New Developments in Diagnosing and Treating Diabetic Foot Infections

DIABETES/METABOLISM RESEARCH AND REVIEWS REVIEW ARTICLEDiabetes Metab Res Rev 2008; 24(Suppl 1): S66S71.Published online 8 April 2008 in Wiley InterScience (www.interscience.wiley.com) DOI: 10.1002/dmrr.828

New developments in diagnosing and treatingdiabetic foot infections

Benjamin A. Lipsky*

University of Washington, USA;Primary Care Clinic, VA Puget SoundHealth Care System, 1660 S.Columbian Way (S-111-PCC),Seattle, Washington 98108-1597,USA

*Correspondence to:Benjamin A. Lipsky, Primary CareClinic, VA Puget Sound Health CareSystem, 1660 S. Columbian Way(S-111-PCC), Seattle, Washington98108-1597, USA.E-mail: [email protected]

This article is a U.S. Governmentwork and is in the public domain inthe U.S.A.

Received: 9 October 2007Revised: 17 December 2007Accepted: 2 January 2008

Summary

Foot infections are common in persons with diabetes and are often theproximate cause of lower extremity amputation. There have been manypublications in the past few years dealing with the appropriate ways todiagnose and treat diabetic foot infections. This review presents informationgathered from a comprehensive, ongoing surveillance of the literature(published and abstracts) over the past 4 years. Prospective studies havenow defined the epidemiology of diabetic foot infections, as well as methodsto score and classify the wounds. Several recently published guidelinescan assist clinicians in managing these infections. The etiologic agents ofinfection have been well-defined, and the prevalence of multi-drug-resistancepathogens is growing. Molecular methods offer great promise for quicker andmore sensitive diagnosis of infection. New antimicrobial agents, both systemicand topical, as well as novel local treatments, have been shown to be effectivein various studies. Improved methods of deploying older agents have addedto the variety of treatment approaches now available. Several adjunctivetreatments may benefit some patients but their role is as yet unclear. Whilethere is much yet to learn about the most cost-effective ways to diagnoseand treat diabetic foot infections the main effort is now to disseminate theavailable information and facilitate employing the evidence-based guidelinerecommendations. Published in 2008 by John Wiley & Sons, Ltd.

Keywords diabetic foot infection; diagnosis of infection; antimicrobial therapy;microbiology

Introduction

Since the last International Symposium on diabetic foot in 2003, there hasbeen a good deal of research into the infectious aspects of complicationsaffecting the foot in persons with diabetes. The increase in investigativeactivity in this field was likely catalysed by the publication of two sets ofguidelines specifically concerning diabetic foot infections (DFIs). The first, aproduct of a consensus meeting of the International Working Group on theDiabetic Foot (IWGDF) at the last International Symposium, was published in2004 [1]. The second was released soon thereafter by a committee designatedby the Infectious Diseases Society of America (IDSA) [2]. Most recently, aset of guidelines was published from French-speaking experts, with a shorterversion in English [3]. Other recent guidelines have also addressed infectionas part of a larger overview of diabetic foot complications [35]. Finally, aprogress report on diagnosing and treating diabetic foot osteomyelitis waspresented at the 5th International Symposium on the Diabetic Foot. Theseguidelines have largely presented similar sets of recommendations, helpingto codify an approach to diagnosing and treating DFIs.

Published in 2008 by John Wiley & Sons, Ltd.

