Documenti di Didattica
Documenti di Professioni
Documenti di Cultura
Diabetic foot infections frequently cause morbidity, hospitalization, and amputations. Gram-positive cocci,
especially staphylococci and also streptococci, are the predominant pathogens. Chronic or previously treated
wounds often yield several microbes on culture, including gram-negative bacilli and anaerobes. Optimal culture
specimens are wound tissue taken after debridement. Infection of a wound is defined clinically by the presence
of purulent discharge or inflammation; systemic signs and symptoms are often lacking. Only infected wounds
require antibiotic therapy, and the agents, route, and duration are predicated on the severity of infection.
Mild to moderate infections can usually be treated in the outpatient setting with oral agents; severe infections
require hospitalization and parenteral therapy. Empirical therapy must cover gram-positive cocci and should
be broad spectrum for severe infections. Definitive therapy depends on culture results and the clinical response.
Bone infection is particularly difficult to treat and often requires surgery. Several adjuvant agents may be
beneficial in some cases.
Foot infections in diabetic patients usually begin in a
skin ulceration [1]. Although most infections remain
superficial, 25% will spread contiguously from the
skin to deeper subcutaneous tissues and/or bone. Up
to half of those who have a foot infection will have
another within a few years. About 10%30% of diabetic
patients with a foot ulcer will eventually progress to an
amputation, which may be minor (i.e., foot sparing)
or major. Conversely, an infected foot ulcer precedes
60% of amputations [24], making infection perhaps
the most important proximate cause of this tragic
outcome.
PATHOPHYSIOLOGY
Among the factors predisposing diabetic patients to
foot infections are poorly understood immunologic disturbances, such as impaired polymorphonuclear leukocyte migration, phagocytosis, intracellular killing,
and chemotaxis [5]. The prevalence of these defects
appears to be correlated, at least in part, with the ad-
or symptoms of inflammation (warmth, redness, pain or tenderness, and induration). In chronic wounds, additional signs
suggesting infection may include delayed healing, abnormal
coloration, friability, or foul odor. Infection should be suspected
at the first appearance of a foot problem and at evidence of a
systemic infection or of a metabolic disorder. Peripheral neuropathy or ischemia can either mask or mimic inflammation.
Occasionally, inflammatory signs may be caused by other noninfectious disorders; on the other hand, some uninflamed ulcers
may be associated with underlying osteomyelitis [18]. Signs of
systemic toxicity are surprisingly uncommon in diabetic foot
infections [19], even those that are limb threatening. Proper
evaluation of a diabetic foot infection requires a methodical
approach [20]. Whenever infection is considered, this diagnosis
should be pursued aggressively; these infections can worsen
quickly, sometimes in a few hours.
Clinical presentation. Almost two-thirds of patients with
a diabetic foot infection have evidence of peripheral vascular
disease, and 80% have lost protective sensation [1]. Infections
most often involve the forefoot, especially the toes and metatarsal heads, particularly on the plantar surface. About half of
the patients in reported series have received antibiotic therapy
for the foot lesion by the time they present, and up to onethird have had a foot lesion for 11 month. Many patients do
not report pain, and more than half, including those with serious infections, do not have a fever, elevated WBC count, or
elevated erythrocyte-sedimentation rate [1921].
Assessing severity. Several classification systems have been
proposed for diabetic foot lesions, none of which is universally
accepted. Keys to classifying a foot wound are assessing the
depth of the lesion (by visually inspecting the tissues involved
and by estimating the depth in millimeters) and checking for
ischemia (absent pulses or diminished blood pressure in the
foot) and for infection [22]. Whereas mild infections are relatively easily treated, moderately severe infections may be limb
threatening, and severe infections may be life threatening. Assessing the severity of infection is essential to selecting an antibiotic regimen, influences the route of drug administration,
and helps determine the need for hospitalization. Severity of
infection also helps assess the potential necessity and timing of
surgery and the likelihood of amputation [22]. The wound
should be carefully explored to seek foreign or necrotic material,
and it should be probed with a sterile metal instrument. Deep
space infections often have deceptively few superficial signs.
The clinician should suspect spread of infection when there is
inflammation distant from the skin wound, or when suppurative lesions persist despite apparently appropriate therapy
[23]. A knowledgeable surgeon should evaluate any patient with
systemic toxicity for an occult deep space infection [9]. Clinical
features that help define the severity of infection are shown in
table 1.
Diabetic Foot Treatment CID 2004:39 (Suppl 2) S105
Table 1.
