Data Trace, the publisher of the Handbook of Lower Extremity Infections, 3^rd Edition, has started a bit of a marketing “blitz” in response to the recent release of the book.  I want to take this opportunity to welcome those of you who have just come across this blog either through the recent direct mailing or the ads in PM News or Podiatry Management Magazine.  The purpose of this site is twofold; to allow me to interact with anyone interested in the treatment of lower extremity infections and to give me an opportunity to update the readership on new developments in infectious diseases as they become available.  I regularly review the ID literature for manuscripts that have a direct bearing on the way we treat the lower extremity and attend ID meetings.  This blog allows me to disseminate that information rapidly which would be impossible if I had to wait for my next book revision.

I envision this site as being interactive.  If you have a question about an interesting case (you can even post pictures), have recently heard a lecture, been detailed by an antibiotic representative or just randomly thought of a question on which you would like my thoughts, ASK AWAY!  I will do my best to answer in a timely manner with the best available evidence to support what I say, not to mention a dose of my opinion/experience.    In the future I hope to start running the occasional poll to capture what others may do in a given situation.  If you have any other ideas for this site, please let me know.  I am open to suggestions on how to make it of value to you.

Last week I was invited by Bret Ribotsky, DPM to participate in one of his “Meet the Masters” telephone conferences (www.podiatricsuccess.com).  We had an interesting conversation covering topics such as my definition of “success”, the Journal of the APMA, and my take on some current infectious diseases topics.  After the conference Bret posted a comment on PM News Online (www.podiatrym.com) asking for others’ thoughts on my comments about so-called escalation vs. de-escalation therapy for MRSA.  I felt that I should discuss my thinking on this in a bit more detail.

Traditional approaches to empiric antibiotic selection suggests that you should chose the narrowest spectrum antibiotic against the organisms you suspect are causing the infection.  This, of course, would then be modified based on definitive culture results (if obtained) and the patient’s clinical response. Until relatively recently I would NOT have included MRSA coverage in my empiric selection for most patients.  I believed that beginning therapy against MSSA would be, for most cases except the most severe life and limb threatening infections, sufficient and then, if MRSA was cultured I could always ESCALATE therapy to include MRSA coverage.  My thinking on this approach starting changing about a year or so ago when I was called in to see a patient in our Emergency Department.  This 36 y/o healthy male had no history of any hospitalizations and related not remembering ever taking any antibiotics.  He had dropped a trash can on his foot at work and thought nothing of it until the 1^st MTP joint started becoming hot, red and painful.  During the History, I even specifically asked him “Have you or any of your family members ever had MRSA”.  Now, you pretty much have to be living under a rock not to have heard about MRSA given all of the press coverage.  His answer to me was a simple “What’s that”.  With this History and that response I turned to the Resident and basically stated that I would “eat my hat” if this guy has MRSA.  We started him on non-MRSA coverage.  Well, I think you can imagine what happened.  48 hours later the C&S was returned as CA-MRSA (Picture below is from after initial I&D by my podiatric surgical colleague).  From this point on I have started to practice DE-ESCALATION therapy.  I start the vast majority of my patients, particularly those being hospitalized, as if they have MRSA and will de-escalate to remove the MRSA therapy if MSSA or no staph is found.  Frankly, I don’t remember the last time I was even ABLE to de-escalate.  That is how prevalent MRSA is in our local hospital.

Now, this is NOT to say that my approach is appropriate in every clinical setting and every community.  In the outpatient setting in a locale with a relatively low MRSA rate, you can still begin coverage as if there is only MSSA and switch if the patient does not respond.  Notice I said, “NOT RESPOND” and not, “what the culture report says”!  I continue to believe that patients should be treated, not lab results.  Many studies have shown that, for most uncomplicated skin and skin structure infections, I&D without antibiotic therapy is still an appropriate approach to an abscess caused by MRSA.  If you want to escalate to anti-MRSA therapy then I do believe that doxycycline or minocycline is preferred over trimethoprim/sulfamethoxazole (TMP/SMX).  The reason for this is the significant rate of adverse events found in TMP/SMX and the lack of clinical evidence supporting it.  (I will try to cover this in a future post.  I do cover it in the 3^rd Edition of the Handbook)

I am pleased to announce that we have just posted a few pages from the Ulceration and Infection section of the newly revised Diabetic Foot Infection chapter of the 3rd Edition of the Handbook. Just go to “Preview the Book” in the header above and you will find the pdf link.

