Professional Documents
Culture Documents
DOI: 10.1111/ijcp.13006
CONSENSUS
1
Forth Valley Royal Hospital, Larbert, UK
2
Abstract
Monklands Hospital, Airdrie, UK
3 Background: Healthcare events related to diabetic foot disease carry a burden of morbid-
Queen Elizabeth University Hospital,
Glasgow, UK ity, mortality and economic cost. Prompt identification of clinical infection with appropri-
4
Hairmyres Hospital, East Kilbride, UK ate tissue sampling limits use of broad spectrum empirical antibiotics and improves
5
Edinburgh Royal Infirmary, Edinburgh, UK antibiotic stewardship. Staphylococcus aureus remains the commonest infecting organism
6
Aberdeen Royal Infirmary, Aberdeen, UK
and high-dose flucloxacillin remains the empirical antibiotic of choice for antibiotic naïve
7
Ninewells Hospital, Dundee, UK
patients. Barriers to microbe-specific treatment include: adequate tissue sampling, delays
Correspondence in culture results, drug allergies and the emergence of multidrug-resistant organisms
Nicholas D. Barwell, Consultant Physician,
Department of Diabetes and Endocrinology,
which can complicate the choice of targeted antibiotics. Even appropriate antibiotic treat-
Forth Valley Royal Hospital, Larbert, UK. ment carries a risk of adverse events including the selection of resistant organisms.
Email: nicholas.barwell@nhs.net
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.
Int J Clin Pract. 2017;e13006. wileyonlinelibrary.com/journal/ijcp © 2017 John Wiley & Sons Ltd | 1 of 10
https://doi.org/10.1111/ijcp.13006
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2 of 10 BARWELL et al.
Foot ulceration and infection continue to represent an important Severity of Infection Description
1,2
source of morbidity in people with diabetes mellitus. In an acute pre- 1. No infection
sentation with diabetic foot infection (DFI), there is frequently a delay 2. Mild (Grade 2)
in the identification of the causative organism, which may compel use No systemic illness with either:
of empirical antibiotic(s).3,4 Whilst this allows the prompt initiation of
Two or more features of inflammation:
antimicrobial therapy, it carries a risk of treatment failure, the selection
Swelling/Induration, Erythema, Pain, Warmth, Pus
of resistant organisms and complications related to drug toxicity and
Or
alteration of the host microbiome.5
Cellulitis < 2 cm. Confined to skin/subcutaneous tissue
The lifetime risk of foot complication within the diabetic popu-
3. Moderate (Grade 3)
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 Above with either:
associated with an increased risk of lower extremity amputation and lymphatic streaking, deep tissue infection
death.7-10
In addition to these outcomes, diabetic foot ulceration is (subcutaneous fascia, tendon, bone), abscess
associated with hospital admission, prolonged inpatient length of stay Or
and physical and psychological morbidity.7,8,11 Cellulitis > 2 cm
Sharp debridement of ulcers, combined with pressure offloading, 4. Severe (Grade 4)
management of infection and the involvement of a multidisciplinary Any infection with systemic toxicity (fever, shock, vomiting,
team to optimise glycaemia, cardiovascular risk, assess potential re- confusion, metabolic instability). Presence of critical
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- bone in an infected ulcer increases the likelihood that osteomyelitis
mended early in the natural history of the ulcer. 14-19 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
2 | IDENTIFICATION OF DFI high sensitivity for the diagnosis of osteomyelitis.32,33 The removal of
bone fragments during debridement is consistent with osteomyelitis
Establishing presence of infection is an important component of and these fragments should be sent for culture in a sterile container.34
ulcer care. Not all ulcers are infected and given increasing antibiotic Clinical findings such as a globally inflamed digit which has lost its
resistance and risk of antibiotic-related adverse events including di- usual contours and skin markings (“sausage” digit) also suggest under-
arrhoea and Clostridium difficile infection, the goal for antibiotic use lying osteomyelitis but may also be observed in fracture or Charcot
in foot ulceration is to treat an active infective process, aiming to neuroarthropathy.35,36 Differentiation of infection vs Charcot neuro-
tailor therapy to the appropriate pathogen(s).20 The presence of mi- arthropathy is often clinically challenging, however detailed discussion
crobes within clinically non-infected ulcers does not influence rates of the exploration of these two diagnoses is beyond the scope of this
of healing.21 In the absence of infection, antibiotic therapy represents article.
