Medical therapy of diabetic foot infections

Warren S. Joseph, DPM, FIDSA,a and Benjamin A. Lipsky, MD, FACP, FIDSA, FRCP,b Philadelphia, Pa;
and Seattle, Wash
Diabetic foot infections are a common and often serious problem, accounting for a greater number of hospital bed days
than any other complication of diabetes. Despite advances in both antibiotic therapy and surgical management, these
infections continue to be a major risk factor for amputations of the lower extremity. Although a number of wound size
and depth classification systems have been adapted for use in codifying diabetic foot ulcerations, none are specific for
infection. In 2003, the International Working Group on the Diabetic Foot developed guidelines for managing diabetic
foot infections, including the first severity scale specific for these infections. The following year, the Infectious Diseases
Society of America (IDSA) published their Diabetic Foot Infection Guidelines. In this article, we review some of the
critical points from the Executive Summary of the IDSA document and provide a commentary following each issue to
update the reader on any pertinent changes that have occurred since the publication of the original document in 2004.
The importance of a multidisciplinary limb salvage team, apropos this special joint issue of the American Podiatric
Medical Association and the Society for Vascular Surgery, cannot be overstated. ( J Vasc Surg 2010;52:67S-71S.)

Until 20 years ago, what little literature there was

available on treating infections of the foot in persons with
diabetes suggested that: almost all were polymicrobial;
gram-negative bacilli and obligate anaerobes were frequent
pathogens; virtually all such patients needed to be hospitalized; and they should be treated with parenteral, broadspectrum antibiotic therapy. Studies published since 1990
have demonstrated that most of these assertions were at
least exaggerations, if not myths. With the accumulating
case series and investigations on treatment of diabetic
foot infections (DFIs), especially randomized clinical
trials and carefully conducted microbiological studies, by
the early 2000s, it was time for convening experts in the
field to develop evidence-based guidelines on diagnosing
and treating DFIs.
In 2003, the International Working Group on the
Diabetic Foot (IWGDF) appointed a committee that
drafted DFI guidelines1 that were approved by members
from over 60 participating countries and subsequently published and distributed in multiple languages on DVD (www.
iwgdf.org). The following year, the Infectious Diseases Society of America (IDSA) empanelled an expert committee to
draft diabetic foot infection clinical guidelines that were published in 2004.2 These included an infection severity classification scale that was subsequently validated and shown to
predict clinical outcomes.3 These documents, taken together,
From the Roxborough Memorial Hospital, Philadelphia;a University of
Washington and Primary Care Clinic, Antibiotic Research, VA Puget
Sound HCS, Seattle.b
Competition of interest: Dr Joseph is on the Speakers Bureau and is a
consultant for Pfizer & Merck.
This article is being co-published in the Journal of Vascular Surgery and the
Journal of the American Podiatric Medical Association.
Reprint requests: Dr Warren S. Joseph, 1109 Old Ford Rd., Huntingdon
Valley, PA 19006 (e-mail: wsjoseph@comcast.net).
The editors and reviewers of this article have no relevant financial relationships
to disclose per the JVS policy that requires reviewers to decline review of any
manuscript for which they may have a competition of interest.
0741-5214/$36.00
Copyright 2010 by the Society for Vascular Surgery and the American
Podiatric Medical Association.
doi:10.1016/j.jvs.2010.06.010

represent the most comprehensive multinational attempt to

codify a treatment approach to a condition that contributes to
71,000 lower extremity amputations per year in the United
States alone (www.diabetes.org). Although an updated set of
DFI Guidelines is slated to be published by the IDSA Committee sometime in 2010, and several new studies specifically
investigating antibiotic treatment of DFIs have been published in the past 6 years,4 many of the original points presented in the Executive Summary of the original document are
still valid and deserving of review. Furthermore, the validated
severity classification scale is now widely accepted and used to
classify patients enrolled in DFI studies and will remain unchanged in the updated document.
SEVERITY SCALE
Many classification systems have been developed to
categorize diabetic foot wounds (especially ulcerations),
some of which include the presence or absence of infection.
None of these, however, have specifically classified the
severity of infection. Probably the most recognized, and
most venerable, system was that proposed by Wagner.5 In
this classification with four grades, more useful as a descriptor of size and depth of a wound, the presence of an
infection is not considered until a Grade III ulceration,
which is described as a deep ulcer with abscess, osteomyelitis, or joint sepsis. It is reasonable to ask, why cant a less
extensive Grade 0, I, or II ulcer become infected? A newer,
validated system first proposed by investigators at the
University of Texas diabetic foot group is a derivation of
the Wagner scheme.6 This system includes infection as a
comorbidity modifier that can be added to any wound
depth category, but it does not specify the severity of the
infection.
In order to address the lack of an adequate severity
score for DFI, the IWGDF and the IDSA have each developed a mostly interchangeable, four level grading system
specifically for infection (Table I). The presence of infection in a foot wound is defined clinically, not by a positive
culture. Ulcerations are classified as either uninfected (lack67S