New Developments in Diabetic Foot Infections S67

Guidelines and classifications

An important aspect of the International Working Groupon the Diabetic Foot and Infectious Diseases Society ofAmerica guidelines is that they developed criteria bywhich to classify the severity of a DFI. This classificationhelps clinicians recognize severe infections, which mayrequire hospitalization, broad-spectrum and parenteralantibiotic therapy, or urgent diagnostic or surgical inter-ventions. Generally, mild infections are relatively super-ficial and limited, moderate infections involve deepertissues, and severe infections are accompanied by systemicsigns or symptoms of infection or metabolic perturbations.Using the data from a prospective study of patients whodeveloped a foot infection, Lavery et al. were able tovalidate the Infectious Diseases Society of America clas-sification system [6]. They found that with increasingseverity of infection there was a statistically significanttrend for increasing rates of lower extremity amputation,higher anatomic levels of amputation, and higher ratesof hospitalization for treatment. Another newly reportedfinding is that one can predict the outcome of infec-tion by the presence and severity of selected clinical andlaboratory findings [7]. Among 402 clinically evaluatedpatients enrolled in a prospective antibiotic treatmentstudy, baseline factors significantly associated by univari-ate analysis with treatment failure were severe (versusmoderate) University of Texas (UT) wound grade; ele-vated white blood cell count; elevated C-reactive proteinor erythrocyte sedimentation rate; high wound severityscore; hospitalization for treatment; low serum albumin;male sex; and, skin temperature of affected foot >10 Cabove that of unaffected foot [7]. By multivariate logisticregression only severe University of Texas wound gradeand elevated white blood cell count remained statisticallysignificant predictors. Clinical failure rates were 46% forpatients with both risk factors compared with 10% forpatients with no risk factors and 17% for patients with onerisk factor. Increased white blood cell count and severeUniversity of Texas wound grade at baseline, but not otherfeatures were significant independent and additive riskfactors for clinical failure in patients treated for a DFI [7].

Wound scoring system

Another advancement has been the development andvalidation of a DFI wound scoring system [8]. Lipsky et al.formulated a preliminary version of this score for use intwo previous studies of antibiotic therapy for DFIs [912],then used a slightly modified version for the SIDESTEPantibiotic study [13]. Investigators noted the presenceof drainage (purulent or non-purulent), then graded anyerythema, induration, tenderness, pain, and local warmthfor severity. This score, combined with measurements ofwound size and depth, gave a total wound score. Among373 patients evaluated, a higher score was associated witha significantly reduced infection cure rate. This scoringsystem thus appears to offer clinicians an objective way

to classify the severity of an infected diabetic foot wound,and this correlates with clinical outcome.

Epidemiology

An important advancement in this field has come from tworecent studies that have finally provided some prospectivedata on the occurrence of DFIs. Lavery et al. reported theresults of 1666 diabetic persons in a health maintenanceorganization in Texas for a mean of just over 2 years[14]. Despite the fact that the patients were screened forfoot problems both at enrollment and regularly thereafter,and educated in how to prevent foot problems, 151 (9%)developed 199 infections of the foot. All but one infectionoccurred in the setting of a wound or penetrating injury;most involved only the soft tissue but 20% had boneculture-proven osteomyelitis. Those who developed a footinfection had a dramatically higher risk of hospitalizationand lower extremity amputation. Significant independentrisk factors for foot infection from a multivariate analysisincluded wounds that penetrated to bone, had a duration>30 days, were recurrent, or associated with a traumaticetiology, and the presence of peripheral vascular disease[14]. The second report came from the Eurodiale studyof diabetic patients with a foot ulcer in 14 Europeanhospitals in ten countries [15]. Among 1229 patients, 58%had a clinically infected wound. The severity of diabeticfoot ulcers at presentation was greater than previouslyreported, and one-third had peripheral arterial disease inaddition to infection. The majority of foot ulcers werenon-plantar, especially in patients with severe disease,and serious co-morbidity increased with the severity offoot disease [15]. Thus, DFIs are common, typically occurin a traumatic wound, affect the majority of foot ulcers,and are associated with limb ischaemia.

Microbiology

Many studies have reported causative organisms in aseries of patients with DFI. The results of these stud-ies vary with the severity of the infection, whether ornot the patients had recently received antibiotic therapy,as well as with the quality of the culture proceduresused. Although many studies have demonstrated thesuperiority of deep (preferably tissue) specimens oversuperficial swabs [16,17], especially for bone infections[1820], most clinicians persist in sending wound swabs.In a recent, large, prospective antibiotic trial most speci-mens were obtained with optimal technique and sent toa research laboratory for optimal microbiological eval-uation [21]. Among 427 positive cultures, 84% werepolymicrobial; almost half grew only aerobes, but 47%had both aerobes and anaerobes. There was an aver-age of 2.7 organisms per culture for aerobes and 2.3for anaerobes. As has been found in most other stud-ies, the predominant aerobic organisms (in descending