a risk for the selection of drug-resistant pathogens and therapeutic Further specific assessment of the infective burden associated
21-23
complications. with a foot ulcer can be categorised using the Infectious Disease
The identification of an infective process within a diabetic foot Society of America (IDSA) grading tool (Table 1). Based on current ev-
ulcer is predicated on clinical assessment combined with supportive idence review, the authors would not suggest any update or addition
investigations.23-25 Inflammatory change within the ulcer bed and the to the previous consensus statement from 200923 and would reiterate
presence of increasing exudate or pus is suggestive of infection.24-26 the use of high dose, narrow-spectrum antibiotics for relatively short
The validity of these clinical factors has been challenged by a study duration. In the context of empirical therapy, previous positive mi-
which has shown poor correlation between microbial load and the crobiology results should always be considered and cover for specific
presence of clinical signs.22 However, the IDSA criteria have been pathogens might be indicated in relation to the clinical context (eg,
27,28
validated as a useful tool for grading foot infections. Coexisting methicillin-resistant S. aureus in people in long-term care).37,38
skin and/or soft tissue infection (SSTI) in association with the ulcer Assessment of ulcer characteristics including infection can be stan-
border also suggests an active infective process, usually seen as red, dardised using validated classifications schemes such as the University
warm, swollen and inflamed skin.3,24-26 This may be accompanied by of Texas rating,39 SINBAD 40
or IWGDF PEDIS.41 The current itera-
a change in odour from the ulcer or the development of pain (unusual tion of the Scottish National Diabetes Database (SCI-Diabetes) utilises
in a neuropathic foot).22,28 The diagnosis of deep infection such as assessment tools based on the University of Texas system. An ulcer
osteomyelitis is, despite the development of new imaging modalities, grading system helps to standardise assessment, indicates prognosis
often made using serial plain radiography.29,30 The ability to probe to and forms a useful basis for audit and research.42
BARWELL et al. |
3 of 10
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. |
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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
depending on microbiology
antimicrobial therapy and improve outcomes.
Ceftriaxone 2g (IV)
Teicoplanin (IV)
Or
clindamycin, co-
amoxiclav, quinolones, piperacillin-
tazobactam and
7-10 days (including IV to oral switch)
sensitive to Clindamycin,
Co-trimoxazole
patients with more severe infection with sepsis or associated skin and
is usually
switch)
Or
Or
susceptibility and antibiotic availability (Table 2). For this reason, these pertinent in the current climate of admission avoidance and outpa-
recommendations may be of more practical use to UK-based clinicians. tient management. The decision to utilise empirical therapy coupled
The duration of antibiotic therapy remains a contentious subject. with potentially suboptimal tissue sampling creates an opportunity
Superficial SSTI can be assessed clinically and 1-2 weeks of ther- for more prolonged use of broad-spectrum agents. These cannot
apy is usually adequate.24,25,80,81 However, deep-
seated infection necessarily be adequately rationalised before inducing antibiotic re-
or osteomyelitis may require prolonged antibiotic therapy and fur- sistance in the infecting pathogen. They may even encourage com-
ther assessment may benefit from re-imaging (eg, MRI).51 Traditional mensal proliferation which could become problematic in chronic
advice favouring 6-12 weeks of treatment with antibiotics for non- wound situations.
surgically treated osteomyelitis is supported by heterogeneous The diabetic foot ulcer prevalence of MRSA of between 20% and
25
data from retrospective studies. There is inadequate evidence to 30% in some countries88 has lead to a return to use of non-β-lactam
support treatment beyond 6 weeks from randomised controlled tri- antimicrobial agents, such as rifampicin, fusidic acid, trimethoprim
als.80,81 A recent French study suggested that resolution of osteomy- and sulphamethoxazole. These agents can prove effective for both
elitis occurred in around two-thirds of patients treated for 6 weeks. susceptible S. aureus and MRSA in various combinations but would
In this study, not all patients received intravenous antibiotics and rapidly encourage antibiotic resistance if used in isolation.89 The ox-
many received narrow-spectrum therapy because of the use of bone azolidinone agent linezolid is also active against MRSA but as an es-
sampling and avoidance of empirical therapy where clinically appro- sentially bacteriostatic agent, may also induce resistance.90 Linezolid
priate.53 Both the 2012 IDSA and the 2016 IWGDF guidelines con- has well documented risks of peripheral and optic neuropathy, lactic
sider that a minimum of 4 weeks of antibiotic therapy is required in acidosis, bone marrow toxicity (requiring full blood count monitoring),
the presence of infected or necrotic bone.20,24,25 In the absence of is subject to potential drug interactions including serotonin syndrome
surgical intervention, 6 weeks of antibiotic therapy is suggested24 al- when co-prescribed with SSRIs and reduced concentration when co-
though patients who do not undergo any surgical resection may need prescribed with rifampicin. Linezolid may also affect insulin sensitivity
24,25
a longer duration. to alter risk of hypoglycaemia.91 Despite these limitations, linezolid
Retrospective analysis of clinical osteomyelitis treatment in a gen- can permit outpatient management, thus saving costs and with careful
eral diabetic foot ulcer population has shown resolution with medical monitoring may be an appropriate alternative to outpatient parenteral
treatment alone in 66.9% of cases.82 Ulcers were considered healed antibiotic therapy (OPAT).92 The duration of Linezolid therapy for the
with sustained skin closure at 3 months after antibiotic completion majority of patients is usually limited to 2 weeks, although a small pro-
(Personal communication Rajbhandari SM, 2015). Around 50% of these portion may require 4 weeks of treatment.92 The novel cephalosporin
82
patients required multiple antibiotic courses. A randomised controlled agent ceftaroline fosamil has shown efficacy in intravenous treatment
trial in a single specialist centre achieved similar (75%) healing rates in of Gram-positive infections, including MRSA, and has been effective
patients with forefoot osteomyelitis; these patients received medical in treatment of diabetic foot infections (DFI).93,94 Ceftaroline may be
treatment and showed comparable healing rates to those treated with considered for use in DFI for inpatients for whom the usual glycopep-
a primarily surgical approach (86.3%, P = .33). Patients with peripheral tide therapy has proved unsuccessful or is contraindicated. This agent
arterial disease, exposed bone and poorly controlled diabetes (HbA1c may be considered for use in circumstances where either linezolid or
−1 83
>10%/85.8 mmol.mol ) were excluded. These are all features com- daptomycin would be an alternative option.
