Minocycline and the Treatment of Multidrug-Resistant Acinetobacter baumannii

December 15th, 2014 by Warren S. Joseph DPM FIDSA
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When most of us think about minocycline it is for the oral treatment of gram positive infection, in particular MRSA.  In fact, the drug is effective against multidrug resistant gram negative organisms, including Acinetobacter baumannii (AB). This point was driven home to me recently when I saw that my favorite ID journal Clinical Infectious Diseases just published a supplement on the topic.  Here is the link to the Table of Contents.  All of the articles are available as free full text and can be downloaded from this link:

http://cid.oxfordjournals.org/content/59/suppl_6.toc#MINOCYCLINEFORTHETREATMENTOFMULTIDRUG-RESISTANTACINETOBACTERBAUMANNII

This supplement was sponsored by The Medicines Company www.themedicinescompany.com who are now marketing an IV formulation of minocycline for this purpose so take that into account while reading the papers. That being said, both of the Guest Editors, Debra Goff, PharmD and Keith Kaye MD, MPH are top quality, fair balanced researchers and authors. (Disclosure: I have NO financial relationship with this company)

The efficacy of minocycline against AB should not come as a huge surprise.  Tigecycline, a minocycline derivative, is often considered one of the drugs of choice for both ESBL and CRE producing gram negatives including MDR-AB.

Also of interest in this Supplement is a brief obituary for one of the true giants in the field of Infectious Diseases, Robert Moellering, Jr, MD.  I had the opportunity to meet Bob on a few occasions at various meetings and advisory boards.  He was a true gentleman who worked closely with the podiatrists at The Beth Israel Deaconess in Boston.  Over the years I have read his work and marveled at his brilliance.  He will be missed.

Posted in Antibiotics, Infection control, Infections, MRSA | No Comments »

The Press Reporting of ID and Antibiotics

December 12th, 2014 by Warren S. Joseph DPM FIDSA
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USA Today ran an interesting story yesterday about a 19 year old woman given an antibiotic by a friend for a “sore throat” who developed Stevens Johnson Syndrome.  This is a terrible incident and my thoughts and prayers go out to the young woman and her family.  What bothered me however was the way in which USA Today reported it.  Here is the link:

http://www.usatoday.com/story/news/nation/2014/12/11/teen-antibiotic-burn-inside-out/20249585/

Yes, it was reported that there was a teen who took an antibiotic making her “Burn From the Inside Out”.  Talk about sensationalism!  It appears that they got that phrase from a physician they contacted.  Now, I’m not questioning the accuracy of that description but it is the use of it in the headline that makes me shake my head.  CNN reported the same story with a more sedate headline: “A friend gave her an antibiotic; now she’s fighting for her life”

http://www.cnn.com/2014/12/10/health/california-antibiotic-allergic-reaction/index.html?hpt=hp_t2

This just got me thinking about other ways in which the lay press reports on infectious diseases and antibiotics.  How many articles have been written on “Super Bugs”?  What ARE “super bugs” anyway?  In one story they may be MRSA, in another CREs.  What about “flesh eating bacteria”?  Some of us remember back about 15 years ago when this term first became popularly used in the press.  It referred to a series of cases of Group A Streptococcal necrotizing fasciitis.  This was hardly a new infection, even back then.  It has probably been around since the beginning of time but boy did they run with it.  Then, within the past few years “flesh eating bacteria” somehow morphed from Group A Strep to MRSA.  Which is it?  Is it both?  I guess.

Finally, since I have been asked frequently, let’s look at Ebola.  Now I am not, and have never claimed to be an expert on viral diseases in general and Ebola in specific.  I have never seen or treated a case and hope to never come across it.  However, just a few weeks ago you could not turn on the TV, pick up a newspaper or magazine and not read about this terrible disease.  In fact, Time Magazine, rightly IMHO, just named those who fight Ebola as their “People of the Year”.  However, let’s put this into perspective.  To the best of my knowledge there were only TWO cases actually contracted in the US and both of those were health care workers directly treating the first unfortunate patient in Dallas.  That did not stop the news sources from rolling out expert after expert about how this disease could potentially spread here in the States, or maybe not.  People were freaking out.   For the first time in all my years of travel I was seeing folks wearing surgical masks on airplanes and taking out sanitizing wipes to treat the airplane seats and trays before sitting down (actually, probably not a bad idea!).  But, as the old saying goes, “today’s news is tomorrow’s fish wrapper”. Other than the Time story, I don’t think I have seen anything about the disease in a few weeks.

