A reader of this site, Dr. Steven Klein, emailed me to ask the following questions.  I have obtained his permission to use his excellent thoughts as a “jumping off” point for this post and some subsequent ones to follow:

You recently posted about the article:  ”Systemic Antibiotic Therapy for Chronic Oysteomyelitiis in Adults.” Spellberg, Brad and Lipsky, BA. Clinc Inf Dis (Advance Access published 12-12-11). p 1-15.  The article begs the question –  How important is antibiotic bone penetration in treatment of chronic osteomyelitis?  I’d like to know if there are good studies of this issue and your opinion. Or, on the other hand, perhaps studies support good outcomes without regard to bone penetration, but instead using an antibiotic based on cultures, senstivites and MICs from bone culture.  

For example, according to Table 1 in this article, “Bone Penetration of Parental Antibiotics: Data from Clinical Studies”, vancomycin has poor penetrations and concentration in bone. And, according to Table 3, “Cure Rates of Non randomized Clinical Trials of Parental Agents for Chronic Osteomyelitis With or Without Infected Prosthesis in Adults”, vancomycin has the lowest cure rate ( 54% ) with debridement or prosthesis removal., of all listed antibiotics. Yet vancomycon is commonly used for MRSA osteomyelitis. Perhaps we need to re think that. 

On another point, you have expressed your dislike of using Trimethoprim/Sulfamethoxazole. However on reading this article TMP/SMX seems to be one of the oral antibiotics of choice. What are your criticisms of this drug? I’d like to know the down side before deciding on whether to use it (probably with rifampin).

I would like to address the first of these questions/issues with this entry to the blog and discuss a few others in the near future.

How important is bone penetration? -  I have a slide I have used for years in my osteomyelitis lectures entitled  “The Myth of Bone Penetration”…I guess that tells you right there what I think!  Actually, that is a bit of an oversimplification.  The fact is I don’t believe anyone really has a good answer to this question.  It makes empirical sense; if an antibiotic can penetrate bone, the antibiotic should be effective.  There are a number of problems to this thinking.  It does not take into account the bacteria in the bone that is causing the osteomyelitis.  This is one of the reasons many docs continue to use ciprofloxacin for osteo.  They were told by some drug rep 20 years ago that “Cipro penetrates bone” therefore it should be first line therapy for osteo.  What they were failed to be told was that the drug had/has relatively poor activity against Staphylococcus, by far the most common pathogen and that resistance develops rapidly.  In fact, the package insert for the drug shows that it is only indicated for “Bone and Joint Infections caused by Enterobacter cloacae, Serratia marcescens, or Pseudomonas aeruginosa”.  None of this stops many docs from still using it for S. aureus osteo because of the ingrained perception of “good penetration”.  

Eric Senneville (http://www.ncbi.nlm.nih.gov/pubmed/18184898 ) has shown that bone culture directed antibiotic therapy was the single factor predictive of success in the treatment of diabetic patients treated medically for osteomyelitis of the foot.  This study has been picked up upon by the International Working Group on the Diabetic Foot (IWGDF) who just updated some of their recommendations on the diagnosis and treatment of osteomyelitis as recently as February 2012 (http://www.ncbi.nlm.nih.gov/pubmed/22271738 &  http://www.ncbi.nlm.nih.gov/pubmed/22271739 ).  I am not aware that any of these reviews promotes bone penetration as an important measure of success.

Furthermore, until recently there was not a really good, standardized approach to determine bone penetration.  Frequently the tested bone came from arthritic femoral heads removed during hip arthroplasty.  This is not the same as looking at osteomyelitic bone.  There were also different techniques used to measure the antibiotic level in the bone.  I have always quoted a paper by my mentor in ID, Jack LeFrock, which to this day I am unfortunately never able to find the reference, in which he searched the literature for bone levels following a one gram dose of cefazolin.  Levels ranged from 4 micrograms to 43 micrograms depending on the technique used.  Fortunately, this may be changing.  Previously on this site I have written about the microdialysis technique being championed by Dr. Dave Nicolau and others.  This technique, in which a small catheter is inserted into bone, lactated ringers in dripped in and then pulled out and the antibiotic level measured, may finally give us some validated, objective measure of antibiotic penetration.