mon to “real-world” diabetes foot clinics. However, there is developing In addition to a return to use of older antibiotics for MRSA, use
evidence that many diabetic foot ulcers with osteomyelitis can be man- of other agents with Gram-positive activity such as the tetracycline
aged by conservative, non-surgical treatment. group and co-trimoxazole, has been included in local guideline devel-
Studies are underway to assess whether the strategy of using oral opment. The prevalence of MRSA infections in Scotland has declined
therapy (usually utilising oral bio-available agents with appropriate in recent years, partly as a result of both universal and targeted screen-
spectrum of activity and good bone penetration) is non-inferior to ing programmes and better antimicrobial stewardship.95-97 Although
traditional IV therapy in bone and joint infection (including diabetes- there are concerns regarding CDI risk with quinolone antibiotics, cip-
84
associated osteomyelitis). A published Cochrane review of a small rofloxacin represents a suitable oral option for Gram-negative cover,
number of appropriate studies has suggested equipoise,85 except in and in combination (eg, rifampicin) for treatment of S. aureus, demon-
patients with septicaemia. strates good tissue penetration in skin and soft tissue as well as bone.
Attempts to assess the efficacy of specific antibiotic regimens for Levofloxacin has similar oral bioavailability and bone penetration
diabetic foot ulcers are complicated by the heterogeneous nature of properties to ciprofloxacin and may be considered in some susceptible
study design. In many studies, it is unclear the extent to which “usual Gram-positive bone infections, usually in combination. Fluoroquinolone
care” includes core factors such as sharp debridement and offloading. antibiotics should be used cautiously in people with risk factors98 for
In addition, those with osteomyelitis and peripheral arterial disease QTc prolongation (including the co-prescription of some antidepres-
are frequently excluded from studies and there is a lack of consistency sants) and pretreatment and follow-up ECGs are advisable in these
with respect to reporting of severity criteria and end-point data.86,87 circumstances.99 Consideration should also be given to the potential
The paucity of novel antibiotic therapies is an important factor ecological impact of the fluoroquinolone, including the risk of multi-
in the ongoing clinical decision-making process. This is particularly drug resistance in commensal Gram-negative organisms,100 methicillin
BARWELL et al. |
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6 | OUTPATIENT INTRAVENOUS
ANTIBIOTIC THERAPY (OPAT)
F I G U R E 2 Key points for treatment of DFI
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
K Hill, Antimicrobial Pharmacist, NHS Tayside and the members of 16. Wang C, Mai L, Yang C, et al. Reducing major lower extremity ampu-
the Scottish Antimicrobial Prescribing Group for reviewing the article. tations after the introduction of a multidisciplinary team in patient
with diabetes foot ulcer. BMC Endocr Disord. 2016;16:38.
17. Trautner C, Haastert B, Mauckner P, Gatcke LM, Giani G. Reduced
AUTHOR CONTRI B UTI O N S incidence of lower-limb amputations in the diabetic population of
a German city, 1990-2005: results of the Leverkusen Amputation
All authors contributed to the planning, writing and editing of the Reduction Study (LARS). Diabetes Care. 2007;30:2633‐2637.
18. Krishnan S, Nash F, Baker N, Fowler D, Rayman G. Reduction in dia-
manuscript.
betic amputations over 11 years in a defined U.K. population: bene-
fits of multidisciplinary team work and continuous prospective audit.
Diabetes Care. 2008;31:99‐101.
D ISCLOSURE
19. Gottrup F, Holstein P, Jorgensen B, Lohmann M, Karlsmar T. A new
None. concept of a multidisciplinary wound healing center and a national
expert function of wound healing. Arch Surg. 2001;136:765‐772.
20. Abbas M, Uckay I, Lipsky BA. In diabetic foot infections antibiotics
O RCI D are to treat infection, not to heal wounds. Expert Opin Pharmacother.
2015;16:821‐832.
Nicholas D. Barwell http://orcid.org/0000-0001-8870-8123 21. Gardner SE, Haleem A, Jao YL, et al. Cultures of diabetic foot ulcers
without clinical signs of infection do not predict outcomes. Diabetes
Care. 2014;37:2693‐2701.