I guess the upside to all of this reporting is that it DOES make people more aware of infectious diseases and the potential dangers of inappropriately used antibiotics.  If just one person thinks twice and refuses an antibiotic proffered by a friend for a probable viral infection and remembers this poor woman and her fight with SJS, I guess the Press did their job.

 

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Medscape Interview about Diabetic Foot Osteomyelitis

December 8th, 2014 by Warren S. Joseph DPM FIDSA
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Just over a week ago my good friend and colleague in lower extremity ID, Mark Kosinski, DPM, FIDSA and I were interviewed by Miriam Tucker, a reporter for Medscape, about a recent paper that compared 6 weeks vs 12 weeks of antibiotic therapy for DFO that did not undergo surgical debridement.  The impetus for this interview was a study published in Diabetes Care by Tone, et.al.  Here are links to the PubMed abstract for that paper, and the original interview on Medscape along with a link to David Armstrong’s excellent “diabeticfootonline” blog where, with his permission and my thanks to him, I am cutting and pasting his reporting of this below. Although the article is a bit longer than my usual posting, I think it is worth reading as both Mark and I discuss what is unique and interesting about this excellent study.

http://www.ncbi.nlm.nih.gov/pubmed/25414157

http://diabeticfootonline.blogspot.com/2014/11/short-course-oral-antibiotics-as-good.html

http://www.medscape.com/viewarticle/835503

Dr. Armstrong’s Report:

Here’s a great summary and commentary regarding the work by Tone, et al that we previously posted featuring our SALSAmigos Warren S. Joseph and Mark Kosinski.  By Miriam E. Tucker (Medscape)

UPDATED November 27, 2014 // Six weeks of antibiotics may be sufficient for treating patients with diabetic foot osteomyelitis even in the absence of surgery, a new randomized prospective trial finds.

The results from 40 patients seen at five French general hospitals between 2007 and 2009 were  published onlineNovember 20 in Diabetes Care by infectious disease specialist Dr Alina Tone (Gustave Dron Hospital, Tourcoing, France) and colleagues.

Current guidelines by the Infectious Diseases Society of America (IDSA) call for 3 months or more of antibiotic therapy when diabetic foot osteomyelitis is not treated surgically or when residual dead bone remains after surgery. But in the new study, remission was achieved in about two-thirds of patients following either protocol (6 or 12 weeks of treatment).

The main finding of the study shows that “one can treat patients with diabetic foot osteomyelitis with only 6 weeks of treatment, despite infected bone [not being] removed,” principal investigator Dr Eric Senneville (Gustave Dron Hospital) told Medscape Medical News.

The primary aim of reducing the duration of antibiotic therapy “is to limit the pressure on bacteria and therefore to decrease the emergence of bacterial résistance,” he added, although he noted that the design of the current study did not allow this issue to be examined.

Also important and demonstrated in the trial, Dr Senneville said, was to reduce the number of adverse events related to antibiotics and risk of drug–drug interactions “because these patients usually have a lot of medications due to the frequent comorbidities reported in this population.”

Accumulating Evidence Addresses Several Important Issues 

This is a “good, well-done, high level of evidence study. It’s what we need in these patients,” said Dr Warren S Joseph, consultant in lower-extremity infectious diseases (Roxborough Memorial Hospital, Philadelphia, Pennsylvania) and coauthor of the IDSA guidelines along with Dr Senneville, when asked for comment.

Dr Joseph pointed out that the results address several areas of debate in the field. Not only did the study authors find 6 weeks of treatment to be as good as 12 weeks, but antibiotics were primarily given orally rather than intravenously, and in half of patients they were not given empirically but started once culture results were obtained, with no difference in outcomes.

And, the study also reinforces the overall idea—still under debate—that nonsurgical treatment is acceptable for selected patients with osteomyelitis.

