Antibiotic therapy for the treatment of methicillin‐resistant Staphylococcus aureus (MRSA) in non surgical wounds

Abstract

Background

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 4 2013); 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.

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.

Plain language summary

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. Methicillin‐resistant 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 MRSA‐infected 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.

Summary of findings

Summary of findings for the main comparison. Antibiotic therapy for treatment of MRSA in non surgical wounds.

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)	No of participants (studies)	Quality of the evidence (GRADE)
	Assumed risk	Corresponding risk
	Control	Antibiotic therapy for treatment of MRSA
Daptomycin versus vancomycin or semisynthetic penicillin	667 per 1000	747 per 1000 (373 to 1000)	RR 1.13 (0.56 to 2.25)	14 (1 study)	⊕⊝⊝⊝ very low1,2
Ertapenem versus piperacillin/tazobactam	333 per 1000	237 per 1000 (20 to 1000)	RR 0.71 (0.06 to 9.1)	10 (1 study)	⊕⊝⊝⊝ very low1,2
Moxifloxacin versus piperacillin/tazobactam followed by amoxycillin/clavulanate	833 per 1000	725 per 1000 (467 to 1000)	RR 0.87 (0.56 to 1.36)	23 (1 study)	⊕⊝⊝⊝ very low1,2
*The basis for the assumed risk is the control group risk across studies. The corresponding risk (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 Moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: 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

¹ The trials were at high risk of bias.
 ² The confidence intervals overlapped 0 and 0.75 and/or 1.25. There were fewer than 300 events in the two groups.

Background

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.

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.

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.

Methods

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 participants

Any person (irrespective of age) with a non surgical wound with established MRSA colonisation or infection.

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 Table 1. 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 Table 1.

Search methods for identification of studies

Electronic searches

We searched the following electronic databases to identify reports of relevant RCTs: 

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 4 2013);

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 EMBASE and EBSCO CINAHL. We combined the Ovid MEDLINE 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) (http://www.controlled‐trials.com/mrct/) and the ICTRP (International Clinical Trials Registry Platform) portal maintained by World Health Organization (http://apps.who.int/trialsearch/) on 11th December 2012. 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.

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.

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.

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 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 1998.

Assessment of heterogeneity

We planned to explore heterogeneity by means of the Chi² test, with significance set at P value 0.10, and measure the quantity of heterogeneity using the I² statistic (Higgins 2002).

Thresholds for the interpretation of the I² statistic can be misleading. A rough guide to interpretation is as follows (Deeks 2011).

1. 0% to 40%: might not be important.

2. 30% to 60%: may represent moderate heterogeneity.

3. 50% to 90%: may represent substantial heterogeneity.

4. 75% 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 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.

Summary of findings

We presented a 'Summary of findings' table for all the primary and secondary outcomes (Schünemann 2011).

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 Chi² test to identify the differences between subgroups.

Sensitivity analysis

We planned to perform a sensitivity analysis by imputing data for binary outcomes using various scenarios such as best‐best, best‐worst, 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.

Results

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.

1.

Study flow diagram

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.

2.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies

3.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study

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 post‐randomisation 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: Table 1

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.

1.1. Analysis.

Comparison 1 Antibiotic therapy for treatment of MRSA, Outcome 1 Eradication of MRSA.

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.

Discussion

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 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 Table 1, 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 MRSA‐infected 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. Thus, short of another systematic review with individual patient data, the current evidence appears to be the best level of evidence available.

Agreements and disagreements with other studies or reviews

This is the first systematic review on this topic, so we are not able to assess its agreement or disagreement with other studies or reviews.

Authors' conclusions

Implications for practice.

There is currently no evidence to recommend any specific antibiotic in the treatment of methicillin‐resistant Staphylococcus aureus (MRSA)‐infected non surgical wounds. There is currently no evidence that antibiotic therapy is required for MRSA‐colonised non‐surgical wounds.

Implications for research.

Further well‐designed RCTs are necessary in which randomisation should be performed after confirmation of the presence of MRSA. Such trials should include outcomes such as mortality, quality of life, and health resource utilisation.

Data and analyses

Comparison 1. Antibiotic therapy for treatment of MRSA.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Eradication of MRSA	3		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
1.1 Daptomycin versus vancomycin or semisynthetic penicillin	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
1.2 Ertapenem versus piperacillin/tazobactam	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
1.3 Moxifloxacin versus piperacillin/tazobactam followed by amoxycillin/clavulanate	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Lipsky 2005.

