Warren S Joseph, DPM, FIDSA reviews the classification system developed and introduced by the Infectious Disease Society of America. Through a case example, Dr Joseph makes recommendations regarding the appropriate sequence of interventions, the importance of thorough debridement, the indications for wound culture and antibiotic treatment. He emphasizes the importance of de-escalation of antibiotic therapy by targeting bacteria based on culture and sensitivity results for a specified period of time. He also performs a literature review to illustrate his points.
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Release Date: 03/16/2018 Expiration Date: 12/31/2018
Warren Joseph, DPM
Roxborough Memorial Hospital
Editor - Journal of the APMA
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Male Speaker: Now what were the discussions on infections be without having our perennial lecturer on bugs and drugs in diabetic foot infections come and talk to us. Warren Joseph comes to us from the Philadelphia area. He's, as I said, a very, very popular speaker in this regard. I always turn to him for the latest and greatest in adjunctive antimicrobial therapy. I think, Warren also is going to agree that antibiotics are indeed an adjunctive therapy in addition to our other appropriate managements for infection. So let's welcome Dr. Joseph to the panel.
Dr. Warren Joseph: Adjunct to not an osteomyelitis necessarily but that was already covered. Thanks for having me. I really appreciate everybody from Superbones inviting me and this wonderful crowd we have this afternoon. I just appreciate you sticking around and being here. Let me talk a little bit about the Infectious Disease Society of America Diabetic Foot Infection guidelines. We published our first set of evidence based guidelines in 2004. That’s now outdated. I will tell you the good news is that the new guidelines are completed. They’ve been through both external and internal review at IDSA, hopefully for publication some time end of this year, early 2012. When their first publish will be published in clinical infectious diseases NCID, the IDSA has changed their rules now and they will only publish the executive summary. I will tell you that once it has been published the executive summary in clinical infectious diseases, we will plan on publishing the entire document in Journal of the American Podiatric Medical Association. Of course nowadays, it helps that I’m editor but I have to put it through the Clinical Practices Committee of the APMA, hopefully, for approval. I'm going to talk a little bit about that and some of the changes and some of the things that are going on with the IDSA guidelines. I direct you to my blog, Leighton commercial blog here even though it's a noncommercial blog, www.leinfections.com for lower extremity, leinfections.com, where I just blog about things that happen to turn me on about lower extremity infections. Again, the blog itself is noncommercial but it is put up by my publisher, DataTrace, who has my book, "Handbook of Lower Extremity Infections". And now, for the blatant commercial blog, I'll be outside signing copies after the break or at the break. Anyway, let's give you a case, let's start with a case. This was a patient I saw a number of months ago. Sixty-one-year-old male presented to the emergency department with a history of present illness of having a “few-week’” duration of an ulcer. He self-treated with hydrogen peroxide and dressing changes and he told us he walked 1 mile about a week ago because after all, these patients do know that they’re supposed to stay active to keep their glucose down. So despite having a large hole on his foot, he decided to walk for a mile. Of course, after he took that little walk, he had a recent increase in swelling, pain and redness. On examination, blood work was drawn in the emergency department. His white blood count was 17.3, glucose 220, creatinine 1.1, BUN 14, temperature 101.5, and x-rays revealed some soft tissue gas localized to the first MTP. And it is MTP joint, ladies and gentlemen, it is not MPJ. So there was some gas -- especially we have a lot of residents here today, please start using the proper terminology. So, we did have some gas localized. So the first question I'm going to ask you, well, once I show you the pictures, this is how the patient looked on admission. You could see these two sinuses along the medial aspect of the foot draining rather foul smelling drainage. This was the initial ulcer which he had plantarly. Again, you could see this is what he walked upon. This is the dorsum of the foot. You can see pretty significant cellulitis. You could see the erythema up to about the midfoot or a little proximal to the midfoot, almost to the ankle and you can see swelling even above the ankle so you’ve got all the classic clinical signs and symptoms of infection here. So, first question I'm going to ask you is how would you classify this wound? Would you call this an IDSA mild infection? Actually, just a slight minimal correction to Dr. Jacobs is that in fact he was using like 0, 1, 2, 3, that’s the PEDIS classification, which is the international working group on the diabetic foot. I don’t use that. I just use our definition which was IDSA mild, IDSA moderate, or IDSA severe, or you don’t know any classification schemes other than Wagner, which, by the way, the name of the original Wagner paper, anybody, other than Dr. Freiburg?
