Rifampicin–ofloxacin oral regimen for the treatment of mild to moderate diabetic foot osteomyelitis

Eric Sennevillea,*, Yazdan Yazdanpanaha, Marie Cazaubielb, Muriel Cordonnierb, Michel Valettea, Eric Beltrandc, Alexan Khazarjiane, Laurence Maulina, Serge Alfandaria, Michèle Caillauxd, Luc Dubreuila and Yves Moutona

a Service des Maladies Infectieuses et Tropicales , b Service d'Endocrinologie, c Service d'Orthopédie-Traumatologie and d Laboratoire de Microbiologie, Hôpital Dron, 135 rue du Pr Coty, F-59200 Tourcoing; e Service de Médecine Nucléaire Hôpital Victor Provo, F-59100 Roubaix, France


    Abstract
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 Abstract
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 Materials and methods
 Results and discussion
 References
 
Seventeen diabetic patients with moderate to mild foot lesions associated with 20 osteomyelitic bones diagnosed by both bone scan and bone biopsy received rifampicin plus ofloxacin for a median duration of 6 months. Cure was defined as disappearance of all signs and symptoms of infection at the end of the treatment and absence of relapse during follow up. At the end of the treatment period, cure was achieved in 15 patients (88.2%) and was maintained in 13 patients (76.5%) at the end of an average post-treatment follow-up of 22 months. No serious drug-related adverse events were recorded.


    Introduction
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 Abstract
 Introduction
 Materials and methods
 Results and discussion
 References
 
The aim of the study was to evaluate the efficacy and tolerability of a rifampicin–ofloxacin combination for treating diabetic patients with pedal osteomyelitis reliably documented by the culture of a surgical bone biopsy. These antibiotics were chosen because they are currently considered to be the most appropriate for the treatment of chronic osteomyelitis.1 This is, to our knowledge, the first report of the use of this antibiotic combination in such patients.


    Materials and methods
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 Abstract
 Introduction
 Materials and methods
 Results and discussion
 References
 
Patients included in this study were inpatients and outpatients with infected foot ulcers who attended a diabetes clinic in Northern France from December 1996 to June 1999. Osteomyelitis was suspected if two or more of the following criteria were fulfilled: history of a previous osteomyelitis, duration of >2 weeks, location (bony prominence), size (surface area >2 cm2, depth >3 mm), exposed bone, bone probe, erythrocyte sedimentation rate > 60 min. All enrolled patients underwent a radiographic and/or a scintigraphic investigation, followed by biopsy of the infected bony site(s). Scintigraphic investigations were performed using coupled gallium (67Ga citrate)–technetium (99mTc-diphosponate) radionuclide or Sulesomab scintigraphy (anti-granulocyte antibody Fab' fragment labelled with 99mTc).2 The ulcer crater was swabbed following light cleansing of the ulcer with sterile saline. Surgical bone biopsies were performed using a 14-gauge trocar placed through a 5–10 mm incision in an area of skin at least 20 mm distant from the ulcer and through the dorsal face of the foot in the case of plantar ulcer(s). One bone fragment was put directly into Rosenow liquid medium (Bio-Rad, Marnes La Coquette, France) and another into standard brain–heart broth (bioMérieux, Marcy l'Étoile, France) and immediately transported to the laboratory where cultures were maintained for 2 weeks.

Study patients received ofloxacin 200 mg po tds with food and rifampicin 600 mg po bd 30 min before or 2 h after food. Antibiotic dosages and duration were adapted from the French guidelines for treating chronic osteomyelitis.3 High doses of ofloxacin (i.e. 400 mg bd) were not used because they are not always tolerated by the elderly. We used a tds regimen to avoid the low blood levels observed in some patients due to inter-individual differences in fluoroquinolone metabolism.4 Initial iv administration of the study treatment was accepted. After 3 months of treatment, patients with a satisfactory clinical and radionuclide evaluation were permitted to stop the treatment, although they were encouraged to complete 6 months of treatment.

The primary outcome of the study was clinical response defined as cure (disappearance of all signs and symptoms associated with the initial ulcer at the end of the treatment and no relapse occurring during the post-treatment follow-up period) or failure (any other outcome). Relapse and superinfection were defined as appearance of an active infection at the site of the initial infection or contiguous to it due to a pathogen identical to or different from the pathogen isolated at enrolment in the study, respectively. Bone scan assessment was graded as: significant improvement or normalization of the bone uptake, no improvement or deterioration. After hospital discharge, patients were followed up at 3 and 6 months by the infectious diseases consultant and monthly by the endocrinologist.

Patients with infections caused by pathogens resistant to rifampicin or ofloxacin were excluded from the study.


    Results and discussion
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 Abstract
 Introduction
 Materials and methods
 Results and discussion
 References
 
Pedal osteomyelitis was confirmed by the results of both bone scan and biopsy in 31 of the 130 diabetic patients (23.8%) with an infected foot lesion who attended our clinic. Among them, 17 patients with 20 osteomyelitic bones were treated with the combination of rifampicin and ofloxacin, and these constituted the study population.

The median age of the study patients was 62 years (range 51–77 years) and 13 (76.5%) were male; all patients had non-insulin-dependent diabetes mellitus with a median duration of 16 years (range 9–30 years). Most foot lesions (15/20) were graded with a Wagner score of 3 (Table 1Go). Only one patient had fever at entry (patient 9). Fifteen patients underwent plain radiographs of the foot, among which 12 were abnormal, showing bone demineralization in 10 cases and a cortical defect in two cases.


