|

Received: 20 May 2017    Accepted: 19 August 2017

DOI: 10.1111/ijcp.13006

CONSENSUS

Diabetic foot infection: Antibiotic therapy and good practice

recommendations

Nicholas D. Barwell1  | Marion C. Devers2 | Brian Kennon3 | Helen E. Hopkinson3 | 

Claire McDougall4 | Matthew J. Young5 | Hannah M. A. Robertson6 | Duncan Stang4 | 
Stephanie J. Dancer4 | Andrew Seaton3 | Graham P. Leese7 | on behalf of the Scottish
Diabetes Foot Action Group

1
Forth Valley Royal Hospital, Larbert, UK
2
Monklands Hospital, Airdrie, UK
3 Background: Healthcare events related to diabetic foot disease carry a burden of morbid-
Queen Elizabeth University Hospital,
Glasgow, UK
4
Hairmyres Hospital, East Kilbride, UK
5
Edinburgh Royal Infirmary, Edinburgh, UK
6
Aberdeen Royal Infirmary, Aberdeen, UK
7
Ninewells Hospital, Dundee, UK
Correspondence
Nicholas D. Barwell, Consultant Physician,
Department of Diabetes and Endocrinology,
Forth Valley Royal Hospital, Larbert, UK.
Email: nicholas.barwell@nhs.net
Abstract
ity, mortality and economic cost. Prompt identification of clinical infection with appropri-
ate tissue sampling limits use of broad spectrum empirical antibiotics and improves
antibiotic stewardship. Staphylococcus aureus remains the commonest infecting organism
and high-­dose flucloxacillin remains the empirical antibiotic of choice for antibiotic naïve
patients. Barriers to microbe-­specific treatment include: adequate tissue sampling, delays
in culture results, drug allergies and the emergence of multidrug-­resistant organisms
which can complicate the choice of targeted antibiotics. Even appropriate antibiotic treat-
ment carries a risk of adverse events including the selection of resistant organisms.
Aims: Multidisciplinary clinical assessment of a diabetic foot infection is supported by
the use of appropriate imaging modalities and deep tissue sampling, both of which are
encouraged to enhance sampling accuracy. Narrow-­spectrum, high dose, short dura-
tion antimicrobial therapy is ideal. Further clarity in these areas would be of benefit to
clinicians involved in management of diabetic foot infections.
Methods: A combination of literature review with expert discussion was used to gen-
erate consensus on management of diabetic foot infection, with a specific focus on
empirical antimicrobial therapy.
Results: Gram positive organisms represent the commonest pathogens in diabetic foot
infection. However there are developing challenges in antimicrobial resistance and
antibiotic availability.
Discussion: Recommendations for empirical therapy, including the choice of alterna-
tive oral agents and use of outpatient antibiotics would be of benefit to those involved
in diabetic foot care.
Conclusion: This paper provides advice on empirical antibiotic therapy that may be
used as a framework for local guideline development to support clinicians in the man-
agement of diabetic foot infection.

This update on antimicrobial recommendations for diabetic foot ulcer treatment is a consensus statement based on clinical trial evidence, review of international guidelines and expert opinion.
In the context of individual treatment decisions, local microbiology results and advice should be paramount in informing responsible clinicians. However, the spectrum of infecting pathogens
causing foot infection is consistent and supports the consideration of empirical antibiotic advice. These recommendations are suggested to support clinicians and in conjunction with regional
pathogen variations and antibiotic susceptibilities, provide a basis for local guideline development.

