An Overview of Foot Infections in Diabetes

Abstract

Patients with diabetes are prone to ulcerations of the lower extremities, frequently complicated by infection, and are then reliant upon their caregivers for preservation of their limbs without the dreaded outcome of amputation. The enormous tolls of foot infections in diabetes, in terms of both health-related quality of life issues and associated economic burdens, have only been fully realized within the last few decades, and it is anticipated that these burdens will only increase over time. Early and appropriate antibiotic treatment targeting the most likely etiologic pathogens is a cornerstone of management of foot infections in diabetes, but these decisions are now complicated by the emergence of resistant organisms, particularly methicillin-resistant Staphylococcus aureus and multidrug-resistant Gram-negative species. This review will examine the impact of foot infections in diabetes and the overall care and management of the diabetes patient with foot infection, including the potential value of emerging antibiotic therapies within the milieu of antibiotic resistance.

Introduction

I t was estimated in 2007 that 7.8% of the U.S. population suffers from diabetes, an estimate that yields approximately 23.6 million people.¹ Diabetes was the seventh leading cause of death listed on U.S. death certificates in 2006, and even this onerous figure is thought to be under-reported, as the deaths of individuals with diabetes are most often attributed to cardiovascular and renal disease as opposed to causes uniquely linked to diabetes.^1,2 Globally, diabetes is thought to be the fifth leading cause of death.² The prevalence of diabetes for all age groups is predicted to double by the year 2030 should obesity levels remain constant, but this, too, is likely to be proven an underestimation given the more probable scenario that global levels of obesity will continue to rise and that improving rates of survival in developing countries may inflate this figure further still.³ Exacerbating this plight is the likelihood that many of these patients are likely to have only limited or infrequent access to multidisciplinary treatment centers.⁴

Foot infections in diabetes are the most frequent cause of hospitalization related to diabetes.⁵ In 2004, approximately 71,000 nontraumatic lower-limb amputations were performed on U.S. patients with diabetes,¹ while on a global scale a lower limb is lost as a complication of diabetes every 30 s.⁶ Approximately half of all foot ulcers will be clinically infected by the time a patient presents to a clinician, and if a foot ulcer is left untreated, even superficial infections can spread to the subcutaneous tissues, ultimately involving muscle, tendons, bones, and joints.⁷ The median time to healing is in excess of 2 months, and only two-thirds of foot ulcers in diabetes will heal in the absence of a surgical intervention.⁸

The quality of life for the non-healing diabetes patient with foot infection is reduced by approximately 10–40% of that found in nonulcerative patients, not only in terms of their physical health, but the impact can also extend to their psychological, social, and economic well-being, and these effects are even more pronounced in patients who have undergone amputation of a limb.⁹ Furthermore, a diabetes patient with a history of foot ulcers is at greater than a twofold hazard risk for mortality compared with those without diabetes and at 47% increased risk of mortality compared with diabetes patients without a history of foot ulcers.⁴

Management of the Foot in Diabetes

The effects of an infection can significantly impair wound healing, lead to additional loss of tissue, or eventually precipitate a loss of limb.⁸ The severity of these infections can range from mild and self-limited to limb-threatening or even life-threatening scenarios, and ascertaining the degree of severity is a critical step in the determination of an appropriate treatment regimen.

The presence of a bacterial infection must first be differentiated from contamination and colonization, and therefore any microbiological findings must be interpreted within the context of the full clinical picture.¹⁰ Contamination is defined as the presence of bacteria without multiplication, whereas colonization is defined as the presence of bacteria with multiplication, and infection is defined as the presence of bacteria with multiplication accompanied by a host response.¹¹ Although these descriptions are helpful, they are by no means definitive. The key message is that the simple presence of microbes is not necessarily indicative of a wound infection,¹² and because microorganisms are present in every skin wound, the diagnosis of infection should not be based solely on microbiological findings. In fact, contamination and colonization by microbes may have little effect on wound healing, and it can be difficult to define at what point colonization progresses to infection. The search for an easy line of demarcation has led to a proposed “critical colonization” point, although this is certainly not a clearly defined term.¹²

Because not every ulcer will be infected, the presence of an infection is typically diagnosed based on clinical signs and symptoms that include purulent secretions and distinct manifestations of inflammation, such as redness, warmth, swelling or induration, and pain or tenderness;¹³ once identified, the infection is then further stratified based upon its severity. The Infectious Diseases Society of America and the International Working Group on the Diabetic Foot have proposed a classification scheme that separates infected wounds into categories designated as “mild,” “moderate,” or “severe” (Table 1).^13
–15

Table 1.

