Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

5th International Symposium on the Diabetic Foot

Noordwijkerhout, The Netherlands / May 9-12, 2007

According to Dr. Benjamin Lipsky, Primary Care and Antibiotic Research Clinic, University of Washington, Seattle, antimicrobial therapy in diabetic foot infections is “a four-part puzzle.” First, the clinician must assess the clinical severity of the wound, consider the effect of any recent antibiotics, establish if the patient has bone infection and determine their vascular status. The clinician must then decide whether the patient is immunologically compromised or allergic to any antibiotics, whether they have hepatic or renal issues and whether oral or intravenous administration would be appropriate. Thirdly, the clinician can usually make only “the best guess” about the likely etiological agent and must take local resistance into account. Finally, potential drug interactions need careful consideration because diabetic patients are often on multiple treatments. The clinician will prefer those that have a good safety profile, need only infrequent dosing, are available in formularies and have proven therapeutic efficacy.

Available Strategies

Infectious disease specialists believe that narrow-spectrum therapies should be chosen, Dr. Lipsky observed. “However, while all wounds are colonized, at least half of patients are clinically infected. There are organisms resistant to the usual antibiotics and in patients with possible or proven resistant bacteria, therapy must be targeted specifically against these.” Once the microbial culture results are available and response to treatment assessed, narrowing the spectrum of therapy might be possible.

As indicated by Dr. Lipsky, therapy can be topical, parenteral or oral, with topical application being usual for infected surface wounds. Parenteral therapy with systemic agents is the preferred delivery method, especially in severely ill patients and when specific intravenous (i.v.) agents such as vancomycin are needed. Oral agents are effective for less severe infections, but are fewer, and they must be bioavailable. Because most diabetic foot infections could be polymicrobial, clinicians usually choose combination therapy, although single broad-spectrum agents are available. In the US, levofloxacin is the most frequently chosen oral antibiotic for diabetic foot infections, used in 28% of cases, followed by ciprofloxacin (13%), metronidazole (13%), linezolid (12%), cephalexin (12%), clindamycin (10%), amoxicillin/clavulanate (6%) and erythromycin 6%.

Because methicillin-resistant Staphylococcus aureus (MRSA) is “a major problem” both in hospitals and the community, relatively broad-spectrum parenteral agents are used, led by vancomycin (19%) and followed by piperacillin/tazobactam (17%), ampicillin-sulbactam (16%), and levofloxacin (13%). However, 83% of hospitalized diabetic foot infection patients receive i.v. dosing.

“MRSA isolation is vital,” Dr. Lipsky stated. “MRSA is associated with longer healing, more amputations and perhaps higher mortality.” Linezolid and vancomycin, both designed to counter MRSA, have similar clinical and microbiological outcomes in diabetic foot infection patients. “However, surgery is often crucial.”

The broad-spectrum fluoroquinolone moxifloxacin, which covers gram-positive and gram-negative anerobes, and the very broad-spectrum piperacillin/tazobactam/amoxicillin/clavulanate combination has similar bacteriological response rates (68% and 61%, respectively), which suggests that for diabetic foot infections, a fluoroquinolone is a good option. However, at least in skin and skin-structure infections, it may not be critical that patients receive an agent active against the organism because wounds can be debrided or abscesses drained, Dr. Lipsky noted.

Study Findings

The largest and best-designed diabetic foot infection trial so far, Dr. Lipsky observed, is SIDESTEP (Study of Infections in Diabetic Feet Comparing Efficacy, Safety and Tolerability of Ertapenem vs. Piperacillin/tazobactam). As a carbapenem in the betalactam class of antibiotics, ertapenem covers most pathogens involved in complicated skin and skin-structure diabetic foot infections except for most Enterococcus or Pseudomonas spp. While the study showed ertapenem to be “at least as effective as the piperacillin/tazobactam i.v. combination,” ertapenem’s once-daily parenteral dosing (vs. every six hours for the i.v. combination) made it a convenient alternative in hospital and especially useful for outpatient treatment.

It was noteworthy, Dr. Lipsky remarked, that although ertapenem has a somewhat narrower spectrum than meropenem and imipenem, and does not cover enterococcus or pseudomonas, whereas tazobactam does, the clinical response rates of the two treatment groups in the trial were similar. “The reason for this,” he suggested, “appears to be that most of the time, enterococcus and pseudomonas are polymicrobial infections, seldom primary pathogens. This means that a more narrow-spectrum drug such as ertapenem can cover these polymicrobial infections quite effectively.” Dr. Lipsky noted that a subsequent theoretical pharmacoeconomic study indicated that using ertapenem once daily saved money as opposed to tazobactam three or four times daily.

