Potential Pathogens In Diabetic Foot Infections
Dr. Armstrong: I would like to talk briefly about other organisms like anaerobes. We used a research lab, the R.M. Alden lab, in the SIDESTEP study, in order to obtain very high quality results, especially in isolating anaerobes. Based on your knowledge of the study, were obligately anaerobic organisms commonly isolated?
Dr. Lavery: Infection was caused solely by anaerobes in only 8 percent of the patients. Aerobes were exclusively cultured in 36 percent of the patients. Mixed anaerobe and aerobic isolates were cultured in 27 percent of the wounds, which is actually low. Obviously, the most common pathogen was Staph aureus, which was isolated in 42 percent of patients.6
Dr. Lipsky: There were 169 isolates of Staph aureus, 80 percent of which were methicillin-sensitive.6
Dr. Joseph: The anaerobes have been talked about as the major organisms that have been isolated since the early studies on severe diabetic foot infections were done. Studies that were done in the 1970s looked at aerobic gram-positive cocci as being the most common organism.24 Then with the work by Sapico and Witte, the study by LeFrock and other studies that emerged in the late 1970s and early 1980s, the prevailing thinking was that all of these diabetic foot infections are probably microbial and they all are loaded with aerobes, anaerobes, gram positives and gram negatives.25,26 Then the landmark work by Dr. Lipsky and Dr. Pecoraro started turning people away from anaerobes and gram negatives as being primary pathogens in diabetic foot infections and looking at these infections as being gram-positive organisms.27
It almost feels we have come full circle from the thinking in the 1960s and the 1970s through the times when anaerobes were such a hot topic and now we are back to the notion of “Yes, we know we have anaerobes here. That is why they smell. That is why they call it the fetid foot.” The question I raise is how important are those pathogens and do we really need to treat them given what Dr. Lavery was saying about surgical debridement and I&Ds? Is the best antibiotic against anaerobes oxygen?
Dr. Lipsky: I would agree that while we began to question the role anaerobes were playing in diabetic foot infections, we have come around to thinking that, in some cases, covering anaerobic organisms can be advantageous. In many cases where the patient has adequate arterial flow to the foot, if you adequately debride the wound and remove the necrotic tissue, that may be sufficient to remove anaerobes. Patients with ischemia may need revascularization or some other approach to increase blood flow (and therefore oxygen) to the infected wound. I think that anaerobes probably have less of a role than some originally thought but are true pathogens in many moderate to severe infections.
Dr. Sheehan: I am familiar with work from Phil Bowler, MD, that the anaerobes, at least in vitro, are permissive bacteria.28-30 As opposed to being truly pathogens, they allow the growth of more virulent pathogens to overwhelm the rest. We have been talking about resistant pathogens responding to treatment — wouldn’t it be interesting if the anaerobes do play a role here and that by eliminating anaerobic flora, either surgically or with antimicrobials, you inhibit the growth of the true pathogens?
Dr. Armstrong: This is interesting thinking. Perhaps they are not just fellow travelers.
Dr. Joseph: Didn’t Alice Bessman, MD, show that about 20 years ago, Dr. Lipsky?31
Dr. Lipsky: Yes, she published some data on the role of relatively avirulent bacteria (e.g., corynebacteria) and of polymicrobial infection in the diabetic foot.32,33 Dr. Sheehan, you have added a whole new dimension to the discussion. This is a fascinating area.
Dr. Sheehan: I think that anaerobes are so difficult to culture that clinicians have ignored them over the years.
Is There A Need For Specific Anti-MRSA Therapy?
Dr. Armstrong: Can we revisit the subject of MRSA? Neither ertapenem nor piperacillin/tazobactam are active against MRSA yet people in the SIDESTEP study did pretty well when they were treated with either drug. Dr. Joseph, what is your perspective on this?
Dr. Joseph: In the SIDESTEP study, approximately 14 percent of the S. aureus isolates were MRSA and there was a favorable clinical response rate in 73 percent of those patients.6 From my understanding of the study, the protocol allowed for the addition of vancomycin but very few patients actually had the vancomycin added. It raises the question about the importance of MRSA just like we have questions about the importance of Pseudomonas and Enterococcus. This is not new. The thinking that we may not need to cover every organism including MRSA is not new.
While Dang, et. al., had significantly more MRSA cases in their study of MRSA in a diabetic foot clinic, they found that the MRSA did not need to be treated with specific anti-MRSA therapy.34
While the Fridkin study in The New England Journal of Medicine did not specifically look at the diabetic foot, they showed there was no difference in clinical outcomes in patients who had MRSA-specific therapy versus those who did not have anti-MRSA-specific therapy.35
Now the SIDESTEP study suggests that we may not have to use specific therapy directed against MRSA.6 Just to clarify, I am in no way shape or form saying we should ignore MRSA, especially if we have it in a good reliable deep tissue culture and the wound has a lot of pus, etc. However, if MRSA is just one of many isolated organisms, maybe we sthould start looking at this like Pseudomonas.
Dr. Lavery: Just a side note here. Among patients who were MRSA positive, there was a favorable clinical response of 77.8 percent in the ertapenem group and 66.7 percent in the piperacillin/tazobactam group.6 This was not affected by the administration of vancomycin.
Dr. Lipsky: Just to follow up on what Dr. Lavery was saying, a total of 12 patients received vancomycin in the SIDESTEP study. Five of seven who got vancomycin and had MRSA had a good clinical response. Three of the five patients who did not get vancomycin had a good clinical response but these numbers are too small to be statistically different.6
Dr. Armstrong: Dr. Sheehan, if a patient grows out MRSA or another resistant organism but he or she is responding well to ertapenem, are you going to change that drug? Are you going to add a glycopeptide or oxazolidinone?
Dr. Sheehan: Even after this discussion, I would still, in practice, add a specific MRSA agent because I am not 100 percent confident in my theoretical approach to foot infections and there are also medical-legal concerns if a patient should relapse or get worse. If I am convinced a patient has a somewhat polymicrobial infection. I will continue a broader spectrum agent as well. So I would probably add — but not substitute — a specific agent against MRSA.
Dr. Lipsky: In regard to MRSA and the previous discussion about Enterococcus and Pseudomonas, in the majority of cases in the SIDESTEP study, these organisms were not isolated from a monomicrobial infection. They were mostly involved in mixed infections. In the case of Enterococcus, in 83 percent of the patients, it was isolated from a polymicrobial infection, while it was 71 percent for Pseudomonas. Similarly, in the case of MRSA, it was usually not the sole isolate.6 When we are making antibiotic choice decisions, the question is whether these organisms that are mixed among others require additional therapy as opposed to when they are the sole pathogen.
