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Meta-Analysis
. 2015 Sep 4;2015(9):CD009061.
doi: 10.1002/14651858.CD009061.pub2.

Systemic antibiotics for treating diabetic foot infections

Anna Selva Olid  1 , Ivan Solà, Leticia A Barajas-Nava, Oscar D Gianneo, Xavier Bonfill Cosp, Benjamin A Lipsky
Affiliations
Meta-Analysis

Systemic antibiotics for treating diabetic foot infections

Anna Selva Olid et al. Cochrane Database Syst Rev. .

Abstract

Background: 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.

Objectives: To determine the effects and safety of systemic antibiotics in the treatment of DFIs compared with other systemic antibiotics, topical foot care or placebo.

Search methods: 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(HTA; The Cochrane Library), the National Health Service Economic Evaluation Database (NHS-EED; The Cochrane Library), unpublished literature in OpenSIGLE and ProQuest Dissertations and on-going trials registers.

Selection criteria: 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.

Data collection and analysis: 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.

Main results: 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.

Authors' conclusions: 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.

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Conflict of interest statement

Anna Selva: none known. Leticia Andrea Barajas Nava: none known. Oscar Gianneo: none known. Xavier Bonfill Cosp: none known. Ivan Solà Arnau: none known. Benjamin A. Lipsky: consulting with Pfizer, Merck, Wyeth‐Ayerst, Cubist, Ortho‐McNeil and Novartis in an advisory capacity, I do not believe that these consultations have impaired my ability to work on this review. Also, I am a full‐time employee of the US Federal Government (Department of Veterans Affairs). I am an investigator in some trials included in this review, but had no involvement in the selection of studies, or the assessment of risk of bias, analysis and interpretation of the included trials. I provided expertise content, and contributed substantial clinical content to the review.