22. Gardner SE, Hillis SL, Frantz RA. Clinical signs of infection in diabetic
REFERENCES
foot ulcers with high microbial load. Biol Res Nurs. 2009;11:119‐128.
23. Leese GP, Nathwani D, Young MJ, et al. Good practice guidance for
1. Skrepnek GH, Mills JL Sr, Armstrong DG. A Diabetic Emergency One
the use of antibiotics in patients with diabetic foot ulcers. Diabetes
Million Feet Long: disparities and Burdens of Illness among Diabetic
Foot J. 2009;12:62‐78.
Foot Ulcer Cases within Emergency Departments in the United
24. Lipsky BA, Aragon-Sanchez J, Diggle M, et al. IWGDF guidance
States, 2006-2010. PLoS ONE. 2015;10:e0134914.
on the diagnosis and management of foot infections in persons
2. Apelqvist J, Larsson J, Agardh CD. Long-term prognosis for diabetic
with diabetes. Diabetes Metab Res Rev. 2016;32(Suppl 1):45‐74.
patients with foot ulcers. J Intern Med. 1993;233:485‐491.
**Detailed review of most recent evidence in management of diabetic
3. Lipsky BA. Empirical therapy for diabetic foot infections: are there
foot infections
clinical clues to guide antibiotic selection? Clin Microbiol Infect.
25. Lipsky BA, Berendt AR, Cornia PB, et al. 2012 Infectious Diseases
2007;13:351‐353.
Society of America clinical practice guideline for the diagno-
4. Richard JL, Sotto A, Lavigne JP. New insights in diabetic foot infec-
sis and treatment of diabetic foot infections. Clin Infect Dis.
tion. World J Diabetes. 2011;2:24‐32.
2012;54:e132‐e173. **Represents current best practice in understand-
5. Selva Olid A, Sola I, Barajas-Nava LA, Gianneo OD, Bonfill Cosp X,
ing when to utilise antimicrobial therapy in diabetic foot infection.
Lipsky BA. Systemic antibiotics for treating diabetic foot infections.
26. Lipsky BA, Berendt AR, Deery HG, et al. Diagnosis and treatment of
Cochrane Database Syst Rev. 2015;(9):Cd009061.
diabetic foot infections. Clin Infect Dis. 2004;39:885‐910.
6. Hartemann-Heurtier A, Senneville E. Diabetic foot osteomyelitis.
27. Lavery LA, Armstrong DG, Murdoch DP, Peters EJ, Lipsky BA.
Diabetes Metab. 2008;34:87‐95.
Validation of the Infectious Diseases Society of America’s diabetic
7. Foot Care for People with Diabetes: The Economic Case for Change
foot infection classification system. Clin Infect Dis. 2007;44:562‐565.
[press release]. UK: NHS Diabetes, 2011.
28. Pickwell K, Siersma V, Kars M, et al. Predictors of lower-extremity
8. Boulton AJ, Vileikyte L, Ragnarson-Tennvall G, Apelqvist J. The global
amputation in patients with an infected diabetic foot ulcer. Diabetes
burden of diabetic foot disease. Lancet. 2005;366:1719‐1724.
Care. 2015;38:852‐857.
9. Young MJ, McCardle JE, Randall LE, Barclay JI. Improved sur-
29. Dinh MT, Abad CL, Safdar N. Diagnostic accuracy of the physical
vival of diabetic foot ulcer patients 1995-2008: possible impact
examination and imaging tests for osteomyelitis underlying diabetic
of aggressive cardiovascular risk management. Diabetes Care.
foot ulcers: meta-analysis. Clin Infect Dis. 2008;47:519‐527.
2008;31:2143‐2147.
30. Peters EJ. Pitfalls in diagnosing diabetic foot infections. Diabetes
10. Kennon B, Leese GP, Cochrane L, et al. Reduced incidence of lower-
Metab Res Rev. 2016;32(Suppl 1):254‐260.
extremity amputations in people with diabetes in Scotland: a nation-
31. Lam K, van Asten SA, Nguyen T, La Fontaine J, Lavery LA. Diagnostic
wide study. Diabetes Care. 2012;35:2588‐2590.
accuracy of probe to bone to detect osteomyelitis in the diabetic
11. Habacher W, Rakovac I, Gorzer E, et al. A model to analyse costs and
foot: a systematic review. Clin Infect Dis. 2016;63:944‐948.
benefit of intensified diabetic foot care in Austria. J Eval Clin Pract.
32. Aragon-Sanchez J, Lipsky BA, Lazaro-Martinez JL. Diagnosing dia-
2007;13:906‐912.
betic foot osteomyelitis: is the combination of probe-to-bone test
12. Apelqvist J, Ragnarson-Tennvall G, Persson U, Larsson J. Diabetic foot
and plain radiography sufficient for high-risk inpatients? Diabet Med.
ulcers in a multidisciplinary setting. An economic analysis of primary
2011;28:191‐194.
healing and healing with amputation. J Intern Med. 1994;235:463‐471.
