Antibiotic therapy for the treatment of methicillin-resistant Staphylococcus aureus(mrsa) in non surgical wounds(review)

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1 Cochrane Database of Systematic Reviews Antibiotic therapy for the treatment of methicillin-resistant Staphylococcus aureus(mrsa) in non surgical wounds (Review) GurusamyKS,KotiR,ToonCD,WilsonP,DavidsonBR GurusamyKS,KotiR,ToonCD,WilsonP,DavidsonBR. Antibiotic therapy for the treatment of methicillin-resistant Staphylococcus aureus(mrsa) in non surgical wounds. Cochrane Database of Systematic Reviews 2013, Issue 11. Art. No.: CD DOI: / CD pub2. Antibiotic therapy for the treatment of methicillin-resistant Staphylococcus aureus(mrsa) in non surgical wounds(review) Copyright 2013 The Cochrane Collaboration. Published by John Wiley& Sons, Ltd.

2 T A B L E O F C O N T E N T S HEADER ABSTRACT PLAIN LANGUAGE SUMMARY SUMMARY OF FINDINGS FOR THE MAIN COMPARISON BACKGROUND OBJECTIVES METHODS RESULTS Figure Figure Figure DISCUSSION AUTHORS CONCLUSIONS ACKNOWLEDGEMENTS REFERENCES CHARACTERISTICS OF STUDIES DATA AND ANALYSES Analysis 1.1. Comparison 1 Antibiotic therapy for treatment of MRSA, Outcome 1 Eradication of MRSA CONTRIBUTIONS OF AUTHORS DECLARATIONS OF INTEREST SOURCES OF SUPPORT DIFFERENCES BETWEEN PROTOCOL AND REVIEW INDEX TERMS i

3 [Intervention Review] Antibiotic therapy for the treatment of methicillin-resistant Staphylococcus aureus (MRSA) in non surgical wounds Kurinchi Selvan Gurusamy 1, Rahul Koti 1, Clare D Toon 2, Peter Wilson 3, Brian R Davidson 1 1 Department of Surgery, Royal Free Campus, UCL Medical School, London, UK. 2 Public Health, West Sussex County Council, Chichester, UK. 3 Department of Microbiology & Virology, University College London Hospitals, London, UK Contact address: Kurinchi Selvan Gurusamy, Department of Surgery, Royal Free Campus, UCL Medical School, Royal Free Hospital Rowland Hill Street, London, NW3 2PF, UK. kurinchi2k@hotmail.com. Editorial group: Cochrane Wounds Group. Publication status and date: New, published in Issue 11, Citation: Gurusamy KS, Koti R, Toon CD, Wilson P, Davidson BR. Antibiotic therapy for the treatment of methicillin-resistant Staphylococcus aureus (MRSA) in non surgical wounds. Cochrane Database of Systematic Reviews 2013, Issue 11. Art. No.: CD DOI: / CD pub2. Background A B S T R A C T Non surgical wounds include chronic ulcers (pressure or decubitus ulcers, venous ulcers, diabetic ulcers, ischaemic ulcers), burns and traumatic wounds. The prevalence of methicillin-resistant Staphylococcus aureus (MRSA) colonisation (i.e. presence of MRSA in the absence of clinical features of infection such as redness or pus discharge) or infection in chronic ulcers varies between 7% and 30%. MRSA colonisation or infection of non surgical wounds can result in MRSA bacteraemia (infection of the blood) which is associated with a 30-day mortality of about 28% to 38% and a one-year mortality of about 55%. People with non surgical wounds colonised or infected with MRSA may be reservoirs of MRSA, so it is important to treat them, however, we do not know the optimal antibiotic regimen to use in these cases. Objectives To compare the benefits (such as decreased mortality and improved quality of life) and harms (such as adverse events related to antibiotic use) of all antibiotic treatments in people with non surgical wounds with established colonisation or infection caused by MRSA. Search methods We searched the following databases: The Cochrane Wounds Group Specialised Register (searched 13 March 2013); The Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 2); Database of Abstracts of Reviews of Effects (2013, Issue 2); NHS Economic Evaluation Database (2013, Issue 2); Ovid MEDLINE (1946 to February Week ); Ovid MEDLINE (In-Process & Other Non- Indexed Citations, March 12, 2013); Ovid EMBASE (1974 to 2013 Week 10); EBSCO CINAHL (1982 to 8 March 2013). Selection criteria We included only randomised controlled trials (RCTs) comparing antibiotic treatment with no antibiotic treatment or with another antibiotic regimen for the treatment of MRSA-infected non surgical wounds. We included all relevant RCTs in the analysis, irrespective of language, publication status, publication year, or sample size. Data collection and analysis Two review authors independently identified the trials, and extracted data from the trial reports. We calculated the risk ratio (RR) with 95% confidence intervals (CI) for comparing the binary outcomes between the groups and planned to calculate the mean difference (MD) with 95% CI for comparing the continuous outcomes. We planned to perform the meta-analysis using both fixed-effect and random-effects models. We performed intention-to-treat analysis whenever possible. 1

