Antibiotics for treating chronic osteomyelitis in adults
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To determine the effectiveness of antibiotics in the treatment of chronic osteomyelitis.
We will examine the following hypotheses:
1. Different antibiotic treatment regimes in terms of duration and methods of administration may have different effectiveness in chronic osteomyelitis.
2. Patients with infection caused by different bacteria may have different rates of sustained remission after antibiotic therapy.
Background
Osteomyelitis is an inflammation of the bone and bone marrow caused by pyogenic bacteria, mycobacteria or fungi. Based on aetiological considerations, traditionally osteomyelitis has been classified as either hematogenous, secondary to a contiguous focus of infection or those associated with peripheral vascular disease. (Cunha 2002; Mader 1997a; Mader 1999a; Waldvogel 1970). In hematogenous osteomyelitis, blood‐born bacteria reach bone from a remote portal of entry. It is predominantly encountered in paediatric populations. Osteomyelitis secondary to a contiguous focus of infection results either from a direct inoculation of bacteria into the bone at the time of trauma, or during surgical reduction and internal fixation of fractures, or from an adjacent focus (e.g., decubitus ulcer, soft tissue trauma). Whatever the route of access, in order to start the infection, the microorganism Staphylococcus aureus, adheres to fibronectin's receptors or other membrane proteins of the bone marrow. Subsequently bacteria is covered by a layer of fibrinogen (slimy coat) and protected from host defence mechanism and antibiotics. In osteomyelitis resulting from contiguous spread of infection, injury from local inflammation or trauma may devitalise the bone and tissue, providing an inert matrix upon which microorganisms thrive (Ciampolini 2000; Gristina 1990; Haas 1996; Mader 1997a; Waldvogel 1970). Bacteria can also elude host defence mechanism by hiding intracellularly and by acquiring a very slow metabolic rate.
All aetiological classes of osteomyelitis may progress to a chronic process. Chronic osteomyelitis occurs when bone tissue dies as a result of the lost blood supply and it can persist intermittently for years with frequent therapeutic failure (Huber 2002; Mader 1993). The hallmark of chronic osteomyelitis is the simultaneous presence of organism, necrotic bone and compromised soft‐tissue envelope (Bamberger 1993; Haas 1996; Mader 1997a; Mader 1997b).
Chronic osteomyelitis usually occurs in adults, generally secondary to an open injury to the bone, or after surgery for reconstruction of the bone (Holtom 1999; Lazzarini 2002; Mader 1999b). Infection associated with prostheses are also common (Carek 2001; Haas 1996; Lew 1997). 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 of patients and a substantial financial burden to health system (Huber 2002).
From cultures of operative specimens, Staphylococcus aureus is the main causative agent of chronic osteomyelitis, followed by, Pseudomonas spp and Enterobacteriaceae (Carek 2001; Mader 1992; Waldvogel 1980).
Chronic osteomyelitis is generally treated with antibiotics and surgical debridement which intends to remove all the dead bone tissue. 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. Laser doppler flowmetry can be used to ensure that the remaining bone is viable (Swiontkoski 1990). Adequate debridement may leave a large bone defect known as dead space. The dead space should be filled with local tissue flaps, or free flaps, or temporarily with poly methylmethacrylate beads. 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; Lew 1997; Mader 1997a; Mader 1999b; Waldvogel 1980).
Despite advances in both antibiotics and surgical treatment, the long‐term recurrence rate remains at approximately 20‐30% (Gentry 1990; Mader 1990; Rissing 1997; Waldvogel 1970; Waldvogel 1980). Evaluating the success of treatment is difficult as many studies show promising initial results but long‐term follow up data are frequently lacking (Mader 1992). According to some authors, the tendency for infection to relapse, sometimes years after apparently successful therapy, suggests remission (or arrest) rather than cure of treated osteomyelitis (Haas 1996; Mader 1999b).
The optimal duration of antibiotic therapy has not been well defined. Four to six weeks of parenteral antibiotic therapy after surgery has become the standard treatment of chronic osteomyelitis. The rationale behind this regimen is the recognition that three to four weeks are required for the bone to revascularise, and in the experience obtained in treating children with acute osteomyelitis (Carek 2001; Gentry 1990; Mader 1992; Mader 1999a; Stengel 2001). However, because the failure rates in clinical studies, some authors advocate longer treatment with six to eight weeks of intravenous therapy followed by a course of three months or longer of oral therapy. Besides the doubts related to the duration of chronic osteomyelitis treatment, there are some controversies about the best method of antibiotic administration to treat it. Some reports show 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; Greenberg 2000; Rissing 1997; Swiontkowski 1999; Mader 2001).
