2021 IDSA Diabetic foot infection

Clinical Infectious Diseases
IDSA GUIDELINES
IWGDF/IDSA Guidelines on the Diagnosis and Treatment

of Diabetes-related Foot Infections (IWGDF/IDSA 2023)
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Éric Senneville,1,2 Zaina Albalawi,3 Suzanne A. van Asten,4 Zulfiqarali G. Abbas,5 Geneve Allison,6 Javier Aragón-Sánchez,7 John M. Embil,8
Lawrence A. Lavery,9 Majdi Alhasan,10 Orhan Oz,11 Ilker Uçkay,12 Vilma Urbanč ič -Rovan,13 Zhang-Rong Xu,14 and Edgar J. G. Peters15,16,17
1
Gustave Dron Hospital, Tourcoing, France; 2Univ-Lille France, Lille, France; 3Department of Medicine, Division of Endocrinology, Memorial University, St. John’s, Newfoundland and Labrador,
Canada; 4Department of Medical Microbiology, Leiden University Medical Centre, Leiden, The Netherlands; 5Abbas Medical Centre, Muhimbili University of Health and Allied Sciences, Dar es
Salaam, Tanzania; 6Department of Medicine, Tufts Medical Center, Boston, Massachusetts, USA; 7La Paloma Hospital, Las Palmas de Gran Canaria, Spain; 8Department of Medicine, Section of
Infectious Diseases, University of Manitoba, Winnipeg, Manitoba, Canada; 9Department of Plastic Surgery, UT Southwestern Medical Center, Dallas, Texas, USA; 10Department of Medicine, Prisma
Health-Midlands, Columbia, South Carolina, USA; 11UT Southwestern Medical Center, Dallas, Texas, USA; 12Balgrist University Hospital, Zurich, Switzerland; 13Faculty of Medicine, University
Medical Centre, University of Ljubljana, Ljubljana, Slovenia; 14Diabetes Centre, Beijing, China; 15Department of Internal Medicine, Amsterdam UMC, Vrije Universiteit Amsterdam, Section of
Infectious Diseases, Amsterdam, The Netherlands; 16Amsterdam Movement Sciences, Rehabilitation and Development, Amsterdam, The Netherlands; and 17Amsterdam Infection & Immunity,
Infectious Diseases, Amsterdam, The Netherlands
The International Working Group on the Diabetic Foot (IWGDF) has published evidence-based guidelines on the management and
prevention of diabetes-related foot diseases since 1999. The present guideline is an update of the 2019 IWGDF guideline on the
diagnosis and management of foot infections in persons with diabetes mellitus.
The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) framework was used for the
development of this guideline. This was structured around identifying clinically relevant questions in the P(A)ICO format,
determining patient-important outcomes, systematically reviewing the evidence, assessing the certainty of the evidence, and
finally moving from evidence to the recommendation. This guideline was developed for healthcare professionals involved in
diabetes-related foot care to inform clinical care around patient-important outcomes. Two systematic reviews from 2019 were
updated to inform this guideline, and a total of 149 studies (62 new) meeting inclusion criteria were identified from the updated
search and incorporated in this guideline. Updated recommendations are derived from these systematic reviews, and best
practice statements made where evidence was not available. Evidence was weighed in light of benefits and harms to arrive at a
recommendation. The certainty of the evidence for some recommendations was modified in this update with a more refined
application of the GRADE framework centred around patient important outcomes. This is highlighted in the rationale section
of this update. A note is also made where the newly identified evidence did not alter the strength or certainty of evidence for
previous recommendations.
The recommendations presented here continue to cover various aspects of diagnosing soft tissue and bone infections, including
the classification scheme for diagnosing infection and its severity. Guidance on how to collect microbiological samples, and how to
process them to identify causative pathogens, is also outlined. Finally, we present the approach to treating foot infections in persons
with diabetes, including selecting appropriate empiric and definitive antimicrobial therapy for soft tissue and bone infections; when
and how to approach surgical treatment; and which adjunctive treatments may or may not affect the infectious outcomes of
diabetes-related foot problems.
We believe that following these recommendations will help healthcare professionals provide better care for persons with diabetes
and foot infections, prevent the number of foot and limb amputations, and reduce the patient and healthcare burden of diabetes-
related foot disease.
Keywords. diabetic foot; diagnosis; foot ulcer; guidelines; infection.
Abbreviations
CRP C-reactive protein
DFI diabetes-related foot infection
Received 22 June 2022; accepted 23 June 2023; published online 2 October 2023 DFO diabetes-related osteomyelitis of the foot
Correspondence: Éric Senneville, Infectious Diseases Department; Gustave Dron Hospital, DFU diabetes-related foot ulcer
135 rue du Président Coty, Tourcoing 59200, France (senneric670@gmail.com). ESR erythrocyte sedimentation rate
Clinical Infectious Diseases®
© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases
HBOT hyperbaric oxygen therapy
Society of America. HMPAO Hexa Methyl Propylene Amine Oxime
This is an Open Access article distributed under the terms of the Creative Commons Attribution-
IDFU infected diabetes-related foot ulcer
NonCommercial-NoDerivs licence (https://creativecommons.org/licenses/by-nc-nd/4.0/), which
permits non-commercial reproduction and distribution of the work, in any medium, provided IDSA infectious diseases society of America
the original work is not altered or transformed in any way, and that the work is properly cited. IWGDF international working group on the diabetic foot
For commercial re-use, please contact journals.permissions@oup.com
https://doi.org/10.1093/cid/ciad527 MRI magnetic resonance imaging
IWGDF/IDSA Guidelines on the Diagnosis and Treatment of Diabetes-related Foot Infections (IWGDF/IDSA 2023) • CID • 1
PACO population assessment control outcome from soft tissue or bone samples in a patient with a DFI.
diabetes-related (Strong; Moderate).
PCR polymerase chain reaction 7. Recommendation 7
PCT procalcitonin In a person with diabetes, consider using a combination
PET positron emission tomography of probe-to-bone test, plain X-rays, and ESR, or CRP, or
PICO population intervention control outcome PCT as the initial studies to diagnose osteomyelitis of the
SPECT single photon emission computed tomography foot. (Conditional; Low).

SR systematic review 8. Recommendation 8
TDM tomodensitometry Perform magnetic resonance imaging (MRI) when the
diagnosis of diabetes-related osteomyelitis of the foot re-
mains in doubt despite clinical, plain X-rays and laboratory
1 LIST OF RECOMMENDATIONS
findings. (Strong; Moderate).
9. Recommendation 9
1. Recommendation 1 Consider using positron emission tomography (PET),
(a) Diagnose a soft tissue diabetes-related infection clini- leucocyte scintigraphy, or single photon emission comput-
cally based on the presence of local or systemic signs ed tomography (SPECT) as an alternative to MRI for the
and symptoms of inflammation. (Grading of diagnosis of diabetes-related osteomyelitis of the foot.
Recommendations, Assessment, Development, and (Conditional; Low).
Evaluation (GRADE) recommendation:Strong; 10. Recommendation 10
Certainty of evidence: Low) In a person with diabetes for whom there is a suspicion
(b) Asses the severity of any Diabetes-related foot infec- of osteomyelitis of the foot (before or after treatment),
tion (DFI) using the International Working Group bone (rather than soft tissue) samples should be obtained
on the Diabetic Foot (IWGDF)/Infectious Diseases for culture, either intraoperatively or percutaneously.
Society of America (IDSA) classification scheme. (Conditional; Moderate).
(Strong; Low). 11. Recommendation 11
2. Recommendation 2 Do not treat clinically uninfected foot ulcers with sys-
Consider hospitalising all persons with diabetes and a temic or local antibiotic therapy when the goal is to reduce
foot infection who have either a severe foot infection as the risk of new infection or to promote ulcer healing. Best
classified by the IWGDF/IDSA classification or a moderate Practice Statement.
infection which is associated with key relevant morbidities. 12. Recommendation 12
(Conditional; Low). (a) Use any of the systemic antibiotic regimens that have
3. Recommendation 3 been shown to be effective in published randomised
Assess inflammatory serum biomarkers such as controlled trials at standard (usual) dosing to treat a
C-reactive protein (CRP), erythrocyte sedimentation rate person with diabetes and a soft tissue infection of the
(ESR), or procalcitonin (PCT) in a person with diabetes foot. (Strong; High).
and a possible infected foot ulcer for whom the clinical ex- (b) Administer antibiotic therapy to a patient with a skin
amination is diagnostically equivocal or uninterpretable. or soft tissue diabetic foot infection for a duration of
(Best Practice Statement). 1–2 weeks. (Strong; High).
4. Recommendation 4 (c) Consider continuing treatment, perhaps for up to
For diagnosing diabetes-related foot soft-tissue infec- 3–4 weeks, if the infection is improving but is extensive
tion, we suggest not using foot temperature (however mea- and is resolving slower than expected or if the patient
sured) or quantitative microbial analysis. (Conditional; has severe peripheral artery disease (PAD).
Low). (Conditional, Low).
5. Recommendation 5 (d) If evidence of infection has not resolved after 4 weeks
In a person with suspected soft tissue DFI, consider a of apparently appropriate therapy, re-evaluate the pa-
sample for culture to determine the causative microorgan- tient, and reconsider the need for further diagnostic
isms, preferably by aseptically collecting a tissue specimen studies or alternative treatments. (Strong; Low).
(by curettage or biopsy) from the wound. (Conditional; 13. Recommendation 13
Moderate). Select an antibiotic agent for treating a DFI based on the
6. Recommendation 6 likely or proven causative pathogen(s) and their antibiotic
Use conventional, rather than molecular, microbiology susceptibilities; the clinical severity of the infection; pub-
techniques for the first-line identification of pathogens lished evidence of the efficacy of the agent for infections
2 • CID • Senneville et al.

of the diabetes-related foot; the risk of adverse events in- diabetes-related osteomyelitis of the foot. (Conditional;
cluding collateral damage to the commensal flora; the like- Low).
lihood of drug interactions; agent availability and costs. 22. Recommendation 22
Best Practice Statement. Consider antibiotic treatment without surgery in case of
14. Recommendation 14 (i) forefoot osteomyelitis without an immediate need for
Target aerobic gram-positive pathogens only (beta- incision and drainage to control infection, (ii) without
haemolytic streptococci and Staphylococcus aureus includ- PAD, and (iii) without exposed bone. (Conditional; Low).