Figures

1
1
Study flow diagram
2
2
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
3
3
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
1.1
1.1. Analysis
Comparison 1 A. Anti‐pseudomonas penicillins: piperacillin‐tazobactam vs ticarcillin‐clavulanate, Outcome 1 Clinical resolution of the infection.
2.1
2.1. Analysis
Comparison 2 A. Anti‐pseudomonal penicillins: piperacillin‐tazobactam vs ampicillin‐sulbactam, Outcome 1 Clinical resolution of the infection.
2.2
2.2. Analysis
Comparison 2 A. Anti‐pseudomonal penicillins: piperacillin‐tazobactam vs ampicillin‐sulbactam, Outcome 2 Adverse effects.
2.3
2.3. Analysis
Comparison 2 A. Anti‐pseudomonal penicillins: piperacillin‐tazobactam vs ampicillin‐sulbactam, Outcome 3 Amputations.
3.1
3.1. Analysis
Comparison 3 A. Anti‐pseudomonal penicillins: piperacillin‐tazobactam vs imipenem‐cilastatin, Outcome 1 Clinical resolution of the infection.
3.2
3.2. Analysis
Comparison 3 A. Anti‐pseudomonal penicillins: piperacillin‐tazobactam vs imipenem‐cilastatin, Outcome 2 Adverse effects.
3.3
3.3. Analysis
Comparison 3 A. Anti‐pseudomonal penicillins: piperacillin‐tazobactam vs imipenem‐cilastatin, Outcome 3 Amputations.
3.4
3.4. Analysis
Comparison 3 A. Anti‐pseudomonal penicillins: piperacillin‐tazobactam vs imipenem‐cilastatin, Outcome 4 Recurrence.
4.1
4.1. Analysis
Comparison 4 B. Broad‐spectrum penicillins: ampicillin‐sulbactam vs cefoxitin, Outcome 1 Clinical resolution of the infection.
4.2
4.2. Analysis
Comparison 4 B. Broad‐spectrum penicillins: ampicillin‐sulbactam vs cefoxitin, Outcome 2 Adverse effects.
4.3
4.3. Analysis
Comparison 4 B. Broad‐spectrum penicillins: ampicillin‐sulbactam vs cefoxitin, Outcome 3 Amputations.
5.1
5.1. Analysis
Comparison 5 C. Cephalosporins: ceftobiprole vs ceftazidime + vancomycin, Outcome 1 Clinical resolution of the infection.
6.1
6.1. Analysis
Comparison 6 C. Cephalosporins: ceftriaxone + metronidazole vs ticarcillin‐clavulanate, Outcome 1 Clinical resolution of the infection.
7.1
7.1. Analysis
Comparison 7 D. Carbapenems: ertapenem vs piperacillin‐tazobactam, Outcome 1 Clinical resolution of the infection.
7.2
7.2. Analysis
Comparison 7 D. Carbapenems: ertapenem vs piperacillin‐tazobactam, Outcome 2 Adverse effects.
8.1
8.1. Analysis
Comparison 8 D. Carbapenems: imipenem‐cilastatin vs piperacillin + clindamycin, Outcome 1 Clinical resolution of the infection.
8.2
8.2. Analysis
Comparison 8 D. Carbapenems: imipenem‐cilastatin vs piperacillin + clindamycin, Outcome 2 Adverse effects.
8.3
8.3. Analysis
Comparison 8 D. Carbapenems: imipenem‐cilastatin vs piperacillin + clindamycin, Outcome 3 Recurrence.
9.1
9.1. Analysis
Comparison 9 D. Carbapenems: imipenem‐cilastatin vs ampicillin‐sulbactam, Outcome 1 Clinical resolution of the infection at the completion of therapy.