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68S Joseph and Lipsky

Table I. Clinical classification schemes (Infectious Diseases Society of America [IDSA] and International Working
Group on the Diabetic Foot [IWGDF]) for a diabetic foot infectiona
Clinical manifestations of infection
Wound lacking purulence or any manifestations of inflammation
Presence of purulence or 2 manifestations of inflammation (pain, tenderness, erythema,
warmth, or induration), but any cellulitis/erythema extends 2 cm around the ulcer,
and infection is limited to the skin or superficial subcutaneous tissues; no other local
complications or systemic illness.
Infection (as defined above) in a patient who is systemically well and metabolically stable,
but which is associated 1 of the following characteristics: cellulitis extending 2 cm,
lymphangitic streaking, spread beneath the superficial fascia, deep-tissue abscess,
gangrene, and involvement of muscle, tendon, joint, or bone.
Infection in a patient with signs or symptoms of systemic toxicity (eg, fever, chills,
leukocytosis) or metabolic instability (eg, tachycardia, hypotension, confusion,
vomiting, acidosis, severe hyperglycemia, or azotemia)

IDSA infection
severity

IWGDF PEDIS
gradeb

Uninfected
Mild

1
2

Moderate

Severe

The presence of critical ischemia of the affected limb often increases the severity of the infection.
International Consensus on the Diabetic Foot PEDIS system: perfusion, extent/size, depth/tissue loss, infection, and sensation.

Table II. Suggested antibiotic regimens for diabetic foot infections, based on clinical severity
Agent(s)
Advised route
Dicloxacillin
Clindamycin
Cephalexin
Trimethoprim-sulfamethoxazole
Amoxicillin/clavulanate
Levofloxacin
Cefoxitin
Ceftriaxone
Ampicillin/sulbactam
Linezolida aztreonam
Ertapenem
Cefuroxime metronidazole
Ticarcillin/clavulanate
Piperacillin/tazobactam
Levofloxacin or ciprofloxain clindamycin
Imipenem-cilastatin
Vancomycina ceftazidime metronidazole

Mild

Moderate

Severe

Oral for most

Oral or parenteral, based on clinical

situation and agent(s) selected

Intravenous, at least
initially

Similar agents of the same class may be substituted. Some of these regimens may not have FDA approval for complicated skin and skin structure infections, and
only linezolid is currently specifically approved for diabetic foot infections.
Reprinted from Lipsky et al.2
a
Where methicillin-resistant Staphylococcus aureus infection is proven or likely.

ing clinical evidence of purulence or inflammation) or

infected, with a severity of mild, moderate, or severe. The
differentiation between these categories is based on clinical
signs and symptoms, thus corroborating the importance of
making a clinical diagnosis of infection, as spelled out in
point #5 of the Executive Summary described below. This
scale has been validated in a prospective observational study
published by Lavery et al.3 When applied to 1666 patients
with a foot ulceration, there was a significant increase in
rates of hospitalization and lower extremity amputation
with increased severity of the infection. These classification
systems have now been widely accepted and are being
employed in academic and clinical circles. Some clinicians
have taken to combining systems that rate the size/depth

of a wound, with infection severity (eg, the patient presents with a University of Texas 2B wound with an IDSA
category moderate infection). One of the benefits of the
infection severity scheme is that it can be used to help select
an appropriate antibiotic regimen for DFIs, as shown in
Table II.
EXECUTIVE SUMMARY REVIEW
The IDSA DFI guidelines contained a 19-point Executive Summary with the key recommendations for diagnosing and treating these infections. The recommendations
still remain valid and are critical to a successful approach to
managing DFIs. We will address a few of the most important recommendations numbering them as they were in the