Classifications of Severity in the Foot in Diabetes

Grade	Findings
Uninfected	Wound lacks purulence or any manifestations of inflammation
Mild	Two or more manifestations of inflammation:
	• Purulence or erythema
	• Pain
	• Tenderness
	• Warmth
	• Induration
	Any cellulitis or erythema extends ≤2 cm around ulcer
	Infection limited to skin or superficial subcutaneous tissue
	No local complications or systemic illness
Moderate	Infection in a patient who is systemically well and metabolically stable, but exhibits one or more of the following:
	• Cellulitis extending >2 cm around the ulcer
	• Lymphangitis
	• Spread to beneath the fascia
	• Deep tissue abscess
	• Gangrene
	• Muscle, tendon, joint, or bone involvement
Severe	Infection in a patient with systemic toxicity or metabolic instability (e.g., fever, chills, tachycardia, hypotension, confusion, vomiting, leukocytosis, acidosis, hyperglycemia, or azotemia)

The classification scheme is based on that proposed by the Infectious Diseases Society of America and the International Working Group on the Diabetic Foot.^14
–16

Infections that are deemed as only mild are nevertheless differentiated from uninfected lesions under this classification scheme, whereas severe infections require immediate hospitalization and empirical, broad-spectrum antibiotic therapy. The moderate designation covers the broadest spectrum of wounds, and this category can also encompass lesions that are quite complex and even limb-threatening.¹³ Increasing wound severity within this classification system has been shown to correlate with an increasing risk for lower-extremity comorbidities in a cohort of 1,666 diabetes patients, as well as an increased frequency of lower-extremity amputation, thereby serving to validate the clinical value of this grading tool in the prediction of clinical outcomes.¹⁴

Following the diagnosis of infection, the stepwise medical and surgical management of a foot infection in diabetes will include incision and drainage, debridement to remove infected and necrotic tissue, investigation of wound depth to determine the likelihood of osteomyelitis or joint infection, wound lavage, and antibiotic treatment, followed by wound closure and revascularization as appropriate.⁷ The judicious use of amputation is considered as a last resort.

Debridement for the removal of infected or necrotic tissue that is no longer viable may shorten healing processes, and it is following debridement that assessments can be made as to the depth of the wound and whether osteomyelitis might be present. For the detection of osteomyelitic disease, palpation of bone with a sterile probe in patients with diabetes has been shown to be strongly correlated with the presence of osteomyelitis, particularly in clinical settings that have a high pre-test probability (a high prevalence) of bone infection.^15

–18 Although there is no single feature that reliably excludes the presence of osteomyelitis,¹⁸ there are data to suggest that a negative test is correlated with a negative predictive value.⁵ For infections of the bone without surgical debridement, the generally recommended duration of antibiotic therapy is 6 weeks, although antibiotic treatment for foot osteomyelitis in diabetes for 3 months or longer is not uncommon.⁸ If the bone is debrided, antibiotic duration is often much shorter.

Microbiology of the Foot in Diabetes

It is important to recognize that the progression from colonization to clinical infection cannot be predicted by the presence of a specific pathogen, nor does the presence of a specific organism imply a role in the underlying pathology.^7,19 In fact, the majority of foot infections in diabetes will be polymicrobial,^20,21 and the prevalence of polymicrobial infections has been clearly demonstrated by Citron et al.,²² who examined 427 culture-positive specimens and found that only 16.2% had growth of a single organism; the remaining specimens were polymicrobial, with 43.7% yielding four or more organisms. Hospitalization and prolonged wound duration are associated with increasingly complex polymicrobial infections.²³

The most frequently reported microorganisms revealed by microbiologic analyses include Staphylococcus aureus, coagulase-negative staphylococci, Streptococcus spp., Enterococcus spp., Corynebacterium spp., Enterobacteriaceae, and Pseudomonas aeruginosa (Table 2).^{22,24

–28} Aerobic Gram-positive cocci, particularly staphylococci, are the most frequent cause of foot infections in diabetes, although mixed infections with aerobic Gram-negative bacilli or obligate anaerobes are also common.²⁹ The successful identification of anaerobic organisms will be strongly dependent on the sophistication of sample collection, its transportation, and subsequent incubation methods,^19,30
–32 and the predominant anaerobes identified will likely include Gram-positive cocci, Porphyromonas spp., Prevotella spp., and Bacteroides fragilis, although these species are generally less common and frequently occur in the presence of aerobic species.²⁷

Table 2.

