A few weeks ago my old Podiatric College roommate sent me a link to a fascinating YouTube video.  I then sent it to a few friends who, in turn, posted it on a few other blogs so it has become a minor viral (or should I say “bacterial”) success.  This lecture, by Professor Eshal Ben-Jacob of Tel Aviv University, covers aspects of bacterial communication and their “social interactions” as regulated by various stimuli.  It is an utterly fascinating subject presented in a clear, understandable manner with incredible videos and photographs.  This work has major implications in the way bacteria become pathogenic, are currently treated and some future directions that could be considered.  Just as a “heads-up” it will take a commitment of time from you, the viewer, as the lecture is an hour long but please don’t let that keep you from viewing it in its entirety.  It is absolutely worth it.  http://www.youtube.com/watch?v=yJpi8SnFXHs

One of the trickiest issues in prescribing linezolid for patients with MRSA or VRE infections is the potential for a drug-drug interaction, leading to serotonin syndrome (SS), with various serotonergic psychiatric medications.  It seems that every pharmacy computer system in the world goes crazy with warnings when you attempt to write for this antibiotic while the patient is on these meds.  The package insert for linezolid states that it is contraindicated to use linezolid in combination with SSRIs, tricyclic antidepressents, triptans, meperidine or buspirone “Unless patients are carefully observed for signs/or symptoms of serotonin syndrome…”

On October 20 the FDA updated information on this potential interaction. (http://www.fda.gov/Drugs/DrugSafety/ucm276251.htm).  They are now saying that not all serotonergic psychiatric drugs have an equal capacity to cause SS.  Most patients reported to the FDA with SS were taking SSRIs or serotonin norepinephrine reuptake inhibitors (SNRI).  They report that it is currently unknown whether co-administration of linezolid in patients taking other psychiatric drugs carries a comparable risk.  SSRIs and SNRIs that have been implicated include the following drugs commonly seen in lower extremity practice; paroxetine (Paxil, Paxil CR), fluoxetine (Prozac), citalopram (Celexa), escitalopram (Lexapro), venlafaxine (Effexor) and duloxetine (Cymbalta).  The FDA lists the risk as “unclear” in tricyclic antidepressants, MAO inhibitors and a number of other psychiatric drugs.   The reader is directed to the above link for the full list. 

What does all of this mean to the practicing provider?  A review of the literature reveals a number of isolated case reports of SS in patients receiving linezolid.  There are few large patient series reported.  In 2006 Taylor et al from the Mayo Clinic reported on a retrospective review of 52 patients who received concomitant linezolid and SSRI therapy while 20 received therapy within 14 days of each other but not concomitantly ( http://www.ncbi.nlm.nih.gov/pubmed/16779744).  They found only 2 patients (3%) had a “high probability of SS”.    They concluded that “…if the clinical situation warrants use of linezolid in a patient receiving an SSRI, linezolid may be used concomitantly with SSRIs, without a 14-day washout perioed and with careful monitoring (my italics to show this is in line with the package insert) for signs and symptoms of SS.” 

As with any antibiotic selection there is a risk-benefit ratio that should be weighed.  In a patient who NEEDS linezolid, even if they are on a SSRI, they can still receive the drug, as long as they are monitored for signs of SS.  What the new FDA information says is that not all of these psychiatric drugs are “created equal” and a blanket pharmacy warning should be carefully evaluated. 

(Disclaimer: I am a consultant/speaker for Pfizer and have received honoraria)

Perhaps I should have written this post earlier in the summer season, before many of you went on vacation to the seashore…but then again, maybe not.

I know that sometimes my posts can be a bit esoteric discussing the minutia of antibiotic dosing, findings in the literature, etc.  So, to change gears a bit, I would like to make this a rather basic clinical discussion.  I know that some of you may find this too simplistic but given the number of residents and students who read this blog I feel it is an important topic.

Since the very first edition of my Handbook of Lower Extremity Infections I have made sure that somewhere within the first page or two of text is a statement along that lines that “Infection is a CLINICAL condition and its diagnosis is made on CLINICAL grounds” (pg 4 of the 3^rd edition). You diagnose infection by looking for the classic signs of infection including; erythema, edema, warmth, tenderness, loss of function and purulent drainage.  You then take a culture, not to diagnose the infection, but rather to tell you what organism is causing the infection and what antibiotic you need to treat it.

Of course, this definition is all well and good but there are conditions that mimic these signs and symptoms of infection and are frequently misdiagnosed as such when the patient is admitted to the hospital or seen by their physician. The classic one is an acute gout attack.  In that situation you have essentially all of the requisite clinical findings including drainage but no infection.  I recently was consulted on a patient (unfortunately, I can not find the pictures) who presented with a hot, red swollen first MTP joint admitted with the diagnosis of “cellulitis and osteomyelitis”.  All of the clinical findings were there, but what made me suspicious that his foot was not infected, was the drainage.  Instead of being your typical creamy, runny or smelly pus you see from foot infections the drainage was pure white and chalky.  Furthermore, the x-ray findings looked like the classic Martel’s Sign you see in gouty arthritis with a “rat-bite” appearance. Along with sending off a culture, which came back as no growth, we also sent the drainage to pathology for microscopy.  As expected, crystals were found. I was able to discontinue the IV antibiotics.