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2004 guidelines, to make for easier reference to the original

document. The original text is in bold italicized print,
followed by our commentary.
2. Diabetic foot infections require attention to local
(foot) and systemic (metabolic) issues and coordinated
management, preferably by a multidisciplinary footcare team. The team managing these infections should
include, or have ready access to, an infectious diseases
specialist or a medical microbiologist. Apropos this
special issue jointly published by the American Podiatric Medical Association and the Society for Vascular
Surgery, the concept of a multidisciplinary team approach cannot be overstated. The team requires members trained in the skill set necessary for limb salvage
and includes those concentrating on not only the
anatomic disturbances of the lower extremity but also
the perfusion to the limb. This approach (ie, care for
the diabetic foot wound by at least an irreducible team
of a foot specialist and a vascular surgeon) is aptly
named the toe and flow concept (Armstrong, DA
personal communication), an issue recognized in #14
below.
4. Aerobic gram-positive cocci (especially Staphylococcus
aureus) are the predominant pathogens in diabetic
foot infections. Patients who have chronic wounds, or
who have recently received antibiotic therapy, may
also be infected with gram-negative rods, and those
with foot ischemia or gangrene may have obligate anaerobic pathogens. It has become increasingly clear that
Staphylococcus aureus, including methicillin-resistant
strains (MRSA), and Streptococcus spp, most often Group
B, are the primary pathogens in most DFI. A number of
studies have shown that antibiotic therapy directed at just
these organisms can be successful, even when culture
results demonstrate various other gram-negative bacteria
or obligate anaerobes. This has led to the promulgation
of the Head of the Snake conceptthe aerobic grampositive bacteria constitute the crucial head of the snake,
while other isolated organisms are part of the body. If
antibiotic therapy is directed at the primary organisms,
thereby cutting off the head of the snake, the residual
body would die. Thus, antibiotic therapy can often be
narrowly targeted at only aerobic gram-positive cocci.
5. Wound infections must be diagnosed clinically on the
basis of local (and occasionally systemic) signs and
symptoms of inflammation. Laboratory (including
microbiological) investigations are of limited use for
diagnosing infection, except in cases of osteomyelitis.
This point represents a cultural shift away from oftpracticed technology- (mostly imaging) based approach to diagnosis. In order to diagnose infection in
a diabetic foot wound, the patient should present with
at least two of the clinical signs and symptoms of
inflammation including; erythema, edema, warmth,
tenderness, induration, or pain. Cultures should be
obtained, not to diagnose the infection, but rather to
determine which organism is causing the clinically

Joseph and Lipsky 69S

diagnosed infection in order to aid in antibiotic selection. A recent IWGDF consensus statement on diabetic foot osteomyelitis suggests that culture-based
diagnosis and treatment are likely the best predictors of
a positive outcome.7 Even in cases of osteomyelitis, the
role of diagnostic imaging studies has been recently
challenged. Currently, magnetic resonance imaging is
the best imaging study for defining both soft tissue and
bone infections.8 Other studies have been investigated, however, with positron emission tomography
(FDG-PET) combined with computed tomography
scanning being the most promising.9
9. Available evidence does not support treating clinically uninfected ulcers with antibiotic therapy. Antibiotic therapy is necessary for virtually all infected
wounds, but it is often insufficient without appropriate wound care. Inappropriate use of antibiotics leads
to bacterial resistance. This observation has gained
greater importance with the development of resistance
of the common gram-positive pathogens, especially
MRSA.10,11 An increasing threat of treating soft tissue
infections, including DFI, is the varying levels of tolerance of formerly susceptible microorganisms to vancomycin.12 This can take the form of just increasing
minimum inhibitory concentrations (MIC creep) or
frank resistance (vancomycin-resistant S. aureus, or
VRSA). In fact, the first two reported cases of VRSA13
back in 2002 were isolated from diabetic foot wounds.
With advances in the agents available for antibiotic
treatment of these resistant gram-positive organisms
has come a newer threat (eg, multi-drug resistant
(MDR) gram-negative bacteria). Organisms, such as
species of Klebsiella and Proteus, once relatively susceptible to a wide range of antibiotics, now may produce
extended-spectrum beta-lactamases (ESBL) or carbapenemases, rendering them resistant to most commonly
used drugs.14 A major reason for the emergence of
these resistant organisms is inappropriate, typically unnecessary, and overlong, antibiotic treatment.
10. Select an empirical antibiotic regimen on the basis of
the severity of the infection and the likely etiologic
agent(s). Therapy aimed solely at aerobic grampositive cocci may be sufficient for mild-to-moderate infections in patients who have not recently received
antibiotic therapy. Broad-spectrum empirical therapy
is not routinely required but is indicated for severe
infections, pending culture results and antibiotic susceptibility data. Take into consideration any recent
antibiotic therapy and local antibiotic susceptibility
data, especially the prevalence of methicillin-resistant
S. aureus (MRSA) or other resistant organisms. Definitive therapy should be based on both the culture
results and susceptibility data and the clinical response to the empirical regimen. The previously discussed head of the snake paradigm addresses initiating antibiotic therapy aimed principally (if not solely)
at aerobic gram-positive organisms for many DFI.
Even the 2004 Guidelines acknowledged the increas-

