Systemic antibiotics for treating diabetic foot infections
Abstract
Background
Foot infection is the most common cause of non‐traumatic amputation in people with diabetes. Most diabetic foot infections (DFIs) require systemic antibiotic therapy and the initial choice is usually empirical. Although there are many antibiotics available, uncertainty exists about which is the best for treating DFIs.
Objectives
To determine the effects and safety of systemic antibiotics in the treatment of DFIs compared with other systemic antibiotics, topical foot care or placebo.
Search methods
In April 2015 we searched the Cochrane Wounds Group Specialised Register; The Cochrane Central Register of Controlled Trials (CENTRAL; The Cochrane Library); Ovid MEDLINE, Ovid MEDLINE (In‐Process & Other Non‐Indexed Citations); Ovid EMBASE, and EBSCO CINAHL. We also searched in the Database of Abstracts of Reviews of Effects (DARE; The Cochrane Library), the Health Technology Assessment database (HTA; The Cochrane Library), the National Health Service Economic Evaluation Database (NHS‐EED; The Cochrane Library), unpublished literature in OpenSIGLE and ProQuest Dissertations and on‐going trials registers.
Selection criteria
Randomised controlled trials (RCTs) evaluating the effects of systemic antibiotics (oral or parenteral) in people with a DFI. Primary outcomes were clinical resolution of the infection, time to its resolution, complications and adverse effects.
Data collection and analysis
Two review authors independently selected studies, assessed the risk of bias, and extracted data. Risk ratios (RR) were estimated for dichotomous data and, when sufficient numbers of comparable trials were available, trials were pooled in a meta‐analysis.
Main results
We included 20 trials with 3791 participants. Studies were heterogenous in study design, population, antibiotic regimens, and outcomes. We grouped the sixteen different antibiotic agents studied into six categories: 1) anti‐pseudomonal penicillins (three trials); 2) broad‐spectrum penicillins (one trial); 3) cephalosporins (two trials); 4) carbapenems (four trials); 5) fluoroquinolones (six trials); 6) other antibiotics (four trials).
Only 9 of the 20 trials protected against detection bias with blinded outcome assessment. Only one‐third of the trials provided enough information to enable a judgement about whether the randomisation sequence was adequately concealed. Eighteen out of 20 trials received funding from pharmaceutical industry‐sponsors.
The included studies reported the following findings for clinical resolution of infection: there is evidence from one large trial at low risk of bias that patients receiving ertapenem with or without vancomycin are more likely to have resolution of their foot infection than those receiving tigecycline (RR 0.92, 95% confidence interval (CI) 0.85 to 0.99; 955 participants). It is unclear if there is a difference in rates of clinical resolution of infection between: 1) two alternative anti‐pseudomonal penicillins (one trial); 2) an anti‐pseudomonal penicillin and a broad‐spectrum penicillin (one trial) or a carbapenem (one trial); 3) a broad‐spectrum penicillin and a second‐generation cephalosporin (one trial); 4) cephalosporins and other beta‐lactam antibiotics (two trials); 5) carbapenems and anti‐pseudomonal penicillins or broad‐spectrum penicillins (four trials); 6) fluoroquinolones and anti‐pseudomonal penicillins (four trials) or broad‐spectrum penicillins (two trials); 7) daptomycin and vancomycin (one trial); 8) linezolid and a combination of aminopenicillins and beta‐lactamase inhibitors (one trial); and 9) clindamycin and cephalexin (one trial).
Carbapenems combined with anti‐pseudomonal agents produced fewer adverse effects than anti‐pseudomonal penicillins (RR 0.27, 95% CI 0.09 to 0.84; 1 trial). An additional trial did not find significant differences in the rate of adverse events between a carbapenem alone and an anti‐pseudomonal penicillin, but the rate of diarrhoea was lower for participants treated with a carbapenem (RR 0.58, 95% CI 0.36 to 0.93; 1 trial). Daptomycin produced fewer adverse effects than vancomycin or other semi‐synthetic penicillins (RR 0.61, 95%CI 0.39 to 0.94; 1 trial). Linezolid produced more adverse effects than ampicillin‐sulbactam (RR 2.66; 95% CI 1.49 to 4.73; 1 trial), as did tigecycline compared to ertapenem with or without vancomycin (RR 1.47, 95% CI 1.34 to 1.60; 1 trial). There was no evidence of a difference in safety for the other comparisons.
Authors' conclusions
The evidence for the relative effects of different systemic antibiotics for the treatment of foot infections in diabetes is very heterogeneous and generally at unclear or high risk of bias. Consequently it is not clear if any one systemic antibiotic treatment is better than others in resolving infection or in terms of safety. One non‐inferiority trial suggested that ertapenem with or without vancomycin is more effective in achieving clinical resolution of infection than tigecycline. Otherwise the relative effects of different antibiotics are unclear. The quality of the evidence is low due to limitations in the design of the included trials and important differences between them in terms of the diversity of antibiotics assessed, duration of treatments, and time points at which outcomes were assessed. Any further studies in this area should have a blinded assessment of outcomes, use standardised criteria to classify severity of infection, define clear outcome measures, and establish the duration of treatment.
PICOs
Plain language summary
Antibiotics to treat foot infections in people with diabetes
Review question
We reviewed the effects on resolution of infection and safety of antibiotics given orally or intravenously (directly into the blood system) in people with diabetes that have a foot infection.
Background
One of the most frequent complications of people with diabetes is foot disorders, specially foot ulcers or wounds. These wounds can easily become infected, and are known as a diabetic foot infections (DFIs). If they are not treated, the infection can progress rapidly, involving deeper tissues and threatening survival of the limb. Sometimes these infections conclude with the affected limb needing to be amputated.
Most DFIs require treatment with systemic antibiotics, that is, antibiotics that are taken orally, or are inserted straight into the bloodstream (intravenously), and affect the whole body. The choice of the initial antibiotic treatment depends on several factors such as the severity of the infection, whether the patient has received another antibiotic treatment for it, or whether the infection has been caused by a micro‐organism that is known to be resistant to usual antibiotics (e.g. methicillin‐resistant Staphylococcus aureus ‐ better known as MRSA). The objective of antibiotic therapy is to stop the infection and ensure it does not spread.
There are many antibiotics available, but it is not known whether one particular antibiotic ‐ or type of antibiotic ‐ is better than the others for treatment of DFIs.
The investigation
We searched through the medical literature up to March 2015 looking for randomised controlled trials (which produce the most reliable results) that compared different systemic antibiotics against each other, or against antibiotics applied only to the infected area (topical application), or against a fake medicine (placebo) in the treatment of DFIs.
Study characteristics
We identified 20 relevant randomised controlled trials, with a total of 3791 participants. Eighteen of the 20 studies were funded by pharmaceutical companies. All trials compared systemic antibiotics with other systemic antibiotics.
Key results
It is unclear whether any particular antibiotic is better than any another for curing infection or avoiding amputation. One trial suggested that ertapenem (an antibiotic) with or without vancomycin (another antibiotic) is more effective than tigecycline (another antibiotic) for resolving DFI. It is also generally unclear whether different antibiotics are associated with more or fewer adverse effects. The following differences were identified:
1. carbapenems (a class of antibiotic) combined with anti‐pseudomonal agents (antibiotics that kill Pseudomonas bacteria) produced fewer adverse effects than anti‐pseudomonal penicillins (another class of antibiotic);
2. daptomycin (an antibiotic) caused fewer adverse effects than vancomycin or other semi‐synthetic penicillins (a class of antibiotic);
3. linezolid (an antibiotic) caused more harm than ampicillin‐sulbactam (a combination of antibiotics);
4. tigecycline produced more adverse effects than the combination of ertapenem with or without vancomycin.
Quality of the evidence
There were important differences between the trials in terms of the diversity of antibiotics assessed, the duration of treatments, and the point at which the results were measured. The included studies had limitations in the way they were designed or performed, as a result of these differences and design limitations, our confidence in the findings of this review is low.
Authors' conclusions
Background
Description of the condition
Among the serious complications of diabetes, disorders of the feet (ulceration, infection, gangrene and amputation) are among the most frequent causes of morbidity, and a leading cause of hospitalisation (Boulton 2005; Frykberg 2006; IDSA 2012; Nelson 2006a). Foot infection is the most common precipitating cause of non‐traumatic amputations, hospitalisation and reduction of quality of life in people with diabetes (Blanes 2011; IDSA 2012; Pecoraro 1990; Raspovic 2014; Reiber 1999). Approximately 15% of people with diabetes will have a foot ulcer during their life, with an annual incidence of 1% to 4% (Blanes 2011). Foot ulcers are clinically infected in just over half of patients at presentation (Lavery 2003; Prompers 2007). A diabetic foot infection (DFI) is defined as any type of skin, soft tissue or bone infection affecting tissues below the ankle in people with diabetes. These infections include cellulitis (in deep skin), paronychia (around nails), abscesses, myositis (in muscle), tendonitis (in tendons), necrotising fasciitis (infection that kills tissue), osteomyelitis (in bone) and septic arthritis (in joints; Lipsky 2004a). The major predisposing factor to these infections is foot ulceration, which is usually a consequence of peripheral neuropathy (nerve damage), and is often accompanied by peripheral arterial disease, or trauma. Ulcers cause disruption of the protective skin barrier, which exposes the underlying soft tissue to bacterial colonisation (i.e. proliferation of a micro‐organism that does not cause cell damage or an inflammatory host response). Once the foot wound is colonised it may become actively infected, which can cause further destruction of the tissues and, in severe cases, systemic (whole body) inflammatory responses. The sequence from uninfected to infected foot wound can progress relatively quickly, within a few days, but occasionally within even hours. When infection progresses without interruption to involve deeper tissues, it becomes potentially limb‐threatening, and even life‐threatening (Bader 2008; Lipsky 2004b; West 1995). Although rare, infection can occasionally develop without any remembered ulceration or traumatic lesion (Bader 2008). In addition to the associated morbidity, DFI is also a costly complication, with a total cost (including direct and indirect costs) that ranges from EUR 9273 to EUR 16,835, with the highest cost related to hospitalisation (Prompers 2008).
A DFI is defined clinically, not microbiologically, by the presence of systemic signs of infection apparently related to a foot lesion, purulent secretions, or at least two classic signs or symptoms of inflammation (redness, warmth, pain or tenderness, and tissue hardening; IDSA 2012). Sometimes it is difficult to decide whether a chronic ulcer (i.e. a lesion that has been present for several weeks and exhibits delayed or stalled healing) is infected (Bradley 1999; Edmonds 2005). This is especially true in people with peripheral neuropathy or vascular insufficiency (impaired blood flow), which may conceal or mimic infection. Furthermore, people with diabetes may not show the typical inflammation response to an infection (Bader 2008).
All infected diabetic foot wounds require treatment, which almost always includes antimicrobial therapy. This therapy is almost always an antibiotic agent, given through a topical (surface application) or systemic route. The available evidence does not support administration of antibiotic therapy for diabetic foot wounds that are not clinically infected, though they obviously require appropriate local care (Lipsky 2004b).
Description of the intervention
Most DFIs require systemic antibiotic therapy in addition to other treatments, such as debridement (removal of dead tissue), drainage, dead space management, dressing and correction of any metabolic abnormalities (Bader 2008; IDSA 2012). Another Cochrane review will review the effects of topical antimicrobials for infections of the foot in diabetes (Lipsky 2014).
Since DFIs can progress relatively rapidly, and infection is defined clinically rather than microbiologically, there is no reason to delay starting antibiotic therapy if infection is suspected. The selection of an antibiotic regimen should take into consideration the particular needs and comorbidities of the individual patient as well as the proven or suspected pathogens and their antibiotic susceptibilities. Then, the clinician can decide which specific drug or combination is needed, including the optimal route of administration and the treatment duration required.
The choice of initial antibiotic therapy is usually empirical (i.e. based on the best guess of the nature of the causative organism(s) and made before the results of wound cultures are available). Treatment selection should take into account the severity of the foot infection, any history of recent antimicrobial treatment, previous infection with antibiotic‐resistant organisms, recent culture results, current Gram‐stained smear findings and various patient factors (Lipsky 2007). This empirical therapy should then be reassessed and modified, when needed, on the basis of the patient’s clinical response, the cultural results, and the sensitivity of the pathogens identified (Bader 2008; IDSA 2012).
Almost all mild, and many moderately severe, infections in patients who have not recently received antibiotic therapy can be treated with an oral antibiotic regimen with a relatively narrow spectrum of activity, such as cephalexin, clindamycin or amoxicillin‐clavulanate. For more extensive moderate infections and all severe infections, treatment should usually be parenteral (typically intravenous) at least until the patient is stable, and employ relatively broad‐spectrum antibiotics such as piperacillin‐tazobactam, clindamycin plus ciprofloxacin, imipenem‐cilastatin or clindamycin plus tobramycin plus ampicillin (IDSA 2012).
The selected antibiotic therapy should always cover Staphylococcus aureus, as it is the most frequent and virulent pathogen isolated in DFI. The decision to provide coverage for metcillin‐resistantS aureus (MRSA; also known as 'methicillin‐resistant S aureus) depends on the overall local prevalence of that micro‐organism, the presence or absence of risk‐factors for MRSA infection, and the severity of the infection. Other organisms that may cause DFIs that raise concerns about antibiotic resistance are Pseudomonas aeruginosa, which is resistant to many commonly prescribed antibiotics, and various Gram‐negative isolates that produce extended spectrum beta‐lactamases or carbapenemase (Lipsky 2007).
How the intervention might work
The objective of antibiotic therapy for DFIs is to kill micro‐organisms and thus, achieve resolution of the clinical signs and symptoms of infection and avoid the consequences of infection spreading, that is, tissue destruction, lower‐extremity amputation, sepsis or death of patients (IDSA 2012). Prompt resolution of the signs of infection also reduces the need for hospitalisation with its associated financial cost and potential morbidity, and hastens healing of the wound (Prompers 2008). At the same time, optimally, systemic antibiotic therapy should avoid being associated with adverse effect. Among the more common of these are allergic reactions, renal insufficiency or the development of Clostridium difficile disease (a bacterial infection that can affect the digestive system and commonly affects people who have been treated with antibiotics). The available antibiotic agents have different propensities for causing these problems. Furthermore, deployment of antibiotic therapy should be rational in order to avoid the risk of inducing antibiotic resistance through excessive, overly broad or unnecessarily prolonged therapy (OMS 2014).
While all infected foot lesions in a person with diabetes likely require antibiotic therapy, it is often not sufficient. Appropriate surgical procedures (particularly incision and drainage, resection of deep, infected tissues) and wound care are almost always needed.