4 Main results We identified three trials that met the inclusion criteria for this review. In these, a total of 47 people with MRSA-positive diabetic foot infections were randomised to six different antibiotic regimens. While these trials included 925 people with multiple pathogens, they reported the information on outcomes for people with MRSA infections separately (MRSA prevalence: 5.1%). The only outcome reported for people with MRSA infection in these trials was the eradication of MRSA. The three trials did not report the review s primary outcomes (death and quality of life) and secondary outcomes (length of hospital stay, use of healthcare resources and time to complete wound healing). Two trials reported serious adverse events in people with infection due to any type of bacteria (i.e. not just MRSA infections), so the proportion of patients with serious adverse events was not available for MRSA-infected wounds. Overall, MRSA was eradicated in 31/47 (66%) of the people included in the three trials, but there were no significant differences in the proportion of people in whom MRSA was eradicated in any of the comparisons, as shown below. 1. Daptomycin compared with vancomycin or semisynthetic penicillin: RR of MRSA eradication 1.13; 95% CI 0.56 to 2.25 (14 people). 2. Ertapenem compared with piperacillin/tazobactam: RR of MRSA eradication 0.71; 95% CI 0.06 to 9.10 (10 people). 3. Moxifloxacin compared with piperacillin/tazobactam followed by amoxycillin/clavulanate: RR of MRSA eradication 0.87; 95% CI 0.56 to 1.36 (23 people). Authors conclusions We found no trials comparing the use of antibiotics with no antibiotic for treating MRSA-colonised non-surgical wounds and therefore can draw no conclusions for this population. In the trials that compared different antibiotics for treating MRSA-infected non surgical wounds, there was no evidence that any one antibiotic was better than the others. Further well-designed RCTs are necessary. P L A I N L A N G U A G E S U M M A R Y Antibiotic therapy for the treatment of methicillin-resistant Staphylococcus aureus (MRSA)-infected or colonised non surgical wounds Non surgical wounds include chronic skin ulcers (such as pressure sores or diabetic ulcers), burns and traumatic wounds. Methicillinresistant Staphylococcus aureus (MRSA) can be present in 7% to 30% of such wounds, and the MRSA may spread into the bloodstream, causing a life-threatening illness. A proportion of the wounds in which MRSA was present show signs of infection such as redness, pain, and pus discharge. The presence of MRSA without infection is called colonisation. It is not clear whether antibiotics should be used in MRSA colonised non-surgical wounds. The antibiotic that has to be used in MRSA-infected wounds is also not clear. We tried to find this out by performing a thorough search of the medical literature for studies that compared different antibiotic treatments for MRSAinfected or MRSA-colonised non surgical wounds. We included only randomised controlled trials, as, if they are conducted properly, they provide the best information. We included all relevant randomised controlled trials irrespective of the language in which the study was reported, the year of publication, and the number of people included in them. Two review authors independently identified the trials and extracted the relevant information in order to decrease the chance of an error occurring during this process. We identified three trials that provided some information on this topic. A total of 47 people with MRSA-infected diabetic foot infections were randomised to six different antibiotic treatments (choice of treatment determined by a method similar to coin tossing). The only outcome reported was the eradication of MRSA. The trials reported none of the other outcomes that are important for patients and healthcare funders, such as death, quality of life, length of hospital stay, use of healthcare resources and time to complete wound healing. Each trial compared different antibiotics, and in each comparison there was no difference in the effectiveness of the antibiotics in eradicating MRSA. The three trials were very small and had a number of design faults, so it is still not possible to say which antibiotic is the most effective in eradicating MRSA from non-surgical wounds. Because there were no trials at all comparing the use of antibiotics with no antibiotic we do not know whether using antibiotics at all makes a difference for people with MRSA-colonised non-surgical wounds. Further well-designed randomised controlled trials are necessary to determine the best treatment for non surgical wounds containing or infected with MRSA. 2

5 S U M M A R Y O F F I N D I N G S F O R T H E M A I N C O M P A R I S O N [Explanation] Eradication of MRSA Patient or population: patients with MRSA-infected non surgical wounds Settings: primary or secondary care Intervention: antibiotic therapy for treatment of MRSA Comparisons Illustrative comparative risks*(95% CI) Relative effect (95% CI) Daptomycin versus vancomycin or semisynthetic penicillin Assumed risk Control 667per1000 Ertapenem versus 333per1000 piperacillin/ tazobactam M oxifloxacin versus piperacillin/ tazobac- 833per1000 tam followed by amoxycillin/ clavulanate Corresponding risk Antibiotic therapy for treatmentofmrsa 747per1000 (373 to 1000) 237per1000 (20 to 1000) 725per1000 (467 to 1000) RR 1.13 (0.56 to 2.25) RR 0.71 (0.06 to 9.1) RR 0.87 (0.56 to 1.36) No of participants (studies) 14 (1 study) 10 (1 study) 23 (1 study) Quality of the evidence (GRADE) verylow 1,2 verylow 1,2 verylow 1,2 *The basis for theassumedrisk is the control group risk across studies. Thecorrespondingrisk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; RR: risk ratio. GRADE Working Group grades of evidence High quality: further research is very unlikely to change our confidence in the estimate of effect M oderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Lowquality: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate Very low quality: we are very uncertain about the estimate 3

6 1 The trials were at high risk of bias. 2 The confidence intervals overlapped 0 and 0.75 and/or There were fewer than 300 events in the two groups. xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 4