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1 |  INTRODUCTION
Foot ulceration and infection continue to represent an important
1,2
source of morbidity in people with diabetes mellitus. In an acute pre-
sentation with diabetic foot infection (DFI), there is frequently a delay
in the identification of the causative organism, which may compel use
of empirical antibiotic(s).3,4 Whilst this allows the prompt initiation of
antimicrobial therapy, it carries a risk of treatment failure, the selection
of resistant organisms and complications related to drug toxicity and
alteration of the host microbiome.5
The lifetime risk of foot complication within the diabetic popu-
lation is considered to be around 25%,6 with a point prevalence of
around 2%7 and the development of a diabetes-­related foot ulcer is
associated with an increased risk of lower extremity amputation and
death.7-10
In addition to these outcomes, diabetic foot ulceration is
associated with hospital admission, prolonged inpatient length of stay
and physical and psychological morbidity.7,8,11
Sharp debridement of ulcers, combined with pressure offloading,
management of infection and the involvement of a multidisciplinary
team to optimise glycaemia, cardiovascular risk, assess potential re-
vascularisation and surgical intervention are considered to be the basis
of ulcer care.12-15 In order to promote wound healing and reduce risk
of amputation, involvement of the multidisciplinary team is recom-
mended early in the natural history of the ulcer. 14-19
2 |  IDENTIFICATION OF DFI
Establishing presence of infection is an important component of
ulcer care. Not all ulcers are infected and given increasing antibiotic
resistance and risk of antibiotic-­related adverse events including di-
arrhoea and Clostridium difficile infection, the goal for antibiotic use
in foot ulceration is to treat an active infective process, aiming to
tailor therapy to the appropriate pathogen(s).20 The presence of mi-
crobes within clinically non-­infected ulcers does not influence rates
of healing.21 In the absence of infection, antibiotic therapy represents
a risk for the selection of drug-­resistant pathogens and therapeutic
21-23
complications.
The identification of an infective process within a diabetic foot
ulcer is predicated on clinical assessment combined with supportive
investigations.23-25 Inflammatory change within the ulcer bed and the
presence of increasing exudate or pus is suggestive of infection.24-26
The validity of these clinical factors has been challenged by a study
which has shown poor correlation between microbial load and the
presence of clinical signs.22 However, the IDSA criteria have been
27,28
validated as a useful tool for grading foot infections. Coexisting
skin and/or soft tissue infection (SSTI) in association with the ulcer
border also suggests an active infective process, usually seen as red,
warm, swollen and inflamed skin.3,24-26 This may be accompanied by
a change in odour from the ulcer or the development of pain (unusual
in a neuropathic foot).22,28 The diagnosis of deep infection such as
osteomyelitis is, despite the development of new imaging modalities,
often made using serial plain radiography.29,30 The ability to probe to
T A B L E   1   IDSA guideline for infection grading, incorporating
infection component of IWGDF PEDIS classification23,25
Severity of Infection Description
1. No infection
2. Mild (Grade 2)
No systemic illness with either:
Two or more features of inflammation:
Swelling/Induration, Erythema, Pain, Warmth, Pus
Or
Cellulitis < 2 cm. Confined to skin/subcutaneous tissue
3. Moderate (Grade 3)
Above with either:
lymphatic streaking, deep tissue infection
(subcutaneous fascia, tendon, bone), abscess
Or
Cellulitis > 2 cm
4. Severe (Grade 4)
Any infection with systemic toxicity (fever, shock, vomiting,
confusion, metabolic instability). Presence of critical
bone in an infected ulcer increases the likelihood that osteomyelitis
is present, but is not pathognomonic of osteomyelitis.14,31 It is, how-
ever, an independent predictor of lower extremity amputation (LEA).28
The combination of both radiography and positive probe-­to-­bone has
high sensitivity for the diagnosis of osteomyelitis.32,33 The removal of
bone fragments during debridement is consistent with osteomyelitis
and these fragments should be sent for culture in a sterile container.34
Clinical findings such as a globally inflamed digit which has lost its
usual contours and skin markings (“sausage” digit) also suggest under-
lying osteomyelitis but may also be observed in fracture or Charcot
neuroarthropathy.35,36 Differentiation of infection vs Charcot neuro-
arthropathy is often clinically challenging, however detailed discussion
of the exploration of these two diagnoses is beyond the scope of this
article.
Further specific assessment of the infective burden associated
with a foot ulcer can be categorised using the Infectious Disease
Society of America (IDSA) grading tool (Table 1). Based on current ev-
idence review, the authors would not suggest any update or addition
to the previous consensus statement from 200923 and would reiterate
the use of high dose, narrow-­spectrum antibiotics for relatively short
duration. In the context of empirical therapy, previous positive mi-
crobiology results should always be considered and cover for specific
pathogens might be indicated in relation to the clinical context (eg,
methicillin-­resistant S. aureus in people in long-­term care).37,38
Assessment of ulcer characteristics including infection can be stan-
dardised using validated classifications schemes such as the University
of Texas rating,39 SINBAD 40
or IWGDF PEDIS.41 The current itera-
tion of the Scottish National Diabetes Database (SCI-­Diabetes) utilises
assessment tools based on the University of Texas system. An ulcer
grading system helps to standardise assessment, indicates prognosis
