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Antibiotic treatment of infected diabetic foot ulcers

Antimicrobial treatment can be effective in diabetic foot ulcers. However, choosing the appropriate regimen depends on the clinical and microbial presentation. This review describes the factors practitioners need to consider
cellulitis; osteomyelitis; sharp debridement; antibiotic resistance
S.J. Sheppard, RGN, Clinical Nurse Specialist Tissue Viability, Rotherham General Hospital NHS Trust, Rotherham, UK. Email: stephanie.sheppard @rothgen.nhs.uk

f left undetected or treatment is delayed or inappropriate, diabetic foot ulcers can become limb- and life-threatening. In an attempt to reduce morbidity and mortality rates, efforts are being made, through good glycaemic control and patient/staff education, to prevent diabetic foot ulcers occurring.1 When this approach fails, effective diagnostic, prognostic and therapeutic strategies must be employed to reduce the human and nancial costs.2 Infection is often difcult to detect in patients with diabetes, possibly due to a reduced inammatory response. Furthermore, local clinical signs such as erythema, oedema and induration may not be immediately obvious,3 and the patient may not complain of signicant pain as autonomic neuropathy is common in diabetes mellitus. A full assessment that includes clinical signs and measurement of markers of infection, inammation and poor glycaemic control may aid diagnosis of infection and the selection of appropriate treatment. The presence of crepitus, abscesses or sinus tracts provides strong evidence of infection. However, the use of X-rays and ultrasound in the detection of osteomyelitis lacks sensitivity. Grayson et al. described the effective use of probing infected foot ulcers down to the bone to detect osteomyelitis.4 This compared favourably with the reported sensitivity, specicity and positive predictive values of other tests, although it should be noted this was a small study of hospitalised patients with severe infection. Nevertheless, this is an easy and costeffective assessment tool.

