David G. Armstrong, DPM, MSc, PhD: Can you comment on the Infectious Diseases Society of America (IDSA) infection classification and how it has had an impact on the current standard of care? How does this relate to international classifications of the International Working Group for the Diabetic Foot? How are these two classifications interrelated?

Benjamin Lipsky, MD: Having chaired both committees, it is a pleasure for me to be able to discuss these classification schemes. In May 2003, the guidelines from the International Working Group for the Diabetic Foot were published on a DVD and are partially accessible on the Web site www.iwgdf.org. I also authored a summary of these guidelines that was published in 2004.1,2 In October 2004, the IDSA guidelines were published, first in Clinical Infectious Diseases, an official journal of the IDSA, and later in the Journal of the American Podiatric Medical Association (JAPMA).3,4 These guidelines have received a good deal of press coverage and I have received much feedback from colleagues that they are useful and clinically practical.
We spent a great deal of time on the classification schemes. Since there are so many classifications for diabetic foot wounds but relatively few for infections, we tried to come up with a scheme that would be fairly easy to remember and usable.

For the International Work Group, we use the acronym PEDIS.5
P = perfusion
E = extent or size
D = depth or tissue loss
I = infection
S = sensation or neuropathy

Infection has the following grades:
Grade 1: no signs or symptoms of infection
Grade 2: in subcutaneous tissue only
Grade 3: extensive erythema, infection of deeper tissue
Grade 4: systemic inflammatory response indicating severe infection

These grades of infection correlate exactly with the IDSA categories (i.e., no infection, mild, moderate and severe) and were intended to do that. I think they provide a reasonably useful, easy to remember classification that facilitates easy clinical application.

Understanding The Different Classes Of Bacteria
Warren Joseph, DPM: These are two incredibly complex and thorough but easy to use documents. Both documents are still relatively new with the IDSA classification being the newer of the two.
In my perspective, the whole concept of aerobic gram positive cocci as a vital part of diabetic foot infections is the single most important “take home” message from the new classifications. For years, this has gone in circles. Back in the ‘60s and the ‘70s, people used to say that all infections were caused by Staph and Strep. Then in the late ‘70s and into the ‘80s, work by Sapico, Wheat, LeFrock and others showed that these diabetic foot infections are polymicrobial infections.6 However, none of these studies classified the infections. They all looked at diabetic foot infections as one big group.

Around 1990, the work of Drs. Lipsky and Pecoraro started shifting people back to the earlier thinking that the aerobic gram positive cocci are the most important organisms for mild and even moderate diabetic foot infections.7 I tend to stress this point when I lecture on these guidelines. It is great to have the classification system but I think we have to get away from the overall thinking that every diabetic foot infection is polymicrobial, that every diabetic foot infection needs incredibly broad spectrum coverage. It is true for the more severe infections but might not be the case for the milder to moderate infections.
Dr. Armstrong: Are gram negatives important when isolated in diabetic foot infections? What about enterococci, Pseudomonas or obligate anaerobes? Should we provide coverage for all of these or not? Should we use a broad-spectrum agent like an extended spectrum penicillin plus a beta-lactamase inhibitor combination or a carbapenem class antibiotic? Is that preferable initially instead of using a first-generation cephalosporin or a simple penicillin?
Dr. Lipsky: The first part of that question concerns the relative importance of different classes of bacteria. We talk about the different categories of organisms because we know these categories require specifically targeted therapies. Let us begin with the question of aerobic gram-negative rods. We generally think of them as two major groups: the Enterobacteriaceae (which includes such bacteria as E. coli and Proteus) and the non-fermentative gram-negatives, especially Pseudomonas. Pseudomonas is important, of course, because it is resistant to many of the commonly used antibiotics. The Enterobacteriaceae are isolated in a fairly high percentage of diabetic foot infections, particularly those that occur in patients who have been hospitalized with severe infection or who have failed previous therapy with other kinds of antibiotic agents.
However, the clinical importance of these organisms is open to some doubt because several trials that have treated patients only with agents that cover gram positive organisms have shown good outcomes despite not covering the gram negative organisms. Pseudomonas is an organism that lives in water. Many of these patients who have been soaking their feet will have Pseudomonas cultivated from their feet. There are various opinions on the importance of this organism. Dr. Cunha has written that Pseudomonas organisms are never an important cause of diabetic foot infections, even when they are isolated in wound cultures.8 Others believe one should certainly think about them when selecting antibiotic coverage and consider covering them when they are isolated.3,4,9,10