and forms a useful basis for audit and research.42
BARWELL et al.
F I G U R E   1   Example guidance on use of deep tissue or bone
biopsy by percutaneous route in suspected deep seated foot
infection in patients with diabetes48–50
3 | IMAGING IN THE DIAGNOSIS OF DFI
The sensitivity of plain X-­ray in detecting osteomyelitis has been
recorded at 54%,29 but is much greater with serial plain X-­ray.43
The extent of deep tissue involvement including osteomyelitis may
not be clinically apparent, even with the use of sterile metal probes
and serial plain X-­ray imaging.30 The presence of a non-­healing ulcer
may raise clinical suspicion of deep tissue infection, although this
was not a contributory factor in a recent study of chronic ulcera-
tion.44 Both isotope white cell scans and triple phase bone scans
are highly sensitive in detecting osteomyelitis and deep tissue in-
fection but lack specificity (being unable to distinguish between
inflammatory changes related to Charcot neuroarthropathy), ana-
tomical resolution and may continue to show positive results for
45,46
long periods after clinical resolution. MRI scanning is between
90% and 100% sensitive for osteomyelitis but alone, has a speci-
ficity of <80%. Imaging protocols which combine Single Positron
Emission Computed Tomography (SPECT) and MRI may improve
the sensitivity and specificity of detection of foot infection.47 An
alternative diagnostic combination using SPECT–CT scanning with
67
the radioisotope Ga and aseptic bone puncture results in even
greater specificity (>93%) than hybrid SPECT/MRI.48 Benefits in-
clude direct bone sampling to enhance pathogen detection, with
potential reduction in false positive microbiology because of com-
mensal contamination. In participants with a positive SPECT-­CT
but negative bone puncture, none had evidence of persisting ul-
ceration or clinical suspicion of osteomyelitis at 1-­year follow up.48
This technique represents a potential advance in supporting clinical
decision-­making with respect to the diagnosis of osteomyelitis and
may provide a greater degree of confidence in pathogen detection
67
and treatment. However, SPECT-­CT with Ga imaging is not a
widely available imaging modality (Personal communication Colville
D, 2015) and the bone puncture process is invasive and requires
stringent asepsis and preparation. Histological analysis of bone may
be of benefit in differentiation between Charcot neuroarthropathy
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      3 of 10
and infection. The presence of inflammatory infiltrates, bone loss
and marrow oedema is observed in both conditions, but predomi-
nance of osteoclasts over osteoblasts is more indicative of Charcot
neuroarthropathy.35 Despite these limitations, the authors support
the use of bone biopsy for pathogen detection or to resolve diag-
nostic uncertainty between infection and Charcot neuroarthopathy.
The development of local protocols which consider available imag-
ing and surgical resource is recommended, based on bone sampling
principles outlined in Figure 1.48-50
For forefoot ulcers complicated by osteomyelitis, use of MRI scan-
ning in a small cohort was shown to support clinical decision-­making,
specifically duration of antibiotic therapy and requirement for surgical
intervention.51 Three-­monthly MRI scanning was used to determine if
an osteomyelitic bone signal had changed. Although the relapse rate
(initial healing, followed by recurrence of a lesion) at 31 months was
low (13%) compared with other studies,52 this approach did promote
prolonged antibiotic therapy (median 6 months, range 3-­12). Other
groups have reported resolution of osteomyelitis with much shorter
courses of antibiotics53,54 and we would advise caution with the length
of treatment as described.
4 | DIAGNOSTIC MICROBIOLOGY IN DFI
Wound bioburden in the absence of clinical infection should not result
in the initiation of antimicrobial therapy.21,25 However, it is accepted
that culture results may be limited by culturing/sampling techniques
and previous antibiotic exposure.21,55 The role of polymicrobial infec-
tion and the degree to which microbe-­produced biofilm influences
culture results are controversial. It is likely that adherent biofilm pro-
duced by microbes such as S. aureus contributes to the antimicrobial
resistance of the organism in acute infection.56,57 Biofilm may also
shield other pathogens from detection,58 as the combination of mo-
lecular techniques and deep tissue sampling often reveals a polymi-
crobial presence.59,60
A French group has utilised molecular techniques to determine the
pathogenicity of microbes detected in foot ulcers. Oligonucleotide mi-
croarrays determining the expression of virulence factors from S. au-
reus combined with detection of S. aureus clones considered to be
“actively infecting” show promise in establishing which ulcers contain
a bioburden likely, or unlikely, to cause harm and therefore may help
choose antibiotic therapy.61
Further studies in small cohorts of people with diabetic foot ul-
cers have been performed by the same group.62 These studies not
only identify a much more diverse bacterial flora within the ulcer, but
appear to be able to distinguish actively pathogenic organisms, from
non-­
pathogenic or colonising organisms with pathogenic potential
and have greater sensitivity in detecting pathogenic species in deep
tissue samples. The presence of ‘colonising’ bacteria (with pathogenic
potential) may be a predictor of relapsing foot infection or chronic
persistent ulceration.63,64 The presence of additional-­site methicillin-­
resistant S. aureus carriage (eg, nasal/perineal) may also predispose to
re-­infection.65,66 These issues highlight known limitations in current
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T A B L E   2   Empirical antibiotic guideline for diabetic foot infection

