News Story About Pharma Industry Payments – Response

March 13th, 2013 by Warren S. Joseph DPM FIDSA
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I am sorry that it has been so long since I put up a post.  Things have been slightly hectic. Unfortunately, instead of reporting on new infectious disease information, with this entry I find myself responding to a story about my receiving payments to lecture from the pharmaceutical industry.  The story ran today (3/13/13) in the Philadelphia Inquirer and online at www.philly.comhttp://www.philly.com/philly/health/20130312_Philly_foot_doc_among_highest_paid_by_Big_Pharma.html

When the original print story was run I had not had a chance to respond to the author, reporter Sam Woods.  I give Mr. Woods credit for updating the online story in response to some of my comments, reproduced below, which I emailed to him this morning.  

I feel that the Pharma Industry has done an excellent job in disseminating important information that may otherwise not be available to those of us interested in saving limbs of patients with diabetes.  This is done in an unbiased, government approved and monitored way, under strict federal guidance.  My lectures are randomly, and independently audited for compliance with these guidelines and I have never been found to be deficient. 

Here is my response to Mr. Wood in its entirety:

Sam

I read your article from today in Philly.com.  Just to respond to a few items: 

1.   I did not call you yesterday since my family was at my father’s deathbed.  We lost him last night at 7PM.  You will probably see the obit in the Inquirer in the next day or so.  I had every intention of contacting you this morning (as I am doing now)

2.  As to responding to ProPublica, they phoned me while I was out of the country lecturing at a continuing education (non Pharma sponsored) meeting.

3.  All of my lectures given for the Pharma industry follow strict FDA guidelines and are consistent with the corporate integrity agreements entered into between the companies and the government.  There is full disclosure of this fact at all lectures. 

4.  I have not worked at the Coatesville VA in a number of years.  I strictly work out of Roxborough and am a private, self-employed citizen; not an employee of any company, government, hospital, or health care organization. 

5.  Thank you for at least quoting the article from last year.  I stand by what I said there.  Some organizations have an agenda to make interactions between Pharma and doctors somehow seem nefarious.  Let me give you some statistics if you want the REAL story:  There are 28 million people in the US with diabetes.  About 350 million worldwide (and yes, I have lectured around the world on this topic).  It used to be said that someone in the world loses a limb to diabetes every 30 seconds.  That is now down to every 20 seconds.  Diabetes is the cause for about 70-80,000 amputations per year in the US alone.  The single greatest cause. The 5 year mortality of people who present to their doctors for the first time with a diabetic foot ulceration is HIGHER than the 5 year mortality for breast cancer, prostate cancer and Hodgkin’s lymphoma.  If you add peripheral arterial disease to that, the 5 year mortality is even higher than colorectal cancer.  Diabetic foot infection accounts for about 33% of the >$100 BILLION spent on patients with diabetes each year and accounts for the greatest number of hospital days YET the NIH only provides <0.2% of all of their diabetes funding to study foot complications (soon to be presented new data).  The vast majority of research in the treatment of diabetic foot infections has been done by the private sector including the Pharma industry.  Yes, I go out and spread this information to my colleagues and it is often paid for by industry. However, by doing so I know I have saved countless limbs and lives.  Frankly, I don’t see anything nefarious about that…only good. 

Kind Regards,

Warren Joseph, DPM, FIDSA

Consultant, Lower Extremity Infectious Diseases

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New 2012 IDSA Diabetic Foot Infection Guidelines

May 22nd, 2012 by Warren S. Joseph DPM FIDSA
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As promised, I would post a link to the newly revised, updated IDSA DFI Guidelines as soon as they were available.  Well, I am honored, proud and excited to be able to let my readership know that after about 6 years in writing, multiple levels of peer review and well over 60 individual review comments, that the newly revised guidelines have been posted by IDSA on their website. Here is the link:    http://www.idsociety.org/uploadedFiles/IDSA/Guidelines-Patient_Care/PDF_Library/2012%20Diabetic%20Foot%20Infections%20Guideline.pdf