Common Pathogens Isolated from Foot Infections in Diabetes

Bacteria	Pathogens
Aerobic Gram-positive	Staphylococcus spp.
	S. aureus
	Coagulase-negative spp.
	Enterococcus spp.
	E. faecalis
	Streptococcus spp.
	S. pyogenes
	Corynebacterium spp.
Aerobic Gram-negative	Proteus spp.
	P. mirabilis
	Klebsiella spp.
	K. pneumoniae
	K. oxytoca
	Enterobacter spp.
	E. cloacae
	P. aeruginosa
	E. coli
	M. morganii
Anaerobic Gram-positive	Peptostreptococcus spp.
	P. anaerobius
	P. asaccharolyticus
	F. magna
Anaerobic Gram-negative	Bacteroides spp.
	B. fragilis
	Prevotella spp.
	Porphyromonas spp.

Infections classified as mild to moderate will generally yield Gram-positive organisms, whereas moderate to severe infections are likely to be revealed as polymicrobial, involving Gram-negative species, and nearly half will include anaerobic organisms.^19,22 Anaerobes such as Peptostreptococcus spp., Bacteroides spp., and Prevotella spp. are most significant in patients with ischemia of the foot or gangrene, although the overall importance of anaerobic organisms is unclear.²⁷ S. aureus is typically acknowledged as the most broadly causative pathogen, but geographical variations do exist, as demonstrated by reports from India that reveal a predominance of Gram-negative aerobic species.^25,28 Gram-negative bacilli such as Enterobacteriaceae are often isolated from previously treated infections, and Pseudomonas spp. are frequently found in wounds that have been soaked or treated with wet dressings.³³ Outpatients with acute wounds who have not recently received antibiotics are more likely to yield aerobic, Gram-positive cocci, whereas other patients are more likely to exhibit a polymicrobial infection involving Gram-negative and obligate anaerobic organisms.³⁴

Given the commonality of S. aureus infection, the emergence of methicillin-resistant S. aureus (MRSA) represents a growing problem at both the healthcare and community level, whereas the emergence of extended-spectrum β-lactamases pose a greater challenge in developing countries. In diabetes patients with infected or uninfected foot ulcers, the prevalence of MRSA is as high as 20–50%, and the presence of this organism can significantly prolong healing.^21,35
–37

Frequent use of antibiotics combines with immune system dysfunction in diabetes patients to increase the risk of colonization and subsequent infection of these patients by antibiotic-resistant organisms, particularly MRSA.³⁸ The isolation of MRSA appears to be a significant factor associated with treatment failure in diabetes patients with foot infections,²⁰ and chronic wounds, inpatient care, and chronic kidney disease have each been shown to independently predispose a patient to MRSA infection and subsequent treatment failure.^20,23 Antibiotic coverage for MRSA should be considered in patients with prior hospitalization for the same ulcer, chronic ulceration, or renal impairment.²³

Current Antibiotic Regimens

At present, there is no conclusive evidence to recommend one specific antimicrobial agent over another, either intravenous or oral; a systematic examination of published reports found the strength of evidence to guide the selection of antimicrobial agents for the treatment of foot ulcerations in diabetes is poor in terms of the quality and size of available trials and, in many cases, a lack of replication.³⁹ Most of the common antibiotics or combinations of antibiotics demonstrate similar efficacy, irrespective of their spectrum of activity and the susceptibility of the isolated bacteria.²⁰ It is important to note, however, that the sum total of data specific to foot infections in diabetes is actually quite modest, as it is only over the past few decades that the full impact of this pathology on both patients and healthcare systems has been fully realized, leading to specific and increasing interest in the management of the foot in diabetes.

Appropriate antibiotic therapy is nevertheless a cornerstone of managing the infected lower extremity, with peripheral vascular insufficiency and an increasing prevalence of antibiotic resistance serving as the primary barriers to successful clinical outcomes.³⁸ Initial antibiotic therapy will typically be empirical: an informed choice based on the clinical severity of the infection, patient-specific factors that might include allergies or comorbidities, and any epidemiological clues available to the practitioner.^7,38 Cultures of an infected wound are critical in guiding the choice of antibiotic therapy, and optimal methods for specimen collection are vital for accurate culture results.³⁸

Subsequent modifications in the initial therapeutic regimen, ideally from a broad spectrum of coverage to a more targeted narrow spectrum, will be guided by microbiology reports, antibiotic sensitivity findings, and the patient response to the current therapy already in place.