The dysvascular foot. It did not necessarily have anything to do with diabetic foot wounds. Yeah, thank you Bob, I know you know the reference. Or A, you don’t believe in classification schemes because they don’t assist in management. Anybody, give me a shout-out. This is an IDSA severe diabetic foot infection. This would be an IDSA severe diabetic foot infection. Now, what is the classification? We kept it very straightforward. Here's my problem with Wagner. What grade Wagner ulceration do you have to have before the word infection appears? Absolutely. You have to have Wagner 3. Well, can't you have a Wagner 1 that’s infected or Wagner 2 that’s infected? Absolutely, you can. We do have the Texas system because the Texas system you can put the modifier for infection. Anybody here know the Texas system? Recite it for me. That’s a grade 3 BAC 4F. The fact is, we did what you would expect a bunch of antibiotics needs to do. I mean basically, we sat there and say, “Is the wound infected or noninfected? If it is infected, how badly is it infected?” And once we know how badly it's infected, what organism is causing the infection and what antibiotic you need to treat it? And we kept it very straightforward. The wound is either noninfected as a mild, a moderate, or a severe infection. Well, noninfected is just that. Let me go back here a second. Noninfected, no signs or symptoms of infection. I know there was some discussion by a Dr. Jake and by Larry and some talk about these blunting of clinical signs and symptoms. Yeah, maybe that’s true. I don’t know that the evidence there is necessarily to support that. My feeling is, and the feeling of our particular committee was that you diagnose an infection by looking for clinical signs and symptoms of infection. When I teach diabetic foot, I teach a mantra. It goes like this, “No signs of infection, no infection. No infection, no culture. No infection, no antibiotics.” Let's get back to that. No signs of infection, no infection, that’s exactly what I'm talking about here. This is by definition. No signs of infection, no infection. No infection, no culture. Now, we take a fairly strong stance here. I know Dr. Jacobs, he just walked out just as I was ready to challenge him on this. He's coming back. Dr. Jacobs was talking about surveillance cultures. They're all well and good. If you want to take a surveillance swab, be my guest but what are you going to do with that information? Because the surveillance swab is going to grow three, four, five organisms. When this patient eventually does get infected, if they do get infected, it doesn’t tell you anything. You don’t know what the infecting organism is. I’m not sold, I mean, it's all well and good if you want to do it, do it. I agree with him 100% that you better really carefully document that this a surveillance swab. You were taking it just to find what the colonies are and that you are in no way doing it to identify an infection and put everything he talked about. No signs of erythema, warmth, tenderness, all that classic stuff. We basically just say, “If you don’t have a clinical sign of infection, you don’t need to take a culture.” And then part three, no clinical signs of infection, no infection, no infection, no culture, no infection, no antibiotics. Why? Overuse of antibiotics leads to resistance. The first two reported case is in the United States of vancomycin-resistant Staph aureus, VRSA, occurred in diabetic foot wounds. So please be aware of overuse of culturing in diagnosis. Well, we defined a mild infection as having purulence or at least two signs of inflammation, erythema, warmth, tenderness, induration cannot extend more than 2 centimeters. This is a very localized process, alright? So this is mild. Moderate and severe, we don’t differentiate on how the foot looks. The foot is going to look exactly the same, greater than two of the following. Cellulitis extending more than 2 centimeters, lymphangitic streaking, spread beneath superficial fascia, deep tissue abscess, gangrene. You can read this as easily as I can recite them to you. The way we differentiate moderate from severe is in our moderate infections the patient is systemically well and metabolically stable and our severe infections, the patients are systemically unwell, metabolically unstable. They display some of these signs of sepsis, the so-called systemic inflammatory response syndrome. You can see the definition of two or more of these particular findings that were first published quite awhile ago as definition of sepsis.
