Antibiotic Therapy of Diabetic Foot Infections: A Systematic Review of

Randomized Controlled Trials

Accepted Article
Huidi TCHERO MD,1* Pauline KANGAMBEGA MD,2 Lazarre NOUBOU MD,1 Beatrice

BECSANGELE,3 Sergiu FLUIERARU MD,4 Luc TEOT MD PhD,4

Author Affiliations:
1
Department of Trauma and Orthopedics Surgery and Wound Healing Unit, Centre Hospitalier

de Saint Martin BP 381 - Spring Concordia, 97150 SAINT MARTIN, Guadeloupe, France
2
Division of Diabetes, Endocrinology and Metabolism, CHRU de Pointe-A-Pitre, Pointe-A-Pitre,

Guadeloupe, France
3
Wound Healing Unit, Centre Hospitalier de Saint Martin, BP 381 - Spring Concordia, 97150

SAINT MARTIN, Guadeloupe, France

4
Department of reconstructive and plastic surgery, and Wound Healing Unit, Montpellier,

France

*
Corresponding Author: Huidi TCHERO

Address: Centre Hospitalier de Saint Martin Louis Constant Fleming (Saint-Martin): BP 381 -

Spring - Concordia – 97054 Saint-Martin Cedex.

Telephone: 00590690660959; Fax: 00590590875294.

Email: h.tchero@chsaintmartin.fr or tcherobert@yahoo.fr

Running Head: Antibiotics for diabetic foot infections

This article has been accepted for publication and undergone full peer review but has not
been through the copyediting, typesetting, pagination and proofreading process, which
may lead to differences between this version and the Version of Record. Please cite this
article as doi: 10.1111/wrr.12649
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 Keywords: Antibiotics; Diabetic foot infection; Diabetes Mellitus; Systematic Review
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Glossary of Abbreviations: DFIs: Diabetic foot infections, DM: Diabetes Mellitus, IDSA:

Infectious Diseases Society of America PIP/TAZ: Pipracillin/tazobactam, ROB: Risk of bias.

Compliance with Ethical Standards

Conflicts of interest: None to declare

Funding sources: None

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 ABSTRACT

Diabetic foot infection is a common diabetic complication that may end in lower limb amputation

if not treated properly. We performed this systematic review to assess the clinical efficacy of
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different antibiotic regimens, whether systemic or topical, in the treatment of moderate to severe

diabetic foot infections. We searched Medline, Web of Science, SCOPUS, Cochrane CENTRAL and

ScienceDirect for randomized controlled trials that evaluated the efficacy of antibiotic regimens in

moderate to severe diabetic foot infections. The primary outcome of interest was the clinical efficacy

(cure/improvement rates) of the regimens. We included 16 trials (4158 patients) in this review, from

which we extracted 10 comparisons: some trials compared systemic antibiotics to each other, others

compared systemic to topical agents, while one study compared the combined topical and systemic

agents to systemic antibiotics alone. Qualitative analysis of the findings of these studies showed that:

(1) pipracillin/tazobactam was superior to ertapenem in severe infections (clinical resolution rate:

91.5% compared with PIP/TAZ 97.2%, p <0.04), but had similar efficacy in moderate infections, (2)

ertapenem was more effective than tigecycline in moderate to severe infections (Absolute difference

−5.5, [95% CI −11.0, 0.1]), (3) the adjuvant use of topical agents with systemic antibiotics improved

the outcomes, compared to systemic antibiotics alone (p=0.024), (4) the rates of recurrence and re-

ulceration were significantly lower in patients using the amino-penicillin regimen, compared to those

using oral/intravenous ofloxacin, and (5) lower rates of complications accompanied the

imipenem/cilastatin regimen, compared to the pipracillin/tazobactam regimen (p=0.13). In

conclusion, data from the included studies showed better results for ertapenem when compared to

tigecycline; however, it was inferior to pipracillin/tazobactam in severe infections. The adjuvant use

of topical agents improves the efficacy of systemic antibiotics in diabetic foot infection.