I know it makes empiric sense but I admit to being biased against the concept that bone penetration is a predictor of success in the treatment of osteomyelitis.  I just don’t feel that there is good enough evidence to support it at this time.  We know that some antibiotics DO penetrate bone well.  The tetracyclines are notorious for how they stain bones and teeth, so they obviously get into the bone.  Early work by one of my heroes in the ID world, Dr. Carl Norden, showed in his elegant rabbit studies that clindamycin was one of the most effective antibiotics in the treatment of experimental osteo.  I am just not sold that penetration, in and of itself, is that important of a goal.

I recently came across some fascinating data which breaks down the number of outpatient prescriptions written by podiatrists for all different classes of drug in 2010.  Unlike various surveys that have been done over the years by different magazines, this is hard data based on the actual number of scripts.  I would like to comment on some findings I find interesting in the use of antibiotics. 

Antibiotics were the third most commonly prescribed class of drug following narcotic analgesics and NSAIDs with over 1.6 million scripts written.  This is followed closely by antifungals at about 1.4 mil prescriptions. (Perhaps a topic for a future post?).  I don’t think it would come as any surprise that cephalexin is the most prescribed (530,000) and is actually the second most common drug written by DPMs.  The number two most common antibiotic would also probably not come as a big surprise, amoxicillin/clavulanic acid (Augmentin) down the line a bit at number 15 (177K).  Although amox/clav is a good antibiotic with a favorable spectrum for more complicated lower extremity infections, it is probably a bit unnecessarily broad spectrum for everyday use. I have started to limit my use of this drug after I personally had to take it for an endodontic problem.  First, the 875mg is an amazingly large pill which is not easy to swallow.  Also, I always knew that the drug could be a bit hard on the GI tract and I knew to take it with food and a full glass of water.  Despite those precautions, about 20 minutes after I took each dose, I found my stomach wanting to jump out of my abdomen!  It is true what they say about how a physician can change his way of treating folks after he becomes a patient. 

The third most commonly used antibiotic is trimethoprim/sulfamethoxazole (Bactrim/Septra) with 117K Rx’s.  Not surprisingly, this drug’s use has increased dramatically over the past few years with as few as 34K scripts only 2 years before, a stunning increase in such a short period of time.  Probably all of this usage is for the presumptive treatment of MRSA even before cultures have been returned.  I have said it before; I will repeat is again here, I do NOT like to routinely use this drug.  There are reasons this drug was rarely used before the MRSA epidemic we find ourselves facing.  Although broad spectrum, generic and inexpensive it is not benign. Toxicities range from life threatening skin reactions, such as Stevens-Johnson syndrome to renal, neurologic, psychiatric and hematologic problems, not to mention sulfa allergy, drug-drug interactions with other sulfa based drugs and the inability to use in patients with a G6PD deficiency (and, YES, you will see this as I recently did in a patient with a multi-drug resistant Enterobacter cloacae where the ONLY drug to which the organism was reported as susceptible was TMP/SMX).  Because of the lack of studies showing clinical efficacy against MRSA there is also some question as to how it should be dosed for MRSA infections.  It has been suggested that the usual 1DS b.i.d. is insufficient and that should be routinely increased to 2DS b.i.d. thus potentially increasing the rate of adverse events even further.  That is not to say I don’t use TMP/SMX, I just don’t routinely give it to every patient empirically to cover MRSA or even with a positive MRSA culture unless there are other reasons to use it, such as a mixed infection where the use of one drug obviates the need for combination therapy. 

I often get asked the question; “if not TMP/SMX, then what oral antibiotic you using for your MRSA cases”.  That depends on severity.  For my more mild infections where most of you are probably using TMP/SMX, I much prefer doxycycline 100mg q12h.  Minocycline can also be used.  I find that there is more data to support their use and they are well tolerated even for longer courses of therapy such as in osteomyelitis.  Interestingly, NEITHER of these antibiotics is found in the top 60 drugs written by podiatrists.  I would like to see that change.