Published in 2008 by John Wiley & Sons, Ltd. Diabetes Metab Res Rev 2008; 24(Suppl 1): S66S71.DOI: 10.1002/dmrr

S68 B. A. Lipsky

order) were Staphylococcus aureus, coagulase-negativestaphylococci, Streptococcus species, Enterococcus species,Corynebacterium species, Enterobacteriaceae, and Pseu-domonas aeruginosa. The predominant anaerobes weregram-positive cocci, Prevotella species, Porphyromonasspecies, and Bacteroides fragilis group. The fact thata majority of patients with oxacillin-resistant S. aureus(MRSA), Staphylococcus epidermidis, or P. aeruginosa hada mixed infection [21] is worthy of note. These data sup-port the results of many other studies that have foundthat aerobic gram-positive cocci (particularly staphylo-cocci) are the most frequent causes of DFIs, but thatmixed infections, with aerobic gram-negative bacilli orobligate anaerobes, are common as well [22].

Antibiotic-resistant pathogens

One major change in the causative organisms of DFIs inthe past few years is the increasing frequency of isolationof MRSA [2325]. Several studies have found that3050% of S. aureus isolated from diabetic foot ulcers areMRSA [26,27]. This is noteworthy because MRSA requiresspecifically targeted antibiotic therapy. Because the rateof MRSA isolation varies considerably from one locationto another, it is essential that clinicians are aware of theirlocal situation. In one report the prevalence of MRSA wassignificantly higher in patients with clinically infectedfoot ulcers than in those with just colonization [28].Interestingly, in this study MRSA infection or colonizationwas not associated with previously reported predisposingfactors, e.g. prior hospitalization or use of antibiotics.Isolating MRSA from a diabetic foot wound is related tonasal colonization with the organism [24]. Presumably,eradication of colonization may require eliminating thenasal colonization. Some studies have also reported anincrease in the frequency of antibiotic-resistant (includingextended-spectrum beta-lactamase producing) gram-negative organisms, particularly Pseudomonas species[25,29,30] In one study of 102 diabetic patients witha foot wound, the significant risk factors for havinga multi-drug resistant diabetic foot pathogen wereprevious antibiotic therapy and its duration, frequency ofhospitalization for the same wound, duration of hospitalstay, and the presence of osteomyelitis [31].

Rapid diagnostic methods

Wound cultures may not adequately identify pathogens,especially when they are not obtained or processed cor-rectly or when the patient is on antimicrobial therapy.Even when pathogens grow, it takes at least 2448 hto identify them and obtain antibiotic sensitivity results.One method of getting rapid information about the likelycausative organisms in a DFI is to do a gram-stainedsmear of tissue from the wound [32]. Newer technologiesmay enable rapid identification of causative pathogens[33]. One technique, the polymerase chain reaction (PCR)

assay, has been shown to be effective at identifying manygram-positive, gram-negative and anaerobic organismsin various types of wounds. Another potentially usefulnew diagnostic technology is the oligonucleotide arrayfor detecting various genes, including those coding resis-tance, toxins and specific species [34] A recent studyinvestigated 72 diabetic patients hospitalized with a footulcer who had monomicrobial colonization or infectionwith S. aureus. Few of the clinically uninfected ulcers hadvirulence genes, while they were present in almost allthe infected ulcers [35]. The presence of these virulencefactors also predicted a worse clinical outcome. Real timepolymerase chain reaction may allow clinicians to dis-criminate infected from colonized wounds, which couldhelp direct antibiotic therapy. It also allows the labora-tory to identify the infecting pathogens in hours ratherthan days, whether or not the patient has been treatedwith anti-microbials and with far greater sensitivity thanstandard culture methods [36].

Imaging techniques

One other area in which there have been newdevelopments in diagnosis is imaging of soft tissue andbone infections. While magnetic resonance imaging (MRI)has emerged as the preferred imaging modality for DFIs[37,38], several new nuclear medicine techniques havebeen introduced. These include directly targeting whiteblood cells by radiolabelling receptors in vivo, attemptingto target live bacteria with antimicrobial labels, usinganalogues of natural mammalian antimicrobial agentsand targeting fungi with labelled antifungal agents[39]. Another approach has been to combine standardimaging methods, like labelled leukocyte scans, withpositron emission tomography and computed tomography(PET/CT) scans [40]. This offers correlated acquisition ofmetabolic and anatomic data, providing high diagnosticaccuracy. The proper circumstances in which to considerusing these and similar methods, and their cost-effectiveness, are as yet unknown.