Wound screening
Microbiological screening of the wound is an essential part of the diagnostic process. However, evidence suggests that the method of collecting samples can cause variations in the results,5 mainly as a result of contamination. As most wounds in clinical practice are sampled using a cotton-tipped applicator, clinicians need to be aware of the susceptibility to anaerobic bacterial contamination
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during the collection process, and caution is advisable when evaluating the results. It would be prudent to observe the wound itself for evidence of anaerobic bacteria. The presence of odour and the distinctive grey colour of the wound bed, alongside evidence of fever, suggest that anaerobes are likely to be present.6 In patients previously untreated with antibiotics, an acute skin infection is frequently colonised with Staphylococcus aureus.7 If there has been recent antibiotic treatment, then a diverse range of microorganisms is often present, which needs to be borne in mind when prescribing.8 However, this evidence contradicts Sapico et al. who suggested that prior antibiotic therapy does not appear to inuence the nature of the microorganisms isolated.6 In contrast, Lipsky et al.9 suggested that previous topical treatment with antibiotics and contact with health-care institutions could increase the acquisition of antibiotic-resistant organisms. They also reported a high incidence of Pseudomonas aeruginosa in ulcers treated with wet dressings, and anaerobes in ischaemic wounds that have become necrotic.9 Before exploring treatments in depth, it is worth considering the following points: Bacteria normally considered avirulent may be found in mild infection. For example, Staphylococcus epidermidis is often isolated,9 but if detected as a sole isolate from deep unexposed sites of a diabetic ulcer it should be treated as pathogenic10 Providing antibiotic cover for certain bacteria may result in the propagation of other species that are not susceptible to the antimicrobial being used.11 Before deciding on an antimicrobial regimen, the severity of the infection should be established. If this is categorised correctly, evidence suggests that certain pathogens will be present in the wound. Therefore, an antimicrobial regimen can be started before the microbiological results are obtained. Infected diabetic foot ulcers can be broadly categorised into the three groups.
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Mild to moderate infection
This is generally found in supercial ulcers but presents as purulent discharge and possible cellulitis extending up to 2cm around the wound. While the patient may have a mildly raised plasma glucose, there is no evidence of osteomyelitis, signicant vascular disease or systemic toxicity.10 It is therefore not considered limb threatening. In a small randomised prospective trial, Lipsky et al.9 found that Staphylococcus aureus was the most common micro-organism in infected diabetic foot ulcers. Although the patients had not received systemic or topical antimicrobial treatment in the previous two weeks, the organism was found exclusively in almost half of them. Gerding retrieved from wound curettage microbiological isolates that showed aerobic and anaerobic organisms.5 The Gram-negative isolates were present in a quarter of cases and were part of a polymicrobial infection. The microbiology results appear to correlate with the action of the two oral antibiotics used, clindamycin and cephalexin, which had a success rate of 75% after two weeks of treatment. It can be argued that longer treatment periods may have resulted in a better success rate. Patients also underwent sharp debridement as needed. This may have had a positive effect on cure rates, particularly in patients treated with clindamycin, as the anaerobe count may have been mechanically reduced. A similar study on uncomplicated foot ulcers using amoxycillin and clavulanic acid versus placebo showed different results.12 The outcome measure was a healed ulcer. The results showed that the chosen antibiotics made no difference to healing but it was not stated if the infection was cured. This makes the results of this small study difcult to interpret and a type 2 statistical error cannot be ruled out. Furthermore, there was no record of the degree of wound debridement. It could be hypothesised that the use of such a broad-spectrum antibiotic may have been inappropriate for this type of infection. Goldstein et al. also studied microbiological isolates from mild to moderately infected diabetic foot ulcers and evaluated the antimicrobial response.13 Unlike the studies by Lipsky et al.9 and Chantelau et al.,12 40% of the patients had previously been treated with antibiotics, although no time limit was given. Together with the collection methods (curettage and aspiration) and the ulcer durations, this presumably had an effect on the range of isolates detected. Of the 10 oral antibiotics analysed, the uoroquinolones had broad general activity against both aerobic and anaerobic isolates, with approximately a third of cases in this study having a resistant isolate obtained on culture. Amoxicillin/ clavulanic acid also exhibited good activity, but a higher rate of resistant isolates was obtained, particularly methicillin-resistant Staphylococcus aureus
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(MRSA) and Pseudomonas spp. Despite good retrieval and identication methods, this in vitro study should be interpreted with caution as the synergistic effects of the polymicrobial growth within the wound cannot be mirrored in the laboratory. Uncomplicated non-limb-threatening infected ulcers with an adequate blood supply and no recent prior use of antibiotics may be treated on an outpatient basis with normal doses of microbiologicalguided oral antibiotics for seven to 14 days as the rst treatment option.2,7,10

References
1 Calhoun, J.H., Overgaard, K.A., Stevens, C.M. et al. Diabetic foot ulcers and infections: current concepts. Adv Skin Wound Care 2002; 15: 31-45. 2 Pittet, D., Wyssa, B., Herter-Clavel, C. et al. Outcome of diabetic foot infections treated conservatively. Arch Intern Med 1999; 159: 851-856. 3 Senior, C. Assessment of infection in diabetic foot ulcers. J Wound Care 2000; 9: 313-317. 4 Grayson, L.M., Gibbons, G.W., Balogh, K. et al. Probing to bone in infected pedal ulcers: a clinical sign of underlying osteomyelitis in diabetic patients. JAMA 1995; 273: 721-723. 5 Gerding, D.N. Foot infections in diabetic patients: the role of anaerobes. Clinical Infectious Diseases 1995; 20: S283-S288. 6 Sapico, F.L., Witte, J.L., Canawatti, H.N. et al. The infected foot of the diabetic patient: quantitative microbiology and analysis of clinical features. Reviews of Infectious Diseases 1984; 6: S171-S176. 7 Calhoun, J.H., Eng, M., Cantrell, J. et al. Treatment of diabetic foot infections: Wagner classication, therapy and outcome. Foot Ankle 1988; 9: 101-105. 8 Lipsky, B.A. Evidencebased antibiotic therapy of diabetic foot infections. FEMS Immunol Med Microbiol 1999; 26: 267-276. 9 Lipsky, B.A., Pecoraro, R. E., Larson, S.A., Ahroni, J.H. Outpatient management of uncomplicated lowerextremity infections in diabetic patients. Arch Int Med 1990; 150: 790-797. 10 Temple, M.E., Nahata, M. C. Pharmacotherapy of lower limb diabetic ulcers. J Am Geriatr Soc 2000; 48: 822-828. 11 Rotstein, O.D., Pruett, T.L., Simmons, R.L. Mechanisms of microbial synergy in polymicrobial surgical infections. Rev Infect Diseas 1985; 7: 151-170. 12 Chantelau, E., Tanudjaja,
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Moderate to severe infection

