the surgeon xxx (xxxx) xxx

An evidence based narrative review on treatment

of diabetic foot osteomyelitis

Rocco Aicale a,b,*, Lucio Cipollaro a,b, Silvano Esposito c,

Nicola Maffulli a,b,d,e
a
Department of Musculoskeletal Disorders, Faculty of Medicine and Surgery, University of Salerno, 84084 Baronissi,
Italy
b
Clinica Ortopedica, Ospedale San Giovanni di Dio e Ruggi D'Aragona, 84131, Salerno, Italy
c
Department of Infectious Diseases, School of Medicine and Surgery, University of Salerno, Salerno, Italy
d
Queen Mary University of London, Barts and the London School of Medicine and Dentistry, Centre for Sports and
Exercise Medicine, Mile End Hospital, 275 Bancroft Road, London, E1 4DG, UK
e
Keele University, School of Medicine, Institute of Science and Technology in Medicine, Guy Hilton Research Centre,
Thornburrow Drive, Hartshill, Stoke-on-Trent, ST4 7QB, UK

article info abstract

Article history: Objective: The diagnosis of diabetic food infection is usually clinical, and its severity is
Received 24 March 2019 related to location and depth of the lesion, and the presence of necrosis or gangrene.
Received in revised form Osteomyelitis of the foot and ankle can be extremely debilitating, and, in the preantibiotic
18 December 2019 era acute staphylococcal osteomyelitis carried a mortality rate of 50%. The microbiology of
Accepted 14 January 2020 diabetic foot osteomyelitis (DFO) is usually polymicrobial. Indeed, gram-negative and
Available online xxx gram-positive bacilli can be identified using molecular techniques applied to bone biopsies
compared to conventional techniques. The aim of the present study is to report a complete
Keywords: overview regarding medical and surgical management of diabetic foot osteomyelitis (DFO)
DFO in combination or alone.
Diabetes Materials and methods: We performed a search in PubMed and Scopus electronic databases
Diabetic foot (up to January 2019) of articles assessing the epidemiology, diagnostic strategy and phar-
Infection macological treatment of diabetic foot infection. In the search strategy, we used various
combinations of the following key terms: infection, orthopaedic, diabetic foot, manage-
ment, DFO.
Results: This article discusses the definition, epidemiology, microbiological assessment,
clinical evaluation, pharmacological and surgical management and a comparison between
them, of DFO. After the initial literature search and removal of duplicate records, a total of
756 potentially relevant citations were identified. After a further screening and according to
the inclusion criteria, a total of 65 articles were included in the present review.
Conclusion: The association of antibiotic and surgical therapy seems to be more effective
compared to each one alone. The lack of comparison studies and randomized controlled
trials makes it difficult to give information about the efficacy of the different management
therapies.
© 2020 Royal College of Surgeons of Edinburgh (Scottish charity number SC005317) and
Royal College of Surgeons in Ireland. Published by Elsevier Ltd. All rights reserved.

* Corresponding author. Department of Musculoskeletal Disorders, Faculty of Medicine and Surgery, University of Salerno, 84084
Baronissi. Italy.
E-mail addresses: aicale17@gmail.com (R. Aicale), l.cipollaro87@gmail.com (L. Cipollaro), s.esposito@unisa.it (S. Esposito), n.maffulli@
qmul.ac.uk (N. Maffulli).
https://doi.org/10.1016/j.surge.2020.01.007
1479-666X/© 2020 Royal College of Surgeons of Edinburgh (Scottish charity number SC005317) and Royal College of Surgeons in Ireland.
Published by Elsevier Ltd. All rights reserved.