7 B A C K G R O U N D Description of the condition Methicillin-resistant Staphylococcus aureus (MRSA) - isolates of the bacterium Staphylococcus aureus that are not susceptible to the antibiotic methicillin - was first discovered in 1961 (Barber 1961; Jevons 1961; Knox 1961), and outbreaks of MRSA have been reported since the 1970s (Klimek 1976; O Toole 1970). MRSA infection is associated with significant mortality and morbidity. In the European Union member states, Norway and Iceland, MRSA infections cause an estimated one million extra hospital stays and cost an estimated EUR 600 million annually (ECDC 2009a), while in the USA they cause an estimated 125,000 hospitalisations annually (Kuehnert 2005). Although there has been a decrease in the incidence of MRSA in some countries such as the USA (Kallen 2010) - probably as a result of measures to combat MRSA infections (ECDC 2009b) - there has also been an increase in the incidence of infections in Nordic countries (Skov 2005). Methicillin (meticillin) resistance is a marker of resistance to some beta-lactam antibiotics (i.e. the penicillin antibiotics and most cephalosporin antibiotics, which are some of the most commonly used antibiotics) (Otter 2011). In addition to beta-lactam antibiotics, MRSA may be resistant to many other commonly-used antibiotics, such as erythromycin, clindamycin, gentamycin, ciprofloxacin and fusidic acid (Otter 2011). So, even though methicillin is not commonly used at present, methicillin resistance is an indicator of resistance to a wide range of antibiotics. MRSA can either be acquired in the hospital or in the community. It should be pointed out that the antibiotic resistance profile of community-acquired MRSA is different from hospital-acquired or healthcare-associated MRSA. Generally, community-acquired MRSA is resistant to fewer antibiotics than hospital-acquired MRSA (Fey 2003). Non surgical wounds include chronic ulcers (pressure or decubitus ulcers, venous ulcers, diabetic ulcers, ischaemic ulcers) (Roghmann 2001), burns and traumatic wounds. The prevalence of MRSA colonisation (i.e. presence of MRSA in the absence of clinical features of infection such as redness or pus discharge) or infection in chronic ulcers varies between 7% and 30% (Cataldo 2010; Dumville 2009; Roghmann 2001). The incidence of MRSA infection in burn wounds in hospitalised patients varies between 1% and 24% (Ganesamoni 2010; Kaiser 2011; Wibbenmeyer 2010). People with large burn wounds that are colonised or infected with MRSA may be reservoirs of MRSA (Boyce 1994). The incidence or prevalence of MRSA in traumatic wounds in the general population has not been extensively investigated. In one small study of war wounds, 3% of wounds had MRSA isolated on culture (Murray 2006). MRSA colonisation or infection of non surgical wounds can result in MRSA bacteraemia (infection of the blood) (Bang 2004; Roghmann 2001). The proportion of people with chronic ulcers colonised by MRSA who develop MRSA bacteraemia in the community setting is not known. In patients treated in critical care hospital settings in USA including people who had undergone surgical procedures and those who had soft tissue infections, MRSA was present in 166/545 (30%) of wounds (Roghmann 2001). MRSA bacteraemia developed in 28/166 (17%) of these patients (Roghmann 2001). A Brazilian study of hospital patients with pressure ulcers of at least Stage II, 63/145 (43%) of ulcers were colonised (13/145; 9%) or infected (50/145; 34%) with MRSA (Pirett 2012). MRSA bacteraemia developed in 1/13 (8%) of MRSA-colonised ulcers and in 11/22 (22%) of MRSA-infected ulcers (Pirett 2012). MRSA bacteraemia is associated with a 30- day mortality of about 28% to 38% (Lamagni 2011; Lewis 2011; Wang 2010), and a one-year mortality of about 55% (Kaye 2008). Thus, MRSA colonisation or infection of non surgical wounds is not a trivial issue. Description of the intervention The Oxford English Dictionary defines an antibiotic substance as one of a class of substances produced by living organisms that is capable of destroying, or inhibiting the growth of, micro-organisms, and is especially used for therapeutic purposes. Synthetic organic compounds that have similar properties are also called antibiotics (OED 2011). A variety of antibiotics, including beta-lactams (cephalosporins such as cefazolin), glycopeptide antibiotics (e.g. vancomycin, teicoplanin), clindamycin, trimethoprim-sulfamethoxazole (TMP-SMX), tetracyclines (doxycycline or minocycline), linezolid, daptomycin, telavancin, rifampicin, gentamycin and fluoroquinolone, can be used for the treatment of MRSA since MRSA, which is resistant to some antibiotics, is sensitive to one or more of the above antibiotics (Liu 2011). Different antibiotics are administered in different ways, with the common routes being oral, intravenous and topical (external) administration (Liu 2011). Antibiotics can be given as single agents or in combination (Liu 2011). How the intervention might work Antibiotics work by destroying, or inhibiting the growth of, MRSA. The mechanisms of action vary for different types of antibiotic, but in general terms they either destroy MRSA or prevent the bacteria from dividing (i.e. reproducing). The intervention might decrease the complications related to MRSA infection by preventing MRSA infection of the colonised wound or by treatment of the existing infection. Antibiotics may also prevent the spread of MRSA deep into tissues, including bones - which causes bone destruction (MRSA osteomyelitis) - and into the blood stream, thereby preventing MRSA bacteraemia and its consequences. 5