ing methicillin-resistant strains if indicated) for people 23. Recommendation 23
with a mild DFI, who have not recently received antibiotic We suggest not using the following treatments to ad-
therapy, and who reside in North America or Western dress DFIs: (a) adjunctive granulocyte colony-stimulating
Europe. Best Practice Statement. factor (G-CSF) treatment or (b) topical antiseptics, silver
15. Recommendation 15 preparations, honey, bacteriophage therapy, or negative-
Do not empirically target antibiotic therapy against pressure wound therapy (with or without instillation).
Pseudomonas aeruginosa in cases of DFI in temperate cli- (Conditional; Low).
mates, but use empirical treatment of P. aeruginosa if it 24. Recommendation 24
has been isolated from cultures of the affected site within We suggest not using topical (sponge, cream, and ce-
the previous few weeks, in a person with moderate or se- ment) antibiotics in combination with systemic antibiotics
vere infection who resides in Asia or North Africa. Best for treating either soft-tissue infections or osteomyelitis of
Practice Statement. the foot in patients with diabetes. (Conditional; Low).
16. Recommendation 16 25. Recommendation 25
Consider a duration of up to 3 weeks of antibiotic ther- We suggest not using Hyperbaric oxygen (HBO) therapy
apy after minor amputation for diabetes-related osteomy- or topical oxygen therapy as an adjunctive treatment for
elitis of the foot and positive bone margin culture and the sole indication of treating a DFI. (Conditional; Low).
6 weeks for diabetes-related foot osteomyelitis without
bone resection or amputation. (Conditional; Low). Note: the available data did not allow making a recommenda-
17. Recommendation 17 tion on the use of rifampicin for the treatment of diabetes-
Use the outcome at a minimum follow-up duration of related osteomyelitis of the foot.
6 months after the end of the antibiotic therapy to diagnose
remission of diabetes-related osteomyelitis of the foot. Best
2 INTRODUCTION
Practice Statement.
18. Recommendation 18 The prevalence of diabetes continues to increase globally and
The urgent surgical consultation should be obtained in the International Diabetes Foundation has estimated that 537
cases of severe infection or moderate DFI complicated by million adults aged between 20 and 79 years worldwide were
extensive gangrene, necrotising infection, signs suggesting living with diabetes in 2021.1 This situation leads to a rising in-
deep (below the fascia) abscess, compartment syndrome, cidence of foot complications, including infections.1 DFIs are
or severe lower limb ischaemia. Best Practice associated with substantial morbidities, requiring frequent
Recommendation. healthcare provider visits, daily wound care, antimicrobial
19. Recommendation 19 therapy, surgical procedures, and high healthcare costs.2 Of
Consider performing early (within 24–48 h) surgery particular importance, DFIs remain the most frequent
combined with antibiotics for moderate and severe DFIs diabetes-related complications requiring hospitalisation and
to remove the infected and necrotic tissue. (Conditional; the most common precipitating events leading to lower ex-
Low). tremity amputation.3,4 Outcomes in patients presenting with
20. Recommendation 20 an infected diabetes-related foot ulcer (DFU) are suboptimal
In people with diabetes, PAD and a foot ulcer or gan- in one large prospective study, at the end of 1 year, the ulcer
grene with infection involving any portion of the foot ob- had healed in only 46% (and it later recurred in 10% of these),
tain an urgent consultation by a surgical specialist as well as while 15% had died and 17% required a lower extremity
a vascular specialist in order to determine the indications amputation.5
and timings of a drainage and/or revascularisation proce- Managing DFIs requires careful attention to properly diag-
dure. Best Practice Statement. nose the condition, obtain appropriate specimens for culture,
21. Recommendation 21 thoughtfully select antimicrobial therapy, quickly determine
Consider performing surgical resection of infected bone when surgical interventions are required, and provide any
combined with systemic antibiotics in a person with needed additional wound and overall patient care. A systematic,
evidence-based approach to managing DFIs likely improves dysfunction. A patient with diabetes-related complications
outcomes, specifically the resolution of difficult cases of may need to undergo lower extremity amputation to control in-
infection, and helps avoid complications, such as life- fection or develop multiorgan failure without local clinical
threatening infections and limb loss. This is best delivered by signs that define a DFI, but this is highly uncommon.
interdisciplinary teams, which should include among the mem- Although rarely the primary cause of foot ulcers, the presence
bership, whenever possible, infectious diseases or clinical/med- of PAD increases the risk of an ulcer becoming infected4,15–17
ical microbiology specialist.6 This team should also attempt to and adversely affects the outcome of infection.4,18,19 Because

ensure optimal local wound care (e.g., cleansing and debride- the combination of infection with PAD is associated with a
ment), pressure off-loading, peripheral vascular assessment markedly increased risk of poor healing and amputation, clini-
(with revascularisation if needed), and metabolic (particularly cians should evaluate the state of wound perfusion and the po-
glycaemic) control. For these aspects, the reader is referred to tential need for a revascularisation procedure as soon as
the other chapters of the IWGDF guideline on the management possible in all patients with a DFI.7
of diabetes-related foot ulcers in this special issue.7–9 If these as- Factors that predispose to foot infection include having a
pects are not adequately addressed, and the focus is only on in- wound that is deep, long-standing, recurrent, or of traumatic
fection, the chance of treatment failure is greatly increased. aetiology; the presence of diabetes-related immunological per-
Several guidelines are available to assist clinicians in manag- turbations, particularly neutrophil dysfunction; and having
ing DFIs. The IDSA produced a guideline in 2004, which was concomitant chronic renal failure.16,18–23 Although examined
updated in 2012.10,11 A panel of experts convened by IWGDF in only a few studies, a history of chronic hyperglycaemia
has published widely used guideline documents quadrennially may predispose to DFIs, and the presence of hyperglycaemia
since 2004.12 The present 2023 edition of the IWGDF guide- at presentation may suggest a rapidly progressive or destructive
lines on the management of DFI updates the content of the (necrotising) infection.24,25
2019 edition on the diagnosis and treatment of DFIs and is While most DFIs are relatively superficial at presentation, mi-
part of the aforementioned guidelines.13 The IWGDF and croorganisms can spread contiguously to subcutaneous tissues,
IDSA have now agreed to provide a combined intersociety including fascia, tendons, muscles, joints, and bones. The anato-
guideline on the diagnosis and treatment of DFIs; as a result, my of the foot, which is divided into several separate but inter-
the expert panel involved in the creation of the new guideline communicating compartments, fosters the proximal spread of
document included for the first time members from both infection.26 The inflammatory response induced by infection
IWGDF and IDSA working on a single document. may cause compartmental pressure to exceed capillary pressure,
leading to ischaemic tissue necrosis in the affected compartment
and thereby progressive infection.27,28 The tendons within the
3 BACKGROUND
compartments facilitate the proximal spread of infection, which
Infections of the skin and soft tissues of the foot in a person usually moves from higher to lower pressure areas. Bacterial vir-
with diabetes most often follow a break in the protective skin ulence factors may also play a role in these complex infec-
envelope. The most common such break is a DFU, which usu- tions.29,30 Systemic symptoms (e.g., feverishness or chills),
ally involves at least the epidermis and part of the dermis. This marked leucocytosis, or major metabolic disturbances are un-
complication most often occurs in those with peripheral neu- common in patients with a DFI, but their presence denotes a
ropathy, and frequently those with PAD.14 Infection follows more severe, potentially limb-threatening (or even life-
the colonisation of the wound by a complex microbiological threatening) infection.4,31,32 If not quickly diagnosed and prop-
flora. Wound colonisation by bacteria is a constant phenome- erly treated, DFIs tend to progress, sometimes rapidly.33 Thus,
non, defined by the presence of bacteria on the wound surface an experienced medical specialist (or team) with experience in
but without evidence of invasion of the host tissues. Wound in- infectious diseases should evaluate a patient with a severe DFI
fection is a pathological state caused by the invasion and mul- within 24 h34 Accumulations of purulent secretions, especially
tiplication of microorganisms in host tissues that induce an if under pressure or associated with necrosis, require prompt
inflammatory response, usually followed by tissue damage. (usually within 24 h) surgical decompression and drainage.
Since all wounds are colonised (often with potentially patho- Although bone and/or joint resection (preferably using a conser-
genic microorganisms), wound infection cannot be defined us- vative approach, with limited resection and avoiding amputa-
ing only the results of wound cultures. Instead, DFIs are defined tion, if possible) may be required for successfully treating
clinically based on the presence of manifestations of an inflam- osteomyelitis, it is usually an infection of the soft tissues that re-
matory process involving a foot wound located below the mal- quires urgent antimicrobial therapy and surgical intervention.
leoli. In persons with diabetes-related foot complications, signs This document aims to provide a comprehensive, evidence-
and symptoms of inflammation may, however, be masked by based overview of guidelines for the diagnosis and treatment of
the presence of peripheral neuropathy, PAD, or immune foot infections in people with diabetes. These are intended to be

of practical use for treating clinicians based on all available sci- meetings of the working group. After discussion, a voting
entific evidence. procedure was used for each recommendation to grade
the direction of the recommendation as ‘for’ or ‘against’
4 METHODOLOGY
the particular intervention (or ‘either the intervention or
The GRADE framework was used for developing this guide- the comparison’), and the strength of each recommenda-
line.35 This is structured around identifying key clinical question as ‘strong’ or ‘conditional’. A quorum of 60% of mem-
tions in the Population, Assessment, Comparison, Outcome bers was needed to be present for a discussion and vote to