Please cite this article as: Aicale R et al., An evidence based narrative review on treatment of diabetic foot osteomyelitis, The Surgeon,
https://doi.org/10.1016/j.surge.2020.01.007
2 the surgeon xxx (xxxx) xxx

DFO supported by the most recent evidence in the available

Introduction scientific literature, thus permitting to identify inappropriate
management requiring to be addressed through educational
In 1980, the Word Health Organization (WHO) defined diabetes strategies.”
mellitus (DM) as “a chronic hyperglycemia state supported by
genetic and exogenus factors which often act together”. DM is
a metabolic disorder with different etiology characterized by
chronic hyperglycemia associated with glucidic, lipidic and
Materials & methods
protein metabolism alterations, secondary to a variation of
We performed a search in PubMed and Scopus electronic da-
normal insulin secretion and its function.1,2
tabases (up to 2019 and without date limits) of articles
The American Diabetes Association (ADA) classification is
assessing the epidemiology, diagnostic strategy and pharma-
based on DM etiopathogenesis and the other types of hyper-
cological treatment of diabetic foot infection. In the search
glycemia,3 identifying:
strategy, we used various combinations of the following key
terms: infection, orthopaedic, diabetic foot, management,

DM type 1, characterized by destruction of beta-cells in
diabetes, osteomyelitis, DFO, Diabetic foot osteomyelitis,
pancreatic insulae, insulin-deficiency and a tendency to
management, surgical treatment. We considered for inclusion
ketoacidosis;
in the present study only articles that investigated the various

DM type 2, typically associated with obesity. It is a het-
options for treatment of DFO (medical and surgical) in com-
erogenic group of disorders characterized by variable-
bination or alone, with no limit of year of publication nor
grades of insulin-resistance, alteration in insulin secre-
language. Case reports, editorials, technical notes, replies,
tion, and higher hepatic production of glucose;
letters and narrative review articles and book chapters were

Other types of DM (Maturity onset diabetes of young
excluded independently from their level of evidence. Two
(MODY), mitochondrial genes alterations, leprechaunism).
orthopedic residents (RA and LC) performed the search and
evaluated the articles independently. A researcher experi-
In the long term, DM induces progressive development of
enced (NM) in systematic reviews solved cases of doubt. Each
complications such as retinopathy, nephropathy which can
investigator read the abstracts of all the articles, selected the
evolve into renal insufficiency, neuropathy with the risk of
relevant ones according to the inclusion and exclusion criteria
foot ulcers, amputations, and autonomic dysfunctions. DM
previously determined, and then compared the results with
patients have an increased risk of cardiovascular and cere-
the other examiner. The articles were evaluated regarding
brovascular conditions, and peripherical vasculopathy4,5
definition, epidemiology, microbiological assessment, clinical
Diabetic Foot has been defined by the International
evaluation, pharmacological and surgical management of
Working Group on the Diabetic Foot (IWGDF) as an infectious
DFO (Fig. 1).
condition, and deep tissues ulceration and destruction asso-
After the initial literature search and removal of duplicate
ciated with neurological abnormalities and lower limb pe-
records, a total of 756 potentially relevant citations were
ripheral vasculopathy.6e9
identified. After a further screening and according to the in-
The most common diabetic foot problems are plantar
clusion criteria, a total of 65 articles were included in the
infected ulcers from overloading skin or lesions.10,11 There are
present review.
no standard criteria to define such infection.12 Indeed, the
One reviewer extracted the data from the full-text articles
classic infection features such as pain, swelling and purulence
to a Microsoft Excel software spreadsheet in a structured table
can be all present, but none of these are pathognomonic.
to analyse studies in a descriptive fashion. The second
These alterations can be caused by peripheral neuropathy
researcher independently double checked the extraction of
which makes ischemia asymptomatic, and may produce an
primary data from all the articles. Doubts and inconsistencies
alteration in inflammatory response, making the diagnosis
were followed and solved by discussion.
very hard.13 Many risk factors, including immunological al-
terations, are implicated in the development of infection, but
neuropathy plays a central role.14e17 Epidemiology
The aim of this review is to report a complete overview
regarding medical and surgical management of diabetic foot The Centers for Disease Control and Prevention (CDC) and the
osteomyelitis (DFO) in combination or alone. Furthermore National Center for Health Statistics report that DM is increas-
epidemiology, clinical elements, diagnosis and treatment are ingly common.18 Currently, life expectancy has increased
described. through advances in the management of the condition, and 15%
The present study is a comprehensive overview regarding of diabetic patients will have a foot ulcer during their lifetime
DFO and the different strategies to approach and manage this with danger of amputation.6 The incidence of diabetic foot in-
condition; the true limitation was probably the absence of the fections is 36.5 per 1000 persons per year.19e21 85% of all ampu-
use of a specific protocol to conduct the search (ie. PRISMA tation begins with an ulcer, and 84% of amputation are
protocol). However, the quality of the search was sured by the performed as a result of an infected or unhealed ulcer.22,23
use of two different database and by the possibility to follow Osteomyelitis of the foot and ankle can be extremely
every passage of the research by the description. This article debilitating. In the preantibiotic era, acute staphylococcal
gives a picture of the different management strategies to treat osteomyelitis carried a mortality rate of 50%.24 Underlying