Why it is important to do this review
The systematic reviews on antibiotic treatment of DFI that are available do not support the superiority of any single drug or combination of antibiotics (Berendt 2008; Nelson 2006a; Peters 2012). However, these systematic reviews have become out of date as new randomised clinical trials are now available for consideration. This systematic review should help to determine whether any specific systemic antibiotic agents or regimens are associated with better clinical outcomes or fewer adverse effects when used to treat DFIs.
Objectives
To determine the effects and safety of systemic antibiotics in the treatment of DFIs compared with other systemic antibiotics, topical foot care or placebo.
Methods
Criteria for considering studies for this review
Types of studies
We included randomised controlled trials (RCTs) that allocated people individually or by cluster. Non‐randomised or quasi‐randomised controlled trials were not eligible for inclusion.
Types of participants
We included studies of people with diabetes mellitus (type 1 or 2) with any type of foot wound (e.g. ulcers of neuropathic or ischaemic aetiology, or traumatic wounds) that had been diagnosed as infected (using any definition reported by the study authors), or people with diabetes mellitus with any infection located in the foot that was ‐ or was not ‐ associated with a wound. If studies included both diabetic and non‐diabetic participants, they were included only if it was possible to obtain separate data for the participants with diabetes.
We considered studies conducted in all settings (e.g. hospital, primary healthcare centre, home care) and excluded people with diabetic foot ulcers that were not infected.
Types of interventions
We included any type of systemic antibiotic regimen (either oral or parenteral, i.e. intravascular) with any number of agents, in any dose, frequency of administration or duration of therapy used for treating DFIs, that was compared with any other antibiotic control group (either oral or parenteral), placebo or topical foot care. We did not consider primary interventions of topical (non‐systemic) antimicrobials (antiseptics or antibiotics), although they were eligible as comparators to a systemic antibiotic regimen.
Types of outcome measures
In order to be included, studies needed to report at least one of the outcomes of interest to the review.
Primary outcomes
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Clinical resolution of the infection, defined as the resolution of all acute signs and symptoms related to the infection, or improvement such that additional antimicrobial therapy of any kind was not required (Lipsky 2007). This outcome was not initially defined in the protocol, as it was integrated in the 'time to resolution of the infection' outcome. We later decided to separate these two outcomes in order not to lose important information (see Differences between protocol and review).
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Time to resolution of the infection, defined as the time needed to reach clinical resolution of the infection (as defined above).
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Adverse effects of treatment (allergic reactions, organ toxicity, intolerance, etc.).
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Serious infections or complications of infection (for example, septicaemia, septic shock or amputation ‐ major amputation is defined as an amputation above the ankle and minor amputation as an amputation limited to the foot).
Secondary outcomes
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Infection‐related mortality.
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Health‐related quality of life, as assessed by any standardised instrument.
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Length of hospitalisation.
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Wound healing, evaluated by objective measures such as the change in ulcer size (area or radius), the proportion of people whose ulcer completely healed within the trial period, and the time to complete healing.
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Recurrence of wound infections.
Search methods for identification of studies
Electronic searches
In April 2015 we searched the following electronic databases for potentially relevant RCTs:
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The Cochrane Wounds Group Specialised Register (searched 1 April 2015);
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The Cochrane Metabolic and Endocrine Disorders Group Specialised Register (latest);
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The Cochrane Central Register of Controlled Trials (CENTRAL; The Cochrane Library 2015, Issue 2);
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The Database of Abstracts of Reviews of Effects (DARE; The Cochrane Library 2015, Issue 2);
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The Health Technology Assessment Database (HTA; The Cochrane Library 2015, Issue 2);
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NHS Economic Evaluation Database (NHSEED; The Cochrane Library 2015, Issue 2);
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Ovid MEDLINE (1946 to March 30 2015);
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Ovid MEDLINE (In‐Process & Other Non‐Indexed Citations, 30 March 2015);
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Ovid EMBASE (1974 to 1 April 2015);
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EBSCO CINAHL (1982 to 1 April 2015).
We used the following search strategy for the Cochrane Central Register of Controlled Trials (CENTRAL)
#1 MeSH descriptor Foot Ulcer explode all trees
#2 MeSH descriptor Diabetic Foot explode all trees
#3 diabet* NEAR/3 ulcer*: ti,ab,kw
#4 diabet* NEAR/3 (foot or feet):ti,ab,kw
#5 diabet* NEAR/3 wound*:ti,ab,kw
#6 (#1 OR #2 OR #3 OR #4 OR #5)
#7 MeSH descriptor Anti‐Bacterial Agents explode all trees
#8 antibiotic*:ti,ab,kw
#9 nafcillin or oxacillin or ampicillin or dicloxacillin or ticarcillin* or piperacillin* or amoxicillin* or clindamycin or vancomycin or tobramycin or levofloxacin or ciprofloxacin or moxifloxacin or tigecycline or doxycycline or cefazolin or ceftazidime or cephalexin or cefepime or cefotaxime or ceftriaxone or cefazolin or cefoxitin or cefotetan or imipenem* or meropenem or ertapenem or aztreonam or metronidazole or sulfamethoxazole* or trimethoprim or cilastatin*:ti,ab,kw
#10 (#7 OR #8 OR #9)
#11 (#6 AND #10)
This search strategy was adapted to search Ovid MEDLINE (Appendix 1), Ovid EMBASE (Appendix 2) and EBSCO CINAHL (Appendix 3). 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 and CINAHL searches with the trial filters developed by the Scottish Intercollegiate Guidelines Network (SIGN 2011). There were no restrictions on the basis of date or language of publication.
We also searched the following websites to identify ongoing clinical trials (Appendix 4):
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ClinicalTrials.gov (https://www.clinicaltrials.gov/);
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Controlled trials (www.controlled‐trials.com).
Searching other resources
To identify additional studies we reviewed the reference lists of all selected articles. We searched the OpenSIGLE database to identify grey literature and the ProQuest Dissertations and Theses to retrieve dissertation theses related to our topic of interest. These search strategies can be found in Appendix 5 and Appendix 6.
Data collection and analysis
Selection of studies
We managed the citations using a reference management software program (ProCite). Two review authors independently assessed the titles and abstracts of citations identified by the search strategy. The review authors were not blinded to the study authors or the names of the publications. We retrieved full reports of all potentially relevant trials for further assessment of eligibility based on the inclusion criteria. We resolved any disagreements through discussion or, if required, through consultation with a third review author.
Data extraction and management
We designed a data extraction form and tested it before recording the results. For eligible studies, three review authors extracted data regarding the study objective; date of publication; country; sponsorship; patients' baseline data; type of antibiotic, route of administration and dosage compared; and outcomes of interest (Types of outcome measures). Discrepancies were resolved through discussion. We entered data into Review Manager 5.3 software (RevMan 2014), and checked the data for accuracy. When any information collected on the extraction form was missing or unclear, we attempted to contact the authors of the original reports to request further details. When we located duplicate publications for the same trial, we assessed them and extracted the maximum amount of data from them. Both publications were cited under the same study ID.
Assessment of risk of bias in included studies
Two review authors independently assessed each included study using the Cochrane Collaboration tool for assessing risk of bias (Higgins 2011; Appendix 7 provides details of criteria on which the judgements were based). We considered blinding and completeness of outcome data for the main outcome 'clinical resolution of the infection'. To assess selective outcome reporting, we actively sought trial protocols; when they were not available, we assessed whether all outcomes mentioned in the methods section had been reported in the results section of trial reports. Where we suspected reporting bias, we attempted to contact study authors to ask them to provide the missing outcome data.
We considered that overall risk of bias was low when allocation concealment was adequate and outcome assessors were blinded to the allocation, and high where the rest of the domains were either unclear or judged to be at a high risk of bias.
We discussed any disagreement amongst all authors to achieve a consensus.
We have presented our assessment of risk of bias using two 'Risk of bias' summary figures; one is a summary of bias for each item across all studies, and the other shows a cross‐tabulation of each trial by all of the risk of bias items.
Measures of treatment effect
We assessed dichotomous outcomes using the risk ratio (RR) with 95% confidence intervals (CI) and continuous outcomes (e.g. health‐related quality of life, length of hospitalisation) using mean difference (MD). We planned to compute hazard ratios (HR) for time‐to‐event variables (time to resolution of the infection, time to healing). If the papers did not report HR, we planned to compute these following the formula of Parmar 1998, implemented in a freely‐available spread sheet (Tierney 2007).
Dealing with missing data
We addressed missing data for dichotomous outcomes by performing an intention‐to‐treat analysis based on a 'worst‐case' scenario (Gamble 2005). We considered all randomised participants: we assumed that participants for whom there was no information about the outcome of interest had not had a positive result. We planned to perform the analysis of continuous outcomes with available data only.
Assessment of heterogeneity
To assess heterogeneity we examined the forest plot visually to see whether CIs for individual study estimates overlapped, and examined the Chi² statistic. To quantify heterogeneity we used the I² statistic (Higgins 2003), and interpreted it according to the following thresholds:
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0% up to 40%: might not be important;
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40% up to 60%: may represent moderate heterogeneity;
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More than 60%: represents important heterogeneity.
Data synthesis
We reported data narratively by outcome and then by comparison. We considered pooling when there were sufficient studies that were clinically similar. If heterogeneity was absent or low (I² up to 40%) we used a fixed‐effect model and if it was moderate (I² of 40% to 60%) we used the random‐effects model. However we did not plan to pool the data if heterogeneity was very high (I² over 60%). If data were available for pooling, we used RR with 95% CI for dichotomous outcomes, and the pooled mean difference or the standardised mean difference (SMD) with 95% CI for continuous outcomes, depending on whether the outcomes were measured using the same scales.
Subgroup analysis and investigation of heterogeneity
We planned to investigate potential causes of heterogeneity, such as diversity in characteristics of included patients, intervention characteristics (different doses or duration) or study methods, by performing subgroup analysis. However, pooling data was only possible with very few trials (three or fewer) in only two outcomes from two different comparisons.
Sensitivity analysis
We planned to explore whether analysing studies stratified by quality (overall low risk of bias versus high risk of bias) produced similar or different results. However, included studies were very heterogeneous (with respect to their populations, design and use of different regimens), which precluded any sensitivity analysis.
Results
Description of studies
See: Characteristics of included studies; Characteristics of excluded studies; Characteristics of studies awaiting classification; Characteristics of ongoing studies.
Results of the search
In total, we identified 941 references: 929 were found by electronic literature searching and 12 were found by reviewing the list of references of the included studies. We excluded 877 references after examining the title and abstract and obtained full text copies of the remaining 64 references for more detailed examination. We also identified two ongoing trials in ongoing trial registers (see Characteristics of ongoing studies). We finally included 24 references that provided information from 20 different studies. We have detailed our reasons for excluding the remaining 40 references in the Characteristics of excluded studies section and in a PRISMA flow diagram (Figure 1).
Study flow diagram
Included studies
Twenty RCTs that included 3791 patients with DFIs met our inclusion criteria. A detailed description of the included trials is provided in Characteristics of included studies. Fourteen studies were multicentred while the remaining six were single‐centred. All included studies compared a systemic antibiotic regimen against another systemic antibiotic regimen. An overview of the comparisons addressed by trials is provided in Table 1 and in more detail in Table 2.