Feature
Mild infection
Severe infection
Presentation
Ulceration
Slowly progressive
Involves only skin
Tissues involved
Cellulitis
Local signs
Epidermis, dermis
Minimal (!2 cm around ulcer rim)
Limited inflammation
Systemic signs
None or minimal
Metabolic control
Foot vasculature
Complicating features
Table 2. Factors that may influence antibiotic treatment of diabetic foot infections
(specific agents, route of administration, and
duration of therapy).
Factor
Clinical severity of the infection
Etiologic agent(s) (known or presumed)
Recent antibiotic therapy
Bone infection
Vascular status at infected site
Allergies to antibiotics
Renal or hepatic insufficiency
Gastrointestinal absorption impairment
Drug toxicity (interactions) potential
Local antibiotic susceptibility data
Formulary and cost considerations
Patient preferences
Published efficacy data
and daptomycin) are under way. New antibiotics are introduced, and some older ones are made obsolete by the emergence of resistance or newly appreciated toxicities. Understanding the principles of antibiotic therapy is therefore more
important than knowing the specific agents that are currently
in vogue [51, 68]. Whereas the US Food and Drug Administration has approved all the above agents (and others) for treating complicated skin and soft-tissue infections, the only drugs
specifically approved for diabetic foot infections are trovafloxacin (which is now rarely used) and linezolid.
Cost of therapy is also an important factor in selecting a
regimen. A large prospective study of deep foot infections in
Sweden found that antibiotics accounted for only 4% of the
total costs of treatment; costs of topical wound treatments were
considerably higher [69]. Variables that explained 95% of the
total treatment costs were the time intervals between diagnosis,
the final required procedure, and wound healing and the number of surgical procedures performed [69]. One American study
demonstrated that therapy with ampicillin/sulbactam was significantly less expensive than therapy with imipenem/cilastatin,
for limb-threatening diabetic foot infections, primarily because
of the lower drug and hospitalization costs and the less severe
side effects associated with the former treatment [70]. More
comparative trials and economic analyses are needed. Published
suggestions on specific antibiotic regimens for diabetic foot
infections vary but are more alike than different. My empirical
antibiotic recommendations, by type of infection, are given in
table 3.
Duration of therapy. The optimal duration of antibiotic
therapy for diabetic foot infections has not been studied. For
mild to moderate infections, a 12-week course has been found
to be effective [10], whereas for more serious infections, treatment has usually been given for 2 weeks, sometimes longer.
Table 3.
Treatment of Osteomyelitis
Recommended
Alternative
d,e
Ampicillin/sulbactam
(3.0 g q.i.d.)
d,e
Regimen should be given at usual recommended doses for serious infections; modify for conditions such as azotemia.
Figure 1.
of cases [71, 72]. Furthermore, oral antibiotics with good bioavailability (e.g., fluoroquinolones and clindamycin) may be
adequate for most, or perhaps all, of the therapy. If all the
infected bone is removed, a shorter course of antibiotic therapy
(e.g., 2 weeks) may be sufficient. For some patients, long-term
suppressive therapy, or intermittent short courses of treatment
for recrudescent symptoms, may be the most appropriate approach. Some data suggest that antibiotic-impregnated beads
(made of methylmethacrylate or other materials) may be useful
for delivering high antibiotic concentrations to infected bones
while also filling dead space [47]. Antibiotic-impregnated orthopedic implants have shown success in treating osteomyelitis
in a few small series [48]. Evidence of resolution of osteomyelitis includes a drop in the erythrocyte sedimentation rate
to normal or a loss of increased uptake on leukocyte scan [25].
Adjuvant Therapies
Several additional measures have been used to improve infection resolution, wound healing, and host response. Those for
which there are published data are briefly reviewed here.
Recombinant granulocyte-colony stimulating factor (GCSF). A randomized controlled study from England of 40
diabetic patients with serious foot infections showed that adding
(to the usual care, including antibiotic therapy) subcutaneous
injections of G-CSF (filgrastim) led to significantly more rapid
resolution of infection and to better outcomes [73]. To the contrary, another randomized controlled trial conducted in Italy
found that there was no significant improvement in cure rates
or microbiological results with adjuvant G-CSF (lenograstim)
among 40 patients with limb-threatening diabetic foot infections
at 3 or 9 weeks after enrollment [74]. The amputation rate was,
Figure 2. Approach to selecting antibiotic therapy for a foot infection in a patient with diabetes. GNR, gram-negative rods; GPC, gram-positive
cocci; MRSA, methicillin-resistant Staphylococcus aureus.
Acknowledgments
Financial support. The author has received research support from
Pfizer (formerly Pharmacia) and Merck.