9.2
9.2. Analysis
Comparison 9 D. Carbapenems: imipenem‐cilastatin vs ampicillin‐sulbactam, Outcome 2 Clinical resolution of the infection at the end of follow‐up.
9.3
9.3. Analysis
Comparison 9 D. Carbapenems: imipenem‐cilastatin vs ampicillin‐sulbactam, Outcome 3 Adverse effects.
9.4
9.4. Analysis
Comparison 9 D. Carbapenems: imipenem‐cilastatin vs ampicillin‐sulbactam, Outcome 4 Amputations.
9.5
9.5. Analysis
Comparison 9 D. Carbapenems: imipenem‐cilastatin vs ampicillin‐sulbactam, Outcome 5 Recurrence.
10.1
10.1. Analysis
Comparison 10 E. Fluoroquinolones: fourth‐generation fluoroquinolones vs anti‐pseudomonal penicillins, Outcome 1 Clinical resolution of the infection.
11.1
11.1. Analysis
Comparison 11 E. Fluoroquinolones: moxifloxacin vs amoxicillin‐clavulanate, Outcome 1 Clinical resolution of the infection.
12.1
12.1. Analysis
Comparison 12 E. Fluoroquinolones: third‐generation fluoroquinolone vs extended‐spectrum penicillin, Outcome 1 Clinical resolution of the infection.
13.1
13.1. Analysis
Comparison 13 E. Fluoroquinolones: second‐generation fluoroquinolone vs extended‐spectrum penicillin, Outcome 1 Clinical resolution of the infection.
13.2
13.2. Analysis
Comparison 13 E. Fluoroquinolones: second‐generation fluoroquinolone vs extended‐spectrum penicillin, Outcome 2 Adverse effects.
13.3
13.3. Analysis
Comparison 13 E. Fluoroquinolones: second‐generation fluoroquinolone vs extended‐spectrum penicillin, Outcome 3 Amputations.
14.1
14.1. Analysis
Comparison 14 F. Other antibiotics: daptomycin vs control, Outcome 1 Clinical resolution of the infection.
14.2
14.2. Analysis
Comparison 14 F. Other antibiotics: daptomycin vs control, Outcome 2 Adverse effects.
15.1
15.1. Analysis
Comparison 15 F. Other antibiotics: linezolid vs aminopenicillin + beta lactamase inhibitor, Outcome 1 Clinical resolution of the infection.
15.2
15.2. Analysis
Comparison 15 F. Other antibiotics: linezolid vs aminopenicillin + beta lactamase inhibitor, Outcome 2 Adverse effects.
16.1
16.1. Analysis
Comparison 16 F. Other antibiotics: clindamycin vs cephalexin, Outcome 1 Clinical resolution of the infection.
16.2
16.2. Analysis
Comparison 16 F. Other antibiotics: clindamycin vs cephalexin, Outcome 2 Adverse effects.
16.3
16.3. Analysis
Comparison 16 F. Other antibiotics: clindamycin vs cephalexin, Outcome 3 Ulcer healing.
17.1
17.1. Analysis
Comparison 17 F. Other antibiotics: tigecycline vs ertapenem, Outcome 1 Clinical resolution of the infection.
17.2
17.2. Analysis
Comparison 17 F. Other antibiotics: tigecycline vs ertapenem, Outcome 2 Adverse events.
17.3
17.3. Analysis
Comparison 17 F. Other antibiotics: tigecycline vs ertapenem, Outcome 3 Septicaemia.
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Update of