| Study ID | Intervention | Comparison |
| A | Anti‐pseudomonal penicillins | |
| Anti‐pseudomonal penicillins | Anti‐pseudomonal penicillins | |
| Piperacillin‐tazobactam 3 g/375 mg iv every 6 h (min 5 days) | Ticarcillin‐clavulanate 3 g/100 mg iv every 6 h (min 5 days) | |
| Anti‐pseudomonal penicillins | Broad‐spectrum penicillins | |
| Piperacillin‐tazobactam 4 g/0.5 g iv every 8 h (4‐14 days, max 21 days) | Ampicillin‐sulbactam 2 g/1 g iv every 6 h (4‐14 days, max 21 days) | |
| Anti‐pseudomonal penicillins | Carbapenems | |
| Piperacillin‐tazobactam 4.5 g iv every 8 h (14 days) | Imipenem‐cilastatin 500 mg iv every 6 h (14 days) | |
| B | Broad‐spectrum penicillins | |
| Broad‐spectrum penicillins | Cephalosporins | |
| Ampicillin‐sulbactam 3 g iv every 6 h (min 5 days) | Cefoxitin 2 g iv every 6 h (min 5 days) | |
| C | Cephalosporins | |
| Fifth‐generation cephalosporins | Third‐generation cephalosporins + glycopeptide | |
| Ceftobiprole 500 mg iv every 8 h (7‐14 days) | Vancomycin 1000 mg iv every 12 h plus ceftazidime 1000 mg iv every 8 h (7‐14 days) | |
| 2. | Third‐generation cephalosporin + nitroimidazole | Anti‐pseudomonal penicillin |
| Ceftriaxon ‐metronidazole 1 g/1 g iv every 24 h (duration not described) | Ticarcillin‐clavulanate 3.1 g iv every 6 h (duration not described) | |
| D | Carbapenems | |
| Carbapenems | Anti‐pseudomonal penicillins | |
| Ertapenem | Piperacillin‐tazobactam | |
| Ertapenem 1 g iv every 24 h (min 5 days). Switch to amoxicillin‐clavulanate 875 mg/125 mg po every 12 h | Piperacillin‐tazobactam 3 g/375 mg iv every 6 h (min of 5 days). Switch to amoxicillin‐clavulanate 875 mg/125 mg po every 12 h | |
| Ertapenem 1 g iv every 24 h (7‐14 days) | Piperacillin‐tazobactam 3 g/375 mg iv every 6 h (7‐14 days) | |
| Imipenem + cilastatin | Piperacillin + clindamycin | |
| Imipenem‐cilastatin 500 mg iv every 6 h (10 days) | Piperacillin 3 g iv every 6 h plus clindamycin 600 mg iv every 8 h (10 days) | |
| Carbapenems | Broad‐spectrum penicillins | |
| Imipenem‐cilastatin 500 mg iv every 6 h (5 days) | Ampicillin‐sulbactam 2 g/1 g iv every 6 h (5 days) | |
| E | Fluoroquinolones | |
| Fourth‐generation fluoroquinolones | Anti‐pseudomonal penicillins | |
| Moxifloxacin 400 mg every 24 h (iv for 3 days, then po for 7‐14 days) | Piperacillin‐tazobactam 3 g/375 mg iv every 6 h (3 days). Then amoxicillin‐clavulanate 800 mg po every 12 h (7‐14 days) | |
| Moxifloxacin 400 mg every 24 h (iv for 3 days, then 400 mg every 12 h po for 7‐21 days) | Piperacillin‐tazobactam 4 g/0.5 g iv every 8 h. Then amoxicillin‐clavulanate 875 mg/125 mg po every 12 h (7‐21 days) | |
| Cinafloxacin 200 mg iv every12 h (max 14 days), then 200 mg po every 12 h | Piperacillin‐tazobactam 3 g/375 mg po every 6 h. Then amoxicillin‐clavulanate 500 mg po every 8 h | |
| Fourth‐generation fluoroquinolones | Broad‐spectrum penicillins | |
| Moxifloxacin 400 mg iv every 24 h for 3 days, then po for 7‐21 days | Amoxicillin 1000 g‐clavulanate 200 mg iv every 8 h for 3 days, then 500 mg/125 mg po every 8 h for 7‐21 days | |
| Third‐generation fluoroquinolones | Antipseudomonal penicillins | |
| Levofloxacin 750 mg iv or po every 24 h (7‐14 days) | Ticarcillin‐clavulanate 3.1g every iv 4 h‐6 h, then changed to amoxicillin‐clavulanate 875 mg po every 12 h (7‐14 days) | |
| Second‐generation fluoroquinolones | Broad‐spectrum penicillins | |
| Ofloxacin 400 mg iv every 12 h (then switch to po; 14‐28 days) | Ampicillin‐sulbactam 1‐2 g/0.5‐1 g iv every 6 h. Switch to amoxicillin‐clavulanate 500 mg/125 mg po every 8 h (14‐28 days) | |
| F | Other antibiotics | |
| Daptomycin 4 mg/kg iv every 24 h (7‐14 days) | Vancomycin 1 g iv every 12 h (7‐14 days) | |
| Linezolid 600 mg iv or po every 12 h (≥ 7 days ≤ 28) | Ampicillin/sulbactam 1.5 g‐3 g iv every 6 h OR amoxicillin/clavulanate 500 mg/875mg po every 12 h (≥ 7 days ≤ 28) | |
| Clindamycin 300 mg iv every 6 h (14 days) | Cephalexin 500 mg every 6 h po (14 days) | |
| Tigecycline 150 mg iv every 24 h (28 days) | Ertapenem 1 g iv every 24 h (28 days) | |
Abbreviations
h: hour(s)
iv: intravenous
max: maximum
min: minimum
po: per oral (by mouth)
| Ticarcillin‐clavulanate iv | Ampicillin‐sulbactam iv | Ceftriaxone‐metronidazol iv | Ceftazidime‐vancomicyn iv | Cefoxitin iv | Ertapenem iv | Ertapenem iv followed by amoxicillin‐clavulanate po | Imipenem‐cilastatin iv | Moxifloxacin iv followed by po | Cinafloxacin iv followed by po | Levofloxacin iv | Ofloxacin iv followed by po | Linezolid iv or po | Clindamycin iv | Tigecycline | Vancomycin | |
| Anti‐pseudomonal penicillins |
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| Piperacillin‐tazobactam iv | 1 Tan 1993 | |||||||||||||||
| Piperacillin‐tazobactam iv followed by amoxicillin po | ||||||||||||||||
| Ticarcillin‐clavulanate iv |
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| Ticarcillin‐clavulanate iv followed by amoxicillin‐clavulanate po |
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| Piperacillin‐clindamycin iv |
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| Broad‐spectrum penicillins |
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| Amoxicillin‐clavulanate iv followed by po |
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| Ampicillin‐sulbactam iv |
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| Ampicillin‐sulbactan followed by amoxicillin‐clavulanate po |
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| Cephalosporins |
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| Ceftobiprole iv |
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| Ceftriaxone‐metronidazol iv |
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| Ceftazidime‐vancomicyn iv |
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| Cefoxitin iv |
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| Cephalexin iv |
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| Carbapenems |
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| Ertapenem iv |
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| Ertapenem iv followed by amoxicillin‐clavulanate po |
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| Imipenem‐cilastatin iv |
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| Fluoroquinolones |
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| Moxifloxacin iv followed by po |
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| Cinafloxacin iv followed by po |
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| Levofloxacin iv |
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| Ofloxacin iv followed by po |
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| Other antibiotics |
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| Daptomycin iv |
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| Linezolid iv or po |
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| Clindamycin iv |
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| Tigecycline |
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| Vancomycin |
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This table shows all the comparisons included in the review and the number of evaluations for each comparison. To simplify, only different type of antibiotics are represented, irrespective of dose. The grey shaded areas represent comparisons between the same antibiotic. The numbers in the cells shown refer to number of RCT assessing that comparison.
Population
Trials differed with respect to their populations: 12 studies included only diabetic participants with foot infections, whilst eight trials included both diabetic and non‐diabetic participants with skin or skin structure‐related infections (but including at least some with a DFI).
Only five studies reported the type of diabetes (type 1 or type 2) of their participants (Bouter 1996; Erstad 1997; Lauf 2014; Lipsky 2004; SIDESTEP Study). In all included studies the participants had either type 1 or 2 diabetes.
Sex of participants
Only 11 studies provided disaggregated data on the sex of participants with DFI (Arbeit 2004; Bouter 1996; Clay 2004; Grayson 1994; Harkless 2005; Lauf 2014; Lipsky 1990; Lipsky 1997Lipsky 2004; Saltoglu 2010; SIDESTEP Study). Only men were enrolled in the Clay 2004 and Lipsky 1990 studies. When these two studies were excluded, the remaining studies included an average of 62% men. One study did not describe the sex of participants (Erstad 1997), and the rest of the studies did not provide data separately for patients with DFI (Giordano 2005; Graham 2002a; Graham 2002b; Noel 2008a; RELIEF Study; Siami 2001; STIC Study; Tan 1993).
Age of participants
Twelve studies provided age data for participants with DFI (Arbeit 2004; Bouter 1996; Clay 2004; Erstad 1997; Grayson 1994; Harkless 2005; Lauf 2014; Lipsky 1990; Lipsky 1997; Lipsky 2004; Saltoglu 2010; SIDESTEP Study). The mean age of included participants was 61.40 years. The rest of the studies included participants with skin or soft tissue infections that were not DFIs and they did not provide disaggregated age data for participants relevant to this review (Giordano 2005; Graham 2002a; Graham 2002b; Noel 2008a; RELIEF Study; Siami 2001; STIC Study; Tan 1993).
Characteristics of the diabetic foot infection (DFI)
All but two studies provided the definition they used for diagnosing a DFI (Bouter 1996; Saltoglu 2010). However, these definitions were heterogeneous, with some using only clinical signs or symptoms (e.g. erythema, purulent discharge, pain) while others also considered various laboratory parameters (e.g. leukocytosis).
It is remarkable that 11 studies excluded patients with osteomyelitis (Arbeit 2004; Clay 2004; Graham 2002a; Graham 2002b; Harkless 2005; Lipsky 1997; Lipsky 1990; Noel 2008a; Siami 2001; SIDESTEP Study; Tan 1993). While the Lauf 2014 trial excluded patients with baseline osteomyelitis from the main study, these patients were included in a prespecified sub study. Anatomic location of the DFI was reported in only four trials (Clay 2004; Lipsky 1990; Lipsky 2004; SIDESTEP Study).
Thirteen trials reported severity of infection (using various definitions). Although the majority of studies included participants with what appeared to be moderate to severe infection (as defined by the Infectious Diseases Society of America (IDSA) guidelines; IDSA 2012), most of them did not report which classification system they used for this designation. The systems that trials reported using included the: Wagner scale (Bouter 1996; Clay 2004; Saltoglu 2010; STIC Study); University of Texas system (Harkless 2005; SIDESTEP Study); PEDIS scale (Lauf 2014), and a combination of all three that did not report the final distribution of infection severity (RELIEF Study). Erstad 1997 and Tan 1993 used their own bespoke scales. The review authors attempted to transform the definitions of severity reported by some studies into the IDSA scale (Appendix 8). According to our interpretation, two studies included patients with mild to moderate infections (Clay 2004; Lipsky 1990); seven studies included mild to severe infections (Bouter 1996; Erstad 1997; Graham 2002a; Harkless 2005; Lauf 2014; Lipsky 2004; RELIEF Study); seven studies included moderate to severe infections (Arbeit 2004; Giordano 2005; Graham 2002b; Saltoglu 2010; SIDESTEP Study; STIC Study; Tan 1993); and one included only severe infections (Siami 2001).
The presence or absence of peripheral vascular disease, using a variety of definitions, was reported by Grayson 1994 (undefined, but present in 81% of patients), Bouter 1996 (ankle/brachial index mean (standard deviation (SD)) 0.71 (0.22) classified as mild artery disease), Erstad 1997 (ankle‐brachial index range 0.83 to 0.90), Harkless 2005 (41% of participants had “peripheral vascular disease”), Lipsky 2004 (40% had critical limb ischaemia), Clay 2004 (28% had “peripheral artery disease”), Saltoglu 2010 (19% with “ischemia”), SIDESTEP Study (normal dorsalis pedis and posterior tibial pulse in 16% to 19% of patients and those “requiring vascularization” were excluded) and Noel 2008a (exclusion of patients with “critical limb ischemia”).
Setting
Six trials were conducted entirely on an inpatient basis (Bouter 1996; Erstad 1997; Giordano 2005; Grayson 1994; Saltoglu 2010; Tan 1993); one trial entirely on an outpatient basis (Lipsky 1990); seven trials started with inpatients who could be discharged later to continue to participate on an outpatient basis (Arbeit 2004; Graham 2002a; Graham 2002b; Harkless 2005; Lauf 2014; Lipsky 1997; Siami 2001); and two trials allowed participants who were inpatients or outpatients (Lipsky 2004; SIDESTEP Study). The study setting was not defined in four studies, but we assumed participants were likely to be inpatients as the antibiotic treatment was intravenous (Clay 2004; Noel 2008a; RELIEF Study; STIC Study).
Intervention
Antibiotic agents and regimens
Studies compared a variety of different antibiotic agents and regimens. Overall, there were 16 different comparisons. We have categorized comparisons by antibiotic groups or classes:
-
anti‐pseudomonal penicillins;
-
broad‐spectrum penicillins;
-
cephalosporins;
-
carbapenems;
-
fluoroquinolones;
In many instances a study compared drugs from two different groups; in those cases we assigned the study to the group corresponding to the antibiotic considered to be the intervention, as opposed to the control or comparator according to the trial authors' judgement. In the review text, doses are presented as stated as in the original papers.
Route of administration
Trials also differed in the route of drug administration: 10 trials used parenterally administered antibiotics (Bouter 1996; Clay 2004; Erstad 1997; Graham 2002a; Grayson 1994; Harkless 2005; Lauf 2014; Noel 2008a; Saltoglu 2010; Tan 1993); one used only oral antibiotic agents (Lipsky 1990); and, in two the intervention drug could be given either orally or intravenously (Graham 2002b; Lipsky 2004). The rest of the included trials started with a parenteral regimen that was switched to an oral one (Arbeit 2004; Giordano 2005; Lipsky 1997; RELIEF Study; Siami 2001; SIDESTEP Study; STIC Study).
Duration of antibiotic treatment
The duration of antibiotic treatment also varied across studies: in the STIC Study parenteral antibiotic was administered for a minimum of three days and then oral agents were given for seven to 21 days; in three studies antibiotics were administered for a minimum of five days (Erstad 1997; Grayson 1994; Tan 1993); the SIDESTEP Study administered parenteral antibiotics for a minimum of five days and continued with oral antibiotics until day 28. In nine studies antibiotics were administered for 14 days or less (Arbeit 2004; Bouter 1996; Giordano 2005; Graham 2002a; Graham 2002b; Harkless 2005; Lipsky 1990; Noel 2008a; Siami 2001). In Saltoglu 2010 treatment lasted for 14 days or less unless there was a diagnosis of osteomyelitis, in which case antibiotic therapy was continued for 28 days from the time of debridement, if performed. In the RELIEF Study antibiotics were administered for seven to 21 days. In three studies intravenous antibiotic therapy lasted for 28 days or less (Lauf 2014; Lipsky 1997;Lipsky 2004). The Clay 2004 study did not provide information regarding the duration of parenteral antibiotic therapy.
Co‐interventions
Some studies allowed participants to receive antibiotics other than the ones specifically being studied. Two studies allowed the addition of vancomycin to both study groups when meticillin‐resistant Staphylococcus aureus (MRSA) or meticillin‐resistant S epidermidis (MRSE) was suspected or isolated (Harkless 2005; SIDESTEP Study). Lauf 2014 also allowed investigators, at their discretion, to use adjunctive vancomycin (a placebo was given in its place in the group randomised to tigecycline and real vancomycin in the group randomised to ertapenem). Siami 2001 allowed the addition of treatment with vancomycin under the same conditions for the control group (piperacillin/tazobactam) but not the clinafloxacin group. In the RELIEF Study, participants could be treated with additional narrow‐spectrum antibiotic agents (which were not specified) if polymicrobial infection with MRSA, MRSE or vancomycin‐resistant enterococci was confirmed. In Lipsky 1997, if there was no improvement in infection, metronidazole could be added to the group treated with ofloxacin, while intravenous gentamicin or oral trimethoprim‐sulfamethoxazole could be added to the group treated with ampicillin‐sulbactam. In Noel 2008a, metronidazole could be added to the study treatment after reviewing the culture results. In Lipsky 2004, participants from both study groups could have aztreonam added to the regimen if Gram‐negative pathogens were suspected; only participants in the control group could receive additional vancomycin if there was an MRSA infection. In Arbeit 2004, aztreonam could be added to cover suspected or proven polymicrobial infection with Gram‐negative bacteria and metronidazole could also be added to the study regimen to cover obligate anaerobic bacteria. In the Saltoglu 2010 study, glycopeptides were added to the study drugs if cultures confirmed the presence of antibiotic‐resistant enterococci or MRSA. A switch of antibiotics was performed in Bouter 1996; participants from either study group (imipenem/cilastatin or piperacillin‐clindamycin) diagnosed with chronic osteomyelitis were switched to ciprofloxacin or ofloxacin and/or clindamycin. Graham 2002b excluded participants who need additional antibiotics.
In five studies other treatments, such as surgical debridement or drainage, were specifically allowed if necessary (Lauf 2014; Lipsky 1990; Siami 2001; STIC Study; Tan 1993). Saltoglu 2010 allowed vacuum‐assisted closure in both study groups, when considered necessary.
Hypothesis and sample size
In eight studies the study design was to test superiority of the intervention drug (Bouter 1996; Clay 2004; Erstad 1997; Grayson 1994; Lipsky 1990; Lipsky 1997Saltoglu 2010; Tan 1993), five studies tested equivalence between the study drugs (Graham 2002a; Graham 2002b; Harkless 2005; Lipsky 2004; Siami 2001), and seven tested non‐inferiority of the intervention drug (Arbeit 2004; Giordano 2005; Lauf 2014; Noel 2008a; RELIEF Study; SIDESTEP Study; STIC Study).
Only five studies reported a sample size calculation and also reached the sample size required (Graham 2002a; Grayson 1994; RELIEF Study; Siami 2001; SIDESTEP Study). In three studies the sample size calculation was reported, but was not reached (Arbeit 2004; Harkless 2005; Tan 1993); the remaining 12 studies did not report a sample size calculation (Bouter 1996; Clay 2004; Erstad 1997; Giordano 2005; Graham 2002b; Lauf 2014; Lipsky 1990; Lipsky 1997Lipsky 2004; Noel 2008a; Saltoglu 2010; STIC Study).
