Effectiveness of an Antibiotic-impregnated Bioabsorbable Carrier for the Treatment of Chronic Intramedullary and Diffuse Osteomyelitis

INTRODUCTION

Chronic intramedullary osteomyelitis in long bones presents a significant treatment challenge and remains a major cause of morbidity.¹ It has considerable health–economic implications in terms of the use of antimicrobials, hospital stay, and cost of surgery.^2–5 Chronic osteomyelitis can be classified by the Cierny–Mader staging system (Table 1), which is clinically relevant and easily understood. It is based upon the anatomical location of the infection but importantly also accounts for the immunocompetence of the host, which may impact physiological response to infection and surgical intervention.⁶ In stages I–III, overall integrity of the bone is retained, whilst stage IV (diffuse osteomyelitis) there is circumferential involvement with loss of stability, as in an infected non-union. The host is defined as either type A, B, or C. The A hosts are patients without systemic or local compromising factors. Type B hosts are affected by one or more compromising factors whereas C hosts are patients so severely compromised that the radical treatment necessary would have an unacceptable risk-benefit ratio.^7,8

The principles of surgery for the eradication of infection include surgical debridement of non-viable bone and soft tissue and delivery of high concentration antibiotics, usually given systemically and often supplemented by local delivery through antibiotic-impregnated carriers.⁸ Six weeks of systemic therapy is most often used.⁹ When surgical debridement of necrotic and infected tissue is performed, a cavity is produced, this is no different following debridement of intramedullary osteomyelitis. Common practice for the management of this intramedullary dead-space is through placement of antibiotic-impregnated cement within the canal. However, these depots of local antibiotics vary in their elution properties and require removal. The presence of cement does not encourage bone regrowth. For medually infection, ‘cement nails’ are often used. However, these do not provide sufficient stability in the majority of situations with diffuse osteomyelitis and may fracture, complicating removal.

An alternative to deliver local antibiotics is antibiotic-impregnated calcium sulphate (Stimulan®, Biocomposites Ltd, Keele, England), a synthetic high purity calcium sulphate biocompatible bone graft material that is resorbable. It has some osteoconductive properties that are favourable to subsequent bone formation and has been shown, in some circumstances, to stimulate new bone formation comparable with autogenous bone.^10–12 It can be mixed safely with antibiotics and has favourable elution properties.^13,14 It has the advantage of being easier to instil than cement, but most importantly, does not require removal due to its eventual resorption. The use of antibiotic-impregnated carriers delivers high levels of antibiotics and obliterates the dead-space that occurs after bone debridement.^15–18 Although numerous successful experimental studies have been performed in animal models using bioabsorbable carriers to treat infection. There are few human clinical studies in the literature.¹⁹

In our institution, it has become standard practice to use a bioabsorbable synthetic carrier to deliver local antibiotics in the treatment of intramedullary osteomyelitis following debridement. The objective of this retrospective study was to evaluate the effectiveness of this approach in patients with chronic osteomyelitis classified as either intramedullary or diffuse with intramedullary extension (Cierny–Mader stage I or IV).

MATERIALS AND METHODS

The local institution review board approved data collection for this review. Consecutive cases of chronic osteomyelitis involving the medullary canal, treated using antibiotic-impregnated calcium sulphate (Stimulan®, Biocomposites Ltd, Keele, England) as an adjunct in management from 2006 were identified. Data were collected from patient records including patient demographics, aetiology of osteomyelitis, details of primary or prior interventions (if any), smoking status, medical co-morbidities, and estimated duration of osteomyelitis. Clinical symptoms and signs were documented at consultation and used to aid in the assessment of the limb to determine the likelihood of infection. In all patients presenting to the outpatients, preoperative serological investigations (white cell count, C-reactive protein, and erythrocyte sedimentation rate) were performed. Further assessments included radiological investigations of plain radiography in two orthogonal planes, computed tomography (CT) and magnetic resonance imaging (MRI). Specific features that were suggestive of infection on radiological studies were recorded. Patients with Cierny–Mader stage I (intramedullary) or stage IV (diffuse) but with evidence intramedullary spread were included. We did not identify any patients with stage III disease (cortical sequestration and cavitation). We have noted that in our practice, this is an unusual form of presentation of chronic osteomyelitis. Host immunocompetence was recorded.