Patients with mild-to-moderate infections who have not been previously treated with antibiotics can generally be treated with relatively narrow-spectrum antibiotics, typically for 1–2 weeks, with an oral agent targeting staphylococci and streptococci.^7,38,40 Chronic ulcers in which an infection has proven unresponsive will often demand parenteral, broad-spectrum therapy, such as a β-lactam plus β-lactamase inhibitor combination (ampicillin/sulbactam, piperacillin/tazobactam), clindamycin plus a quinolone, imipenem/cilastatin, newer fluoroquinolones (levofloxacin and ciprofloxacin), or third- or fourth-generation cephalosporins (ceftazidime and cefuroxime).^7,8 In the event of a polymicrobial infection, combination therapy is often required to ensure adequate coverage of organisms.³⁸ In the event of osteomyelitic infection, S. aureus should always be covered by empirical therapy and adjusted as necessary based on bone cultures as opposed to soft tissue or sinus tract cultures.²⁹

The Potential of New Antibiotics in This Milieu

Early institution of antibacterial therapy for infected foot ulcers and foot infections has been shown to reduce the risk of amputations, in addition to the significant costs associated with lower-extremity amputations.⁶ Limited data are available on many emerging antimicrobial agents in foot infections in diabetes specifically, but because several of these agents demonstrate activity against MRSA and other resistant organisms, there is a potential role for many of these newer agents in the treatment of foot infections in diabetes (Table 3).

Table 3.

Spectra of Coverage for Emerging Antimicrobial Agents

Antimicrobial	MRSA coverage	Common pathogens in foot infections in diabetes outside the spectrum of coverage
Linezolid	Yes	Gram-negative species
		Anaerobic species
Ertapenem	No	Most enterococci
		P. aeruginosa
Ceftobiprole	Yes	ESBL-producing Enterobacteriaceae
		Ampicillin-resistant enterococci
		B. fragilis
Daptomycin	Yes	Gram-negative species
		Anaerobic species
Dalbavancin	Yes	Gram-negative species
		Vancomycin-resistant enterococci
Iclaprim	Yes	Anaerobic species
		P. aeruginosa
Moxifloxacin	No	P. aeruginosa
Tigecycline	Yes	Non-fermentative Gram-negative bacilli
		Proteus spp.
		P. aeruginosa
Quinopristin/dalfopristin	Yes	E. faecalis
		P. aeruginosa

ESBL, extended-spectrum β-lactamase; MRSA, methicillin-resistant S. aureus.

Among these newer agents, there does appear to be adequate evidence for the use of linezolid over vancomycin in patients with confirmed infections of MRSA,^21,41,42 although linezolid is not effective against Gram-negative and anaerobic microorganisms.^11,43 Good penetration into bone, fat, muscle, and soft tissue suggests activity against staphylococcal infections even when concentrations at the infection site are diminished because of impaired blood flow.^21,43 In a randomized, open-label study to compare the efficacy of intravenous and oral formulations of linezolid with that of intravenous ampicillin/sulbactam and intravenous/oral amoxicillin/clavulanate, clinical cure rates were significantly higher among the subset of patients with infected foot ulcers treated with linezolid (P=0.018) and for those patients without osteomyelitis (P=0.003).⁴¹ Although the use of linezolid was associated with more adverse events, primarily gastrointestinal and hematologic, the majority of events were mild and reversible and did not necessitate discontinuation.⁴¹ Linezolid is expensive, however, and clinicians may choose to reserve its use for documented infection with antibiotic-resistant organisms.⁴¹

The carbapenem antibiotic ertapenem has a range of activity that covers most pathogens implicated in foot infections in diabetes, but the spectrum for this agent does not include MRSA, P. aeruginosa, or most Enterococcus.³⁴ When the drug was evaluated in a cohort of 576 patients with diabetes and a foot infection classified as moderate to severe, a randomized, double-blind trial (SIDESTEP) found clinical success rates of 94.2% for the ertapenem group and 92.2% for the piperacillin/tazobactam comparator group, with no differences in the incidence of drug-related adverse events or the rates of microbiological eradication.³⁴

The ceftobiprole spectrum of activity includes MRSA and vancomycin-intermediate S. aureus, vancomycin-resistant Enterococcus faecalis, and P. aeruginosa but does not include B. fragilis.^11,44,45 In a double-blind trial of complicated skin and skin structure infections patients randomized to ceftobiprole or to ceftazidime plus vancomycin, the subset (222 of 729) of diabetes patients with moderate-to-severe foot infections exhibited similar cure rates in either arm, although the mean duration of treatment was significantly shorter in the ceftobiprole group (8.7 vs. 9.5 days, P<0.05).⁴⁵ Simultaneous coverage of both MRSA and P. aeruginosa is a unique trait that might make ceftobiprole an attractive agent for the management of foot infections in persons with diabetes, but this agent is no longer available in the United States or most other locations in the world.