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 INTRODUCTION

Diabetic foot infection (DFI) is a common complication of diabetic polyneuropathy that occurs

in about 15 to 25% of diabetic patients (1, 2). Its burden is expected to increase, especially with
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the considerable rise in the prevalence of diabetes mellitus (DM) despite the increasing

understanding of its pathophysiology and molecular mechanisms (3, 4). According to the

Infectious Diseases Society of America, the clinical definition of DFI is the presence of infection

signs, apparently related to a foot lesion, purulent secretions, or at least two classical signs or

symptoms of inflammation (erythema, hotness, pain or tenderness, and tissue inflammation) (5,

6). The updated International Working Group for Diabetic Foot guideline recommends the use of

the Infectious Diseases Society of America (IDSA) classification system to establish the clinical

severity of DFIs (7).

Treatment of DFIs usually includes antibiotic agents whether topical, oral or parenteral (8, 9).

Almost all antibiotic families with a range of all possible routes of administration, doses and

durations of treatment have been proposed for DFI treatment (10-12). The efficacy of any

antibiotic could be affected by a variety of factors, such as the severity of the wound (13, 14) and

susceptibility of the causative organism (15, 16). The current practice guidelines recommend

initial empirical treatment once signs and symptoms of infection are established, and then shift to

a more specific regimen according to bacterial culture of the wound (5, 17). This practice is still

widely adopted because no firm evidence has yet been produced for a better protocol. However,

other factors, such as cost-effectiveness and safety may affect the treatment decision (18-20).

All antibiotic agents have advantages and disadvantages when it comes to treating DFIs (10).

The most important advantage is cure of wounds and prevention of deep extension, and thus

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 decreasing the rates of lower limb amputations in diabetic patients (1, 21). Moreover, they are

generally of lower cost as compared to surgical treatment. The major disadvantages of antibiotics

treatment are the development of resistant bacteria due to prolonged use (22) and the adverse
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events of the drugs, such as hypersensitivity, renal impairment and digestive tract infection with

Clostridium difficile bacteria (23).

Despite the publication of new randomized controlled trials (RCTs) studying the efficacy of

different antibiotic agents in DFI treatment, none of them provided solid evidence regarding the

superiority of an antibiotic regimen over the other. To our knowledge, this is the first review to

include purely diabetic population with complicated DFIs and to assess the efficacy of both

topical and systemic antibiotic agents in these lesions.

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 MATERIALS AND METHODS

2.1. Criteria for considering studies for this review

We included RCTs (whether open labelled or blinded) that met the following criteria: (1)
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Patients: both sexes, older than 18 years old, with type I or II DM, moderate to severe DFIs,

complicated by skin and subcutaneous tissue infection and ulceration not extending above the

knees, with/without osteomyelitis, (2) Intervention: We included all antibiotic regimens (topical,

oral or intravenous) at any dose, frequency or duration of administration, (3) Comparator: other

antibiotics, placebo, topical foot care, a combination of topical and systemic antibiotic regimen

or conservative surgery and (4) Outcomes: including

Primary outcome: Clinical cure and/or improvement rate which is defined as resolution of all

baseline signs and symptoms of infection and/or improvement of at least 1, but not all, of the

baseline signs and symptoms of infection (Lipsky 2012).

Secondary outcomes: included the rate of conversion into surgical treatment/ reoperation/

amputation and complications (re-ulceration, recurrence of infection, death due to infection).

We managed the citations using the reference management software (Endnote X7). Review

authors assessed the titles and abstracts of citations identified by the search strategy, and then

retrieved the full-text articles of all potentially relevant trials for further assessment. We resolved

any disagreements by discussion or, if required, through consultation with a third review author.

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 2.2. Search methods for identification of studies

In November 2017, we searched the following databases for relevant RCTs to be included in our

review: The Cochrane Central Register of Controlled Trials (CENTRAL), Ovid SP (MEDLINE
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and Science Direct), Ovid SP (Web of Science), PubMed (the NCBI website) and Scopus. The

full search strategies of each database are illustrated in Supplementary file 1.

We combined the Ovid MEDLINE search with the Cochrane Highly Sensitive Search Strategy

for identifying RCTs in MEDLINE: sensitivity- and precision-maximizing version. We

combined the Web of Science and MEDLINE search keywords to match the filters used in

Scopus database. The English language was used as a limitation in Scopus search filters.

Otherwise, no restrictions based on date or language of publication were selected. We also

searched the ClinicalTrials.gov (www.clinicaltrials.gov/) and the EU Clinical Trials Registers

(www.clinicaltrialsregister.eu/). Moreover, we checked the reference lists of all included trials to

identify other eligible studies for this review.