Surgical treatment was in accordance with an established protocol for the unit and involved the removal of orthopaedic hardware, resection of necrotic or infected bone and soft tissue and intramedullary debridement using reamers followed by copious saline lavage of the residual dead-space. Of note in the technique of debridement is the establishment of a distal portal in communication with the medullary canal (Fig. 1). This allowed retrograde reaming and lavage of the intramedullary canal in addition to the standard antegrade procedures. At least five samples of bone and tissue were taken for microbiological analysis as well as samples for histology. Following debridement and lavage, the entire surgical team is re-attired with clean gowns and gloves and there is a complete change of the surgical instruments. The limb is re-prepped and re-draped before insertion of the calcium sulphate carrier with antibiotic. Stimulan® is available in pellet form or as an injectable paste which is easy to apply via a syringe or pressurised gun (Fig. 1). It is mouldable and sets rapidly and tends to be resorbed over 6–8 weeks. All patients had the aminoglycoside antibiotic gentamicin impregnated into the Stimulan® using a mix of 160 mg gentamicin with every 10 cc. All cases were treated with systemic antibiotic therapy for 6 weeks as guided by microbiology results and following discussions with specialist microbiologists. Residual bone defects, when present, were treated either by bone grafting or through bone transport when clinical evidence of sepsis was not evident and often after 6–8 weeks of the primary surgery (Fig. 2).

The primary outcome measure was clinical recurrence of infection by most recent clinical follow-up. The diagnosis of recurrence of infection was based on several parameters and not a single entity or result of investigation. To be deemed free of infection, there had to be the absence of any local symptoms or signs, such as pain, swelling, erythema, discharge or systemic signs of malaise, sweats, fever in the entire follow-up period. Radiographs taken after treatment and at latest follow-up had to show no evidence of new bone lysis at the site of original infection or elsewhere. Serological investigations did not serve a useful monitor owing to the procedures that had to be undertaken for treating residual bone defects (bone transport, bone grafting, etc.) which would have caused an elevation of inflammatory markers in the interim periods. Likewise, periosteal new bone formation in relation to the procedures above for bone union in the reconstruction of the residual bone defect were excluded. Recorded secondary outcome measures included clinical and functional assessment of the joints above and below the diaphyseal bone involved (AOFAS-Ankle, IOWA knee, Oxford Hip, and DASH scores) and a general health outcome questionnaire (SF36). Data were analysed descriptively by using proportions and frequencies for categorical variables. Means, standard deviations, and ranges were used for continuous variables as appropriate.

RESULTS

Thirty-four patients were identified with chronic intramedullary or diffuse osteomyelitis with medullary extension. There were 24 male and 10 female patients. The mean age at presentation was 46.8 years (20–67). There were 14 cases involving the femur (41%), 16 involving the tibia (47%), and 4 in the upper limb (12%, 1 radial and 3 humeral). Twenty-eight cases (82%) were postoperative infections (20 closed and 6 open fractures) and six (18%) were of haematogenous, non-surgical, origin. There were 13 cases classified as stage IV and 21 classified as stage I, according to Cierny and Mader. All but 4 patients were classified as type A hosts, the rest being type B. Only 2 patients had no prior operations on their limb (four cases of infection from haematogenous sources had previous debridement). For the 32 cases who had undergone previous surgeries, the mean number of operations prior to the index surgery with the use of antibiotic-impregnated calcium sulphate was 1.8 (range 0–5, standard deviation 1.2). In 21 cases there were previous interventions for documented osteomyelitis. In 13, there was no previous osteomyelitis documented. The estimated duration of osteomyelitis prior to presentation and subsequent treatment had a median of 1.5 years (range 3 weeks–50 years). Of the 28 cases treated surgically the initial fixation performed was intramedullary nailing in 23 (82%), plating in 2 (7%) and external fixation in 3 (11%).

DISCUSSION

The treatment of chronic osteomyelitis remains challenging despite advances in diagnosis, techniques to reconstruct defects created by debridement, and antibiotics. The most important steps in the management of this condition are surgical debridement, dead-space management, and the targeted use of antibiotics. Antibiotics delivered locally have advantages over the parenteral route; much higher concentrations are achieved without producing systemic toxicity. Several studies have looked at the different means local antibiotic delivery with the commonly used carriers being bone cement (Polymethylmethacrylate—PMMA), bone graft substitute (calcium sulphate), synthetic polymer, and metal (titanium).²⁰

Gentamicin belongs to the protein synthesis inhibitor family of antibiotics, binding to the bacterial ribosomal 30S subunit to achieve a bacteriostatic effect through transcription errors during cell division. It also has bactericidal properties by disrupting the bacterial cell membranes.²¹ This antibiotic is broad spectrum in action, and with high local concentrations, can be effective against gram-negative organisms and some gram-positive organisms such as Staphylococcus.²²