Please cite this article as: Aicale R et al., An evidence based narrative review on treatment of diabetic foot osteomyelitis, The Surgeon,
https://doi.org/10.1016/j.surge.2020.01.007
 the surgeon xxx (xxxx) xxx
Fig. 1 e Flow diagram of literature review.
osteomyelitis is present in 20%e68% of diabetic foot ul-
cers.25,26 The presence of osteomyelitis in diabetic foot in-
fections carries an amputation rate of up to 66%,26,27with in-
hospital mortality associated with osteomyelitis of 1.6%.28
The economic burden of osteomyelitis is severe, with a me-
dian length of stay of 7 hospital days, mean hospital expense
of US dollars 19,000, and direct costs of amputation associated
with osteomyelitis exceeding US dollars 34,000.20,28,29
Diabetic foot osteomyelitis (DFO)
The diagnosis of infection is usually clinical, and microbio-
logical characterization allows identification of the bacteria
involved and deriving the correct antibiotic treatment. The
severity of infection is related to the location, depth (fascia,
muscles, tendons, joints or bone) of the lesion and the pres-
ence of necrosis or gangrene.30,31
Gram positive bacteria such as Staphylococcus aureus are the
most frequently involved in diabetic foot infections (DFI). With
the increase of antibiotics resistance in diabetic patients,
multiple drug resistant organisms (MDRO) are becoming very
common in DFI. Hospitalization, surgical procedures and long
antibiotic therapy (AT) induce the development of methicillin-
resistant Staphylococcus aureus (MRSA) and/or other MDRO.32e34
Osteomyelitis is a common consequence of diabetic foot
ulcers (DFUs) infection, appearing in the 10%e15% of moder-
ate and in the 50% of severe infections.10 Often DFUs
Please cite this article as: Aicale R et al., An evidence based narrative review on treatment of diabetic foot osteomyelitis, The Surgeon,
https://doi.org/10.1016/j.surge.2020.01.007
3
complicated by osteomyelitis require surgical treatment and
prolonged antibiotic treatment.35e37 DFO is usually conse-
quent to non-healing ulcers, and it is associated with a high
risk of major amputation.38,39 Furthermore, DFO is the
consequence of a soft tissue infection that spreads into the
bone, involving the cortex first and then the bone marrow.
The best management of these potentially devastating
conditions depends on a multidisciplinary approach, which
can reduce the number of major amputations, decrease the
probability of ulceration, prevent infection, maintain skin
integrity and improve function36,40
Possible bone involvement should be suspected in all DFUs
patients with clinical findings of infection, in chronic wounds
and in cases of ulcer recurrence.30 Any bone can be affected by
osteomyelitis, but this is more frequent in the forefoot (90%),
followed by the midfoot (5%) and the hindfoot (5%). Forefoot
osteomyelitis has a better prognosis than midfoot and hind-
foot osteomyelitis, and the risk of ankle amputation is
significantly higher for hindfoot (50%), than midfoot (18.5%)
and forefoot (0.33%) osteomyelitis.41e43 An early and accurate
diagnosis is required to ensure effective treatment, and
reduce the risk of minor and major amputation.44,45
DFO is usually polymicrobial,46 and in most instances S.
aureus is the commonest pathogen cultured from bone sam-
ples.47,48 In warm climate countries, Gram-negative bacilli
(especially Pseudomonas aeruginosa and Escherichia coli) are
more common than S. aureus.49 Other gram-positive cocci
frequently isolated are S. epidermidis and other coagulase-
4 the surgeon xxx (xxxx) xxx
negative staphylococci, beta-hemolytic streptococci, and
diphtheroids. Enterobacteriaceae, E. coli, K. pneumoniae, and
Proteus spp. are the most common pathogens followed by P.
aeruginosa. Obligate anaerobes (e.g. Finegoldia magna, Clos-
tridium spp., or Bacteroides spp.) can be found depending on
the method of sampling and transportation of the bone frag-
ments, and they are generally less frequently cultured.50 A
recent prospective study has indicated that more anaerobes
and gram-positive bacilli can be identified using molecular
techniques (16S rRNA sequencing) applied to bone biopsies
compared to conventional techniques (86.9% vs. 23.1%,
p ¼ 0.001 and 78.3% vs. 3.8%, p < 0.001, respectively).51
Diagnosis
Clinical assessment