  Mild Moderate Severe Osteomyelitis

Antibiotic naive Flucloxacillin 1q QDS (oral) Flucloxacillin 1 g QDS (oral) Flucloxacillin 2 g QDS (IV) Acute (IDSA/IWGDF-PEDIS Grade 4) Flucloxacillin 2 g QDS
Or 2g QDS (IV) + Clindamycin 600 mg QDS (IV) (IV)
+/− Metronidazole 400 mg TDS +/− Gentamicin (IV) (Max 4 days) or + Clindamycin 600 mg TDS (oral)
(oral) Aztreonam 2 g TDS (IV) +/− Gentamicin (IV) (Max 4 days) or
+/− Metronidazole 400 mg TDS (oral) or Aztreonam 2 g TDS (IV) or Ciprofloxacin 750 mg BD (oral)
500 mg TDS (IV) Non-Acute (IDSA/IWGDF-PEDIS Grade 2-3)
Clindamycin 600 mg TDS (oral)
+ Ciprofloxacin 750 mg BD (oral)
Non-Antibiotic Doxycycline 100 mg BD (oral) Clindamycin 600 mg TDS (oral) Piperacillin-­Tazobactam 4.5 g TDS (IV) Acute
naive Or or 600 mg QDS (IV) + Clindamycin 600 mg QDS (IV) Vancomycin (IV)
Clindamycin 450 mg TDS Or + Clindamycin 600 mg TDS (oral)
(oral) Co-­amoxiclav 625 mg TDS +/− Gentamicin (IV) (Max 4 days) or
(oral) or 1.2 g Aztreonam 2 g TDS (IV) or Ciprofloxacin
TDS (IV) 750 mg BD (oral)
Penicillin allergy   Clindamycin 600 mg TDS (oral) Vancomycin (IV) Non-Acute
or + Clindamycin 600 mg QDS (IV) Clindamycin 600 mg TDS (oral) +
600 mg QDS (IV) +/− Gentamicin (IV) (Max 4 days) or Ciprofloxacin 750 mg BD (oral)
Aztreonam 2 g TDS (IV)
+/− Metronidazole 400 mg TDS (oral) or
500 mg TDS (IV)
Duration/ Notes 7 days 7 days (including IV to oral 7-­10 days (including IV to oral switch) 6-­12 weeks therapy. Usually at least 2 weeks of IV therapy in
switch) 14 days IV therapy if S. aureus bacteraemia acute setting but oral therapy may be suitable in non-­acute
Review need for Gram-­negative cover and setting
rationalise therapy depending on microbiology Review need for Gram-­negative cover and rationalise therapy
depending on microbiology
MRSA known Doxycycline 100 mg BD (oral) Vancomycin (IV) Vancomycin (IV) Acute
carrier or Or Or + Clindamycin 600 mg QDS (IV) Vancomycin (IV)
proven Clindamycin 600 mg TDS Clindamycin 600 mg QDS (IV) Consider additional Gram-­negative and + Rifampicin 450 mg BD (oral) or Sodium fusidate 500 mg
infection (oral) Or anaerobic cover TDS (oral)
Or Co-­trimoxazole 960 mg BD (IV) Consider additional Gram-­negative and anaerobic cover
Co-­trimoxazole 960 mg BD Or if Resistant to above: Non-Acute
(oral) Linezolid 600 mg BD Usually combination therapy depending on sensitivities and
Or if Resistant to above: infection specialist advice
Linezolid 600 mg BD (oral)