Methods	Randomised clinical trial
Participants	Country: worldwide multicentred study Number randomised: 10 Post‐randomisation drop‐outs: not stated Revised sample size: 10 Average age: not stated Male:female ratio: not stated Aetiology and types of non surgical wound: diabetic foot ulcer Setting: inpatients or outpatients: not stated Colonisation or wound infection: infection Resistance profile: not stated Inclusion criteria: people with diabetes, aged 18‐85 years, who required hospitalisation for an infected ulcer that was known or suspected (based on a Gram‐stained smear) to be caused by a Gram‐positive organism Exclusion criteria: 1. people with minor or superficial skin infections, uncomplicated cellulitis, myositis, multiple infected ulcers at distant sites, infected third‐degree burn wounds, osteomyelitis, known bacteraemic shock, hypotension, or any disorder that could interfere with the treatment evaluation 2. pregnancy 3. infection due to an organism known to be resistant to any study drug before study entry 4. body weight < 40 kg 5. history of hypersensitivity reaction to any study drug 6. need for haemodialysis or peritoneal dialysis 7. impaired renal function (creatinine clearance less than 30 mL/min) 8. immunosuppression, serum creatine phosphokinase > 50% above the upper limit of normal 9. use of any 3‐hydroxy‐3‐methylglutaryl co‐enzyme reductase inhibitor statin drugs 10. > 24 h of systemic antibiotic therapy for infected ulcer within previous 48 h, unless the infecting Gram‐positive organism was resistant to that therapy, or it was clinically ineffective
Interventions	Participants randomly assigned to two groups Group 1: antibiotic 1 (n = 1), daptomycin (7‐14 day course; 4 mg/kg every 24 h IV over 30 min) Group 2: antibiotic 2 (n = 9), vancomycin 1 g every 12 h IV over 60 min or a semi‐synthetic penicillin (nafcillin, oxacillin, cloxacillin or flucloxacillin, according to the investigator’s choice) given in equally divided doses totaling 4‐12 g/day IV (duration of treatment not stated)
Outcomes	Eradication of MRSA
Notes	This trial included 133 participants with diabetic foot ulcers with Gram‐positive or suspected Gram‐positive organisms. For this review, we obtained information only on MRSA‐positive diabetic foot ulcers. There were no significant differences in proportions of participants with serious adverse events when all participants included in this trial were considered Source of funding: Cubist Pharmaceuticals, Lexington, MA, USA We attempted to contact the authors in February 2013
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: this information was not available
Allocation concealment (selection bias)	Unclear risk	Comment: this information was not available
Blinding of participants and personnel (performance bias) All outcomes	High risk	Quote: "investigator‐blinded Phase III trials"
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "investigator‐blinded Phase III trials"
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Comment: this information was not available
Selective reporting (reporting bias)	High risk	Comment: important clinical outcomes were not reported

Lipsky 2005a.