The diagnosis of DFO should be based on clinical signs of
infection at first, then supported by laboratory, microbiolog-
ical and imaging evaluation. However, the diagnosis of DFO
remains a challenge because it is not easily recognized in its
initial phases. Infected wounds usually show purulent secre-
tions or at least two signs of inflammation (swelling, ery-
thema, blood serum secretion or simply blood with or without
bone fragments).52 However, DFO can occur without any local
sign of inflammation. Systemic symptoms such as fever are
rare, especially in chronic osteomyelitis but, fortunately,
many clinical findings can help clinicians in detecting bone
infection. There are two specific clinical signs predictive of
osteomyelitis. The first is the width and depth of the foot
ulcer. Ulcers larger than 2 cm2 have a sensitivity of 56% and a
specificity of 92% for DFO, and a depth greater than 3 mm is
more frequently associated with an underlying osteomye-
litis.41 The second diagnostic criterion is the “probe-to-bone
test” (PTB), which is performed probing the ulcer area with a
sterile blunt probe. The test is positive when the probe reaches
the bone surface. In a study involving 75 diabetic patients, PTB
showed a sensitivity of 66%, a specificity of 85% and a positive
predictive value of 89%.53 The same test, evaluated in a pro-
spective study, and compared with the culture of infected
bones, showed a sensitivity of 87%, a specificity of 91%, a
positive predictive value of only 57% and a negative predictive
value of 98%.54 A positive PTB test is highly suggestive of
osteomyelitis, but a negative test does not exclude it. Instead,
in the presence of an ulcer without clinical signs of infection, a
positive test may be not specific for osteomyelitis, while a
negative PBT test should exclude a bone infection.55 The
combination of the PTB test with plain radiography improves
the sensitivity and specificity in the diagnosis of DFO.56
Serum inflammatory markers such as white blood cells
(WBC), C-reactive protein, erythrocyte sedimentation rate
(ESR) and procalcitonin (PCT) are usually higher in DFO than in
soft-tissue infections. However, while WBC and procalcitonin
may be negative, the ESR >60 mm/h and/or CRP >3.2 mg/dL in
the presence of an ulcer deeper than 3 mm are significantly
predictive of DFO.20 Furthermore, by three weeks after the
treatment of both soft tissue and bone infection, WBC, CRP
and PCT values return to their normal range, while ESR usu-
ally remains high only in osteomyelitis.57
Please cite this article as: Aicale R et al., An evidence based narrative review on treatment of diabetic foot osteomyelitis, The Surgeon,
https://doi.org/10.1016/j.surge.2020.01.007
Microbiological assessment
Bacteria are responsible for the majority of DFO episodes, and
the role of other agents such as fungi or dermatophytes is
marginal.10 Bacteria involved in DFO originate from the skin
surface, and the composition of the bacterial flora present in
the superficial tissues is different from that of deeper ones,
especially in bones, although the distribution of the bacterial
groups is likely similar.58 The concordance between cultures
from a soft tissue swab and cultures from bone is generally
low, well below 50%.42,59,60 Cultures of bone specimens pro-
vide more accurate microbiological data than do those of soft
tissue specimens in patients with DFO.48,51
Commonly, three techniques are used to obtain a wound
culture: swabs, tissue biopsy or needle aspiration. However,
wound cultures are not recommended for clinically unin-
fected wounds, and repeated cultures are not necessary, un-
less patient do not respond to antibiotic therapy. Cultures
obtained from cotton swabs are commonly used in the clinical
setting, but they do not always reflect the true microbiology
present in the deeper tissues.9 There may be a mixture of
pathogens, contaminants and colonizing organisms. Biopsy of
deep tissues, obtained with curettage of the base of a diabetic
ulcer, usually reveals the true pathogens. Last, needle aspi-
ration of purulent secretions obtains microbes below the
surface of the wound; yet, it is invasive and may be painful.61
The gold standard for the diagnosis of osteomyelitis is bone
biopsy, which provides histological and microbiological find-
