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 »

A New Review of Antibiotic Therapy for Osteomyelitis

January 4th, 2012 by Warren S. Joseph DPM FIDSA
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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!

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

SCIP Surgical Prophylaxis?

November 13th, 2011 by Warren S. Joseph DPM FIDSA
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One of the most frequent questions I am used to be asked is about when antibiotic prophylaxis should be used in performing foot and ankle surgery.  I have an entire lecture on this topic where I go through the data, or lack thereof, on the subject and suggest the clinical situations where prophy has traditionally been utilized (i.e. surgery longer than 2 hours, trauma surgery, immunocompromised hosts, etc).  More and more the question posed to me has become: “Warren, my hospital requires me to use prophylactic antibiotics even when I don’t feel they are necessary.  They have actually threatened to take away my surgical privileges if I don’t use them.  What can I do about that?”  Unfortunately, the answer is…not much.

Why is this happening?  What has changed?  In my opinion there are two main reasons we have come to be in this situation. 1) The Surgical Care Improvement Project (SCIP) 2) Changes in CMS guidelines that will not reimburse a hospital for a re-admission for a nosocomial infection. 

Point #2 is fairly self explanatory.  Hospitals don’t get paid if a patient is readmitted with a diagnosis of a nosocomial post operative infection.  Therefore, they need to try everything in their power to prove that any infection that does occur is not their fault and they did everything possible to prevent that infection.  Chief amongst these is demanding prophylactic antibiotics be given to everyone undergoing surgery.  Then, when the patient gets infected they can always claim that the infection was community acquired and not nosocomial.   

Point #1, SCIP, may not be as well known by the average lower extremity surgeon and is a bit more complicated.  Back in 2005 a national initiative was developed to attempt to reduce post operative complication rates by 25% in a 5 year period.  A set if 20 measures were developed, 9 are publicly reportable, 6 of which focused specifically on postoperative infection prevention.  4 of these are directly relatable to lower extremity work.  These include:

1.  INF-1:  Patients need to receive prophylactic antibiotics within one hour prior to surgical incision or 2 hours if using vancomycin.

2.  INF-2: Patients receive prophylactic antibiotics recommended for their specific surgical procedure

3.  INF-3: Patients prophylactic antibiotics are discontinued within 24 hours after surgical end time

4.  INF-6: Surgery patients should have appropriate hair removal with a clippers or depilatory, if at all (no razors)

I think that all readers would agree that this is a lofty and worthy goal.  The program is “voluntary” although CMS reduces hospital reimbursement by 2% if they fail to report performance on the various measures.  Probably, for this reason, the participation rate is around 95% of all hospitals.  Now the bad news…IT MAY NOT BE WORKING! 

In the June 23, 2010 issue of the Journal of the American Medical Association, Stulberg and colleagues published a retrospective cohort analysis of over 400,000 patient discharges between 2006 and 2008 (PubMed Link: http://www.ncbi.nlm.nih.gov/pubmed?term=Stulberg%20JJ%20AND%20SCIP ).  They found that when the measures were taken all together in an “all or none” infection prevention score, there was a lower probability of developing a post operative infection.  However, adherence to any individual measure (such as the use of prophylactic antibiotics) was NOT associated with a significantly lower probability of infection.

There are some other interesting tidbits to take away from this study.  The category of “Neck, Back or Extremity Surgery” presented with the overall lowest rate of post operative infection at only 0.19%.  Also, in fairness, although not reaching a level of statistical significance, the use of prophy did decrease the overall risk of infection from 21.0 to 7.5 per 1000 discharges (unfortunately, this was not broken out by procedure type).  I would also point out that the SCIP protocols do not demand all patients receive antibiotics, just that the “recommended” antibiotic, according to nationally accepted guidelines, is given.  Somehow this seems to have been morphed into a requirement to administer them.

So what does this all mean to the lower extremity surgeon?  The risk of infection for our surgery remains very low, somewhere probably well below 1.0%.  In the largest study of its type, published in JFAS in 2004, Zgonis retrospectively looked at charts from 555 patients undergoing elective foot and ankle surgery and found no statistically significant difference in infection rate in the group that received prophy vs. those who did not (PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/15057856 ).  The bottom line is that prophylactic antibiotic use is probably not medically necessary in these patients.  Unfortunately, unless you are ready to really “battle City Hall”, from a practical standpoint you are going to continue to be coerced into using antibiotics you suspect are not beneficial. 