2.3. Data extraction and management

We designed a data extraction form and extracted all data from eligible studies regarding the

study objective, date of publication, country, inclusion and exclusion criteria, type of antibiotic,

route of administration and dosage and outcomes of interest. Discrepancies were resolved

through discussion. When any information was missing or unclear, we attempted to contact the

authors of the original reports to request further details. When one study had two major and

minor arms, both were treated as separate studies and were cited under the same study ID.

All data were available for the primary outcome (clinical cure/improvement rate). However,

when data were missing for our secondary outcomes, we assumed participants did not achieve

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 the outcome of interest (i.e. worst-case scenario), unless authors mentioned that the outcome is

negative for participants at the end of follow up. Data extracted from included studies were

reported in the form of comparisons. We planned to pool data whenever heterogeneity is

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excluded. However, this was not possible for any of the included studies due the considerable

heterogeneity among them.

2.4. Assessment of risk of bias (ROB) in included studies

Review authors independently assessed the ROB of each included study following the domain-

based evaluation, described in the Cochrane Handbook for Systematic Reviews of Interventions

(Supplementary file 2) (24). We discussed any discrepancies and achieved consensus on the final

assessment. We presented the results of ROB assessment as a summary for each study with the

seven items of ROB assessment summarized horizontally in a cross-tabulation pattern whether

low (green colour), high (red colour), or unclear (yellow colour) ROB.

RESULTS

3.1. Description of studies: We identified 106 references in total (86 by electronic literature

search and 20 by manual screening). Finally, 16 trials (4158 participants) were included in this

systematic review (18, 22, 25-38). We also identified one ongoing trial in the trial registers;

however, it was unclear whether it met the inclusion criteria of our review (39). We have

summarized the search results in a PRISMA flow diagram (Figure 1). Some trials compared

systemic antibiotics to each other, others compared systemic to topical agents, while Lipsky et

al., 2012 compared the combined topical and systemic agents to systemic antibiotics alone and

L´azaro-Mart´ınez et al., 2014 compared conservative antibiotic therapy to surgical management

of DFIs (Tables 1 and 2).

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 3.2. Characteristics of trial participants and studied DFIs: All patients suffered either type I

or II DM with moderate to severe diabetic lower extremity infection that did not extend above

the knees. All studies included both sexes except for one study (18), which included men only.
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Moreover, the study by Grayson et al. (26) did not report the percentage of each sex in their

sample. When both studies were excluded, the remaining studies included an average of 42.66%

women. All studies provided data regarding the age of participants except for two studies

[Grayson et al. 1994 (26) and Lipsky et al. 1997 (30)]. The mean age of participants, excluding

the former two studies was 57 years.

All but one study (34) provided the definition they used for DFI diagnosis. The used definitions

varied between studies with some using only clinical signs or symptoms (e.g. body temperature,

hotness, purulent discharge, redness, pain), while others considered other laboratory findings

(e.g. leukocytosis). Lipsky et al. (2012) provided a definition for moderate DFIs that was

provided by the IDSA guideline criteria (33). However, Lipsky et al. (2007) used what they

called “investigator defined DFIs” for inclusion: patients with an infection of sufficient severity

to require hospitalization and intravenous antimicrobial therapy (31).

3.3. Risk of bias in included studies: Generally, the included studies did not report enough

details about their methodology to help us assess the ROB (e.g. only one third of included studies

provided data regarding selective reporting bias). The main limitation of the included trials

concerned the blinding procedures, especially for participants and personnel (detection bias) (see

Figure 2). Further details on ROB assessment reasons are illustrated in Supplementary file 2.

3.4. Efficacy of the interventions

Outcome 1: Clinical cure/improvement rate

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 Almost all included trials compared antibiotic regimens with each other (18, 22, 25-27, 29-38).

Only one study (28) compared systemic antibiotics to conservative surgery. We extracted 10

comparisons from the 16 included studies.