The next most commonly prescribed antibiotics drive me crazy!  They are ciprofloxacin at 101K followed by levofloxacin at 75K.  Those who have heard me lecture know that I have been preaching avoidance of quinolones, particularly ciprofloxacin since it was first released and people were sold a “bill of goods” about how broad spectrum it was and how wonderfully it penetrated bone.  As time has gone on, my feelings have only intensified. If I am going to use a quinolone, it is levofloxacin rather than ciprofloxacin because of its better gram positive activity and the once daily dosing.  The only time I see a use for ciprofloxacin is for a documented Pseudomonas infection, something that is extremely rare in lower extremity infections (see post on “Pseudomonaphobia”).   Even then, there is no data to suggest that levofloxacin would not be equally efficacious.  Another quinolone, moxifloxacin, has the advantage of better anaerobic coverage in the case of a diabetic foot infection.  My quinolone usage is on a significant decline.  As a class, these drugs can potentiate the development of MRSA infections, have significant toxicities and, probably most importantly, have been implicated in the development of multi-drug resistant (MDRO) gram negative infections.  In fact, at Roxborough a recent antibiogram shows only about 50% of our E. coli still susceptible to ciprofloxaxin.  Furthermore, I have been noticing lately that every patient who gets sent out on a quinolone invariably returns to the hospital but now with an organism resistant to the entire class.  PLEASE, use these drugs sparingly and only when appropriate!!

The final drug on the list I would like to discuss is amoxicillin, currently being prescribed 28,000 times per year.  This, I just don’t understand at all.  Frankly, I don’t think I have ever written for straight amoxicillin nor do I see any reason to ever do so.  Perhaps, if the patient presents with an infection solely caused by Enterococcus or a straight Streptococcal infection, then it may be a reasonable choice but these are extremely rare and I seriously doubt they are occurring 28K times.  This leads me to believe that there is some inappropriate use of amoxicillin in the profession.  Please remember that this drug is not beta-lactamase stable and is therefore ineffective against essentially all clinically relevant S. aureus. 

These data reveals some interesting information about how lower extremity infections are being treated.  Overall, I find the usage pretty reasonable however, when it comes to what I perceive as an overuse of TMP/SMX, quinolones and amoxicillin, we can always do better.

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

I wish all of my readers a healthy, happy and prosperous 2012.  With this post I am trying something a bit different.  In the past I usually waited to put up a post until I come up with an “ah ha” moment on something I have seen, heard or read about which I then pontificate on this site.  These could occur only days apart, but usually it was a much longer time period leading to relatively infrequent additions to the blog.  My “resolution” for 2012 is to try to put up more frequent, quick hits where I don’t have as much to write and you don’t have as much to read.  That’s not to say that I won’t still post the occasional tome on a particular topic.  Sometimes, I just have to vent!  I have one coming up shortly on antibiotic usage in podiatric medicine…just a heads up.

A recent paper has been published in Clinical Infectious Diseases by Brad Spellberg at UCLA and Ben Lipsky at the Puget Sound VA titled Systemic Antibiotic Therapy for Chronic Osteomyelitis in Adults (http://www.ncbi.nlm.nih.gov/pubmed?term=Spellberg%20B%20AND%20Lipsky%20BA).  I consider it a MUST READ for followers of this site.  This excellent review covers topics including the pharmacology of osteo therapy (i.e. parenteral vs. oral, bone penetration), animal models of osteo, human non-randomized clinical trials and randomized clinical trials.  It is THOROUGH yet quite readable at only 11 pages (there are, however, 172 references!) with 5 tables outlining all of the studies discussed. 

The authors arrive at 4 conclusions which I quote directly from the paper:

1.  “Oral antibiotic therapy with highly bioavailable agents is an acceptable alternative to parenteral therapy.”

2.   “Adding rifampin to a variety of antibiotic regimens has been shown to improve cure rates”

3.   “Clinicians must individualize the duration of antibiotic therapy based on the patient’s clinical and radiographic response…”

4.   “Surgical resection of necrotic and infected bone, in conjunction with antibiotic therapy, appears to increase the cure rate of chronic osteomyelitis. However, not all cases of chronic osteomyelitis require surgical debridement for cure, and we need studies to clarify which may and which may not.”

None of these conclusions should come as a surprise to regular readers of this blog or those who have heard me lecture on the topic, as I have discussed these very points in the past.  Dr. Lipsky and I collaborate frequently and I find it almost frightening how often we agree.  In this one paper he and Dr. Spellberg have eloquently laid out all of the evidence supporting these positions.  If I have said it once, I have said it a thousand times…We MUST rethink the universally pervasive dogma of 4-6 weeks of IV antibiotic therapy for osteomyelitis based on the best available evidence!