The clinical and microbiological efficacy of daptomycin is similar to that of vancomycin for the treatment of foot infections in diabetes,⁴⁶ although dosages should be increased to >4 mg/kg.⁴⁷ In vitro, the bactericidal activity of daptomycin is rapid against MRSA, penicillin-resistant streptococci, and vancomycin-resistant enterococci,⁴⁶ but its lack of Gram-negative and anaerobic activity may necessitate combination therapy for moderate and severe foot infections in diabetes if the presence of such organisms is suspected.¹¹

Among the glycopeptide class of agents, dalbavancin possesses good activity against Gram-positive bacteria but no activity against Gram-negative organisms.⁴⁸ Dalbavancin is not active against vancomycin-resistant enterococci but has excellent activity against MRSA, Streptococcus pyogenes, and Streptococcus pneumoniae, as well as vancomycin-susceptible enterococci.⁴⁹ Combination therapy with an agent active against Gram-negative organisms and anaerobes may be necessary for moderate to severe foot infections in diabetes.¹¹ In vitro studies reveal that dalbavancin is generally at least twofold more active than vancomycin and daptomycin and fourfold more active than linezolid against MRSA, methicillin-sensitive S. aureus, and coagulase-negative Staphylococcus isolates.⁴⁸ Telavancin, an analog of vancomycin, has demonstrated in vitro activity against MRSA, penicillin-resistant S. pneumoniae, glycopeptide-intermediate S. aureus, and Van A-type enterococci.⁴⁹ The semisynthetic glycopeptide oritavancin shows rapid, concentration-dependent bactericidal activity, with a concentration-dependent post-antibiotic effect, against vancomycin-resistant enterococci and MRSA and a spectrum of activity similar to that of vancomycin.⁴⁹

Iclaprim, a dihydrofolate reductase inhibitor, possesses an extended spectrum of activity and is more potent than trimethoprim against major Gram-positive pathogens, particularly S. aureus and other streptococci, including strains resistant to trimethoprim, methicillin, and oxacillin, macrolides, quinolones, and glycopeptides, including vancomycin-intermediate and -resistant S. aureus.⁵⁰ Iclaprim exhibits poor antipseudomonal activity, however, and varied activity against anaerobic species.⁵¹

The use of quinolones for the treatment of osteomyelitis is an established therapeutic approach,⁵² and moxifloxacin may have potential utility as a monotherapeutic regimen for foot infections in diabetes.⁵³ Moxifloxacin is not reliable against MRSA, however, and exhibits only limited activity against P. aeruginosa, but otherwise this agent demonstrates good activity against most aerobic and anaerobic microorganisms.^53,54 In a study by Edmiston et al.⁵⁵ incorporating 900 surgical isolates from both foot infections and intra-abdominal infections in diabetes, moxifloxacin exhibited good-to-excellent antimicrobial activity against most aerobic (90.8%) and anaerobic (97.1%) bacteria, including all streptococcal isolates.

Tigecycline, the first commercially available glycylcycline and a derivative of minocycline, is of interest because its broad spectrum of activity against MRSA, Gram-negative organisms, and anaerobes makes it potentially useful as a single agent for the treatment of moderate and severe foot infections in diabetes.¹¹ In a study examining 315 isolates from foot ulcers in diabetes, tigecycline was active against 83.7% of strains, including Gram-positive cocci (97.3%), MRSA (96%), Enterobacteriaceae (88.5%), and 100% of anaerobic species. Not covered by tigecycline in this study were P. aeruginosa or Proteus spp., and tigecycline exhibited poor activity against non-fermentative Gram-negative bacilli.²⁴ Unlike other new agents for Gram-positive cocci, tigecycline also has activity against Gram-negative pathogens, including Haemophilus influenzae, Neisseria spp., Enterobacteriaceae, and non-lactose fermenters other than P. aeruginosa, demonstrating a potential for tigecycline in the treatment of foot infections in diabetes when there is a need for both Gram-positive and Gram-negative coverage.⁴⁹ A recent pooled analysis of all clinical trials in which patients were treated with tigecycline for both approved and unapproved indications found a numerically increased risk of mortality in foot infections in diabetes with the use of tigecycline (seven of 553 [1.3%] of patients) versus ertapenem with or without vancomycin (three of 508 [0.6%] of patients), although this risk difference was not statistically significant (0.7% [95% confidence interval −0.5, 1.8]).⁵⁶

Quinupristin/dalfopristin is active against MRSA, S. pneumoniae, and Gram-positive anaerobes such as Clostridium spp., Peptococcus spp., and Peptostreptococcus spp.⁴⁹ It is effective against both vancomycin-sensitive and -resistant Enterococcus faecium but has little in vitro activity against E. faecalis and P. aeruginosa.^49,57 This agent will likely be confined to a last resort of treatment given an inconvenient administration schedule and frequent adverse events.