Those of you familiar with the 2004 document will immediately notice the changes.  All IDSA Guidelines are now standardized to a “question, recommendation, evidence summary” format.  Each committee is assigned to determine which are the most critical questions that need to be answered.  In this case, we came up with 10 questions that cover everything from diagnosis to antibiotics, to osteomyelitis and wound care.  There are 44 evidenced based recommendations that  guide the clinician in the answers to those 10 questions.  The evidence is then summarized and graded by the British Medical Journal “GRADE” system.  This common sense approach matches the strength of the recommendation with the level of the evidence.  This is given in plain English.  For example “Strong, Low” means that there is a strong recommendation but a relatively low level of evidence on which the decision has been based.

I hope that you all find the new Guidelines helpful in your management of these patients.  I look forward to your comments

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Antibiotic Bone Penetration and Osteomyelitis

April 2nd, 2012 by Warren S. Joseph DPM FIDSA
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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/22271738http://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.

 

 

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The Attack of the MDROs (ESBL, KPC, NDM-1, NDM-2)

March 27th, 2011 by Warren S. Joseph DPM FIDSA
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I just returned from the DFCON meeting in Los Angeles, always my favorite scientific conferences of the year (I have blogged about it previously http://www.leinfections.com/diabetic-foot/the-olmos-award-and-dfcon-2010/).  My topic this year was “Drugs and Bugs 2011”.  Since I gave a similar talk last year I had to try to find a few “hot” topics to update the talk.  Without a doubt, the most important development in Infectious Diseases over the past year has been the increasing prevalence of multi-drug resistant organisms (MDRO), in particular the gram negative rods harboring extended spectrum beta-lacatamase (ESBL), Klebsiella pneumoniae carbapenemase (KPC) and the New Delhi metallo-beta-lactamases (NDM-1, NDM-2).  In fact, as I was in my hotel in L.A. polishing up my lecture for later that afternoon of Friday 3/25, I had Good Morning America (GMA) on the TV in the background.  A story was announced on the latest “Superbug”.  These fear-mongering sorts of titles always get my attention so I stopped work on the lecture and listened.  Sure enough, they were reporting on an outbreak of Carbapenem resistant Kleb pneumo (CRKP) in 350 patients right there in Southern California.  Needless to say, it was immediately added to my lecture, although I doubt that Good Morning America would be considered an appropriate peer reviewed, primary reference for a scientific publication! When I arrived home the next day, there was an email from a friend/colleague asking about CRKP since the news headline also hit our local all-news radio station.  I realized that, although I speak about them frequently at lectures, I have never written about them here.  It is past due.

Although I may give a more complete scientific explanation in a future post, I just wanted to pique your interest so that you can do some reading and exploration on your own about this major threat.  In the most basic terms, ESBLs are enzymes that inactivate most current beta-lactam antibiotics including cephalosporins and penicillins.  The most common organism in which the ESBLs are found seem to be E. coli and Proteus mirabilis.  Many of us of a certain generation remember a time when these organisms were so susceptible to antibiotics that you could pretty much choose any drug with basic gram negative activity and it would be effective.  Now, there are isolates of these organism resistant to most commonly used antibiotics and only susceptible to traditionally thought of “big guns” such as carbapenems, and tigecylcine.  And, don’t think these are only found in urinary tract infections, bacteremia, pneumonia or other severe hospital based infections, I have seen them in diabetic foot infections on a number of occasions.

As the name implies, KPCs are enzymes that not only inhibit the previously mentioned antibiotics but also one of the remaining choices effective for ESBLs…carbapenems.  Needless to say, this makes these organisms extremely difficult to treat.  Tigecycline resistance has been reported.  In severe, life threatening infections caused by KPC containing organism the “last ditch” treatment has become either polymyxin-B or colistin.  These are nasty drugs with rather significant adverse event profiles, mostly renal toxicity.  The problem is that, as recently as the past month or two there have been reports of both polymyxin and colistin resistant strains reported in the literature leaving, essentially, no good treatment.  This is why the physician interviewed for the GMA story reported 40%+ mortality related to this organism.  To date the vast majority of these cases are occurring in debilitated hospitalized patients but, the very first KPC in our hospital occurred in a patient I was seeing with a diabetic foot infection. 