So, you can't differentiate moderate from severe. So looking at our foot that I showed you, we can't differentiate moderate from severe just by looking at the foot. We need to have that blood work. Given the fact that the patient had a 101 fever, a 22,000 white count, this is now an IDSA severe diabetic foot infection. This probably might have been shown a couple of times already. Larry did a wonderful job of applying the IDSA classification system to owe his cohort of 1,666 patients, 1,666 to Dr. Lavery, that’s the same as the 999. Just trying to make it a topical sort of lecture here. So he applied the IDSA classification to the 1,666 patients in his cohort and what he found is that as you increase from mild through moderate to severe, between mild and severe, there were statistically significant increases in rates of hospitalization and amputation and this was published in Clinical Infectious Diseases back in 2007. So, next question for you. What are the key steps in the early management of one of these infections? How would you prioritize the [indecipherable] [11:20]? What would be first? A, getting a vascular consult, B, debridement and drainage of the wound, C, contacting a malpractice carrier, D, initiating I.V. antibiotics, or E, probing the wound. What's most critical? Drano. Yeah, incision and drainage is most critical. As my mentor in infectious disease, Dr. Jack Le Frock used to teach, Drano is the best antibiotic known to man. There is no known resistance. You’ve got to debride, you’ve got to drain this wound. Currently in the United States, only three antibiotics actually carry an FDA indication that rids complicated skin and skin structure infections including diabetic foot infections without concomitant osteomyelitis. And very interestingly, that complicated skin and skin structure guidance, no longer exists. So there's a possibility, the FDA about a year ago, put out new draft guidance for industry on the classification of skin and skin structure infections and they got rid of the old one and it's now just called acute bacterial skin and skin structure infections, ABSSSI, and I will tell you that diabetic foot is not included. So there's a possibility that no new antibiotic will be FDA approved for diabetic foot which is kind of scary and we’re going to work on that a little bit with the agency. But currently in the US, only three antibiotics do hold the FDA indication for diabetic foot. They are ertapenem, usual dosing, 1 gram q. 24 hours, piperacillin/tazobactam, usual dosing 3.375 q. 6, some people go 4.5 q. 8, and linezolid, 600 mg either I.V. or PO q. 12 hours. Linezolid of course is to be used for MRSA, only when you got MRSA infections because that its spectrum. Why no osteomyelitis drugs? I think Allen and Larry really covered it. You heard two excellent lectures by top people in this profession in the area of osteomyelitis. What did you hear from both of them? There's no data. There is no agreement on any of this. The reason why we have no antibiotics FDA approved in the last say 15 years for osteomyelitis is because the FDA doesn’t have guidelines for industry on how to do an osteomyelitis study. So if Merck or Pfizer or Cubist went to the FDA and said, "We want to get an indication for osteomyelitis.” The FDA would say, “That’s nice. We don’t know how to tell you to do it.” And you can't blame the FDA because look at what Allen and Larry just showed you. How do you diagnose osteo? We can't even agree on this. How do you treat it? Got four to six weeks of I.V. antibiotic, don’t buy it. You know where that’s based on? Forty-year-old rabbit tibia studies. There's no human evidence to support the concept of four to six weeks of I.V. antibiotics for the treatment of osteomyelitis. And then the big question, and I believe both of them raised it, is what's the end point? How do you know you’ve cured your osteomyelitis? I've sat on advisory boards with people a lot smarter than I am and no one can come up with that answer. So that’s why -- In fact, the international working group, Larry alluded to Tony Berendt’s work for the IWGDF, you can find it at iwgdf.org, their consensus document, their systematic review of the literature on osteomyelitis basically came out and said, “There is no data to support just about any of these questions, to answer any of these questions.”
They actually found only one thing that they could definitively say, there was one item, there was a predictor of a positive outcome in the antibiotic treatment of osteomyelitis. Anyone know what it was? Bone culture directed antibiotic therapy. That’s it. And in fact what's very telling about the IWGDF document, their systematic review of the literature. They started out with over 1,100 papers they were reviewing for this systematic review. They found three randomized controlled trials. That’s it. Three randomized controlled trials in the treatment of diabetic foot osteomyelitis. What about the need for MRSA coverage? Well, I think most of us in this room, if I were to ask you, do you empirically start MRSA coverage on your moderate to severe diabetic foot infections? You would say, yes. This brings up the concept of escalation versus de-escalation. In the infectious disease in pharmacy world right now, there's a big buzz word that's going around. It's called antimicrobial stewardship. Basically all that means in English is using the right antibiotic for the shortest period of time. But de-escalation is a major player in that stewardship thought process. What it means is you start broad, 48 hours later, cultures come back, you narrow down, you de-escalate therapy to what you have in your particular infection. So that’s the concept