Conclusions

Once healed, an infected foot in a patient with diabetes must still be regarded as a lifelong condition and must be treated accordingly to prevent a recurrence of infection. The human and economic burdens imposed by the pathology of foot infections in diabetes are enormous, and projected increases in its prevalence should serve as a clarion call for concerted, global initiatives to curtail the spread of this epidemic. On the whole, the unfortunate truth is that robust clinical studies specifically addressing foot infections in diabetes are few as of yet, with little published evidence to support specific interventions that may nevertheless prove themselves useful tools in reducing the physical, emotional, and financial tolls of foot infections in diabetes.

Footnotes

Acknowledgments

Editorial support for the preparation of this manuscript, funded by Pfizer, was provided by Hessam Alimohammadi (Sanatoga, PA).

Disclosure Statement

No competing financial interests exist.

References

Centers for Disease Control and Prevention. National Diabetes Fact Sheet, 2007. Atlanta: Centers for Disease Control and Prevention, U.S. Department of Health and Human Services, 2007.

Roglic

, Unwin

, Bennett

, Mathers

, Tuomilehto

, Nag

, Connolly

, King

. The burden and mortality attributable to diabetes: realistic estimates for the year 2000. Diabetes Care, 2005; 28:2130–2135.

Wild

, Roglic

, Green

, Sicree

, King

. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care, 2004; 27:1047–1053.

Iversen

, Tell

, Riise

, Hanestad

, Østbye

, Graue

, Midthjell

. A history of foot ulcer increases mortality among persons with diabetes: a 10-year follow-up of the Nord-Trøndelag Health Study, Norway. Diabetes Care, 2009; 32:2193–2199.

Lavery

, Armstrong

, Peters

, Lipsky

. Probe-to-bone test for diagnosing diabetic foot osteomyelitis: reliable or relic? Diabetes Care, 2007; 30:270–274.

Chow

, Lemos

, Einarson

. Management and prevention of diabetic foot ulcers and infections: a health economic review. Pharmacoeconomics, 2008; 26:1019–1035.

Armstrong

, Lipsky

. Diabetic foot infections: stepwise medical and surgical management. Int Wound J, 2004; 1:123–132.

Jeffcoate

, Lipsky

, Berendt

, Cavanagh

, Bus

, Peters

, van Houtum

, Valk

, Bakker

. International Working Group on the Diabetic Foot. Unresolved issues in the management of ulcers of the foot in diabetes. Diabet Med, 2008; 25:1380–1389.

Winkley

, Stahl

, Chalder

, Edmonds

, Ismail

. Quality of life in people with their first diabetic foot ulcer: a prospective cohort study. J Am Podiatr Med Assoc, 2009; 99:406–414.

10.

Ndip

, Bowling

, Stickings

, Rayman

, Boulton

. The diabetic foot in 2008: an update from the 12^th Malvern Diabetic Foot Meeting. Int J Low Extrem Wounds, 2008; 7:235–238.

11.

Kosinski

, Joseph

. Update on the treatment of diabetic foot infections. Clin Podiatr Med Surg, 2007; 24:383–396.

12.

Howell-Jones

, Wilson

, Hill

, Howard

, Price

, Thomas

. A review of the microbiology, antibiotic usage and resistance in chronic skin wounds. J Antimicrob Chemother, 2005; 55:143–149.

13.

Lipsky

, Berendt

, Deery

, Embil

, Joseph

, Karchmer

, LeFrock

, Lew

, Mader

, Norden

, Tan

. Infectious Diseases Society of America. Diagnosis and treatment of diabetic foot infections. Clin Infect Dis, 2004; 39:885–910.

14.

Lavery

, Armstrong

, Murdoch

, Peters

EJG

, Lipsky

. Validation of the Infectious Diseases Society of America's diabetic foot infection classification system. Clin Infect Dis, 2007; 44:562–565.

15.

Apelqvist

, Bakker

, van Houtum

, Schaper

. International Working Group on the Diabetic Foot (IWGDF) Editorial Board. Practical Guidelines on the management and prevention of diabetic foot. Diabetes Metab Res Rev, 2008; 24,Suppl 1:S181–S187.

16.

Newman

, Waller

, Palestro

, Schwartz

, Klein

, Hermann

, Harrington

, Roman

, Stagnaro-Green

. Unsuspected osteomyelitis in diabetic foot ulcers. Diagnosis and monitoring by leukocyte scanning with indium In 111 oxyquinoline. JAMA, 1991; 266:1246–1251.

17.

Grayson

, Gibbons

, Balogh

, Levin

, Karchmer

. Probing to bone in infected pedal ulcers: a clinical sign of underlying osteomyelitis in diabetic patients. JAMA, 1995; 273:721–723.

18.