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Pipracillin/tazobactam plus amoxicillin–clavulanate (PIP/TAZ + AMC) versus

moxifloxacin (MXF)

Two studies compared these two regimens (details on the doses and durations of adminstration

are illustrated in table 2) (31, 36). In Schaper 2012, the clinical cure/improvement rate was

similar between the two treatment groups at the test of cure visit (TOC) in both the per-protocol

(PP) population (MXF 76.4% [95% confidence interval (CI): 14.5%] versus PIP/TAZ–AMC

78.1% [95% CI: 9.0%]) and the intent-to-treat (ITT) populations (MXF 69.9% [95% CI: 12.4%]

versus PIP/TAZ–AMC 69.1% [95% CI 12.1%]) (36). Results were not much different in the

study by Lipsky et al. (2007) in which the clinical cure rates at TOC were similar for MXF and

PIP/TAZ/AMC (68% versus 61%) in patients with investigator-defined infection (p=0.54) (31).

Pipracillin-tazobactam (PIP/TAZ) versus ertapenem

Two studies compared these two antibiotic regimens (Table 2) (29, 38). Xu and colleagues

measured the clinical cure/improvement at discontinuation of intravenous therapy (DCIV) at

which 93.6% of patients in the ertapenem group and 97.3% in the PIP/TAZ group had a

favourable clinical response (Difference: 23.8%, 95% CI [28.3%, 0%], p <0.05). However, in

patients with severe DFIs, ertapenem caused a significantly lower clinical resolution rate at

DCIV (91.5% compared with PIP/TAZ 97.2%, p <0.04) (38). In the study by Lipsky et al.

(2005), treatment responses were similar between the two groups (94% vs 92%, respectively,

between treatment difference 1.9%, [95% CI -2·9 to 6·9]) measured after 10 days of therapy

discontinuation (29).

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 Other studies comparing PIP-TAZ to other antibiotic agents:

Harkless et al. (2005) compared PIP-TAZ (given iv as 4.5 g every 8 hours) to iv

ampicillin/sulbactam (3 g every 6 hours). The clinical efficacy was statistically similar between
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both groups (81% for PIP-TAZ vs. 83.1% for ampicillin/sulbactam) (27). Saltoglu et al. (2010)

compared PIP-TAZ (given as 4.5 g iv every 8 hrs) to imipenem/cilastatin (0.5 g iv every 6 hrs).

A successful clinical response was noted in 46.7% of patients in the PIP/TAZ group and in

28.1% of patients in the imipenem/cilastatin group (relative risk (RR) 1.6 [95% CI 0.84–3.25],

p= 0.13], denoting no significant difference in this outcome (34).

Topical pexaganan acetate versus ofloxacin

Lipsky et al. (2008) compared the daily application of topical antimicrobial cream pexiganan

acetate to 200 mg of ofloxacin orally twice daily for 14 to 28 days. The authors analysed the

results of two separate studies (33, 34). Clinical cure or improvement rates were 78.8% in the

pexaganan cream arm and 83.9% in the oral ofloxacin arm (Difference -5.05, 95% CI [-10.41 to

0.31]) (32).

Topical gentamycin collagen sponge with system antibiotics versus systemic antibiotics

alone

Lipsky and colleagues (2012) compared the daily topical application of gentamycin collagen

sponge given together with oral/iv 750 mg levofloxacin to the sole use of levofloxacin for 28

days in DFIs. The clinical cure rates were measured at the TOC and were found to be 100% in

intervention group versus 70% in control group (p=0.02) (33).

Empirical systemic antibiotic versus conservative surgery

L´azaro-Mart´ınez et al. (2014) compared the three empirical antibiotic regimens to conservative

surgery in which only the infected bone was removed with no amputation. Their results showed

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 no significant difference (p= 0.33) in the rate of primary healing (75% in the antibiotics group

and 86.3% in the surgery group) (28).

Metronidazole plus ceftriaxone (MTZ/CTX) versus Ticarcillin/clavulanate (T/C)

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Clay et al. (2004) compared MTZ (1 g iv) plus CTX (1 g iv) once daily to ticarcillin/clavulanate

(3.1 g iv every 6 hrs). Successfully treated patients constituted 72% and 76% in the MTZ/CTX

and T/C groups, respectively (p > 0.05) (18).

Imipenem/cilastatin (I/C) versus ampicillin sulbactam (A/S)

Grayson et al. (1994) compared the use of 500 mg iv dose of imipenem/cilastatin every 6 hrs to

the use of iv ampicillin/sulbactam (3 g total) every 6 hrs for 14 to 21 days. Although the cure rate

was similar between the two groups (81% for A/S vs. 85% for l/C), the risk of inaccurately

reported outcomes was high due to dose adjustments in patients with other co-morbidities who

were not excluded from the study (26).