33. Alvaro-Afonso FJ, Lazaro-Martinez JL, Aragon-Sanchez J, Garcia-
13. Apelqvist J, Larsson J. What is the most effective way to reduce in-
Morales E, Garcia-Alvarez Y, Molines-Barroso RJ. Inter-observer re-
cidence of amputation in the diabetic foot? Diabetes Metab Res Rev.
producibility of diagnosis of diabetic foot osteomyelitis based on a
2000;16(Suppl 1):S75‐S83.
combination of probe-to-bone test and simple radiography. Diabetes
14. Hingorani A, LaMuraglia GM, Henke P, et al. The management of diabetic
Res Clin Pract. 2014;105:e3‐e5.
foot: a clinical practice guideline by the Society for Vascular Surgery in
34. Lesens O, Desbiez F, Vidal M, et al. Culture of per-wound bone spec-
collaboration with the American Podiatric Medical Association and the
imens: a simplified approach for the medical management of diabetic
Society for Vascular Medicine. J Vasc Surg. 2016;63(2 Suppl):3s‐21s.
foot osteomyelitis. Clin Microbiol Infect. 2011;17:285‐291.
15. Bakker K, Apelqvist J, Schaper NC. Practical guidelines on the man-
35. Ertugrul BM, Lipsky BA, Savk O. Osteomyelitis or Charcot neuro-
agement and prevention of the diabetic foot 2011. Diabetes Metab
osteoarthropathy? Differentiating these disorders in diabetic
Res Rev. 2012;28(Suppl 1):225‐231.
BARWELL et al. |
9 of 10
patients with a foot problem. Diabet Foot Ankle. 2013, doi: 10.3402/ 54. Zeun P, Gooday C, Nunney I, Dhatariya K. Predictors of outcomes
dfa.v4i0.21855. in diabetic foot osteomyelitis treated initially with conservative
36. Rajbhandari SM, Sutton M, Davies C, Tesfaye S, Ward JD. ‘Sausage toe’: (nonsurgical) medical management: a retrospective study. Int J Low
a reliable sign of underlying osteomyelitis. Diabet Med. 2000;17:74‐77. Extrem Wounds. 2016;15:19‐25.
37. Epstein L, Mu Y, Belflower R, et al. Risk factors for invasive 55. Dancer SJ. The effect of antibiotics on methicillin- resistant
methicillin-resistant staphylococcus aureus infection after recent Staphylococcus aureus. J Antimicrob Chemother. 2008;61:246‐253.
discharge from an acute-care hospitalization, 2011-2013. Clin Infect 56. Dancer SJ. How antibiotics can make us sick: the less obvious ad-
Dis. 2016;62:45‐52. verse effects of antimicrobial chemotherapy. Lancet Infect Dis.
38. Marwick C, Santiago VH, McCowan C, Broomhall J, Davey P. 2004;4:611‐619.
Community acquired infections in older patients admitted to hospi- 57. McCarthy H, Rudkin JK, Black NS, Gallagher L, O’Neill E, O’Gara JP.
tal from care homes versus the community: cohort study of microbi- Methicillin resistance and the biofilm phenotype in Staphylococcus
ology and outcomes. BMC Geriatr. 2013;13:12. aureus. Front Cell Infect Microbiol. 2015;5:1.
39. Monteiro-Soares M, Martins-Mendes D, Vaz-Carneiro A, Sampaio 58. Bhinu VS. Insight into biofilm- associated microbial life. J Mol
S, Dinis-Ribeiro M. Classification systems for lower extremity am- Microbiol Biotechnol. 2005;10:15‐21.
putation prediction in subjects with active diabetic foot ulcer: 59. Dowd SE, Wolcott RD, Sun Y, McKeehan T, Smith E, Rhoads D.
a systematic review and meta- analysis. Diabetes Metab Res Rev. Polymicrobial nature of chronic diabetic foot ulcer biofilm infections
2014;30:610‐622. determined using bacterial tag encoded FLX amplicon pyrosequenc-
40. Ince P, Abbas ZG, Lutale JK, et al. Use of the SINBAD classification ing (bTEFAP). PLoS ONE. 2008;3:e3326.
system and score in comparing outcome of foot ulcer management 60. Bjarnsholt T. The role of bacterial biofilms in chronic infections.
on three continents. Diabetes Care. 2008;31:964‐967. APMIS Suppl. 2013;136:1‐51.
41. Chuan F, Tang K, Jiang P, Zhou B, He X. Reliability and validity of the 61. Sotto A, Richard JL, Messad N, et al. Distinguishing colonization from
perfusion, extent, depth, infection and sensation (PEDIS) classifica- infection with Staphylococcus aureus in diabetic foot ulcers with min-
tion system and score in patients with diabetic foot ulcer. PLoS ONE. iaturized oligonucleotide arrays: a French multicenter study. Diabetes
2015;10:e0124739. Care. 2012;35:617‐623.