This type of infection is described as deep tissue ulceration with extreme purulent discharge and cellulitis extending over 2cm around the ulcer.10 Bony involvement may occur alongside signicant ischaemia and systemic toxaemia. Gangrene may also be present. The difculty in diagnosing infection means that, even at this stage, the patient may only present with increased wound drainage, leg pain and crepitus, which can lead to difculty in deciding on appropriate treatment. A small retrospective trial involved patients with diabetic foot ulcers with overt osteomyelitis.14 Subjects had received a prolonged course of conventional doses of antibiotics on an outpatient basis. The clinicians used their own preference, but the options included broad-spectrum antibiotics, ensuring an emphasis on aerobic Gram-positive and anaerobic organisms. The most frequently used antibiotic was clindamycin, which had the added advantage of achieving good bone penetration. Limited debridement was undertaken on these wounds. As in other studies, Staphylococcus aureus was the most common organism found. As this is a relatively old study (19821992), it can be assumed that traditional wound swabbing methods were used, which may not have revealed the true polymicrobial nature of the wounds. Although these patients did not undergo bone biopsy or scanning, possibly due to problems relating to cost or availability, the authors detected unequivocal bone infection from clinical presentation and X-rays. Wound probing was not undertaken, even though it has a high positive predictive value for osteomyelitis.4 Again, the fact that this is an old study may explain why this diagnostic tool was not used as part of the assessment. The accuracy of X-rays in diagnosising infection may be questioned due to the difculty in distinguishing the typical features (interruption of bone cortex with or without gross disorganisation) from the similar destructive effects of diabetic osteopathy (Charcots joint).15 Overall, the microbial studies and diagnosis of osteomyelitis can be questioned. This raises questions about the severity of the infection in the study group. While antibiotic treatment without surgery appeared

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Box 1. Summary of the main ndings
Infection is difcult to detect in patients with diabetes. Diabetic patients previously untreated with antibiotics who develop an acute skin infection are often colonised with Staphylococcus aureus. In patients who have recently received antibiotic treatment and then develop an infection, a broad range of microorganisms is likely to be present Before selecting an antibiotic, the severity of the infection must be determined. Providing the categorisation is correct, antibiotic treatment can be started before microbiological results are obtained Mild to moderate infection presents as purulent discharge and possible cellulitis extending up to 2cm around the wound. There is no evidence of osteomyelitis, signicant vascular disease or systemic toxicity. If there has been no recent prior use of antibiotics, then these infections can usually be treated on an outpatient basis with normal doses of oral antibotics for 714 days Moderate to severe infection presents as deep tissue ulceration with extreme purulent discharge and cellulitis extending over 2cm around the ulcer. Approximately 5060% of serious foot infections have osteomyelitis, for which long-term antibiotics and debridement are necessary. Failing that surgical resection or amputation may be required Life-threatening infection is often characterised by marked necrosis and gangrene. Patients generally present with pyrexia. Staphylococcus aureus and Bacteroides fragilis are often involved. Surgery and the timely delivery of parenteral antibiotic treatment are vital