of de-escalation. We do start MRSA coverage but we based that on the fact that in our hospital, we've got a lot of MRSA. In your hospitals, you probably have a lot of MRSA. The lowest MRSA rate I found in the continental United States so far was about two months ago, I was in Fargo, North Dakota, at their hospital, they’ve got a 40% MRSA rate, that’s the lowest I found. Cold kills everything. You want to get away from MRSA, move to Fargo. It's actually a nice little hospital, Sanford Hospital it’s called. What we did, and this is controversial, I'm not sure it's going to end up in the final document because it's a relatively controversial concept we came up with and there was a lot of questions from the reviewers. We stated that you should start MRSA therapy based on your pretest probability of having MRSA. In other words, if you are not treating a mild infection, we don’t really care that much about MRSA. You can have as high as a 60% MRSA rate in your hospital and probably not need to treat MRSA empirically. But look what happens as we go to moderate to severe. The rates come down. The threshold at which you need to start MRSA therapy comes down. So going in severe infections, you better have a 5 to 10%. That’s it. If you even have a 10% chance of MRSA, you need to start MRSA therapy. The only place you're going to get that, the Netherlands. Alright. They're at about 2%. So you can certainly not going to get it anywhere here in the United States. What about this one? Pseudomonas. Well, in my blog, about a couple of months ago, I put up a post I called “pseudomonaphobia” because, frankly in podiatry, we’re all scared to death of pseudomonas. I don’t think anyone in this room who’s a resident or a way past residency like some of us has ever gone to a residency interview where you weren’t ask the question, how do you treat pseudomonas? And you know what, there's only one clinical scenario in which pseudomonas can be reliably considered a pathogen. Anybody? Puncture wound osteomyelitis, about 80% of the time. Certainly not skin and skin structure, not diabetic foot. Let's look at the data. This is the Graham study, this was the pivotal study on which ertapenem received its indication for complicated skin infections. Ertapenem has no activity against pseudomonas. Pip/tazo of course does have activity against pseudomonas. In patients who grew pseudomonas, there was a positive clinical response, 70% of the time in those who were given ertapenem, 60% of the time in those who got pip/tazo. A closely related study, the SIDESTEP study published by Ben Lipsky and Lantz in 2005, was the pivotal trial in which ertapenem got their diabetic foot indication, 445 evaluable patients. Ertapenem, 76.9% positive clinical response in those who grew pseudomonas, pip/tazo, 70%. I’m in no way, shape or form, saying ertapenem is a better antipseudomonal drug, I'm saying it doesn’t matter. Let's forget ertapenem and pip/tazo. Let's go to a new drug, relatively new drug, fifth generation cephalosporin, first anti-MRSA cephalosporin, ceftaroline. They published the canvas one in two trials. There are large, 1,300-patient studies on complicated skin and skin structure infections.
By the way, they excluded diabetic foot, but 50% were in the lower extremity so they were probably treating a lot of venous stasis ulcers which have a lot of pseudomonas. Yet in those patients, 80% had a positive clinical response rate who grew pseudomonas. So that led to this conclusion. The demonstration of efficacy in patients with pseudomonas aeruginosa receiving ceftaroline, a pathogen against which ceftaroline has little activity, most probably reflects the presumptive role of pseudomonas as a colonizer rather than a true pathogen in many of these infections. So please folks, you can see all these references in my blog post on “pseudomonaphobia.” Don’t rush to always treat pseudomonas. Basically, there's been one study that looked at this on maybe patients have pseudomonas, they have a poor outcome, that was Lipsky’s study published last year. I talked to him about this, they really couldn’t stratify, really didn’t know what it meant. So let's get back to our case. This is after the initial incision and drainage. I don’t like the look of this. It’s still erythematous. It's still swollen. And I particularly don’t like the look of this area here. It was a little bit friable. It was a little bit white and black. It just didn’t look good. So I called the podiatric surgeon who did the initial I&D and I said, “You know what, I think you need to go a little bit more aggressively.” And he did. So you could see how he extended it proximally up to where that area was. Now this looks gorgeous. I'm happy with this. We've got that postinflammatory erythema. It's no longer that fire engine red cellulitis. C&S results grew methicillin-susceptible staph, group B beta-hemolytic strep and Proteus mirabilis and non-ESBL producer. What do you do in this case? We had the patient on vanco or ertapenem. What do you do in a case like this? We de-escalate it. We discharge the patient, quite simply on cefazolin, gave him two weeks of cefazolin in the sniff and then discharged him from the sniff on cephalexin. He was followed outpatient in our hospital’s wound care center. About three weeks later, I happened to be walking by the wound care center and just stopped in to say hi to some of the people there and the patient happened to be sitting there and this was the outcome. So we can treat this, again usually moderate to severe. We start broader, usually with MRSA coverage. We don’t worry about antipseudomonal coverage and we de-escalate once we know what the organisms are. Thank you very much.