Butalia

, Palda

, Sargeant

, Detsky

, Mourad

. Does this patient with diabetes have osteomyelitis of the lower extremity? JAMA, 2008; 299:806–813.

19.

Gerding

. Foot infections in diabetic patients: the role of anaerobes. Clin Infect Dis, 1995; 20,Suppl 2:S283–S288.

20.

Vardakas

, Horianopoulou

, Falagas

. Factors associated with treatment failure in patients with diabetic foot infections: an analysis of data from randomized controlled trials. Diabetes Res Clin Pract, 2008; 80:344–351.

21.

Majcher-Peszynska

, Haase

, Sass

, Mundkowski

, Pietsch

, Klammt

, Schareck

, Drewelow

. Pharmacokinetics and penetration of linezolid into inflamed soft tissue in diabetic foot infections. Eur J Clin Pharmacol, 2008; 64:1093–1100.

22.

Citron

, Goldstein

, Merriam

. Bacteriology of moderate-to-severe diabetic foot infections, in vitro activity of antimicrobial agents. J Clin Microbiol, 2007; 45:2819–2828.

23.

Yates

, May

, Hale

, Allard

, Rowlings

, Freeman

, Harrison

, McCann

, Wraight

. Wound chronicity, inpatient care, and chronic kidney disease predispose to MRSA infection in diabetic foot ulcers. Diabetes Care, 2009; 32:1907–1909.

24.

Sotto

, Bouziges

, Jourdan

, Richard

, Lavigne

. In vitro activity of tigecycline against strains isolated from diabetic foot ulcers. Pathol Biol (Paris), 2007; 55:398–406.

25.

Shankar

, Mohan

, Premalatha

. Bacterial etiology of diabetic foot infections in South India. Eur J Intern Med, 2005; 16:567–570.

26.

Richard

, Sotto

, Jourdan

, Combescure

, Vannereau

, Rodier

, Lavigne

. Nîmes University Hospital Working Group on the Diabetic Foot (GP30). Risk factors and healing impact of multidrug-resistant bacteria in diabetic foot ulcers. Diabetes Metab, 2008; 34:363–369.

27.

, MacDonald

, Hait

, Lipsky

, Zasloff

, Holroyd

. Microbiological profile of infected diabetic foot ulcers. Diabet Med, 2002; 19:1032–1034.

28.

Gadepalli

, Dhawan

, Sreenivas

. A clinico-microbiological study of diabetic foot ulcers in an Indian tertiary care hospital. Diabetes Care, 2006; 29:1727–1732.

29.

Lipsky

. New developments in diagnosing, treating diabetic foot infections. Diabetes Metab Res Rev, 2008; 24,Suppl 1:S66–S71.

30.

Louie

, Bartlett

, Tally

, Gorbach

. Aerobic and anaerobic bacteria in diabetic foot ulcers. Ann Intern Med, 1976; 85:461–463.

31.

Sapico

, Canawati

, Witte

, Montgomerie

, Wagner

, Bessman

. Quantitative aerobic and anaerobic bacteriology of infected diabetic feet. J Clin Microbiol, 1980; 12:413–420.

32.

Hunt

. Foot infections in diabetes are rarely due to a single microorganism. Diabet Med, 1992; 9:749–752.

33.

Lipsky

. Evidence-based antibiotic therapy of diabetic foot infections. FEMS Immunol Med Microbiol, 1999; 26:267–276.

34.

Lipsky

, Armstrong

, Citron

, Tice

, Morgenstern

, Abramson

. Ertapenem versus piperacillin/tazobactam for diabetic foot infections (SIDESTEP); prospective, randomized, controlled, double-blinded multicentre trial. Lancet, 2005; 366:1695–1703.

35.

Tentolouris

, Jude

, Smirnof

, Knowles

, Boulton

AJM

. Methicillin-resistant Staphylococcus aureus: an increasing problem in a diabetic foot clinic. Diabet Med, 1999; 16:767–771.

36.

Dang

, Prasad

YDM

, Boulton

AJM

, Jude

. Methicillin-resistant Staphylococcus aureus in the diabetic foot clinic: a worsening problem. Diabet Med, 2003; 20:159–161.

37.

Lagace-Wiens

PRS

, Ormiston

, Nicolle

, Hilderman

, Embil

. The diabetic foot clinic: not a significant source of acquisition of methicillin-resistant Staphylococcus aureus. Am J Infect Control, 2009; 37:587–589.

38.

Armstrong

, Lipsky

. Advances in the treatment of diabetic foot infections. Diabetes Technol Ther, 2004; 6:166–177.

39.