Methods	Randomised clinical trial
Participants	Country: worldwide multicentred study Number randomised: 34 Post‐randomisation drop‐outs: 20 (58.8%) Revised sample size: 14 Average age: not stated Male:female ratio: not stated Aetiology and types of non surgical wound: diabetic foot ulcer Setting: inpatients or outpatients: both Colonisation or wound infection: infection Resistance profile: not stated Inclusion criteria: adults with diabetes mellitus (type 1 or type 2, controlled by diet or medications) who had a foot infection that did not extend above the knee Exclusion criteria: 1. people with mild infections that did not require parenteral antibiotic therapy; known at entry to be caused by pathogens resistant to either study drug; predominantly caused by thermal burns; categorised as necrotising fasciitis; known or suspected to be associated with underlying osteomyelitis, unless all the infected bone was removed within 48 h after initiating study therapy; complicated by indwelling foreign or prosthetic material; or associated with gangrenous tissue that could not be adequately removed by surgical debridement 2. women who were pregnant, nursing, or fertile and not using contraception 3. people with a history of a serious reaction to any beta‐lactam antibiotic 4. need for any additional concomitant systemic antibacterial agent other than the study drug(s) or vancomycin 5. diabetes or impaired glucose tolerance that was secondary 6. arterial perfusion insufficiency of the affected limb, requiring a revascularisation procedure 7. any rapidly progressive, or terminal, illness 8. a requirement for dialysis 9. immunosuppression from any cause 10. receiving corticosteroid therapy (≥ 40 mg prednisone daily or its equivalent) 11. markedly abnormal liver function tests 12. haematocrit < 25%, haemoglobin < 8 g/L, platelet count < 75,000/mm3; or coagulation test results > 1.5 times the upper limit of normal (unless on anticoagulant therapy) 13. people who had been treated for > 24 h with systemic antibiotic therapy likely to be effective for their infection within the 72 h before study screening, unless there was clinical evidence of treatment failure with an associated deep‐tissue culture that yielded pathogen(s)
Interventions	Participants randomly assigned to 2 groups Group 1: antibiotic 1 (n = 8), ertapenem (1 g IV bolus, followed by saline placebo every 6 h daily for 5‐28 days) Group 2: antibiotic 2 (n = 6), piperacillin/tazobactam (3·375 g IV every 6 h daily for 5‐28 days) After 5 days of IV therapy the investigator could elect to switch patients in either group to oral antibiotic therapy with amoxicillin/clavulanic acid (875 mg/125 mg every 12 h) if they met pre‐specified criteria
Outcomes	Eradication of MRSA
Notes	This trial included 586 participants with diabetic foot ulcers. For this review, we obtained information only on MRSA‐positive diabetic foot ulcers. There were no significant differences in proportions of participants with serious adverse events when all participants included in this trial were considered Reasons for post‐randomisation drop‐outs: not stated Source of funding: Merck and Co, West Point, PA, USA We attempted to contact the authors in February 2013
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Merck and Co provided blocks of computer‐generated allocation numbers and open‐label study drug to an unblinded pharmacist at every site"
Allocation concealment (selection bias)	Low risk	Quote: "The pharmacist was responsible for randomising patients (1:1 ratio), and prepared intravenous therapy to be administered by clinical personnel (unaware of treatment allocation)"
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "The pharmacist was responsible for randomising patients (1:1 ratio), and prepared intravenous therapy to be administered by clinical personnel (unaware of treatment allocation)"
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: " . . . we did a prospective, randomised, double‐blinded, multicentre trial . . . The pharmacist was responsible for randomising patients (1:1 ratio), and prepared intravenous therapy to be administered by clinical personnel (unaware of treatment allocation)"
Incomplete outcome data (attrition bias) All outcomes	High risk	Comment: this trial included 586 patients with diabetic foot ulcers. There were post‐randomisation drop‐outs for various reasons. For this review, we obtained information only on MRSA‐positive diabetic foot ulcers. There were a total of 34 MRSA isolates. The report contains the results of 14 patients only
Selective reporting (reporting bias)	High risk	Comment: important clinical outcomes were not reported

Schaper 2010.

Methods	Randomised clinical trial
Participants	Country: multicentred study (Europe and USA) Number randomised: 23 Post‐randomisation drop‐outs: not stated Revised sample size: 23 Average age: not stated Male:female ratio: not stated Aetiology and types of non surgical wound: diabetic foot infections Setting: inpatients or outpatients: not stated Colonisation or wound infection: infection Resistance profile: not stated Inclusion criteria: people with diabetic foot infections
Interventions	Participants were randomly assigned to 2 groups Group 1: antibiotic 1 (n = 11), moxifloxacin (oral or IV 400 mg IV 4 times a day for 7‐21 days) Group 2: antibiotic 2 (n = 12), piperacillin/tazobactam (4.0 g/0.5 g 3 times a day followed by amoxycillin/clavulanate 875 mg/125 mg twice a day for 7‐21 days)
Outcomes	Eradication of MRSA
Notes	This trial included 206 participants with diabetic foot infections. For this review, we obtained information only on MRSA‐positive diabetic foot infections Source of funding: not stated We attempted to contact the authors in February 2013
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: this information was not available
Allocation concealment (selection bias)	Unclear risk	Comment: this information was not available
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "This was a double‐dummy, double‐blind, randomised, controlled, multinational trial"
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "This was a double‐dummy, double‐blind, randomised, controlled, multinational trial"
Incomplete outcome data (attrition bias) All outcomes	High risk	Comment: this trial included 233 participants with diabetic foot ulcers of whom 198 had bacteriological information. The report contains success rates for 187 patients. It was not clear whether any participants with MRSA were excluded from the analysis
Selective reporting (reporting bias)	High risk	Comment: important clinical outcomes were not reported