Sample sizes of participants with DFIs ranged from 36 to 955 (Erstad 1997; Lauf 2014, respectively), with a mean sample size for all studies of 189.60 participants (median of 94.50, standard deviation (SD) 220.58).
Excluded studies
Thirty‐four studies did not fulfil our inclusion criteria and so were excluded. We excluded most because they not provide disaggregated data for the subset of participants with DFIs. See Characteristics of excluded studies for a detailed account of the reasons for exclusion for each of these studies.
Risk of bias in included studies
The risk of bias of the studies is described in detail in the 'Risk of bias' tables in the Characteristics of included studies section. In general, the included studies did not report enough details for us to assess their possible limitations in the design or execution (e.g. only one‐third of studies reported enough information for us to assess patient allocation in the study groups). The main limitation of the included trials concerned the blinding procedures, especially for outcome assessment (see Figure 2; Figure 3).
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Allocation
Only nine of the included trials reported an adequately generated random sequence. Noel 2008a did not provide details of the method used to generate the random sequence, but randomised participants through a central interactive voice response system. Eight studies reported computer‐generated sequences of random numbers (Bouter 1996; Clay 2004; Grayson 1994; Lauf 2014; RELIEF Study; Saltoglu 2010; SIDESTEP Study; Tan 1993). In two studies the random sequence was prepared by the study sponsor (RELIEF Study; SIDESTEP Study). The other 11 trials included in the review did not provide enough data to assess the adequacy of the randomizations sequence.
Only five studies accurately concealed the randomisation sequence by requesting the study drug to be selected by an independent unit (Grayson 1994; Saltoglu 2010), or via a remote call system (Lauf 2014; Noel 2008a; RELIEF Study). The random sequence in the SIDESTEP Study could be exposed to bias because an unblinded pharmacist randomised participants. Fourteen trials did not provide the information needed for us to assess whether allocation concealment was ensured.
Blinding
In nine of the included trials, study personnel knew the treatment allocation resulting in a high risk of performance bias (Bouter 1996; Clay 2004; Graham 2002b; Harkless 2005; Lipsky 1990; Lipsky 1997Lipsky 2004; Saltoglu 2010; STIC Study). Five studies did not provide details that allowed us to assess the risk of performance bias (Arbeit 2004; Erstad 1997; Giordano 2005; Grayson 1994; Tan 1993). Only six trials described how the intervention was blinded for both participants and healthcare personnel (Graham 2002a; Lauf 2014; Noel 2008a; RELIEF Study; Siami 2001; SIDESTEP Study), with a double‐dummy design used in two studies (RELIEF Study; SIDESTEP Study).
Since the main outcomes of this review required investigators to make judgements about the severity of infection and the presence of clinical signs and symptoms to determine whether the infection had resolved clinically, it was especially important that those involved in the outcome assessment were unaware of the treatment assigned to participants. Detection bias was avoided in nine trials that blinded outcome assessment (Arbeit 2004; Clay 2004; Graham 2002a; Grayson 1994; Lauf 2014; Lipsky 1990; Noel 2008a; RELIEF Study; SIDESTEP Study). In two trials study investigators assessed the outcomes in an unblinded fashion (Graham 2002b; STIC Study), which exposed these trials to a high risk of bias. The rest of the studies did not provide sufficient details for us to be able to assess this domain.
Incomplete outcome data
Seven included trials did not address missing outcome data correctly (Arbeit 2004; Giordano 2005; Graham 2002b; Harkless 2005; Lipsky 1997; Lipsky 2004; Tan 1993). These studies had no data that we could evaluate for a range of 15% to 30% of randomised participants (Arbeit 2004; Lipsky 1997; Lipsky 2004; and Graham 2002b; Harkless 2005, respectively). Two trials were underpowered and at very high risk of attrition bias because they had data for only 40% or 45% of participants randomised (Giordano 2005; Tan 1993, respectively). The remaining 11 studies provided sufficient data for us to assess how the investigators managed withdrawals and losses to follow‐up.
Selective reporting
Most studies reported enough information to ensure that the outcomes planned in their protocols were adequately described when their findings were published (Arbeit 2004; Bouter 1996; Erstad 1997; Giordano 2005; Graham 2002a; Graham 2002b; Harkless 2005; Lauf 2014; Lipsky 1990; Lipsky 2004; RELIEF Study; Saltoglu 2010; Siami 2001). We could not assess this domain for six studies (Clay 2004; Grayson 1994; Lipsky 1997; Noel 2008a; STIC Study; Tan 1993). The SIDESTEP Study report did not provide data for some of the secondary outcomes included in the trial protocol.
Other potential sources of bias
Whether the 'Risk of bias' assessment should include information about the funding source of a trial is a controversial area (Bero 2013; Sterne 2013); nonetheless, we collected data on funding from the included trials. Only Saltoglu 2010 explicitly reported that his group did not receive funding from private sources for developing the trial. Bouter 1996 did not provide information about this issue. Biopharmaceutical industry sponsors funded the remaining 18 trials and study authors from 12 trials were employed by the sponsor that provided funding for the study (Arbeit 2004; Clay 2004; Giordano 2005; Graham 2002a; Graham 2002b; Harkless 2005; Lauf 2014; Noel 2008a; RELIEF Study; Siami 2001; SIDESTEP Study; STIC Study).
Effects of interventions
Outcome 1: Clinical resolution of the infection
The included studies measured the outcome of clinical resolution of infection at different time points after the initiation of study antibiotic treatment. Most studies assessed this variable at a variety of times after completion of the study antibiotic regimens: two studies assessed this during the first week after completion of antibiotic treatment (Graham 2002b; Lipsky 1997); five assessed between the first and second week after completion of antibiotic treatment (Lipsky 1990; Noel 2008a; Siami 2001; SIDESTEP Study; Tan 1993); and six during the four weeks after completion of treatment (Arbeit 2004; Graham 2002a; Harkless 2005; Lipsky 2004; RELIEF Study; STIC Study). Studies that made more long‐term evaluations included Giordano 2005 (between 10 and 42 days after treatment), Grayson 1994 (at the end of therapy and 13 weeks later), and Lauf 2014 (between 12 and 92 days after the last dose of antibiotic in the main study and after 25 to 27 weeks in the sub study of participants with osteomyelitis). However, four trials measured the clinical resolution only on the final day of antibiotic therapy (Bouter 1996; Clay 2004; Erstad 1997; Saltoglu 2010).
A. Anti‐pseudomonal penicillins
Anti‐pseudomonal penicillin versus anti‐pseudomonal penicillin
Piperacillin‐tazobactam versus ticarcillin‐clavulanate
Tan 1993 compared the administration of piperacillin‐tazobactam 3 g/375 mg intravenously (iv) every six hours (h) for a minimum of five days and at least 48 h after resolution of signs and symptoms of infection with the administration of ticarcillin‐clavulanate 3 g/100 mg iv every 6 h for the same time period. At 10 to 14 days after the end of antibiotic therapy there was no difference between the groups in the proportion of participants with clinical resolution of the infection (37.50% versus 32.25%, RR 1.16, 95% CI 0.59 to 2.29; 1 trial, 63 participants, 22 events; Analysis 1.1).
Anti‐pseudomonal penicillin versus broad‐spectrum penicillin
Piperacillin‐tazobactam versus ampicillin‐sulbactam
Harkless 2005 compared the administration of piperacillin‐tazobactam 4 g/0.5 mg iv every 8 h with the administration of ampicillin‐sulbactam 2 g/1 g iv every 6 h. Both treatments were administered for between 4 to 14 days, up to a maximum of 21 days. At 14 to 21 days after the end of therapy there was no difference in the proportion of participants with clinical resolution of the infection (63.87% versus 62.89%, RR 1.02, 95% CI 0.86 to 1.20; 1 trial, 314 participants, 199 events; Analysis 2.1).
Anti‐pseudomonal penicillin versus carbapenems
Piperacillin‐tazobactam versus imipenem‐cilastatin
Saltoglu 2010 found no clear difference in the proportion of participants with clinical resolution of the infection between the groups treated with piperacillin‐tazobactam 4.5 g iv every 8 h and the group treated with imipenem‐cilastatin 0.5 g iv every 24 h (45.16% versus 27.27%; RR 1.66, 95% CI 0.84 to 3.26; 1 trial, 64 participants, 23 events; Analysis 3.1). Two participants in the piperacillin‐tazobactam group and one in the imipenem‐cilastatin group received a glycopeptide in addition to the study drugs because cultures confirmed the presence of a drug‐resistant Enterococcus or MRSA.
B. Broad‐spectrum penicillins
Broad‐spectrum penicillin versus cephalosporin
Ampicillin‐sulbactam versus cefoxitin
In a small study involving only 36 participants, Erstad 1997 reported fewer participants treated with ampicillin‐sulbactam 3 g iv every 6 h (5.55%) achieved clinical resolution of the infection at the end of ≥5 days' therapy compared with those treated with cefoxitin 2 g iv every 6 h (38.88%). This difference was not statistically significant (RR 0.14, 95% CI 0.02 to 1.05; 1 trial, 36 participants, 8 events; Analysis 4.1).
C. Cephalosporins
Fifth‐generation cephalosporin versus third generation cephalosporin plus glycopeptide
Ceftobiprole versus ceftazidime plus vancomycin
Noel 2008a compared ceftobiprole 500 mg iv every 8 h with ceftazidime 1 g iv every 8 h plus vancomycin 1 g iv every 12 h, for 7 to 14 days. Metronidazole could be added at the discretion of the investigators in either group if the culture grew obligate anaerobes. There was no clear difference in the proportion of participants with clinical resolution of the infection at 7 to 14 days after the end of therapy (74.40% versus 70.79%, RR 1.05, 95% CI 0.90 to 1.23; 1 trial, 257 participants, 188 events; Analysis 5.1). Metronidazole was administered to 22 (13%) of the participants treated with ceftobiprole and to 17 (19%) participants treated with ceftazidime plus vancomycin.
Third‐generation cephalosporin plus nitroimidazole versus anti‐pseudomonal penicillin
Ceftriaxone plus metronidazole versus ticarcillin‐clavulanate
Clay 2004 compared ceftriaxone 1 g plus metronidazole 1 g, both given iv every 24 h for a mean of 6.7 days with ticarcillin‐clavulanate 3.1 g iv every 6 h for a mean of 6.7 days. There was no clear difference in the proportion of participants with clinical resolution of the infection on the final day of therapy (72.22% versus 76.47%, RR 0.94, 95% CI 0.72 to 1.24; 1 trial, 70 participants, 52 events; Analysis 6.1). There was a change in the antibiotic regimen before the final evaluation in 41.60% of participants treated with ceftriaxone plus metronidazole and in 35.29% of those treated with ticarcillin‐clavulanate; these changes were predominantly switches to oral therapeutic equivalents at the time of hospital discharge, and there was no statistically significant difference between groups.
D. Carbapenems
Carbapenems versus anti‐pseudomonal penicillins
Ertapenem versus piperacillin‐tazobactam
Two RCTs compared ertapenem 1 g iv every 24 h with piperacillin‐tazobactam 3.4 g iv every 6 h (Graham 2002a; SIDESTEP Study). In the SIDESTEP Study participants received parenteral treatment for a minimum of five days, after which oral amoxicillin‐clavulanate 875 mg/125 mg every 12 h could be given for up to 28 days in both groups. In Graham 2002a, the parenteral antibiotic could be given for 7 to 14 days. These studies were pooled (random effects) and there was no difference in the proportion of participants with clinical resolution of the infection two to five days after the end of antibiotic treatment (65.80% versus 63.63%, RR 1.07, 95% CI 0.96 to 1.19; I² 0%; 2 trials, 684 participants, 439 events; Analysis 7.1).
Imipenem‐cilastatin versus piperacillin plus clindamycin
Bouter 1996 compared imipenem‐cilastatin 500 mg iv every 6 h with piperacillin 3 g iv every 6 h plus clindamycin 600 mg iv every 8 h, with both regimens given for at least 10 days. There were no difference in the proportions of participants with clinical resolution of the infection after completion of antibiotic therapy (18.18% versus 25.00%, RR 0.73, 95% CI 0.24 to 2.24; 1 trial, 46 participants, 10 events; Analysis 8.1).
Carbapenems versus broad‐spectrum penicillins
Imipenem‐cilastatin versus ampicillin‐sulbactam
Grayson 1994 compared imipenem‐cilastatin 500 mg iv every 6 h (given for a mean of 15 days) with ampicillin‐sulbactam 2 g/1 g iv every 6 h (given for a mean of 13 days). As a unit of analysis this trial used 'infection episodes' rather than participants. There was no difference in the proportion of infection episodes that were clinically cured, either at the completion of parenteral therapy (81.25% versus 85.41%, RR 0.95, 95% CI 0.80 to 1.14; 1 trial, 93 participants, 96 episodes; Analysis 9.1), or after 13 weeks of follow‐up (56.25% versus 68.75%, RR 0.82, 95% CI 0.60 to 1.12; 1 trial, 93 participants, 96 episodes; Analysis 9.2).
E. Fluoroquinolones
Fourth‐generation fluoroquinolones versus anti‐pseudomonal penicillins
Moxifloxacin or clinafloxacin versus piperacillin‐tazobactam
Three RCTs pooled using a fixed effect model (I2=0%) found no difference in the proportion of participants with clinical resolution of the infection when the administration of a fourth‐generation fluoroquinolone was compared with piperacillin‐tazobactam (RR 1.03, 95% CI 0.89 to 1.20; 3 RCTs, 387 participants, 239 events; Analysis 10.1; Giordano 2005; RELIEF Study; Siami 2001). Two of these studies compared the administration of 400 mg of moxifloxacin iv every 24 h for at least three days followed by the same dose orally for 7 to 19 more days versus piperacillin‐tazobactam at a total dose of 13.5 g a day for at least three days, followed by amoxicillin‐clavulanate 875 mg/125 mg orally every 12 h (Giordano 2005; RELIEF Study). The third study compared the administration of clinafloxacin 200 mg iv every 12 h for at least three days followed by the same dose orally versus piperacillin‐tazobactam 3.4 g iv every 6 h followed by amoxicillin‐clavulanate 500 mg orally every 8 h (Siami 2001).