8 Why it is important to do this review Previous non-cochrane systematic reviews concerning people with non surgical wounds found weak evidence that linezolid was better than vancomycin in eradication of MRSA (microbiological outcomes) (Bounthavong 2010; Dodds 2009), without any significant differences in clinical outcomes. Clinical practice guidelines produced by the Infectious Diseases Society of America suggest that empirical treatment of non surgical wounds, such as infected burns and ulcers, should be by using one of a list of antibiotics (Liu 2011), although the same clinical guidelines provide specific antibiotic treatments for some other clinical situations (for example, mupirocin 2% topical ointment for minor skin infections in children). The evidence-base for the clinical guidelines was not stated. Thus, evidence-based clinical practice guidelines are lacking in this important area concerning prevention of MRSA bacteraemia and its associated mortality. Thus far, there has been no Cochrane systematic review that compared antibiotics for the treatment of MRSA infection in non surgical wounds. Information to inform clinical guidelines, microbiologists, physicians and policy-makers in the treatment of MRSA infections in non surgical wounds is needed. O B J E C T I V E S To compare the benefits (such as decreased mortality and improved quality of life) and harms (such as adverse events related to antibiotic use) of all antibiotic treatments in people with non surgical wounds with established colonisation or infection caused by MRSA. M E T H O D S Criteria for considering studies for this review Types of studies We included randomised clinical trials (RCTs), irrespective of their use of blinding, language of publication, publication status, date of publication, study setting or sample sizes. We planned to include cluster randomised clinical trials if the effect estimate was available after adjusting for clustering effect. We excluded other study designs such as quasi-randomised studies, cohort studies or case-control studies. Types of interventions We considered antibiotic treatment compared with no antibiotic treatment (placebo or intervention, different antibiotic (any antibiotic) treatments (and regimens) and comparisons of the same antibiotic with different dose, frequency or duration regimens. We included a combination of antibiotics as a complex intervention, i.e. considered the combination as a package. A complex intervention is one that can be divided into one or more individual components, but the component that causes the treatment effect is not known. Types of outcome measures Primary outcomes 1. All-cause mortality (at maximal follow-up, i.e. until the last visit of the patient or by other methods of follow-up). 2. Other serious adverse events, defined as any event that would increase mortality; is life-threatening; requires inpatient hospitalisation; results in a persistent or significant disability; or any important medical event that might have jeopardised the patient or requires intervention to prevent it (ICH-GCP 1996). 3. Quality of life (as defined by study authors). Secondary outcomes 1. Length of hospital stay (including any readmissions until resolution of infection). 2. Use of healthcare resources (e.g. hospital visits, outpatient appointments, general practitioner visits, community nurse visits). 3. Eradication of MRSA (at least three consecutive samples negative for MRSA separated by a time interval of at least two days between samples, or as defined by study authors) at maximal follow-up. 4. Time to complete wound healing (as defined by authors). Of these, eradication of MRSA is a microbiological outcome. All other outcomes are clinical outcomes. We planned to report all the outcomes for all the comparisons with at least two trials in Summary of findings for the main comparison. For the comparisons with only one trial, we planned to present the information in an additional table. However, since only one trial was included in each comparison, we have presented all the information in the Summary of findings for the main comparison. Search methods for identification of studies Types of participants Any person (irrespective of age) with a non surgical wound with established MRSA colonisation or infection. Electronic searches We searched the following electronic databases to identify reports of relevant RCTs: 6

9 1. The Cochrane Wounds Group Specialised Register (searched 13 March 2013); 2. The Cochrane Central Register of Controlled Trials (CENTRAL) (2013, Issue 2); 3. Database of Abstracts of Reviews of Effects (2013, Issue 2); 4. NHS Economic Evaluation Database (2013, Issue 2); 5. Ovid MEDLINE (1946 to February Week ); 6. Ovid MEDLINE (In-Process & Other Non-Indexed Citations, March 12, 2013); 7. Ovid EMBASE (1974 to 2013 Week 10); 8. EBSCO CINAHL (1982 to 8 March 2013). We used the following search strategy in the Cochrane Central Register of Controlled Trials (CENTRAL): #1 MeSH descriptor Skin Ulcer explode all trees #2 MeSH descriptor Leg Ulcer explode all trees #3 MeSH descriptor Foot Ulcer explode all trees #4 MeSH descriptor Diabetic Foot explode all trees #5 MeSH descriptor Pressure Ulcer explode all trees #6 MeSH descriptor Pilonidal Sinus explode all trees #7 MeSH descriptor Wounds, Penetrating explode all trees #8 MeSH descriptor Lacerations explode all trees #9 MeSH descriptor Burns explode all trees #10 MeSH descriptor Wound Infection explode all trees #11 MeSH descriptor Bites and Stings explode all trees #12 ((plantar or diabetic or heel* or foot or feet or ischaemic or ischemic or venous or varicose or stasis or arterial or decubitus or pressure or skin or leg or mixed or tropical or rheumatoid or sickle cell) near/5 (wound* or ulcer* or sore*)) #13 (bedsore* or bed sore*) #14 (pilonidal sinus* or pilonidal cyst*) #15 (cavity wound* or sinus wound*) #16 (laceration* or gunshot or stab or stabbing or stabbed or bite*) #17 (burn or burns or burned or scald* or thermal injur*) #18 (wound near/5 infection*) #19 ((malignant or experimental or traumatic) near wound*) # 20 ((infusion or donor or wound) near site*) # 21 (skin abscess* or skin abcess*) # 22 #1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9 or #10 or #11 or #12 or #13 or #14 or #15 or #16 or #17 or #18 or #19 or #20 or #21 # 23 MeSH descriptor Methicillin Resistance explode all trees # 24 MeSH descriptor Staphylococcal Infections explode all trees # 25 MeSH descriptor Staphylococcus aureus explode all trees # 26 #24 or #25 # 27 #23 and #26 # 28 MeSH descriptor Methicillin-Resistant Staphylococcus aureus explode all trees # 29 (methicillin-resistan* or meticillin-resistan* or MRSA) # 30 #27 or #28 or #29 # 31 MeSH descriptor Anti-Bacterial Agents explode all trees # 32 MeSH descriptor Penicillins explode all trees # 33 MeSH descriptor Cephalosporins explode all trees # 34 MeSH descriptor Tetracycline explode all trees # 35 (antibiotic* or penicillin* or beta-lactam* or cephalosporin* or clindamycin or trimethoprim* or tetracycline* or doxycycline or minocycline or linezolid or vancomycin or daptomycin or telavancin or rifampicin or gentamycin or gentamicin or fluoroquinolone) # 36 #31 or #32 or #33 or #34 or #35 # 37 #22 and #30 and #36 We adapted this strategy to search Ovid MEDLINE, Ovid EM- BASE and EBSCO CINAHL. We combined the Ovid MED- LINE search with the Cochrane Highly Sensitive Search Strategy for identifying randomised trials in MEDLINE: sensitivity- and precision-maximising version (2008 revision) (Lefebvre 2011). We combined the EMBASE search with the Ovid EMBASE filter developed by the UK Cochrane Centre (Lefebvre 2011). We combined the CINAHL searches with the trial filters developed by the Scottish Intercollegiate Guidelines Network (SIGN 2011). We did not restrict studies with respect to language, date of publication or study setting. We searched the metaregister of Controlled Trials (mrct) ( and the ICTRP (International Clinical Trials Registry Platform) portal maintained by World Health Organization ( on 11th December The metaregister includes the ISRCTN Register and the NIH ClinicalTrials.gov Register among others. The ICTRP portal includes these trial registers, along with trial registry data from a number of countries. Searching other resources We searched the references of the relevant identified trials to identify further relevant trials. We also contacted experts in MRSA infection to identify further trials. Data collection and analysis We performed the systematic review following the instructions in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011a). Selection of studies Two review authors (KG and RK) independently identified the trials for inclusion by first screening the titles and abstracts of the search results, and then obtaining the full text of the selected references. We obtained the full text if at least one of the review authors selected the title or abstract. RK and CT performed further selection of studies by going through the full text of the studies. We have listed the excluded studies with reasons for their exclusion (Characteristics of excluded studies). KG resolved any differences in study selection of full text by discussion with RK and CT until a consensus agreement was reached. 7

