Randomized prospective controlled trial of recombinant granulocyte colony-stimulating factor as adjunctive therapy for limb-threatening diabetic foot infection. Evaluation of granulocyte-colony stimulating factor (Filgrastim) in infected diabetic foot ulcers. Randomised placebo-controlled trial of granulocyte-colony stimulating factor in diabetic foot infection. Effects of granulocyte-colony stimulating factor in the treatment of diabetic foot infection. Conservative surgical approach versus non-surgical management for diabetic neuropathic foot ulcers: a randomized trial.
Adult diabetic patients admitted to our Diabetes Center from September 1996 to January 1998 for severe, limb-threatening foot infection were consecutively enrolled in a prospective, randomized, controlled clinical study aimed at assessing the safety and efficacy of recombinant human granulocyte colony-stimulating factor (G-CSF) (lenograstim) as an adjunctive therapy for the standard treatment of diabetic foot infection. Forty patients, all of whom displayed evidence of osteomyelitis and long-standing ulcer infection, were randomized 1:1 to receive either conventional treatment (i.e., antimicrobial therapy plus local treatment) or conventional therapy plus 263 microg of G-CSF subcutaneously daily for 21 days. The empiric antibiotic treatment (a combination of ciprofloxacin plus clindamycin) was further adjusted, when necessary, according to the results of cultures and sensitivity testing. Microbiologic assessment of foot ulcers was performed by both deep-tissue biopsy and swab cultures, performed at enrollment and on days 7 and 21 thereafter. Patients were monitored for 6 months; the major endpoints (i.e., cure, improvement, failure, and amputation) were blindly assessed at weeks 3 and 9. At enrollment, both patient groups were comparable in terms of both demographic and clinical data. None of the G-CSF-treated patients experienced either local or systemic adverse effects. At the 3- and 9-week assessments, no significant differences between the two groups could be observed concerning the number of patients either cured or improved, the number of patients displaying therapeutic failure, or the species and number of microorganisms previously yielded from cultures at day 7 and day 21. Conversely, among this small series of patients the cumulative number of amputations observed after 9 weeks of treatment appeared to be lower in the G-CSF arm; in fact, only three patients (15%) in this group had required amputation, whereas nine patients (45%) in the other group had required amputation (P = 0.038). In conclusion, the administration of G-CSF for 3 weeks as an adjunctive therapy for limb-threatening diabetic foot infection was associated with a lower rate of amputation within 9 weeks after the commencement of standard treatment. Further clinical studies aimed at precisely defining the role of this approach to this serious complication of diabetes mellitus appear to be justified. To re-evaluate the use of Granulocyte-Colony Stimulating Factor (G-CSF) in the treatment of infected diabetic foot ulcers.
                Thirty-seven diabetic subjects were randomised to Granulocyte-Colony Stimulating Factor (G-CSF) (n=20) or placebo (n=17). The primary endpoint was resolution of cellulitis, which was evaluated clinically and with an infection summary score. Patients were hospitalised for 10 days and received subcutaneously either 5 microg/kg G-CSF or placebo daily. Ulcers were treated with a standard wound protocol and the patients were instructed to stay in bed. All subjects received antibiotics (clindamycin and ciprofloxacin) intravenously until the inflammation had subsided.
                Patients who received G-CSF did not have an earlier resolution of clinically defined cellulitis (p=0.57). The infection summary score declined, but comparably, in both groups (G-CSF: 29.5+/-18.4 to 6.7+/-6.3 p<0.001, placebo: 24.2+/-16.9 to 8.9+/-7.2 p<0.001). The ulcer volume, which was not greater among placebo patients, was reduced by 59% in G-CSF and by 35% in placebo patients.
                We conclude that antibiotic and non weight-bearing therapy (bed rest) accelerated the resolution of cellulitis in infected foot ulcers. Additional treatment with G-CSF had no further beneficial effect. Diabetic foot infections cause substantial morbidity and mortality. Neutrophil superoxide generation, a crucial part of neutrophil bactericidal activity, is impaired in diabetes. Granulocyte-colony stimulating factor (G-CSF) increases the release of neutrophils from the bone marrow and improves neutrophil function. We assessed G-CSF as adjuvant therapy for the treatment of severe foot infections in diabetic patients.
                40 diabetic patients with foot infections were enrolled in a double-blind placebo-controlled study. On admission, patients were randomly assigned G-CSF (filgrastim) therapy (n = 20) or placebo (n = 20) for 7 days. Both groups received similar antibiotic and insulin treatment. Neutrophils from the peripheral blood of these participants and from healthy controls were stimulated with opsonised zymosan, and superoxide production was measured by a spectrophotometric assay (reduction of ferricytochrome C).
                G-CSF therapy was associated with earlier eradication of pathogens from the infected ulcer (median 4 [range 2-10] vs 8 [2-79] days in the placebo group; p = 0.02), quicker resolution of cellulitis (7 [5-20] vs 12 [5-93] days; p = 0.03), shorter hospital stay (10 [7-31] vs 17.5 [9-100] days; p = 0.02), and a shorter duration of intravenous antibiotic treatment (8.5 [5-30] vs 14.5 [8-63] days; p = 0.02). No G-CSF-treated patient needed surgery, whereas two placebo recipients underwent to amputation and two had extensive debridement under anaesthesia. After 7 days' treatment, neutrophil superoxide production was significantly higher in the G-CSF group than in the placebo group (16.1 [4.2-24.2] vs 7.3 [2.1-11.5] nmol per 10(6) neutrophils in 30 min; p < 0.0001). G-CSF therapy was generally well tolerated.