 The “MDRO of MDROs” has to be those containing the NDM-1 gene.  This gene was first reported in 2008 in Sweden in a patient hospitalized in India and has a greater ability to rapidly spread to other bacteria than does KPC.  This has become a huge issue in Asia and Europe but has now also spread to the US with, at last count, I believe 4 reported cases.  All patients had some relationship to the Indian subcontinent either having come from there or visited as a tourist.  These bacteria have a similar antimicrobial susceptibility pattern as the KPCs but tend to develop resistance more rapidly.  In the February 2011 issue of Clinical Infectious Diseases an Editorial Commentary says it all just by its’ title “New Delhi Metallo-β-lactamase and Multidrug Resistance: A Global SOS?  http://cid.oxfordjournals.org/content/52/4/485.extract.  To only make matters worse, as recently as last week I saw the first report of an Acinetobacter with a brand new variant, the NDM-2 gene http://jac.oxfordjournals.org/cgi/content/abstract/dkr135v1.   

Unfortunately, there is not a lot of promise for new antibiotic development to fight these MDROs.  The Pharma industry does not make its money on new antibiotic development as most of these drugs are only given for a short period of time in contrast to therapies for hypertension, GERD and cholesterol. To this end the Infectious Diseases Society of America has developed the “Bad Bugs Need Drugs, 10 by 20” campaign  (http://idsociety.org/10×20.htm) a collaboration between the IDSA, Industry and the Government to developed 10 new antibiotics by 2020. I urge all of the readership to check out this website and others to educate yourselves on the risks and dangers these new organisms cause.

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What Would You Do – Prophylaxis: Responses

December 10th, 2010 by Warren S. Joseph DPM FIDSA
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Well, the comments have come in and this is what I received – my comments, if any, are in italics:

- Interesting question as I just received a memo from the dental school at the University asking my preferences regarding antibiotic prophylaxis with implant (hardware) patients and dental surgery. The letter outlined the 2003 decision with the ADA and AAOS as well as followup decisions by both organizations. My take is that one has no choice but to recomend AP due to the medical-legal questions. There is little evidence suggesting it is required but one has to take this time honored procedure into consideration.  This is an interesting point.  Originally, the ADA and AAOS actually came out in a joint statement and concluded that it was NOT routinely needed to prophylax a patient for dental work even if they have a prosthetic joint unless the patient was undergoing a “high risk” dental procedure. As recently as Nov 2009 they changed their position to recommend prophy in these patients prior to any dental procedure!  As you will see below, this is not supported by science. As to the medico-legal issue, there is no question that this does come into play, unfortunately, when making medical decisions.  I think it is time (call be an idealist) we should practice medicine based on science and not fear of repercussions.

- No to both unless prior infection. Actually, this is the “correct” answer based on the paper I will share with you below.

- Related question: 30 yo F w/ Mitral Valve Prolapse. Need ABX prophy for foot or ankle surgery w/ or wo/ implants? Absolutely NONE!  The American Heart Association guidelines for prophylaxis against endocarditis are clear on this point (I think I see another blog post idea).  In 2007 they backed off many recommendations for prophy and now only recommend it when surgically manipulating an actual infection (abscess, cellulitis, etc) in a patient with a “high risk” for infective endocarditis.  These high risks are mostly prosthetic heart valves and other major cardiac conditions and do NOT include MVP. Clean elective surgery through surgically prepared skin has not required prophy since their 1997 Guidelines.