Fourth‐generation fluoroquinolones versus broad‐spectrum penicillins
Moxifloxacin versus amoxicillin‐clavulanate
One trial compared moxifloxacin 400 mg iv every 24 h for at least three days, followed by the same dose orally for 7 to 21 days, versus amoxicillin 1000 mg plus clavulanate 200 mg iv every 8 h for at least three days, followed by the same antibiotic, that is, amoxicillin‐clavulanate 500 mg/125 mg orally every 8 h for 7 to 21 days (STIC Study). The difference in rates of clinical resolution of infection was not statistically significant (47.62% with moxifloxacin versus 60.56% with amoxicillin‐clavulanate, RR 0.79, 95% CI 0.57 to 1.08; 1 trial, 134 participants, 73 events; Analysis 11.1). However as with most of these studies the study is too small to exclude a potentially important treatment effect.
Third‐generation fluoroquinolones versus anti‐pseudomonal penicillins
Levofloxacin versus ticarcillin‐clavulanate
One trial compared levofloxacin 750 mg iv or orally given once daily for seven to 14 days versus ticarcillin‐clavulanate 3.1 g iv every 4 h to 6 h, followed by amoxicillin‐clavulanate 875 mg orally every 12 h (Graham 2002b). There was no evidence of a difference in the proportion of participants with clinical resolution of the infection (50.00% versus 51.61%, RR 0.97, 95% CI 0.60 to 1.55; 1 trial, 67 participants, 34 events; Analysis 12.1).
Second‐generation fluoroquinolones versus broad‐spectrum penicillins
Ofloxacin versus ampicillin‐sulbactam
One trial compared ofloxacin 400 mg iv every 12 h, with a switch to oral when indicated, for a total of 14 to 28 days, versus ampicillin‐sulbactam 1 g to 2 g/0.5 g to 1 g iv every 6 h, with a switch to oral amoxicillin–clavulanate 500 mg/125 mg every 8 h (Lipsky 1997). There was no statistically significant difference in the proportion of participants with clinical resolution of the infection (72.73% versus 64.15%, RR 1.13, 95% CI 0.88 to 1.47; 1 trial, 108 participants, 74 events; Analysis 13.1). Additional antibiotics could be added in both groups if there was not sufficient clinical improvement: five (9%) participants treated with ofloxacin also received metronidazole and 42 (79%) treated with ampicillin‐sulbactam also received either gentamicin or trimethoprim‐sulfamethoxazole (Chi² 54.04 and P value < 0.001 for the difference between the two groups in the percentage of participants who received an additional drug).
F. Other antibiotics
Daptomycin versus vancomycin
Arbeit 2004 compared seven to 14 days of treatment with daptomycin 4 mg/kg iv every 24 h with a control group treated with either vancomycin 1 g iv every 12 h or a semi‐synthetic penicillin (nafcillin, oxacillin, cloxacillin or flucoxacillin) 4 g to 12 g iv every 24 h. The addition of aztreonam was allowed to cover Gram‐negative bacteria in suspected or proven polymicrobial infections and was administered to 29.50% of participants in the intervention group and 31.94% of participants in the control group. There was no evidence of a difference between the groups in the proportion of participants with clinical resolution of the infection at six to 20 days after completion of the study drug (50.81% versus 54.16%, RR 0.94, 95% CI 0.68 to 1.30; 1 RCT, 133 participants, 56 events; Analysis 14.1).
Linezolid versus aminopenicillin plus beta‐lactamase inhibitors
Lipsky 2004 compared linezolid 600 mg iv or orally every 12 h with a combination of aminopenicillin and beta‐lactamase inhibitors (ampicillin‐sulbactam 1.5 g/3 g iv every 6 h or amoxicillin‐clavulanate 500 mg/875 mg orally every 8 to 12 h), both given for between seven and 28 days. Participants were assessed 15 to 21 days after completing treatment; there was no evidence of a difference in the proportion of participants with clinical resolution of the infection (68.46% versus 64.16%, RR 1.07 95% CI 0.91 to 1.25; 1 trial, 361 participants, 242 events; Analysis 15.1). Participants with MRSA infection in the control group could receive vancomycin 1 g iv every 12 h; five participants in the control group received vancomycin, as did (by error) one participant in the linezolid group. Aztreonam could be added if Gram‐negative pathogens were suspected in either study group; 12 participants in the linezolid group and three participants in the control group received aztreonam.
Clindamycin versus cephalexin
Lipsky 1990 compared clindamycin hydrochloride 300 mg orally every 6 h with cephalexin 500 mg orally every 6 h, each regimen given for 14 days. At the end of treatment there was no evidence of a difference between groups in the proportion of participants with clinical resolution of the infection (77.77% versus 72.41%, RR 1.07, 95% CI 0.79 to 1.45; 1 trial, 56 participants, 42 events; Analysis 16.1).
Tigecycline versus ertapenem with or without vancomycin
Lauf 2014 trial compared tigecycline 150 mg iv every 24 h with ertapenem 1 g iv every 24 h with or without vancomycin (dose not specified). Both drugs were given for 28 days in participants with DFI without osteomyelitis. Investigators could add adjunctive vancomycin (placebo vancomycin in the tigecycline group and real vancomycin in the ertapenem group) at their discretion for coverage of MRSA, coagulase‐negative staphylococci or enterococci. At 12 to 92 days after the end of treatment, clinical resolution of infection was more likely to have occurred in participants treated with ertapenem with or without vancomycin than in those treated with tigecycline (76.90% versus 39.00%, RR 1.09, CI 95% 1.01 to 1.18; 1 trial, 955 participants, 703 events; Analysis 17.1). In absolute terms, this means that for every 1000 participants treated with ertapenem with or without vancomycin instead of tigecycline, 65 more people would show clinical resolution of the infection (95% confidence interval 7 to 120 more assuming the risk of the control group as a baseline risk). This study was at low risk of bias.
In a pre‐planned sub study of participants who had osteomyelitis at baseline, participants received the same antibiotic regimens but for a longer time (up to 42 days). At 25 to 27 weeks after the last dose of antibiotic, participants treated with ertapenem with or without vancomycin had higher rates of clinical resolution of the infection than participants treated with tigecycline (51.21% versus 24.67%, RR 2.08, 95% CI 1.27 to 3.39; 1 trial, 118 participants, 40 events; Analysis 17.1).
Vancomycin placebo was administered to 10.30% (84/483 participants) of the tigecycline group, while adjunctive vancomycin was given to 15.50% (73/472 participants) of the ertapenem group in the primary study. There was no statistically significant difference between groups in the proportion of participants who received non‐pharmacologic treatments or procedures in the main study (35% of participants treated with tigecycline versus 38% of participants treated with ertapenem).
Outcome 2: Time to clinical resolution of the infection
None of the studies reported on time to clinical resolution of the infection.
Outcome 3: Adverse effects of treatments
A. Anti‐pseudomonal penicillins
Anti‐pseudomonal penicillins versus anti‐pseudomonal penicillins
Piperacillin‐tazobactam versus ticarcillin‐clavulanate
Although the Tan 1993 trial investigated piperacillin‐tazobactam versus ticarcillin‐clavulanate, the trial report did not provide disaggregated adverse event data for diabetic participants.
Anti‐pseudomonal penicillins versus broad‐spectrum penicillins
Piperacillin‐tazobactam versus ampicillin‐sulbactam
Harkless 2005 found no difference between piperacillin‐tazobactam and ampicillin‐sulbactam in the rate of adverse events (75.48% versus 66.04 %, RR 1.14, 95% CI 0.99 to 1.32; 1 trial, 314 participants, 222 events), or the rate of treatment‐related adverse events (18.7% versus 13.2%, RR 1.42, 95% CI 0.85 to 2.37; 1 trial, 314 participants, 50 events; Analysis 2.2) or the rate of serious adverse events (27.09% versus 28.93%, RR 0.94, 95% CI 0.66 to 1.34; 1 trial, 314 participants, 88 events; Analysis 2.2). The most commonly reported treatment‐related adverse events were diarrhoea and nausea, and the most commonly reported serious adverse events were amputations, infection, peripheral vascular disorder, and osteomyelitis.
Anti‐pseudomonal penicillins versus carbapenems
Piperacillin‐tazobactam versus imipenem‐cilastatin
Saltoglu 2010 reported more adverse events in participants treated with piperacillin‐tazobactam (29.03%)compared with imipenem‐cilastatin (9.09%), although this difference did not reach conventional levels of statistical significance (RR 3.19, 95% CI 0.95 to 10.72; 1 trial, 64 participants, 12 events; Analysis 3.2). There were more cases of hepatotoxicity and nephrotoxicity in the group treated with piperacillin‐tazobactam, although differences were not statistically significant (for hepatotoxicity:16.13% versus 3.03%, RR 5.32, 95% CI 0.66 to 43.05; 6 events; for nephrotoxicity: 19.35% versus 3.03%, RR 6.36, 95% CI 0.81 to 50.09; 7 events; Analysis 3.2). There was one case of nausea in the imipenem‐cilastatin group versus none in the piperacillin‐tazobactam group. Two participants treated with piperacillin‐tazobactam developed haematological side effects. This study was very small and therefore important differences in adverse events cannot be ruled out.
B. Broad‐spectrum penicillins
Broad‐spectrum penicillins versus cephalosporins
Ampicillin‐sulbactam versus cefoxitin
Erstad 1997 found no difference between ampicillin‐sulbactam and cefoxitin in the rate of adverse events, which were mostly gastrointestinal disturbances of minor clinical importance (39% versus 33%, RR 1.17, 95% CI 0.49 to 2.79; Analysis 4.2).
C. Cephalosporins
Fifth‐generation cephalosporins versus third‐generation cephalosporins plus glycopeptide
Ceftobiprole versus ceftacidime‐vancomycin
The Noel 2008a trial did not provide disaggregated data for diabetic participants for adverse effects.
Third‐generation cephalosporin plus nitroimidazole versus anti‐pseudomonal penicillins
Ceftriaxoneplusmetronidazole versus ticarcillin‐clavulanate
The Clay 2004 trial (70 participants) reported no cases of adverse effects in any group.
D. Carbapenems
Carbapenems versus anti‐pseudomonal penicillins
Ertapenem versus piperacillin‐tazobactam
The SIDESTEP Study found no clear difference between ertapenem and piperacillin‐tazobactam in the rate of drug‐related adverse events (14.90% versus 19.58%, RR 0.76, 95% CI 0.53 to 1.09; 1 trial, 586 participants, 101 events; Analysis 7.2). There were no differences in the proportion of participants with nausea (RR 0.83, 95% CI 0.44 to 1.58; 1 trial, 586 participants, 35 events) or in the proportion of participants with headache (RR 0.62, 95% CI 0.28 to1.34; 1 trial, 586 participants, 26 events; Analysis 7.2). Treatment with ertapenem caused fewer cases of diarrhoea (RR 0.58, 95% CI 0.36 to 0.93; 1 trial, 586 participants, 65 events; Analysis 7.2). That means that for every 1000 participants treated with ertapenem instead of piperacillin‐tazobactam, 59 fewer would present with diarrhoea (from 10 to 90 participants fewer; assuming the risk of the control group as a baseline risk).
Imipenem‐cilastatin versus piperacillin plus clindamycin
Bouter 1996 reported a significantly lower rate of adverse effects in participants treated with imipenem‐cilastatin than in those treated with piperacillin plus clindamycin (13.63% versus 50.00%, RR 0.27, 95% CI 0.09 to 0.84; 1 trial, 46 participants, 15 events; Analysis 8.2). Diarrhoea was the single most commonly reported side effect (4 participants in both groups; no disaggregated data reported).
Carbapenems versus broad‐spectrum penicillins
Imipenem‐cilastatin versus ampicillin‐sulbactam
Grayson 1994 found no differences in the proportion of infection episodes associated with any type of adverse effects in the two groups (35.41% versus 33.33%, RR 1.06, 95% CI 0.61 to 1.85; 1 trial, 93 participants, 96 episodes; Analysis 9.3). There were no significant differences in the proportion of episodes with 'significant' adverse effects, defined as a severe reaction necessitating withdrawal of the study agent or specific treatment (18.75% versus 14.58%, RR 1.29, 95% CI 0.52 to 3.17; 1 trial, 96 episodes; Analysis 9.3).
E. Fluoroquinolones
Fourth‐generation fluoroquinolones versus anti‐pseudomonal penicillins
Moxifloxacin or clinafloxacin versus piperacillin‐tazobactam
The included studies did not provide disaggregated data for diabetic participants for adverse events.
Fourth‐generation fluoroquinolones versus broad‐spectrum penicillins
Moxifloxacin versus amoxicillin clavulanate
The STIC Study did not provide disaggregated data for diabetic participants for adverse events.
Third‐generation fluoroquinolones versus anti‐pseudomonal penicillins
Levofloxacin versus ticarcillin‐clavulanate
Graham 2002b did not provide disaggregated data for diabetic participants for adverse events.
Second‐generation fluoroquinolone versus broad‐spectrum penicillins
Ofloxacin versus ampicillin‐sulbactam
Lipsky 1997 reported that 30.90% of participants in the ofloxacin group and 16.98% in the aminopenicillin‐sulbactam group developed an adverse effect, but this difference was not statistically significant (RR 1.82; 95% CI 0.89 to 3.72; 1 trial, 108 participants, 26 events; Analysis 13.2). No adverse effect led to discontinuation of treatment and none was rated as severe.
F. Other antibiotics
Daptomycin versus vancomycin
Arbeit 2004 reported significantly fewer adverse effects in the daptomycin group compared with the group treated either with vancomycin or a semi‐synthetic penicillin (31.4% versus 51.38%, RR 0.61, 95% CI 0.39 to 0.94; 1 RCT, 153 participants, 56 events; Analysis 14.2). This means that for every 1000 participants treated with daptomycin instead of vancomycin, 200 fewer would experience adverse effects (from 31 to 313 participants fewer; assuming the risk of the control group as a baseline risk). One participant in the daptomycin group and six participants in the control group developed a severe adverse effect.
Linezolid versus aminopenicillins plus beta‐lactamase inhibitors
Lipsky 2004 reported more adverse effects with linezolid than ampicillin‐sulbactam (27% versus 10 %, RR 2.66; 95% CI 1.49 to 4.73; 1 trial, 361 participants, 76 events; Analysis 15.2). This means that for every 1000 participants treated with linezolid instead of ampicillin‐sulbactam, 166 more would experience adverse effects (from 49 to 373 participants more; assuming the risk of the control group as a baseline risk). The most frequent adverse effects were diarrhoea (18 versus 4 participants), nausea (14 versus 0), anaemia (11 versus 0), thrombocytopenia (9 versus 0), vomiting (4 versus 1), decreased appetite (3 versus 0) and dyspepsia (3 versus 1).
Clindamycin versus cephalexin
Lipsky 1990 reported a case of mild diarrhoea caused by Clostridium difficile in the clindamycin group and two cases of mild nausea and diarrhoea in the cephalexin group (RR 0.47, 95% CI 0.04 to 4.84; 1 trial, 56 participants, 3 events; Analysis 16.2), this result was not statistically significant.