ings.10,62 A bone biopsy provides reliable data on the organ-
isms responsible for the infection and allows to determine
their profile of susceptibility to antimicrobial agents.63 How-
ever, only one retrospective multicenter study reported that
bone culture-guided antibiotic treatment was associated with
a significantly better clinical outcome than treatment guided
by soft tissue culture results.64 Histological criteria for diag-
nosis include bone erosion, marrow edema, fibrosis, necrosis,
presence of inflammatory cells (both acute and chronic).30
In cases of bone infection, superficial swabs show a low
sensitivity: in only 38% of case there is a reliable correspon-
dence between bacteria isolated from bone biopsy and swab
culture.58 The pathogens isolated from culture of deep tissues
are very similar to those obtained from bone biopsies (74.3% vs
82.8%).65
Transcutaneous bone biopsy is not routine practice in most
diabetic foot centres66 because it is usually thought that this
procedure can introduce bacteria in bone or fracture the bio-
psied bone, although these complications have not been re-
ported.47,48,53 Bone biopsies can be performed preferably after
an antibiotic-free period of at least two weeks because of the
prolonged release of some antibiotics from bones, provided the
infection is not severe and the patient does not need urgent
antibiotic therapy.67 Performing bone biopsy under fluoro-
scopic control is likely to prevent errors in the biopsied site.47
Radiography assessment
Radiographic examinations are usually required to detect
bone involvement in case of suspected osteomyelitis without
clinical signs of infection or to confirm the clinical suspicion
and distinguish DFO from soft tissue infection. Radiography is
 the surgeon xxx (xxxx) xxx
the first tool used to detect infection during the initial phase.
Clear signs related to DFO are not evident until 30%e50% of
the bone has been involved, usually after 2e3 weeks. Imaging
is characterized by bone sequestration, erosion of cortical
bone, osteopenia, cortical lysis, osteolysis, periosteal thick-
ening.26,27 Common radiographic criteria of bone healing
include well organised consolidation of periosteum, reduction
of bone lucency with neoformation of mineralized bone in
destroyed areas and reduction of pathological fractures.68
Scintigraphic examinations are more sensitive than simple
radiographies to discriminate between soft tissues and bone
infection, in particular during the first stage of bone
infection.69
Leucocyte scans are more specific than triple-phase bone
scans, even though their spatial resolution can be a limiting
factor: also, labelled leukocyte imaging is more useful than
bone scans for diagnosis and follow-up during medical treat-
ment.70 Combined 99mTc white blood cell-labeled single-
photon emission computed tomography and computed to-
mography (99mTc WBC labelled-SPECT/CT) imaging provide
good spatial resolution with the three-dimensional CT scan
images, and WBC uptake intensity yielding more information
about the location and extension of the infection.71,72 Indeed,
99mTc WBC labelled-SPECT/CT has been used to identify the
complete resolution of infection at follow-up of patients
treated with antibiotics.73 Positron emission tomography-
computed tomography (PET/CT) with fluorine-18-
fluorodeoxyglucose (18F-FDG) can be used to distinguish soft
tissues from bone infections, because 18F-FDG uptake in-
creases in the infection and inflammation areas.74,75
Magnetic resonance imaging (MRI) with gadolinium shows
a high sensitivity (90%) and specificity (85%): the gadolinium
uptake to allows differentiation between soft tissues and bone
better than CT and scintigraphic methods.76 The typical
changes, evident after only 3 days from the onset of infection
in the bone marrow and predictive for osteomyelitis, are high
signal intensity on T2-weighted sequences and low signal
intensity on T1-weighted sequences. The major limit is the
lower resolution in the evaluation of cortical bone, which does
not allow to diagnose osteitis or to distinguish other causes of
bone injury.77,78
The guidelines suggest that the combination of different
diagnostic tests such as PTB, serum inflammatory markers,
radiography, MRI or radionuclide scanning are the best
approach to diagnose DFO. Radiography should be always the