T., Altenhofer, F. et al. Antibiotic treatment for uncomplicated neuropathic forefoot ulcers in diabetes: a controlled trial. Diabet Med 1996; 13: 156-159. 13 Goldstein, E.J.C., Citron, D.M., Nesbit, C.A. Diabetic foot infections: bacteriology and activity of ten oral microbial agents against bacteria isolated from consecutive cases. Diabet Care 1996; 19: 638-641. 14 Venkatesan, P., Lawn, S., Macfarlane, R.M. et al. Conservative management of osteomyelitis in the feet of diabetic patients. Diabet Med 1997; 14: 487-490. 15 Shea, K.W. Antimicrobial therapy for diabetic foot infections: a practical approach. Postgrad Med 1999; 106: 1, 85-94. 16 Eckman, M.H., Greeneld, S., Mackey, W.C. et al. Foot infections in diabetic patients: decision and cost-effective analysis. JAMA 1995; 273: 712-720. 17 Lipsky, B.A., Baker, P.D., Landon, G.C., Fernau, R. Antibiotic therapy for diabetic foot infections: comparison of two parenteral-to-oral regimens. Clin Infect Dis 1997; 24: 643-648. 18 Van der Meer, J.W.M., Koopmans, P.P., Lutterman, J.A. Antibiotic therapy in diabetic foot infections. Diabet Med 1995; 18: S48-S51. 19 Akova, M., Ozcebe, O., Gullu Unal, S. et al. Efcacy of sulbactam-ampicillin for the treatment of severe diabetic foot infections. J Chemother 1996; 8: 284-289. 20 Sapico, F.L., Bessman, A. N., Canawati, H.N. Bacteraemia in diabetic patients with lower extremity infections. Diabet Care 1982; 5: 101-106. 21 Gwilt, P.R., Nahhas, R.R. Tracewell, W.G. The effects of diabetes mellitus on
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to work in many cases, the study was too small to draw conclusions, particularly given the methodology used. In a study of this type, without extremely accurate medical notes, it can be difcult to extrapolate what could be viewed as subjective data. In a study involving diabetic patients with similar wounds, Eckman et al. recommended that patients with suspected osteomyelitis should have a 10-week course of culture-guided oral antibiotic therapy following surgical debridement.16 The investigators stressed that non-invasive tests add to the expense with little improvement in outcomes. The key factor, therefore, is not the accuracy of the noninvasive tests but rather the availability of safe, convenient and effective oral antibiotic regimens. Approximately 5060% of serious foot infections are complicated by osteomyelitis.17 Many studies do not appear to have sampled the bone either by biopsy or surgical excision/debridement. Lipsky found that the microbiological cause of osteomyelitis did not correlate with samples from infected soft tissue.17 While some believe there may be a risk to undertaking a bone biopsy, such as inducing infection or necrosis, this is the only way of accurately diagnosing osteomyelitis, and thus of improving success rates of culture-guided antibiotic treatment.15,16 Further larger randomised controlled trials need to be undertaken to assess this. Following a diagnosis of osteomyelitis, the hypoxic environment needs to be taken into account. Antibiotics thus need to be selected that will penetrate bone to ensure adequate bioavailability. Traditionally, parenteral antibiotics were chosen, but newer oral agents such as uoroquinolones, as well as ampicillin/sulbactam (clavulanic acid), are able to reach therapeutic levels.18 The literature supports the view that long-term antibiotics are required for this type of wound. Indeed, Akova et al. demonstrated an 86% cure rate for osteomyelitis and 100% for soft-tissue infection using ampicillin/sulbactam.19 Again, despite being a small, non-randomised trial, it does provide additional evidence. Although there is evidence to suggest that infection, including osteomyelitis, can be treated conservatively with antibiotics and debridement, clinicians must use their clinical judgement when deciding if surgical resection and amputation are appropriate.