42. O’Loughlin A, McIntosh C, Dinneen SF, O’Brien T. Review paper: 62. Dunyach-Remy C, Cadiere A, Richard JL, et al. Polymerase chain
basic concepts to novel therapies: a review of the diabetic foot. Int J reaction- denaturing gradient gel electrophoresis (PCR- DGGE): a
Low Extrem Wounds. 2010;9:90‐102. promising tool to diagnose bacterial infections in diabetic foot ul-
43. Markanday A. Diagnosing diabetic foot osteomyelitis: narrative re- cers. Diabetes Metab. 2014;40:476‐480.
view and a suggested 2-step score-based diagnostic pathway for 63. Smith K, Collier A, Townsend EM, et al. One step closer to under-
clinicians. Open Forum Infect Dis. 2014;1:ofu060. standing the role of bacteria in diabetic foot ulcers: characterising
44. Musa HG, Ahmed ME. Associated risk factors and management of the microbiome of ulcers. BMC Microbiol. 2016;16:54.
chronic diabetic foot ulcers exceeding 6 months’ duration. Diabet 64. van Asten SA, La Fontaine J, Peters EJ, Bhavan K, Kim PJ, Lavery LA.
Foot Ankle. 2012, doi: 10.3402/dfa.v3i0.18980. The microbiome of diabetic foot osteomyelitis. Eur J Clin Microbiol
45. Palestro CJ, Love C. Radionuclide imaging of musculoskeletal infection: Infect Dis. 2016;35:293‐298.
conventional agents. Semin Musculoskelet Radiol. 2007;11:335‐352. 65. Lavery LA, Fontaine JL, Bhavan K, Kim PJ, Williams JR, Hunt NA. Risk
46. Palestro CJ, Love C. Nuclear medicine and diabetic foot infections. factors for methicillin-resistant Staphylococcus aureus in diabetic foot
Semin Nucl Med. 2009;39:52‐65. infections. Diabet Foot Ankle. 2014, doi: 10.3402/dfa.v5.23575.
47. Zavadovskaya VD, Zorkal’tsev MA, Udodov VD, et al. [Possibilities of 66. Stanaway S, Johnson D, Moulik P, Gill G. Methicillin- resistant
a software-based hybrid single photon emission computed tomog- Staphylococcus aureus (MRSA) isolation from diabetic foot ul-
raphy/magnetic resonance imaging in the diagnosis of complicated cers correlates with nasal MRSA carriage. Diabetes Res Clin Pract.
diabetic foot syndrome]. Vestn Rentgenol Radiol. 2015;(6):24‐29. 2007;75:47‐50.
48. Aslangul E, M’Bemba J, Caillat-Vigneron N, et al. Diagnosing diabetic 67. Mottola C, Mendes JJ, Cristino JM, Cavaco-Silva P, Tavares L,
foot osteomyelitis in patients without signs of soft tissue infection Oliveira M. Polymicrobial biofilms by diabetic foot clinical isolates.
by coupling hybrid 67 Ga SPECT/CT with bedside percutaneous Folia Microbiol. 2016;61:35‐43.
bone puncture. Diabetes Care. 2013;36:2203‐2210. **Recommended 68. Uckay I, Aragon-Sanchez J, Lew D, Lipsky BA. Diabetic foot infec-
to encourage development of local/regional guidelines combining en- tions: what have we learned in the last 30 years? Int J Infect Dis.
hanced imaging and bone biopsy. 2015;40:81‐91.
49. Senneville E, Melliez H, Beltrand E, et al. Culture of percutaneous 69. Hesstvedt L, Arendrup MC, Poikonen E, Klingpor L, Friman V, Nordoy
bone biopsy specimens for diagnosis of diabetic foot osteomyelitis: I. Differences in epidemiology of candidaemia in the Nordic coun-
concordance with ulcer swab cultures. Clin Infect Dis. 2006;42:57‐62. tries -what is to blame? Mycoses. 2017;60:11‐19.
50. Senneville E, Morant H, Descamps D, et al. Needle puncture and 70. Hsueh PR, Chen WH, Luh KT. Relationships between antimicrobial
transcutaneous bone biopsy cultures are inconsistent in patients use and antimicrobial resistance in Gram-negative bacteria causing
with diabetes and suspected osteomyelitis of the foot. Clin Infect Dis. nosocomial infections from 1991-2003 at a university hospital in
2009;48:888‐893. Taiwan. Int J Antimicrob Agents. 2005;26:463‐472.
51. Valabhji J, Oliver N, Samarasinghe D, Mali T, Gibbs RG, Gedroyc WM. 71. Lee CM, Lai CC, Wang YY, Lee MC, Hsueh PR. Impact of susceptibil-
Conservative management of diabetic forefoot ulceration compli- ity profiles of Gram-negative bacteria before and after the introduc-
cated by underlying osteomyelitis: the benefits of magnetic reso- tion of ertapenem at a medical center in northern Taiwan from 2004
nance imaging. Diabet Med. 2009;26:1127‐1134. to 2010. Diagn Microbiol Infect Dis. 2013;75:94‐100.