Conflict of interest. The author is a member of the speakers bureaus
and advisory boards for Pfizer (formerly Pharmacia) and Merck.
References
1. Lipsky BA. Infectious problems of the foot in diabetic patients. In:
Bowker JH, Pfeifer MA, eds. The diabetic foot. 6th ed. St. Louis: Mosby,
2001: 46780.
2. International Working Group on the Diabetic Foot. International consensus on the diabetic foot. Amsterdam, 1999: 196.
3. Pecoraro RE, Ahroni JH, Boyko EJ, Stencil VL. Chronology and determinants of tissue repair in diabetic lower-extremity ulcers. Diabetes
1991; 40:130513.
4. Reiber GE, Pecoraro RE, Koepsell TD. Risk factors for amputation in
patients with diabetes mellitus: a case control study. Ann Intern Med
1992; 117:97105.
5. Wilson RM. Neutrophil function in diabetes. Diabet Med 1986; 3:
50912.
6. McMahon MM, Bistrian BR. Host defenses and susceptibility to infection in patients with diabetes mellitus. Infect Dis Clin North Am
1995; 9:110.
7. Sentochnik DE, Eliopoulos GM. Infection and diabetes. In: Kahn CR,
Weir GC, eds. Joslins diabetes mellitus. 13th ed. Philadelphia: Lea &
Febiger, 1994: 86788.
8. Breen JD, Karchmer AW. Staphylococcus aureus infections in diabetic
patients. Infect Dis Clin North Am 1995; 9:1124.
9. Bridges RM, Deitch EA. Diabetic foot infections. Pathophysiology and
treatment. Surg Clin North Am 1994; 74:53755.
10. Lipsky BA, Pecoraro RE, Larson SA, Ahroni JH. Outpatient management of uncomplicated lower-extremity infections in diabetic patients.
Arch Intern Med 1990; 150:7907.
11. Lipsky BA, Pecoraro RE, Wheat JL. The diabetic foot: soft tissue and
bone infection. Infect Dis Clin North Am 1990; 4:40932.
12. Wheat LJ, Allen SD, Henry M, et al. Diabetic foot infections: bacteriologic analysis. Arch Intern Med 1986; 146:193540.
13. Sapico FL, Witte JL, Canawati HN, Montgomerie JZ, Bessman AW.
The infected foot of the diabetic patient: quantitative microbiology and
analysis of clinical features. Rev Infect Dis 1984; 6(Suppl 1):1716.
14. Gerding DN. Foot infections in diabetic patients: the role of anaerobes.
Clin Infect Dis 1995; 20(Suppl 2):S2838.
15. Tentolouris N, Jude EB, Smirnof I, Knowles EA, Boulton AJM. Methicillin-resistant Staphylococcus aureus: an increasing problem in a diabetic foot clinic. Diabet Med 1999; 16:76771.
16. Lipsky BA, Hiatt HI, Holroyd KJ. Results and prognostic value of Gram
stain of tissue curettage specimens of infected diabetic foot ulcers [abstract 145]. In: Proceedings of the 37th annual meeting of the Infectious
Diseases Society of America (Philadelphia). Alexandria, VA: Infectious
Diseases Society of America, 1999.
17. Redkar R, Kalns J, Butler W, et al. Identification of bacteria from a
non-healing diabetic foot wound by 16 S rDNA sequencing. Mol Cell
Probes 2000; 14:1639.
18. Newman LG, Waller J, Palestro CJ, et al. Unsuspected osteomyelitis in
diabetic foot ulcers: diagnosis and monitoring by leukocyte scanning
with indium 111 oxyquinoline. JAMA 1991; 266:124651.
19. Eneroth M, Apelqvist J, Stenstrom A. Clinical characteristics and outcome in 223 diabetic patients with deep foot infections. Foot Ankle
Int 1997; 18:71622.
20. Edelson GW, Armstrong DG, Lavery LA, Caicco G. The acutely infected
diabetic foot is not adequately evaluated in an inpatient setting. Arch
Intern Med 1996; 156:23738.
21. Armstrong DG, Perales TA, Murff RT, Edelson GW, Welchon JG. Value
of white blood cell count with differential in the acute diabetic foot
infection. J Am Podiatr Med Assoc 1996; 86:2247.
22. 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; 21:8559.
23. Ger R. Newer concepts in the surgical management of lesions of the
foot in the patient with diabetes. Surg Gynecol Obstet 1984; 158:2135.
24. Frykberg RG, Mendeszoon ER. Charcot arthropathy: pathogenesis and
management. Wounds 2000; 12(Suppl B):35B42B.