In 1970, Buchholz and Engelbrecht²³ reported that bone cement mixed with antibiotics was effective in the treatment and prophylaxis of infection in total hip arthroplasty. A literature review reveals good results with PMMA mixed with different antibiotics.^24–26 It is widely used and represents a standard as an antibiotic delivery vehicle in orthopaedic surgery.²⁵ However, the elution of antibiotics from PMMA is variable and can drop to below MIC (mean inhibitory concentration) levels after 2 weeks. Furthermore, non-biodegradable carriers such as PMMA can attract glycocalyx-producing bacteria despite the presence of antibiotics. The resulting biofilm can act as a foreign body and a surface for bacterial colonization which could lead to a secondary infection.²⁷ A further procedure is needed for its removal. Furthermore, PMMA has no osteoconductive or osteoinductive potential and defect management, after extraction of the PMMA, will be required either through bone grafting or other techniques. The biodegradable carriers have advantages: additional surgery for their removal is not needed; the elution of antibiotics extends beyond 2 weeks owing to the continual breakdown of the carrier and release of more antibiotics.^7,28,29 Calcium sulphate releases its entire antibiotic load on resorption and has been shown to deliver adequate concentration locally for up to 4 weeks with safe serum levels.^30,31 It is safe, well tolerated and has a low systemic exposure in patients.³² Studies have also shown that the level of serum calcium does not rise in human as calcium is absorbed.^27,33

Several different biodegradable carriers have been studied in animal models and in humans including calcium hydroxyapatite, plaster of Paris and chitosan.^{19,29,34–36} Calcium sulphate has a rapid resorption profile and carries some osteoconductive properties.^25,29 In some instances, this can avoid a further bone grafting procedure although this was not the experience from this cohort.³³ The cohort in this study represented patients with intramedullary or diffuse (with intramedullary extension) chronic osteomyelitis and the resultant bone defects after debridement made additional bone grafting or bone reconstruction procedures necessary.

McKee et al.³³ showed that tobramycin-impregnated calcium sulphate eradicated osteomyelitis in 92% (2 recurrences) of cases after a mean follow-up of 28 months. The success rate in treating chronic osteomyelitis using gentamicin with calcium sulphate in our study was very similar. Humm et al.,³⁷ in their retrospective study, showed that when OSTEOSET®-T (calcium sulphate pellets preloaded with 4% tobramycin) was used as adjuvant therapy, this eradicated chronic osteomyelitis of the tibia in 95% of patients in their sample. It is not clear whether these patients had diffuse intramedullary osteomyelitis or localised osteomyelitis.

Some authors have advocated the addition of demineralised bone matrix to calcium sulphate to achieve osteoconductive and osteoinductive properties. Beardmore et al.³⁸ showed that tobramycin-impregnated calcium sulphate pellets and demineralised bone matrix were effective in preventing intramedullary Staphylococcus aureus infection in contaminated goat fracture model. All patients in our study cohort had been prepared for two stages in treatment for chronic osteomyelitis, and as such, no attempts were made to add demineralised bone matrix or bone graft at the index operation.

These results from the use of gentamicin-loaded calcium sulphate are promising. This is especially when the chronicity of the osteomyelitis (mean 7.2 years) and the anatomical extent (intramedullary or diffuse with intramedullary extension) are considered. The authors maintain that the key steps in surgical treatment of chronic bone infection involve a meticulous debridement (of at least marginal or wide boundaries), dead-space management and targeted antibiotics. Of special mention is the attention to detail when debridement is performed in intramedullary osteomyelitis: in addition to sequential reaming and lavage, the most distal end of the medullary cavity needs to be accessed in order to ensure this too is cleaned out at surgery. The availability of biodegradable antibiotic carriers has provided an improved elution profile of high concentration local antibiotics to the arsenal.

The extend of disease involvement was determined using a combination of clinical examination and imaging which included plain radiographs, CT scans, and MRI scans. All four components as well as consideration of patient’s past surgical history had an influence on surgical strategy. Out with the study period, the use of PET-CT scan to determine the extent of bone involvement has become used more frequently, results are currently being evaluated in a separate study.

Chronic osteomyelitis affecting the long bones of either the upper or lower extremity impacts greatly on physical function, despite successful treatment. The data on patient outcomes in this work highlight this clearly. The joint function measures (Oxford hip, IOWA knee, AOFAS, DASH) show residual limitations which are reflected in the physical function scales and PCS of the SF36. These data may caution against over-optimism when counselling patients on likely outcomes after treatment. However, treatment does improve the emotional and MH well-being of patients and most had scored close to the population norm.

There are several limitations to the work presented. The short follow-up (mean 2.5 years) in some patients is a relative weakness of this study. Both the recurrences that occurred in our study were 3 years post-initial treatment for chronic osteomyelitis. Additionally, there is a relatively small number of patients and no control group. Both these will affect the extrapolation of the conclusions obtained herewith.

In patients with intramedullary osteomyelitis, debridement of non-viable tissue, dead-space management with antibiotic-impregnated calcium sulphate in addition to systemic antibiotics was effective in eradicating bone infection in 32 out of 34 patients. This study supports the continued use of bioabsorbable carriers of antibiotics as efficacious adjuncts to surgical treatment of intramedullary osteomyelitis.

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