first imaging evaluation, MRI is the first choice when more
specific imaging is required, while white blood cell-labelled
radionuclide scan, SPECT/CT and 18F-FDG PET/CT are used
only if MRI is contraindicated.10,62
Bone biopsy
The gold standard for the diagnosis of osteomyelitis is bone
biopsy, which provides suitable histological and microbio-
logical findings.10,62 Some histological features, such as bone
erosion, marrow edema, fibrosis, necrosis and presence of
inflammatory cells (both acute and chronic), help in the
diagnosis. Furthermore, bone biopsy allows to identify pre-
cisely the bacteria involved in the infectious process and to
evaluate the susceptibility to antibiotic therapy.
Please cite this article as: Aicale R et al., An evidence based narrative review on treatment of diabetic foot osteomyelitis, The Surgeon,
https://doi.org/10.1016/j.surge.2020.01.007
5
Bone can be removed by a percutaneous approach
through uninfected skin or during open surgical procedures.
In case of bone infection, superficial swabs show low sensi-
tivity. Indeed, the correspondence between bacteria isolated
from bone biopsy and swab culture is approximately only
38%.58 Therefore, superficial swabs should not be used in
case of DFO. Bone biopsy is the most accurate test (preferably
after 10e14 days of antibiotic suspension), even though in
many patients this may not be technically feasible. However,
the pathogens isolated from the culture of deep tissues are
very similar to those obtained from bone biopsy (74.3% vs
82.8%).65
Management of DFO
Medical management
The main advantage to treating DFO medically is the absence
of the biomechanical changes that may occur after surgical
procedures, and a better costeeffectiveness profile. Prolonged
antibiotic therapy, chosen on the basis of non-bone tissues
(swabs or deeper samples), has been classically used with
apparent good results.79e81 However, these studies were
retrospective and did not include a sufficiently long post-
treatment follow-up (i.e. at least one year) to detect late re-
lapsing episodes of DFO.
In a recent retrospective study of 50 consecutive patients
with DFO managed with antibiotic therapy alone, remission
was reported in 32 (64%) patients.64 The medical approach is
limited by prolonged administration of antibiotics, which fa-
vors drug-related side-effects (including Clostridium difficile
diarrhea and the emergence of antibiotic resistant organisms),
the risk of relapsing infections (from the uncertainty of ster-
ilization of bone tissue) and the persistence of bone deformity
at the origin of the foot ulcer. Indeed, the absence of protective
sensation and dry from to peripheral autonomic neuropathy
predispose to skin break, which may result from excessive
pressure in case of a deformed foot. Surgery is effective in
reducing rapidly the bacterial load in the infected site,
removing necrotic tissues that cannot be reached by antibi-
otics, and may also correct bone deformity that can be at the
origin of foot ulcer.28,82 Furthermore, failure of medical
treatment of DFO could lead to a more proximal level of
amputation when compared to early surgery.28
The current available data provided evidence-based rec-
ommendations on the management of patients with DFO. In
particular, we tried to ascertain which antibiotics regimens
produce better results, their routes of administration, and the
duration of therapy.60 Given the chronic nature of osteomye-
litis and the prolonged duration of the treatment, preference
should be given to antibiotics that exhibit high diffusion into
bone (i.e. a bone/blood ratio >0.3) and have good oral
bioavailability (i.e. >90%). Interestingly, antibiotics which
achieve the highest bone to serum concentration ratios (i.e.
fluoroquinolones, sulfamides, cyclines, macrolides, rifam-
picin, fusidic acid, and oxazolidinones) are also those with the
highest oral bioavailability, making these agents good candi-
dates for prolonged treatment of outpatients with osteomye-
litis83 (Table 1).
6 the surgeon xxx (xxxx) xxx
Table 1 e Doses and potential adverse events of antibiotics with oral bioavailability and bone diffusion for the treatment of
DFO (data from 83,102).
Antibiotic: oral administration Bone/Blood
concentration Bioavailability (%)
ratio (%)
Fluoroquinolones 65e80