Treatment

In the past few years many studies have reportedthe results of treatments for DFIs. These includeantimicrobial agents of various types, delivered indifferent ways, as well as several kinds of adjunctivetreatments. Unfortunately, there is still little evidenceto support the effectiveness of many treatments. Infact, a recent systematic review of the effectivenessof antimicrobial treatments for diabetic foot ulcerssummarized the results of papers published up untilNovember 2002 [41]. The authors, after reviewingthe 23 eligible randomized or controlled clinical trials,concluded that the evidence is too weak to recommendany particular antimicrobial agent. Large studies areneeded of the effectiveness and cost-effectiveness of



antimicrobial interventions. [41] Let us review some ofthe studies that have been published in the 4 years sincethis review.

Topical and local anti-microbials

Topical antimicrobial therapy continues to be an appeal-ing method for treating infected wounds. Several newsilver-based products have been marketed, but a recentCochrane systematic review that examined papers pub-lished through 2004 concluded that, [d]espite thewidespread use of dressings and topical agents contain-ing silver for the treatment of diabetic foot ulcers, norandomised trials or controlled clinical trials exist thatevaluate their clinical effectiveness. [42]. Similarly, thereare few studies of the efficacy (or safety) of topical iodidesin treating DFIs [43]. Investigational topical agents fortreating DFI include antimicrobial peptides, such as Pex-iganan [44], and superoxidized water solutions, such asDermacyn [45,46]. Studies to determine the usefulness ofseveral of these new agents are currently being developed.

A variety of antibiotic delivery mechanisms have beentried for treating open diabetic foot wounds. Theseinclude biodegradable materials, such as vancomycinimpregnated calcium sulphate beads and gentamicinincorporated into collagen [4749]. These devices candeliver high local antibiotic concentrations, for a sustainedperiod of time with minimal systemic levels. Anothernew method of instilling antibiotics into a wound isdesigned to work in conjunction with the vacuum-assisted closure (VAC) device [50]. This device can beapplied within 24 h after a wound has been adequatelysurgically debrided, and usually in conjunction withsystemic antibiotic therapy. Another novel method oftreating infected foot ulcers is the so-called Biogun.[51,52] This device ionizes molecular oxygen andgenerates superoxide radical anions (O2) that havea bactericidal effect against micro-organisms. In apilot study of 15 patients with MRSA colonization ofdiabetic foot ulcer, this device eradicated the organismfrom 60%. Honey, a topical agent that has beenused for many years, has recently been promoted fortreating MRSA infections, and the American Academyof Family Physicians is co-sponsoring a randomizedcontrolled trial for treating diabetic foot ulcers. Anotherexample of an older approach being resurrected in thesetimes of increasing antibiotic resistance is therapy withbacteriophages. These viruses that kill bacteria werediscovered 90 years ago, but fell out of use in mostparts of the world after the discovery of antibiotics[53]. One review of over 1300 patients with infectionscaused by multi-resistant bacteria who were treatedwith specific bacteriophages reported full recovery in85% and transient improvement in another 11% [54].Yet another long-used form of biotherapy, maggotdebridement, has also been found to be effective ineradicating MRSA colonization of diabetic foot ulcers[55]. Determining which of these old or new remedies

may prove useful in treating DFIs will require propercontrolled trials.