Tigecycline versus ertapenem with or without vancomycin
Lauf 2014 reported more adverse effects with tigecycline than ertapenem with or without vancomycin (56.36% versus 82.61%, RR 1.47, 95% CI 1.34 to 1.60; 1 trial, 955 participants, 665 events; Analysis 17.2). This means that for every 1000 participants treated with tigecycline instead of ertapenem (with or without vancomycin), 265 more would experience adverse effects (from 192 to 338 participants more; assuming the risk of the control group as the baseline risk). The most frequent adverse events in the group treated with tigecycline were nausea (39.34%) and vomiting (24.43%), while those in the ertapenem group were diarrhoea (9.75%) and nausea (8.26%). Participants treated with tigecycline developed significantly higher rates of nausea (36.34% versus 8.26%, RR 4.76, 95% CI 3.46 to 6.56; 1 trial, 955 participants, 229 events; Analysis 17.2) and vomiting (24.43% versus 4.66%, RR 5.24, 95% CI 3.39 to 8.12; 1 trial, 955 participants, 140 events; Analysis 17.2) than those in the ertapenem arm. The tigecycline treated participants also developed more cases of osteomyelitis (4.26% versus 2.23%, RR 1.95, 95% CI 0.96 to 3.99; 1 trial, 955 participants, 33 events; Analysis 17.2), although this difference did not reach statistically significance. There were no statistically significant differences between groups for the following adverse events: fever, headache, pain, hypertension, anaemia, increase in serum glutamic oxaloacetic transaminase, increase in serum glutamic pyruvic transaminase and hypoglycaemia.
Outcome 4: Serious infections or complications of infection: lower extremity amputation
A. Anti‐pseudomonal penicillins
Anti‐pseudomonal penicillins versus anti‐pseudomonal penicillins
Piperacillin‐tazobactam versus ticarcillin‐clavulanate
Tan 1993 did not report on serious infections or complications of infection.
Anti‐pseudomonal penicillins versus broad‐spectrum penicillins
Piperacillin‐tazobactam versus ampicillin‐sulbactam
Harkless 2005 found no difference in the rate of amputations (combining amputations of toe, foot, or leg) between participants treated with piperacillin‐tazobactam versus ampicillin‐sulbactam (RR 0.97, 95% CI 0.51 to 1.84; 1 trial, 314 participants, 33 events; Analysis 2.3).
Anti‐pseudomonal penicillins versus carbapenems
Piperacillin‐tazobactam versus imipenem‐cilastatin
Saltoglu 2010 found no difference in rates of lower extremity amputations between piperacillin‐tazobactam and imipenem‐cilastatin group (RR 0.87, 95% CI 0.59 to 1.28; 1 trial, 64 participants, 40 events; Analysis 3.3).
B. Broad‐spectrum penicillins
Ampicillin‐sulbactam versus cefoxitin
Erstad 1997 found no difference in rates of lower extremity amputations between ampicillin‐sulbactam and cefotoxitin (RR 1.00, 95% CI 0.48 to 2.08; 1 trial, 16 events; Analysis 4.3).
C. Cephalosporins
Noel 2008a and Clay 2004 did not report on serious infections or complications of infection.
D. Carbapenems
Carbapenems versus antipseudomonal penicillins
Ertapenem versus piperacillin‐tazobactam
Neither the Graham 2002a study nor the SIDESTEP Study reported on serious infections or complications of infection.
Imipenem‐cilastatin versus piperacillin plus indamicin
Bouter 1996 reported that none of the participants underwent an amputation.
Cabapenems versus broad‐spectrum penicillins
Imipenem‐cilastatin versus ampicillin‐sulbactam
Grayson 1994 reported no difference in the risk of amputation from infection between imipenem‐cilastatin (28 or 58.33% amputations) compared with 33 amputations (68.75%) in the ampicillin‐sulbactam group. The difference was not statistically significant (RR 0.85, 95% CI 0.62 to 1.15; 1 trial, 96 episodes; Analysis 9.4). There was one case of major amputation in the imipenem‐cilastatin group and three cases in the ampicillin‐sulbactam group.
E. Fluoroquinolones
Fourth‐generation fluoroquinolones versus anti‐pseudomonal and broad‐spectrum penicillins
No trial reported on serious infections or complications of infection.
Third‐generation fluoroquinolones versus anti‐pseudomonal penicillins
No trial reported on serious infections or complications of infection.
Second‐generation fluoroquinolones versus broad‐spectrum penicillins
Ofloxacin versus ampicillin‐sulbactam
Lipsky 1997 found no clear evidence of a difference in amputation rates between ofloxacin and aminopenicillin‐sulbactam (RR 0.11, 95% CI 0.01 to 1.94; 1 trial, 108 participants, 4 events; Analysis 13.3).
F. Other antibiotics
Daptomycin versus vancomycin
Arbeit 2004 did not report on serious infections or complications of infection.
Linezolid versus aminopenicillins plus beta‐lactamase inhibitors
Lipsky 2004 did not report on serious infections or complications of infection.
Clindamycin versus cephalexin
Lipsky 1990 reported only one case of minor amputation in the group treated with clindamycin (RR 3.21, 95% CI 0.14 to 75.68; 1 trial, 1 event).
Tigecycline versus ertapenem with or without vancomycin
Lauf 2014 did not report on serious infections or complications of infection.
Outcome 5: Serious infections or complications of infection: septicaemia
Only one study reported on this outcome. Lauf 2014 found no difference in the risk of developing septicaemia between tigecycline and ertapenem (3.93% versus 5.08%; RR 0.77, 95% CI 0.43 to 1.39; 1 trial, 955 participants, 43 events; Analysis 17.3). Similarly, in this trial’s sub study of participants with osteomyelitis at baseline there were no notable differences (2.6% versus 2.44%; RR 1.06, 95% CI 0.10 to 11.40; 1 trial, 118 participants, 3 events; Analysis 17.3).
Outcome 6: Infection‐related mortality
Four studies reported on this outcome. Harkless 2005 reported three deaths in the piperacillin‐tazobactam group, but none of them was considered to be related to study medication. Bouter 1996 reported one death due to cardiac arrest in the group treated with imipenem‐cilastatin and four deaths in the group treated with piperacillin‐clindamycin. Of these four cases, two were from heart failure and two from uncontrolled infection at the site of the leg ulcer. Lipsky 1990 reported five deaths, but all were unrelated to the foot infection. The study did not provide information regarding how many deaths occurred in each study group. Lauf 2014 reported seven deaths in the group treated with tigecycline (six in the main study and one in the sub study) and three deaths in the group treated with ertapenem (two in the main study and one in the sub study). None of these deaths was considered to be related to study drug by the investigator, most were cardiovascular in nature and all occurred after the antibiotic treatment had finished.
Outcome 7: Length of hospitalisation
Only Erstad 1997 reported on this outcome. The duration of hospitalisation was longer in the group treated with ampicillin‐sulbactam (mean of 21.10 days (minimum‐maximum: 6.00 to 58.00)) than in the group treated with cefoxitin (mean of 12.10 days (minimum‐maximum: 4.00‐39.00)), although this difference was not statistically significant at conventional levels (P value 0.06) it was very underpowered with only 36 participants.
Outcome 8: Ulcer healing
Only the Lipsky 1990 study reported this outcome; 40% of participants treated with clindamycin and 33% participants treated with cephalexin experienced wound healing (RR 1.20, 95% CI 0.59 to 2.46; 1 trial, 19 events).
Outcome 9: Recurrence of ulcer infection
Four studies reported on this outcome. Saltoglu 2010 noted that two participants (6%) treated with imipenem had a relapse at the end of two months of follow‐up, while there were no relapses in the group treated with piperacillin‐tazobactam. In Bouter 1996, three participants (13.6%) treated with imipenem‐cilastatin developed a recurrence but there were none in the group treated with piperacillin‐clindamycin. Grayson 1994 reported a recurrence rate of 31.25% in episodes treated with imipenem‐cilastatin compared with 43.75% in episodes treated with ampicillin‐sulbactam (RR 0.71, 95% CI 0.42 to 1.21; 1 RCT, 36 events; Analysis 9.5). In Lipsky 1990 there were eight cases (15.68%) of recurrence or persistence of the ulcer infection during long‐term follow‐up, but the study did not report how many were in each treatment group.
Outcome 10: Health‐related quality of life
No study reported results on any measure of health‐related quality of life.
Discussion
This systematic review summarizes the available evidence on the effects of systemic antibiotic therapy for treating DFIs. The review includes 20 randomised controlled trials with a total of 3791 participants with a DFI. The studies tested various antibiotic agents, either singly or in combination, administered in a variety of regimens to evaluate their effectiveness for treating these difficult infections. The antibiotics used varied in the specific agent, the route of administration and the duration of therapy. Furthermore, the studies differed in whether, and which, co‐interventions of various types were allowed. To help organise the data, we have grouped the antibiotic agents into six large groups. We assessed their effectiveness based on the resolution of the clinical signs and symptoms of the infection, as it is the presence of these clinical findings that are used to define DFIs. It is difficult to state what overall rate of resolution of findings of infection should be expected for DFIs, as this varies considerably and depends upon the severity of infection of participants enrolled in the trial, the presence of certain complications (such as concomitant bone infection) or co‐morbidities (such as severe arterial insufficiency) and what the trialists considered constituted resolution. Our analysis of the results demonstrated that no one antibiotic treatment showed a statistically significant clinical effect over comparators, with the exception of one trial that showed better results for patients receiving ertapenem with or without vancomycin compared to tigecycline in the clinical resolution of the infection (Lauf 2014).
Foot infections in people with diabetes are common and associated with serious potential consequences, including impaired wound healing, contiguous spread to deeper tissues, necessity for lower extremity amputation, and, occasionally death. The advent of antibiotic therapy in the late 1930s with sulpha drugs (Regan 1949), and in the early 1940s with penicillin (McKittrick 1946), was associated with a marked reduction in lower extremity (especially above the knee) amputations, as well as mortality. Since then, many new antibiotic agents have been used to treat these infections. Over the past few decades microbiological studies, have revealed that aerobic Gram‐positive cocci, especially Staphylococcus aureus, are the most common pathogens in these infections (IDSA 2012). More recent studies, however, have shown that aerobic Gram‐negative bacilli are common co‐pathogens in patients who have received antibiotic therapy or who live in hot climates. Similarly, molecular microbiological techniques have shown that obligate anaerobes can frequently be isolated from polymicrobial infections. In the past decade, multidrug‐resistant bacteria, especially MRSA, but also highly resistant Gram‐negative bacilli, have become more common pathogens in DFIs. Thus, many different types of antibiotics have been investigated to see which might be most effective and safe for treating these dreaded infections.
Summary of main results
The 20 studies that met our inclusion criteria were published between 1990 and 2014. The investigations were almost exclusively conducted in North American and European countries, and the majority of enrolled patients were late middle‐aged men. Most subjects were treated as inpatients with intravenous antibiotic therapy, at least initially. Thus, any conclusions we can draw from this systematic review apply largely to patients with these characteristics.
Efficacy of antibiotic treatment
A. Anti‐pseudomonal penicillins
Although Pseudomonas aeruginosa is a relatively uncommon pathogen in uncomplicated DFI, antibiotics active against this organism are often preferred because it is isolated from selected groups of patients. These include people who have recently received antibiotic therapy (in whom P aeruginosa is selected out by its resistance to many commonly used antibiotics) or who live in hot climates in low‐income countries (where it is often the most common causative organism). Overuse of these agents is a problem, however, because P aeruginosa is also a common colonising organism, especially in patients treated with some form of hydrotherapy, which exposes them to this water‐borne agent. Newer penicillins developed to be active against P aeruginosa, as well as carbapenems, are the mainstays of parenteral anti‐pseudomonal treatment. Three trials included in the review showed no significant differences of anti‐pseudomonal penicillins in achieving a clinical resolution of the infection or avoiding amputations, when compared to piperacillin‐tazobactam, ticarcillin‐clavulanate (Tan 1993), ampicillin‐sulbactam (Harkless 2005), and, imipenem–cilastatin (Saltoglu 2010).
B. Broad‐spectrum penicillins
Broad‐spectrum penicillins have activity against the most common Gram‐positive, Gram‐negative (Enterobacteriaceae) and anaerobic pathogens that cause DFIs. Thus, they are a popular choice to use against these infections. Only one study compared a broad‐spectrum penicillin (ampicillin‐sulbactam) to another agents (cefoxitin, a second‐generation cephalosporin) and found no significant difference in clinical resolution of the infection, reduction in the rate of amputations or length of hospitalisation for DFIs (Erstad 1997).
C. Cephalosporins
Depending upon which generation is used, cephalosporins generally have a similar spectrum of activity to their beta‐lactam relatives, the broad‐spectrum penicillins. Some of the higher generation agents are active against Pseudomonas species and the newest fifth‐generation agents have also been formulated to have activity against MRSA. Again, the two included studies showed no differences between cephalosporins and other beta‐lactam antibiotics in the clinical resolution of infection (Clay 2004; Noel 2008a).
D. Carbapenems
Carbapenems generally have a very broad spectrum of activity. Group 1 agents are active against most aerobic Gram‐positive bacteria (except MRSA) and most Gram‐negative organisms (except Pseudomonas species), while group 2 agents add coverage of non‐fermentative Gram‐negatives, such as Pseudomonas species. The available studies included in this review did not demonstrate differences between carbapenems (the group 1 ertapenem or group 2 imipenem‐cilastatin) and anti‐pseudomonal penicillins (piperacillin‐tazobactam, piperacillin plus clindamycin; Bouter 1996; Graham 2002a; SIDESTEP Study), or broad‐spectrum penicillins (ampicillin‐sulbactam) in clinical resolution of DFIs (Grayson 1994).
E. Fluoroquinolones
Fluoroquinolone antibiotics, which also are classified by generation, are characterised by their broad‐spectrum of activity and good oral bioavailability. Our systematic review found that third‐ or fourth‐generation agents (levofloxacin and clinafloxacin or moxifloxacin, respectively) do not differ from anti‐pseudomonal penicillins in effectiveness in clinical resolution of DFIs (Giordano 2005; Graham 2002b; RELIEF Study; Siami 2001). There is also no evidence that fourth‐ (moxifloxacin) and second‐generation (ofloxacin) fluoroquinolones differ from broad‐spectrum penicillins on the same outcome measurements (Lipsky 1997; STIC Study). However, the study that compared ofloxacin with a broad‐spectrum penicillin (ampicillin‐sulbactam) showed a significantly higher proportion of participants treated with ampicillin‐sulbactam who required additional antibiotics because of non‐improvement (42 participants (79.40%) received gentamicin or trimetroprim‐sulfamethoxazole) than those treated with ofloxacin (5 participants (9%) received metronidazole; Lipsky 1997). This difference in the additional antibiotic requirement could have an impact in the results observed for clinical resolution in this study.