I chose this section to include in the book and as a preview since I feel it is important information for anyone treating lower extremity infections to understand. It contains the entire “Executive Summary” of the Infectious Diseases Society of America (IDSA) diabetic foot infection guidelines published in 2004. The Guidelines in their entirety can be found at www.idsociety.org by clicking on the link for “Clinical Practice Guidelines”. These are evidenced based recommendations based on the best available data at the time they were written. The DFI guidelines have been revised and a draft is being presented at the IDSA meeting in Philadelphia later this month  with the hopes of publishing sometime in 2010. This summary includes important points such as #4 – almost all DFIs are caused by gram positive cocci. #5 – Wound infections should be based on clinical, not laboratory grounds. #9 – evidence does not support the antibiotic treatment of clinically uninfected ulcerations, along with 16 other recommendations.

Also in this preview section is the IDSA DFI severity classification system. Unlike other classifications that look at diabetic foot ULCERATIONS, this one is specific for severity of INFECTION. It is easy to understand with only 4 categories and has been independently validated by Larry Lavery and colleagues in a paper published in Clinical Infectious Diseases in 2007 showing that, as the severity increases so do the number of hospitalizations and amputations. This system has now been accepted by most investigators in DFI and is widely used in clinical trials of the condition. It can also be used by everyday clinicians in their clinical practice. For example, under your patient assessment, consider using this system. i.e. “Patient presents today with an IDSA Moderate DFI of the 2nd metatarsal region”.

I hope that you find this new Preview interesting and useful.

It has been about 2 weeks since my first post about ICAAC which has given me some time to ruminate a bit over the happenings there. I have always enjoyed this meeting because its emphasis on new antibiotic development, an area of great interest to me. It is sometimes a bit short on clinical information relevant to lower extremity infections and this year was no different. In fact, other than my poster on the use of daptomycin in diabetic foot infections there were only two other posters, out of thousands, in which the term “diabetic foot infection” even appeared. Both of those studies supported the efficacy of linezolid in the treatment of DFI caused by MRSA. To review some other information I found interesting:

1. During a major symposium on the treatment of gram positive infections, Robert Moellering, MD, one of the gram positive deities in the ID world from Harvard, discussed vancomycin dosing with a lecture entitled “New Approaches to Vancomycin Dosing: Does a higher trough help”. He discussed the new guidelines suggesting troughs between 15-20, a topic I have addressed in this blog. Once again, at least to me, it became clear that the data to support this is very limited, is based on a pharmacokinetic theory, and mostly deals with pneumonia. Dr. Moellering suggested using the vancomycin MIC as a surrogate marker for the appropriate trough for which to aim. The most surprising statement he made was that for an MRSA with a vanco MIC of >1 there is no way to achieve a high enough trough that would still be safe and alternative treatments should be considered (my emphasis). Considering many of us don’t remember the last time we saw an MIC of <1, maybe it is time to finally put vanco to bed??

2. During that same symposium another speaker, David Snydman, MD out of Tufts, discussed linezolid and daptomycin resistance reports. What I found most interesting out of this lecture is that, even after 9+ years of clinical use, the current resistance rates of MRSA for linezolid are sitting at 0.03%. This is a pretty amazingly low number that belays the conventional wisdom, stated throughout the Handbook, that the bugs are always going to be smarter than us. In fairness, resistance rates of coagulase negative staphylococci to linezolid are higher, in some series approaching 5%.

3. I don’t know if the timing of the announcement coinciding with ICAAC was planned or not, but it was announced that another antibiotic, Telavancin, has been approved by the FDA for the treatment of complicated skin and skin structure infections caused by MRSA. This makes the 5th drug for this indication behind vancomycin, linezolid, daptomycin and tigecylcine. Telavancin (Vibativ), developed by Theravance and Astellas, is an IV only lipoglycopeptide. I saw some of their early data a few years ago but am not up on the latest so I really don’t know how to place this drug yet. I am also concerned about some adverse event rates and black box warnings. More to come in the future on this one.