Ciprofloxacin 500 mg every 12 h >90

Levofloxacin 500 mg every 12/24 h
Clindamycin 600 mgevry 6/8 h >90
Rifampicin 600/900 mg every 24 h >90
Cotrimoxazole (TMP-SMX) 70e90
(800/160 mg every 8/12 h
Linezolid 600 mg every 12 h >90
Tetracyclines >90

doxycycline, 100 mg every 12 h

minocycline, 100 mg every 12/24 h
Combinations of two agents with high oral availability and
bone diffusion have been shown to arrest DFO. Rifampicin,
fluoroquinolone (ofloxacin, ciprofloxacin, levofloxacin or
moxifloxacin) and beta-lactam fluoroquinolones combina-
tions seem appropriate for the treatment of, respectively,
staphylococcal and Gram-negative DFO.84,85 The antibiotic
combination should be continued until completion of the
treatment for staphylococcal DFO because the risk of emer-
gence of resistant mutants is particularly high with these
bacteria.86
Given the limitations in the diffusion into infected bones
and diminished susceptibility of bacteria involved in chronic
osteomyelitis, antibiotics should be administered at high daily
doses. This may nevertheless be limited by the risk of adverse
events, especially for antibiotics with potential renal or liver
toxicity in patients who are likely to have comorbidities and
receive multiple treatments. Traditionally, antibiotic therapy
in chronic osteomyelitis should be administered parenterally
and for prolonged periods.87 These requirements are justified
for an antibiotic therapy with betalactam, but are question-
able for those antibiotics which exhibit almost complete oral
bioavailability and can achieve high bone concentrations such
as fluoroquinolones, rifampicin, cycline agents, clindamycin,
linezolid, fusidic acid, and trimethoprim-sulfamethoxazole.83
When the patient's condition has improved, the switch to oral
therapy can be implemented early with these antibiotics.
There is no statistically significant difference between oral
versus parenteral antibiotics for the treatment of osteomye-
litis if the bacteria are sensitive to the antibiotic used.83,88
After surgery, or for other reasons, some patients with DFO
may receive anticoagulation, and, if prolonged parenteral
outpatient antibiotic treatment is required, this is adminis-
tered through a central venous catheter or an implantable
port: but this may expose up to 21% of patients to catheter-
related complications such as pneumothorax, haematoma,
bacteraemia, thrombosis or migrations of the tip of the cath-
eter89 (Table 1).
The emergence of community-associated MRSA and
glycopeptide tolerance of S. aureus underlines the importance
of the newer anti-MRSA agents, particularly in the manage-
ment of complicated skin and soft tissue infections such as
DFO. A novel type of antibiotic is the cyclic lipopeptide group
Please cite this article as: Aicale R et al., An evidence based narrative review on treatment of diabetic foot osteomyelitis, The Surgeon,
https://doi.org/10.1016/j.surge.2020.01.007
Oral Main adverse effects
55 Tendinopathy, renal, cardiac and neurological toxicity
>50
40e67 Diarrhea, including CDAD
40e90 Nausea, vomiting, liver toxicity
50 Allergy, bone marrow and renal toxicity
>70 Bone marrow toxicity, peripheral neuropathy, serotonin
syndrome, lactic acidosis
>70 Esophageal and gastroduodenal toxicity, skin intolerance,
vertigo and DRESS (minocycline
such as daptomycin, which shows marked in vitro activity
against MRSA compared with both vancomycin and line-
zolid.90,91 Daptomycin binds to the bacterial cell membrane
and effects rapid depolarization of membrane potential
resulting in inhibition of protein, DNA and RNA synthesis.90
An important point which makes this drug attractive is the
need of only once daily dose, lack of need for monitoring of
concentrations in serum, and its favourable toxicity
profile.90,92
Surgical management
Surgery has been long considered the gold standard in the
treatment of DFO to complement the action of the antibiotics
and/or to replace them.50 Many factors, such as micro and
macrovascular complications, the chronic nature of bone
infection that affects preferentially the cortical part of the
bone, and the stationary growth-phase concur to decrease the
efficacy of antibiotics in these settings.50 Surgery is rapidly
effective in reducing the bacterial load at the infected site and
to remove necrotic tissues, and it may also be
prophylactic.43,59
Debridement of the infected tissue is the most common
surgical intervention,93 and is aimed at removing the necrotic