and patient/population, intervention, comparison, outcomes go ahead and a majority vote of those present was needed
format, determining patient-important outcomes, presenting for final decisions on each recommendation. The outcomes
the evidence, assessing the certainty of the evidence, and finally of the voting are provided in the summary of judgement
moving from evidence to the recommendation. tables in the supplemental information of the guideline
The IWGDF editorial board appointed a multidisciplinary documents.
working group of independent experts (the authors of this Based on the summary of judgement tables, the rationales
guideline) to update the previously published 2019 guidelines. for the recommendations were written by the same team of
In addition, three members were delegated by the IDSA to join two assessors of the working groups. These rationales are nar-
the committee. rative (systematic) descriptions of how the working group
The key clinical questions were developed by revising the came to the direction and strength of the recommendation
2019 guideline PICOs and refining each component to reflect and summarises the research evidence for the items in the
clinical relevance. Guidance is aimed at clinicians and other summary of judgement tables.35,40 In addition, expert opin-
healthcare professionals involved in the diagnosis and man- ion, and aspects relevant to communicating to the reader re-
agement of DFIs. Patient important outcomes were generated garding the intervention or recommendation can be added to
and then classified based on their importance for decision- these rationales.
making. Outcomes defined by Jeffcoate et al were also used Finally, all recommendations, with their rationales, were col-
as a reference guide.36 All members voted on the outcomes, lated into a consultation (draft) guideline manuscript that was
and those identified by consensus as “critically important” reviewed by the same international external experts and per-
were included. The editorial board reviewed and approved sons with lived experience who reviewed the clinical questions
the final set of P(A)ICOs through a consultation process and outcomes, as well as by the IWGDF Editorial Board. The
with external experts from various geographical regions working group then collated, reviewed and discussed all feed-
and the IDSA. back on the consultation manuscript and revised accordingly
The committee members then systematically reviewed the to produce the final guidelines.
literature to address the set of pre-specified P(A)ICOs. The In the publication “Standards for the development and
two updated IWGDF systematic reviews supporting this guide- methodology of the 2023 IWGDF guideline”, the details of
line have been completed in accordance with Preferred the methodology for the development of this guideline are
Reporting Items for Systematic Reviews and Meta-Analyses described.41
guidelines, which will be published separately.37 The updated
protocols are available from PROSPERO (CRD42022324795, 5 RECOMMENDATIONS
CRD42022324812).38,39
See Figure 1 for a synthesising overview of the overall diagnosis
After careful weighing of the summary of judgments, the same
and management of patients with DFIs, including diabetes-
teams of two members of the working group determined the di-
related osteomyelitis of the foot.
rection, strength, and wording of the recommendation(s) for the
specific clinical question. Recommendations aimed to be clear,
5.1 Diagnosis
specific, and unambiguous on what was recommended, for which
5.1.1 Clinical question
persons, and under what circumstances. Recommendations were
Can the International Working Group of the Diabetic Foot/
rated as ‘for’ or ‘against’ the particular intervention or ‘either the
IDSA (IWGDF/IDSA) classification system for foot infections
intervention or the comparison’, and the strength of each recom-
in persons with diabetes predict the outcome of such an
mendation was rated as ‘strong’ or ‘conditional’. The certainty of
infection?
evidence, rated as ‘high’, ‘moderate’, ‘low’ or ‘very low’ based on
the critical outcome(s) reviewed for the question in accordance Recommendation 1.
with GRADE, as explained above, was added to the strength of
the recommendation. (a) Diagnosis of a soft tissue diabetes-related infection clini-
Summary of judgements tables and recommendations for cally based on the presence of local or systemic signs and
each question were extensively discussed in online symptoms of inflammation. (Strong; Low)
Figure 1. An overview of the diagnosis and management of patients with Diabetes-related foot infections (DFIs) (from Lipsky et al. DMRR 2019). Perform non-invasive
bedside test for peripheral artery disease (PAD).
(b) Assess the severity of any DFI using the IWGDF/IDSA IWGDF/IDSA classification for the infection component,
classification scheme. (Strong; Low). have been validated with patient data.47,48
Importantly, in the current guideline, we define a DFI based
on the presence of evidence of (a) inflammation of any part of
Rationale. The clinician seeing a patient with diabetes and a the foot, not just of an ulcer, or (b) findings of SIRS. Because of
foot ulcer should always assess for the presence of an infection the important diagnostic, therapeutic, and prognostic implica-
and, if present, classify the infection’s severity.42,43 Experts have tions of osteomyelitis, we separated it out by indicating the
proposed many classification schemes for DFU, many of which presence of bone infection with “(O)” after the grade number
only include the presence or absence of “infection”.9 Previous (3 or 4) (see Table 1). We did not use the term osteitis, which
prospective and retrospective studies have validated all or would be an infection of the cortical bone only, without the in-
part of the IWGDF/IDSA DFI classification as part of a larger volvement of the medulla. Although the pathogens enter the
diabetes-related foot classification system (PEDIS) (see bone through contiguous spread from an ulcer to the cortex
Table 1).4,15 Other classifications for severe infection, for exam- and not by haematological spread to the medulla, it is difficult
ple, National Early Warning Score44,45 or quick sequential to distinguish the cortical bone infection from medullary bone
organ failure assessment,46 were developed for the identifica- infection clinically by imaging or histology. Also, we think that
tion or prediction of outcomes in patients with sepsis. the two entities do not require separate therapeutic interven-
However, there are no data to support changing from using tions. Therefore, we decided to use the term osteomyelitis for
the systemic inflammatory response syndrome (SIRS) that is both disease entities.
part of the IWGDF/IDSA classification to any other classifica- In our systematic review on the diagnosis of foot infection in
tion for DFIs. Two commonly used classifications for DFUs, persons with diabetes,49 new studies with a high risk of bias
Wound, Ischaemia, and foot Infection, and Site, Ischaemia, were identified that examined the outcomes of interest.50–54
Neuropathy, Bacterial Infection, and Depth, which use the The main questions addressed concerned whether there should

Table 1. The classification system for defining the presence and severity Recommendation 2. Consider hospitalising all persons with
of foot infection in a person with diabetes.a diabetes and a foot infection who have either a severe foot
infection as classified by the IWGDF/IDSA classification or a
IWGDF/IDSA
Clinical classification of infection, definitions classification moderate infection which is associated with key relevant mor-
No systemic or local symptoms or signs of infection 1/Uninfected
bidities. (Conditional; Low).
Infected: At least two of these items are present: 2/Mild
• Local swelling or induration Rationale. Regarding the decision to hospitalise a patient with
• Erythema >0.5 but <2 cmb around the wound
a DFI, the IWGDF/IDSA infection classification system

• Local tenderness or pain
• Local increased warmth facilitates risk stratification to inform this decision.4
• Purulent discharge
Hospitalisation is an expensive and finite resource and may
And, no other cause of an inflammatory response of the
skin (e.g., trauma, gout, acute charcot subject the patient to major inconvenience and potential noso-
neuro-arthropathy, fracture, thrombosis, or venous comial risks. But while many patients with a DFI do not need to
stasis)
be hospitalised, some certainly should be. The consideration
Infection with no systemic manifestations and involving: 3/Moderate
• Erythema extending ≥2 cmb from the wound margin, should be given to hospitalise all persons with a severe foot in-
and/or fection to ensure timely and effective management, as well as
• Tissue deeper than skin and subcutaneous tissues (e.g.,
tendon, muscle, joint, and bone)c those with a moderate infection associated with key relevant
Infection involving bone (osteomyelitis) Add “(O)” co-morbidities, in particular, PAD (see details in Table 2).
Any foot infection with associated systemic 4/Severe This is due to a higher risk of poor outcomes in these cases, es-
manifestations (of the systemic inflammatory response
syndrome [SIRS]), as manifested by ≥2 of the following: pecially amputation or death.4,16,17,19 Of note, the presence of
• Temperature, > 38°C or <36°C osteomyelitis does not necessarily require hospitalisation, since
• Heart rate, > 90 beats/min
many of these patients are clinically stable and can be treated
• Respiratory rate, > 20 breaths/min, or PaCO2 < 4.3 kPa
(32 mmHg) with oral antibiotic agents. Hospitalisation may be preferable
• White blood cell count >12,000/mm3, or < 4G/L, or (at least initially) in those patients who require intravenous an-
>10% immature (band) forms
- Infection involving bone (osteomyelitis) Add “(O)”
tibiotic therapy, have substantial associated soft tissue infec-
The presence of clinically significant foot ischaemia makes both diagnosis and treatment of
tion, require special diagnostic testing, or require urgent
infection considerably more difficult. surgical treatment. Fortunately, almost all patients with a
a
infection refers to any part of the foot.
b
mild infection, and many with a moderate infection but with-
in any direction, from the rim of the wound.
c
if osteomyelitis is demonstrated in the absence of ≥2 signs/symptoms of local or systemic out any key relevant morbidities, can be treated in an ambula-
inflammation, classify the foot as either grade 3(O) (if <2 SIRS criteria) or grade 4(O) if ≥2 tory setting. The availability of home parenteral antibiotic
SIRS criteria) (see text).
programs in some countries is another site-dependent factor
that influences the need for hospitalisation.
Most published studies of DFIs have enrolled hospitalised
patients, but over the past 2 decades, several have reported
be modifications of the current IDSA/IWGDF classification by good results with outpatient treatment.51–53 Therefore, it is of
combining the moderate and severe categories and considering utmost importance to correctly assess the infection severity as
risk categories according to soft tissue infections or osteomye- the patient management significantly differs from oral antibiot-
litis. Insufficient quality of evidence led us to not consider ei- ic treatments to complex combinations of surgery and paren-
ther laboratory risk indicators for necrotising fasciitis or SIRS teral broad-spectrum antibiotic regimens. Given the low
as reliable tools for predicting lower extremity amputation, certainty of the evidence, with inconsistency between studies,
mortality, or other health outcomes.52,53 In the absence of ad- and the fact that differences in patient characteristics as well
ditional validation studies, and moderate certainty attributed as health care policies between countries will influence the de-
to the risk of bias, we elected not to alter the IDSA/IWGDF cision to hospitalise, we made a conditional recommendation.
classification, as shown in Table 1.
Defining the infection of the foot in persons with diabetes is Recommendation 3. Assess inflammatory serum biomarkers
of utmost importance, given the possible negative consequenc- such as CRP, ESR, or PCT in a person with diabetes and a pos-
es of missing this diagnosis. Additionally, distinguishing infect- sible infected foot ulcer for whom the clinical examination is
ed from non-infected wounds may help avoid the unnecessary diagnostically equivocal or uninterpretable. (Best Practice
use of antibiotics in the absence of infection. Although based on Statement).
low quality of evidence given the major impact, the use of
the IWGDF/IDSA classification may have on outcome and Rationale. Serum tests for inflammatory biomarkers such as
antibiotic use in persons with DFIs, we made a strong white blood cell (WBC) count, ESR, CRP, and PCT are widely
recommendation. available, easily obtained, and most, except PCT, are relatively
Table 2. Characteristics suggesting a more serious diabetes-related foot infection (DFI) and potential indications for hospitalisation.4,16–18
A. Findings suggesting a more serious diabetes-related foot infection
Wound specific
Wound Penetrates to subcutaneous tissues (e.g., fascia, tendon, muscle, joint, or bone)
Cellulitis Extensive (>2 cm), distant from ulceration, or rapidly progressive (including lymphangitis)
Local signs/symptoms Severe inflammation or induration, crepitus, bullae, discolouration, necrosis or gangrene, ecchymoses or petechiae, and new
anaesthesia or localised pain
General

Presentation Acute onset/worsening or rapidly progressive
Systemic Fever, chills, hypotension, confusion, and volume depletion
Laboratory tests Leucocytosis highly elevated C-reactive protein, or erythrocyte sedimentation rate, severe or worsening hyperglycemia, acidosis,
new/worsening azotaemia and electrolyte abnormalities tests
Complicating features Presence of a foreign body (accidently or surgically implanted), puncture wound, deep abscess, arterial or venous insufficiency,
lymphoedema, immunosuppressive illness or treatment, acute kidney injury
Failing treatment Progression while on apparently appropriate antibiotic and supportive therapy
B. Factors that should lead to considering hospitalisation
Severe infection (see findings suggesting a more serious diabetes-related foot infection above)
Metabolic or haemodynamic instability
Intravenous therapy needed (and not available/appropriate as an outpatient)
Diagnostic tests needed that are not available as an outpatient
Severe foot ischaemia is present
Surgical procedures (more than minor) required
Failure of outpatient management
Need for more complex dressing changes than patient/caregivers can provide
Need for careful, continuous observation
inexpensive. A few studies have investigated other inflammato- and in patients with noninfected DFU than in those with no
ry markers for their role in diagnosing or following DFIs, but foot ulcer, with levels increasing significantly with the severity
they were small and of low quality.11 Most available studies as- of infection.62,63 Compared to WBC and ESR, CRP has shown
sessed the value of these inflammatory biomarkers by compar- higher diagnostic accuracy for grade 2 (infected) DFU.63
ing them with the results of IDSA/IWGDF criteria for Studies of serum PCT levels have also found that levels were
infection.4,54 Unfortunately, the severity of infection in patients significantly higher in infected DFU than noninfected DFU,
included in the available studies was not always clearly defined, but there was little correlation between the values and the infec-
which may account for interstudy differences in findings. In ad- tion severity.54,57,58,64,65 The highly variable cut-off values used
dition, many studies do not specify if enroled patients were re- make it difficult to interpret the results reported in studies that
cently treated with antibiotic therapy, which could affect have investigated these inflammatory markers. Due to their
results.55 Of particular note is the WBC level, as it is used as limited specificity and sensitivity, not exceeding 0.85, when
part of the IDSA/IWGDF criteria for classifying infection as se- used as sole diagnostic tools, inflammatory biomarkers should
vere/grade 4. The available studies56–61 found little correlation be used when uncertainty persists after clinical assessment. We
of WBC with infection severity, with about half of the patients make a Best Practice Statement about the use of ESR, CRP, or
diagnosed with a DFI having a normal WBC.60,61 In most stud- PCT due to the potential harms related to potential over or un-
ies, ESR values have been higher in patients with an infected derdiagnosing DFI, with low certainty of evidence based on
DFU compared with a noninfected DFU.56,57 ESR values can studies of low quality, with inconsistency about the results
be affected by various co-morbidities (e.g., anaemia and azotae- and heterogeneity in cut-off values.
mia) and may not be elevated in acute infections due to the rel-
atively slow response of this inflammatory biomarker. A highly Recommendation 4. For diagnosing diabetes-related foot soft-
elevated ESR (≥70 mm/h) has a sensitivity, specificity, and tissue infection, we suggest not using foot temperature (howev-
AUC for the diagnosis of DFO of 81%, 80%, and 0.84, er measured) or quantitative microbial analysis. (Conditional;
respectively.62 Low).
Compared with ESR, CRP levels tend to rise more quickly
with infection and fall more quickly with the resolution of in- Rationale. While various imaging tests are widely used for
fection. Serum values of CRP have consistently been found to diagnosing bone infection (see below), there are few data on
be significantly higher in infected than noninfected DFUs their usefulness for soft-tissue infections. Other diagnostic