Amoxicillin clavulanate versus placebo

Chantelau et al. (1996) assessed the efficacy of amoxicillin plus clavulanic acid (given as 500 mg

amoxicillin plus 125 mg clavulanic acid till resolution of symptoms) by comparing with a

placebo. The healing rate of ulcers at 20 days was 27.3 % in the intervention group versus 45.5%

in the placebo group. However, a type II statistical error cannot be ruled out in this study due to

the small number of participants (44 patients with 22 in each arm) (25).

Six weeks versus 12 weeks of systemic antibiotic therapy

Tone and colleagues (2015) studied the clinical resolution after application of either a 6-week or

a 12-week antibiotic regimen, given according to culture and sensitivity analysis. However, the

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 results were equivocal in both situations (60% in 6-week protocol versus 70% in 12-week

protocol, p= 0.5) (37).

Tigecycline versus ertapenem

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Lauf et al. (2014) conducted a primary study with diabetic patients who had no osteomyelitis and

a subset study with diabetic patients suffering from foot osteomyelitis. The clinical cure rates for

the primary study were 77.5% for the intervention group versus 82.5% for the control group

(Absolute difference −5.5, [95% CI −11.0, 0.1]). While in the subset study, the cure rates were

31.5% for the intervention group and 54.2% for the control group (22).

Outcome 2: Rate of conversion into surgical treatment/amputation

Four included studies reported on the rate of amputation and conversion to surgery (26, 28, 32,

34). Although considerably variable across different studies, the reported rates of this outcome

were frequently similar between the intervention and control groups in each of the six studies.

Only Grayson et al. (1994) showed a significant difference in the rate of amputations between

the intervention (21.42%) and control (48.5%) groups (26). Lipsky et al. (2008) reported the

rates of amputation in both the intervention and control groups as one value of 2-3% (32).

Saltoglu et al. (2010) showed that 60% and 69% of patients were converted into surgical

treatment in the intervention and control groups, respectively (34). In the study by L´azaro-

Mart´ınez et al., higher rates of surgical interventions were reported in the intervention group

(16.6%), compared to the control group (13.6%) (28).

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 Outcome 3: Complication rates (re-ulceration/ recurrence of infection/ death due to

infection)

Eleven of the included trials reported on the complication rates following primary treatment with
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the antibiotic regimen (18, 25, 28, 30, 32-38). Except for four studies (28, 30, 34, 37), all

reported rates were similar among the intervention and control groups. In Saltoglu et al. (2010),

higher rates of complications were reported among the study intervention group (30%),

compared to the control group (9.4%) (34). The same was reported by Lipsky et al. (1997)

(36.2% in the intervention group versus 22% in the control group) (30). On the contrary, Tone et

al. (2016) reported more frequent complications in the control arm (45%), compared to the

intervention arm (15%) (37). In addition, L´azaro-Mart´ınez and colleagues (2014) concluded

that the rate of re-ulceration was significantly lower in their intervention group (9.8%), compared

to the control group (21%) (28).

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 DISCUSSION

Summary of the main results: In this review, we included 16 trials that compared various

antibiotic agents in the treatment of moderate to severe DFIs (18, 22, 25-38). Because the clinical
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efficacy rates were almost similar between both intervention and control groups across included

studies, few significant outcomes could be reported. Three studies showed significant

differences, favouring one treatment over the other. For example, while ertapenem showed better

results when compared to tigecycline (22), it gave significantly lower results when compared to

PIP/TAZ in severe DFIs (38). Moreover, the adjuvant use of topical agents with systemic

antibiotic regimen was of potential preferable outcome, compared to systemic antibiotics alone

(33).

For the aim of generalization, most participants in the included trials were adult men, suffering

from DFIs of moderate to severe grade, not extending above the knees, mostly without

osteomyelitis. Therefore, the evidence produced from this review should be applied to patients

with the previous characteristics.

Agreements and disagreements with other reviews: A former review by Selva Olid et al.

(2015) exclusively included trials on systemic antibiotics. However, the diversity in design and

execution of included studies hindered any potential appearance of a statistically significant

effect estimate (23). It only recommended the use of ertapenem over tigecycline as per (22).