“The evidence is getting stronger and stronger that there are alternative methods for treating osteomyelitis—some without surgery, some without intravenous antibiotics, for varying lengths of time—that work every bit as well as that old standby of 6 weeks of intravenous therapy,” Dr Joseph told Medscape Medical News.

“That’s why this study is important. It’s adding to the accumulated evidence out there that we have newer ways to treat osteomyelitis than just about everybody in the world thinks is the right way to do it.”

Dr Mark Kosinski (New York College of Podiatric Medicine, NY) agrees: “This is a well-designed, multicenter, prospective randomized study that significantly adds to our knowledge about treating diabetic foot osteomyelitis.”

“It is heartening to see that this study utilized oral meds as its primary treatment regimen,” Dr Kosinski told Medscape Medical News. “Over the years, IV antibiotics have remained for many (for better or worse) the perceived gold standard for treatment of diabetic foot osteomyelitis. Despite emerging evidence to the contrary, many clinicians still doggedly cling to the notion that IV is superior to oral for treating chronic bone infection.”

But “adherence to such dogma leads to overutilization of parenteral meds (which should be best reserved for treating acute infection), increases healthcare costs (increases length of hospital stay, placement of peripherally inserted central catheter lines, infusion nurses, materials associated with IV meds, etc), and presents the possibility of infection of the IV line itself,” he added.

Reducing Antimicrobial Use

In the French study, participants all had osteomyelitis complicating a neuropathic foot without peripheral arterial disease. Empirical antibiotics were prescribed while waiting for culture results only if the treating physician considered it necessary.

Antibiotics were selected based on the culture results and patient comorbidities, and were given orally for the entire time or intravenously for 5 to 7 days followed by oral administration for the rest of the time.

Staphylococcus aureus was the most common organism cultured from bone samples, followed by coagulase-negative staphylococci and gram-negative bacilli. Most of the infections (45%) were polymicrobial.

Oral coamoxiclav was prescribed empirically while waiting for culture results in 45% of patients, and in four of those 18 patients the pathogen turned out to be resistant to the antibiotic.

Empiric use of rifampin was discouraged, with good reason, Dr Senneville told Medscape Medical News. “Rifampin should never be used as an empirical therapy because of the risk of selection of rifampin-resistant bacteria.”

However, rifampin was the most frequently used antibiotic based on culture results (in 76%), followed by a fluoroquinolone (70%). A combination of the two was used in 47%.

Antibiotic-related adverse events occurred in 6 (30%) of the 20 patients randomized to 6-week treatment and 10 (50%) of the 20 patients in the 12-week group. Gastrointestinal symptoms related to rifampin were the most common adverse event (three vs nine episodes in the 6- and 12-week groups, respectively). Other adverse events did not differ between the groups.

Remission, defined as (1) the absence of local or systemic signs of infection, (2) stabilized or improved radiographic abnormalities on plain X-rays assessed at the end of treatment and 1 year, and (3) complete, sustained healing of the wound responsible for the underlying osteomyelitis, occurred in 26 patients (65%).

There was no significant difference in remission rates between the groups, with remission rates achieved in 12 patients (60%) in the 6-week group and 14 patients (70%) in the 12-week group.

The authors couldn’t identify any specific parameter that appeared to be associated with patient outcome, including methicillin-resistant S aureus; five of seven patients with methicillin-resistant S aureus still achieved remission.

The median delay of 14 days between bone biopsy and beginning of documented antibiotic therapy may appear surprising, they note, “but we think that diabetic foot osteomyelitis is not an indication for urgent antibiotic therapy, especially in patients with no signs of inflammation of the foot, which was the case in 22 (55%) of our patients.”

Indeed, there was no difference in outcome between patients treated with antibiotics immediately after bone biopsy compared with those given them after microbiological results were available (= .84).

They conclude that a further larger-scale study is warranted to assess other beneficial effects of a reduction in duration of antimicrobial therapy for diabetic foot osteomyelitis, especially with respect to the emergence of bacterial resistance and antibiotic-related adverse effects.

