For a number of years I have been presenting a lecture entitled “Differentiating infected from non-infected wounds”. As part of that talk I discuss the role of topical antimicrobials in wound healing. Despite there being a countless number of silver impregnated dressings along with multiple other antimicrobial dressings and solutions filled with all different types of product there is little evidence to support that their antimicrobial activity does, in fact, contribute to wound healing. We know that wounds become contaminated with multiple bacteria and we know that at least some of these organisms are capable of forming biofilm over the wound bed. It is felt that the presence of these organisms sets up a low-grade chronic inflammatory process that produces byproducts such as MMPs which inhibit wound healing. The thought behind using a topical antimicrobial is to kill these organisms thus allowing for improved healing. This certainly makes empirical sense since we have always been taught that these bacteria on a wound have to be bad. In my mind, however, there are three questions that should be adequately answered before we haphazardly continue using these dressings.

1. Does the use of a topical antimicrobial decrease the wound of bioburden?

2. By decreasing the wound of bioburden do we hasten wound healing?

3. By decreasing the wound of bioburden do we prevent colonized wounds from becoming clinically infected?

Surprisingly, really none of these questions have been answered to my satisfaction. For this particular discussion I will concentrate on question #2. An interesting study entitled “Bacterial burden and wound outcomes as influenced by negative pressure wound therapy” with just published in the February 2010 issue of Wounds by Boone, Braitman, Gentics, et.al out of St. Luke’s – Roosevelt Hospital in New York City. In this small pilot study using a porcine wound model infected wounds were created using a combination of bacteria including Pseudomonas, Staphylococcus and Bacteroides, and then treated with V.A.C. therapy using either regular or silver impregnated foam along with a moist wound dressing control. Both quantitative and semi-quantitative bacterial cultures were performed. To quote the Abstract “The wounds continue to show gross and microscopic improvement when treated with standard NPWT and NPWT with silver compared to moist wound care controls. However, the bacterial burden in all wounds continued to increase and broaden to include local skin flora, which had been absent immediately after wounding.” The authors concluded that the improvement in healing of the wounds could not be explained by a change in their bacterial burden.

The results of this study are actually similar to some of the earlier work performed using the V.A.C. Wounds healed more rapidly when the device was applied yet, almost paradoxically, the bioburden of the healing wounds seemed to increase rather than decrease as the wounds continued to heal. This certainly seems counterintuitive to the entire concept that the bacteria are somehow inhibiting wound healing. Maybe this all points to the ancient concept of “laudable pus”!  Of course many factors must be considered. Probably more important than the number of bacteria is which types of bacteria are actually present. Certainly there is a difference in pathogenicity of some bacteria over others. Also of interest in this study is that the silver impregnated foam did not decrease the bioburden any more than the standard foam (question #1 anybody?)

Please do not take that to mean that I am somehow “dissing” all antimicrobial wound products.  I certainly use them and will continue to in the foreseeable future.  The bottom line to this entire discussion is that, although we are programmed to feel that somehow all bacteria in wounds are detrimental, perhaps the presence is not always necessary to eliminate. Before we jump on any bandwagon promoting the “latest and greatest” in antimicrobial wound therapies perhaps we should step back and ask the three critical questions I posed above. By prodding industry to produce high levels of evidence-based medicine it can only improve our overall treatment of these difficult patient problems.

Telavancin (Vibativ – Theravance/Astellas) is a novel lipoglycopeptide, related to vancomycin, that has been recently approved by the FDA for the treatment of complicated skin and skin structure infections (cSSSI) caused by MRSA.  Telavancin now joins the ranks of vancomycin, linezolid, daptomycin and tigecycline as being the only 5 antibiotics with this approval.  An excellent review of this drug was published by Saravolatz, Stein and Johnson in the December 15, 2009 issue of Clinical Infectious Diseases.  Here is a link to the Abstract: http://www.journals.uchicago.edu/doi/abs/10.1086/648438 .  I highly recommend anyone interested in this drug to search out this complete article and familiarize yourself with it.

Without going into too much detail (which may infringe on copyright?), I would like to point out a few important take home messages that I got out of this paper and from my review of other literature on the subject. First some of the positives:

1.  The usual dose is 10mg/kg q24h.  Thus, we have the ease of a once daily dosing

2.  The drug is consistently bactericidal against most S. aureus.   Various reviews have shown that this probably has little impact in the treatment of cSSSI and may be more important in blood stream infections for which this drug is not approved.

3.  It is effective against MSSA, MRSA, VISA and hVISA.  It is also effective against daptomycin and linezolid resistant strains.  It does not have activity against the most common strains of VRE.