4. An upstart out of the UK, NovaBiotics, presented 2 posters on a “novel fungicidal peptide” for the treatment of onychomycosis. This was really preliminary, mostly in vitro stuff but I do think that the entire peptide class of antibiotics show promise for lots of different applications (can anyone remember Pexiganin?).

5. David Nicolau, PharmD out of Hartford, has done some great work in skin and skin structure infections. Amongst the many posters he presented was one that looked at the development of carbapenem resistance to Pseudomonas aeruginosa when 25 hospitals started using ertapenem. His results echo that of previous authors who have shown time and time again that Pseudomonal cross resistance to other carbapenems does not occur just because a hospital uses ertapenem. This has been a concern voiced by many ID specialists and pharmacists effectively blocking the use of this once daily drug in many hospitals specifically in diabetic foot infections. It is one of only three drugs (along with linezolid and piperacillin/tazobactam) currently approved for this indication.

Well, that is it for my review of ICAAC. Sorry for the long post but I wanted to get as much information as I could out to you in a timely manner.

I just wanted to drop in a short post to tell everybody that the 3rd Edition of the Handbook of Lower Extremity Infections has been published and is now shipping. For anyone who ordered the book, if you have not received it already, you should be getting your copy soon. For those waiting for the finished product, wait no more! Place your order. Sorry for the commercial nature of this post, but I am really proud of the finished product and wanted to “shout it out” a bit. Many thanks to the entire staff at my new publisher, Data Trace for all of the hard work that went into this project. I have worked with many publishers over the years and Data Trace has done a wonderful job.

This past week I attended the American Society for Microbiology’s 49^th annual Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) held in San Francisco.  ICAAC is the largest conference in the world dealing with infectious diseases and antimicrobial agents.  It routinely gathers over 10,000 microbiologists, infectious diseases specialists, pharmacists, etc. from all over the globe for lectures, posters, symposia dealing with all aspects of antimicrobial therapy and infectious diseases. Although I have attended the meeting many times over the past 25 years this was the first ICAAC in which I actually participated.  I was lead author of a poster on the use of daptomycin in the treatment of diabetic foot infections which was included in the Monday poster session.  I have always liked poster sessions at these meetings since you actually get to meet the author and ask questions one-on-one.  Our poster was no exception with folks coming up throughout the session to discuss diabetic foot infections.

On Tuesday afternoon I was honored to be asked to participate in a “Meet the Expert” session on the treatment of diabetic foot infections along with Dr. Tony Berendt from Oxford, UK.  Although the timing was late in the meeting and late in the day, beginning at 5:30PM, we easily had a few hundred attendees who stayed throughout the entire 75 minute session.  Tony and I decided to try an approach successfully employed for sessions like this by Dr. Ben Lipsky called the “What Do You Want to Learn Today” method.  We started by asking the audience to step to the mic and announce topics they would like to hear covered.  After a few seconds of initial reluctance the floodgates opened and attendees lined up to call out subjects.  We could have spent the entire 75 minutes just listing all of the topics!  Most revolved around the diagnosis and treatment of osteomyelitis, antibiotic selection, length of therapy and the use of “adjunctive” therapies such as hyperbaric oxygen.

Interestingly to both of us, a topic mentioned by a number of attendees seemed so basic that we were surprised that it was a concern…what to do if your surgeon refuses to do surgery? Apparently, there is some reluctance out there for surgeons to do the necessary I&D work not to mention minor amputations of the toe/foot to try to save the leg.  One very prescient question asked if by failing to perform the necessary aggressive surgery we are causing more antibiotic resistance.  I found this a particularly timely and important question since during the session I presented a current case of mine concerning a patient with osteomyelitis of the 2^nd toe and 2^nd metatarsal who adamantly refused to have her toe removed.  Instead of my podiatric surgical colleague being able to essentially “cure” the infection with a scalpel and bone saw I was left sending the patient to an SNF unit with an IV line for 4 weeks of vancomycin.  And we wonder why we have issues with MIC creep!