Evolving Views Regarding Antibiotic Therapy 

Dr Kosinski said he is impressed with the study methodology, particularly the inclusion of a bone-biopsy-recovered pathogen after a 2-week antibiotic-free period. “Bone biopsies are underutilized as a diagnostic modality, yet transcutaneous bone biopsies are easy to do, have a low complication rate, and yield valuable information as to the infecting organism toward which to direct antibiotic therapy.”

However, he noted a limitation of the work: the exclusion of patients with peripheral arterial disease. “It will be interesting to see if future studies will support similar conclusions in patients with compromised arterial supply, which so many of our patients with diabetes suffer from.”

Dr Joseph praised the investigators’ three-pronged definition of remission, noting it has been a matter of debate and is also an issue for the US Food and Drug Administration, which hasn’t approved a new antibiotic for diabetic osteomyelitis in over 20 years.

“FDA doesn’t have good guidance for industry on how to do an osteomyelitis study. No one has ever come up with a good definition on what constitutes a cure of osteomyelitis. [The authors] have done a decent job here—though not perfect—of trying to define it.”

Dr Joseph also pointed out that the guideline recommendations of 6 or 12 weeks of antibiotic therapy for various clinical scenarios does not have good supporting evidence. Moreover, recent studies suggest that in some cases in which surgery is performed, just 3 to 4 weeks therapy, or even no antibiotics, is sufficient.

“What excites me about this paper is it’s just one more piece of the puzzle…here they’re using 6 weeks, but it’s primarily oral [and there was no surgery]. Other studies have used less than 6 weeks when they’ve surgically removed bone. Frankly, [the authors] might have been able to go 4 weeks and get just as good a result as at 6 weeks. They just didn’t test that. That might be a next step.”

Dr Kosinski concurs: “I am also pleasantly surprised to see that the length of treatment may be significantly shorter than once thought,” and that the notion that diabetic foot osteomyelitis is always a surgical disease “is changing.”

“Likewise for the route of administration,” he added. “We now have at our disposal, antibiotics with high bioavailability after oral administration, antibiotics that may help change the widely held notion that parenteral is always better.”

“I have no doubt that by the time of the next incarnation of the IDSA guidelines, studies such as this one will play a role in their revision,” he concluded.

The study authors have reported no relevant financial relationships. Dr Joseph is a consultant to Dipexium Pharmaceuticals and consultant/speaker for Merck. Dr Kosinski had no disclosures.

Diabetes Care. Published online November 20, 2014. Abstract

 

 

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Dalbavancin & Oritavancin – PART 2

November 17th, 2014 by Warren S. Joseph DPM FIDSA
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In my post last week I mentioned I would write a follow up to discuss my opinions on the use of these drugs for lower extremity infections.  I have not yet had the opportunity to try either so these are really “top line” thoughts taken what I know, have read or heard from others, into consideration.

– These drugs are expensive and I wonder who will cover the cost. The two doses of dalbavancin reportedly cost somewhere in the neighborhood of $4500 while the single dose of oritavancin is considerable less at around $2600 for the required single dose. Given hospital pharmacies are always worried about their budgets (they complained about the cost of linezolid when it was originally only about $1500!) can they be convinced to stock these drugs? What about insurance companies when they can demand patients receive generic vancomycin for next to no cost at all?

– The argument is made by the companies that these drugs will keep patients out of the hospital thus saving costs. That does make a lot of sense…on the surface. If you don’t admit the patient you don’t run up costs for the actual stay and only the outpatient treatment. The problem with this line of thinking is that many, especially for profit, hospitals make money by having “heads in beds”. The last thing they would want to do is decrease the number of admissions from the E.D. I make this statement with the disclosure that I am far from expert in hospital reimbursement economics, it’s just what I have been told by some hospital administrators.

– Who will make the decision to administer these drugs? The Emergency Physician? I doubt most would feel comfortable with these antibiotics. Furthermore, would they just stock it in the E.D? Who’s budget does it go under? The Pharmacy or the E.D.? What about the out-patient infusion center. This is probably the most likely scenario, especially if run/owned by an ID specialist, depending or reimbursement considerations.

– If the patient did receive a dose in the E.D. and the decision was made to admit the patient, the patient no longer needs IV antibiotics. Would the admission be denied as not meeting hospital level care?