Another favorite of mine is the patient admitted for “cellulitis” of the foot when, in fact, it is severe dependency rubor from peripheral arterial disease.  I saw a patient about 3 weeks ago admitted for gangrene of the 4^th toe and cellulitis.  Certainly, the toe was gangrenous and there was quite an odor coming from the foot since the patient had not bathed or changed clothes in quite awhile.  There was also some slight drainage coming from between the toes but this was not causing the significant erythema the patient exhibited.  This patient had the most marked “rubor on dependency, pallor on elevation” (Samuel’s Test) I had ever seen. Usually the color change may take a few minutes but in this patient it was almost immediate.  His foot blanched totally.  A true infectious cellulitis will not behave this way and residual erythema will still be seen.  Cultures only grew diptheroids (which CAN be pathogenic and a topic for a different post).  Unfortunately, the patient refused all vascular testing and was discharged back to his bording home.

The third example I want to use is the patient admitted with “cellulitis of bilateral legs”.  The most recent patient I saw with this diagnosis was about 250 lbs and sat in a chair almost all day with her legs in a dependent position.  She presented with massive edema of both legs, marked erythema bilaterally and multiple serous filled vesicles around the circumference of the her legs. She had been admitted on IV antibiotics.  When I saw the patient on consultation it was my opinion that the patient and venous insufficiency and not an infection.  True infectious cellulitis does not usually occur as a bilateral and symmetrical condition.   When I spoke to the attending I got push-back on that diagnosis since, afterall, the patient “was doing well on IV antibiotics” with reduction in both the erythema and edema.  Of course, IMHO the patient was doing well, not because of the IV antibiotics but because she was IN BED with her LEGS ELEVATED!

A key buzzphrase in the infectious diseases community nowadays is “Antibiotic Stewardship”.  Although much has been written about it and, at least in California it is now mandated that hospitals develop stewardship programs, the concept is fairly straightforward.  Basically, it means that antibiotics should only be used when appropriate and then the right drug should be employed for the diagnosis. The most fundamental idea I would put forward is that sometimes “infections” are not infections and antibiotics are not necessary.

I am sure that all of you reading this can think of other similar situations.  PLEASE SHARE your thoughts!

I received this question from a reader: In suspected osteomyelitis do you stop antibiotics prior to obtaining a bone culture? For how long?

This comment came in under my entry on the VULCAN trial but I actually covered the question in a post almost exactly a year ago.  I am reprinting my response here for more recent readers who may not have reviewed all of the earlier posts I will also summarize my current thinking at the bottom:

The question of whether or not the patient needed to be off of all antibiotic therapy prior to the culture was always less clearly delineated.  It was almost an empirical belief that if a patient was on antibiotics at the time of the culture then the results would be unreliable.  After all, if a culture is reported as showing “no growth” was this because the specimen was poor, the patient never had osteomyelitis in the first place, or the antibiotics had prevented the organism from growing?

A recent study by Louis Bernard and colleagues out of University Hospital of Geneva Switzerland, and published in the September 6, 2009 issue of the International Journal of Infectious Diseases challenges much of what we currently hold as sacrosanct.  In this non-randomized, prospective trial 141 patient with 154 episodes of osteomyelitis each underwent 4 microbiological samplings.  Sample “A” consisted of 2 consecutive sinus tract cultures with bone contact (“A1” & “A2”) after only local cleansing of the sinus tract with 0.9% saline.  Sample “B” consisted of a surgical bone biopsy through the sinus.  Sample “C” was a surgical biopsy obtained through an uninfected sited, referred to as the “gold standard”.  Their results showed that when both sinus tract cultures “A1 & A2” revealed the same organism the concordance between “A” and gold standard “C” was 96%.  They calculated the sensitivity as 91%, specificity as 86% and accuracy as 90%.  On top of that, they found that the result was not affected depending on whether the patient was on antibiotics prior to the cultures or not.

In their Discussion the authors go out of their way to state that “in no way should these consecutive deep sinus tract specimens replace bone culture in situations where a biopsy can be readily obtained because bone culture remains the gold standard for the microbiological diagnosis of osteomyelitis”.  There are sometimes, however, when a surgical culture is just not practical and that patient has already been started on antibiotic therapy, as the authors call it “clinical reality”.