I will include some interesting tidbits I picked up at ICAAC in a subsequent post.

With the news of the imminent release of the 3^rd Edition tentatively scheduled for 9/25 it is time to update the blog. Over the next few days I hope to get a few more posts up covering some recent literature of interest and my experiences at the recent ICAAC meeting.  I would also like to bring your attention to the fact that we have posted a Preview of the MRSA Chapter.  This is a brand new section of the book covering a vitally important topic that, in earlier editions, only merited a few paragraphs.  MRSA has become a primary pathogen to the point that I have begun to pretty much cover virtually ALL of my hospitalized patients as if they have MRSA until proven otherwise.  This is what is known as “De-escalation therapy”.  You cover the patient broadly, as if they have MRSA, and then “de-escalate” to non-MRSA specific therapy if or when preliminary culture results (or surveillance screening) come back as being negative for MRSA. I cover more about this in the book itself.

The chapter preview includes my “History of Staph” where I review how we have come from the early days of penicillin sensitive staphylococcus, the development of penicillin, beta-lactamase forming staph, penicillinase resistant penicillins and finally MRSA…all in about a 50 year period.  The preview section also discusses the most recent classification of MRSA including the differences between CA- and HA-MRSA, clinical presentation and various virulence factors of each.  In the non-previewed section I go on to discuss the treatment approach including older and newer agents and importance of “MIC creep” amongst other subjects.

In the near future I hope to have posted the final preview section which will include the beginning of the newly revised diabetic foot infection chapter.  This section will include a discussion on the Infectious Diseases Society of America diabetic foot infection classification.

Needless to say, I am really excited about the book finally being published and ready to ship.  I hope you enjoy both the preview chapters and the new book itself.

It has been difficult to get any new posts up on the blog lately with an incredibly busy travel/lecture schedule.  In the past 2-3 weeks I have been in Toronto for the very successful APMA National, Indianapolis for the Drum Corps International World Championships (not work related for a change!), Las Vegas this past week for 3 well attended lectures and both South Carolina and Georgia Monday and Tuesday of this week.  This has not left much time for scanning the recent literature to update the blog.

One question that arises consistently at almost all of these lectures is the role of newer antibiotics in the treatment of osteomyelitis and why none of them are FDA approved.   During the course of these talks I invariably ask the audience “name for me an antibiotic FDA approved for osteomyelitis in the past 15 or so years”.  This is followed by the usual litany of newer antibiotics being mentioned by audience members.  Actually, it is a bit of a trick question.  NO antibiotic has received an indication for osteomyelitis in that period of time.  Of course, this is not a reflection on the quality or efficacy of the newer drugs, it is just the symptom of the Food and Drug Administration, Center for Drug Evaluation and Research (FDA/CDER) never developing “Guidance for Industry” on how to perform an osteomyelitis trial.  What this means is that if Merck, Pfizer, Wyeth, Cubist, whoever, goes to the Agency and tells them they want to receive an indication for osteomyelitis, there are no specific guidelines set by the FDA to tell them what to use for endpoints and how to perform the trial.

Of course, this is an understandable situation given the difficulty this disease presents.  Think about this yourself.  If you were the FDA, how would YOU want the study to be performed?  What are the proper diagnostic criteria? What role, if any, should surgery play? What is the appropriate endpoint? What sort of follow-up should be required to prove the cure or relapse?  The potential questions just go on and on.

This is not to say that some companies have not attempted to do a study.  A survey of www.clinicaltrials.gov using the search terms “osteomyelitis, diabetic foot infections” yield only two results.  Most recently Wyeth attempted to study tigecyline vs. ertapenem +/- vancomycin for diabetic foot infections including osteomyelitis.  Clinicaltrials.gov has the study has the study listed as completed but no osteo data has been presented from it to the best of my knowledge. The second study is taking place in France.  Removing the search term “diabetic foot infection”, Cubist is currently recruiting patients for a prosthetic joint osteomyelitis study of daptomycin.