tests studied for assessing DFI include photographic foot unusual or antibiotic-resistant pathogens (e.g., based on specif-
imaging and infrared thermography. Several studies with these ic exposures or previous culture results), selecting empiric ther-
instruments have examined their value in predicting the occur- apy without culture may be reasonable. In other situations,
rence of foot ulcerations. Overall, employing either infrared or despite superficial swabs being easier to perform, we advise col-
digital thermography does not appear to provide substantial lecting a soft tissue specimen on the basis of two systematic re-
help in diagnosing infection or predicting the clinical outcome views73,74 (with low-quality evidence), one small prospective
in patients with a DFU seen in the hospital setting.66–69 While study75 and one well-designed prospective study,76 which re-

infrared imaging likely causes no harm, its use is limited by low ported higher sensitivity and specificity of tissue specimens
availability. for culture results than superficial swabs. Collecting a tissue
Some advocate using the presence of high numbers of bacte- specimen may require slightly more training and pose a slight
ria on culture (usually defined as ≥105 colony-forming units risk of discomfort or bleeding, but we believe the benefits clear-
per gram of tissue) as a basis for differentiating infected from ly outweigh this minimal risk of harm. The evidence informing
uninfected DFUs.70,71 However, there is no convincing data which method of specimen collection to use is limited by the
(from studies using either conventional culture or molecular absence of a definitive criterion standard for defining the ulcer
methods) supporting this concept.72 In published studies that infection.
assessed the validity of clinical signs for the diagnosis of DFI us- Repeating cultures may be useful for a patient who is not re-
ing microbial analysis as a referent test, the criteria used to de- sponding to apparently appropriate therapy, but this may result
fine infection varied among the authors, and even between in isolating antibiotic-resistant strains likely to be contami-
studies conducted by the same team. In some microbial analysis nants rather than pathogens. A key caveat is that the accuracy
studies, patients receiving antibiotics at the time of the wound of culture results depends on the quality of the information
sampling (which may suppress bacterial growth and cause di- provided between clinical and microbiology staff throughout
minished organism counts) were included, while others failed the sample pathway, from collecting, to transporting, to pro-
to provide information on this important confounding issue. cessing and reporting. Clinicians should provide key clinical
Of note, these methods for measuring what is sometimes called details associated with the patient and the sample, and clinical
“wound bioburden” are time-consuming and relatively expen- microbiology services should provide adequate comprehensive
sive. Furthermore, neither quantitative classical culture nor and clear reporting of the isolated organisms and their suscept-
molecular quantitative techniques are currently available to ibility profiles. For persons presenting in a low-income limited
most clinicians in their daily care of patients. Our recommen- resource setting without ready access to culture or follow-up
dation against these diagnostic methods is based on the limited care, performing a Gram-stained smear of material from a
data to support the use of these time- and resource-consuming DFI could be a relatively easy and inexpensive way to visualise
techniques, which are frequently unavailable, and may lead to the class of the likely causative pathogens, thus helping direct
overdiagnosing (and unnecessarily treating) IDFU. The recom- empiric therapy.77 The recommendation is conditional with a
mendation is conditional based on low certainty of evidence. moderate certainty of evidence based on clinical studies with
varying quality, including one large prospective study.
5.1.2 Clinical question
In a person with diabetes and infection of the foot, which test(s) Recommendation 6. Use conventional, rather than molecular,
can best identify the causative pathogen(s), and result in tai- microbiology techniques for the first-line identification of
lored use of antibiotics? pathogens from soft tissue or bone samples in a patient with
a DFI (Strong; Moderate).
Recommendation 5. In a person with suspected soft tissue DFI,
consider a sample for culture to determine the causative micro- Rationale. Molecular microbiology techniques have demon-
organisms, preferably by aseptically collecting a tissue speci- strated that the flora in most DFIs is more diverse and abun-
men (by curettage or biopsy) from the wound. (Conditional; dant than that revealed using conventional culture
Moderate). methods.78–82 Our systematic review identified 4 recent single-
centre prospective studies that compared the results of different
Rationale. In the great majority of cases, obtaining a specimen non-culture (molecular microbiological) methods to those of
(after cleansing and debridement and trying to avoid contam- conventional culture.49,83–86 These studies addressed this ques-
ination) for culture from a DFI provides useful information on tion in both skin and soft-tissue infections and osteomyelitis of
the causative pathogen(s) and their antibiotic susceptibility, al- the foot. They consistently found an agreement of more than
lowing appropriate selection of antibiotic therapy. In cases of 0.70 between molecular microbiology and conventional culture
an acute, non-severe DFI in a patient who has not recently re- methods regarding the most clinically relevant pathogens iden-
ceived antibiotic therapy and has no other risk factors for tified, except for anaerobes, which are more frequently
identified by non-culture techniques.82 The studies also con- underlying any foot wound, especially those that have been pre-
firmed that non-culture techniques, especially metagenomic sent for many weeks or that are wide, deep, located over a bony
next-generation sequencing (mNGS) (NGS), identify more prominence, showing visible bone, or accompanied by an ery-
bacteria from tissue samples, including bone, than convention- thematous, swollen (“sausage”) toe.88
al cultures.83–86 Currently, the use of mNGS techniques does Diagnosis of bone infection of the foot is of paramount im-
not lead to a shorter time until pathogen identification, but portance, given that its presence greatly increases the risk of
this might change with the deployment of newer techniques. minor and major amputations. The investigation of diabetes-

These techniques may help choose the empirical antibiotic related foot wounds suspected of having bone infection usually
therapy and reduce the risk of inappropriate treatment (i.e., includes a physical examination and a conventional radio-
failing to cover bacteria involved, including multiresistant graph, while some blood biomarkers might be of interest; these
ones). On the other hand, as molecular microbiology tech- issues are discussed below. An accurate diagnosis of DFO is es-
niques are currently unable to distinguish dead from living bac- sential to initiate appropriate therapy and to avoid unjustified
terial cells, there are concerns that they may lead to the prolonged antibiotic treatment and surgery in patients who
unjustified use of broad-spectrum antibiotics. The studies do not have a DFO.
that addressed molecular microbiology for either STI or DFO
included relatively few subjects, were at high risk of bias, and Probe-to-bone test
did not provide information on the value of the findings for Among clinical examinations of the foot, the PTB test is the
guidance on clinical management. Specifically, we do not most useful, but the performing clinician’s technique and expe-
know which of the many bacterial genera identified using mo- rience, the location of ulcer, and its aetiology may affect the test
lecular methods contribute to the clinical state of infection or reliability.89,90 A systematic review of the PTB test found that
require targeted antibiotic therapy. Overall, we acknowledge for detecting DFO, the sensitivity was 0.87 and specificity
the essential role of molecular microbiology techniques in the 0.83.91 Overall, in diagnosing DFO, the PTB test suggests the
understanding of the pathophysiology of DFIs, and that these diagnosis if it is positive in a high-risk patient and helps rule
are promising techniques for application in clinical practice it out if it is negative in a low-risk patient. The procedure is
in the future. We do not, however, recommend their use in dai- easy to learn and perform, requiring only a sterile blunt metal
ly practice, given the unclear significance of positive results, ab- probe (gently inserted into the wound, with a positive test de-
sence of demonstrated impact on antibiotic treatment, high fined by feeling a hard, gritty structure), is inexpensive and es-
costs, and limited availability. This is a strong recommendation sentially harmless, but interobserver agreement is only
against the use of non-culture techniques, based on a moderate moderate.92 Of note, if clinicians are not skilled in this test,
certainty of evidence from prospective studies with a high risk they should not rely on its results as it may have been per-
of bias, the relative high costs and the lack of information to formed incorrectly, resulting in incorrect results.
what extent these techniques will influence clinical manage-
ment. Thus, for now, clinicians should continue to request con- Plain X-ray
ventional cultures of specimens to determine the identity of Any patient with a possible bone infection should initially have
causative microorganisms and their antibiotic sensitivities. plain X-rays of the foot. Interpreted by an experienced reader,
characteristic findings of bone infection (see Table 3) are highly
5.1.3 Clinical question suggestive of osteomyelitis, but similar abnormal findings can
In a person with diabetes and suspected bone or joint infection be caused by Charcot osteoarthropathy and other disorders.
of the foot, which tests have the best correlation with BonE As plain X-rays are relatively inexpensive, widely available,
BiOPsy (BeBoP) results for diagnosing diabetes-related osteo- and cause minimal harm, we recommend them as part of the
myelitis, including residual/postoperative osteomyelitis)? routine assessment of patients presenting with a DFI. This im-
aging exam provides useful information, especially about the
Recommendation 7. In a person with diabetes, consider using a status of the underlying osteoarticular tissues, the presence of
combination of probe-to-bone test, plain X-rays, and ESR, or gas in deep tissues, and the presence of any radio-opaque for-
CRP, or PCT as the initial studies to diagnose osteomyelitis eign body. In addition, the image can be used as a reference
of the foot. Conditional; Low. against which to compare new images if the patient presents
with another foot problem. Because plain X-rays are insensitive
Rationale. The diagnosis of osteomyelitis in the foot of a per- to acute osteomyelitis, it is often useful to repeat a normal ex-
son with diabetes may be difficult partly because of a lack of amination in 2–3 weeks when the suspicion of osteomyelitis
a universally accepted definition or criterion standard, and is still high.93 A retrospective study of patients with histologi-
partly related to low levels of inter-test agreement among com- cally proven DFO found that after adjusting for confounders,
monly used diagnostic tests.87 Osteomyelitis may be present inflammatory biomarkers, and plain X-rays were actually