10 Data extraction and management Three review authors (KG, RK and CT) independently extracted the following data. 1. Year and language of publication. 2. Country in which the trial was performed. 3. Year(s) of conduct of the trial. 4. Inclusion and exclusion criteria. 5. Sample sizes. 6. Aetiology (cause) of non surgical wound. 7. Types of wound (e.g. venous ulcers, pressure ulcers). 8. Setting (inpatients versus outpatients). 9. Colonisation (without features of infection such as redness, pus discharge) versus wound infection. 10. Data on resistance profiles. 11. Details of antibiotic treatment including dose(s), route(s), frequency and duration(s). 12. Outcomes (as described above). 13. Risk of bias (as described below). Where multiple reports existed for a trial, we examined all the reports for information. We sought clarification for any unclear or missing information by contacting the authors of the individual trials. If there was any doubt about whether the trials shared the same participants - completely or partially (by identifying common authors and centres) - we planned to contact the study authors of the trials to check whether the trial report had been duplicated. We resolved any differences in opinion through discussion amongst the review authors. Assessment of risk of bias in included studies We followed the guidance in the Cochrane Handbook for Systematic Reviews of Interventions to assess risk of bias in included studies (Higgins 2011b). According to empirical evidence (Kjaergard 2001; Moher 1998; Schulz 1995; Wood 2008), we assessed the risk of bias of the trials on the following domains. Sequence generation 1. Low risk of bias: the method used was either adequate (e.g., computer-generated random numbers, table of random numbers) or unlikely to introduce confounding. 2. Uncertain risk of bias: there was insufficient information to assess whether the method used was likely to introduce confounding. 3. High risk of bias (the method used was improper and likely to introduce confounding (e.g., quasi-randomised studies). Such studies were excluded. Allocation concealment 1. Low risk of bias: (the method used was unlikely to induce bias on the final observed effect (e.g. central allocation). 2. Uncertain risk of bias: there was insufficient information to assess whether the method used was likely to induce bias on the estimate of effect. 3. High risk of bias: the method used was likely to induce bias on the final observed effect (e.g. open random allocation schedule). Blinding of participants and personnel 1. Low risk of bias: blinding was performed adequately, or the outcome measurement was not likely to be influenced by lack of blinding. 2. Uncertain risk of bias: there was insufficient information to assess whether the type of blinding used was likely to induce bias on the estimate of effect. 3. High risk of bias: no blinding or incomplete blinding, and the outcome or the outcome measurement was likely to be influenced by lack of blinding. Blinding of outcome assessors 1. Low risk of bias: blinding was performed adequately, or the outcome measurement was not likely to be influenced by lack of blinding. 2. Uncertain risk of bias: there was insufficient information to assess whether the type of blinding used was likely to induce bias on the estimate of effect. 3. High risk of bias: no blinding or incomplete blinding, and the outcome or the outcome measurement was likely to be influenced by lack of blinding. Incomplete outcome data 1. Low risk of bias: the underlying reasons for missing data were unlikely to make treatment effects depart from plausible values, or proper methods had been employed to handle missing data such as intention-to-treat analysis or multiple imputation methods. 2. Uncertain risk of bias: there was insufficient information to assess whether the missing data mechanism in combination with the method used to handle missing data was likely to induce bias on the estimate of effect. 3. High risk of bias: the crude estimate of effects were clearly biased due to the underlying reasons for missing data, and the methods used to handle missing data were unsatisfactory (e.g. complete case estimate). Selective outcome reporting 1. Low risk of bias: the trial protocol was available and all of the trial s pre-specified outcomes that were of interest in the review have been reported; if the trial protocol was not available, all the primary outcomes in this review were reported. 8