Since this original post, my thought process has not changed much.  I still believe that, if they have not yet been started, it is best to HOLD antibiotics if at all possible, until after the patient is taken to the OR for deep bone (or, for that matter, soft tissue) cultures. The “real world” gets involved, however, when you admit a patient through the Emergency Dept for the stated diagnosis of “infection” and do not plan on taking the pt to the OR until the next day. Unfortunately, in a case like this, you cannot realistically hold antibiotics or the hospital runs the risk of losing the admission.  If the patient is going to the OR later the same day then I believe in holding the drug unless the pt is sick i.e. metabolically unstable, systemically unwell or septic.

What if the patient has already been started on antibiotics?  Conventional wisdom still calls for the pt to be off antibiotics for at least 48 hours.  I don’t believe there is any evidence to support that thinking.  The Bernard study cited above does give us some hope that it doesn’t matter if the patient is still on antibiotics or not but I would still recommend, again if at all possible, taking the patient off the drugs for as long as it is feasible. Heck, I would go for a week if you can.  There is no magic to 48 hours.  The problem is that if the culture is negative, you don’t know whether it is negative because it is not osteo or if it is negative just because of the antibiotics.  Also, the International Working Group on the Diabetic Foot (www.iwgdf.org) has shown in their diabetic foot osteomyelitis guidelines that the only independent factor leading to a positive response to antibiotic therapy for osteo is bone culture directed antibiotic therapy.  We could really use those deep reliable cultures!

Right off the top, I apologize for the obviousness of the Mr. Spock reference.  I couldn’t resist! A few months ago I was invited by Robert Kirsner, MD, PhD and Stephanie Wu, DPM to write a chapter on “Antimicrobial Therapy” in their upcoming Wound Healing Society Yearbook. The design of the chapter is a review of a recently published primary study and 2 or more secondary studies.  Although I was extremely familiar with the primary topic, the randomized controlled trial on pexiganin vs. ofloxacin by Ben Lipsky, MD, one of the secondary papers really struck a chord with me.  The study in the British Journal of Surgery by Micahels, et al out of the UK reported on the VULCAN trial, a large randomized trial looking at the use of silver dressing in venous leg ulcerations (VLU) http://www.ncbi.nlm.nih.gov/pubmed/19787753

This study of 213 recruited patients not only looked at wound healing differences between silver containing dressings and non-silver low adherence dressings in the treatment of VLU but also the cost effectiveness of the two.  The primary measure was complete ulcer healing at 12 weeks with secondary measures being; time to healing, quality of life and the aforementioned cost-effectiveness.  Although I do have some issues with the study design including the leeway given in dressing selection, compression definition and number of visits, I do find the results interesting. 

As one might reasonably expect given the paucity of good evidence on the effectiveness of silver dressings as a class, the VULCAN study found that there were no significant differences between dressings in the number of ulcers healed at 12 weeks (59.6% silver, 56.7% non-sliver) nor to median time to healing. As could also be expected, silver dressings cost significantly more to use ($46.60 vs. $8.70 as converted from the reported £).  The authors concluded that “There was no evidence to support the routine use of silver-donating dressings beneath compression for venous ulcerations”. 

This finding won’t surprise anyone who has heard me lecture on “Differentiating infected from non-infected wounds” as I did at the APMA meeting, who has read the chapter on Diabetic Foot Infections in the 3^rd Edition (specifically page 120), or has read my blog post from March 3, 2010 entitled “Bioburden and Wound Healing”.  Silver dressings are everywhere.  Just about every wound healing product line includes a number of silver donating products in every imaginable format.  Yet, there is little to no evidence to support that they are of any benefit in wound healing or preventing wound infection.  This revelation first came to me upon reading the Cochrane Collaborative systematic review of the literature on silver dressings which, like the VULCAN trial, found little evidence to support their routine use.  This does not mean I don’t use them.  Like most clinicians, if I see a heavily colonized wound I am seemingly genetically programmed to reduce the bioburden and kill the bugs. 

What I am saying is that we should be practicing evidenced based medicine and not costing our patients or the health care system dollars that none of us can afford to spend on a therapy without solid science behind it.  So, next time a sales rep comes to speak to you about their latest and greatest silver product, ask for scientific proof, not some pretty “before and after” pictures, that it contributes to wound healing.  Unfortunately, I doubt you will get much.  These products are all approved by the FDA as 510k medical devices.  Therefore, there is little clinical science necessary to get them approved.   

REFERENCES

Lipsky BA, Holroyd KJ, Zasloff M. Topical versus systemic antimicrobial therapy for treating mildly infected diabetic foot ulcers: a randomized, controlled, double-blinded, multicenter trial of pexiganan cream. Clin Infect Dis.  2008;47:1537-45.

Michaels JA, Campbell B, King B, Palfreyman SJ, Shackley P, Stevenson M. Randomized controlled trial and cost-effectiveness analysis of silver-donating antimicrobial dressings for venous leg ulcers (VULCAN trial). Br J Surg. 2009;96:1147-56.

 Vermeulen H, van Hattem JM, Storm-Versloot MN, Ubbink DT. Topical silver for treating infected wounds. Cochrane Database Syst Rev. 2007 Jan 24;(1):CD005486