Table 3. Features characteristic of diabetes-related osteomyelitis of the review of plain X-rays of the foot, we recommend testing for
foot on plain X-rays. ESR, CRP, or PCT. However, this recommendation is condi-
• New or evollistaving radiographic featuresa on serial radiographs,b including: tional because of the risk of over- or under-diagnosis of bone
⚬ Loss of bone cortex, with bony erosion or demineralisation infection, based on a low quality of evidence with inconsistency
⚬ Focal loss of trlistaabecular pattern or marrow radiolucency
(demineralisation) in the data on diagnostic accuracy results.
⚬ Periosteal reaction or elevation
• Bone sclerosis, with or without erosion Recommendation 8. Perform MRI when the diagnosis of
• Abnormal soft tissue density in the subcutaneous fat, or gas density,

extending from skin towards underlying bone, suggesting a deep ulcer or
diabetes-related osteomyelitis of the foot remains in doubt de-
sinus tract spite clinical, plain X-rays and laboratory findings. (Strong;
• Presence of sequestruma: devitalised bone with radiodense appearance Moderate).
separated from normal bone
• Presence of involucruma: layer of new bone growth outside previously
existing bone resulting, and originating, from stripping off the periosteum Recommendation 9. Consider using PET, leucocyte scintigra-
• Presence of cloacaea: opening in the involucrum or cortex through which phy, or SPECT as an alternative to MRI for the diagnosis of
sequestrum or granulation tissue may discharge
diabetes-related osteomyelitis of the foot. (Conditional; Low).
a
some features (e.g., sequestrum, involucrum, and cloacae) are seen less frequently in
diabetes-related foot osteomyelitis than in younger patients with osteomyelitis of larger
bones. Rationale. Depending on the patient setting, advanced imaging
b
usually spaced several weeks apart.
for diagnosing osteomyelitis is not needed in many patients.
When needed, MRI has been the most commonly ordered ad-
vanced imaging technique to diagnose DFO, with moderate
more useful than MRI.94 Because interpretation of plain X-rays
costs (but about 10 times higher than that of plain X-rays)
can be difficult (even for an experienced reader) when non-
and wide availability in high-income countries. Besides being
infectious changes (especially those related to neuro-
used as a (very sensitive) diagnostic tool, MRI gives a good
osteoarthropathy) are present, advanced imaging techniques
overview of the anatomy of soft tissues as well as bones and
or even bone culture may ultimately be needed to confirm or
joints, which can be of aid for detecting pre-operatively any pu-
exclude osteomyelitis in the foot.
rulent collections or the extent of bone involvement. Among
advanced imaging techniques, MRI has been the most studied,
Serum biomarkers is associated with lower costs than some other advanced imag-
In a systematic published in 2019, it was found that ESR ing techniques, and gives an overview of the presence and ex-
≥70 mm/hr had a sensitivity, specificity, and AUC of 0.81, tent of both soft tissue and bone infections in the foot.98,99 It
0.8 and 0.84, respectively, while the value of PCT could not is important to note that the presence of reactive bone marrow
be assessed due to paucity of the data.62 oedema from non-infectious pathologies, such as trauma, pre-
A more recent systematic review and meta-analysis pub- vious foot surgery or Charcot neuroarthropathy, lowers its spe-
lished in 2022 found that PCT had the highest diagnostic test cificity and positive predictive value.100,101 In selected patients
accuracy when compared to that of ESR, WBC and ESR with with possible neuro-osteoarthropathy, newer techniques such
sensitivity, specificity, and AUC of 0.85, 0.67 and 0.844 at a cut- as MR angiography, dynamic contrast-enhanced MRI or neu-
off value of 0.33 ng/mL.63,95 Given the lack of inter-operator rography may better distinguish Charcot arthropathy from os-
variability, the use of either ESR, CRP, or PCT as a sole bio- teomyelitis.102–105 The accuracy of MRI findings can be
marker for the detection of DFO in a patient with soft tissue improved by using the results of a second read by an expert
DFI is not appropriate, but their use in combination with other musculoskeletal radiologist.107 Another finding likely to aug-
diagnostic tests may be useful. A large-scale retrospective ment the sensitivity of MRI for the diagnosis of DFO is the de-
single-centre study with high risk of bias that used the results tection of an increased ratio of marrow region of interest
of culture and/or histology of bone samples as a reference stan- (ROI)/joint fluid ROI on T2/Short Tau Inversion Recovery
dard found that ESR >60 mm/hr plus CRP ≥80 mg/L had a (STIR) sequences.106 A systematic review and meta-analysis
high positive predictive value, but a modest negative predictive that compared the diagnostic accuracy of imaging tests (plain
value, for the diagnosis of DFO.96 In another study, the combi- X-rays, scintigraphy, MRI, SPECT and PET) for the diagnosis
nation of elevated ESR (>43 mm/h) with a positive PTB test of DFO showed that 18F-fluorodeoxyglucose (FDG)–PET and
99
showed a high correlation with having positive bone culture mTc- exametazime Hexa Methyl Propylene Amine Oxime la-
and/or histology results.97 belled WBC scintigraphy offer the highest specificity (0.92 for
Overall, neither plain x-ray, inflammatory biomarkers (ESR, both).107 In patients with a contraindication to MRI, clinicians
CRP and PCT) nor probe-to-bone tests can one their own sole- may choose other imaging techniques (e.g., FDG-PET/CT,
ly and reliably rule in or rule out the diagnosis of DFO. When HMPAO-labelled leucocyte scintigraphy or 99mTc labelled
diagnostic doubt persists after the clinical assessment and Ubiquicidin (UBI) SPECT/CT).107–112
Compared to nuclear (e.g., leukocyte) imaging, PET, espe- In order to provide the most accurate assessment of true
cially combined with CT scan, offers high spatial resolution, pathogens, and to avoid contamination of the bone samples us-
precise anatomic localization, possibly higher sensitivity for ing the skin flora, it is important to collect a bone specimen in
chronic infection, easier performance, faster results, and low an aseptic manner (i.e., percutaneously via intact and uninfect-
radiation exposure. Overall, the available studies that compared ed skin, or intraoperatively).115 A prospective direct compari-
the diagnostic accuracy of MRI and nuclear imaging techniques son of 46 paired per-wound versus transcutaneous bone
in patients with a suspicion of DFO show conflicting re- biopsies in patients with suspected DFO found that results
sults.105,106,109,113 MRI and FDG PET/CT have several advan- were identical in only 42%.120 To avoid a false-negative culture,

tages compared to other anatomical and functional imaging some experts suggest delaying BeBoP in a patient who is receiv-
methods, including short acquisition time, high resolution, ing antibiotics until they have been off therapy for at least a few
low radiation dose, and better tolerability.110 The availability days, and ideally for at least 2 weeks. This is still a matter of de-
and cost of these advanced imaging techniques may vary in dif- bate, and the optimal duration of any antibiotic-free period be-
ferent geographic locations, but they might be useful in situa- fore the biopsy is not known. In recent studies, a history of
tions when the diagnosis remains in doubt, and when there prior antibiotic therapy was associated with an increased like-
are limited options to obtain a BeBoP. lihood of false negative bone culture.121,122 Available published
For the diagnostic accuracy of advanced imaging in DFO, the studies have established that obtaining percutaneous and intra-
overall certainty of the evidence is moderate because of serious operative bone biopsies are both safe. Percutaneous biopsy is
inconsistency, imprecision, and indirectness of results in the generally not painful (as the majority of affected patients
included studies. Although the certainty of evidence was mod- have sensory neuropathy, and local anaesthetics can be of-
erate, a strong recommendation is made regarding MRI use in fered), and complications are rare.116,117 Obtaining a bone sam-
DFO because of the high accuracy in results, especially regard- ple generally requires the services of a surgeon or radiologist,
ing the information on both soft tissue and bone and joint but recent studies suggest it can be performed safely at the bed-
structures. Despite the certainty of evidence being moderate, side by any trained medical caregiver.123,124 Bedside percutane-
a conditional rather than a strong recommendation is made re- ous biopsy may make it easier to obtain a bone culture when
garding SPECT/CT & PET/CT use in DFO because of the lack operating/imaging facilities are not feasible or available. Of
of accessibility and feasibility of this modality and the great re- note, BeBoP may not be needed if an aseptically collected speci-
sources and expertise required to implement this technique. men from a deep soft tissue infection grows only a single viru-
lent pathogen, especially S. aureus.11 Culture of bone has the
Recommendation 10. In a person for whom there is suspicion of advantage of determining the causative pathogen, but histology
osteomyelitis of the foot (before or after treatment), consider may be more sensitive if the patient is on antibiotic therapy,
obtaining bone (rather than soft tissue) samples for culture, and more specific if the specimen contamination is a concern.
either intraoperatively or percutaneously. (Conditional; Several studies have shown one-to two-thirds of patients
Moderate). who undergo bone resection and from whom the surgeon ob-
tains a sample of retained bone (variously called “marginal,”
Rationale. Obtaining a bone specimen to diagnose osteomyeli- “distal,” or “proximal” bone) that appears clinically uninfected
tis is the generally accepted criterion standard for diagnosing will have culture or pathological evidence of residual infec-
the infection, and the only definitive way to determine the caus- tion.125–129 The possibility that many of the theses positive re-
ative pathogen(s). BonE BiOPsy is, however, usually not per- sidual bone cultures are false positives is supported by the
formed in most cases of suspected DFO due to the absence of finding of a substantially lower rate of positive histology on
a health care professional adequately trained to perform the the same specimen in two studies.128,129 Of note, cultures
procedure and/or the fear of possible adverse effects, especially may also be falsely negative, especially in patients treated
fracture or induced infection of the bone.114 Published studies with antibiotics or when samples are not appropriately trans-
consistently report a low correlation between bone and non- ported to and processed by the microbiology laboratory. The
bone culture results, most <50%, with the highest correlation low inter-rater agreement among pathologists on the diagnosis
for Staphylococcus aureus.115–117 This is of potential impor- of osteomyelitis by histopathology130 and the weak concor-
tance, as incorrect identification of the bone pathogens could dance between histopathology and culture of foot bone speci-
increase the risk of treatment failure, although this has only mens127 are subjects of debate.131 This question was
been reported in one published study.118 An ongoing multi- addressed in two more recent studies, but these also provide
centre, prospective, randomised study (BeBoP trial) is designed conflicting results.132,133
to determine if treatment outcomes of DFO differ depending Since there are no available data demonstrating a clear ben-
on the chosen diagnostic strategy, that is, a culture of bone ver- efit of using BeBoP results on the outcome of patients treated
sus one of wound.119 for a DFO, and facilities for obtaining BeBoP are not always

available, our recommendation for undertaking a BeBoP in pa- therapy, and who reside in North America or Western
tients with a suspicion of DFO was graded “conditional”. The Europe. Best Practice Statement.
certainty of the evidence is moderate, based on several retro-
spective studies with consistency in the results regarding the di- Recommendation 15. Do not empirically target antibiotic thera-
agnostic accuracy of bone cultures compared to no-bone py against Pseudomonas aeruginosa in cases of DFI in temper-
cultures and the safety of the procedure established in these ate climates, but use empirical treatment of P. aeruginosa if
studies. it has been isolated from cultures of the affected site within