Systemic anti-microbials

Several studies of systemic antibiotic therapy of DFIs havebeen published in the past few years. In the light ofthe concern for MRSA infections, one study comparedlinezolid, a newly developed oxazolidinone antibioticactive against almost all gram-positive organisms,against an aminopenicillin/beta-lactamase inhibitor [10].Although other specified antibiotics that are active againsteither gram-negative organisms (for the patients onlinezolid) or MRSA (for the patients on the comparator)could have been added, they rarely were. Nevertheless,linezolid was at least as effective as the broader-spectrumagent, with a similar safety profile. In another study ofa subset of patients with a DFI, daptomycin, anothernew anti-MRSA drug, was compared to vancomycin(for patients with MRSA infection) or a semi-syntheticpenicillin (for patients with a methicillin-sensitiveinfection) [56]. The clinical and microbiological efficacyand safety were similar for all three arms of the study.More recently, ertapenem, a new once-daily dosed class 1carbapenem antibiotic was compared with the somewhatbroader-spectrum agent piperacillin/tazobactam in alarge group of patients with a DFI [13]. Again, theclinical and microbiological outcomes and safety profilewere similar for the two study drugs. Finally, in yetanother study of patients with DFIs, moxifloxacin, a broad-spectrum fluoroquinolone, had comparable outcomes topiperacillin/tazobactam (IV) or amoxicillin/clavulanate(orally) [57]. While these studies do not allow us toselect any one agent as preferable to others, they dodemonstrate the effectiveness of several new antibiotics.On the basis of these studies, linezolid, ertapenem,and piperacillin/tazobactam have been approved bythe US FDA specifically for treating DFIs (but not forosteomyelitis).

A number of investigational antibiotic agents, includingceftobiprole and dalbavancin, appear to be promising fortreating DFIs based on their pharmacological propertiesand effectiveness in vitro against strains of bacteriathat were recovered from clinical DFIs [58,59]. Ofnote is that some older agents that were supplantedby newer drugs or were largely discarded because ofconcerns about toxicity have been used to treat resistantinfections. In two reports, the polymixin agent colistinthat is rarely used now was found to be effective,alone or in combination with other anti-microbials,in treating a series of diabetic patients with softtissue or bone infections caused by multi-drug resistantP. aeruginosa [60,61]. In a similar vein, optimizinghow we use available agents can lead to better clinicaloutcomes. One pharmacokinetic analysis of therapy withoral and parenteral amoxicillin/clavulanate in patientswith a DFI found that a reduction in viable bacteria wasreached significantly earlier with continuous IV infusioncompared with intermittent dosing [62].


S70 B. A. Lipsky

Adjunctive therapies

Finally, several therapies that are not directly antimi-crobial have been used in conjunction with antibioticsor other treatments in an attempt to improve out-comes in DFIs. Certainly, all patients need supportivetherapy including optimal glycaemic control and properwound dressings, and fluid and electrolyte resuscitationfor severely ill patients. Most patients also need somekind of surgical procedure, ranging from bedside or clinicdebridement, through incision and drainage or opera-tive debridement, to bone resection, revascularization,or amputation. Among the more widely used adjunctivetreatments is systemic hyperbaric oxygen. It is difficult tointerpret the results of the many published case series,but a systematic review of four randomized controlledtrials with a total of 147 patients concluded that therewas some benefit to the therapy, especially in reducingmajor amputations [63]. The studies are methodolog-ically weak, however and the one study with a shamtreatment arm showed no effect [64]. Another expen-sive new technology is granulocyte colony stimulatingfactor (G-CSF). A systematic review of the five pub-lished randomized controlled trials with a total of 167patients found that the various regimens used affordedno improvement in resolving infection but they wereassociated with significantly fewer operative interven-tions (including amputations) [65]. Additional studiesare needed to determine if the substantial resources con-sumed by these expensive treatments could be betterspent on other measures.

Summary

We have made much progress in understanding how todiagnose and treat foot infections in patients with dia-betes. More investigators are asking and answering keyquestions in this arena, and the addition of new treat-ments and refinements of older ones have likely improvedthe outlook for patients with a DFI. Most studies now showthat more than 80% of patients with a soft tissue infec-tion and over 60% with osteomyelitis can expect clinicalresolution. New guidelines have codified the principles ofmanaging DFIs. The job is now to disseminate this infor-mation and facilitate employing the recommendations.

Conflict of interestThe author has either served as a consultant to, or hasreceived research funding from, Merck, Pfizer, Wyeth-Ayerst, Bayer, Cubicin and Johnson & Johnson/OrthoMcNeil.

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New Developments in Diagnosing and Treating Diabetic Foot Infections