Life-threatening infection
These infections not only present with deep ulceration and purulent discharge but also may have marked necrosis and gangrene. Patients generally present with pyrexia, reecting the bacteraemia that may progress to full-blown septic shock.10 Symptoms can present suddenly and require urgent expert attention. Again, Staphyloccocus aureus and anaerobes such as Bacteroides fragilis are often involved.20 With such an acute infection in a structure like the

foot, conservative treatment is not appropriate. Surgery is needed to remove the necrotic tissue and pus and relieve the pressure within the compartment.8 However, antibiotic therapy also plays a pivotal role. Pittet et al. assessed 20 patients with gangrene as part of a larger study investigating all categories of infection in the diabetic foot ulcer.2 They recorded a 93% failure rate with conservative treatment, dened as surgery not being performed within ve days of admission. Presumably, ethics committees would not approve a prospective randomised trial in which surgery is denied to a patient. Due to the severe nature and systemic effects of this type of infection, parenteral antibiotics are needed to help ensure adequate and timely delivery to the site of infection. A broad-spectrum regimen aimed at Staphylococcus aureus and anaerobes is needed. Serum and tissue antibiotic levels must be taken into account as there may be a degree of vascular or microvascular disease, while necrotic tissue may reduce the amount of antimicrobials reaching the wound. Gwilt et al. found a 26% decrease in the absorption of orally administered ampicillin in diabetics compared with non-diabetics.21 However, this was not consistent with other studies.18,19 Storm et al. showed evidence of adequate serum levels of cefuroxime, but not necessarily detectable concentrations in the ischaemic tissue of the diabetic foot.22
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A small study evaluating antibiotic tissue concentrations using a variety of antibiotic regimens showed poor serum concentrations and even lower tissue concentrations.23 Only patients receiving ampicillin/sulbactum, ticarcillin/clavulanate or clindamycin were able to achieve tissue concentration above the minimum inhibitory concentration. While this should be viewed with caution due to the study size, the lack of a diabetic control group and the use of single-dose antibiotics, it does give the clinician an idea of the differences between antibiotics, which may need to be taken into account when choosing a regimen. In another study high doses of intravenous clindamycin in patients with vascular insufciency led to adequate tissue concentrations following multiple dosing.24 As in other studies, there was no control group and only a small number of participants. Nephrotoxic antibiotics should be used with extreme caution in diabetic patients to prevent possible further renal damage.10 Dosage adjustment and monitoring of serum drug levels may also be required. have been carried out.8 However, as the studies differ so greatly in their methodology, target groups and denitions, it is extremely hard to make comparisons. This makes it difcult to draw conclusions and advocate a particular regimen. Nevertheless, the studies do highlight the need to understand the principles involved in treating infected diabetic foot ulcers, including recognition of the severity and extent of infection as well as deciding whether to treat on an inpatient or outpatient basis. Choosing the most appropriate antibiotic regimen, while essential, must be done in conjunction with debridement and vascular reconstruction as necessary. The emergence of new bacteria and increasing bacterial resistance to antibiotics, along with the development of new antibiotics, will result in changes to antibiotic treatment strategies in the future. Furthermore, with an increasingly aged population and paralleled by an increase in the incidence of infected diabetic foot ulcers, further research is necessary in this area. Large multicentre trials following the same methodology are required. This might ensure that the health professional can provide cost-effective quality care, thus reducing the complication rate and the potential for unnecessary drainage of resources.
pharmacokinetics and pharmacodynamics in humans. Clin Pharmacokinet 1991; 6: 477-490. 22 Storm, A.J., Bouter, K.P., Diepersloot, R.J.A. et al. Tissue concentrations of an orally administered antibiotic in diabetic patients with foot infections. J Antimicrob Chemother 1994; 34: 449-451. 23 Seabrook, G.R., Edmiston, C.E., Schmitt, D. D. et al. Comparison of serum and tissue antibiotic levels in diabetes-related foot infections. Surgery 1991; 110: 671-677. 24 Duckworth, C., Fisher, J. F., Carter, S.A. Tissue penetration of clindamycin in diabetic foot infections. J Antimicrob Chemother 1993; 31: 581-590.

Conclusion
It is only in the past two decades that trials using various regimens of antibiotics for these patients