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Offering key insights on choosing antibiotics for diabetic foot infections, the panelists discuss the spectrum of activity for ertapenem and piperacillin/tazobactam, and the role of culturing in clinical decision-making.
Dr. Armstrong: What are the similarities and differences in spectrum between ertapenem and piperacillin/tazobactam?
Dr. Joseph: These two drugs are both very effective against most aerobic gram-positive cocci, particularly the Staphylococcus and the Streptococcus species. Staph aureus and group B-Streptococcus are the two most common organisms that you see in diabetic foot infections. Ertapenem and piperacillin/tazobactam are both very fine drugs against anaerobes. They are not only effective against the gram positives like Peptostreptococcus but the gram-negative anaerobes as well.
|  | | “Staph aureus and group B Streptococcus are the two most common
organisms that you see in
diabetic foot infections.”
– Dr. Joseph |
They are essentially very broad-spectrum drugs. In terms of differences, piperacillin/tazobactam has more inherent activity against Pseudomonas derived from the piperacillin molecule. Interestingly enough, the tazobactam does not add anti-pseudomonal coverage because tazobactam does not inhibit the particular beta-lactamase, which you find in Pseudomonas aeruginosa. The inherent anti-pseudomonal activity of piperacillin would seem to give it an advantage because ertapenem tends to be weaker against Pseudomonas.
The other difference is piperacillin/tazobactam is probably a better drug against Enterococcus spp, again with the piperacillin being the part of the combination therapy that lends that activity. You do not have as much coverage against enterococcal organisms with ertapenem.
In summary, they are both good anaerobic drugs. They provide good gram-positive and gram-negative coverage. Piperacillin/tazobactam has an advantage when it comes to Enterococcus and Pseudomonas but neither of these organisms really seems to matter in the diabetic foot.
Dr. Lipsky: And neither drug covers MRSA.
Dr. Joseph: Absolutely.
What The Literature Reveals About
The Role Of Pseudomonas And Enterococcus In DFIs
Dr. Armstrong: Strangely enough, even among those patients that grew out Pseudomonas in the SIDESTEP study, patients did just as well in the ertapenem arm as those in the piperacillin/tazobactam arm.6 How do you explain that, Dr. Lavery?
Dr. Lavery: When we are talking about mixed foot infections — gram-negative, gram-positive, anaerobes — it is often difficult to know the importance of each of the organisms isolated. Are they colonizers, are they contaminants or are they true pathogens? The results of this study give us some evidence that perhaps we do not have to treat every bug that we identify from the wound.
Pseudomonas is not an especially common pathogen in diabetic foot infections. In my clinical experience, it is probably seen in 10 or 15 percent of diabetic foot infections.14-18 Pseudomonas is more common in puncture wounds and is probably more common in people who soak their feet. In the SIDESTEP study, Pseudomonas was in 28 isolates, about 6 percent of the patients. When clinicians think about diabetic foot infections, this is probably not the pathogen they need to concentrate on when they are choosing their antibiotic.
Enterococcus species comprised less than 2 percent of the organisms isolated ICD. Methicillin-resistant Staph aureus (MRSA) accounted for a little more than 8 percent of the isolated organisms.6
In regard to the antibiotic susceptibility of Enterococcus isolates, ertapenem was active against 46 percent and piperacillin/tazobactam was active against 93 percent.6 That being said, it did not make a difference in the clinical response. The clinical response was not significantly different in either of the treatment arms.
Dr. Lipsky: We found an 87 percent favorable clinical response for patients with an Enterococcus isolate in the ertapenem arm versus 81 percent in the piperacillin/tazobactam arm. The clinical response was 83 percent for those with an isolate of Pseudomonas in the ertapenem arm versus 70 percent for those in the piperacillin/tazobactam arm.6
Dr. Joseph: This data is not unique to SIDESTEP. If you look at the Graham study published in Clinical Infectious Diseases, which was the pivotal data for ertapenem’s complicated skin-skin structure infection indication, the authors of the study also looked at Pseudomonas.19 They found that patients whose infection grew Pseudomonas had a better clinical response on ertapenem than on piperacillin/tazobactam, which is counterintuitive given the drugs’ spectrum of activity.
|  | | For the SIDESTEP study, investigators were discouraged from obtaining swab cultures (as shown above). Dr. Lavery notes that appropriate deep tissue cultures were emphasized. |
Dr. Lipsky: The ertapenem STITCH study of intraabdominal infections showed the same findings.20 Namely, the presence of Pseudomonas, which was not common, or Enterococcus, which was more common, did not make any difference in the clinical response when piperacillin/tazobactam and ertapenem were compared.
Dr. Sheehan: I agree with everything that has been said and I think this can be generalized beyond just Pseudomonas. The response to antimicrobials that we see with infection is probably due to certain bacteria or certain groups of bacteria that are really driving the infection. What we learned from the linezolid study is that the gram positives really have primacy in terms of diabetic foot infections.10
Emphasizing The Importance Of Taking Appropriate Cultures
Dr. Sheehan: With respect to infectious disease colleagues of mine, I think we have been archaic in the way we are assessing infections with artificial culture medium. Again, there may be bacteria in there that we have not yet identified that may be the driving the infection. Investigators have used molecular techniques such as PCR to look at the microflora of the intestine, for example, and where they have isolated 300 different species, only half of which can survive in artificial culture.21 There is a lot to be learned from this clinically. The fact that what should be resistant foot infections still respond to antibiotics suggests that some other bacteria may have primacy over the “pathogens.”