52. Game FL, Jeffcoate WJ. Primarily non-surgical management of os- 72. Taori SK, Wroe A, Hardie A, Gibb AP, Poxton IR. A prospective study
teomyelitis of the foot in diabetes. Diabetologia. 2008;51:962‐967. of community-associated Clostridium difficile infections: the role of
53. Tone A, Nguyen S, Devemy F, et al. Six-week versus twelve-week antibiotics and co-infections. J Infect. 2014;69:134‐144.
antibiotic therapy for nonsurgically treated diabetic foot osteomyeli- 73. Reilly J, Cairns S, Fleming S, et al. Results from the second
tis: a multicenter open-label controlled randomized study. Diabetes Scottish national prevalence survey: the changing epidemiol-
Care. 2015;38:302‐307. **Supports consideration of shorter courses of ogy of healthcare-associated infection in Scotland. J Hosp Infect.
antimicrobial therapy for osteomyelitis 2012;82:170‐174.
|
10 of 10 BARWELL et al.
74. Bloomfield LE, Riley TV. Epidemiology and risk factors for community- 95. Lawes T, Lopez-Lozano JM, Nebot CA, et al. Effects of na-
associated Clostridium difficile infection: a narrative review. Infect Dis tional antibiotic stewardship and infection control strategies on
Ther. 2016;5:231‐251. hospital-associated and community-associated meticillin-resistant
75. Fellmeth G, Yarlagadda S, Iyer S. Epidemiology of community-onset Staphylococcus aureus infections across a region of Scotland: a non-
Clostridium difficile infection in a community in the South of England. linear time-series study. Lancet Infect Dis. 2015;15:1438‐1449.
J Infect Public Health. 2010;3:118‐123. 96. Cairns S, Packer S, Reilly J, Leanord A. Targeted MRSA screening can
76. Bignardi GE. Risk factors for Clostridium difficile infection. J Hosp be as effective as universal screening. BMJ. 2014;349:g5075.
Infect. 1998;40:1‐15. 97. Lawes T, Edwards B, Lopez-Lozano JM, Gould I. Trends in
77. Collier A, McLaren J, Godwin J, Bal A. Is Clostridium difficile associ- Staphylococcus aureus bacteraemia and impacts of infection control
ated with the ‘4C’ antibiotics? A retrospective observational study in practices including universal MRSA admission screening in a hospital
diabetic foot ulcer patients. Int J Clin Pract. 2014;68:628‐632. in Scotland, 2006-2010: retrospective cohort study and time-series
78. Noor S, Ahmad J, Parwez I, Ozair M. Culture-based screening of intervention analysis. BMJ Open 2012;2:e000797. doi: 10.1136/
aerobic microbiome in diabetic foot subjects and developing non- bmjopen-2011-000797
healing ulcers. Front Microbiol. 2016;7:1792. 98. Tsai LH, Weng YM, Lin CC, Kuo CW, Chen JC. Risk screening for long
79. Hatipoglu M, Mutluoglu M, Turhan V, et al. Causative pathogens and QT prior to prescribing levofloxacin. Am J Emerg Med. 2014;32:1153.
antibiotic resistance in diabetic foot infections: a prospective multi- e1-3.
center study. J Diabetes Complications. 2016;30:910‐916. 99. Panicker GK, Karnad DR, Kadam P, Badilini F, Damle A, Kothari S.
80. Grigoropoulou P, Eleftheriadou I, Jude EB, Tentolouris N. Diabetic Detecting moxifloxacin-induced QTc prolongation in thorough QT
foot infections: an update in diagnosis and management. Curr and early clinical phase studies using a highly automated ECG analy-
DiabRep. 2017;17:3. sis approach. Br J Pharmacol. 2016;173:1373‐1380.
81. Peters EJ, Lipsky BA, Berendt AR, et al. A systematic review of the 100. Yanat B, Rodriguez-Martinez JM, Touati A. Plasmid-mediated quino-
effectiveness of interventions in the management of infection in the lone resistance in Enterobacteriaceae: a systematic review with
diabetic foot. Diabetes Metab Res Rev. 2012;28(Suppl 1):142‐162. a focus on Mediterranean countries. Eur J Clin Microbiol Infect Dis.
82. Acharya S, Soliman M, Egun A, Rajbhandari SM. Conservative man- 2017;36:421‐435.
agement of diabetic foot osteomyelitis. Diabetes Res Clin Pract. 101. Weber SG, Gold HS, Hooper DC, Karchmer AW, Carmeli Y.
