G-CSF in the Treatment of Diabetic Foot Ulcers
G-CSF in the Treatment of Diabetic Foot Ulcers
Abstract & Commentary
Synopsis: In a randomized, controlled trial, patients with diabetic foot ulcers treated with a 21-day course of G-CSF (in addition to standard treatment) along with antibiotic therapy had a lower rate of bone amputation at 9 weeks than patients treated with antibiotics alone.
Source: de Lalla F, et al. Antimicrob Agents Chemother. 2001;45:1094-1098.
Patients with severe diabetic foot infections were randomized to receive either standard treatment (local care and antibiotics) or standard treatment plus recombinant granulocyte-colony stimulating factor (G-CSF) at a dose of 263 mg subcutaneously each day for 21 days. Empiric antibiotic therapy consisted of ciprofloxacin and clindamycin; therapy was adjusted based on the results of deep ulcer cultures. Patients with severe limb ischemia (ankle/brachial blood pressure index < 0.5) were excluded. Twenty patients were enrolled in each group. The 2 groups were similar in terms of age, ulcer severity, laboratory parameters, and microbiology of lesions. Based on culture results, initial antibiotic therapy was adjusted in 60% of patients in each group. All patients had osteomyelitis as documented by bone exposure or probe. Ulcer assessment was carried out by a plastic surgeon who was blinded as to study group assignment. de Lalla and associates defined clinical failure as absence of clinical improvement, or as amputation (consisting of any excision of bone segment) performed after 15 days of appropriate antibiotic therapy.
At 9 weeks, 7 (35%) patients in each group were cured. Five patients receiving G-CSF demonstrated clinical failure compared with 9 control patients (25% vs 45%; P = .19). Amputation as a cause of failure occurred in 3 patients receiving G-CSF compared with 9 control patients (15% vs 45%; P = .038). No patients had adverse reactions to G-CSF.
Comment by Robert Muder, MD
Infection is a major contributor to limb loss in diabetic patients. In addition to vascular disease and peripheral neuropathy, diabetics demonstrate a number of defects in polymorphonuclear leukocyte function that impair the ability to contain and eradicate microorganisms. These include abnormalities in migration, chemotaxis, phagocytosis, and intracellular killing of bacteria.
G-CSF is an endogenous glycoprotein that stimulates proliferation and differentiation of granulocytic precursors into mature neutrophils. In addition, G-CSF enhances the phagocytic and bactericidal activity of both normal and abnormal neutrophils. G-CSF is often used in patients rendered neutropenic by cancer chemotherapy or marrow transplantation in order to decrease the duration of neutropenia. Studies in non-neutropenic animals have shown improved outcome after admistration of G-CSF in experimental infection. A previous randomized, placebo-controlled trial found that a 7-day course of G-CSF therapy was associated with earlier eradication of pathogens, quicker resolution of inflammation, and a shorter duration of antibiotic therapy than standard therapy.1 Neutrophil superoxide production was significantly increased in G-CSF-treated patients, confirming its effect on neutrophil function in diabetic patients.
G-CSF appears to be a promising adjunctive agent in the treatment of diabetic foot infections. The clinical trials reported thus far have several limitations—the most notable being small numbers of patients. In the study of de Lalla et al, the decision to perform amputation was made by orthopedic surgeons who were not members of the study team and not blinded as to treatment assignment. Thus, it is not clear that uniform criteria for amputation were followed in all patients.
However, these preliminary studies are encouraging and should provide the impetus for larger, randomized trials of G-CSF in the treatment of diabetic foot infections. (Dr. Muder is Hospital Epidemiologist, Pittsburgh VA Medical Center, Pittsburgh, Pa.)
Reference
1. Gough A, et al. Lancet. 1997;350:855-859.
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