I find this all rather ironic.  In an environment where hospitals are being required (at the risk of the same possible decrease in reimbursement) to have Antimicrobial Stewardship programs to effectively decrease antibiotic usage, physicians are being told by those same administrations that they need to use antibiotics that are probably not necessary.

Post operative infection

 

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

New FDA Safety Communication on Linezolid and Psychiatric Medications

October 26th, 2011 by Warren S. Joseph DPM FIDSA
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One of the trickiest issues in prescribing linezolid for patients with MRSA or VRE infections is the potential for a drug-drug interaction, leading to serotonin syndrome (SS), with various serotonergic psychiatric medications.  It seems that every pharmacy computer system in the world goes crazy with warnings when you attempt to write for this antibiotic while the patient is on these meds.  The package insert for linezolid states that it is contraindicated to use linezolid in combination with SSRIs, tricyclic antidepressents, triptans, meperidine or buspirone “Unless patients are carefully observed for signs/or symptoms of serotonin syndrome…”

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

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

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

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

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Literature Update – Antimicrobial Agents and Chemotherapy, Sept, 2011

September 7th, 2011 by Warren S. Joseph DPM FIDSA
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As I have mentioned in a previous post there are a number of journals I follow to stay abreast of developments in the ID, microbiology and antibiotic world.  For updates on the latest in antibiotic development from pre-clinical through clinical testing no journal beats the American Society of Microbiology’s Antimicrobial Agents and Chemotherapy (http://asm.org/).  Just to give a taste of how relevant this publication can be to those of us treating lower extremity infections, in the current September 2011 issue of AAC there at least 5 papers that present useful information.  In this “Literature Update” I will list these manuscripts, give the PubMed link to their Abstracts, and give a summary of what the authors reported.

Richter SS, et.al. Activity of ceftaroline and epidemiologic trends in S. aureus isolates collected from 43 medical centers in the United States in 2009.   (http://www.ncbi.nlm.nih.gov/pubmed?term=Richter%20SS%20ceftaroline).  The authors looked at the results of a nationwide S. aureus surveillance program collecting clinical isolates from 43 medical centers throughout the US during 2009.  Hospitals each submitted 100 consecutive isolates to a reference laboratory for in depth testing including PCR to determine the exact strain and presence of absence of Panton-Valentine leukocidin (PVL) production along with microbroth dilution testing to determine susceptibility to a broad range of antibiotics.  4,210 isolates were tested. The so-called “Community associated” strains, genotype USA300 and USA100, constituted almost 40% of all isolates (MRSA and MSSA) with the USA300 being the most commonly found single strain of MRSA at 50.6% of isolates.  As one would expect it was, by far, the most commonly isolated from wound and abscess specimens and therefore continues to be the type of most importance to those of us treating the lower extremity.  Turning to the question of antibiotic susceptibility for the USA300 strains resistance rates were as follows: erythromycin, 90.9%; levofloxacin, 49.1%; clindamycin, 7.6%; tetracycline, 3.3%; trimethoprim/sulfa, 0.8%; daptomycin 0.4%; ceftaroline and linezolid, 0%. 

Wiskirchen DE, et.al. Determination of tissue penetration and pharmacokinetics of linezolid in patients with diabetic foot infection using in vivo microdialysis. (http://www.ncbi.nlm.nih.gov/pubmed/21709078).  I have been an unabashed fan of the work by David Nicolau and his Center for Anti-infective Research and Development at Hartford Hospital.  In particular, their work in the area of microdialysis (“micro-D”) to determine tissue penetration in both bone and soft tissue has been, in my mind, groundbreaking.  It is a standardized proven methodology for determining antibiotic levels in different tissues, something that has been sorely lacking.  In this paper they turn their catheters on to the study of linezolid levels in infected diabetic foot wounds.  The micro-D technique is described in detail in the paper but basically a catheter is inserted into the tissue in question and the catheters are continuously perfused with Lactated Ringer’s. Dialysate samples are then collected from the catheters and antibiotic levels are measured. In this study the catheters were placed in uninfected thigh tissue and within 10cm of the infected foot wound.  9 patients were evaluated.  The patients were brought to steady state on IV linezolid and serum samples were collected at the same time as catheter samples to compare the two.  Again, the results of this elegant study should be read in their entirety but the conclusion was that “…linezolid penetrated equally well into both healthy thigh tissue and infected wound tissue as demonstrated by the tissue penetration ratios (AUCtissue/AUCplasma) of 1.42 in thigh tissue and 1.27 in wound tissue.”   There was fairly wide variation between patients which is not at all surprising considering the normal differences we see in this population.  Interestingly, these numbers where higher than an earlier study done in normal volunteers.