Nonspecific blood tests like erythrocyte sedimentation rate, C‐reactive protein, alpha‐1 acid glycoprotein, are widely employed in 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 post‐operative bone infection. Its reduction during the course of antibiotic therapy is a favourable prognostic sign (Bourguignat 1996; Ferard 2002).
Nowadays the increasing antibiotic resistance is of great concern worldwide. Therefore the length of antibiotic therapy for the treatment of chronic osteomyelitis has to be defined based on good quality research.
Objectives
To determine the effectiveness of antibiotics in the treatment of chronic osteomyelitis.
We will examine the following hypotheses:
1. Different antibiotic treatment regimes in terms of duration and methods of administration may have different effectiveness in chronic osteomyelitis.
2. Patients with infection caused by different bacteria may have different rates of sustained remission after antibiotic therapy.
Methods
Criteria for considering studies for this review
Types of studies
Randomised or quasi‐randomised (e.g. date of birth, alternation) controlled trials. Trials will be included irrespective of publication status, and blinding.
Types of participants
Adults diagnosed with chronic osteomyelitis will be included.
The diagnosis of chronic osteomyelitis will defined by: clinical pattern evolved over months or years and characterised by low‐grade inflammation, presence of pus, microorganisms, and presence of dead bone (sequestra), demonstrated by plain film, computed tomography or magnetic resonance imaging, and isolation of bacteria from the bone lesion (Lew 1997). Diabetic foot osteomyelitis and implant‐associated osteomyelitis will be not included. Sternal and vertebral osteomyelitis will also be excluded.
Types of interventions
Comparative studies of antibiotics treatment of chronic osteomyelitis. Trials comparing different antibiotics, different antibiotic routes of administration or different duration of treatment will be included. The bacteria should have documented sensitivity to the antibiotics used. The patients should be submitted to surgical management of infection with adequate and extensive debridement of all necrotic tissue. Obliteration of dead space, stabilisation of the bone and adequate soft tissue coverage should be done if necessary.
Types of outcome measures
Primary outcomes
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Duration of antibiotic treatment to obtain sustained remission of infection; (Sustained remission will be defined as the resolution of all signs and symptoms of active infection at the end of therapy and after a minimal post‐treatment observation period of 1 year (Carek 2001; Gentry 1990; Mader 1992)).
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Number of patients who present resolution of all signs and symptoms of active infection at the end of therapy;
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Number of patients who present resolution of disease at least 1 year after therapy.
Secondary outcomes
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Number of patients with failure and number of patients with early and late relapse. (We will use the following definitions: Failure will be defined as a lack of apparent response to therapy, as evidenced by one or more of the following: persistence of drainage; recurrence of sinus tract or failure of sinus tract to close; persistence of systemic signs of infection (chills, fever, weight loss, bone pain), or progression of bone infection shown by imaging methods (Gentry 1990; Mader 1992); early relapse will be defined as recurrence of signs and symptoms plus isolation of the same pathogen(s) within 4‐6 weeks after discontinuation of antibacterial therapy) (Gentry 1990; Mader 1992); late relapse will be will be defined as recurrence occurring after 6 weeks and up 12 month after the end of therapy (Gentry 1990; Mader 1992);
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Number of patients who obtained sustained remission of symptoms according to antibiotic methods of administration (parenteral, oral or parenteral switch to oral).
Adverse events
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Orthopaedic sequels like residual pain, residual non‐union;
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Number of amputations done;
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Cost of different antibiotics used for treatment;
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Number of days of hospitalisation;
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Squamous cell carcinoma;
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Death.
Search methods for identification of studies
We will search the Cochrane Bone, Joint and Muscle Trauma Group trials register (to present), the Cochrane Central Register of Controlled Trials (The Cochrane Library current issue), MEDLINE (January 1966 to present), EMBASE (January 1980 to present) (seeAppendix 1), and reference list of articles. We will also contact first authors of trials and researchers in the field. No language restrictions will be applied.
In MEDLINE (OVID WEB) the search strategy will be combined with the revised optimal trial search strategy (Robinson 2002), and modified for use in other databases (seeAppendix 2).
Data collection and analysis
Selection of studies
Two reviewers (LOC, CSF) will independently inspect each reference identified by the search that meets the inclusion criteria. For possible relevant articles, or in case of disagreement between the two reviewers, the full article will be obtained and inspected independently by the two reviewers. Any uncertainties will be resolved by contacting the authors.
Data extraction and management
Two reviewers (LOC, CSF) will independently extract and evaluate the data of trials. A data extraction tool, which will be based on the generic evaluation tool developed by the Cochrane Bone, Joint and Muscle Trauma Group, will be used. Disagreement will be resolved by consensus. If necessary, the authors of the trials will be contacted for clarification.