Another comprehensive review by Dumville et al. (2017) tried to generate evidence on the use of

topical antibiotics in DFIs. However, due to the heterogeneity of included studies and high risk

of detection bias, it could not provide a solid recommendation regarding topical antibiotics'

safety and efficacy. They could only conclude (1) the preferred use of local antimicrobial agents

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 over non-antimicrobial agents to increase the healing rate and (2) the lack of difference in

adverse events between systemic and local antibiotic agents (40). Our review differs from these

two in that it combines trials of all antibiotic agents whether topical or systemic. We only
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included studies whose participants were all diabetic, not due to trauma, burns, bites or any other

possible cause of foot wound infection. This is responsible for the discrepancy in included

studies found between our review and the former two reviews (23, 40).

Strength points: We tried to reduce the risk of publication bias by designing a search strategy

that covers all possible keywords, medical subject headings and cross combination of both to

obtain the largest possible number of matched articles. For reproducibility, we adequately

described the implemented search strategy for this review in supplementary appendices. Further

screening through references of included studies helped narrowing the risk of publication bias.

However, we cannot rule out this risk because the grey literature was not included in our search,

yet, we identified two ongoing trials to be checked for inclusion in further reviews. Not all

studies reported on the rate of surgical conversion. However, being not evaluated in any

systematic review before, surgical conversion was of significance because it gives better insights,

besides clinical efficacy, as to how efficient the treatment is on the long run. Moreover, our

review is the first to discuss the potential benefit of combining topical and systemic antibiotics.

Limitations: The applicability of our results can be hindered by the marked heterogeneity

among included studies regarding their inclusion criteria, population size and used antibiotic

regimens. Moreover, the lack of fully reported secondary outcomes to aid in decision making

adds to our limitations. Most of included studies suffered high risk of detection bias that

investigators of the outcomes were un-blinded to the treatment provided. Except for the few

significant outcomes reported earlier, no solid conclusion can be drawn out of this review

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 regarding a specific antibiotic regimen. The primary outcome reported in this review was the

clinical cure/improvement rate. This outcome had been measured at different time points in each

study, as the follow up period varied greatly among included trials. Although time to clinical
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resolution is of potential significance in determining which antibiotic agent is cost-effective for

management of DFIs, the paucity of studies reporting this outcome hindered its use as a primary

outcome in our review.

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 CONCLUSIONS

Implications for practice: Our review included 16 studies with 4158 participants and 10

different comparisons with different endpoints measured at variable timings after discontinuation
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of therapy. The outcome of interest was clinical resolution of all signs and symptoms of

infection. Summarizing the findings of included studies, ertapenem showed better results when

compared to tigecycline; however, it was inferior to PIP/TAZ in the treatment of severe DFIs.

The adjuvant use of topical agents improved the efficacy of systemic antibiotics. The current

practice entails starting treatment of DFIs by empirical antibiotic agents. Shifting into a more

specific regimen occurs after obtaining the results of bacteriogram. Clinicians should consider

other outcomes, such as safety and/or cost of included regimens till better evidence is drawn

regarding the clinical efficacy.

Implications for research: Future studies should use more standardized criteria in classifying

wound infection severity and defining the key outcomes (whether clinical, laboratory or

according to previously published definitions) with standard durations of treatment. Moreover,

outcomes should be stratified according to priority for clinical decision-making (clinical efficacy

first followed by the rates of complications/re-ulcerations or amputations). The blinding of

outcome assessors and appropriate reporting of outcome data are necessary to improve the level

of evidence in future reviews. The cost-effectiveness and safety of different regimens should also

be considered for more sound decision making.

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 Acknowledgement: None to declare
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 Figure Legends

Figure 1: PRISMA flow diagram of literature search and study selection.

Figure 2: Risk of bias summary of included studies according to the Cochrane risk of bias tool
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(Red: High risk of bias, Green: Low risk of bias and Yellow: Unclear risk of bias).

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Accepted Article

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Accepted Article

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Accepted Article
Table 1. Summary of the characteristics of included studies with brief description of their comparisons.