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70S Joseph and Lipsky

ing prevalence of MRSA, but the problem has clearly

worsened in most parts of the world. At the time the
Guidelines were prepared, clinical trials specifically
looking at antimicrobial management of DFI were
sparse, and rates of MRSA isolation were 10% or less.
More recent work has shown that these rates are increasing.15 In some institutions, MRSA has supplanted
methicillin-susceptible S. aureus (MSSA) as the primary pathogen isolated in DFI. This raises the important question: When should empiric MRSA coverage
be instituted? As stated in the summary point, the
decision to cover MRSA should be based on knowledge of local prevalence, but at what breakpoint is
the decision made? Unfortunately, there are no hard
(or easy) and fast rules. The severity of the infection
along with the risk tolerance of the clinician should
each probably play a role. For mild infections, clinicians may tolerate a higher local prevalence or risk of
MRSA infection before initiating empiric MRSA therapy, since the patient may do well with local wound
care regardless of whether or not the organism is
covered. However, for moderate to severe infections,
the threshold for initiating anti-MRSA therapy should
be lower (eg, an expected prevalence of 10%) given
the potential for serious sequelae if aggressive antibiotic therapy is not initiated. This has given rise to the
concept of escalation or de-escalation therapies
for empiric MRSA coverage. If the organism is not
empirically covered, the clinician can always escalate
(broaden the spectrum) the choice of therapeutic
agents to include MRSA once initial culture results are
received. Likewise, if there is a greater concern that it
may be present, broader spectrum empiric coverage is
begun with the option of de-escalation (narrowing
the spectrum) if cultures reveal only susceptible organisms. The availability of several new anti-MRSA antibiotic agents has made covering this organism easier
than it was a decade ago.16
14. Seek surgical consultation and, when needed, intervention for infections accompanied by a deep abscess,
extensive bone or joint involvement, crepitus, substantial necrosis or gangrene, or necrotizing fasciitis.
Evaluating the limbs arterial supply and revascularizing when indicated are particularly important.
Surgeons with experience and interest in the field
should be recruited by the foot-care team, if possible.
This final point is at the heart of the entire toe and
flow concept. By the definition used by the US Food
and Drug Administration, a complicated skin and skin
structure infection (cSSSI) is one in which the patient
either has a significant underlying medical comorbidity
or an immunocompromising disease; in these cases,
the potential for greater severity of the infection may
require more aggressive surgical approaches (eg, incision and drainage or resection of infected and necrotic
tissue). Although appropriate antibiotic therapy can be
critical in achieving optimal outcomes, for many moderate to severe DFI, surgical intervention can be key to