Dr. Lavery: Obviously, these are good antibiotics and there was a protocol for good wound care. We talked about this at the beginning of this discussion. Care of infected wounds does not occur in a vacuum. We are obviously not going to get the same results without going through each of these steps: evaluating perfusion, debriding a wound, giving the right antibiotic and culturing the wound appropriately. One of the strengths of this study was the educational component for the investigators. Obtaining appropriate cultures was emphasized and investigators were discouraged from just swabbing the wound. There are several papers that compare swab cultures versus tissue samples.22
Dr. Sheehan: I agree with Dr. Lavery that, when performed, we need to utilize appropriate methodologies for cultures. In other words, we need to avoid swabbing and take deep tissue cultures.
|  | | “What we learned from the linezolid study is the gram
positives really have primacy in terms of diabetic foot infections.” – Dr. Sheehan |
However, I believe one of the take-home messages of the SIDESTEP study is that these infections should be treated empirically and empiric therapy should be continued if the patient is responding, independent of what the culture shows. I have no evidence of this but I think there are other factors, other bacteria that are not cultured, that may be important here as well.
When To Act And When Not To Act On Culture Results
Dr. Armstrong: Dr. Lipsky, say a patient starts out on a very broad-spectrum drug like ertapenem and is doing well. Then the patient grows out a single aerobic gram-positive organism like Staph aureus, which he or she is probably going to grow out 80 percent or more of the time. In this case, shouldn’t we be narrowing that spectrum? Dr. Lipsky, do you agree with Dr. Sheehan?
Dr. Lipsky: The comments Dr. Sheehan made are fascinating. He is correct that with infectious diseases, we are beginning to understand that the methods we have been using for over a hundred years to assess the etiologic agents of infection may not be as accurate as we once thought. Having said that, I would like to provide a slightly different definition of the spectrum of activity of ertapenem. While it has been referred to as a very broad-spectrum drug, its spectrum is a bit narrower than other drugs that are commonly lumped into that category.
Dr. Joseph has already mentioned that ertapenem has a more narrow spectrum of activity compared with piperacillin/tazobactam based upon less coverage of Pseudomonas on the gram-negative side and Enterococcus on the gram-positive side. However, when you compare a Group I carbapenem like ertapenem with a Group II carbapenem like imipenem/cilastatin, it has a much narrower spectrum. One of the lessons of the SIDESTEP study is that a narrower spectrum drug is equivalent to a somewhat broader spectrum drug for diabetic foot infections.
The role of culture is a controversial one. I might actually accept the notion that a poorly done culture is worse than no culture since organisms that represent contaminants or colonizers might cause clinicians to use a broader spectrum than is clinically necessary.
|  | | Here is a small plantar wound probing directly to the calcaneus. Intraoperative cultures yielded MRSA and MRSE. |
The main reason to get a culture in a diabetic foot infection, especially with patients who have not recently had antibiotic therapy and therefore are not likely to have resistant or unusual organisms, is protection in the event that a patient fails to respond to your empiric therapy. Then you are ahead of the game by knowing what organisms grew and their susceptibilities. Accordingly, you know which agent you might want to switch to for the patient.
However, I would agree with Dr. Sheehan that, in most instances, if a patient is clinically responding to the empiric therapy, I would certainly not add drugs to cover organisms that are resistant to the drug the patient is getting. In some instances, I would consider narrowing the spectrum of treatment if the patient, for example, only grew out Staph aureus or Streptococcus and we put him or her on a broader spectrum therapy than was necessary. This is particularly important in those few patients, such as those with osteomyelitis, who need long-term therapy. Again, we do this with an eye toward trying to reduce the growing incidence of antibiotic resistance that is driven by unnecessary use of long-term, broad-spectrum therapy.
Dr. Sheehan: I agree. Dr. Lipsky, you and I are the internists here. I remember going through this in the treatment of pneumonia. We would gram stain the sputum and then culture. Then when the bronchoscopies came around, clinicians said that sputum analysis was not accurate and you had to get a bronchoscopic sample. Then people fought with each other whether it was a proximal or distal sample that was more accurate, and, in the end, the culture had little bearing on the clinical outcomes. It all evolved into just empiric therapy of either community-acquired and nosocomial pneumonia, based on historically identified organisms. Unless the patient does not respond to empiric therapy, the culture is not a paramount issue in the clinical decision-making.
Dr. Lipsky: Right. We have analogous studies in the diabetic foot infection field. They go from studies with very narrow spectrum agents such as linezolid, which only covers gram positives — mostly the aerobes, a few anaerobes — all the way to studies with imipenem/cilastatin, which is a very broad-spectrum drug.10,23 They all look like they have fairly similar clinical response rates, regardless of the pathogens isolated on culture. I think Dr. Sheehan, as a non-infectious disease person, has really sort of unrobed the emperor by asking what do we really understand about how the causative organisms may be different from what we isolate on culture.
Dr. Joseph: In the IDSA diabetic foot infection guidelines, we come right out and say there is no need to take a culture for mild infections.2 There is no real evidence to show that culture is necessary in these cases. However, I do agree with Dr. Lipsky that most of us would take it and use it more as a “In case of failure, break glass” sort of thing. We now know what it is.
Also, Dr. Lipsky mentioned ertapenem, linezolid and imipenem/ cilastatin.6,10,23 If you look at the spectrum of activity of those drugs, what they all share in common is Staph aureus and possibly the different Streptococcus. The bottom line is these are the organisms we need to treat when dealing with the diabetic foot. |
