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.

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)

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.

The more I read the infectious disease literature the more my diet becomes limited. It seems that new reports of contaminated food are published regularly.  It gets to a point where you don’t know what you should and should not eat!  I have always been wary of raw foods and rarely eat sushi especially after an article was published in Clinical Infectious Diseases a number of years ago complete with pictures of the worm coughed up by a patient who ate salmon sushi (I apologize for not being able to find the reference and to those of you who love to eat sushi, it’s just not for me). But even cooked foods I thought would be safe are suspect.  Take for example the report I read back in 1998 of a botulism outbreak from baked potatoes that were wrapped in foil. (PubMed: http://www.ncbi.nlm.nih.gov/pubmed?term=baked%20potato%20food%20poisoning ). More recently there has been the incredibly deadly Shiga toxin producing E. coli outbreak centered in Hamburg and Lubeck, Germany, the mystery fortunately solved one week before my wife and I visited both of those wonderful cities on vacation.  If these examples weren’t enough to cause consternation, consider two papers published in the July 15, 2011 issue of Journal of Infectious Diseases. This first is an Editorial Commentary by Daniel Bausch: Ebola virus as a foodborne pathogen? Cause for consideration, but not panic.   EBOLA VIRUS!!??  That deadly organisms from Africa that kills 90% of all whom it infects?  In food?  Fortunately, there really is no reason for panic.  The author discusses how a variant of the virus, known as the Reston EBOV, which is not known to be pathogenic in humans, has been found in pigs in the Philippines…but, still…

A second article in the same issue by Behravesh, et al; Deaths Associated with bacterial pathogens transmitted commonly through food, is an analysis of the Foodborne Diseases Active Surveillance Network (FoodNet). Fortunately, death from foodborne illness remains relatively rare, reported at just 0.5% of cases with most being in adults >65.  Salmonella and Listeria were the most common causes followed closely by Vibrio, which brings us to the following:

I have always been fascinated by infections caused by various Vibrio species found primarily in raw oysters.  Early in my ID career I attended the Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) one of the great antibiotic and microbiology meetings, when it was held in New Orleans in 1986.  3 years later a study was published by Lowry, et al, in Journal of Infectious Diseases which reported on Vibrio gastroenteritis in attendees of the meeting who ingested raw oysters (PubMed: http://www.ncbi.nlm.nih.gov/pubmed/2584764). The authors found that 12% of respondents reported diarrhea and the risk was significantly higher in those who ate raw or cooked oysters. Furthermore, they found that cultures of raw and cooked seafood at local restaurants yielded 5 different species of Vibrio!  Searching of PubMed reveals outbreaks of this type reported with oyster consumption from all over the world including different locales in the US.  Fortunately, I seem to remember the University of Louisiana did do a study and found that the use of Tabasco sauce was protective against infection (again, I apologize but I cannot find the reference either in my files or doing a PubMed search).

By this point, you may be wondering what any of this has to do with the lower extremity. Vibrio species, in particular V. vulnificus has the ability to cause rapidly progressive, frequently fatal necrotizing infections of the lower extremity in two ways.  First, direct inoculation of the organism into the soft tissues has been reported when marine water comes in contact with an open wound or if someone cuts themselves on a contaminated item in the marine environment (now, not only do I have to watch what I eat but I avoid swimming in the ocean too! ). But, the more common and deadly infection occurs after a patient ingests infected seafood and develops a Vibrio bacteremia and septicemia which then causes severe necrotizing skin and soft tissue infections.  A recent review by Horseman et al in the International Journal of Infectious Diseases (PubMed: http://www.ncbi.nlm.nih.gov/pubmed/21177133) reports a mortality rate exceeding 50%.  The authors opine that the antimicrobial regimen of choice is doxycycline combined with ceftazidime and aggressive surgical debridement.  Another study from just this year published by Tsai, et al in the American JBJS (PubMed: http://www.ncbi.nlm.nih.gov/pubmed/21266641) compares necrotizing infections by V. vulnificus and MRSA and finds the Vibrio infection progresses more rapidly and can be more deadly. They declare it to be a “surgical emergency”.

This case photograph was sent to me by Desmond Bell, DPM, CWS, a top podiatric wound authority and co-founder and Executive Director of the Save A Leg, Save a Life Foundation (SALSAL,  http://www.savealegsavealife.org/) I have known Des since his days as one of my students and have lectured a number of times at the SALSAL scientific meeting being held this year in Orlando October 27-30, 2011.  He received the photo courtesy of a colleague of his, Michael Baxley, MD.  The photograph shows a food wound in a patient who had developed Vibrio sepsis after ingesting oysters in coastal Alabama.  The patient fortunately survived the sepsis but now has skin wounds of varying severity on his hands, legs and feet.

Perhaps I should have written this post earlier in the summer season, before many of you went on vacation to the seashore…but then again, maybe not.