limb salvage. A recent consensus statement from the

IWGDF7 classified DFI surgery as being urgent only
in cases of necrotizing or deep soft tissue infections,
major abscess, or gangrene. Nonurgent surgery may
be needed when there is risk of significant compromise
of the soft tissue envelope, loss of mechanical function,
or if the degree of bone involvement is life- or limbthreatening. However, none of this toe surgery can
be accomplished without adequate flow to the limb.
Likewise, antibiotic therapy of the toe infection
needs adequate flow to achieve therapeutic levels (of
antibiotic and leukocytes) in the target infected tissues.
Thus, a full circle is completed from the first executive
summary review point to the last. A team approach is
required, with specialists who are interested in foot
infections and who possess the necessary skill set to
succeed at diabetic limb salvage. Optimal outcomes for
patients presenting with DFIs have repeatedly been
shown to depend on care by a team of specialists, including those with training in podiatric and vascular surgery
along with infectious diseases, diabetes, wound care, and
internal medicine. To this end, the IDSA DFI Committee has been expanded to include stakeholders from
specialties across the spectrum of diabetic foot care,
including podiatric surgery and vascular surgery. All of
these voices will be included in the 2010 update.
REFERENCES
1. Lipsky BA. A report from the international consensus on diagnosing and
treating the infected diabetic foot. Diabetes Metab Res Rev 2004;20
(Suppl 1):S68-77.
2. Lipsky BA, Berendt AR, Deery HG, Embil J, Joseph WS, Karchmer
AW, et al. Infectious Disease Society of America. Diagnosis and treatment of diabetic foot infections. Clin Infect Dis 2004;39:885-910.
3. Lavery LA, Armstrong DG, Murdoch DP, Peters EJ, Lipsky BA. Validation of the Infectious Diseases Society of Americas diabetic foot
infection classification system. Clin Infect Dis 2007;44:562-5.
4. Rao N, Lipsky BA. Optimising antimicrobial therapy in diabetic foot
infections. Drugs 2007;67:195-214.
5. Van Acker K, De Block C, Abrams P, et al. The choice of diabetic foot
ulcer classification in relation to the final outcome. Wounds 2002;14:
16-25.
6. Armstrong DG, Lavery LA, Harkless LB. Validation of a diabetic
wound classification system. The contribution of depth, infection, and
ischemia to risk of amputation. Diabetes Care 1998;21:855-9.
7. Berendt AR, Peters EJ, Bakker K, Embil JM, Eneroth M, Hinchliffe RJ,
et al. Diabetic foot osteomyelitis: a progress report on diagnosis and a
systematic review of treatment. Diabetes Metab Res Rev 2008;24
(Suppl 1):S145-61.
8. Teh J, Berendt T, Lipsky BA. Rational imaging. Investigating suspected
bone infection in the diabetic foot. BMJ 2009;339:b4690.
9. Nawaz A, Torigian DA, Siegelman ES, Basu S, Chryssikos T, Alavi A.
Diagnostic performance of FDG-PET, MRI, and plain film radiography
(PFR) for the diagnosis of osteomyelitis in the diabetic foot. Mol
Imaging Biol 2010;12:335-42.
10. Bowling FL, Jude EB, Boulton AJ. MRSA and diabetic foot wounds:
contaminating or infecting organisms? Curr Diab Rep 2009;9:440-4.
11. Dang CN, Prasad YD, Boulton AJ, Jude EB. Methicillin-resistant
Staphylococcus aureus in the diabetic foot clinic: a worsening problem.
Diabet Med 2003;20:159-61.
12. Gould IM. Clinical relevance of increasing glycopeptide MICs
against Staphylococcus aureus. Int J Antimicrob Agents 2008;31
(Suppl 2):1-9.

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13. Centers for Disease Control and Prevention (CDC). Vancomycinresistant Staphylococcus aureusPennsylvania, 2002. MMWR Morb
Mortal Wkly Rep 2002;51:902.
14. Varaiya A, Dogra J, Kulkarni M, Bhalekar P. Extended spectrum beta
lactamase (ESBL) producing Escherichia coli and klebsiella pneumoniae in diabetic foot infection. Indian J Med Microbiol 2008;26:
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15. Lipsky BA, Tabak YP, Johannes RS, Vo L, Hyde L, Weigelt JA. Skin and
soft tissue infections in hospitalised patients with diabetes: culture
isolates and risk factors associated with mortality, length of stay and
cost. Diabetologia 2010;53:914-23.
16. Nicolau DP, Stein GE. Therapeutic options for diabetic foot infections:
a review with an emphasis on tissue penetration characteristics. J Am
Podiatr Med Assoc 2010;100:52-63.