11 2. Uncertain risk of bias: there was insufficient information to assess whether the magnitude and direction of the observed effect was related to selective outcome reporting. 3. High risk of bias: not all of the trial s pre-specified primary outcomes had been reported. We considered trials classified as being at low risk of bias in all the above domains to be low bias-risk trials. We considered the other trials to be high bias-risk trials. included under that outcome, fully recognising that this form of imputation might decrease the weight of the study for calculation of mean differences and bias the effect estimate to no effect in case of standardised mean difference (Higgins 2011d). For time-to-event outcomes, if the hazard ratio and 95% CI were not reported, we planned to obtain the logarithm of hazard ratios (ln(hr)) and the standard error (SE) of ln(hr) according to the methods described by Parmar Measures of treatment effect For dichotomous variables, we calculated the risk ratio (RR) with 95% confidence interval (CI). Risk ratio calculations do not include trials in which no events occurred in either group, whereas risk difference calculations do. We will report the risk difference where the results obtained by using this association measure were different from risk ratio. For continuous variables, we planned to calculate the mean difference (MD) with 95% CI for outcomes that can be quantified (such as hospital stay), and standardised mean difference (SMD) with 95% CI for quality of life, where different assessment scales might be used. For time-to-event outcomes such as survival at maximal follow-up, we planned to calculate the hazard ratio (HR) with 95% CI. Unit of analysis issues The unit of analysis was individual people with MRSA colonisation or MRSA infection. Dealing with missing data We performed an intention-to-treat analysis whenever possible (Newell 1992). We planned to impute missing data for binary outcomes using various scenarios such as best-best, best-worst, worst-best, and worst-worst (Gurusamy 2009). In the best-best scenario, the outcomes of people with missing data in both groups are assumed to be good. In the best-worst scenario, the outcomes of people with missing data in the intervention group are assumed to be good while the outcomes of people with missing data in the control group are assumed to be bad. The worst-best scenario is the opposite of the best-worst scenario, i.e. the outcomes of people with missing data in the intervention group are assumed to be bad while the outcomes of people with missing data in the control group are assumed to be good. In the worst-worst scenario, the outcomes of people with missing data in both groups are assumed to be bad. For continuous outcomes, we planned to use available-case analysis. We planned to impute the standard deviation from P values according to the instructions in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011c), and use the median for the meta-analysis when the mean was not available. If it was not possible to calculate the standard deviation from the P value or the confidence intervals, we planned to impute the standard deviation as the highest standard deviation in the other trials Assessment of heterogeneity We planned to explore heterogeneity by means of the Chi 2 test, with significance set at P value 0.10, and measure the quantity of heterogeneity using the I 2 statistic (Higgins 2002). Thresholds for the interpretation of the I 2 statistic can be misleading. A rough guide to interpretation is as follows (Deeks 2011). 1. 0% to 40%: might not be important % to 60%: may represent moderate heterogeneity % to 90%: may represent substantial heterogeneity % to 100%: indicates considerable heterogeneity. Assessment of reporting biases We plan to use visual asymmetry on a funnel plot to explore reporting bias once we have 10 trials included in the review (Egger 1997; Macaskill 2001). We plan to perform the linear regression approach described by Egger 1997 to determine the funnel plot asymmetry. Selective reporting was also considered as evidence for reporting bias. Data synthesis For the comparison of antibiotic with placebo (or no intervention), we planned to perform the meta-analysis only if there was sufficient clinical homogeneity in terms of people included in the trials. This decision would be based on our clinical judgement. For the comparison of different antibiotics, we planned to perform the meta-analysis only if there was sufficient clinical homogeneity in terms of people included in the trials and antibiotics used (i.e. similar class of antibiotics with similar bactericidal profile). We planned to perform the meta-analyses using the software package Review Manager 5 (RevMan 2011), and following the recommendations of The Cochrane Collaboration (Deeks 2011). We planned to use both a random-effects model (DerSimonian 1986), and a fixed-effect model (DeMets 1987), in meta-analyses. Should discrepancy between the two models be identified from the pooled estimates and their confidence intervals, we planned to report both results; otherwise we planned to report the results of the fixed-effect model. With regard to dichotomous outcomes, risk ratio calculations do not include trials in which no events occurred in either group in the meta-analysis, whereas risk difference calculations do. We planned to report the risk difference (RD) when the results produced with this association measure led to different conclusions to those that would be reached if risk ratio was 9

12 used. However, we planned to use risk ratio as the measure used to arrive at conclusions, since risk ratios perform better when there are differences in the control event rate (proportion of people who develop the event in the control). Differences in conclusions using risk ratios and risk difference would have resulted in a decreased confidence in the results. We planned to use the generic inverse variance method to combine the hazard ratios for time-to-event outcomes. Sensitivity analysis We planned to perform a sensitivity analysis by imputing data for binary outcomes using various scenarios such as best-best, bestworst, worst-best, and worst-worst scenarios as described previously (Gurusamy 2009). We also planned to perform a sensitivity analysis by excluding the trials in which the mean and the standard deviation were imputed. Summary of findings We presented a Summary of findings table for all the primary and secondary outcomes (Schünemann 2011). R E S U L T S Subgroup analysis and investigation of heterogeneity We planned to perform the following subgroup analyses. 1. Trials with low risk of bias compared to trials with high risk of bias. 2. Trials in which people had MRSA infection (however defined by authors) compared to trials in which people had MRSA colonisation (presence of MRSA in wound culture without evidence of infection such as redness or pus discharge) and to those in which both groups of participants (MRSA colonisation and MRSA infection) were included. 3. Adults versus paediatric participants. 4. Different antibiotics (if they were meta-analysed on the basis of similar class of antibiotics with similar bactericidal profile). 5. Different regimens of antibiotics. 6. Different types of wound. We planned to use a P value of less than 0.05 for the Chi 2 test to identify the differences between subgroups. Description of studies Results of the search We identified a total of 476 unique references through electronic searches. We excluded 391 clearly irrelevant references through reading titles and abstracts. We retrieved 85 references in full for further assessment. We did not identify any additional references to trials by scanning reference lists of included trials. We did not identify any new trials through other searches or through contact with experts in the field. We excluded 80 references because of the reasons mentioned in the Characteristics of excluded studies section. We are awaiting the full text of one reference (Characteristics of studies awaiting classification). Three trials (four citations) met the inclusion criteria and were included in this review (Lipsky 2005; Lipsky 2005a; Schaper 2010). The reference flow is shown in Figure 1. 10

