What You Should Know About Antibiotic Bone Penetration And Osteomyelitis

Warren S. Joseph DPM FIDSA

Steven Klein, DPM, a reader of this blog, 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 Osteomyelitis in Adults.”1 (See http://www.podiatrytoday.com/blogged/new-review-antibiotic-therapy-osteo... ) The article begs the question: How important is antibiotic bone penetration in the 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, sensitivities 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 vancomycin is commonly used for MRSA osteomyelitis. Perhaps we need to rethink that.

On another point, you have expressed your dislike of using trimethoprim/sulfamethoxazole (TMP/SMX). However, after 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 downside before deciding 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 what I think!

Actually, that is a bit of an oversimplification. The fact is I do not 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. However, 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 osteomyelitis. They were likely told by some drug rep 20 years ago that “Cipro penetrates bone” and therefore, it should be first-line therapy for osteomyelitis. What the drug rep may have failed to point out 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 osteomyelitis because of the ingrained perception of “good penetration.”

Eric Senneville, MD, and colleagues have shown that bone culture directed antibiotic therapy was the single factor predictive of success in the treatment of patients with diabetes treated medically for osteomyelitis of the foot.2 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 2012.3,4 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. In this study (which I unfortunately am never able to find the reference for), Dr. LeFrock 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 blog (see http://www.podiatrytoday.com/blogged/closer-look-recent-literature-infec... ), I have written about the microdialysis technique being championed by David Nicolau, PharmD, FCCP, FIDSA, and others.5 With this technique, one basically inserts a catheter into the tissue in question and continuously perfuses the catheters with lactated Ringer’s solution. Clinicians then collect dialysate samples from the catheters and measure antibiotic levels. This technique 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 do not 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. Carl Norden, MD, one of my heroes in the ID world, showed in his early, elegant rabbit studies that clindamycin was one of the most effective antibiotics in the treatment of experimental osteomyelitis.6 I am just not sold that penetration, in and of itself, is that important of a goal.

References

1. Spellberg B, Lipsky BA. Systemic antibiotic therapy for chronic osteomyelitis in adults. Clin Infect Dis. 2011 Dec. 12 (Epub ahead of print).

2. Senneville E, Lombart A, Beltrand E, et al. Outcome of diabetic foot osteomyelitis treated nonsurgically: a retrospective cohort study. Diabetes Care. 2008;31(4):637-42.

3. Lipsky BA, Peters EJ, Senneville E, et al. Expert opinion on the management of infections in the diabetic foot. Diabetes Metab Res Rev. 2012;28 Suppl 1:163-78.

4. Peters EJ, Lipsky BA, Berendt AR, et al. A systematic review of the effectiveness of interventions in the management of infection in the diabetic foot. Diabetes Metab Res Rev. 2012;28 Suppl 1:142-62.

5. Wiskirchen DE, Shepard A, Kuti JL, Nicolau DP. Determination of tissue penetration and pharmacokinetics of linezolid in patients with diabetic foot infection using in vivo microdialysis. Antimicrob Agents Chemother. 2011; 55(9):4170-5.

6. Norden CW, Shinners E, Niederriter K. Clindamycin treatment of experimental chronic osteomyelitis due to Staphylococcus aureus. J Infect Dis. 1986;153(5):956-9.

Editor’s note: This blog was originally published at http://www.leinfections.com/category/uncategorized/ and has been adapted with permission from Warren Joseph, DPM, FIDSA, and Data Trace Publishing Company. For more information about the Handbook of Lower Extremity Infections, visit www.leinfections.com/ .

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