F. Other antibiotics
In a large, well‐designed study (sponsored by the manufacturers of tigecycline), ertapenem with or without vancomycin showed significantly better results than tigecycline in clinical resolution of DFIs in patients with and without osteomyelitis at baseline (Lauf 2014). However, there were no differences in the risk of developing septicaemia in the two patient groups.
Among other antibiotics with varied antimicrobial spectra, no differences in clinical resolution of infection were found in the following comparisons: daptomycin versus vancomycin (each of which is usually selected for its activity against MRSA); linezolid versus aminopenicillins combined with beta‐lactamase inhibitors; or, clindamycin versus cephalexin.
Four studies reported rates of patient mortality, but in only one was the outcome related to the DFI; Bouter 1996 reported two cases of infection‐related mortality in patients treated with piperacillin‐clindamycin.
Only one study reported on length of hospital stay and found no differences between participants treated with ampicillin‐sulbactam and those treated with cefoxitin (Erstad 1997). Similarly, only one study reported on ulcer healing and found no differences between participants treated with clindamycin and those treated with cephalexin (Lipsky 1990). In four studies that reported on recurrence of ulcer infection there were no statistically significant differences between piperacillin‐tazobactam and imipenem‐cilastatin (Saltoglu 2010), imipenem‐cilastatin and piperacillin‐clindamycin (Bouter 1996), imipenem‐cilastatin and ampicillin‐sulbactam (Grayson 1994), or clindamycin and cephalexin (Lipsky 1990). No study reported data on health‐related quality of life.
Safety of antibiotic treatment
A. Anti‐pseudomonal penicillins
In one study there was no difference in the rate of treatment‐related adverse events between an anti‐pseudomonal penicillin (piperacillin‐tazobactam) and a broad‐spectrum penicillin (ampicillin‐sulbactam; Harkless 2005). In another, more participants treated with piperacillin‐tazobactam developed adverse events (hepatotoxicity and nephrotoxicity) compared to those treated with a carbapenem (imipenem‐cilastatin; Saltoglu 2010), but this difference was based on only 12 events and was not statistically significant.
B. Broad‐spectrum penicillins
One study reported no differences between ampicillin‐sulbactam and cefoxitin (a cephalosporin) in the rate of adverse events, all of which were of minor clinical importance (Erstad 1997).
C. Cephalosporins
The one study that reported on the safety of antibiotic treatment noted no adverse events in either study group (ceftriaxone plus metronidazole versus ticarcillin‐clavulanate; Clay 2004).
D. Carbapenems
Carbapenems, either alone or combined with an anti‐pseudomonal agent, were associated with fewer cases of diarrhoea than piperacillin‐tazobactam (anti‐pseudomonal penicillin; Bouter 1996; SIDESTEP Study). However, no differences in adverse events were found when a carbapenem (imipenem‐cilastatin) was compared with a broad‐spectrum penicillin (ampicillin‐sulbactam; Grayson 1994).
E. Fluoroquinolones
No study reported data on adverse effects for third‐ or fourth‐generation fluoroquinolones. One study reported no differences in the rate of adverse events between ofloxacin (a second‐generation fluoroquinolone) and ampicillin‐sulbactam (a broad‐spectrum penicillin; Lipsky 1997).
F. Other antibiotics
Daptomycin was associated with a statistically significant 39% reduction in the rate of adverse events compared to vancomycin or a semi‐synthetic penicillin (Arbeit 2004). Linezolid was associated with a 16% increase in the rate of adverse events compared to ampicillin‐sulbactam, especially diarrhoea, nausea and anaemia (Lipsky 2004). Tigecycline was associated with a significantly higher rate of adverse events (47%), most frequently nausea and vomiting, compared to ertapenem with or without vancomycin (Lauf 2014). There were no differences in the rate of adverse events between participants treated with clindamycin versus cephalexin (Lipsky 1990).
Overall completeness and applicability of evidence
The applicability of these results is limited, as interpreting the available studies is hampered by heterogeneity in their design, the use of many different antibiotic regimens and the failure to report many key outcomes. Thus, we are not able to determine whether any one antibiotic agent or regimen for treating DFI is better or safer than any other, with the exception of tigecycline being significantly less effective than ertapenem (with or without vancomycin).
Quality of the evidence
We consider the overall quality of evidence on which this review is based to be low. While the quality of the studies varied, almost all had limitations in their design or execution, or both, that limited confidence in their effect estimates. Most importantly, a blinded outcome assessment should have been conducted for the main outcome of treatment, considering that both the diagnosis of infection and its resolution require a judgement by the investigator of the clinical signs and symptoms. Such a blinded assessment was only completed in nine of the 20 included trials (Arbeit 2004; Clay 2004; Graham 2002a; Grayson 1994; Lauf 2014; Lipsky 1990; Noel 2008a; RELIEF Study; SIDESTEP Study), while in two the assessment was by an unblinded person (Graham 2002b; STIC Study). In addition, only about one‐third of the studies accurately concealed the randomisation sequence for assigning participants to one of the study treatments (Grayson 1994; Lauf 2014; Noel 2008a; RELIEF Study; Saltoglu 2010).
Our confidence in the effect estimates obtained in the review was also diminished by the heterogeneity (inconsistency) of the body of evidence assessed. The 20 trials included had 16 different comparisons of a variety of types of antibiotics. The antibiotic regimens differed in terms of class of drugs, spectrum of antibacterial activity, dosages, routes of drug administration, and duration of treatment. Furthermore, they differed in which, if any, antibiotic co‐interventions could be administered. Finally, outcomes assessed varied and were categorised at different time points after the end of antibiotic therapy.
Most antibiotics were compared in single trials with a range of different controls. The limited sample size in the majority of included trials made the possibility of detecting clinically important differences impossible and for every comparison differences in benefits and harms cannot be ruled out.
It is remarkable that all but two of the trials received funding from pharmaceutical industry‐sponsors of at least one of the agents compared in the study. This is an important issue as a Cochrane Review found that industry sponsored drug and device studies are associated with more favourable results and positive conclusions than studies sponsored by other sources (Lundh 2012).
Potential biases in the review process
To minimize the ever‐present risk of publication bias we conducted an exhaustive search in numerous databases and tried to locate grey literature. Nevertheless, we cannot exclude the possibility that publication bias affected the papers we were able to find. The low number of studies included in the meta‐analysis precluded the realization of a funnel plot or a statistical test to explore the presence of publication bias.
Agreements and disagreements with other studies or reviews
Several other researchers and scientific organisations have investigated whether there is an optimal antibiotic treatment for DFI. A systematic review published in 2008 by members of the International Working Group on the Diabetic Foot (IWGDF) assessed the effectiveness of treatments for diabetic foot osteomyelitis and concluded that no data supported the superiority of any particular route of delivery of systemic antibiotics or informed the optimal duration of antibiotic therapy (Berendt 2008). Four years later the same organization conducted a systematic review of all interventions in the management of infection in the diabetic foot, and specifically considered antibiotic treatment (Peters 2012). The review included 11 randomised controlled trials (RCTs) with data on antibiotic therapy for skin and soft‐tissue DFIs without bone involvement and found no significant benefit for any specific antibiotic agent, route of administration or duration of treatment. Seven additional RCTs that contained data on infections with bone involvement also reported no differences between treatment regiments, except in one trial. The IWGDF review also included the study by Erstad 1997, for which the authors referred to the P value reported by the primary study, but did not report an effect estimate. In our review, we re‐calculated the effect estimate from the data provided by the primary study, and obtained a relative risk with a 95% confidence interval that included the null value 1.
A previous review of eight trials investigated antibiotics for DFI (Nelson 2006a). The authors considered that the available trials were underpowered and too dissimilar to be pooled and concluded there was no strong evidence for recommending any particular antimicrobial agent for the prevention of amputation, resolution of infection, or ulcer healing. Crouzed 2011 reported a 'critical review' of RCTs on antibiotic therapy for DFI focusing on study quality and endpoints. After reviewing 14 papers that met their inclusion criteria they concluded that “discrepancies in study design, inclusion criteria, statistical methodology, and the varying definitions of both clinical and microbiological endpoints between the published studies, make it difficult to compare them, as well as to determine which regimen may be the most appropriate for patients with diabetic foot infection.”
Our conclusions are in broad agreement with recommendations made by clinical practice guidelines on the management of diabetic foot infections. In general, these guidelines conclude that the evidence is insufficient to make recommendations on any particular antibiotic treatment (International Working Group Diabetic Foot 2011; IDSA 2012; NICE 2011). All guidelines recognize the need to start with empirical antibiotic therapy based on infection severity until the results of microbiological culture are available, which will allow a change to a more specific regimen, when needed (CDA 2013, International Working Group Diabetic Foot 2011; IDSA 2012; NICE 2011). They also suggest using antibiotics with activity against Gram‐positive organisms for mild infections (CDA 2013; International Working Group Diabetic Foot 2011; IDSA 2012; NICE 2011). The CDA 2013 suggests that for localized infections that are not limb or life‐threatening clinicians can use oral antibiotics, such as cloxacillin, cephalexin, trimetroprim‐sulfamethoxazole, clindamycin, amoxicillin‐clavulanate, linezolid or doxycycline. The IDSA 2012 guideline suggests that these antibiotics should also be used for moderate infections, while the NICE 2011 guideline, recommends also covering Gram‐negative organisms and anaerobic bacteria.
In case of severe infections, IDSA, IWGDF and NICE recommend covering Gram‐positive and Gram‐negative (including anaerobic) bacteria. IDSA suggests that it is usually unnecessary to target Pseudomonas aeruginosa except for patients with known risk factors for infection with this organism. All guidelines also suggest empirically covering MRSA only in patients with a prior history of MRSA infection (or colonisation), where there is a high local prevalence of MRSA colonisation or infection, or in cases of clinically severe infection.
The IDSA 2012, International Working Group Diabetic Foot 2011, and NICE 2011 guidelines also point that the route of therapy should depend on the severity of infection: intravenous therapy should be used for all severe and some moderate infections, switching to oral agents when the patient is systemically well and culture results available. Oral antibiotics can be used for most mild, and many moderate, infections.
With regard to the duration of antibiotic treatment, the IDSA 2012 suggests an initial antibiotic course for soft‐tissue infections of about one to two weeks for mild infections and two to three weeks for moderate to severe infections.
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Comparison 1 A. Anti‐pseudomonas penicillins: piperacillin‐tazobactam vs ticarcillin‐clavulanate, Outcome 1 Clinical resolution of the infection.
Comparison 2 A. Anti‐pseudomonal penicillins: piperacillin‐tazobactam vs ampicillin‐sulbactam, Outcome 1 Clinical resolution of the infection.
Comparison 2 A. Anti‐pseudomonal penicillins: piperacillin‐tazobactam vs ampicillin‐sulbactam, Outcome 2 Adverse effects.
Comparison 2 A. Anti‐pseudomonal penicillins: piperacillin‐tazobactam vs ampicillin‐sulbactam, Outcome 3 Amputations.
Comparison 3 A. Anti‐pseudomonal penicillins: piperacillin‐tazobactam vs imipenem‐cilastatin, Outcome 1 Clinical resolution of the infection.
Comparison 3 A. Anti‐pseudomonal penicillins: piperacillin‐tazobactam vs imipenem‐cilastatin, Outcome 2 Adverse effects.
Comparison 3 A. Anti‐pseudomonal penicillins: piperacillin‐tazobactam vs imipenem‐cilastatin, Outcome 3 Amputations.
Comparison 3 A. Anti‐pseudomonal penicillins: piperacillin‐tazobactam vs imipenem‐cilastatin, Outcome 4 Recurrence.
Comparison 4 B. Broad‐spectrum penicillins: ampicillin‐sulbactam vs cefoxitin, Outcome 1 Clinical resolution of the infection.
Comparison 4 B. Broad‐spectrum penicillins: ampicillin‐sulbactam vs cefoxitin, Outcome 2 Adverse effects.
Comparison 4 B. Broad‐spectrum penicillins: ampicillin‐sulbactam vs cefoxitin, Outcome 3 Amputations.
Comparison 5 C. Cephalosporins: ceftobiprole vs ceftazidime + vancomycin, Outcome 1 Clinical resolution of the infection.
Comparison 6 C. Cephalosporins: ceftriaxone + metronidazole vs ticarcillin‐clavulanate, Outcome 1 Clinical resolution of the infection.
Comparison 7 D. Carbapenems: ertapenem vs piperacillin‐tazobactam, Outcome 1 Clinical resolution of the infection.
Comparison 7 D. Carbapenems: ertapenem vs piperacillin‐tazobactam, Outcome 2 Adverse effects.
Comparison 8 D. Carbapenems: imipenem‐cilastatin vs piperacillin + clindamycin, Outcome 1 Clinical resolution of the infection.
Comparison 8 D. Carbapenems: imipenem‐cilastatin vs piperacillin + clindamycin, Outcome 2 Adverse effects.
Comparison 8 D. Carbapenems: imipenem‐cilastatin vs piperacillin + clindamycin, Outcome 3 Recurrence.
Comparison 9 D. Carbapenems: imipenem‐cilastatin vs ampicillin‐sulbactam, Outcome 1 Clinical resolution of the infection at the completion of therapy.
Comparison 9 D. Carbapenems: imipenem‐cilastatin vs ampicillin‐sulbactam, Outcome 2 Clinical resolution of the infection at the end of follow‐up.
Comparison 9 D. Carbapenems: imipenem‐cilastatin vs ampicillin‐sulbactam, Outcome 3 Adverse effects.
Comparison 9 D. Carbapenems: imipenem‐cilastatin vs ampicillin‐sulbactam, Outcome 4 Amputations.
Comparison 9 D. Carbapenems: imipenem‐cilastatin vs ampicillin‐sulbactam, Outcome 5 Recurrence.
Comparison 10 E. Fluoroquinolones: fourth‐generation fluoroquinolones vs anti‐pseudomonal penicillins, Outcome 1 Clinical resolution of the infection.
Comparison 11 E. Fluoroquinolones: moxifloxacin vs amoxicillin‐clavulanate, Outcome 1 Clinical resolution of the infection.
Comparison 12 E. Fluoroquinolones: third‐generation fluoroquinolone vs extended‐spectrum penicillin, Outcome 1 Clinical resolution of the infection.
Comparison 13 E. Fluoroquinolones: second‐generation fluoroquinolone vs extended‐spectrum penicillin, Outcome 1 Clinical resolution of the infection.
Comparison 13 E. Fluoroquinolones: second‐generation fluoroquinolone vs extended‐spectrum penicillin, Outcome 2 Adverse effects.
Comparison 13 E. Fluoroquinolones: second‐generation fluoroquinolone vs extended‐spectrum penicillin, Outcome 3 Amputations.
Comparison 14 F. Other antibiotics: daptomycin vs control, Outcome 1 Clinical resolution of the infection.
