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

One of the ideas behind creating this blog was to be able to keep readers apprised of any new, interesting papers published in the infectious diseases and microbiology literature I follow on a regular basis. For background I will tell you that my 3 top journals include:

Clinical Infectious Diseases (CID) – put out by the Infectious Diseases Society of America www.idsociety.org and my favorite clinical ID journal.

Journal of Infectious Diseases (JID) – also an IDSA journal.  Mostly HIV and intense basic research but does occasionally publish in interesting review or bacteriology manuscript.

Antimicrobial Agents and Chemotherapy (AAC)  - this journal, published by the American Society for Microbiology asm.org is the best source for new antibiotic research and clinical microbiology

I periodically also receive manuscript files sent to me by a network of ID friends and colleagues. 

Although I try to review each as they are received I admit that, occasionally, they get lost in a pile on my desk. Because of prior commitments, I admit that this is what has happened over the past 3 months and I have been remiss in my reviewing of these back issues.  So, to bring folks up to speed, here are a few papers of relatively recent vintage that I find interesting.

 Thomas Lodise, et. al. Relationship between initial vancomycin concentration – Time profile and nephrotoxicity among hospitalized patients.  CID, August 15, 2009.  Tom Lodise’s pharmacology group from Albany has been doing some terrific work looking at nephrotoxicity of vancomycin given recent recommendations to increase trough levels to between 15-20mg/L.  Just last year in AAC they published their findings that bumping vanco doses to 4 grams/day (sometimes necessary to achieve these higher peaks) was associated with a significantly higher rate of nephrotoxicity.  In this study they concluded that “The results indicate that a vancomycin exposure – toxicity response relationship exists.  The vancomycin trough value is the pharmacodynamic index that best describes this association.”  I have blogged about this vancomycin dosing issue in the past.  Maybe I am being selective about what I read and share but I still have issues with this concept of bumping vanco trough levels especially given the total lack of data in diabetic foot infections where the patients may already have compromised kidneys. 

 Micheal Ryback, et. al. Vancomycin Therapeutic Guidelines: A summary of consensus recommendations from the IDSA, the American Society of Health System Pharmacists and the Society of Infectious Diseases Pharmacists.  CID, August 1, 2009.  Perhaps I should have listed this article before the one above since this summarizes the guidelines that promote this new dosing regimen and the concept of achieving an AUC/MIC ratio of >400 by using weight based dosing and bumping troughs.  Considering the attention given to these new guidelines my readership should become very familiar with them.  The full, original document can be accessed at http://www.ashp.org/DocLibrary/BestPractices/TPSVanco.aspx

 Shveta Rani Singh, et. al. In vitro 24-hour time-kill studies of vancomycin and linezolid in combination versus methicillin resistant Staphylococcus aureus.  AAC Oct. 2009.  This title is a perfect example of what one can expect reading AAC.  Once you get past the wordy titles there is some great information.  I found this interesting because, apparently, there are clinicians trying all different antibiotic combinations to fight MRSA. The authors found that there was no synergy at all, and, in fact, frank antagonism occurred in 3 out of 5 strains when linezolid was added to vancomycin.  The bottom line…try other combinations if you must, just not this one.

 Stan Deresinski. Vancomycin in combination with other antibiotics for the treatment of serious MRSA infections.  CID Oct 1, 2009.  Stan Deresinski out of Stanford University has become a bit of a “go to guy” when it comes to MRSA and the ID community.  I urge all of my readers to find his 2005 CID review paper  Methicillin-Resistant Staphylococcus aureus: An Evolutionary, Epidemiologic,and Therapeutic Odyssey which remains one of the most easily digestible treatises on the topic.  In this more recent review he scans the literature to find support of the commonly employed practice of combining vancomycin with a second antibiotic usually rifampin or gentamicin and finds to supportive evidence for these combinations but known potential toxicities.   

 Jose L. Del Pozo, et al. The electricidal effect is active in an experimental model of Staphylococcus epidermidis chronic foreign body osteomyelitis.  AAC Oct. 2009. This interesting rabbit study compared low amperage (200 µA) electrical current to IV doxycycline treatment to no treatment for foreign body osteomyelitis in the rabbit tibia.  As expected, both treatment groups were significantly better than the no treatment group.  Interestingly, the electrical current group was significantly more efficacious than the doxycycline group.  They feel that this might be related to the activity of the current against the bacterial biofilms.  This entire area of bioflims as determining factors in the treatment of chronic infections is fascinating and bears watching. 

Let me know what you think of the concept of writing up these reviews, and please suggest other papers you would like to hear my opinion about