Study ID Location Diagnosis Severity scale Study intervention Study control

Chantelau et al., Germany Purely neuropathic Wagner and (Amoxicillin plus Placebo

1996 ulcers (Wagner Harkless clavulanic acid)

grade 1-2, no classification

osteomyelitis)

Clay et al., 2004 USA DM (type I or II), grade 1,2 or 3 (MTZ/CTX) (T/C)

males, no ulcer severity on

osteomyelitis a 5-point

modified Wagner

Scale

Grayson et al., USA DM and lower limb- At least the Imipenem/cilastatin Ampicillin/ sulbactam

1994 threatening infection presence of

cellulitis,

with/without

ulceration or

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Accepted Article purulent

discharge

Harkless et al., USA Moderate-to-severe University of Piperacillin/ tazobactam Ampicillin/ sulbactam

2005 infected diabetic foot Texas Grades IB,

ulcers without ID, IIB and IID

osteomyelitis

L´azaro- Spain DM with foot Empirical treatment Conservative surgery

Mart´ınez et al., osteomyelitis

2014

Lauf et al., 2014 Europe, the United Diabetes Mellitus Tigecycline Ertapenem +

(major study States, Canada, (DM: both type I and PEDIS grade 2-4 vancomycin

without Latin America, II) without

osteomyelitis) Asia, India, osteomyelitis)

Australia and

South Africa

Lauf et al., 2014 Europe, the United DM (both type I and Tigecycline Ertapenem +

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Accepted Article
(subset study States, Canada, II) with PEDIS grade 2-4 vancomycin

with Latin America, osteomyelitis)

osteomyelitis) Asia, India,

Australia, and

South Africa

Lipsky et al., USA Diabetic patients Intravenous ofloxacin (Aminopenicillin

1997 with infections followed by oral intake regimen)

requiring

hospitalization,

without

osteomyelitis

Lipsky et al., USA DM and DFI Intravenous ertapenem Piperacillin/

2005 classified as tazobactam

moderate-to-severe

and requiring iv

antibiotics with or

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Accepted Article without

osteomyelitis

Lipsky et al., USA DM with foot iv moxifloxacin followed iv piperacillin–

2007 infection or ulcer by oral moxifloxacin tazobactam (followed

with or without by amoxicillin–

osteomyelitis clavulanate

Lipsky et al., USA Mildly infected Pexiganan cream Ofloxacin

2008 (studies 33 diabetic foot ulcers

and 34) without

osteomyelitis

Lipsky et al., USA and UK DM with moderately Gentamicin-collagen Levofloxacin alone

2012 infected foot ulcer Lipsky Wound sponge combined with a

with or without Scoring Scale systemic antibiotic

osteomyelitis

Saltoglu et al., Turkey DM with severely Piperacillin/tazobactam Imipenem/cilastatin

2010 infected foot ulcer Wagner grade (2-

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Accepted Article with or without 4)

osteomyelitis

Schaper et al., Belgium, DM with moderate PIP/TAZ–AMC (MXF, intravenous/

2012 Bulgaria, to severe foot PEDIS grade 2-4 oral moxifloxacin)

Germany, Greece, infection (with or

Hungary, Israel, without

Latvia, Lithuania, osteomyelitis)

Poland, Romania,

Russia, South

Africa, Spain,

Ukraine and the

UK

Swati et al., India Moderate diabetic Ceftriaxone Levofloxacin with

2016 foot infection metronidazole

without

osteomyelitis

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Accepted Article
Tone et al., France Type 2 DM and None 6 weeks protocol of 12 weeks protocol

2015 osteomyelitis of the antibiotic as per culture

foot (i.e., below the sensitivity results

ankle).

Xu et al., 2016 China Patients with University of Ertapenem Piperacillin/

moderate to severe Texas Grades IB, tazobactam

DFIs with or without ID, IIB and IID

osteomyelitis

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Accepted Article
Table 2. Summary of the antibiotic regimens used in either arm of the included studies.

Study ID Intervention (dose, regimen, duration) Comparison (Therapy/placebo - dose, duration, Follow up

regimen) Period

Chantelau et al., (Amoxicillin plus clavulanic acid) 500 mg Placebo 20 days

1996 amoxicillin plus till resolution of symptoms

125 mg clavulanic acid

Clay et al., 2004 (MTZ/CTX) 1 g of metronidazole iv and 1 g of (T/C) 3.1 g iv every 6 hours over 30 mins till 4 days or at

ceftriaxone iv once daily over 90 mins till resolution of infection the end of

resolution of infection treatment

Grayson et al., Imipenem/cilastatin (I/C; 500 mg iv every 6 Ampicillin/sulbactam iv (A/S; 2 g ampicillin and 5 days