                G-CSF treatment was associated with improved clinical outcome of foot infection in diabetic patients. This improvement may be related to an increase in neutrophil superoxide production. Foot infections and the subsequent amputation of a lower extremity are the most common cause of hospitalization among patients with diabetes mellitus. Although there are several reasons for susceptibility to infection in diabetic patients, white blood cell dysfunction is considered to be an important cause for this tendency. Granulocyte-colony stimulating factor (G-CSF) increases the release of neutrophils from the bone marrow and improves neutrophil functions. Based on this knowledge, the aim of the present study was to investigate the effects of addition of G-CSF to the treatment of foot infections in diabetic patients.
                Thirty diabetic patients with foot infection were included in the study. Fifteen of the patients received standard treatment consisting of local wound care and antibiotics (standard group), and the other 15 patients received G-CSF besides standard treatment (G-CSF group). The objectives of this study were to determine the time to resolution of infection, time to hospital discharge, need for surgical intervention, and the effects of G-CSF on phagocytosis and respiratory burst of neutrophils.
                Treatment with G-CSF led to significantly higher neutrophil counts on the 5th and 10th days, and at the end of treatment in the G-CSF treated group compared to the standard group. Respiratory burst of neutrophils increased significantly in both the G-CSF group (from 1.6 +/- 0.3 to 2.3 +/- 0.5, p = 0.001) and the standard group (from 2.0 +/- 0.4 to 2.3 +/- 0.4, p = 0.02) with treatment. But, while phagocytosis of neutrophils increased significantly in the G-CSF group (from 70.4 +/- 2.0 to 74.5 +/- 1.9, p = 0.004), it did not change significantly in the standard group (from 68.1 +/- 0.2 to 69.4 +/- 1.9, p = 0.3) with treatment. Duration of hospitalization (26.9 +/- 2.0 vs. 28.3 days, p < 0.05), duration of parenteral antibiotic administration (22.9 +/- 2.0 vs. 23.3 +/- 1.9 days, p < 0.05), time to resolution of infection (23.6 +/- 1.8 vs. 22.3 +/- 1.7 days, p < 0.05), and need for amputation (13.3% vs. 20%, p > 0.05) were similar between the G-CSF and the standard groups.
                Although G-CSF improves neutrophil function as well as increasing the absolute numbers, this improvement is not associated with shortening of duration of antibiotic administration, duration of hospital stay or need for amputation in diabetic foot infection. To test the efficacy of surgical treatment of non-infected neuropathic foot ulcers compared to conventional non-surgical management, a group of diabetic outpatients attending our diabetic foot clinic were studied. All patients who came to the clinic for the first time from January to December 1995 inclusive with an uncomplicated neuropathic ulcer were randomized into two groups. Group A received conservative treatment, consisting of relief of weight-bearing, regular dressings; group B underwent surgical excision, eventual debridement or removal of bone segments underlying the lesion and surgical closure. Healing rate, healing time, prevalence of infection, relapse during a 6-month period following intervention and subjective discomfort were assessed. Twenty-four ulcers in 21 patients were treated in group A (17 Type 2 DM/3 Type 1 DM, age 63.24 +/- 13.46 yr, duration of diabetes 18.2 +/- 8.41 yr, HbA1c 9.5 +/- 3.8%) and 22 ulcers in 21 patients in group B (19 Type 2 DM/2 Type 1 DM, age 65.53 +/- 9.87yr, duration of diabetes 16.84 +/- 10.61 yr; HbA1c 8.9 +/- 2.2%). Healing rate was lower (79.2% = 19/24 ulcers) in group A than in group B (95.5% = 21/22 ulcers; p < 0.05), and healing time was longer (128.9 +/- 86.60 days vs 46.73 +/- 38.94 days; p < 0.001). Infective complications occurred significantly more often in group A patients (3/24, 12.5% vs 1/22, 4.5%; p < 0.05), as did relapses of ulcerations (8 vs 3; p < 0.01). There were only two minor perioperative complications in group B patients. Patients reported a higher degree of satisfaction in group B (p < 0.01) as well as lower discomfort (p < 0.05) and restrictions (p < 0.05). Thus surgical treatment of neuropathic foot ulcers in diabetic patients proved to be an effective approach compared to conventional treatment in terms of healing time, complications, and relapses, and can be safely performed in an outpatient setting.
The available evidence is limited, but suggests that adjunctive G-CSF treatment in people with a diabetic foot infection, including infected ulcers, does not appear to increase the likelihood of resolution of infection or healing of the foot ulcer. However, it does appear to reduce the need for surgical interventions, especially amputations, and the duration of hospitalisation. Clinicians might consider adding G-CSF to the usual treatment of diabetic foot infections, especially in patients with a limb-threatening infection, but it is not clear which patients might benefit.