– What if the patient developed an adverse event (“AE”). Neither of these drugs is dialyzed out of the blood. Will the AE be present for the entire length of the half life? That being said the clinical trials showed that AEs were rare and those that did occur were self limiting. Of course, with widespread use of any new drug previously untoward reactions can be discovered.

I guess my bottom line is that I am totally fascinated by these drugs and their unique pharmacokinetics.  I can see weekly doses to treat osteomyelitis (although neither are FDA approved for this nor even tested).  I can see taking a patient with an infection who is not doing well on an oral MRSA drugs, such as doxycycline or TMP/SMX, and just treating them with an IV dose or two.  Perhaps, treating a patient who, for whatever reason, can’t take oral linezolid or tedizolid but does not require hospitalization for their infection is another potential use. I will continue to watch and learn about these two new drugs whenever I can and pass along any information I can.

Posted in Antibiotics, Infections, MRSA, Osteomyelitis | No Comments »

New Antibiotics – Dalbavancin & Oritavancin PART 1

November 10th, 2014 by Warren S. Joseph DPM FIDSA
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In this entry I will continue to explore some of the new antibiotics that have been recently approved for use in acute bacterial skin and skin structure infections (ABSSSI). I will discuss these two together since they are quite similar in a number of important ways and share many of the same properties.

Both dalbavancin (Dalvance™ – Actavis) and oritavancin (Orbactive™ – The Medicines Company) are classified as “semisynthetic lipoglycopeptide” antibiotics. Both are effective against resistant gram positive organisms including MRSA.  They have both been around for quite awhile having been studied and then turned down for approval by the FDA back around 2007-8 citing lack of sufficient data.  Both were then dropped by their original companies and eventually picked up by others who finished the study process to get them FDA approved.  They also both share similar pharmacokinetics with very long half lives allowing weekly dosing.  Dalbavancin is dosed 1 gram IV on day 1 followed by 500mg on day 8, while Oritavancin is given in a single 1200mg IV dose.

In the Phase III clinical trials for dalbavancin, entitled the “Discover 1 & Discover 2 “ trials (http://www.nejm.org/doi/full/10.1056/NEJMoa1310480 ), dalbavancin given in the 2 dose regimen was found to be noninferior to IV vancomycin followed by po linezolid  (clinical success 90.6% for Dalbavancin vs. 93.8% for the comparator) with adverse events being less frequent in the dalbavancin group.

Similarly, in the two Phase III trials of oritavancin (http://www.nejm.org/doi/full/10.1056/NEJMoa1310422) the single dose regimen was compared to twice daily IV vancomycin for 7 to 10 days.  The primary end point (reduction in lesion size by 20% at 48-72 hours – the current FDA standard and probable topic for a future post) was met in 82.3% for oritavancin vs. 78.9% of the time.  Although adverse event rates were similar, nausea was found more commonly in the oritavancin group.

So, where do these drugs fit in terms of our clinical usage in the management of lower extremity infections? As you can imagine, I have my opinions…but you will have to wait for my next post!

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New Antibiotics – Tedizolid

October 23rd, 2014 by Warren S. Joseph DPM FIDSA
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As I mentioned in my previous post, this has been a pretty exciting time in the area of lower extremity infectious diseases. Not only do we have 2 new drugs for onychomycosis (to be covered in future posts) but we also have 3 new FDA approved antibiotics for the treatment of, in FDA Speak; “acute bacterial skin and skin structure infections” (aBSSSI).  These drugs are tedizolid, dalbavancin and oritavancin.  Of these, the one that I am most interested in, at least at this moment, is tedizolid.

Tedizolid phosphate (Sivextro™, Cubist) is an oxazolidinone antibiotic. This is only the second drug in this class to be approved, the first being linezolid back in 2000.  As with linezolid, its spectrum of activity is essentially gram positive organisms including MRSA and VRE.  The difference between the two drugs is what makes it interesting. Linezolid is dosed 600mg (IV or PO) q12h for 10 days.  Tedizolid is dosed 200mg (IV or PO) once daily for only 6 days. By giving the significantly lower dose for a shorter period of time leading to a much lower total drug exposure, some of the more commonly feared adverse events found with linezolid, in particular myelosuppression and possible serotonin syndrome in patients taking SSRIs, look to be significantly lessened, if not totally eliminated. Furthermore, the cost, always an issue when trying to prescribe linezolid, should also be lower.