Gomez J, et.al. Linezolid plus rifampin as a salvage therapy in prosthetic join infections treated without removing the implant. (http://www.ncbi.nlm.nih.gov/pubmed/21690277) In this study out of Spain the authors evaluated 161 hip and knee prosthetic joint infections which had failed on previous therapies (teicoplanin, ciprofloxacin or TMP/SMX with rifampin).  These patients were switched to linezolid plus rifampin, 600 mg po q12h plus 300 mg po q12h, without removing the implant.  Cultures were positive in 28 cases.  Interestingly, methicillin resistant S. epidermidis was found in 22 while MRSA was found in 6 cases.  The mean duration of therapy was 80.2 days (range 21-180).  At 2 years of follow-up the remission rate was 69.4%.  A large amount of purulent drainage at the initiation of the therapy was a predictor of failure.  3 patients developed thrombocytopenia and 3 developed anemia but the linezolid did not have to be discontinued in any of these cases.  This study, although perhaps not directly applicable to daily practice is worth reading for a number of reasons.  With all of the publicity given to MRSA we sometimes forget the role coagulase negative Staph can cause in prosthetic joint infections.  Also, there has been concern for giving prolonged courses of linezolid because of the risk for myelosuppression. As this, the linezolid package insert, and other studies have demonstrated it certainly can be an issue but it rarely causes a need for discontinuation of therapy.  Upon discontinuation the changes are reversible.  Finally, as I have discussed in a previous post, it is possible that rifampin should be considered as adjunctive therapy when treating bone and joint infections caused by resistant Staph.   

Usually fungal articles in AAC deal with systemic infections.  It is rather uncommon to find articles about tinea pedis and onychomycosis.  This month there were actually 2!  Both are brief reports.

Carrillo-Muñoz AJ, et.al. Sertaconazole nitrate shows fungicidal and fungistatic activities against T. rubrum, t. mentagrophytes and E. floccosum, causative agents of tinea pedis. (http://www.ncbi.nlm.nih.gov/pubmed/21746955) In this brief in vitro study 150 clinical isolates of dermatophytes were tested for fungicidal and fungistatic activity using sertaconazole (Ertaczo).  The testing showed fungicidal activity against all three organisms with better activity against T. rubrum and E. floccosum than against T. mentagrophytes.  According to the authors this result was important since, prior to this study; the only fungicidal data for this drug was limited to two strains of T. mentagrophytes.  Their conclusion was that, although the clinical advantage of fungicidal over fungistatic activity for tinea pedis products remains unclear, “these dual fungicidal and fungistatic activities of sertaconazole are consistent with its efficacy against tinea pedis in randomized, placebo-controlled clinical trials”.  

Krishna G, et.al. Determination of posaconazole levels in toenails of adults with onychomycosis following oral treatment with four regimens of posaconazole for 12 or 24 weeks.  (http://www.ncbi.nlm.nih.gov/pubmed/21746944)  In this pharmacokinetic data reporting from a phase 2 clinical trial, patients were treated with oral posaconazole (100, 200, 400mg) once daily for 24 weeks or 400 qd for 12 weeks.  Drug concentrations from both nail clippings and plasma were collected.  118 patients completed treatment. In the hallux posaconazole was detected as early as 2 weeks in the 200 and 400 mg dose groups.  The levels were dose related and continued to rise even after discontinuation of the drug.  Plasma levels reached steady state and stayed there, declining once the drug was stopped.  The authors opined that posaconazole remained high in the nail after treatment was discontinued “…probably because posaconazole accumulated in the nail matrix via systemic absorption during treatment.  As the nail plate grew out, posaconazole was incorporated into the nail plate moving away from the nail fold, where it persisited at the distal end of the nail plate.” You may now ask yourself “Why have I never heard about this drug?”  Posaconazole was being developed by Schering-Plough for possible oral use in onychomycosis.  SP was bought by Merck and priorities in drug portfolios change.  I am currently uncertain about the fate of this drug’s future development.