Abbreviations

< = less than
 > = more than
 ≥ = more than or equal to
 h = hour(s) 
 IV = intravenous(ly) 
 min = minute(s)

Characteristics of excluded studies [ordered by study ID]

Study	Reason for exclusion
Bucko 2002	Methicillin resistance status not known
Cenizal 2007	No separate data for MRSA‐infected non surgical wounds
Chen 2011	No separate data for MRSA‐infected non surgical wounds
Chuang 2011	Methicillin resistance status not known
Corey 2010	No separate data for MRSA‐infected non surgical wounds
Covington 2011	No separate data for MRSA‐infected non surgical wounds
Craft 2011	No separate data for MRSA‐infected non surgical wounds
Daniel 1999	No separate data for MRSA‐infected non surgical wounds
Deville 2003	No separate data for MRSA‐infected non surgical wounds
Donati 1994	Not a randomised controlled trial
Donati 1998	Not a randomised controlled trial of antibiotic treatment
Dunbar 2011	No separate data for MRSA‐infected non surgical wounds
Duong 2010	No separate data for MRSA‐infected non surgical wounds
Florescu 2008	No separate data for MRSA‐infected non surgical wounds
Friedland 2012	No separate data for MRSA‐infected non surgical wounds
Giordano 2005	No separate data for MRSA‐infected non surgical wounds
Giordano 2006	No separate data for MRSA‐infected non surgical wounds
Goldstein 2002	No separate data for MRSA‐infected non surgical wounds
Graham 2002	No separate data for MRSA‐infected non surgical wounds
Gyssens 2009	No separate data for MRSA‐infected non surgical wounds
Gyssens 2011	No separate data for MRSA‐infected non surgical wounds
Harkless 2005	No separate data for MRSA‐infected non surgical wounds
Huovinen 1994	No separate data for MRSA‐infected non surgical wounds
Itani 2005	No separate data for MRSA‐infected non surgical wounds
Itani 2010	No separate data for MRSA‐infected non surgical wounds
Jauregui 2005	No separate data for MRSA‐infected non surgical wounds
Kaplan 2003	No separate data for MRSA‐infected non surgical wounds
Kidson 1979	Quasi‐randomised study ‐ allocation by alternation
Kohno 2007	No separate data for MRSA‐infected non surgical wounds
Konychev 2012	No separate data for MRSA‐infected non surgical wounds
Krievins 2009	No separate data for MRSA‐infected non surgical wounds
Li 2003	No separate data for MRSA‐infected non surgical wounds
Lin 2008	No separate data for MRSA‐infected non surgical wounds
Lipsky 1999	Methicillin resistance status not known
Liu 2005	Not a randomised controlled trial
Lowbury 1977	Not a randomised controlled trial
Luke 2010	No separate data for MRSA‐infected non surgical wounds
Manaktala 2009	No separate data for MRSA‐infected non surgical wounds
Markowitz 1992	No separate data for MRSA‐infected non surgical wounds
Matthews 2012	No separate data for MRSA‐infected non surgical wounds
McCollum 2007	No separate data for MRSA‐infected non surgical wounds
McGovern 2010	Methicillin resistance status not known
McKinnon 2006	No separate data for MRSA‐infected non surgical wounds
Miller 1989	Methicillin resistance status not known
Nichols 1999	No separate data for MRSA‐infected non surgical wounds
Noel 2008	No separate data for MRSA‐infected non surgical wounds
Noel 2012a	Methicillin resistance status not known
Noel 2012b	No separate data for MRSA‐infected non surgical wounds
O'Riordan 2009	No separate data for MRSA‐infected non surgical wounds
Olderog 2009	No separate data for MRSA‐infected non surgical wounds
Pakrooh 1977	No separate data for MRSA‐infected non surgical wounds
Parish 1986	No separate data for MRSA‐infected non surgical wounds
Postier 2004	No separate data for MRSA‐infected non surgical wounds
Prokocimer 2011	No separate data for MRSA‐infected non surgical wounds
Prokocimer 2013	No separate data for MRSA‐infected non surgical wounds
Rajendran 2007	No separate data for MRSA‐infected non surgical wounds
Ralph 2010	No separate data for MRSA‐infected non surgical wounds
Ramirez 1987	Methicillin resistance status not known
Schmitz 2009	No separate data for MRSA‐infected non surgical wounds
Schmitz 2010	No separate data for MRSA‐infected non surgical wounds
Schrenzel 2004	No separate data for MRSA‐infected non surgical wounds
Sharpe 2005	No separate data for MRSA‐infected non surgical wounds
Siami 2001	No separate data for MRSA‐infected non surgical wounds
Siami 2002	No separate data for MRSA‐infected non surgical wounds
Sinha 1997	Methicillin resistance status not known
Smith 1989	No separate data for MRSA‐infected non surgical wounds
Stevens 2002	No separate data for MRSA‐infected non surgical wounds
Stryjewski 2005	No separate data for MRSA‐infected non surgical wounds
Stryjewski 2006	No separate data for MRSA‐infected non surgical wounds
Stryjewski 2012	No separate data for MRSA‐infected non surgical wounds
Talbot 2007	No separate data for MRSA‐infected non surgical wounds
Tan 1993	No separate data for MRSA‐infected non surgical wounds
Tassler 1993	Methicillin resistance status not known
Valtonen 1989	Methicillin resistance status not known
Vick‐Fragoso 2009	No separate data for MRSA‐infected non surgical wounds
Wacha 2000	No separate data for MRSA‐infected non surgical wounds
Weigelt 2005	No separate data for MRSA‐infected non surgical wounds
Wible 2003	No separate data for MRSA‐infected non surgical wounds
Wilcox 2010	No separate data for MRSA‐infected non surgical wounds
Wilson 2009	No separate data for MRSA‐infected non surgical wounds