The two pivotal clinical trials, titled ESTABLISH -1 (oral only) and ESTABLISH-2 (IV with possible switch to oral;

http://www.ncbi.nlm.nih.gov/pubmed/23403680 http://www.ncbi.nlm.nih.gov/pubmed/24909499

Compared tedizolid 200mg daily for 6 days to linezolid 600mg q12h for 10 days. Both studies found tedizolid to be non-inferior (also FDA speak) to linezolid.

So where does this new drug fit in the treatment of lower extremity infections? Because it was approved under the more recent FDA aBSSSI Guidance as opposed to the previous “complicated skin and skin structure infection” guidance, diabetic foot infections is specifically excluded.  This is a flaw in the current aBSSSI guidance document that some of us have been debating with FDA. That does not mean it won’t work in DFI, just that it was not included in the trials.  Furthermore, just because there were no DFIs does NOT mean that there weren’t any lower extremity infections.  In fact, about 40% of the patients in the trials did, in fact, have infections of the lower extremity including infected ulcers, surgical wounds, abscesses, etc.

Given its narrow spectrum of activity against pathogens we find, shorter duration of therapy and possibly enhanced safety profile, tedizolid seems to fit nicely with current concepts of antimicrobial stewardship. This is one new antibiotic that I feel may have an excellent niche in the treatment of LEIs.

Posted in Antibiotics, Diabetic Foot, Infections, MRSA, Wounds | No Comments »

I’M BAAAACCK

October 20th, 2014 by Warren S. Joseph DPM FIDSA
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Dear Readers,

It’s been awhile. Time really does fly. I realize it has been over a year and a half since my last post. I really don’t have any excuses. Life just seems to happen that way. One day I am posting all sorts of updates on what’s happening in the world of lower extremity infections and then I just stopped. Over these past months, I have had a number of people ask me what ever happened to the blog as they really enjoyed reading it and felt it was valuable. I’ve heard from students, residents, colleagues, my publisher and a surprising number of people I would have never expected to be interested. It made me realize how large my readership and reach really was.

I’ve heard you. I believe that the time is finally right to start things up again. You may have seen the recent ad that DataTrace placed on PM News about the resurrection of the blog. www.podiatrym.com/pmnews.cfm.  There has been quite a bit happening in the world of antibiotics and antifungals for onychomycosis. After having only one FDA approved antibiotic in 5 years, now we have had 3 new drugs released in just a few months. The antifungal situation is even more exciting. It has been 15 years since any new drug has been approved for the treatment of onychomycosis. In just over a month this summer, two new topical agents were approved and are now being marketed. And, that is just the beginning. The literature continues to contain studies on diabetic foot infections, onychomycosis and osteomyelitis at a seemingly increasing rate. I have become a big fan of My NCBI (www.ncbi.nlm.nih.gov/) a free service that allows you to sign up for alerts to newly published literature using any search terms you wish. For example, every Monday morning I receive weekly emails alerting me to papers on the topics of “foot osteomyelitis”, “diabetic foot infections”, and “onychomycosis”.

Over the next few weeks I hope to cover all of these topics and more. I may experiment a bit with format providing some really brief entries to compliment the longer more in-depth posts that really take some time and effort to sit down and write.

I want to thank all of you who have inquired about the blog and asked me to re-start it. Also, thank you to ALL of my readers. The site had quite a nice sized following in the past and I hope to build it back up and surpass that reach in the near future.

Posted in Antibiotics, Diabetic Foot, Osteomyelitis | No Comments »

Off Label Drug Promotion…Coming Soon?

December 12th, 2012 by Warren S. Joseph DPM FIDSA
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(I want to thank my friend and colleague Jeff Karr, DPM (www.osteomyelitiscenter.com) for alerting me to this news story.)