References

References to studies included in this review

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RELIEF Study {published data only}
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Saltoglu 2010 {published data only}
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Siami 2001 {published data only}
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SIDESTEP Study {published data only}
    1. Abramson MA. The SIDESTEP study of diabetic foot infections (DFI): a multicenter,double‐blinded, randomized, controlled trial (RCT) of ertapenem (E)v s. piperacillin/tazobactam (P/T). Diabetologia. 2005; Vol. 48 Suppl 1:A81‐2.
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STIC Study {published data only}
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Tan 1993 {published data only}
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References to studies excluded from this review

Acevedo 1990 {published data only}
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Akova 1996 {published data only}
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Al‐Ebous 2005 {published data only}
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Bradsher 1984 {published data only}
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Cenizal 2007 {published data only}
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Chantelau 1996 {published data only}
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Chen 2013 {published data only}
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Crouzet 2011 {published data only}
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Daniel 1999 {published data only}
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Darwish 1993 {published data only}
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Deresinski 2008 {published data only}
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Edmonds 2004 {published data only}
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Embil 2006 {published data only}
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Fernández Montequín 1991 {published data only}
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File 1983 {published data only}
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File 1994 {published data only}
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Foster 1998 {published data only}
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Gentry 1989a {published data only}
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Gentry 1989b {published data only}
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Hughes 1987 {published data only}
    1. Hughes CE, Johnson CC, Bamberger DM, Reinhardt JF, Peterson LR, Mulligan ME, et al. Treatment and long‐term follow‐up of foot infections in patients with diabetes or ischemia: a randomized, prospective, double‐blind comparison of cefoxitin and ceftizoxime. Clinical Therapeutics 1987;10 Suppl A:36‐49. - PubMed
Itani 2010 {published data only}
    1. Itani KM, Dryden MS, Bhattacharyya H, Kunkel MJ, Baruch AM, Weigelt JA. Efficacy and safety of linezolid versus vancomycin for the treatment of complicated skin and soft‐tissue infections proven to be caused by methicillin resistant Staphylococcus aureus. American Journal of Surgery 2010;199:804‐16. - PubMed
Joshi 2003 {published data only}
    1. Joshi S, Maroli S, Moulick ND, Badhane S, Joshi S, Sthalekar N, et al. Efficacy and tolerability of a combination of ofloxacin and tinidazole in the management of infectious diabetic foot ulcer. Journal of the Indian Medical Association 2003;101:329‐32. - PubMed
Lipksy 2011 {published data only}
    1. Lipsky BA, Itani KM, Weigelt JA, Joseph W, Paap CM, Reisman A, et al. The role of diabetes mellitus in the treatment of skin and skin structure infections caused by methicillin‐resistant Staphylococcus aureus: results from three randomized controlled trials. International Journal of Infectious Diseases 2011;15:140‐6. - PubMed
Lipsky 1999a {published data only}
    1. Lipsky BA, Miller B, Schwartz R, Henry DC, Nolan T, McCabe A, et al. Sparfloxacin versus ciprofloxacin for the treatment of community‐acquired, complicated skin and skin‐structure infections. Clinical Therapeutics 1999;21(4):675‐90. - PubMed
Nelson 2006b {published data only}
    1. Nelson EA, O'Meara S, Golder S, Dalton J, Craig D, Iglesias C. Systematic review of antimicrobial treatments for diabetic foot ulcers. Diabetic Medicine 2006;23(4):348‐59. - PubMed
Noel 2008b {published data only}
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Pérez‐Ruvalcaba 1987 {published data only}
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Peters 2012 {published data only}
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Peterson 1989 {published data only}
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Siami 2002 {published data only}
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Siebert 1985 {published data only}
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Smith 1992 {published data only}
    1. Smith OB, Richards CS, Taylor AT, Nesbit RR, Fisher JF, Willis EB. Prospective, controlled, randomized, evaluator‐blind, comparative study of oral ciprofloxacin with and without oral metronidazole versus intravenous ticarcillin/clavulanic acid followed by oral amoxicillin/clavulanic acid in the treatment of diabetic foot infections. ASHP Midyear Clinical Meeting 1992;27:P‐159R.
Smith 1993 {published data only}
    1. Smith JW, Nichols RL. Comparison of oral fleroxacin with oral amoxicillin/clavulanate for treatment of skin and soft tissue infections. The American Journal of Medicine 1993;94 Suppl 3A:150‐3. - PubMed
Stevens 1999 {published data only}
    1. Stevens DL. Teicoplanin for skin and soft tissue infections: an open study and a randomized, comparative trial versus cefazolin. Journal of Infection and Chemotherapy 1999;5:40‐5. - PubMed
Stevens 2000 {published data only}
    1. Stevens DL, Smith LG, Bruss JB, McConnell‐Martin MA, Duvall SE, Todd WM, et al. Randomized comparison of linezolid (PNU‐100766) versus oxacillin‐dicloxacillin for treatment of complicated skin and soft tissue infections. Antimicrobial Agents and Chemotherapy 2000;44(12):3408‐13. - PMC - PubMed
Stevens 2002 {published data only}
    1. Stevens DL, Herr D, Lampiris H, Hunt JL, Batts DH, Hafkin B. Linezolid versus vancomycin for the treatment of methicillin‐resistant Staphylococcus aureus infections. Clinical Infectious Diseases 2002;34:1481‐90. - PubMed
Stupin 2014 {published data only}
    1. Stupin VA, Prividentsev AI, Goriunov SV, Zhilina SV, Vasin VI. [Vasin new fluoroquinolones in treatment of patients with infectious lesions in diabetic foot syndrome]. Khirurgiia 2014;10:102‐8. [PUBMED: 25484159] - PubMed
Vardakas 2008 {published data only}
    1. Vardakas KZ, Horianopoulou M, Falagas ME. Factors associated with treatment failure in patients with diabetic foot infections: an analysis of data from randomized controlled trials. Journal Diabetes Research and Clinical Practice 2008;80:344‐51. - PubMed
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References to ongoing studies

NCT01199783 {published data only}
    1. NCT01199783. Application of daptomycin in MRSA infected diabetic foot in comparison to vancomycin treatment. clinicaltrials.gov/show/ NCT01199783 (accessed September 2014) 29 April 2010.
NCT01370616 {published data only}
    1. NCT01370616. A phase III, randomized, double‐blind, active comparator‐controlled clinical trial to study the efficacy and safety of ertapenem sodium (MK‐0826) versus piperacillin/tazobactam sodium in the treatment of diabetic foot infections in Chinese adults. clinicaltrials.gov/show/ NCT01370616 (accessed September 2014) 2011.

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