13 Figure 1. Study flow diagram 11

14 Included studies The three trials reported in this review had a total of 925 people who were infected or colonised with multiple pathogens (Lipsky 2005; Lipsky 2005a; Schaper 2010). A total of only 47 people with a foot ulcer infected with MRSA had their outcomes reported separately such that they could be included in this review and they were randomised to six different antibiotic regimens within the three trials. Since only people with MRSA infections were included for this review demographic information could not be obtained. However, two trials stated clearly that they included only adults (Lipsky 2005; Lipsky 2005a). This information was not reported for the third trial (Schaper 2010). Excluded studies A total of 80 references were excluded. Of these 80 references, three studies were not RCTs (Donati 1998; Liu 2005; Lowbury 1977). One study was not a RCT of an antibiotic intervention (Donati 1994). One study was a quasi-randomised study (Kidson 1979). The methicillin resistance status was not reported in 10 studies (Bucko 2002; Chuang 2011; Lipsky 1999; McGovern 2010; Miller 1989; Noel 2008; Ramirez 1987; Sinha 1997; Tassler 1993; Valtonen 1989). In the remaining 65 studies, no separate data were reported for MRSA-infected non surgical wounds (Cenizal 2007; Chen 2011; Corey 2010; Covington 2011; Craft 2011; Daniel 1999; Deville 2003; Dunbar 2011; Duong 2010; Florescu 2008; Friedland 2012; Giordano 2005; Giordano 2006; Goldstein 2002; Graham 2002; Gyssens 2009; Gyssens 2011; Harkless 2005; Huovinen 1994; Itani 2005; Itani 2010; Jauregui 2005; Kaplan 2003; Kohno 2007; Konychev 2012; Krievins 2009; Li 2003; Lin 2008; Luke 2010; Manaktala 2009; Markowitz 1992; Matthews 2012; McCollum 2007; McKinnon 2006; Nichols 1999; Noel 2012a; Noel 2012b; O Riordan 2009; Olderog 2009; Pakrooh 1977; Parish 1986; Postier 2004; Prokocimer 2011; Prokocimer 2013; Rajendran 2007; Ralph 2010; Schmitz 2009; Schmitz 2010; Schrenzel 2004; Sharpe 2005; Siami 2001; Siami 2002; Smith 1989; Stevens 2002; Stryjewski 2005; Stryjewski 2006; Stryjewski 2012; Talbot 2007; Tan 1993; Vick-Fragoso 2009; Wacha 2000; Weigelt 2005; Wible 2003; Wilcox 2010; Wilson 2009). Risk of bias in included studies All the included trials were at high risk of bias as shown in Figure 2 and Figure 3. Figure 2. Risk of bias graph: review authors judgements about each risk of bias item presented as percentages across all included studies 12

15 Figure 3. Risk of bias summary: review authors judgements about each risk of bias item for each included study 13

16 Allocation One trial reported an adequate method of random sequence generation and allocation concealment (Lipsky 2005). This trial was at low risk of selection bias. The other two trials were at unclear risk of selection bias (Lipsky 2005a; Schaper 2010). Blinding Blinding of participants and healthcare providers was performed in two trials considered to be at low risk of performance bias (Lipsky 2005; Schaper 2010). In the third trial, blinding of participants was not performed (Lipsky 2005a), so the trial may be at high risk of performance bias. Blinding of outcome assessors was performed in all three trials, so all three trials were free of detection bias (Lipsky 2005; Lipsky 2005a; Schaper 2010). Incomplete outcome data Post-randomisation drop-outs were reported in two trials (Lipsky 2005; Schaper 2010). In one trial, it was clear that the authors did not provide the information on all the people with MRSA infections (Lipsky 2005). In the other trial, information about the exclusion of any person with MRSA infection was not reported (Schaper 2010). One trial did not provide information on postrandomisation drop-outs (Lipsky 2005a). So, none of the trials was judged to be free from attrition bias. Selective reporting Eradication of MRSA was the only outcome reported in the trials. There was no information about mortality in participants, an outcome that would have been routinely recorded in such trials, so, all three trials suffered from reporting bias. Other potential sources of bias There were no other potential sources of bias in the trials. Effects of interventions See: Summary of findings for the main comparison Antibiotic therapy for treatment of MRSA in non surgical wounds The results are summarised in the Summary of findings table. The only outcome reported for people with MRSA infection in all three trials was the eradication of MRSA (Lipsky 2005; Lipsky 2005a; Schaper 2010). None of the other review outcomes was reported. Eradication of MRSA Overall, MRSA was eradicated in 31/47 (66%) of people included in the three trials (Analysis 1.1). There were no significant differences in the proportions of people in whom MRSA was eradicated in the any of the comparisons as shown below. 1. Daptomycin versus vancomycin or semisynthetic penicillin: RR 1.13; 95% CI 0.56 to 2.25 (14 people (Lipsky 2005)). 2. Ertapenem versus piperacillin/tazobactam: RR 0.71; 95% CI 0.06 to 9.10 (10 people (Lipsky 2005a)). 3. Moxifloxacin versus piperacillin/tazobactam followed by amoxycillin/clavulanate: RR 0.87; 95% CI 0.56 to 1.36 (23 people (Schaper 2010)). Statistical variations Since only one trial was included for each comparison, the issue of analysis with a fixed-effect versus random-effects model did not arise. Since meta-analysis was not performed, we did not assess the impact of calculating the risk difference so that trials with no events in both arms could be included. Subgroup analysis None of the planned subgroup analyses was performed because there was only one trial included for each outcome. Sensitivity analysis The number of people excluded from the different groups was not stated in any of the three trials, so we did not perform a sensitivity analysis imputing missing outcome data under different scenarios. Reporting bias Reporting bias was not reported because of the inclusion of only one trial under each outcome. D I S C U S S I O N Summary of main results The three trials reported in this review had a total of 925 people who were infected or colonised with multiple pathogens (Lipsky 2005; Lipsky 2005a; Schaper 2010). A total of only 47 people were infected with MRSA and had their outcomes reported such that they could be included in this review. The only outcome reported 14