Just this past week the U.S. Second Circuit Court of Appeals ruled to prohibit criminal prosecution for truthful off label promotion of drugs as a First Amendment right. An excellent analysis of the case can by the law firm of Morgan, Lewis and Bockius can be found at:  http://www.morganlewis.com/pubs/WhiteCollar_LF_CriminalProsecutionTruthfulOff-LabelPromotion_6dec12.pdf and I direct anyone interested to read this summary.  I will not go into details but, rather, discuss how this may affect antibiotics and lower extremity infections (LEIs). 

The case, United States v. Caronia, was against a drug rep who was taped on two occasions discussing off label use of a drug, Xyrem used for narcolepsy, which is a misdemeanor.  From my interpretation of the referenced information, it appears that the Court decided that since the Food, Drug and Cosmetic Act allows physicians to legally prescribe any licensed drug for any indication, promotion of such use, as long as it was not false or misleading, was a “lawful activity” protected by the First Amendment. 

I will start by saying that I don’t believe that this will open the floodgates for armies of drug reps knocking down doors to speak about unapproved uses.  This will probably have to go higher in the court system with the next step being the Supreme Court.  Furthermore, many of the Big Pharma players are running somewhat scared of the Feds right now having sustained multi- BILLION dollar fines and signing “Corporate Integrity Agreements” with the Government that puts very strict rules in place on what they can, and cannot, do in terms of promotion. 

How does this impact antibiotics and LEIs?  Currently we only have 3 antibiotics FDA approved for the treatment of Diabetic Foot Infection; ertapenem, linezolid and piperacillin/tazobactam.  This may not change in the near future.  Under the current “Acute Bacterial Skin and Skin Structure Infection” (aBSSSI) guidance being followed by the FDA for new antibiotic approval, diabetic foot infection has been SPECIFICALLY EXCLUDED.  Although I am hoping that will change in the near future, without a pathway for approval, I don’t see any antibiotics being tested for this until there is a change in policy at the Agency.  A similar situation exists with osteomyelitis.  Because the FDA does not currently have Guidance for Industry on performing a clinical trial for osteo, no antibiotic has been approved for the indication in close to 20 years.  In the meantime, there have been a number of excellent antibiotics with good clinical data for both DFI and osteo that have not been promoted for lack of indication.  If this current ruling stands I don’t see why a rep couldn’t speak to a doc in a truthful and scientific manner, using published literature, to discuss the possible off-label use of a given drug.  I really feel that all would benefit.  The physician would be getting sound information to which they may not have been aware and the patient would receive evidenced based therapies which may currently be withheld from them over fears of unlabeled use.  To me, this is a no-brainer.  Thoughts?  Comments?

Posted in Antibiotics, Diabetic Foot, Infections, Osteomyelitis | 2 Comments »

What’s New & Interesting in the Infectious Diseases Literature – Summer 2012

August 13th, 2012 by Warren S. Joseph DPM FIDSA
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I confess…I have been a bit lackadaisical in my scanning through the journals I receive each month.  This point was driven home to me yesterday when I went to find room on my desk to put some work and realized it was totally covered with stacks of journal back issues I had put aside with all good intentions to eventually read through!  It was time to start clearing my desk with the side benefit of realizing I could probably come up with some interesting articles to blog about.  Well, I did.  In fact, I think I have enough for a few upcoming posts.

Those of you who have heard me lecture on MRSA know that I am not a big fan of the use of trimethoprim/sulfamethoxazole for the treatment of even mild outpatient infections.  My main objection has been increased toxicity of this drug vs. other options including; Stevens-Johnson syndrome, renal toxicity, allergies, drug-drug interactions, etc.   However, I have also questioned the evidence supporting its use and have frequently stated that we don’t even know the proper dosing!  Most clinicians use this drug at the “standard” dose of 1 DS tablet bid (160mg/800mg).  However, some authorities have argued that that dose is too low for MRSA and an increased dose of 2 DS tabs bid should be used.  This has always concerned me because of the potential risk for increased adverse events with the higher dose.  A study published in the December 2011 (I told you I was behind on my reading!) Clinical Infectious Diseases by Cadena and colleagues compared the two dosing regimens and found no difference in outcomes with those treated with the higher dose vs. those treated with the lower “standard” dose (http://www.ncbi.nlm.nih.gov/pubmed?term=Cadena%20J%20AND%20trimethoprim). There was no difference in patient and infection characteristics or in clinical response; 73% (n=121) high dose vs. 75% (n=170) low dose P = 0.79.  Although they did not specifically look at the number of adverse events in each group they do comment that none were found with either group “…although one might anticipate a higher rate of adverse events in those who received the higher dose”.   None of this has changed my mind.  I still prefer doxycycline or minocycline to the use of TMP/SMX although I do see situations where this drug would be useful.