(Continues)
BARWELL et al.
BARWELL et al. |
      5 of 10

methods of sampling, culture and organism detection. The combina-

available. Dosing of vancomycin, gentamicin and teicoplanin should be as per local guidance. Be aware of potential drug interactions with rifampicin, doxycycline, ciprofloxacin, metronidazole and linezolid.
This is for guidance only and local practice/ guidance may vary. Infection specialist advice should be sought if any uncertainty. Targeted therapy based on good microbiological sampling is always preferred when
Review need for Gram-­negative cover and rationalise therapy
tion of biofilm,59,67 suboptimal sampling techniques 68
and a more

setting but oral therapy may be suitable in non-­acute setting

+ Clindamycin 600 mg TDS (oral) or Rifampicin 450 mg BD

4-­6 weeks therapy (may require >6 weeks in non-­surgically

diverse ulcer microbiome may contribute to reduced efficacy of anti-

treated). Usually at least 2 weeks of IV therapy in acute

microbial therapy.63,64,67
The use of molecular techniques shows potential to deliver more
rapidly available results along with more comprehensive evaluation of

(oral) or Sodium fusidate 500 mg TDS (oral)

the ulcer microbiome.61,62 However, the availability of advanced mo-
lecular diagnostics is limited in most NHS laboratories. There is also a
paucity of outcome data available to illustrate whether a more com-
plete description of the wound microbiome can direct more effective
Daptomycin 6-­8 mg/kg (IV)

depending on microbiology
antimicrobial therapy and improve outcomes.
Ceftriaxone 2g (IV)

Teicoplanin (IV)

5 | ANTIBIOTIC THERAPY: RISKS,

Osteomyelitis

BENEFITS AND COMPLICATIONS

Or

Or

Antibiotic therapy choice is influenced by efficacy, organism sus-

ceptibility and side effect profile. Any antibiotic may be associated
rationalise therapy depending on microbiology
Not applicable as requires initial hospitalisation

with subsequent C. difficile infection (CDI), especially cephalosporins,

14 days IV therapy if S. aureus bacteraemia
Review need for Gram-­negative cover and

clindamycin, co-­
amoxiclav, quinolones, piperacillin-­
tazobactam and
7-­10 days (including IV to oral switch)

carbapenems. All β-­lactam antibiotics, quinolones and macrolides are

associated with increased selection of methicillin-­resistant S. aureus
(MRSA). In Scotland, MRSA generally does not show greater virulence
than MSSA; however, the efficacy of antimicrobial therapy is reduced.
In addition, carbapenem therapy leads to Candidal overgrowth69
and promotion of resistant coliforms.70,71 Risk of CDI is reportedly
increased in people over 65 years, immunosuppressed, hospital in-
patients,72,73 those on proton pump inhibitor agents and those who
Severe

have previously experienced CDI.74-76 Recent changes in antibiotic

prescribing patterns in Scotland have been associated with changing
Dosing assumes normal renal and hepatic function. Please refer to BNF for dose adjustments.