“We do not know what is the best antibiotic or antibiotic combination for diabetic foot infections,” Dr. Lipsky admitted. If the infection is acute, the patient has not recently received antibiotics and is at low risk of MRSA, then the predominant pathogens in diabetic foot infections—aerobic gram-positive cocci (especially S. aureus)—are all that the clinician needs to worry about and penicillin could be administered, he advised. For MRSA, there are several effective agents. If the condition is chronic or the patient has been previously infected, broader-spectrum therapy for gram-negatives and anerobes must be added. With necrotic infection, gangrene or an ischemic foot, anerobes should certainly be considered, Dr. Lipsky told delegates. The Infectious Diseases Society of America guidelines on diabetic foot infections recommend that antibiotic therapy continue until there is evidence that the infection has resolved, although not necessarily until a wound has healed. “A team approach where you combine supportive therapy, an antibiotic that is most interesting to you and, finally, surgery, will lead to a good outcome,” Dr. Lipsky concluded.

Wider Implications for Public Health

According to Dr. Anthony Berendt, Nuffield Orthopedic Centre NHS Trust, Oxford, UK, the clinical team managing diabetic foot infection must consider not only the choice and use of an antibiotic but also the role of surgery, podiatry and primary care, and the consequences for the patient and for public health in the choices made. “While we may well be saving patients’ feet and limbs, that has wider implications. The prevalence of MRSA in American ICUs is increasing. So is the prevalence of vancomycin-resistant enterococci, of resistant gram-negative rods and of resistant pseudomonas. We must constantly question the ways we use and choose antibiotics.”

Neuropathy is the driving force in ulceration, Dr. Berendt remarked. Ischemia leads to abnormal foot biomechanics, loss of protective sensation, and reduced skin compliance and lubrication. All these lead to ulceration and risk the development of vascular insufficiency and infection. There is “a clear trend” towards increasingly negative outcomes with worsening severity of infection. With the uninfected ulcer, there is inevitable colonization by increasing numbers of organisms. When there is established infection, gram-positive cocci are key pathogens irrespective of severity. As severity increases, there are additional contributions from aerobic gram-negative rods and anerobes. “This means that sampling from the depth of the debrided wound rather than superficially will demonstrate that in mild infections, there is an overwhelming contribution from aerobic gram-positive cocci and in much more severe infections a polymicrobial flora,” Dr. Berendt explained.

Discussing who is at risk of diabetic foot infection, Dr. Maximilian Spraul, Jakobi-Krankenhaus/Mathias-Spital Rheine, Hoerstkamp, Rheine, Germany, referred to a recent study that followed 1,666 consecutive diabetic patients at an outpatient clinic (Lavery et al. Diabetes Care 2006;29(6):1288-93). Over two years, 151 patients (9.1%) developed 199 foot infections, 19.9% having bone culture-proven osteomyelitis. Their risk of hospitalization was 55.7 times greater and their risk of amputation 154.5 times greater than those without foot infection. All but one infection involved a wound or penetrating injury. The study concluded that foot infections in diabetic patients dramatically increase the risk of hospitalization and amputation. Efforts to prevent infections should be targeted at people with traumatic foot wounds, especially those that are chronic, deep, recurrent or associated with peripheral vascular disease.

Significant independent risk factors for foot infection, Dr. Spraul added, included wounds that penetrated to bone (odds ratio [OR] 6.7), which he characterized as an “enormous” risk factor; wounds with a duration exceeding 30 days (OR 4.7), also a very high risk; recurrent wounds (OR 2.4); and traumatic etiology such as ingrowing toenail or burns (OR 2.4). Peripheral vascular disease (OR 1.9) was also a risk, but unexpected. “Moreover, in the US, if a diabetic patient gets an infected foot, it means hospitalization, which is very expensive,” Dr. Spraul remarked.

Summary

Recent guidelines provide a rational framework for standardizing the approach to diabetic foot infection, noted Dr. Berendt. “But huge uncertainties in managing infection remain and we will need large multicentre studies. If we standardize our methods, our language and our ways of evaluating patients, we will have powerful data sets with real answers and, consequently, significant potential individual and societal gains. A logical approach minimizes the clinicians’ fears about tackling diabetic foot infection.”