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Table 1. Characteristics of study patients
 
Gram-positive cocci accounted for >85% of the pathogens isolated from both the ulcer and the bone samples. When comparing the cultures of superficial swabbing and bone biopsy obtained from the same infectious site, identical results were noted in only 4/14 evaluable cases (28.6%). Coagulase-negative staphylococci (CNS) were not cultured from swabs although they were found in eight bone biopsies (P < 0.01), which is likely to be related to the non-report of CNS from superficial samples by our laboratory. Patients with infections caused by Streptococcus spp. and Corynebacterium spp. with intermediate susceptibility to ofloxacin were entered into the study because its bone/blood concentration is high (Table 2Go).4,5 The median duration of the antimicrobial therapy was 6 months (range 3–10 months). Treatment was initially administered iv in five patients for a median duration of 5.5 days (range 3–17 days). Adjunctive surgery consisting of necrotic bone resection was performed in two patients. The median hospital stay duration was 14 days (range 3–53 days), which is shorter than reported in other studies.6 This might be related to the high bioavailability of the study treatment, which allowed a prompt switch to oral treatment.


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Table 2. Bacteria isolated from swabbing and bone biopsy
 
After 3 and 6 months treatment, 15/17 (88.2%) and 12/14 evaluable patients (85.7%), respectively, were cured, which is comparable to previous studies.7 However, cure was maintained in 13 patients (76.5%) for a median period of 22 months (range 12–41 months) following the end of treatment, which is the delay usually reported to correctly assess the outcome of patients with chronic osteomyelitis.8 Two patients with staphylococcal osteomyelitis (patients 8 and 17) failed to respond to the study treatment. The control of the vascular status of these two patients did not show any severe arterial obstructive lesion.

At entry, coupled gallium–technetium bone scan performed in four patients and Sulesomab–technetium performed in the 13 remaining patients showed marked bone uptake consistent with the diagnosis of osteomyelitis. The overall number of improved or normalized bone scans at the end of treatment was 16/17 (94%). Clinical and scintigraphic assessment of the osteomyelitis outcome was concordant in 16 of the 17 episodes for which the comparison was feasible. No adverse events were reported in the 13 patients who underwent repeated Sulesomab scintigraphies.

Fifteen adverse effects, predominantly gastrointestinal and neurological, were reported in nine patients (47%), related to rifampicin and ofloxacin respectively, but did not require the discontinuation of the study treatment. Rifampicin dosage was reduced by 50% in four patients because of nausea. Three patients (3, 7 and 10) died of causes unrelated to the foot infection during the study. The isolation of multi-resistant bacteria in four patients might be the result of prolonged antibiotic therapy and could argue for shorter courses of treatment such as 3 months or less.9


    Notes
 
* Corresponding author. Tel: +33-320-694-591; Fax: +33-320-694-589; E-mail: esenneville{at}ch-tourcoing.fr Back


    References
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 Abstract
 Introduction
 Materials and methods
 Results and discussion
 References
 
1 . Drancourt, M., Stein, A., Argenson, J. N., Zannier, A., Curvale, G. & Raoult, D. (1993). Oral rifampicin plus ofloxacin for treatment of Staphylococcus-infected orthopaedic implants. Antimicrobial Agents and Chemotherapy 37, 1214–8.[Abstract]

2 . Harwood, S. J., Valdivia, S., Hung, G.-L. & Quenzer, R. W. (1999). Use of Sulesomab, a radiolabeled antibody fragment to detect osteomyelitis in diabetic patients with foot ulcers by leukoscintigraphy. Clinical Infectious Diseases 28, 1200–5.[ISI][Medline]

3 . Conférence de Consensus en Thérapeutique Anti-Infectieuse. (1991). Les infections bactériennes ostéo-articulaires en dehors des infections à mycobactéries. Semaine des Hôpitaux de Paris 30, 1389–95.

4 . Kuck, E. M., Bouter, K. P., Hoekstra, J. B. L., Connemans, J. M. H. & Diepersloot, J. A. (1998). Tissue concentrations after a single-dose orally administered ofloxacin in patients with diabetic foot infections. Foot and Ankle International 19, 38–40.[Medline]

5 . Nordern, D. W. (1988). Lessons learned from animal models of osteomyelitis. Reviews of Infectious Diseases 10, 103–10.[ISI][Medline]

6 . Pittet, D., Wyssa, B., Herter-Clavel, C., Kursteiner, K., Vaucher, J. & Lew, D. (1999). Outcome of diabetic foot infections treated conservatively. Archives of Internal Medicine 159, 851–6.[Abstract/Free Full Text]

7 . Venkatesan, P., Lawn, S., Macfarlane, R. M., Fletcher, E. M., Finch, R. G. & Jeffcoate, W. J. (1997). Conservative management of osteomyelitis in the feet of diabetic patients. Diabetic Medicine 14, 487–90.[ISI][Medline]

8 . Lew, D. P. & Waldvogel, F. A. (1997). Osteomyelitis. New England Journal of Medicine 336, 999–1007.[Free Full Text]

9 . Lipsky, B. A. (1999). Evidence-based antibiotic therapy of diabetic foot infections. FEMS Immunology and Medical Microbiology 26, 267–76.[ISI][Medline]

Received 20 April 2001; returned 25 June 2001; revised 6 August 2001; accepted 15 August 2001