25. Lipsky BA. Osteomyelitis of the foot in diabetic patients. Clin Infect
Dis 1997; 25:131826.
26. Grayson ML, Gibbons GW, Balogh K, Levin E, Karchmer AW. Probing
to bone in infected pedal ulcers: a clinical sign of underlying osteomyelitis in diabetic patients. JAMA 1995; 273:7213.
27. Wrobel JS, Connolly JE. Making the diagnosis of osteomyelitis: the
role of prevalence. J Am Podiatr Med Assoc 1998; 88:33743.
28. Harwood SJ, Valdivia S, Hung GL, Quenzer RW. Use of sulesomab, a
radiolabeled antibody fragment, to detect osteomyelitis in diabetic patients with foot ulcers by leukoscintigraphy. Clin Infect Dis 1999; 28:
12005.
29. Enderle MD, Coerpre S, Schweizer HP, et al. Correlation of imaging
techniques to histopathology in patients with diabetic foot syndrome
and clinical suspicion of chronic osteomyelitis. The role of highresolution ultrasound. Diabetes Care 1999; 22:2949.
30. Craig JG, Amin MB, Wu K, et al. Osteomyelitis of the diabetic foot:
MR imaging-pathological correlation. Radiology 1997; 203:84955.
31. Rosenberg ZA, Beltran J, Bencardino JT. MR imaging of the ankle and
foot. Radio Graphics 2000; 20(Special issue):S15379.
32. Jones V. Debridement of diabetic foot lesions. Diabetic Foot 1998; 1:
8894.
33. Sutton P, Harley J, Jacobson A, Lipsky BA. Diagnosing osteomyelitis
with percutaneous bone biopsy in patients with diabetes and foot infection [abstract 30]. In: Proceedings of the 38th annual meeting of
the Infectious Diseases Society of America (New Orleans). Alexandria,
VA: Infectious Diseases Society of America, 2000.
34. Jaegeblad G, Apelqvist J, Nyberg P, Berger B. The diabetic foot: from
ulcer to multidisciplinary team approach; a process analysis [abstract
P87]. In: Abstracts of the 3rd International Symposium of the Diabetic
Foot (Noordwijkerhout, The Netherlands), 1998: 149.
35. Robson MC, Mannari RJ, Smith PD, Payne WG. Maintenance of
wound bacterial balance. Am J Surg 1999; 178:399402.
36. OMeara SM, Cullum NA, Majid M, Sheldon TA. Systemic review of
antimicrobial agents used for chronic wounds. Br J Surg 2001; 88:421.
37. Chantelau E, Tanudjaja T, Altenhofer F, Ersanli Z, Lacigova S, Metzger
C. Antibiotic treatment for uncomplicated neuropathic forefoot ulcers
in diabetes: a controlled trial. Diabet Med 1996; 13:1569.
38. Hirschl M, Hirschl AM. Bacterial flora in mal perforant and antimicrobial treatment with ceftriaxone. Chemotherapy 1992; 38:27580.
39. Foster AVM, Bates M, Doxford M, Edmonds ME. Should oral antibiotics be given to clean foot ulcers with no cellulitis? [abstract O13].
In: Abstracts of the 3rd International Symposium of the Diabetic Foot
(Noordwijkerhout, The Netherlands), 1998.
40. Kuck EM, Bouter KP, Hoekstra JBL, Conemans JMH, Diepersloot RJA.
Tissue concentrations after a single-dose, orally administered ofloxacin
in patients with diabetic foot infections. Foot Ankle Int 1998; 19:3840.
41. Muller M, Brunner M, Hollenstein U, et al. Penetration of ciprofloxacin
into the interstitial space of inflamed foot lesions in noninsulindependent diabetes mellitus patients. Antimicrob Agents Chemother
1999; 43:20568.
42. Marangos MN, Skoutelis AT, Nightengale CH, et al. Absorption of
ciprofloxacin in patients with diabetic gastroparesis. Antimicrob Agents
Chemother 1995; 39:21613.
43. Raymakers JT, Houben AJ, van de Heyden JJ, Tordoir JH, Kitslaar PJ,
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
63.
64.
65.
Schaper NC. The effect of diabetes and severe ischaemia on the penetration of ceftazidime into tissues of the limb. Diabet Med 2001; 18:
22934.
El-Sherif El-Sarkey M. Local intravenous therapy in chronic inflammatory and vascular disorders of the foot. Int Surg 1997; 82:17581.
Dorigo B, Cameli AM, Trapani M, Raspanti D, Torri M, Mosconi G.