2013;101:e18‐e20. Fluoroquinolones and the risk for methicillin-resistant Staphylococcus
83. Lazaro-Martinez JL, Aragon-Sanchez J, Garcia-Morales E. Antibiotics aureus in hospitalized patients. Emerg Infect Dis. 2003;9:1415‐1422.
versus conservative surgery for treating diabetic foot osteomyelitis: 102. Brown KA, Khanafer N, Daneman N, Fisman DN. Meta-analysis of
a randomized comparative trial. Diabetes Care. 2014;37:789‐795. antibiotics and the risk of community-associated Clostridium difficile
84. Li HK, Scarborough M, Zambellas R, et al. Oral versus intravenous infection. Antimicrob Agents Chemother. 2013;57:2326‐2332.
antibiotic treatment for bone and joint infections (OVIVA): study 103. Kim BN, Kim ES, Oh MD. Oral antibiotic treatment of staphylo-
protocol for a randomised controlled trial. Trials. 2015;16:583. coccal bone and joint infections in adults. J Antimicrob Chemother.
85. Conterno LO, Turchi MD. Antibiotics for treating chronic osteomyeli- 2014;69:309‐322.
tis in adults. Cochrane Database Syst Rev. 2013;9:Cd004439. 104. Al-Rubeaan K, Al Derwish M, Ouizi S, et al. Diabetic foot complica-
86. Crouzet J, Lavigne JP, Richard JL, Sotto A. Diabetic foot infection: a tions and their risk factors from a large retrospective cohort study.
critical review of recent randomized clinical trials on antibiotic ther- PLoS ONE. 2015;10:e0124446.
apy. Int J Infect Dis. 2011;15:e601‐e610. 105. Calderon-Ortiz R, Colton-Verge P, Muniz-Ortega M, Lespier L,
87. Jeffcoate WJ, Bus SA, Game FL, Hinchliffe RJ, Price PE, Schaper NC. Cordova H. Life threatening hyperkalemia chronic kidney diseases
Reporting standards of studies and papers on the prevention and patients treated with trimethoprim-sulfamethoxazole: a case series.
management of foot ulcers in diabetes: required details and markers Bol Asoc Med P R. 2011;103:15‐17.
of good quality. Lancet Diabetes Endocrinol. 2016;4:781‐788. 106. Tamma PD, Cosgrove SE, Maragakis LL. Combination therapy for
88. Tascini C, Piaggesi A, Tagliaferri E, et al. Microbiology at first visit of treatment of infections with gram-negative bacteria. Clin Microbiol
moderate-to-severe diabetic foot infection with antimicrobial activ- Rev. 2012;25:450‐470.
ity and a survey of quinolone monotherapy. Diabetes Res Clin Pract. 107. Chapman AL, Dixon S, Andrews D, Lillie PJ, Bazaz R, Patchett JD.
2011;94:133‐139. Clinical efficacy and cost-effectiveness of outpatient parenteral an-
89. Wu WS, Chen CC, Chuang YC, et al. Efficacy of combination oral tibiotic therapy (OPAT): a UK perspective. J Antimicrob Chemother.
antimicrobial agents against biofilm-embedded methicillin-resistant 2009;64:1316‐1324.
Staphylococcus aureus. J Microbiol Immunol Infect. 2013;46:89‐95. 108. Chapman AL, Seaton RA, Cooper MA, et al. Good practice recom-
90. Iguchi S, Mizutani T, Hiramatsu K, Kikuchi K. Rapid Acquisition of mendations for outpatient parenteral antimicrobial therapy (OPAT)
Linezolid Resistance in Methicillin-Resistant Staphylococcus aureus: in adults in the UK: a consensus statement. J Antimicrob Chemother.
Role of Hypermutation and Homologous Recombination. PLoS ONE. 2012;67:1053‐1062. **Useful evidence for local clinicians/groups to
2016;11:e0155512. support the development of OPAT service
91. Walker KTR, Sandeep TC, Devers M, Bain D, Barwell ND. Linezolid- 109. Schaper NC. Diabetic foot ulcer classification system for research
induced hypoglycaemia in a patient with Type 1 Diabetes. Br J purposes: a progress report on criteria for including patients in re-
Diabetes Vasc Dis. 2012;12:186‐188. search studies. Diabetes Metab Res Rev. 2004;20(Suppl 1):S90‐S95.
92. Young MJ, Hodges G, McCardle JE. Cost avoidance using linezolid for
methicillin-resistant Staphylococcus aureus infections in a specialist
diabetes foot clinic. J Antimicrob Chemother. 2012;67:2974‐2975. How to cite this article: Barwell ND, Devers MC, Kennon B,
93. Evans JD, Udeani G, Cole P, Friedland HD. Ceftaroline fosamil for et al; on behalf of the Scottish Diabetes Foot Action Group.
the treatment of acute bacterial skin and skin structure infections in
Diabetic foot infection: Antibiotic therapy and good practice
obese patients. Postgrad Med. 2014;126:128‐134.
94. Lipsky BA, Cannon CM, Ramani A, et al. Ceftaroline fosamil for treat- recommendations. Int J Clin Pract. 2017;e13006. https://doi.
ment of diabetic foot infections: the CAPTURE study experience. org/10.1111/ijcp.13006
Diabetes Metab Res Rev. 2015;31:395‐401.