the previous few weeks, in a person with moderate or severe in-
5.2 Treatment fection who resides in Asia or North Africa. Best Practice
5.2.1 Clinical question Statement.
In a person with diabetes and a soft-tissue infection of the foot,
which specific antibiotic regimen (specific agent[s], route of ad- Rationale. In our systematic review we could not identify data
ministration, duration of therapy) should be chosen when tak- supporting the concept that prescribing antibiotic therapy for
ing into account the resolution and recurrence of infection, and clinically uninfected ulcers either accelerates healing or reduces
the acquisition of antimicrobial resistance? the risk of developing clinically apparent infection.49 Since cul-
tures of such open wounds will usually reveal microorganisms,
Recommendation 11. Do not treat clinically uninfected foot ul- including some that are commonly considered pathogens, this
cers with systemic or local antibiotic therapy when the goal is does not mean it is infected. As about half of all DFUs are clin-
to reduce the risk of new infection or to promote ulcer healing. ically uninfected at presentation, prescribing antibiotic therapy
Best Practice Statement. for these could result in a substantial exposure of patients to po-
tentially unnecessary and often harmful treatment.134 We
Recommendation 12. strongly believe that for patients with a clinically uninfected ul-
cer, the potential harms (to the patient, the health care system,
(a) Use any of the systemic antibiotic regimens that have been and society as a whole) of antibiotic therapy (adverse effects of
shown to be effective in published randomised controlled tri- antibiotic therapy, inconvenience to the patient, cost for the
als at standard (usual) dosing to treat a person with diabetes drug, and likelihood of driving antibiotic resistance) outweigh
and a soft tissue infection of the foot. (Strong; High). any theoretical (but unproven) benefits.
(b) Administer antibiotic therapy to a patient with a skin or Based on many studies (most limited by methodological
soft tissue diabetic foot infection for a duration of 1–2 flaws) that compared various oral or parenteral antibiotic
weeks. (Strong; High). agents in patients with DFI, treatment with any appropriately
(c) Consider continuing treatment, perhaps for up to 3–4 selected agent of most classes of antibiotics by either route is ef-
weeks, if the infection is improving but is extensive and fective in the great majority of cases.135–141 The choice of an an-
is resolving slower than expected or if the patient has severe tibiotic regimen should be based on the
PAD. (Conditional, Low).
(d) If evidence of infection has not resolved after 4 weeks of ap- • Likely or proven causative pathogen(s) and their antibiotic
parently appropriate therapy, re-evaluate the patient and susceptibilities,
reconsider the need for further diagnostic studies or alter- • Availability of the antibiotic,
native treatments. (Strong; Low). • Published evidence of efficacy of the agent for DFIs,
• Clinical severity of the infection
• Experience of the treating team and presence of local
Recommendation 13. Select an antibiotic agent for treating a DFI protocols,
based on the likely or proven causative pathogen(s) and their an- • Presence of patient-related factors, including a history of
tibiotic susceptibilities; the clinical severity of the infection; pub- drug allergies, recent hospitalisation, and comorbidities
lished evidence of the efficacy of the agent for infections of the such as impaired kidney function or renal dialysis,
diabetes-related foot; the risk of adverse events including collater- • Likelihood of adverse events or potential drug interactions,
al damage to the commensal flora; the likelihood of drug interac- • Risk of collateral damage to the commensal flora,
tions; agent availability and costs. Best Practice Statement. • Costs (see our propositions for the antibiotic therapy in
Table 4).
Recommendation 14. Target aerobic gram-positive pathogens
only (beta-haemolytic streptococci and Staphylococcus aureus With appropriately selected antibiotic therapy (combined
including methicillin-resistant strains if indicated) for people with any necessary surgery and proper metabolic control
with a mild DFI, who have not recently received antibiotic and wound care), most DFIs can be treated successfully with
Table 4. Proposals for the empirical antibiotic therapy according to clinical presentation and microbiological data (from Lipsky et al.11).a
Infection severity Additional factors Usual pathogen(s)b Potential empirical regimensc
Mild No complicating features GPC Semisynthetic penicillinase-resistant penicillin (cloxacillin)

1st generation cephalosporin (cephalexin)
ß-lactam allergy or GPC Clindamycin; fluoroquinolone (levo/moxi-floxacin); trimethoprim-sulfamethoxazole;
intolerance doxycycline
Recent antibiotic exposure GPC + GNR ß-lactam- ß lactamase inhibitor1 (amoxicillin/clavulanate, ampicillin/sulbactam)

Fluoroquinolone (levo/moxi-floxacin); trimethoprim-sulfamethoxazole
High risk for MRSA MRSA Linezolid; trimethoprim-sulfamethoxazole; clindamycin; doxycycline,
fluoroquinolone (levofloxacin, moxifloxacin)
Moderate or severed No complicating features GPC ± GNR ß-lactam- ß lactamase inhibitor1 (amoxicillin/clavulanate, ampicillin/sulbactam)
2nd, 3rd generation cephalosporine (cefuroxime, cefotaxime, ceftriaxone)
Recent antibiotics GPC ± GNR ß-lactam- ß lactamase inhibitor2 (ticarcillin/clavulanate, piperacillin/tazobactam)
2nd, 3rd generation cephalosporine (cefuroxime, cefotaxime, ceftriaxone) group 1
carbapenem (ertapenem); (depends on prior therapy; seek advice)
Macerated ulcer or warm GNR, including ß-lactam- ß lactamase inhibitor2 (ticarcillin/clavulanate, piperacillin/tazobactam)
climate Pseudomonas sp. semisynthetic penicillinase-resistant penicillin (cloxacillin) + ceftazidime or
ciprofloxacin group 2 carbapenem (mero/imi-penem)
Ischaemic limb/necrosis/ GPC ± GNR ± strict ß-lactam- ß lactamase inhibitor1 (amoxicillin/clavulanate, ampicillin/sulbactam) or
gas forming anaerobes ß-lactam- ß lactamase inhibitor2 (ticarcillin/clavulanate, piperacillin/tazobactam)
Group 1 (ertapenem) or 2 (mero/imi-penem) carbapenem
2nd (cefuroxime)/3rd (cefotaxime, ceftriaxone) generation cephalosporin +
clindamycin or metronidazole
MRSA risk factors MRSA Consider adding, or substituting with, glycopeptides (vancomycin, teicoplanin);
llLinezolid; daptomycin; fusidic acid, trimethoprim-sulfamethoxazole; doxycycline
Risk factors for resistant ESBL Carbapenem (erta/mero/imi-penem); fluoroquinolone (ciprofloxacin);
GNR Aminoglycoside (amikacin); colistin
Antibiotics enclosed in brackets are cited as examples. High risk for MRSA: previous MRSA infection or colonisation. MRSA risk factors: prolonged hospitalisation, intensive care admission,
recent hospitalisation, recent antibiotic use, invasive procedures, HIV infection, admission to nursing homes, open wounds, haemodialysis, discharge with long-term central venous access.
Abbreviations: ESBL, extended-spectrum ß-lactamase; GNR, gram-negative rod; GPC, gram-positive cocci (staphylococci and streptococci); HIV, human immunodeficiency virus; MRSA,
methicillin-resistant Staphylococcus aureus.
a
Recommendations are based upon theoretical considerations and results of available clinical trials.
b
Refers to isolates from an infected foot ulcer, not just colonisation at another site.
c
Given at the usual recommended doses for serious infections. Where more than one agent is listed, only one of them should be prescribed unless otherwise indicated. Consider modifying
doses or agents selected for patients with comorbidities such as azotaemia, liver dysfunction, and obesity.
d
Oral antibiotic agents should generally not be used for severe infections, except as a follow-on (switch) after initial parenteral therapy.
limited treatment-related harms.140–142 In case of mild infec- As the pathogenic versus colonising role of some bacteria
tions, the most likely causative organisms are gram-positive identified in a wound sample, such as Corynebacterium sp. or
pathogens (beta-haemolytic streptococci and S. aureus).11 coagulase-negative staphylococci, is debatable, the quality of
For these mild infections, there is also time to adjust the anti- the sample is sent to the laboratory is of utmost importance.
biotic therapy if cultures reveal resistant organisms or those The goal is to avoid the presence of colonisers in the sample,
that are not gram-positive cocci. If the infection does not re- thereby limiting the risk of unjustifiably prescribing broad-
solve, therapy should be adjusted to target the bacteria cul- spectrum antibiotic agents. Clinicians should consider consult-
tured from the submitted specimens. Proposals for the ing infectious diseases/microbiology expert about antibiotic
empirical antibiotic therapy of moderate or severe DFIs are therapy for difficult cases, such as those caused by unusual or
presented in Table 4. Pseudomonas species are less commonly highly resistant pathogens.
isolated in studies from North America and Europe, but are No antibiotic class or agent has been found to be superior to
more prevalent in studies from (sub)tropical climates.136 In others for treating DFIs except in two studies, one of which found
light of the complexity and often polymicrobial nature of tigecycline to be significantly worse than ertapenem,138 and an-
DFI, definitive treatment should especially be based on other that found ertapenem to have a slightly lower clinical
principles of antibiotic stewardship: infection source control cure rate than piperacillin-tazobactam139 Two recent retrospec-
with surgery if possible; preferably starting with empiric tive studies,140,141 and one systematic review of RCTs,142 all con-
antibiotic treatment, when appropriate, with the narrowest firmed our previous recommendations regarding the absence of
spectrum, shortest duration, fewest adverse effects, safest evidence to recommend any specific antibiotic choice regarding
and least expensive route; and, switching to targeted (prefer- its efficacy and the final cure of infection. In a country with a
ably oral) antibiotic therapy with agents based on the cultured high prevalence of multi-resistant pathogens, the use of carbape-
pathogens.137 nems was identified as an independent predictor of need for

major amputation, and use of vancomycin was an independent than any other regarding the resolution and recurrence of
predictor of reinfection or death in one study.143 But, as these an- infection?
tibiotics are often used in more severe or non-responsive cases, it
is difficult to draw clear conclusions.143 Recommendation 16. Consider a duration of up to 3 weeks of an-
Given the paucity of data on the resolution of infection, re- tibiotic therapy after minor amputation for diabetes-related os-
currence of infection, and the acquisition of antimicrobial re- teomyelitis of the foot and positive bone margin culture and 6
sistance, our recommendation is to choose any of the weeks for diabetes-related foot osteomyelitis without bone re-