Assessment of risk of bias in included studies
In this review, risk of bias will be assessed indirectly in terms of different aspects of methodological quality.
Trials that fill the review inclusion criteria will be independently assessed for methodological quality by two reviewers (LOC, CSF), and disagreement will be resolved by consensus. The quality assessment will be used only to assist the reader in interpreting the review (Clarke 2003). We will use the Cochrane Bone, Joint and Muscle Trauma Group methodological quality assessment tool. The scoring system uses the following rules:
A. Was the assigned treatment adequately concealed prior to allocation?
2 = method did not allow disclosure of assignment.
1 = small but possible chance of disclosure of assignment or unclear.
0 = states random, but no description or quasi‐randomisation or open list/tables.
B. Were the outcomes of patients who withdrew described and included in the analysis (intention to treat)?
2 = withdrawals well described and intention to treat analysis based on all cases randomised possible or carried out.
1 = states number and reasons for withdrawal but intention to treat analysis not possible.
0 = no mention, inadequate detail, or obvious differences and no adjustment.
C. Were the outcome assessors blinded to treatment status?
2 = effective action taken to blind assessors.
1 = small or moderate chance of unblinding of assessors.
0 = not mentioned or not possible.
D. Were the treatment and control group comparable at entry?
2 = good comparability of groups, or confounding adjusted for in the analysis.
1 = confounding small; mentioned but not adjusted for.
0 = large potential for confounding, or not discussed.
E. Were the subjects blind to assignment status after allocation?
2 = effective action taken to blind subjects.
1 = small or moderate chance of unblinding of subjects.
0 = not possible, or not mentioned (unless double‐blind), or possible but not done.
F. Were the treatment providers blind to assignment status?
2 = effective action taken to blind treatment providers.
1 = small or moderate chance of unblinding of treatment providers.
0 = not possible, or not mentioned (unless double‐blind), or possible but not done.
G. Were care programs, other than the trial options, identical?
2 = care programs clearly identical.
1 = clear but trivial differences.
0 = not mentioned, or clear and important differences in care programs.
H. Were the inclusion and exclusion criteria clearly defined?
2 = clearly defined.
1 = poorly defined.
0 = not defined.
I. Were the interventions clearly defined?
2 = clearly defined interventions are applied with a standardised protocol.
1 = clearly defined interventions are applied but the application protocol is not standardised.
0 = intervention and/or application protocol are poorly or not defined.
J. Were the outcome measures clearly defined?
2 = clearly defined.
1 = poorly defined.
0 = not defined.
K. Was ascertainment of outcomes reliable?
2 = reliable, reproducible method using the same tool and trained observer, with prospective data collection.
1 = unclear method, or reliable method using different observer or tool (e.g. radiological equipment), or interval recall.
0 = unreliable method, including participant recall at end of trial.
L. Was the surveillance active, and the duration clinically appropriate?
2 = active surveillance of greater than six months.
1 = active surveillance from one to six months.
0 = surveillance not active, duration of less than one month, or not defined.
Total quality scores will be calculated as a ratio of the maximum total score of 24. Thus the total quality scores could range from zero to one. Where important information regarding study selection and data extraction are not provided within the primary papers, the authors will be contacted for clarification.
Data analysis
Statistical analysis will be performed using RevMan (RevMan 2003). The unit of analysis will be each patient. For dichotomous outcomes, relative risk will be used as a measure of effect (with 95 per cent confidence intervals). Where continuous outcome are assessed, the weighted mean difference will be used to express results. Pooled analysis will be conducted where appropriate.
Heterogeneity in the results of the trials will be initially assessed by inspection of graphical presentations and by calculating a test of heterogeneity (Chi‐square). We anticipate between‐trial variation in estimation of cure for those patients who receive antibiotic treatment by different administration route (e.g. parenteral or oral), duration of treatment, and among the patients with infection caused by different bacteria (Staphylococcus aureus, Enterobacteriaceae, Pseudomonas spp). Subgroup analyses will be performed in order to assess the impact of these possible sources of heterogeneity on the main results (RevMan 2003).
A funnel plot estimating the precision of trials (plots of logarithm of the relative risk (RR) for efficacy against the sample size will examined in order to estimate potential asymmetry. In addition, the standard normal deviate (SND), defined as the risk relative (RR) divided by its standard error, will be regressed against the estimate's precision (regression equation: SND = a + b x precision) in order to facilitate the prediction of potential heterogeneity or data irregularities in the meta‐analyses (Egger 1997). In this equation, the SND reflects the degree of funnel plot asymmetry as measured by the intercept from regression of standard normal deviates against precision.
A fixed effect model will used throughout the review, except in the event of significant heterogeneity between the trials (P < 0.10), when the random effect model will be chosen.