In one instance, we know Pseudomonas does play an important causative role in osteomyelitis of the heel or calcaneus, especially in children, and particularly in patients who have been wearing sneakers.11 Other than that circumstance, my own view of Pseudomonas is that it is one among several colonizing or contaminating organisms, and is rarely a primary pathogen. We have data, only presented as abstracts to date, from a recent large prospective comparative trial in moderate to severe diabetic foot infections. We compared ertapenem, which does not cover most strains of Pseudomonas, against piperacillin/tazobactam, which covers most of these strains.12 The outcomes were similar clinically and microbiologically in patients who had Pseudomonas isolated in both arms of the study, lending credence to the idea that specifically targeting antimicrobial therapy against Pseudomonas may be unnecessary in many of these patients.
Enterococcus is similar in many ways to Pseudomonas in that it is often a colonizing organism and less frequently a primary pathogen. Again, studies that have treated patients with agents that are not active against Enterococcus have shown similar outcomes to other studies using antibiotics that are active against Enterococcus. Accordingly, I rarely specifically target Enterococcus. The exceptions may be patients who have been infected with that organism previously or perhaps, in some instances, patients who are known to be colonized or infected with vancomycin-resistant Enterococcus.13
The anaerobes are another complex issue. I would like to summarize new information about anaerobes and diabetic foot infection. One of the new studies on the subject will be presented as an abstract by Citron at the 2005 ICAAC annual meeting. The studies were two prospective comparative trials of ertapenem. They compared obligate anaerobes isolated from clinical studies of diabetic foot infection with anaerobes found in another study of intra-abdominal infection.14 They found that the distribution of species of anaerobes was different. The Bacteroides fragilis group was found in only 11 percent of the diabetic foot infections as compared to 45 percent of the intra-abdominal infections. On the other hand, Peptostreptococcus species were found in 47 percent of the diabetic foot infections and only 7.7 percent of the intra-abdominal infections. There were smaller differences amongst other groups of anaerobes.
What we see here is that not all anaerobic infections are the same and therefore the antimicrobials that we select should not necessarily be the same. B. fragilis is typically the anaerobe that is most difficult to target with an antibiotic regimen and it turns out to be less frequent in diabetic foot infections. Even though anaerobes can be isolated in the labs that know how to do it, it may not be important to target antibiotic therapy against anaerobes specifically because it is much easier to cover Peptostreptococcus with commonly used agents.
The other interesting thing that Citron found in this study was that the minimum inhibitory concentrations (MICs) among the isolates from the 236 diabetic foot infections and the 258 intra-abdominal infections differed in terms of their susceptibility to fluoroquinolones.14 They looked at susceptibility to levofloxacin, moxifloxacin, gatifloxacin and ciprofloxacin. Overall, the researchers found the likelihood of fluoroquinolone resistance was higher in diabetic foot infections (49 percent) compared to intra-abdominal infections (38 percent). While fluoroquinolones may have the best activity against aerobic gram-negatives, we probably have to bear in mind that fluoroquinolone resistance is more common with diabetic foot infections. This may be due to the possibility that more of the diabetic foot patients have been previously treated with fluoroquinolones, since they are so commonly used for these infections.

Lawrence Lavery, DPM: Dr. Lipsky, does your interest in empirically treating for anaerobes and Pseudomonas increase with increased severity of the infection as per the IDSA classification?
Dr. Lipsky: Absolutely. If a patient has a serious or severe infection, one can’t afford to be wrong with the initial antibiotic selection, even if there is a relatively low likelihood that Pseudomonas or Enterococcus or obligate anaerobes are part of the primary pathogens or even important secondary pathogens. These infections can progress rapidly. If the patient has a severe infection, is hospitalized and needs parenteral therapy, I would always err on the side of broader spectrum therapy that includes coverage of those organisms, pending culture results that suggest otherwise.

Emphasizing The Clinical Diagnosis Of Infection
Dr. Lavery: One of the real values in the IDSA classification system is having a concise tool to help educate primary care physicians and internists who are often going to be the first line clinicians treating diabetic foot infections. The classification provides a very logical thought process of how to initiate treatment. It facilitates a better understanding of the severity of infection, the treatment thought process and culturing issues. It helps clinicians provide appropriate treatment for every patient with a foot wound even when there are no clinical signs of infection. It gives them a way to start therapy while obtaining consults in their healthcare system.
Dr. Joseph: With the more severe diabetic foot infections, it is important to cover empirically with a broader spectrum drug from a safety standpoint. In regard to clinically non-infected ulcers, one of the important points in the guidelines is the need to evaluate properly for the presence or absence of infection. The guidelines define infection as clinical signs and symptoms, not a positive culture. It is important for the primary care physicians or even our podiatric colleagues to realize we don’t have to use antibiotics when treating a clinically non-infected wound nor do we have to culture a clinically non-infected wound. The guidelines address important issues at both ends of the spectrum of infection.
Dr. Armstrong: Does that mean that empiric coverage of MRSA becomes more necessary as the infection becomes more severe? Furthermore, does that mean if the patient is getting better, even if the particular antibiotic in use is not getting that particular bug, should one change that antibiotic?
Dr. Joseph: One of the points stressed in the guidelines is that infection is a clinical diagnosis. One makes the judgment on the severity of the infection or the classification of the infection based on clinical signs and symptoms. If a patient has a clinical infection, take a culture and start him or her on empiric therapy. The culture may come back 72 hours later and if it shows an organism resistant to the empiric therapy he or she is taking, for example, MRSA or Pseudomonas or Enterococcus, one has to make the judgment call based on the clinical signs and symptoms of infection when following up with that patient. If the patient is looking better, then treat the patient based on clinical signs and symptoms. Don’t treat the patient based on a laboratory report.