systemic antibiotic regimens that have shown to be effective section or amputation. (Conditional; Low).
in published randomised controlled trials to treat a patient
with diabetes and a soft tissue infection of the foot. Antibiotic Rationale. When prescribing antibiotic therapy for DFO, the
dosing for skin and soft tissue infection is usually standard, clinician must consider several issues, in particular achieving
but therapy for DFO may require higher doses than standard a high enough serum level to ensure penetration to the bone.
doses. We refer treating clinicians to their national guidelines It is particularly important to consider the bioavailability of
for dosing advice. We suggest considering beta-lactam antibi- oral agents (i.e., absorption from the gastrointestinal tract
otics (penicillins – with or without beta-lactamase inhibitors, into the bloodstream) if that route of therapy is selected.
cephalosporins, carbapenems), metronidazole (in combination Penetration of antibiotic agents from the blood into the bone
with other antibiotic[s]), clindamycin, linezolid, tetracyclines, is variable but most classes can attain adequate levels in infected
trimethoprim-sulfamethoxazole, daptomycin, fluoroquino- bone.146 We suggest administering antibiotic agents at their up-
lones, or vancomycin, but not tigecycline. Data about new per recommended dosage range, and usually for a total dura-
combinations of beta-lactams plus beta-lactamase inhibitors, tion of treatment (see Table 5) substantially longer than for
new lipoglycopeptides such as dalbavancin or oritavancin are soft-tissue infection. Prescribing long-term suppressive antibi-
insufficient to make any recommendation on their use in otic therapy is generally warranted only for individuals with re-
DFIs. The recommendation on how to treat patients with tained orthopaedic hardware or extensive necrotic bone that is
DFIs with these new antibiotics is conditional, based on mod- not amenable to complete debridement.
erate evidence. Two randomised controlled studies suggest that the total du-
Our systematic review did not find any new studies that jus- ration of antibiotic therapy for DFO treated non-surgically
tify modifying our previous recommendations about the dura- does not need to be more than 6 weeks.147,148 There are only
tion of the antibiotic therapy for soft-tissue DFIs, except for preliminary data available that address the possibility to reduce
post-surgical debridement of moderate or severe DFIs, for this duration to less than 6 weeks, but this is currently under
which a 10-day duration was found sufficient in a recent pilot study. The duration of antibiotic therapy required for patients
prospective study.144 Clinicians frequently monitor serum with DFO who undergo surgical debridement is likely to be
CRP levels during therapy for DFIs, but evidence supporting shorter than that for patients treated non-surgically. In addi-
this is of low quality and based on only one study145 tion, it is unclear whether the level of amputation should play
Compared to our 2019 guideline, in which we advised a dura- a role in deciding antibiotic duration. For instance, a patient
tion of 1–2 weeks for any soft-tissue DFIs, we make a condi- who undergoes toe amputation without successful clinical
tional recommendation for a 10-day duration of the cure can undergo another minor amputation, while a patient
antibiotic therapy following a surgical debridement for moder- who undergoes total transmetatarsal amputation that fails to
ate or severe soft tissue DFIs, with low certainty of evidence respond may need a below-knee amputation. In a prospective,
based on only one study with high risk of bias. For the other sit- randomized, non-inferiority, pilot trial, patients with DFO who
uations, we only made a best practice recommendation because underwent surgical debridement and received either a 3- or
of the lack of data from clinical studies on these questions. The 6-week course of antibiotic therapy had similar outcomes and
specific aspects of the microbiology of DFIs and the potential antibiotic-related adverse events.149 As treatment with oral
severity of these infections are key elements that guided our antibiotic regimens for residual osteomyelitis are associated
recommendations. Our recommendations are in line with the with failure rates similar to those with intravenous regimens,
general rules of the use of antimicrobial agents regarding the this may help reduce the length of hospital stay in those pa-
choice of the molecules, their way of administration and tients.150 The recommendation about the duration and admin-
duration.137 istration of post-surgical antibiotic therapy is conditional with
a low certainty of evidence, based on a few studies with high
5.2.2 Clinical question risk of bias.
In a person with diabetes and a bone or joint infection of the
foot, is any particular antibiotic regimen (specific agent[s], Recommendation 17. Use the outcome at a minimum follow-up
route of administration, total and parenteral duration) better duration of 6 months after the end of the antibiotic therapy to
Table 5. Duration of antibiotic therapy according to the clinical situation.
Route Duration
Infection severity (skin and soft tissues)

Class 2: Mild Oral 1–2 weeksa
Class 3/4: Moderate/severe Oral/initially iv 2–4 weeks
Bone/joint
Resected Oral/initially iv 2–5 days

Debrided (soft tissue infection) Oral/initially iv 1–2 weeks
Positive culture or histology of bone margins after bone resection Oral/initially iv 3 weeks
No surgery or dead bone Oral/initially iv 6 weeks
Abbreviation: iv, intravenous.
a
10 days following surgical debridement.
diagnose remission of diabetes-related osteomyelitis of the foot. which non-surgical (antibiotic only) treatment is as safe and ef-
Best Practice Statement. fective in achieving remission as surgical treatment (combined
with antibiotic therapy)?
Rationale. It may be difficult to know when DFO has been suc-
cessfully treated. For a chronic infection that resolves slowly, Recommendation 18. The urgent surgical consultation should be
and frequently recurs if not adequately treated, we initially pre- obtained in cases of severe infection or moderate DFI compli-
fer using the term remission to cure. This is defined as the ab- cated by extensive gangrene, necrotising infection, signs sug-
sence of any persistent or new episode of DFO at the initial or gesting deep (below the fascia) abscess, compartment
contiguous site, but the delay for which a remission should be syndrome, or severe lower limb ischaemia. Best Practice
assessed is uncertain. Recommendation.
In patients with DFO, there are often few clinical signs and
symptoms to follow, although the resolution of any overlying Recommendation 19. Consider performing early (within 24–
soft tissue infection is reassuring. A decrease in previously ele- 48 h) surgery combined with antibiotics for moderate and se-
vated serum inflammatory markers suggests improving infec- vere DFIs to remove the infected and necrotic tissue.
tion. Plain X-rays showing no further bone destruction and (Conditional; Low).
better yet signs of bone healing also suggest improvement.
Some of the newer advanced imaging studies, for example, Recommendation 20. In people with diabetes, PAD and a foot ul-
WBC-labelled SPECT/CT and FDG PET/CT, may be more sen- cer or gangrene with infection involving any portion of the foot
sitive in assessing the resolution of infection. Long-term (typi- obtain an urgent consultation by a surgical specialist as well as a
cally at least a year) follow-up is classically recommended vascular specialist in order to determine the indications and
before declaring the infection cured. Of note, if the underlying timings of drainage and/or revascularisation procedure. Best
conditions that predisposed the patient to the index episode of Practice Statement.
DFO are not adequately addressed (e.g., pressure off-loading,
surgery to correct foot deformity), another infection at the Rationale. Retrospective studies comparing early surgery (var-
same site may be a new recurrence rather than a relapse. We iously defined, but usually within 72 h of presentation) versus
think that using an overly long post-treatment period to define delayed surgery (3–6 days after admission) in hospitalised pa-
remission may result in calling a new episode of DFO associat- tients with a severe, deep DFI, with or without osteomyelitis
ed with a new DFU, thus overestimating the risk of relapse in have reported lower rates of major lower extremity amputation
these cases. Therefore, we suggest using a minimum follow-up and higher rates of wound healing.151–153 Similarly, patients
duration of 6 months after the end of the antibiotic therapy to with moderate or severe DFIs who had a delayed admission
define the remission of a DFO. In addition, life-long frequent at specialised foot centres were more likely to require major
foot examinations in this population are warranted since amputation.154 We think that surgical therapy should always
most patients with a history of DFI are at high risk of future be at least considered in cases of severe DFI, and in other cases
foot complications.20 for which non-surgical treatment is likely to fail. For such an
evaluation, consultation by a surgical specialist is essential;
5.2.3 Clinical question therefore, we formulated a Best Practice Statement. Severe
In a person with diabetes and moderate or severe infection of DFIs include those described in the background section of
the foot, including osteomyelitis, are there circumstances in the present paper. Current guidelines on PAD associated

with diabetes-related foot highlight that the combination of in- One small study suggests that patients with a concomitant
fection plus PAD portents a poor clinical outcome if both are acute soft-tissue infection and osteomyelitis of the foot not re-
not treated adequately.7 Therefore, in case of infection, the pa- quiring urgent surgical debridement can be treated using a two-
tient should be assessed for the presence and severity of PAD. step approach consisting firstly of antibiotic therapy for the
As clinical assessment is often unreliable, it is important to also soft-tissue infection, and secondly, after a free-antibiotic peri-
perform non-invasive tests, for example, Doppler waveform od, bone culture-guided antibiotics for treatment of DFO.164
analysis combined with ankle pressure measurement, as well Overall, there is inconsistency in results of studies that com-
as toe pressure measurements.7 Based on the assessment of

pared surgical versus medical approaches for DFO between
the wound and the amount of tissue loss, the results of non- the RCT and the cohort studies, and a high risk of bias (in
invasive tests, and the IWGDF/IDSA infection severity score, the cohort studies). The results seem, however, to have no seri-
all patients should be classified according to the WIfI classifica- ous imprecision. Compared to the previous guideline, in which
tion scheme,9 which helps to further determine the need for a strong recommendations were made regarding the indications
vascular intervention as described in the IWGDF PAD for predominantly medical versus surgical approaches for
guidelines.7 DFO, we classified the strength of the recommendation as con-
ditional due to the low certainty of the evidence of the available
Recommendation 21. Consider performing surgical resection of data.
infected bone combined with systemic antibiotics in a person
with diabetes-related osteomyelitis of the foot. (Conditional; 5.2.4 Clinical question
Low). In a person with diabetes and a foot infection, does the addition
of any specific adjunctive or topical antibiotic treatment to sys-
Recommendation 22. Consider antibiotic treatment without sur- temic antibiotic therapy and surgery improve the outcome of
gery in case of (i) forefoot osteomyelitis without an immediate infection?
need for incision and drainage to control infection, (ii) without
PAD, and (iii) without exposed bone. (Conditional; Low). Recommendation 23. We suggest not using the following treat-
ments to address DFIs: (a) adjunctive G-CSF treatment or (b)
Rationale. Surgical resection of infected bone has long been the topical antiseptics, silver preparations, honey, bacteriophage
standard treatment of osteomyelitis, but over the past 2 de- therapy, or negative-pressure wound therapy (with or without
cades, evidence from several retrospective case series,155–157 instillation). Conditional; Low.
retrospective cohort studies,158–160 and one prospective con-
trolled study161 have demonstrated that in properly selected pa- Rationale. According to systematic reviews,49,114 adding
tients mostly with forefoot DFO, antibiotic therapy alone is as G-CSF to a diabetes-related foot treatment does not signifi-
effective as surgery regarding the remission of DFO and need cantly affect the likelihood of resolution of infection, healing
for amputation. This suggestion is largely based on studies of the wound, or the duration of systemic antibiotic therapy.
that have generally not stratified patients with DFO based on It does seem to be associated with a reduced likelihood of lower
the presence or severity of any concomitant soft tissue infec- extremity surgical interventions (including amputation) and a
tion.162 The studies that have addressed this issue have gener- reduced duration of hospital stay, although the profile of pa-
ally found that patients with DFO who had concomitant soft tients who might benefit is unclear, especially in relation to
tissue infection (and perhaps those with PAD) required more the costs and potential adverse effects.
urgent and extensive surgery, had longer lengths of stay, and Various types of topical antiseptics have been used to treat
had worse outcomes.163 DFUs, but the available evidence does not support any benefi-
The subjects in most studies, specifically in the RCT, were ex- cial effect for most of them.165 Silver has been shown to have an
cluded if they obviously needed surgery (e.g., exposed bone, antibacterial effect, and topical silver-containing treatments
compartment syndrome, undrained abscess) and did not (creams, dressings, etc.) are widely used for IDFUs. Silver com-
have PAD. If perfusion is severely compromised, revascularisa- pounds do not offer benefits in ulcer healing (as described in
tion should always be performed (either before or after any soft the IWGDF wound healing guidelines8) and there is no evi-
tissue/bone resection). In a subsequently well-perfused foot, dence to support their effectiveness in the treatment of the in-
the treatment of the DFI should not be different. The dilemma fectious aspects of a DFU. Topical administration of other
will be how to treat a patient with DFO with limited soft tissue agents only seems to have a marginal effect on the outcomes
infection, seemingly mild ischaemia, and no indication for of these infections in low-quality studies.49
drainage. Given the unreliability of any vascular assessment,
there is a clear risk that the perfusion deficit may be underesti- Recommendation 24. We suggest not using topical (sponge,
mated, and any operation could result in a non-healing wound. cream, and cement) antibiotics in combination with systemic
antibiotics for treating either soft-tissue infections or osteomy- recommendation against the use of HBO therapy for DFIs is
elitis of the foot in patients with diabetes. (Conditional; Low). conditional given the absence of compelling data on its efficacy,
based on low certainty of evidence.
Rationale. Treatment with topical antimicrobial therapy has
many theoretical advantages, particularly requiring only a Areas with absent or inconsistent evidence. Bioactive glass com-
small dose directly at the site of infection, thus potentially lim- pounds have been used topically as an adjunctive treatment
iting issues of cost, adverse events, and antibiotic resistance. in surgical cases of DFO, but the insufficient data available pre-