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“PSEUDOMONA-PHOBIA”

May 16th, 2011 by Warren S. Joseph DPM FIDSA
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For a number of years I have referred in my lectures to the word I have termed “Pseudomonaphobia”.  Basically, this is an irrational fear of the organism Pseudomonas aeruginosa (PA) when isolated from a culture of a wound in the foot.  I really believe that this arises in most Podiatrists during the residency interview process when, without fail they are asked by the interviewer “How would you treat a Pseudomonas infection in the foot?”  I remember being prepped for that question way back in 1981 when we were instructed that the correct response was “You use a combination of gentamicin and carbenicillin”.  Unfortunately, that was incorrect even back then since the more “current” schools were teaching their students to respond with a combination of tobramycin & ticarcillin, the so-called T&T therapy. (This may explain why I did not get my first choice of residency program!)  Fortunately, today the well prepared student should be able to recite about a dozen different, non-aminoglycoside options.  But, that is beside the point.  It really is a moot issue.  You see, despite the ability to readily culture the organism from lower extremity wounds, PA is RARELY a pathogen in lower extremity infections.   In fact, I would go as far as saying that about the only time PA should be empirically considered pathogenic is in a case of osteomyelitis following a puncture wound. 

Pseudomonas colonizing a heel wound

A number of randomized, controlled clinical trials have actually substantiated this viewpoint.  Most have looked at the clinical outcome of patients who grew PA from a wound/infection when treated empirically with an antibiotic that was ineffective against PA vs. one which had anti-pseudomonal activity. In this entry I will present 3 such trials.  

In 2002 Graham, et.al. published the results of the pivotal phase III trials comparing ertapenem to piperacillin/tazobactam for complicated skin and skin structure infections (PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/12015692).  Of these two antibiotics ertapenem has no inherent anti-PA activity while pip/tazo does.  Despite this difference in spectrum, the positive clinical response in patients growing PA was 70% for ertapenem and 60% for pip/tazo.  In a very similar trial comparing the same two antibiotics specifically for diabetic foot infection, Lipsky et. al. had similar outcomes with a positive clinical response in 76.9% of patients on ertapenem vs. 70% for pip/tazo. (The SIDESTEP trial http://www.ncbi.nlm.nih.gov/pubmed/16291062).  More recently, in September 2010, Corey, et. al.  published the results of the clinical trials on the new anti-MRSA cephalosporin ceftaroline .  This drug has no inherent anti-PA activity yet there was a positive clinical response in 80% of the patients from which the organism was isolated.   

None of these trials are meant to show that the study drug had some previously undiscovered anti-PA activity.  They just point to the role of PA as a notorious colonizer of lower extremity wounds/infections. Nannini stated it quite succinctly in his review paper of ceftaroline (http://www.ncbi.nlm.nih.gov/pubmed?term=nannini%20ceftaroline):

“The demonstration of efficacy in patients with P. aeruginosa receiving ceftaroline, a pathogen against which ceftaroline has little activity, most probably reflects the presumptive role of P. aeruginosa as a colonizer rather than a true pathogen in many of these infections.”

Please do not misinterpret me.  I am not saying that PA is always a colonizer and is never pathogenic.  If this bug is found from a reliable, deep surgical culture, consideration should be given to covering it. However, this is a ubiquitous organism that has been found in tap water and on plants and vegetables.  Just culturing it from a superficial wound swab will lead the clinician to treat an organism that can most likely be handled with thorough debridement and topical therapy, with an anti-PA antibiotic that may be unnecessary.  This may increase resistance of the organism against these antibiotics so that they are not available for the next time…when we may really need them.

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Bugs and Drugs 2011 (Slide Show)

May 3rd, 2011 by Warren S. Joseph DPM FIDSA
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With this entry onto the blog I am trying something new.  The IT team at Data Trace has been working on a way to post a PowerPoint slide show to the blog.  We believe it is now ready to go.  For this first PowerPoint, I am posting the lecture I gave at DFCON 2011 in Hollywood, CA back in late March.  The topic is “Bugs and Drugs 2011″.  As sometimes happens at that excellent meeting, I did not have enough time to go through the entire talk so, even back then, I offered to put the lecture up on my blog for viewing.  I hope you find the information on the slides interesting and informative.  If you have any questions about any content or see a subject on which you would like me to expound on this site, please let me know.

As always, comments on the site are welcomed.

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

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