4.  Unlike vancomycin, there is no call to monitor serum trough levels

5.  In two pivotal cSSSI clinical trials it was found to be “non inferior” (FDA speak) to vancomycin. 63% of the S. aureus strains were MRSA making it the largest number of MRSA patients in a cSSSI study to date.

Now some downsides:

 1.  It is primarily excreted through the kidneys so significant dosage modification must be made in cases of renal insufficiency. The recommendations are the full 10 mg/kg q24h if the creatinine clearance is >50 mL/min, 7.5 mg/kg if 30-50 and 10 mg/kg q48h if the clearance is <30.

2.  Chronic, infected diabetic foot ulcerations were specifically excluded from the two pivotal trials!  I don’t see this drug receiving the coveted “…including diabetic foot infections” approval anytime soon.

3.  Although the overall safety looked comparable to vancomycin there were higher rates of some significant adverse events including altered taste, nausea and vomiting along with an increase in renal events.  On the other hand, vancomycin had higher rates of infusion reactions

4.  The drug has received a black box warning for fetal risk.

So what is the bottom line?  I agree with the authors of this review that we need new novel antibiotics to combat MRSA especially given all of the increasing reports of vancomycin MIC creep and treatment failures.  Many of the drugs that looked promising earlier in their development have either been slowed considerably (ceftobiprole) or stopped totally (oritavancin, iclaprim) so the once fertile pipeline is looking a bit thin.  Telavancin gives us one more drug to add to that relatively short list of alternatives to vanco especially with organisms that have developed resistance (although extremely rare) to those other antibiotics.  At this early point in its history, I am somewhat concerned about its lack of diabetic foot infection data and its increase in adverse events compared to vanco.  The black box may also impact some potential patients.  Given that we have other vanco alternatives with years of clinical experience, including diabetic foot data, and well known safety profiles I may feel more comfortable seeing more clinical data and published AE experiences before jumping in with both feet.

Some interesting news just came out yesterday.  It looks like J&J’s new anti-MRSA cephalosporin, ceftobiprole has been, once again, turned back by the FDA. See the story here:

http://money.cnn.com/news/newsfeeds/articles/marketwire/0572888.htm

Many of us had pretty high hopes for this antibiotic as it was to be the first cephalosporin active against MRSA.  Although it is IV only, the idea of having a new MRSA agent that was in a class of drugs well liked and trusted by most, was appealing.  It is also broad spectrum against a wide range of other Gram positive and Gram negative organisms. J&J even performed a clinical trial specifically looking at diabetic foot infections with promising results thus hoping to become only the 4^th antibiotic (after linezolid, ertapenem and piperacillin/tazobactam) with that specific FDA indication.  The drug was initially submitted for approval way back in 2007.  The FDA sent an Approvable Letter questioning conduct at some of the study sites.  The action taken yesterday by the Agency now seems to totally question the viability of the two pivotal trials.  This may mean that entirely new studies would have to be completed thus delaying this drug for years more.  It will be interesting to continue to watch this.

In the meantime, all is not lost for anti-MRSA cephalosporins.  The drug most thought would be the late-comer to this party, ceftaroline, seems to be moving ahead.  I will keep you all informed as I hear anything new.

I wish all of my readers a healthy, happy and prosperous, New Year

On Barry Block’s daily PM News (www.podiatrym.com) the other day a colleague presented a case of a neuropathic patient with no wounds presenting with what he felt was osteomyelitis of the 2^nd and 3^rd metatarsals.  Although I did not feel that the case was actually osteomyelitis, a feeling I expressed in a response to that site, I was intrigued by the comment of the original poster that; after giving the patient 8 week of oral ciprofloxacin (another potential misjudgement I discussed in my response), “I just think it is interesting to see how this bone infection responded to very little care.” This comment had me reflecting on what we consider as “Standard of Care” for the treatment of osteomyelitis.

In the 3^rd Edition of the Handbook I review the evidence that shows that perhaps we should rethink this “Standard”.  The entire concept of 4-6 weeks of IV antibiotics as being some magical bullet that will treat osteomyelitis is based on 30-40 year old animal studies.  There is really no human evidence to support that this is the optimum therapy.  In fact, much of the recent data that has been presented, particularly out of Europe, suggests that ORAL antibiotics alone with either NO surgery or just “conservative” debridement of infected bone may be just as effective therapy.  The literature supporting this approach is actually quite a bit more hefty that that supporting the old traditional “standard”.  I explore this question in detail in a lecture I frequently present entitled (thanks to David Armstrong for the catchy title) Antibiotics for Osteomyelitis: Boneheaded or brilliant? One of these presentations can be viewed for free at the website for the always stimulating Diabetic Foot Global Conference (to be held this coming year in Hollywood, CA March 18-20, 2010): http://www.dfcon.com/presentations2009/sat_joseph.html