1994 hours) for 14-21 days 1 g sulbactam (3 g total) every 6 hours) for 14-21

days

Harkless et al., Piperacillin/tazobactam (4 g/0.5 g q8h) for 14 Ampicillin/sulbactam (2 g/1 g q6h) for 14 to 21 14-21 days

2005 to 21 days days

L´azaro- Empirical treatment was applied till results of Conservative surgery (removal of the infected 12 weeks

Mart´ınez et al., culture and sensitivity testing were revealed, it bone without performing amputation of any part

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Accepted Article
2014 consisted of ciprofloxacin 500 mg b.i.d; of the foot)

amoxicillin/clavulanic acid 875/125 mg b.i.d.;

or trimethoprim 160 mg/ sulfamethoxazole 800

mg b.i.d. for 90 days

Lauf et al., 2014 Tigecycline + placebo. 150 mg iv in 100 mL Ertapenem + vancomycin. 1 g iv ertapenem in 92 days

(major study saline for at least 3 days (4 doses) 100 mL saline for at least 3 days

without

osteomyelitis)

Lauf et al., 2014 Tigecycline + placebo. 150 mg iv in 100 mL Ertapenem + vancomycin. 1 g iv ertapenem in 25-27 days

(subset study with saline for at least 3 days (4 doses) 100 mL saline for at least 3 days

osteomyelitis)

Lipsky et al., Intravenous ofloxacin followed by oral Ampicillin/sulbactam followed by oral 7.1-7.8

1997 ofloxacin (400 mg of ofloxacin intravenously amoxicillin/clavulanate (the amino-penicillin days

that was changed when appropriate to 400 mg regimen) 1 –2 g of ampicillin/0.5 –1 g of

of ofloxacin orally every 12 hour) for about 3 sulbactam intravenously every 6 hours that was

weeks changed when appropriate to 500 mg of

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Accepted Article amoxicillin/125 mg of clavulanic acid orally

every 8 hours

Lipsky et al., Intravenous ertapenem Piperacillin/tazobactam (3·375 g every 6 h; for 5- 10 days

2005 (1 g daily bolus followed by 3 placebo doses to 28 days

match pip-taz regimen) for 5-28 days

Lipsky et al., iv piperacillin–tazobactam (3.0/0.375 g every 6 iv moxifloxacin (400 mg/day) for 3 days followed 10-42 days

2007 h) for at least 3 days followed by amoxicillin– by oral therapy with moxifloxacin 400 mg/day for

clavulanate suspension 800 mg every for 7-14 7 to 14 days

days 12 h

Lipsky et al., Pexiganan cream with 2 tablets of placebo 200 mg of ofloxacin in two tablets twice daily 2 weeks

2008 matching oral ofloxacin twice daily for 14-28 with placebo cream for 14-28 days

(Combined days

studies 33 and 34)

Lipsky et al., Daily topical application of Levofloxacin alone single daily dose for 28 days 2 weeks

2012 the gentamicin-collagen sponge combined with

systemic antibiotic therapy (a daily oral or

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Accepted Article intravenous dose of 750 mg of levofloxacin for

28 days

Saltoglu et al., Piperacillin/tazobactam (Pip-Taz 4.5 g Imipenem/cilastatin (IMP) (0.5 g intravenously 2 months

2010 intravenously every 8h) for 14 days or 28 days every 6h) for 14 days or 28 days in osteomyelitis after

in osteomyelitis discharge

Schaper et al., Intravenous piperacillin/tazobactam 4.0/0.5 g (Intravenous/oral moxifloxacin 400 mg q.d, for 7- 14-28

2012 t.d.s. followed by oral amoxicillin/clavulanate 21 days

875/125 mg b.i.d. for 7-21 days

Swati et al., 2016 Ceftriaxone group 1 gm intravenously for 14 Levofloxacin 500 mg orally once daily with 2 weeks

days metronidazole 400 mg orally thrice daily for 14

days

Tone et al., 2015 6 wks protocol. According to culture and 12 weeks protocol, according to culture and 12 months

sensitivity sensitivity

Xu et al., 2016 Ertapenem (1 g once daily) by 30 min iv Piperacillin/tazobactam (4.5 g every 8 h) 30 min 10 days

infusion (followed by two placebo doses to intravenous (iv) infusions for 5-28 days

match treatment with PIP/TAZ regimen) for 5-

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Accepted Article 28 days

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