent therapeutic failure (Huber 2002; Mader 1993).
In recent years, chronic osteomyelitis incidence has apparently increased probably due to population aging, increasing prevalence of diabetes and trauma, and diagnosis improvement (Pollard 2006; Trampuz 2006). Osteomyelitis usually occurs in adults, secondary to an open injury to the bone, or after surgery for reconstruction of the bone (Darouiche 2004; Holtom 1999; Lazzarini 2002; Mader 1999b). Infections associated with prostheses are also common (Carek 2001; Haas 1996; Lew 2004). Chronic osteomyelitis may present as a recurrent or intermittent disease, with periods of quiescence of variable duration. These tend to relapse, after apparently successful therapy, with a major impact on the quality of life and a substantial financial burden to health system (Huber 2002).
Based on bacterial cultures of operative specimens, S. aureus is the main causative agent of chronic osteomyelitis. However, gram negative bacilli (Pseudomonas spp and Enterobacteriaceae) have been more frequently reported, as well as a high proportion of polymicrobial aetiology cases (Carek 2001; Mader 1992; Sheehy 2010; Waldvogel 1980).
The microbiological aetiology of chronic osteomyelitis can be difficult to establish. Bone culture should guide the antimicrobial choice. Superficial samples or swabs from fistulas should not be used for pathogen identification since they present low accuracy when compared with bone biopsy culture (Senneville 2006; Zuluaga 2002)
Non-specific blood tests, such as erythrocyte sedimentation rate, C-reactive protein and alpha-1 acid glycoprotein, are widely employed in assessing chronic osteomyelitis. They are usually elevated but have low sensitivity and specificity. Some authors suggest that they can be helpful to assist the early diagnosis of postoperative bone infection, and to assess the effectiveness during the course of antibiotic therapy (Bourguignat 1996; Ferard 2002).
Description of the intervention
In general, chronic osteomyelitis is treated with antibiotics and surgical debridement to remove all the dead bone tissue (Parsons 2004). Microorganisms residing in the dead bone, if not removed along with sequestra (dead bone), can cause flare-ups many years after the initial attack. The goal of debridement is to reach healthy, viable tissue and to remove the biofilm. Adequate debridement may leave a large bone defect known as dead space. The dead space is usually filled with local tissue flaps, or free flaps, bone graft, calcium hydroxyapatite implants or temporarily with polymethylmethacrylate beads with or without antibiotic. The goal of dead space management is to replace dead bone and scar tissue with durable vascularised tissue. If necessary, measures must be taken to achieve permanent stability of the bone. Skin grafting is used to cover wound sites involving bone that has undergone surgery, or to cover muscle flaps or graft of cancellous bone (bone that has a spongy structure) (Ciampolini 2000; Eckardt 1994; Haidar 2010; Lew 2004; Mader 1997a; Mader 1999b; Parsons 2004; Waldvogel 1980; Walter 2012).
Given the importance of biofilm in the pathophysiology and relapses of chronic osteomyelitis, some experts suggest the use of an antibiotic (e.g. rifampin) with activity against micro-organisms in biofilm as a combination drug in both parenteral and oral regimens. However, there is insufficient evidence for choosing antibiotics based on biofilm antimicrobial susceptibility testing rather than the conventional antimicrobial susceptibility test (Saginur 2006; Walter 2012).
Four to six weeks of parenteral (non-oral administration such as an intravenous injection) antibiotic therapy after surgery has become the standard treatment for chronic osteomyelitis. The rationale for this regimen is that three to four weeks are required for the bone to revascularise, and is based on experience of treating children with acute osteomyelitis (Carek 2001; Gentry 1990; Lazzarini 2002; Lazarini 2005; Mader 1992; Mader 1999a). However, different centres can vary regarding antibiotic use and duration of treatment, depending on the disease stage, pathogen identified or surgical intervention performed (Walter 2012; Spellberg 2012).
How the intervention might work
Despite advances in both antibiotics and surgical treatment, the long-term recurrence rate of chronic osteomyelitis remains at around 20% (Gentry 1990; Mader 1990; Spellberg 2012; Rissing 1997). Evaluating the success of treatment is difficult as many studies show promising initial results but frequently lack long-term follow-up data (Mader 1992).
The optimal duration of antibiotic therapy has not been well-defined. Due to failure rates in clinical studies, some authors advocate longer treatment with six to eight weeks of high doses of intravenous therapy followed by a course of three months or longer of oral therapy (Johnston 2007; Spellberg 2012). Apart from the doubts related to the duration of chronic osteomyelitis treatment, there are some controversies about the best route of antibiotic administration. Some reports suggest that short-term parenteral therapy followed by oral antibiotic therapy for six weeks or oral antibiotic alone may be an effective strategy with more economic benefits than parenteral therapy alone (Gentry 1990; Mader 2001; Rissing 1997; Spellberg 2012; Swiontkowski 1999).
Short-term oral antibiotics for treating chronic osteomyelitis, if as effective as the parenteral route, would be more convenient for patients, with no risk of vascular line infection, and would probably cost less.
Why it is important to do this review
The epidemiology of chronic osteomyelitis has changed in recent years. There has been a significant increase in post-traumatic and post surgical osteomyelitis, especially in developed countries (Trampuz 2006).
Surgical debridement is a mainstay of chronic osteomyelitis treatment (Parsons 2004). However, in current practice, additional treatment with antibiotics is frequently recommended for infection eradication (Spellberg 2012; Walter 2012). Various antibiotic regimens are in use (Lazarini 2005; Walter 2012) and there are many questions regarding the ideal route of antibiotic administration (oral or parenteral). If oral therapy is proven to be similarly or more effective for treating chronic osteomyelitis, it will be preferred because it is generally more comfortable for the patient and less expensive (Johnston 2007; Spellberg 2012; Stengel 2001; Walter 2012).
Currently, increasing antibiotic resistance, due in part to the inappropriate use of antimicrobials, is of great concern worldwide. Many S. aureus acquired infections in the community or in hospital are now resistant to beta-lactamic antibiotics, and the gram negative bacilli have become resistant to beta-lactamic and fluoroquinolones (Lew 2004; Murphy 2011; Sheehy 2010). Therefore, the duration and type of antibiotic regimen to treat chronic osteomyelitis needs to be defined based on good quality research. This is an update of a Cochrane review first published in 2009 (Conterno 2009).