The potential advantage of topical versus systemic antibiotic vent us from providing a recommendation on this therapeutic
therapy is to deliver very high concentrations of antibiotics at approach.176,177 Current treatment guidelines do not endorse
the site of infection that could not be achieved using the sys- any specific antibiotic agent for diabetes-related osteomyelitis
temic route of administration. Another potential advantage is of the foot, but our systematic review identified two retrospec-
to limit potential collateral damage to gut microflora, including tive studies that suggest the addition of rifampicin to combina-
the emergence of multiresistant bacteria and Clostridioides tion antimicrobial regimen results in improved cure rates for
difficile-associated diarrhoea. osteomyelitis.118,178 The certainty of the evidence is low, based
Studies that have addressed the potential benefit of topical on the inconsistency of outcomes. The potential of drug-related
administration of antibiotics as adjunctive treatment to system- adverse events and the risk of drug-drug interactions, especially
ic antibiotic therapy for soft-tissue DFIs have provided conflict- in aged patients usually treated with other medications, justify
ing results.165–171 Limited data from studies with high-risk of obtaining valid data on its potential benefit before considering
bias suggest a potential benefit of antibiotic-loaded cement its routine use.
and intraoperative site vancomycin powder application in pa-
tients with DFO treated by surgical debridement.172–175
Overall, these studies, characterised by a potentially high risk 6 KEY CONTROVERSIES
of bias, inconsistency, imprecision and low certainty, do not Some areas concerning the management of DFIs still need fur-
demonstrate a significant clinical benefit of topical antibiotics ther development. The following questions are those we found
in the treatment of either diabetes-related foot soft tissue or of most interest:
bone infections. There is also insufficient evidence on whether
adjunctive agents meaningfully affect clinical outcome and the • How and when to determine whether an infection, including
safety of routinely using local antibiotics has not yet been clear- soft-tissue and osteomyelitis, has resolved?
ly established. Therefore, we elected to suggest against the use • What are the most useful serum biomarkers to help deter-
of topical antibiotics. Future studies should apply learnings mine whether a DFU is infected and if underlying osteomy-
from prior studies to ensure statistically robust and clinically elitis is present, especially when clinical and imaging
useful RCTs. assessments are inconclusive?
• To what extent can the currently recommended durations of
Recommendation 25. We suggest not using HBO therapy or top- antibiotic therapy be reduced for soft-tissue and
ical oxygen therapy as an adjunctive treatment for the sole in- osteomyelitis?
dication of treating a DFI. (Conditional; Low). • When, and which, available advanced imaging studies should
clinicians order in a patient with a DFI?
Rationale. Hyperbaric oxygen therapy is often used in an at- • Does using information from a BeBoP, including at the am-
tempt to improve DFU healing, but there are few data on its po- putation site, improve outcomes of DFO?
tential role in controlling infection. The results of one RCT • What is the place of various new antibiotics in the manage-
suggested that the use of HBO treatment led to fewer positive ment of DFIs?
wound cultures after treatment, but the study’s high risk of • Is there a definition for, and practical clinical use of, the con-
bias (small study size, poor quality, non-standardised methods, cept of chronic biofilm infection of a DFU?
and non-standardized definitions used) and indirectness of the • Does molecular (genotypic) microbiological testing for DFI
evidence do not offer support for the use of systemic HBO in help guide antimicrobial therapy and improve outcomes?
DFI.49 We found no studies on using topical HBO for infection • What is the potential of the topical administration of antimi-
upon which to base a recommendation. Equity and feasibility crobials to limit the use of systemic antibiotics in DFIs?
are limited due to high costs and low availability of HBO ther-
apy. In the absence of any substantial data to support its effect
Notes
in treating either soft tissue or bone infection or in accelerating
Author Contributions. É. S., E. J. G. P., S. A. van A., and Z. A.
ulcer healing via an antimicrobial effect, we think the costs and participated in the writing of the document, and all the working group
inconvenience outweigh any theoretical benefits. The members participated in the literature search, the evaluation of the content

and quality of the papers selected for the analysis, and the review of the final 5. Ndosi M, Wright-Hughes A, Brown S, et al. Prognosis of the infected diabetic
document. foot ulcer: a 12-month prospective observational study. Diabet Med. 2018;
Acknowledgments. The authors thank the external reviewers: Benjamin 35(1):78–88. https://doi.org/10.1111/dme.13537
A. Lipsky, Bulent Ertugrul, Mohamed El Makki, Jamil Halabi, José Luis 6. Tan TW, Shih CD, Concha-Moore KC, et al. Disparities in outcomes of patients
admitted with diabetic foot infections. PLoS One. 2019; 14(2):e0211481. https://
Lázaro Martínez, Arun Murari, Marcos Coutinho Schechter, Albert
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Sotto, Carlo Tascini, and Oleg Udovichenko for invaluable assistance in ed-
7. Fitridge R, Chuter V, Mills J, et al. The intersocietal IWGDF, ESVS, SVS guide-
iting the document. They also thank Nicolaas Schaper (on behalf of the lines on peripheral artery disease in people with diabetes mellitus and a foot ul-
IWGDF Editorial Board) for his peer review of the manuscript. cer. Diab Metab Res Rev 2023:e3686. https://doi.org/10.1002/dmrr.3686
Financial support. This research did not receive any specific grant from 8. Chen P, Campillo Vilorio N, Dhatariya K, et al. Guidelines on interventions to
funding agencies in the public, commercial, or not-for-profit sectors.

enhance healing of foot ulcers in people with diabetes (IWGDF 2023 update).
Peer review. The peer review history for this article is available at https:// Diab Metab Res Rev 2023:e3644. https://doi.org/10.1002/dmrr.3644
www.webofscience.com/api/gateway/wos/peer-review/10.1002/dmrr.3687. 9. Monteiro-Soares M, Hamilton EJ, Russell DA, et al. Guidelines on the classifica-
Data availability. Data sharing is not applicable to this article as no new tion of foot ulcers in people with diabetes (IWGDF 2023 update). Diab Metab
data were created or analyzed in this study. Res Rev 2023:e3648. https://doi.org/10.1002/dmrr.3648
Ethics statement. Ethics approval was not required for this study. 10. Lipsky BA, Berendt AR, Deery HG, et al. Diagnosis and treatment of diabetic
Disclaimer. The guideline working group is committed to developing foot infections. Clin Infect Dis. 2004; 39(7):885–910. https://doi.org/10.1086/
424846
trustworthy clinical practice guidelines through transparency and full dis-
11. Lipsky BA, Berendt AR, Cornia PB, et al. Infectious Diseases Society of America
closure by those participating in the process of guideline development. In
clinical practice guideline for the diagnosis and treatment of diabetic foot infec-
order to prevent a major Conflict of Interest (COI), members of the guide- tions. Clin Infect Dis. 2012; 54(12):e132–e173. https://doi.org/10.1093/cid/
line group were not allowed to serve as an officer, board member, trustee, cis346
owner, or employee of a company directly or indirectly involved in the 12. Peters EJ, Lipsky BA, Aragon-Sanchez J, et al. Interventions in the management
topic of this guideline. Before the first and last meeting of the guideline of infection in the foot in diabetes: a systematic review. Diab Metab Res Rev.
working group, members were asked to report any COI in writing. In ad- 2016; 32(Suppl 1):145–153. https://doi.org/10.1002/dmrr.2706
dition, at the beginning of each meeting, this question was also asked and if 13. Lipsky BA, Senneville É, Abbas ZG, et al. Guidelines on the diagnosis and treat-
answered yes, the members were asked to submit a COI form. These ment of foot infection in persons with diabetes (IWGDF 2019 update). Diab
COIs included income received from biomedical companies, device man- Metab Res Rev 2020; 36(Suppl 1):e3280. https://doi.org/10.1002/dmrr.3280.
ufacturers, pharmaceutical companies, or other companies producing PMID: 32176444.[
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foot. Med Clin North Am. 2013; 97(5):911–946. https://doi.org/10.1016/j.
disclosed each time and these included ownerships of stocks/options or
mcna.2013.04.005
bonds of a company, any consultancy, scientific advisory committee mem-
15. Lavery LA, Armstrong DG, Wunderlich RP, Mohler MJ, Wendel CS, Lipsky BA.
bership, or lecturer for a company, research grants, and income from pat- Risk factors for foot infections in individuals with diabetes. Diabetes Care. 2006;
ents. These incomes could either be personal or obtained by an institution 29(6):1288–1293. https://doi.org/10.2337/dc05-2425
with which the member had a relationship. All disclosures were reviewed 16. Hao D, Hu C, Zhang T, Feng G, Chai J, Li T. Contribution of infection and pe-
by the chair and secretary of the working groups and can be found at ripheral artery disease to severity of diabetic foot ulcers in Chinese patients. Int J
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pany was involved in the development or review of the guidelines. Nobody 17. Peters EJ, Lavery LA, Armstrong DG. Diabetic lower extremity infection: influ-
involved in the guideline development received any payment or remuner- ence of physical, psychological, and social factors. J Diab Complications. 2005;
ation of any costs, except for travel and accommodation expenses when 19(2):107–112. https://doi.org/10.1016/j.jdiacomp.2004.06.002
meeting on-site. 18. Prompers L, Schaper N, Apelqvist J, et al. Prediction of outcome in individuals
Working group members were additionally requested to declare COI with diabetic foot ulcers: focus on the differences between individuals with and
without peripheral arterial disease. The EURODIALE study. Diabetologia. 2008;
and refrain from the risk of bias scoring process or voting process for par-
51(5):747–755. https://doi.org/10.1007/s00125-008-0940-0
ticular interventions if they had a professional working relationship with
19. Chu Y, Wang C, Zhang J, et al. Can we stop antibiotic therapy when signs and
any of the co-authors on a particular paper. symptoms have resolved in diabetic foot infection patients? Int J Low Extrem
Production of the 2023 IWGDF Guidelines was supported by unrestrict- Wounds. 2015; 14(3):277–283. https://doi.org/10.1177/1534734615596891
ed grants from Advanced Oxygen Therapy Inc., Essity, Mölnlycke, 20. Lavery LA, Peters EJ, Armstrong DG, Wendel CS, Murdoch DP, Lipsky BA. Risk
Reapplix, and Urgo Medical. These sponsors did not have any communi- factors for developing osteomyelitis in patients with diabetic foot wounds.
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Clinical Infectious Diseases

IWGDF/IDSA Guidelines on the Diagnosis and Treatment

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2 • CID • Senneville et al.

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4 • CID • Senneville et al.

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6 • CID • Senneville et al.

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A. Findings suggesting a more serious diabetes-related foot infection

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8 • CID • Senneville et al.

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10 • CID • Senneville et al.

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12 • CID • Senneville et al.

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Infection severity Additional factors Usual pathogen(s)b Potential empirical regimensc

Mild No complicating features GPC Semisynthetic penicillinase-resistant penicillin (cloxacillin)

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14 • CID • Senneville et al.

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Infection severity (skin and soft tissues)

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16 • CID • Senneville et al.

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18 • CID • Senneville et al.

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20 • CID • Senneville et al.

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22 • CID • Senneville et al.

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