So, what is the bottom line?  Until the FDA solidifies Guidance on how to do an osteomyelitis trial, especially in the lower extremity, there will be no formal “approvals” for this disease.  That does not imply that the drugs released in the past 15 years are any less effective than some of the grandfathered antibiotics with an osteo indication (how many of you realized that cephalexin is “approved” for osteomyelitis?).  It just means that the drugs have not been studied to the FDA’s standard and the use is off-label.  There are case series in the literature of many of these antibiotics being used successfully for osteo.  If the drug hits the bug found in the bone (the single most important determinant of success) then you should feel comfortable using any of these newer antibiotics.

You may notice that the top menu bar now has a new selection “Preview the Book”.  My idea in doing this was to get some important content from the book up on this blog to a) be a “public service” to readers of this site and b) act as a bit of a teaser to get the reader interested in purchasing the book in its entirety.  We have now posted the first of the planned previews with the opening 18 pages of Chapter 1 covering the basic principles of diagnosis of lower extremity infections.  This material covers the definition of infection, clinical diagnosis, the physical examination, explanation of fever and laboratory testing.  Readers of earlier editions of the Handbook will recognize that this content has not changed significantly from the previous editions.  Good basic principles are universal and do not change frequently so there was little need to update this material.  In upcoming previews I will include a portion of the totally new chapter on MRSA and a newly revised section of the diabetic foot infection chapter that reviews the Infectious Diseases Society of America diabetic foot infection guidelines.  This is all vital information that I felt was necessary to get on line to as large a readership as possible.  I hope that you find this posted material interesting and useful in everyday practice.

This new consensus document on the use of vancomycin in the treatment of MRSA is a MUST READ for anyone treating MRSA (which pretty much means anyone reading this post!).  The document can be found on the Infectious Diseases Society of America (IDSA) website.  The following address should directly access the document:

http://idsociety.org/WorkArea/showcontent.aspx?id=13052

The panel consisted of representatives from the IDSA, the American Society of Health-System Pharmacists and the Society of Infectious Diseases Pharmacists.  They take an evidence based, detailed look at the pharmacokinetics, dosing recommendations and monitoring of vancomycin for the treatment of MRSA infection.  Little of this information is specific for skin and skin structure infection or diabetic foot infection but there are a number of important issues that are addressed and do directly pertain.  Each recommendation is graded for the level of evidence and the grade of recommendation.  There is also an easy reference table summarizing the major points.

Of particular interest to readers of this blog is a statement, rather buried in the document that mentions how the penetration of vancomycin into tissues of patients with diabetes is significantly lower than those without diabetes.  How this may affect the use vanco in our diabetic foot infection population is never explored.  Also of importance is the formalized recognition that vanco peak levels are not contributory and should not be drawn.  Only serum trough levels give important information that can lead to dosing modification.   The trough should be drawn once the drug reaches steady state which is noted to be after the 4^th dose.  This would mean that the trough should be drawn before the 5^th dose is given.

What concerns me the most, however, is the continued recommendation of increasing the target trough levels from <10 mg/L to between 15-20 mg/L.  This would be accomplished by significantly increasing the drug’s dosing to 15-20 mg/kg (actual body weight) particularly if the isolate’s MIC is 1 or greater.  I should note that the authors grade this as a low level IIIB recommendation.  This concept of increasing the dose and the subsequent trough has been around since the recognition of “MIC creep” (read the book for a full explanation).  In my opinion, it is based more on pharmacokinetics of the drug than on actual clinical data, as evidenced by the low level grading.  The studies that I have reviewed, also reviewed by the panel, show that increasing the dose may prevent the development of further resistance BUT does not translate into increased clinical efficacy and probably increase nephrotoxicity!  The panel recognizes this potential but criticizes the toxicity studies as having technical issues rendering the results as less reliable. The idea of increasing the dose, and even giving a significant loading dose (of up to 30 mg/kg), may be important in the treatment of blood stream infections and pneumonia but I am not clear on its utility in the treatment of lower extremity infections.

Follow this literature…it is fascinating stuff.