17 for people with MRSA infection in all three trials was the eradication of MRSA (Lipsky 2005; Lipsky 2005a; Schaper 2010). The primary (death and quality of life) and secondary outcomes (length of hospital stay, use of healthcare resources and time to complete wound healing) of this review were not reported. Whilst two trials reported serious adverse events in people with infections due to any bacteria (i.e. not just MRSA infections), this information was not available for patients with MRSA infection. Overall, MRSA was eradicated in 31/47 (66%) of people included in the three trials, with no significant differences in the proportion of people in whom MRSA was eradicated in the any of the comparisons, as shown in Analysis 1.1. Thus, there is currently no evidence of any increased benefits or harms associated with a specific antibiotic regimen. However, one must note that the sample size in the trials was small and the confidence intervals were wide, which means that the trials were not sufficiently powered to measure differences in any of the outcomes. The prevalence of MRSA infection was about 5.1% in the three trials included in this review (47 people with MRSA infections in 925 people with diabetic foot infections due to all pathogens). Colonisation with MRSA occurs in 1% to 30% of non surgical wounds (Cataldo 2010; Ganesamoni 2010; Kaiser 2011; Murray 2006; Wibbenmeyer 2010; Roghmann 2001). MRSA colonisation and infection is a major health burden, so it is surprising that we found only three small trails that investigated this. There may be a paucity of information in this field because evidence from spontaneous skin and subcutaneous infections, such as abscesses, has been extrapolated to cover it. However, non surgical wounds have a raw surface (i.e. breach of epithelium with potential discharge of MRSA) as opposed to many skin and subcutaneous infections where the epithelium is not breached. Many of the 60 studies that were excluded on the basis of lack of separate data on MRSA-infected non surgical wounds could have included some people who met the inclusion criteria for this review. However, the information is contaminated by disease conditions that do not involve wounds or by the presence of other non-mrsa organisms. Consequently, this evidence cannot be used in the management of people with MRSA-infected or colonised non surgical wounds. Another possible reason for the paucity of randomised clinical trials is the extrapolation of evidence from observational studies. Randomised clinical trials are currently considered to be the best design to evaluate interventions. Clearly, randomised clinical trials are necessary in this field. A variety of antibiotics, including beta-lactams (cephalosporins such as cefazolin), glycopeptide antibiotics (e.g. vancomycin, teicoplanin), clindamycin, trimethoprim-sulfamethoxazole (TMP- SMX), tetracyclines (doxycycline or minocycline), linezolid, daptomycin, telavancin, rifampicin, gentamycin and fluoroquinolone, can be used for the treatment of MRSA, since MRSA, which is resistant to some antibiotics, is sensitive to one or more of the above antibiotics (Liu 2011). While some of the antibiotics used in the comparisons included in this review, such as daptomycin, and vancomycin are active against MRSA, other antibiotics, such as ertapenem and amoxycillin/clavulanate, have poor activity against it (Livermore 2003). These antibiotics were used in the trials because they were aimed at multiple organisms, and were not specifically targeting MRSA-infected wounds. Future randomised trials should randomise patients after confirmation of infection or colonisation with MRSA. Overall completeness and applicability of evidence Only people with diabetic foot infections were included in the trials included in this review, so the findings in this review are applicable only to people with diabetic foot infections (and not colonisation of diabetic foot ulcers). Two trials clearly stated that they included adults (Lipsky 2005; Lipsky 2005a). The third trial did not state this information (Schaper 2010). However, based on the disease condition, it is likely that the vast majority of participants were adults in the third trial also. Therefore, the findings of this review are applicable only to adults. Quality of the evidence As shown in the Summary of findings for the main comparison, the quality of evidence was very low. There are no insurmountable barriers in obtaining very high quality evidence, unlike some surgical comparisons where it is impossible or unethical to blind participants. Potential biases in the review process We performed a thorough search of the literature without any language or time of publication restrictions. In spite of this, we have not been able or will not be able to identify any trials that were conducted - but not reported - in the pre-mandatory trial registration era. We included only trials in which information on MRSAinfected non surgical wounds was mentioned. As mentioned in the Excluded studies sections, 65 studies were excluded because the information on MRSA-infected non surgical wounds was not available separately. However, because of the nature of the topic, one has to be pragmatic and accept that a significant proportion of such studies would not have summarised this information, and individual patient data meta-analysis - which is resource intensive - has to be performed. According to information from the included studies, the proportion of people with MRSA-infected non surgical wounds is likely to be about 5% (Lipsky 2005; Lipsky 2005a; Schaper 2010); spending significant resources on obtaining information for 5% of participants included in these studies is questionable. The antibiotics might not have been targeted at MRSA specifically in these trials. It should also be pointed out that only a proportion of trial authors provide individual patient data. 15