Another huge area of debate on which I have commented a number of time both here in the blog and when I speak on the topic, is this concept of increasing vancomycin dosing to keep trough levels between 15-20 mg/ml.  I fall strongly on the side that this is not only unnecessary for all skin and skin structure infections (it may be necessary for blood stream or pneumonia but that is outside my scope) but is also extremely dangerous.  I do not think that it improves outcomes and not only believe, but have seen, increased cases of nephrotoxicity (aka “Acute Kidney Injury or AKI” in current parlance).   For a more thorough discussion on my reasoning, just search this site for the term “vancomycin” and you can see my posts on the matter.  I always like seeing new papers that support my opinion on something!  In the December 2011 issue of Antimicrobial Agents and Chemotherapy (AAC), Bosso and colleagues prospectively assessed nephrotoxicity in relation to trough concentrations in patients with MRSA treated with vancomycin.  (http://www.ncbi.nlm.nih.gov/pubmed/21947388)    They found that “Nephrotoxicity was observed for 42 patients (29.6%) with trough concentrations >15 mg/ml and for 13 (8.9%) with trough concentrations ≤15 mg/ml.” They concluded that the increased trough concentrations were associated with 3-fold increased risk of nephrotoxicity.  I have to ask…when will this nonsense stop?!  The entire concept of increasing doses of vancomycin is based on a pharmacodynamic model known as the AUC/MIC ratio.  There is essentially no evidence to show that it increases efficacy of vancomycin for the infections we treat in the lower extremity but it IS more toxic.  Yet, I frequently hear of clinicians and clinical pharmacists pushing for this higher dosing even in skin and skin structure infections – a dosing, by the way, NOT supported by the IDSA MRSA Guidelines. If you feel you need to push vanco this high, then consider alternative agents such as linezolid, daptomycin or ceftaroline.

To change tone completely, I was recently giving some lectures in Florida. I spoke in Miami, Ft. Lauderdale, Hialeah and Lakeland.  Nothing like the heat and humidity of August in the Sunshine State to make me appreciate the heat and relative dryness (I can’t believe I am saying that) of August in Philadelphia! Little did I know that my visit may have put me at risk for exposure to extended spectrum beta-lactamase (ESBLs).  The May 2012 issue of AAC contains an article by Poirel and colleagues “Wild coastline birds as reservoirs of broad spectrum β lactamase producing Enterobacteriaceae in Miami Beach, Florida” (http://www.ncbi.nlm.nih.gov/pubmed/22314536). The investigators collected 53 fecal samples of wild seagulls and 10 specimens from pelicans.  A total of 10 Enterobacteriaceae isolates containing ESBLs were obtained from 8 (14%) specimens.  They go on to discuss the exact phenotypes and the cross-resistance between various antibiotics.   They conclude that “…beaches may play a significant role for dissemination of various resistance determinants and may be a source of (ESBL) community acquired infections.”  I could make some light of this and compare this report to what the movie Jaws did to destroy beach towns back in the 1970s, but I will show restraint.  This is actually a serious issue.  Multi-drug resistant gram negative rods are, in my opinion, the organisms of the future.   Unlike MRSA where we have a number of different viable antibiotic choices, we have precious few resources to use against these organisms.  To see that they can be found in bird droppings at one of the top beach destinations in the World only adds to the urgency that more be done to fight these bugs. 

That is all for now.  As promised, I still have plenty left

Posted in Antibiotics, Diabetic Foot, Infection control, Infections, MRSA, Wounds | No Comments »

Antibiotic Prescribing in Podiatric Medicine

January 24th, 2012 by Warren S. Joseph DPM FIDSA
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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.

Posted in Antibiotics, Diabetic Foot, Infections, MRSA | 3 Comments »

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