In no way do I mean to say that surgery is unnecessary.  In fact, if ablative surgery can be performed, it is curative without the use of any antibiotic therapy.  But, sometimes, patients either do not want, or can’t undergo a surgical procedure.  In those cases I am relieved to see that we do have data to support the non surgical treatment of these cases with oral antibiotics alone.  Of course, this approach is not perfect and there are still unanswered questions.  Probably the greatest is the question of duration of therapy.  Do we only need the orals for 4-6 weeks or longer?  One study, referenced in the lecture, by John Embil incorporated 41 weeks +/- 31 weeks of therapy!  This needs to be addressed.  The other literature I would direct you to review is the consensus statement put out by the International Working Group on the Diabetic Foot (IWGDF) http://iwgdf.org  whose recent systematic reviews of the diagnosis and treatment of diabetic foot osteomyelitis should be reviewed by everyone treating this condition. 

To me, this is one of the most fascinating and important areas that we need to explore in the future.

Osteomyelitis of the 1st MTP Joint

Dr. Todd Divan, a podiatric physician from Potomac, IL, sent me an excellent question via personal email.  On the belief that if one person asks a question, many others may be thinking the same thing, I reprint the question and answer here with Dr. Divan’s kind permission.

Dr. Joseph,

I listened to the lecture you have on PRESENT podiatry for the “Diabetic Foot Infections” involving the IDSA classification system.  This was excellent.  I will also be checking into a slide show share lecture you have placed available online for the “Current Emerging Antibiotics for MRSA”.

I agree that expressing the “tough love” passion with the patient is important.  Some of these patients just don’t get it that they are really suffering increased susceptibility to losing a leg or even a life.

I would like to know any journal readings you would highly recommend regarding this topic.  I have a few thoughts to share.  For example, do we as podiatrist need to worry about Proteus, Serratia, Klebsiella, E. coli, or Citrobacter in the diabetic foot infections?  You mentioned a study which gave the impression we don’t have to worry too much about treating Pseudomonas aeruginosa because there is a fairly high cure rate with the Pseudomonas when treated with a 1st gen cephalosporin (an interesting thought).  However, I think the point should be emphasized to avoid applying this concept across the board on Gram neg infections, with the thinking that they will heal secondarily alongside of therapy focused on Gram pos infections.  My thinking is based a great deal on the fact that once we have taken a culture and the presence of a certain bug is documented in the chart, if we don’t treat because of this concept, then an infection turn bad (and sometimes fast).  I am worried this type of complication could lead us into a higher risk case and expose the practitioner to increased legal liabilities.  Shouldn’t I have to follow the tendency of the infectionist in my area, since working on a multidisciplinary basis is important.   I did pick up on your point that using aztreonam or the like (depending on the culture report) could provide good combination therapy to get coverage for the Gram neg infections.

Thank you for your contributions.  Much appreciated.

Todd Divan, DPM

MY RESPONSE

Todd,

Thank you for the kind words and the thoughtful questions.  I have attached a copy of the Infectious Diseases Society of American Diabetic Foot Guidelines where we go into the concept of gram positive organisms in more detail.  This paper was published in 2004 and we have a new manuscript in the works, hopefully for publication summer of 2010.  The primary importance of gram positive infections does not change with the new document.

When you read the guidelines you will see that we stress the primacy of aerobic gram positive cocci as the major causative organism.  This is particularly true in mild and many moderate infections.  We do say that as the infection becomes more severe, if there is the presence of necrotic tissue, or of the patient has been exposed to previous courses of antibiotics, then gram negative aerobes and anaerobic organisms become more prevalent.  Even if you culture these organisms, the evidence is not clear that you have to treat them.  Tony Berendt, Ben Lipsky and I refer to this as the “head of the snake” philosophy.  In other words, Staph and Strep make up the “head of the snake” and the other bugs you list below make up the body.  If you “cut off the head” i.e. use antibiotic therapy directed at the Staph and Strep, then the “body” dies.  Again, this is primarily true of the mild and moderate levels.  We are NOT advocating only using gram positive coverage for the more severe infections.

Even with this concept, and it is just that, a concept, even though it is based in excellent data, I tend to start empirically with broad spectrum coverage (perhaps partly for the legal exposure reason you mention below).  In the case with our hospital I even need to use MRSA coverage.  Almost all patients are begun on Zosyn + Vanco.  Certainly Invanz can be substituted for the Zosyn and Zyvox for the Vanco depending on your local formulary.  Please note I do NOT use the Zosyn for Pseudomonal coverage.  I am still of the FIRM believe that no evidence supports needing to cover Pseudo empirically in just about any diabetic foot infection.  In fact, I don’t remember the last time I even grew that bug from a DFI.

Regards

Warren

IDSA Moderate DFI

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.

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.