epidemiology of CDI with significantly fewer cases overall but propor-

Community-­associated MRSA

tionally more observed with community-­onset CDI.72,73,77

Linezolid 600 mg BD (oral)
7 days (including IV to oral
Daptomycin 6 mg/kg (IV)

sensitive to Clindamycin,

In all cases, treatment of an infected diabetic foot lesion should be

Ceftriaxone 2 g OD (IV)

focused to a narrow spectrum of pathogen cover, ideally directed by

culture results.24,25 Empirical antibiotic therapy is the first-­line step for
doxycycline and
Teicoplanin (IV)

Co-­trimoxazole

patients with more severe infection with sepsis or associated skin and
is usually

soft tissue infection (Table 1). Wherever possible, appropriate samples

Moderate

switch)

should always be sent for microbiological analysis before initiation

Or

Or

Or

of antibiotic therapy and this group would encourage use of histor-

ical microbiology results to influence choice of empirical therapy. In
Clindamycin, doxycycline and
7 days Community associated
MRSA is usually sensitive to

poorly healing or recurrent ulcers, the authors suggest that clinicians

may also consider the use of screening cultures (eg, nose, perineum,
throat swabs) to provide greater knowledge of the patient’s own skin/
Co-­trimoxazole

mucosal microbiome. These results have the potential to direct paral-

Not applicable

lel eradication therapies (eg, MRSA) and allow an appreciation of re-­

infection risk.65,66 The decision to utilise antibiotic treatment may be
Mild
T A B L E   2   (Continued)

supported using the algorithm in Figure 3.

The International Working Group on the Diabetic Foot (IWGDF) has
published comprehensive guidance on diabetic foot infections.24 Whilst
Duration/Notes

