Review question
We reviewed the effects on resolution of infection and safety of antibiotics given orally or intravenously (directly into the blood system) in people with diabetes that have a foot infection.
Background
One of the most frequent complications of people with diabetes is foot disorders, specially foot ulcers or wounds. These wounds can easily become infected, and are known as a diabetic foot infections (DFIs). If they are not treated, the infection can progress rapidly, involving deeper tissues and threatening survival of the limb. Sometimes these infections conclude with the affected limb needing to be amputated.
Most DFIs require treatment with systemic antibiotics, that is, antibiotics that are taken orally, or are inserted straight into the bloodstream (intravenously), and affect the whole body. The choice of the initial antibiotic treatment depends on several factors such as the severity of the infection, whether the patient has received another antibiotic treatment for it, or whether the infection has been caused by a micro-organism that is known to be resistant to usual antibiotics (e.g. methicillin-resistant Staphylococcus aureus - better known as MRSA). The objective of antibiotic therapy is to stop the infection and ensure it does not spread.
There are many antibiotics available, but it is not known whether one particular antibiotic - or type of antibiotic - is better than the others for treatment of DFIs.
The investigation
We searched through the medical literature up to March 2015 looking for randomised controlled trials (which produce the most reliable results) that compared different systemic antibiotics against each other, or against antibiotics applied only to the infected area (topical application), or against a fake medicine (placebo) in the treatment of DFIs.
Study characteristics
We identified 20 relevant randomised controlled trials, with a total of 3791 participants. Eighteen of the 20 studies were funded by pharmaceutical companies. All trials compared systemic antibiotics with other systemic antibiotics.
Key results
It is unclear whether any particular antibiotic is better than any another for curing infection or avoiding amputation. One trial suggested that ertapenem (an antibiotic) with or without vancomycin (another antibiotic) is more effective than tigecycline (another antibiotic) for resolving DFI. It is also generally unclear whether different antibiotics are associated with more or fewer adverse effects. The following differences were identified:
1. carbapenems (a class of antibiotic) combined with anti-pseudomonal agents (antibiotics that kill Pseudomonas bacteria) produced fewer adverse effects than anti-pseudomonal penicillins (another class of antibiotic);
2. daptomycin (an antibiotic) caused fewer adverse effects than vancomycin or other semi-synthetic penicillins (a class of antibiotic);
3. linezolid (an antibiotic) caused more harm than ampicillin-sulbactam (a combination of antibiotics);
4. tigecycline produced more adverse effects than the combination of ertapenem with or without vancomycin.
Quality of the evidence
There were important differences between the trials in terms of the diversity of antibiotics assessed, the duration of treatments, and the point at which the results were measured. The included studies had limitations in the way they were designed or performed, as a result of these differences and design limitations, our confidence in the findings of this review is low.
The evidence for the relative effects of different systemic antibiotics for the treatment of foot infections in diabetes is very heterogeneous and generally at unclear or high risk of bias. Consequently it is not clear if any one systemic antibiotic treatment is better than others in resolving infection or in terms of safety. One non-inferiority trial suggested that ertapenem with or without vancomycin is more effective in achieving clinical resolution of infection than tigecycline. Otherwise the relative effects of different antibiotics are unclear. The quality of the evidence is low due to limitations in the design of the included trials and important differences between them in terms of the diversity of antibiotics assessed, duration of treatments, and time points at which outcomes were assessed. Any further studies in this area should have a blinded assessment of outcomes, use standardised criteria to classify severity of infection, define clear outcome measures, and establish the duration of treatment.
Foot infection is the most common cause of non-traumatic amputation in people with diabetes. Most diabetic foot infections (DFIs) require systemic antibiotic therapy and the initial choice is usually empirical. Although there are many antibiotics available, uncertainty exists about which is the best for treating DFIs.
To determine the effects and safety of systemic antibiotics in the treatment of DFIs compared with other systemic antibiotics, topical foot care or placebo.
In April 2015 we searched the Cochrane Wounds Group Specialised Register; The Cochrane Central Register of Controlled Trials (CENTRAL; The Cochrane Library); Ovid MEDLINE, Ovid MEDLINE (In-Process & Other Non-Indexed Citations); Ovid EMBASE, and EBSCO CINAHL. We also searched in the Database of Abstracts of Reviews of Effects (DARE; The Cochrane Library), the Health Technology Assessment database (HTA; The Cochrane Library), the National Health Service Economic Evaluation Database (NHS-EED; The Cochrane Library), unpublished literature in OpenSIGLE and ProQuest Dissertations and on-going trials registers.
Randomised controlled trials (RCTs) evaluating the effects of systemic antibiotics (oral or parenteral) in people with a DFI. Primary outcomes were clinical resolution of the infection, time to its resolution, complications and adverse effects.
Two review authors independently selected studies, assessed the risk of bias, and extracted data. Risk ratios (RR) were estimated for dichotomous data and, when sufficient numbers of comparable trials were available, trials were pooled in a meta-analysis.
We included 20 trials with 3791 participants. Studies were heterogenous in study design, population, antibiotic regimens, and outcomes. We grouped the sixteen different antibiotic agents studied into six categories: 1) anti-pseudomonal penicillins (three trials); 2) broad-spectrum penicillins (one trial); 3) cephalosporins (two trials); 4) carbapenems (four trials); 5) fluoroquinolones (six trials); 6) other antibiotics (four trials).
Only 9 of the 20 trials protected against detection bias with blinded outcome assessment. Only one-third of the trials provided enough information to enable a judgement about whether the randomisation sequence was adequately concealed. Eighteen out of 20 trials received funding from pharmaceutical industry-sponsors.
The included studies reported the following findings for clinical resolution of infection: there is evidence from one large trial at low risk of bias that patients receiving ertapenem with or without vancomycin are more likely to have resolution of their foot infection than those receiving tigecycline (RR 0.92, 95% confidence interval (CI) 0.85 to 0.99; 955 participants). It is unclear if there is a difference in rates of clinical resolution of infection between: 1) two alternative anti-pseudomonal penicillins (one trial); 2) an anti-pseudomonal penicillin and a broad-spectrum penicillin (one trial) or a carbapenem (one trial); 3) a broad-spectrum penicillin and a second-generation cephalosporin (one trial); 4) cephalosporins and other beta-lactam antibiotics (two trials); 5) carbapenems and anti-pseudomonal penicillins or broad-spectrum penicillins (four trials); 6) fluoroquinolones and anti-pseudomonal penicillins (four trials) or broad-spectrum penicillins (two trials); 7) daptomycin and vancomycin (one trial); 8) linezolid and a combination of aminopenicillins and beta-lactamase inhibitors (one trial); and 9) clindamycin and cephalexin (one trial).
Carbapenems combined with anti-pseudomonal agents produced fewer adverse effects than anti-pseudomonal penicillins (RR 0.27, 95% CI 0.09 to 0.84; 1 trial). An additional trial did not find significant differences in the rate of adverse events between a carbapenem alone and an anti-pseudomonal penicillin, but the rate of diarrhoea was lower for participants treated with a carbapenem (RR 0.58, 95% CI 0.36 to 0.93; 1 trial). Daptomycin produced fewer adverse effects than vancomycin or other semi-synthetic penicillins (RR 0.61, 95%CI 0.39 to 0.94; 1 trial). Linezolid produced more adverse effects than ampicillin-sulbactam (RR 2.66; 95% CI 1.49 to 4.73; 1 trial), as did tigecycline compared to ertapenem with or without vancomycin (RR 1.47, 95% CI 1.34 to 1.60; 1 trial). There was no evidence of a difference in safety for the other comparisons.