- No to both of these questions. If they had a tooth abscess then I may consider. As far as I know they don’t have people with foot/knee/hip implants take abx everytime they brush their teeth. I Think in the case of bunion surgery on a patient with a known knee prosthesis that preop Ancef is enough. Great point! The issue is the development of bacteremia.  This occurs every time someone brushes their teeth, flosses, eats hard food. You don’t prophy with each of these activities so there is no reason to do it for surgery.  Only when an infection is being manipulated should it be considered.

- In the first scenario, if the patient is immunocompromised in any way, I would advise a cephalosporin. Good suggestion.  Interesting “immunocompromise” of the patient does not seem to come up in any guideline.  I don’t know why.

- In the second scenario, since the joint implant is less than 2 years old, I would recommended prophylactic antibiotics.  Excellent point!  The 2 year rule has been around for a while.  It is presumed that if the implant is in place less than 2 years there is a higher risk of it getting infected.  I am not really certain where that comes from or the validity of it. My only issue would be that if you are not manipulating and infection and are doing your bunion surgery through surgically prepared skin, there should be no bacteremia and no reason to give prophy…just like if it was for endocarditis.

I want to thank those who took the time to respond.  I really enjoyed reading, and thinking about your comments. 

Now here is why I brought it up in the first place:  In the January 1, 2010 issue of Clinical Infectious Diseases there is a study by Berbari et.al. out of the Mayo Clinic entitled “Dental Procedures as Risk Factors for Prosthetic Hip or Knee Infection: A Hospital-Based Prospective Case-Control Study.  (PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/19951109 ) .  This elegantly done study looked at 339 patients admitted with prosthetic joint infections (PJI) vs. 339 admissions of patients with non infected prosthetic joints.  They examined dozens of parameters including; the type of dental procedure, time from implant to the dental procedure, time from dental procedure to current admission, operative factors, diabetes, immunocompromise, organisms recovered and many others.  I think it is important for you to read verbatim what they stated in the Results and Conclusion parts of their Abstract:

RESULTS: A total of 339 case patients and 339 control subjects were enrolled in the study. There was no increased risk of prosthetic hip or knee infection for patients undergoing a high-risk or low-risk dental procedure who were not administered antibiotic prophylaxis (adjusted odds ratio [OR], 0.8; 95% confidence interval [CI], 0.4-1.6), compared with the risk for patients not undergoing a dental procedure (adjusted OR, 0.6; 95% CI, 0.4-1.1) respectively. Antibiotic prophylaxis in high-risk or low-risk dental procedures did not decrease the risk of subsequent total hip or knee infection (adjusted OR, 0.9 [95% CI, 0.5-1.6] and 1.2 [95% CI, 0.7-2.2], respectively).

CONCLUSIONS: Dental procedures were not risk factors for subsequent total hip or knee infection. The use of antibiotic prophylaxis prior to dental procedures did not decrease the risk of subsequent total hip or knee infection.

They go on to question the recent AAOS recommendations since they were seemingly not based on any science.  They recognize in the manuscript: “Although the adverse risk of antibiotic prophylaxis in the individual patient may seem remote and unlikely, the risk to the overall population with a joint arthroplasty and to society at large seems prohibitive”.  I believe that this is something we forget when making decisions on our individual patients.  We do thing, like give possibly unnecessary antibiotics to “cover ourselves” from medico-legal concerns and because, frankly, it probably will not hurt that one patient.  But when you multiply your actions times thousands of practitioners thinking the same thing, times the 10s of thousands of patients being treated we start to have an impact on the global microbiota. 

I urge my readers to seek out this article since there are lots of other interesting points that are made and I don’t have the space to go into with this post.

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New York Clinical Conference

January 24th, 2010 by Warren S. Joseph DPM FIDSA
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To any of my readers planning on attending the NY Clinical Conference this coming weekend, I will be in the exhibit hall at the DataTrace booth on Saturday January 30th.  I will be there to discuss this blog, sign copies of the 3rd Edition (not that it will increase the value of it…heck, it may diminish it!) and just generally hang out and meet anyone interested in discussing lower extremity infectious diseases.  Please come by and say “Hi”.

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