tissue (sequestrum), which is the pathological substratum of
the chronic infection. Furthermore, reconstruction of the lost
bone segment or stabilization of the contiguous bone frag-
ments must be carried out.94 A recent study95 evaluated sur-
gery after previously failed antibiotic therapy (not described in
the study), with debridement and adipose tissue filling of the
bone defect in 8 patients with osteomyelitis of the toe pha-
langes. At a postoperative mean follow-up of 41 months, no
relapse of osteomyelitis was detected neither clinically nor at
MRI, with a success rate for this procedure of 100%.
Simpson et al.96 compared three different surgical tech-
niques (wide resection with >5 mm margin, 15 cases; marginal
resection with <5 mm margin, 29 cases; intralesional biopsy
with debulking of infected area, 6 cases) combined with
standard antibiotic therapy (6 weeks intravenous plus 6 weeks
oral). Success rate was higher and wide resection surgery
(100%) compared with marginal resection (72%) and biopsy
(0%). The widely used Papineau technique has been used
 the surgeon xxx (xxxx) xxx
successfully97 in 41 patients, and reoperation was required in
only 5 patients for infection relapse during the postoperative
period, despite the empiric antibiotic therapy. Only one pa-
tient developed a further ostemyelitis focus after wound
healing.
The effectiveness of surgery in reducing the recurrence of
osteomyelitis has been evaluated in a single prospective
study,42 which enrolled 74 evaluable patients treated with
conservative surgery (CS) (59.3%), minor amputations (39.5%),
and major amputation (1.2%) and a postoperative antibiotic
treatment for a mean of 36 days. Because of persistent infec-
tion in 24.7% of patients, reoperation was required. After a
mean follow-up of 101.8 weeks, wound healing was achieved
in a median of 8 weeks among the 65 patients evaluable for
follow-up after healing. Recurrence and new episodes of
osteomyelitis were recorded in respectively 4.6%, and 16.9% of
the patients, while reulcerations were seen in up to 43% of the
patients.42
Medical versus surgical approach
CS associated with antibiotics increases the healing rate of
DFO compared with medical treatment alone98; the healing
rate was 57% in the group treated by antibiotics treatment
alone versus 78% in the surgical group (p < 0.008), and the
duration of healing was respectively 462 ± 98 days versus
181 ± 30 days (p < 0.008).
Patients who underwent debridement or local limited
amputation experienced a lower rate of above-ankle ampu-
tation than patients treated with antibiotic therapy alone, and
a shorter hospital stay.99 In a retrospective study100 of 147
patients with DFO, 113 patients treated with antibiotic therapy
alone underwent a limb amputation (major in 6 patients and
minor in 28 patients). Remission rates were similar in both
surgical and medical groups (78.6% and 83.3%, respectively).
Recently, a prospective study compared the outcomes of
patients treated with oral antibiotics alone versus patients
who underwent CS.101 After a follow-up period of 12 weeks, 18
patients (75%) achieved primary healing in the antibiotics
group versus 19 (86.3%) in the surgical group (p ¼ 0.33).101 No
difference was found between the two groups regarding time
to healing (7 versus 6 weeks) and minor amputations
(p ¼ 0.336). The authors concluded that antibiotics and sur-
gical treatment have similar outcomes in terms of healing
rates, time to healing, and short-term complications in pa-
tients with neuropathic forefoot ulcers complicated by
osteomyelitis.101
Conclusions
The present article provides a general and updated overlook
on diabetic foot osteomyelitis, especially regarding definition,
diagnosis and treatment. The association of antibiotic and
surgery therapy seems to be more effective than each one
alone, but the lack of comparative studies and randomized
controlled trials makes it difficult to give proper information
about the relative efficacy of the different management mo-
dalities. The heterogeneity of the design of the studies does
not allow direct comparison of the reported results.
Please cite this article as: Aicale R et al., An evidence based narrative review on treatment of diabetic foot osteomyelitis, The Surgeon,
https://doi.org/10.1016/j.surge.2020.01.007
7
Sources of financial support
This research did not receive any specific grant from funding
agencies in the public, commercial, or not-for-profit sectors.
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