Diabetic Foot Infection: Stimulate the Phagocytes
December 15, 1997 6 minutes read
Diabetic Foot Infection: Stimulate the Phagocytes
ABSTRACT & COMMENTARY
Synopsis: The administration of granulocyte-colony stimulating factor was associated with acceleration of improvement in diabetic foot infections in a blinded, placebo-controlled trial.
Source: Gough A, et al. Randomized placebo-controlled trial of granulocyte-colony stimulating factor in diabetic foot infection. Lancet 1997;350:855-859.
Gough and colleagues randomized 40 diabetic patients with "extensive cellulitis" of the foot to receive either G-CSF (filgrastim, Neupogen) or placebo subcutaneously for seven days in a double-blind trial. Extensive cellulitis was defined as acute, spreading infection of the skin with involvement of subcutaneous tissues with erythema and purulent discharge, with or without lymphangitis. All patients received ceftazidime, amoxicillin, flucloxacillin, and metronidazole intravenously. The initial G-CSF dose was 5 mcg/kg with subsequent adjustment by the pharmacist depending upon peripheral WBC. Sixty percent of the patients in each group had osteomyelitis.
The median duration of foot ulceration prior to study entry was approximately twice as long in the patients assigned placebo (39.5 days) compared to those assigned G-CSF (20.0 days). Polymicrobial infections were also more common in the placebo group. The groups were otherwise similar at baseline.
Patients assigned G-CSF had a significantly shorter median time to conversion of surface cultures to negative (4 vs 8 days; P = 0.02), shorter median duration of cellulitis (7 vs 12 days; P = 0.03), shorter median duration of IV antibiotic therapy (8.5 vs 14.5 days; P = 0.02), and shorter median duration of hospital stay (10 vs 17.5 days; P = 0.02). Only four patients had healed their ulcer at seven daysall were in the G-CSF group.
Total neutrophil counts, as expected, rose significantly. Ex vivo study of neutrophils obtained after three and seven days of study from patients receiving G-CSF, but not those receiving placebo, revealed enhanced superoxide production.
COMMENT BY STAN DERESINSKI, MD, FACP
Patients with diabetes mellitus are at increased risk of a variety of infections, but the most troublesome are those involving their feet. Such infections often result in amputations, a procedure that is performed in diabetics at a rate of approximately 80 per 10,000 per year in the United States, with the rate being as high as one in 10 each year in those older than 65. More than one-half of all nontraumatic amputations in the United States are performed in diabetics.
A number of factors account for the frequency and severity of foot infections in diabetics.1 Key among these is peripheral neuropathy, with resultant impaired or absent pain sensation and consequent inability to sense injury, together with impaired sweating as a result of autonomic neuropathy. The latter causes increased friction, resulting in blistering and subsequent infection.
Diabetic foot infections are commonly unaccompanied by some of the usual physical findings of inflammation, particularly erythema. While diminished blood flow and abnormalities of phagocytic function may contribute to this, another important cause of the lack of erythema appears to be impairment of the neurogenic vascular response to stimuli.2 Patients with peripheral neuropathy and foot lesions have evidence of loss of nociceptive C-fiber function, with resultant absent pain sensation and neurogenic inflammation. Loss of integrity of the capillary circulation and of tissue perfusion of the foot is also of key importance in the pathophysiology of this problem and in determining the outcome of therapy.3
The development of foot ulcers may be initiated by a variety of exogenous influences, including mechanical force (from, e.g., a poorly fitting shoe), burns, frostbite, ingrown toenails, and as the result of attempts at self-care, such as inexpert management of nail trimming, calluses, and even the use of over-the-counter "corn cures."4 In one instance, two diabetic patients developed painless ulcers at the site of moxibustion therapy for painful cold feet.5
In addition to these local problems, diabetics exhibit a wide variety of deficits in in vitro neutrophil function, including mobilization, adhesion to nylon fibers or glass wool, plasma chemotactic factor, chemotaxis, opsonic activity, phagocytosis, oxidative burst, and intracellular bactericidal activity.6-16 Some of these defects may be related to abnormal calcium metabolism.17 An additional cause may be the glycosylation of antimicrobial proteins, including bactericidal proteins such as lysozyme, as well as proteins involved in respiratory burst.18,19
G-CSF administration not only increases the concentration of neutrophils in peripheral blood, but also enhances their function, including increasing surface expression of receptors for complement and adhesion, chemotaxis, superoxide production, phagocytosis, and killing. Similar effects are evidenced by GM-CSF, which, in addition, activates monocyte/macrophage function.20 Thus, it is natural to evaluate these colony stimulating factors as adjunctive therapy in a variety of infectious diseases, as well as in attempts to heal chronic skin ulcers. Thus, a single peri-lesional GM-CSF injection was associated with improved healing of chronic leg ulcers in a small, placebo-controlled trial.21
The study reviewed here today shows promise, but its results cannot be accepted as definitive. A major problem in this small study is the imbalances between treatment groups at baseline, which generally favored the group assigned G-CSF. This study should, however, contribute to the momentum for expanded clinical investigation of G-CSF and GM-CSF as adjunctive therapy of wound healing and infectious diseases.
References
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11. Gilbert HS, et al. Effects of acute endotoxemia and glucose administration on circulating leukocyte populations in normal and diabetic subjects. Metabolism 1978;27:889-899.
12. Peterson CM, et al. Reversible hematologic sequelae of diabetes mellitus. Ann Intern Med 1977;86:425-429.
13. Bagdade JD, et al. Impaired granulocyte adherence: a reversible defect in host defense in patients with poorly controlled diabetes. Diabetes 1978;27:677-687.
14. Bagdade JD, Walters E. Impaired granulocyte adherence in mildly diabetic patients: Effects of tolazamide treatment. Diabetes 1980;29:309-311.
15. Shah SV, et al. Chemiluminescence and superoxide anion production by leukocytes from diabetic patients. J Clin Endocrinol Metab 1983;57:402-409.
16. Andersen B, et al. Neutrophilic adhesive dysfunction in diabetes mellitus: The role of cellular and plasma factors. J Lab Clin Med 1988;111:275-285.
17. Alexiewicz JM, et al. Polymorphonuclear leukocytes in non-insulin-dependent diabetes mellitus: Abnormalities in metabolism and function. Ann Intern Med 1995; 123:919-924; Reviewed in Infect Dis Alert 1996;15:75-76.
18. Li YM, et al. Antibacterial activity of lysozyme and lactoferrin is inhibited by binding of advanced glycation-modified proteins to a conserved motif. Nature Med 1995;1:1057-1061.
19. Nielson CP, Hindson DA. Inhibition of polymorphonuclear leukocyte respiratory burst by elevated glucose concentrations in vitro. Diabetes 1989;38:1031-1035.
20. Deresinski SC, Kemper CA. Granulocyte-macrophage colony-stimulating factor (GM-CSF) and Granulocyte Colony Stimulating Factor (G-CSF): A comparison of their potential roles in immunomodulatory therapy of infectious diseases. Infections in Med, in press.
21. Marques da Costa R, et al. Double-blind randomized placebo-controlled trial of the use of granulocyte-macrophage colony-stimulating factor in chronic leg ulcers. Am J Surg 1997;173:165-168.
Which of the following is incorrect?
a. Neutrophil function is commonly abnormal in a diabetic.
b. G-CSF and GM-CSF each can enhance neutrophil function.
c. G-CSF and GM-CSF each can enhance monocyte function.
d. More than one-half of nontraumatic amputations in the United States are performed in diabetics.
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