Characteristics of studies awaiting assessment [ordered by study ID]

Golcman 1997.

Methods	Randomised clinical trial
Participants	Bacterial skin and cutaneous structures infections
Interventions	Cefprozil (500 mg or 20 mg/kg single daily dose) versus cefaclor (750 mg or 20 mg/kg divided in 3 doses) for 10 days
Outcomes	Eradication of pathogens
Notes	It is not clear whether separate data are available for MRSA‐infected non surgical wounds. Full text is awaited

Differences between protocol and review

The effect estimate for all comparisons are presented in Table 1.

Contributions of authors

Kurinchi Gurusamy conceived the review question, developed and co‐ordinated the review, secured funding, was involved in screening the titles and abstracts, arbitration of study selection using full text, performed data extraction of the selected studies, completed the first draft of the review, performed part of the writing or editing, made an intellectual contribution to the review, approved the final version prior to submission and is guarantor of the review.
 Rahul Koti was involved in screening the titles and abstracts, study selection using full text, performed data extraction of the selected studies, made an intellectual contribution to the review and approved the final version prior to submission.
 Clare Toon was involved in study selection using full text, performed data extraction of the selected studies, made an intellectual contribution to the review and approved the final version prior to submission.
 Peter Wilson made an intellectual contribution to the review, advised on the review and approved the final version prior to submission.
 Brian R Davidson conceived the review question, secured funding, made an intellectual contribution to the review, advised on the review and approved the final version prior to submission.

Contributions of editorial base:

Nicky Cullum: edited the review, and advised on methodology, interpretation and review content.
 Sally Bell‐Syer: co‐ordinated the editorial process; advised on methodology, interpretation and content; and edited the review.
 Ruth Foxlee: designed the search strategy and edited the search methods section.

Sources of support

Internal sources

• NIHR/Department of Health (England), (Cochrane Wounds Group), UK.

External sources

• National Institute for Health Research, UK.

  National Institute for Health Research, the health research division of the UK Government Department of Health funds K Gurusamy to complete this review.

Declarations of interest

KS Gurusamy and BR Davidson are funded by a joint funding scheme between the Department of Health and the Wellcome Trust on a completely unrelated project.

R Koti and C Toon ‐ none known.

APR Wilson is a consultant microbiologist in the NHS advising on antibiotic use and advises some private hospitals on infection control. He is a member of a clinical trial drug safety monitoring board for a monoclonal antibody. He has been an expert witness in infection‐related cases. He has a number of non‐commercial grants for research in the area of transmission of infection. APR Wilson was part funded by the UCLH/UCL Comprehensive Biomedical Centre with funding from the Department of Health's NIHR Biomedical Research Centres.

This project was funded by the National Institute for Health Research (NIHR).

Disclaimer

Department of Health disclaimer: The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the NIHR, NHS (National Health Service), or the Department of Health.

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