these guidelines represent the foundation of practice for treatment of

DFI, national and regional variation in pathogens and antimicrobial sus-
OPAT

ceptibility exist in the literature.78,79 The recommendations outlined in

Table 2 reflect consensus on regional/national pathogens, antimicrobial
 
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6 of 10       BARWELL et al.
susceptibility and antibiotic availability (Table 2). For this reason, these
recommendations may be of more practical use to UK-­based clinicians.
The duration of antibiotic therapy remains a contentious subject.
Superficial SSTI can be assessed clinically and 1-­2 weeks of ther-
apy is usually adequate.24,25,80,81 However, deep-­
seated infection
or osteomyelitis may require prolonged antibiotic therapy and fur-
ther assessment may benefit from re-­imaging (eg, MRI).51 Traditional
advice favouring 6-­12 weeks of treatment with antibiotics for non-­
surgically treated osteomyelitis is supported by heterogeneous
25
data from retrospective studies. There is inadequate evidence to
support treatment beyond 6 weeks from randomised controlled tri-
als.80,81 A recent French study suggested that resolution of osteomy-
elitis occurred in around two-­thirds of patients treated for 6 weeks.
In this study, not all patients received intravenous antibiotics and
many received narrow-­spectrum therapy because of the use of bone
sampling and avoidance of empirical therapy where clinically appro-
priate.53 Both the 2012 IDSA and the 2016 IWGDF guidelines con-
sider that a minimum of 4 weeks of antibiotic therapy is required in
the presence of infected or necrotic bone.20,24,25 In the absence of
surgical intervention, 6 weeks of antibiotic therapy is suggested24 al-
though patients who do not undergo any surgical resection may need
24,25
a longer duration.
Retrospective analysis of clinical osteomyelitis treatment in a gen-
eral diabetic foot ulcer population has shown resolution with medical
treatment alone in 66.9% of cases.82 Ulcers were considered healed
with sustained skin closure at 3 months after antibiotic completion
(Personal communication Rajbhandari SM, 2015). Around 50% of these
82
patients required multiple antibiotic courses. A randomised controlled
trial in a single specialist centre achieved similar (75%) healing rates in
patients with forefoot osteomyelitis; these patients received medical
treatment and showed comparable healing rates to those treated with
a primarily surgical approach (86.3%, P = .33). Patients with peripheral
arterial disease, exposed bone and poorly controlled diabetes (HbA1c
−1 83
>10%/85.8 mmol.mol ) were excluded. These are all features com-
mon to “real-­world” diabetes foot clinics. However, there is developing
evidence that many diabetic foot ulcers with osteomyelitis can be man-
aged by conservative, non-­surgical treatment.
Studies are underway to assess whether the strategy of using oral
therapy (usually utilising oral bio-­available agents with appropriate
spectrum of activity and good bone penetration) is non-­inferior to
traditional IV therapy in bone and joint infection (including diabetes-­
84
associated osteomyelitis). A published Cochrane review of a small
number of appropriate studies has suggested equipoise,85 except in
patients with septicaemia.
Attempts to assess the efficacy of specific antibiotic regimens for
diabetic foot ulcers are complicated by the heterogeneous nature of
study design. In many studies, it is unclear the extent to which “usual
care” includes core factors such as sharp debridement and offloading.
In addition, those with osteomyelitis and peripheral arterial disease
are frequently excluded from studies and there is a lack of consistency
with respect to reporting of severity criteria and end-­point data.86,87
The paucity of novel antibiotic therapies is an important factor
in the ongoing clinical decision-­making process. This is particularly
pertinent in the current climate of admission avoidance and outpa-
tient management. The decision to utilise empirical therapy coupled
with potentially suboptimal tissue sampling creates an opportunity
for more prolonged use of broad-­spectrum agents. These cannot
necessarily be adequately rationalised before inducing antibiotic re-
sistance in the infecting pathogen. They may even encourage com-
mensal proliferation which could become problematic in chronic
wound situations.
The diabetic foot ulcer prevalence of MRSA of between 20% and
30% in some countries88 has lead to a return to use of non-­β-­lactam
antimicrobial agents, such as rifampicin, fusidic acid, trimethoprim
and sulphamethoxazole. These agents can prove effective for both
susceptible S. aureus and MRSA in various combinations but would
rapidly encourage antibiotic resistance if used in isolation.89 The ox-
azolidinone agent linezolid is also active against MRSA but as an es-
sentially bacteriostatic agent, may also induce resistance.90 Linezolid
has well documented risks of peripheral and optic neuropathy, lactic
acidosis, bone marrow toxicity (requiring full blood count monitoring),
is subject to potential drug interactions including serotonin syndrome
when co-­prescribed with SSRIs and reduced concentration when co-­
prescribed with rifampicin. Linezolid may also affect insulin sensitivity
to alter risk of hypoglycaemia.91 Despite these limitations, linezolid
can permit outpatient management, thus saving costs and with careful
monitoring may be an appropriate alternative to outpatient parenteral
antibiotic therapy (OPAT).92 The duration of Linezolid therapy for the
majority of patients is usually limited to 2 weeks, although a small pro-
portion may require 4 weeks of treatment.92 The novel cephalosporin