Nelson

, O'Meara

, Golder

, Dalton

, Craig

, Iglesias

. DASIDU Steering Group. Systematic review of antimicrobial treatments for diabetic foot ulcers. Diabet Med, 2006; 23:348–359.

40.

Lipsky

. A report from the international consensus on diagnosing and treating the infected diabetic foot. Diabetes Metab Res Rev, 2004; 20,Suppl 1:S68–S77.

41.

Lipsky

, Itani

, Norden

. Linezolid Diabetic Foot Infections Study Group. Treating foot infections in diabetic patients: a randomized, multicenter, open-label trial of linezolid versus ampicillin-sulbactam/amoxicillin-clavulanate. Clin Infect Dis, 2004; 38:17–24.

42.

Omar

, El-Nahas

, Gray

. Novel antibiotics for the management of diabetic foot infections. Int J Antimicrob Agents, 2008; 31:411–419.

43.

Stein

, Schooley

, Peloquin

, Missavage

, Havlichek

. Linezolid tissue penetration and serum activity against strains of methicillin-resistant Staphylococcus aureus with reduced vancomycin susceptibility in diabetic patients with foot infections. J Antimicrob Chemother, 2007; 60:819–823.

44.

Goldstein

, Citron

, Merriam

, Warren

, Tyrrell

, Fernandez

. In vitro activity of ceftobiprole against aerobic and anaerobic strains isolated from diabetic foot infections. Antimicrob Agents Chemother, 2006; 50:3959–3962.

45.

Deresinski

. The efficacy and safety of a ceftobiprole in the treatment of complicated skin and skin structure infections: evidence from 2 clinical trials. Diagn Microbiol Infect Dis, 2008; 61:103–109.

46.

Lipsky

, Stoutenburgh

. Daptomycin for treating infected diabetic foot ulcers: evidence from a randomized, controlled trial comparing daptomycin with vancomycin or semi-synthetic penicillins for complicated skin and skin-structure infections. J Antimicrob Chemother, 2005; 55:240–245.

47.

Seaton

. Daptomycin: rationale and role in the management of skin and soft tissue infections. J Antimicrob Chemother, 2008; 62,Suppl 3:iii15–iii23.

48.

Goldstein

, Citron

, Warren

, Tyrrell

, Merriam

, Fernandez

. In vitro activities of dalbavancin and 12 other agents against 329 aerobic and anaerobic gram-positive isolates recovered from diabetic foot infections. Antimicrob Agents Chemother, 2006; 50:2875–2879.

49.

Lentino

, Narita

, Yu

. New antimicrobial agents as therapy for resistant gram-positive cocci. Eur J Clin Microbiol Infect Dis, 2008; 27:3–15.

50.

Krievins

, Brandt

, Hawser

, Hadvary

, Islam

. Multicenter, randomized study of the efficacy and safety of intravenous iclaprim in complicated skin and skin structure infections. Antimicrob Agents Chemother, 2009; 53:2834–2840.

51.

Laue

, Weiss

, Bernardi

, Hawser

, Lociuro

, Islam

. In vitro activity of the novel diaminopyrimidine, iclaprim, in combination with folate inhibitors and other antimicrobials with different mechanisms of action. J Antimicrob Chemother., 2007; 60:1391–1394.

52.

Lew

, Waldvogel

. Use of quinolones in osteomyelitis and infected orthopaedic prosthesis. Drugs, 1999; 58,Suppl 2:85–91.

53.

Lipsky

, Giordano

, Choudhri

, Song

. Treating diabetic foot infections with sequential intravenous to oral moxifloxacin compared with piperacillin-tazobactam/amoxicillin-clavulanate. J Antimicrob Chemother, 2007; 60:370–376.

54.

Fritsche

, Sader

, Jones

. Potency and spectrum of garenoxacin tested against an international collection of skin and soft tissue infection pathogens: report from the SENTRY antimicrobial surveillance program (1999–2004) Diagn Microbiol Infect Dis, 2007; 58:19–26.

55.

Edmiston

, Krepel

, Seabrook

, Somberg

, Nakeeb

, Cambria

, Towne

. In vitro activities of moxifloxacin against 900 aerobic and anaerobic surgical isolates from patients with intra-abdominal and diabetic foot infections. Antimicrob Agents Chemother, 2004; 48:1012–1016.

56.

U.S. Food and Drug Administration. FDA Drug Safety Communication: Increased Risk of Death with Tygacil (Tigecycline) Compared to Other Antibiotics Used to Treat Similar Infections. www.fda.gov/Drugs/DrugSafety/ucm224370.htm. 2010 September 9.

57.

Allington

, Rivey

. Quinupristin/dalfopristin: a therapeutic review. Clin Ther, 2001; 23:24–44.