Comparison 14 F. Other antibiotics: daptomycin vs control, Outcome 2 Adverse effects.
Comparison 15 F. Other antibiotics: linezolid vs aminopenicillin + beta lactamase inhibitor, Outcome 1 Clinical resolution of the infection.
Comparison 15 F. Other antibiotics: linezolid vs aminopenicillin + beta lactamase inhibitor, Outcome 2 Adverse effects.
Comparison 16 F. Other antibiotics: clindamycin vs cephalexin, Outcome 1 Clinical resolution of the infection.
Comparison 16 F. Other antibiotics: clindamycin vs cephalexin, Outcome 2 Adverse effects.
Comparison 16 F. Other antibiotics: clindamycin vs cephalexin, Outcome 3 Ulcer healing.
Comparison 17 F. Other antibiotics: tigecycline vs ertapenem, Outcome 1 Clinical resolution of the infection.
Comparison 17 F. Other antibiotics: tigecycline vs ertapenem, Outcome 2 Adverse events.
Comparison 17 F. Other antibiotics: tigecycline vs ertapenem, Outcome 3 Septicaemia.
| Study ID | Intervention | Comparison |
| A | Anti‐pseudomonal penicillins | |
| Anti‐pseudomonal penicillins | Anti‐pseudomonal penicillins | |
| Piperacillin‐tazobactam 3 g/375 mg iv every 6 h (min 5 days) | Ticarcillin‐clavulanate 3 g/100 mg iv every 6 h (min 5 days) | |
| Anti‐pseudomonal penicillins | Broad‐spectrum penicillins | |
| Piperacillin‐tazobactam 4 g/0.5 g iv every 8 h (4‐14 days, max 21 days) | Ampicillin‐sulbactam 2 g/1 g iv every 6 h (4‐14 days, max 21 days) | |
| Anti‐pseudomonal penicillins | Carbapenems | |
| Piperacillin‐tazobactam 4.5 g iv every 8 h (14 days) | Imipenem‐cilastatin 500 mg iv every 6 h (14 days) | |
| B | Broad‐spectrum penicillins | |
| Broad‐spectrum penicillins | Cephalosporins | |
| Ampicillin‐sulbactam 3 g iv every 6 h (min 5 days) | Cefoxitin 2 g iv every 6 h (min 5 days) | |
| C | Cephalosporins | |
| Fifth‐generation cephalosporins | Third‐generation cephalosporins + glycopeptide | |
| Ceftobiprole 500 mg iv every 8 h (7‐14 days) | Vancomycin 1000 mg iv every 12 h plus ceftazidime 1000 mg iv every 8 h (7‐14 days) | |
| 2. | Third‐generation cephalosporin + nitroimidazole | Anti‐pseudomonal penicillin |
| Ceftriaxon ‐metronidazole 1 g/1 g iv every 24 h (duration not described) | Ticarcillin‐clavulanate 3.1 g iv every 6 h (duration not described) | |
| D | Carbapenems | |
| Carbapenems | Anti‐pseudomonal penicillins | |
| Ertapenem | Piperacillin‐tazobactam | |
| Ertapenem 1 g iv every 24 h (min 5 days). Switch to amoxicillin‐clavulanate 875 mg/125 mg po every 12 h | Piperacillin‐tazobactam 3 g/375 mg iv every 6 h (min of 5 days). Switch to amoxicillin‐clavulanate 875 mg/125 mg po every 12 h | |
| Ertapenem 1 g iv every 24 h (7‐14 days) | Piperacillin‐tazobactam 3 g/375 mg iv every 6 h (7‐14 days) | |
| Imipenem + cilastatin | Piperacillin + clindamycin | |
| Imipenem‐cilastatin 500 mg iv every 6 h (10 days) | Piperacillin 3 g iv every 6 h plus clindamycin 600 mg iv every 8 h (10 days) | |
| Carbapenems | Broad‐spectrum penicillins | |
| Imipenem‐cilastatin 500 mg iv every 6 h (5 days) | Ampicillin‐sulbactam 2 g/1 g iv every 6 h (5 days) | |
| E | Fluoroquinolones | |
| Fourth‐generation fluoroquinolones | Anti‐pseudomonal penicillins | |
| Moxifloxacin 400 mg every 24 h (iv for 3 days, then po for 7‐14 days) | Piperacillin‐tazobactam 3 g/375 mg iv every 6 h (3 days). Then amoxicillin‐clavulanate 800 mg po every 12 h (7‐14 days) | |
| Moxifloxacin 400 mg every 24 h (iv for 3 days, then 400 mg every 12 h po for 7‐21 days) | Piperacillin‐tazobactam 4 g/0.5 g iv every 8 h. Then amoxicillin‐clavulanate 875 mg/125 mg po every 12 h (7‐21 days) | |
| Cinafloxacin 200 mg iv every12 h (max 14 days), then 200 mg po every 12 h | Piperacillin‐tazobactam 3 g/375 mg po every 6 h. Then amoxicillin‐clavulanate 500 mg po every 8 h | |
| Fourth‐generation fluoroquinolones | Broad‐spectrum penicillins | |
| Moxifloxacin 400 mg iv every 24 h for 3 days, then po for 7‐21 days | Amoxicillin 1000 g‐clavulanate 200 mg iv every 8 h for 3 days, then 500 mg/125 mg po every 8 h for 7‐21 days | |
| Third‐generation fluoroquinolones | Antipseudomonal penicillins | |
| Levofloxacin 750 mg iv or po every 24 h (7‐14 days) | Ticarcillin‐clavulanate 3.1g every iv 4 h‐6 h, then changed to amoxicillin‐clavulanate 875 mg po every 12 h (7‐14 days) | |
| Second‐generation fluoroquinolones | Broad‐spectrum penicillins | |
| Ofloxacin 400 mg iv every 12 h (then switch to po; 14‐28 days) | Ampicillin‐sulbactam 1‐2 g/0.5‐1 g iv every 6 h. Switch to amoxicillin‐clavulanate 500 mg/125 mg po every 8 h (14‐28 days) | |
| F | Other antibiotics | |
| Daptomycin 4 mg/kg iv every 24 h (7‐14 days) | Vancomycin 1 g iv every 12 h (7‐14 days) | |
| Linezolid 600 mg iv or po every 12 h (≥ 7 days ≤ 28) | Ampicillin/sulbactam 1.5 g‐3 g iv every 6 h OR amoxicillin/clavulanate 500 mg/875mg po every 12 h (≥ 7 days ≤ 28) | |
| Clindamycin 300 mg iv every 6 h (14 days) | Cephalexin 500 mg every 6 h po (14 days) | |
| Tigecycline 150 mg iv every 24 h (28 days) | Ertapenem 1 g iv every 24 h (28 days) | |
| Abbreviations h: hour(s) | ||
| Ticarcillin‐clavulanate iv | Ampicillin‐sulbactam iv | Ceftriaxone‐metronidazol iv | Ceftazidime‐vancomicyn iv | Cefoxitin iv | Ertapenem iv | Ertapenem iv followed by amoxicillin‐clavulanate po | Imipenem‐cilastatin iv | Moxifloxacin iv followed by po | Cinafloxacin iv followed by po | Levofloxacin iv | Ofloxacin iv followed by po | Linezolid iv or po | Clindamycin iv | Tigecycline | Vancomycin | |
| Anti‐pseudomonal penicillins |
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| Piperacillin‐tazobactam iv | 1 Tan 1993 | |||||||||||||||
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| This table shows all the comparisons included in the review and the number of evaluations for each comparison. To simplify, only different type of antibiotics are represented, irrespective of dose. The grey shaded areas represent comparisons between the same antibiotic. The numbers in the cells shown refer to number of RCT assessing that comparison. | ||||||||||||||||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Clinical resolution of the infection Show forest plot | 1 | 63 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.16 [0.59, 2.29] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Clinical resolution of the infection Show forest plot | 1 | 314 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.02 [0.86, 1.20] |
| 2 Adverse effects Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 2.1 Any adverse event | 1 | 314 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.14 [0.99, 1.32] |
| 2.2 Treatment‐related adverse event | 1 | 314 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.42 [0.85, 2.37] |
| 2.3 Serious adverse event | 1 | 314 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.94 [0.66, 1.34] |
| 3 Amputations Show forest plot | 1 | 314 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.97 [0.51, 1.84] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Clinical resolution of the infection Show forest plot | 1 | 64 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.66 [0.84, 3.26] |
| 2 Adverse effects Show forest plot | 1 | 320 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.50 [1.56, 7.86] |
| 2.1 Any adverse event | 1 | 64 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.19 [0.95, 10.72] |
| 2.2 Hepatotoxicity | 1 | 64 | Risk Ratio (M‐H, Fixed, 95% CI) | 5.32 [0.66, 43.05] |
| 2.3 Nephrotoxicity | 1 | 64 | Risk Ratio (M‐H, Fixed, 95% CI) | 6.39 [0.81, 50.09] |
| 2.4 Hematological side effects | 1 | 64 | Risk Ratio (M‐H, Fixed, 95% CI) | 5.31 [0.27, 106.46] |
| 2.5 Nausea | 1 | 64 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.35 [0.01, 8.38] |
| 3 Amputations Show forest plot | 1 | 64 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.87 [0.59, 1.28] |
| 4 Recurrence Show forest plot | 1 | 64 | Risk Ratio (M‐H, Fixed, 95% CI) | 5.31 [0.27, 106.46] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Clinical resolution of the infection Show forest plot | 1 | 36 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.14 [0.02, 1.05] |
| 2 Adverse effects Show forest plot | 1 | 36 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.17 [0.49, 2.79] |
| 3 Amputations Show forest plot | 1 | 36 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.0 [0.48, 2.08] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Clinical resolution of the infection Show forest plot | 1 | 257 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.05 [0.90, 1.23] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Clinical resolution of the infection Show forest plot | 1 | 70 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.94 [0.72, 1.24] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Clinical resolution of the infection Show forest plot | 2 | 684 | Risk Ratio (M‐H, Random, 95% CI) | 1.07 [0.96, 1.19] |
| 2 Adverse effects Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 2.1 Drug related adverse effects | 1 | 586 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.76 [0.53, 1.09] |
| 2.2 Diarrhoea | 1 | 586 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.58 [0.36, 0.93] |
| 2.3 Nausea | 1 | 586 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.83 [0.44, 1.58] |
| 2.4 Headache | 1 | 586 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.62 [0.28, 1.34] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Clinical resolution of the infection Show forest plot | 1 | 46 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.73 [0.24, 2.24] |
| 2 Adverse effects Show forest plot | 1 | 46 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.27 [0.09, 0.84] |
| 3 Recurrence Show forest plot | 1 | 46 | Risk Ratio (M‐H, Fixed, 95% CI) | 7.61 [0.42, 139.47] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Clinical resolution of the infection at the completion of therapy Show forest plot | 1 | 96 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.95 [0.80, 1.14] |
| 2 Clinical resolution of the infection at the end of follow‐up Show forest plot | 1 | 96 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.82 [0.60, 1.12] |
| 3 Adverse effects Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 3.1 Total adverse effects | 1 | 96 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.06 [0.61, 1.85] |
| 3.2 Significant adverse effects | 1 | 96 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.29 [0.52, 3.17] |
| 4 Amputations Show forest plot | 1 | 96 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.85 [0.62, 1.15] |
| 5 Recurrence Show forest plot | 1 | 96 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.71 [0.42, 1.21] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Clinical resolution of the infection Show forest plot | 3 | 387 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.03 [0.89, 1.20] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Clinical resolution of the infection Show forest plot | 1 | 134 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.79 [0.57, 1.08] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Clinical resolution of the infection Show forest plot | 1 | 67 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.97 [0.60, 1.55] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Clinical resolution of the infection Show forest plot | 1 | 108 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.13 [0.88, 1.47] |
| 2 Adverse effects Show forest plot | 1 | 108 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.82 [0.89, 3.72] |
| 3 Amputations Show forest plot | 1 | 108 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.11 [0.01, 1.94] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Clinical resolution of the infection Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 1.1 Daptomycin vs control | 1 | 133 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.94 [0.68, 1.30] |
| 2 Adverse effects Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 2.1 Advese effects related to treatment | 1 | 133 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.61 [0.39, 0.94] |
| 2.2 Severe adverse effects | 1 | 133 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.20 [0.02, 1.59] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Clinical resolution of the infection Show forest plot | 1 | 361 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.07 [0.91, 1.25] |
| 2 Adverse effects Show forest plot | 1 | 361 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.66 [1.49, 4.73] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Clinical resolution of the infection Show forest plot | 1 | 56 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.07 [0.79, 1.45] |
| 2 Adverse effects Show forest plot | 1 | 56 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.47 [0.04, 4.84] |
| 3 Ulcer healing Show forest plot | 1 | 52 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.2 [0.59, 2.46] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Clinical resolution of the infection Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 1.1 Patients without OM (main study) | 1 | 955 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.09 [1.01, 1.18] |
| 1.2 Patients with OM (sub study) | 1 | 118 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.08 [1.27, 3.39] |
| 2 Adverse events Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 2.1 Any adverse event | 1 | 955 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.47 [1.34, 1.60] |
| 2.2 Fever | 1 | 955 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.24 [0.64, 2.41] |
| 2.3 Headache | 1 | 955 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.18 [0.65, 2.14] |
| 2.4 Pain | 1 | 955 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.47 [0.71, 3.01] |
| 2.5 Hypertension | 1 | 955 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.95 [0.60, 1.50] |
| 2.6 Diarrhoea | 1 | 955 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.51 [0.32, 0.82] |
| 2.7 Nausea | 1 | 955 | Risk Ratio (M‐H, Fixed, 95% CI) | 4.76 [3.46, 6.56] |
| 2.8 Vomiting | 1 | 955 | Risk Ratio (M‐H, Fixed, 95% CI) | 5.24 [3.39, 8.12] |
| 2.9 Anemia | 1 | 955 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.70 [0.31, 1.56] |
| 2.10 Insomnia | 1 | 955 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.66 [1.23, 10.96] |
| 2.11 Increase in serum glutamic oxaloacetic transaminase | 1 | 955 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.77 [0.40, 1.50] |
| 2.12 Increase in serum glutamic pyruvic transaminase | 1 | 955 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.81 [0.42, 1.60] |
| 2.13 Hipoglicemia | 1 | 955 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.38 [0.83, 2.30] |
| 2.14 Osteomyelitis | 1 | 955 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.95 [0.96, 3.99] |
| 2.15 Discontinuation of treatment for adverse events | 1 | 955 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.52 [0.95, 2.42] |
| 3 Septicaemia Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 3.1 Patients without osteomyelitis (main study) | 1 | 955 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.77 [0.43, 1.39] |
| 3.2 Patients with osteomyelitis (sub study) | 1 | 118 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.06 [0.10, 11.40] |