agent ceftaroline fosamil has shown efficacy in intravenous treatment
of Gram-­positive infections, including MRSA, and has been effective
in treatment of diabetic foot infections (DFI).93,94 Ceftaroline may be
considered for use in DFI for inpatients for whom the usual glycopep-
tide therapy has proved unsuccessful or is contraindicated. This agent
may be considered for use in circumstances where either linezolid or
daptomycin would be an alternative option.
In addition to a return to use of older antibiotics for MRSA, use
of other agents with Gram-­positive activity such as the tetracycline
group and co-­trimoxazole, has been included in local guideline devel-
opment. The prevalence of MRSA infections in Scotland has declined
in recent years, partly as a result of both universal and targeted screen-
ing programmes and better antimicrobial stewardship.95-97 Although
there are concerns regarding CDI risk with quinolone antibiotics, cip-
rofloxacin represents a suitable oral option for Gram-­negative cover,
and in combination (eg, rifampicin) for treatment of S. aureus, demon-
strates good tissue penetration in skin and soft tissue as well as bone.
Levofloxacin has similar oral bioavailability and bone penetration
properties to ciprofloxacin and may be considered in some susceptible
Gram-­positive bone infections, usually in combination. Fluoroquinolone
antibiotics should be used cautiously in people with risk factors98 for
QTc prolongation (including the co-­prescription of some antidepres-
sants) and pretreatment and follow-­up ECGs are advisable in these
circumstances.99 Consideration should also be given to the potential
ecological impact of the fluoroquinolone, including the risk of multi-
drug resistance in commensal Gram-­negative organisms,100 methicillin
BARWELL et al.
F I G U R E   2   Key points for treatment of DFI
F I G U R E   3   Stepwise approach to antibiotic choice
resistance in S. aureus101 and host C. difficile.102 Whilst oral antibiotic
combination therapy is frequently recommended to reduce the risk of
resistance development in target organisms, combinations may be lim-
ited by drug-­drug interactions. Particular attention is required when
considering combining rifampicin with tetracyclines, sodium fusidate
or Linezolid because of potential reduction in efficacy.103
Chronic kidney disease is a common comorbidity in people with
diabetes which also increases the risk of foot ulceration.104 Direct
nephrotoxic effects from agents with a narrow therapeutic index such
|
      7 of 10
as gentamicin require close monitoring. In addition, side effects such
as hyperkalaemia occur more frequently in people with reduced renal
function.105 Consideration of renal function is therefore encouraged in
both empirical antibiotic choice and dosing in those with chronic kid-
ney disease and in all patients the authors recommend a maximum of
4 days of empirical gentamicin106 (Table 2). An alternative strategy to
limit nephrotoxicity is to consider synergistic dosing of gentamicin in
combination with other agents. Specialist antimicrobial advice should
be sought in this case.
6 | OUTPATIENT INTRAVENOUS
ANTIBIOTIC THERAPY (OPAT)
Inevitably, a minority of patients with deep-­seated diabetic foot infec-
tions will require prolonged IV therapy because of organism suscepti-
bility or intolerance/failure of an otherwise appropriate oral regimen.
In these circumstances and presuming suitability, OPAT can be con-
sidered. The resultant reduction in inpatient stay is associated with
reduced healthcare-­associated costs and complications as well as im-
proved patient satisfaction.107 A number of antibiotics lend themselves
to ease of administration in the OPAT setting including the once daily
agents ceftriaxone, ertapenem, daptomycin and teicoplanin. Depending
on the OPAT service, IV therapy may be self (or carer) administered or
via specialised infusion devices. UK good practice recommendations
for safe OPAT practice have been published.108 In the context of se-
vere infection (Tables 1 and 2), OPAT should only be considered as a
“step-­down” option once the individual is clinically stable enough for
outpatient management and assuming no appropriate oral therapy.
7 | CONCLUSIONS
Foot ulceration in people with diabetes continues to be challenging
for both those affected and the healthcare professionals who look
after them. Identification and treatment of infection is an important
step in management although despite useful progress in both imag-
ing of deep tissues and detection of pathogens, clinical assessment
using parameters such as “sausage” digits, probe-­to-­bone testing and
IDSA infection grading criteria (Table 1)25,109 remain the most useful
and appropriate guidelines. Key points with respect to treating DFI
are summarised in Figure 2. Whilst narrow spectrum, tailored antibi-
otic therapy is recommended, it is accepted that empirical treatment
is often required, ideally after appropriate tissue sampling (Figure 3).
In the absence of novel antibiotics, the attached guideline should
prove to be a useful tool in supporting clinical decision-­making with
respect to antimicrobial therapy (Table 2). Antibiotic choice should
then be reviewed once culture results become available.
AC KNOW L ED G EM ENTS
The authors would like to thank Drs S Jamdar and B Cooke,
Department of Clinical Microbiology, Forth Valley Royal Hospital and
 |
8 of 10       BARWELL et al.

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How to cite this article: Barwell ND, Devers MC, Kennon B,
et al; on behalf of the Scottish Diabetes Foot Action Group.
Diabetic foot infection: Antibiotic therapy and good practice
recommendations. Int J Clin Pract. 2017;e13006. https://doi.
org/10.1111/ijcp.13006