Efficacy of femoral intra-arterial administration of teicoplanin in grampositive diabetic foot infections. Angiology 1995; 46:111522.
Connolly JE, Wrobel JS, Anderson RF. Primary closure of infected
diabetic foot wounds: a report of closed instillation in 30 cases. J Am
Podiatr Med Assoc 2000; 90:17582.
Roeder B, Van Gils CC, Maling S. Antibiotic beads in the treatment
of diabetic pedal osteomyelitis. J Foot Ankle Surg 2000; 39:12430.
Yamashita Y, Uchida A, Yamakawa T, Shinto Y, Araki N, Kato K. Treatment of chronic osteomyelitis using calcium hydroxyapatite ceramic
implants impregnated with antibiotics. Int Orthop 1998; 22:24751.
Kollenberg LO. A new topical antibiotic delivery system. World Wide
Wounds 1998; 1:119. Available at: http://www.worldwidewounds
.com/1998/july/Topical-Antibiotic-Delivery-System/topical-antibiotic
-delivery-system.html. Accessed on 8 July 2004.
Lipsky BA, McDonald D, Litka PA. Treatment of infected diabetic foot
ulcers: topical MSI-78 vs. oral ofloxacin [abstract]. Diabetologia
1997; 40(Suppl 1):482.
Lipsky BA. Evidence-based antibiotic therapy of diabetic foot infections. FEMS Immunol Med Microbiol 1999; 26:26776.
Fierer J, Daniel D, Davis C. The fetid foot: lower extremity infections
in patients with diabetes with diabetic mellitus. Rev Infect Dis 1979;
1:2107.
Hughes CA, Johnson CC, Bamberger DM, et al. Treatment and longterm follow-up of foot infections in patients with diabetes or ischemia:
a randomized, prospective, double-blind comparison of cefoxitin and
ceftizoxime. Clin Ther 1987; 10(Suppl A):3649.
LeFrock JL, Blais F, Schell RF, et al. Cefoxitin in the treatment of diabetic
patients with lower extremity infections. Infect Surg 1983 May: 36174.
File TM, Tan JS. Amdinocillin plus cefoxitin versus cefoxitin alone in
therapy of mixed soft tissue infections (including diabetic foot infections). Am J Med 1983; 80(Suppl):1005.
Anania WC, Chinkes SL, Rosen RC, Turner PR, Helfand AE. A selective
clinical trial of ceftizoxime. J Am Podiatr Med Assoc 1987; 77:648652.
Lipsky BA, Baker PD, Landon GC, Fernau R. Antibiotic therapy for
diabetic foot infections: comparison of two parental-to-oral regimens.
Clin Infect Dis 1997; 24:6438.
Grayson ML, Gibbons GW, Habershaw GM, et al. Use of ampicillin/
sulbactam versus imipenem/cilastatin in the treatment of limb-threatening foot infections in diabetic patients. Clin Infect Dis 1994; 18:
68393.
zcebe O, Gullu U
nal S, et al. Efficacy of sulbactam-amAkova M, O
picillin for the treatment of severe diabetic foot infections. J Chemother
1996; 8:2849.
Zeillemaker AM, Veldkamp KE, van Kraaij MG, Hoekstra JBL, van
Papendrecht AA, Dipersloot RJ. Piperacillin/tazobactam therapy for
diabetic foot infection. Foot Ankle Int 1998; 19:16972.
Graham DR, Talan DA, Nichols RL, et al. Once-daily, high-dose levofloxacin versus ticarcillin-clavulanate alone or followed by amoxicillin-clavulanate for complicated skin and skin-structure infections: a
randomized, open-label trial. Clin Infect Dis 2002; 35:3819.
Peterson LR, Lissack LM, Canter K, Fasching CE, Clabots C, Gerding
DN. Therapy of lower extremity infections with ciprofloxacin in patients with diabetes mellitus, peripheral vascular disease, or both. Am
J Med 1989; 86:8018.
Sesin GP, Paszko A, OKeefe EO. Oral clindamycin and ciprofloxacin
therapy for diabetic foot infections. Pharmacotherapy 1990; 10:1546.
Beam TR, Gutierrez I, Powell S, et al. Prospective study of the efficacy
and safety of oral and intravenous ciprofloxacin in the treatment of
diabetic foot infections. Rev Infect Dis 1989; 11(Suppl 5):S1163.
Diamantopoulos EJ, Haritos D, Yfandi G, et al. Management of severe
66.
67.
68.
69.
70.
71.
72.
73.
74.
75.
76.
77.
78.
79.
80.
81.
82.
83.
84.
85.
86.