Two studies published in the January 7, 2010 issue of the New England Journal of Medicine have received a tremendous amount of play in the popular press.  One paper out of Baylor in Houston looked at comparing chlorhexidine + alcohol vs. povidone iodine as a preoperative surgical prep.  In a total of 849 subjects in the ITT analysis they found that the surgical site infection rate was significantly lower with the chlorhexidine + alcohol than it was with the old “standby” povidone iodine (9.5% v. 16.1% P=0.004) Here is a link to that abstract http://content.nejm.org/cgi/content/short/362/1/18.

The second study, out of the Netherlands, explored the issue of decolonization in nasal carriers of S. aureus.  http://content.nejm.org/cgi/content/short/362/1/9.  A total of 6771 patients were screened on admission using PCR for rapid identification of the Staph.  1270 swabs were positive, 808 underwent a surgical procedure.  The patients were all treated with mupirocin nasal ointment and chlorhexidine soap vs. a placebo.  The rate of S. aureus infection was 3.4% in the treated group vs. 7.7% in the placebo group.    Interestingly, ALL were methicillin susceptible (MSSA) so the study may, or may not be able to be extrapolated to MRSA carriage.

Hospital acquired infections, particularly surgical site infections cause a tremendous amount of morbidity and mortality not to mention costing billions of dollars to treat.  The monetary situation is complicated by CMS guidelines that may not pay a hospital for treatment of any nosocomial infection.  Therefore, new and improved techniques for minimizing these infections are being studied.  Some of what is done today for infection prevention in the surgical suite has not changed much in decades i.e. the use of the povidone iodine prep.  I remember doing those back when I was a surgical resident in the early 1980s!  Chlorhexidine is by no means a new product.  In fact, it may be older than povidone iodine.  A quick PubMed search finds papers going back to the 1960s.  More recently, the combination of chlorhexidine with alcohol has shown to be a better antiseptic with longer activity than chlorhexidine alone.  This is true not only for prepping the patient but also as a hand prep for the physician.  This recent study just shows us that as new high level evidence becomes available, we may have to change some very ingrained thoughts and practices.

As for the nasal carriage paper, I find that interesting and not unexpected.  What needs to be looked at is carriage of MRSA and surgical site infections.  There are some papers out there and I do discuss them in the book.  This is a more involved topic for another post. 

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

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

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)

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.

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.

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.