V. What is the management of MRSA bone and joint infections?

36. Surgical debridement and drainage of associated soft tissue abscesses is the mainstay of therapy and should be performed whenever feasible (A-II). A recommendation made with a high level of evidence that supports the common thinking that surgery is important when practical.  I added the “when practical” because of the increasingly strong body of evidence that supports “medical” or non surgical therapy of osteo.  That being said, those studies have not specifically looked at MRSA.  Whether or not surgery is any more important in MRSA osteomyelitis as compared to other organisms has not been established.

37. The optimal route of administration of antibiotic therapy has not been established. Parenteral, oral, or initial parenteral therapy followed by oral therapy may be used depending on individual patient circumstances (A-III). Much like I have lectured and written on in the past, the whole “6 weeks of IV therapy” thing has never been based in any good human evidence.  In fact, newer and stronger evidence points to alternative regimens like oral alone or short course parenteral followed by oral as effective. I am pleased to see this recognized in this document.

38. Antibiotics available for parenteral administration include IV vancomycin (B-II) and daptomycin 6 mg/kg/dose IV once daily (B-II). Some antibiotic options with parenteral and oral routes of administration include the following: TMP-SMX 4 mg/kg/dose (TMP component) twice daily in combination with rifampin 600 mg once daily (B-II), linezolid 600 mg twice daily (B-II), and clindamycin 600 mg every 8 h (B-III).

39. Some experts recommend the addition of rifampin 600 mg daily or 300–450 mg PO twice daily to the antibiotic chosen above (B-III). For patients with concurrent bacteremia, rifampin should be added after clearance of bacteremia. This is where I find it gets interesting.  Yes, I have known about the concept of adding rifampin to other antibiotics to treat MRSA (NEVER use it single agent.  Resistance develops rapidly) but I have never used it nor felt it was all that necessary. I am surprised to see it mentioned numerous times in this document.  It is listed not only here but also in the “osteoarticular device” related infection section.  Notice the level B-III rating.  This means “moderate level of evidence and a recommendation based on expert opinion, clinical experience…” not randomized controlled trials.  In fact, if you look at the “evidence summary” section that covers rifampin, I remain not terribly convinced. I will have to see if I start incorporating it into my treatment.

40. The optimal duration of therapy for MRSA osteomyelitis is unknown. A minimum 8-week course is recommended (A-II). Some experts suggest an additional 1–3 months (and possibly longer for chronic infection or if debridement is not performed) of oral rifampin-based combination therapy with

TMP-SMX, doxycycline-minocycline, clindamycin, or a fluoroquinolone, chosen on the basis of susceptibilities (C-III). Again, rifampin is added to oral regimens.  This recommendation contains even a lower evidence rating of “C” meaning “poor evidence to support a recommendation”

41. Magnetic resonance imaging (MRI) with gadolinium is the imaging modality of choice, particularly for detection of early osteomyelitis and associated soft-tissue disease (A-II). Erythrocyte sedimentation rate (ESR) and/or C-reactive protein (CRP) level may be helpful to guide response to therapy.  Nothing particularly remarkable here.  I left it in for completeness sake.

VIII. What are the recommendations for vancomycin dosing and monitoring?

These recommendations are based on a consensus statement of the American Society of Health-System Pharmacists, the IDSA, and The Society of Infectious Diseases Pharmacists on guidelines for vancomycin dosing [3, 4].  You can read my earlier post to see what I think about THOSE guidelines!! Recommendations 60-63 drive me crazy.  There is essentially NO good evidence to support bumping vancomycin dose/levels that high.  The concept is based on a pharmacokinetic parameter called an AUC/MIC ratio.  I do not doubt that this is a valid measure. What concerns me is that many pharmacists and IDs have taken this to heart and are significantly increasing vancomycin doses and maintaining troughs of 15-20 despite little evidence of increased efficacy and, IMHO good evidence of increased renal toxicity.  In fact, I personally know of a case of acute renal failure occurring in a diabetic foot infection (no, I did not treat it).  This may be OK in bacteremia and pneumonia but I am not at all comfortable with these recommendations in our diabetic patients, probably with preexisting renal problems.  I will “split the difference”.  I AM OK with keeping the trough between 10-15.  SEE RECOMMENDATION 64…

60. IV vancomycin 15–20 mg/kg/dose (actual body weight) every 8–12 h, not to exceed 2 g per dose, is recommended in patients with normal renal function (B-III). 

61. In seriously ill patients (eg, those with sepsis, meningitis, pneumonia, or infective endocarditis) with suspected MRSA infection, a loading dose of 25–30 mg/kg (actual body weight) may be considered. (Given the risk of red man syndrome and possible anaphylaxis associated with large doses of vancomycin, one should consider prolonging the infusion time to 2 h and use of an antihistamine prior to administration of the loading dose.) (C-III)

62. Trough vancomycin concentrations are the most accurate and practical method to guide vancomycin dosing (B-II). Serum trough concentrations should be obtained at steady state conditions, prior to the fourth or fifth dose. Monitoring of peak vancomycin concentrations is not recommended (B-II). Note the “4^th or 5^th dose” recommendation.  Do not rush to draw a level before that time as many do.

63. For serious infections, such as bacteremia, infective endocarditis, osteomyelitis, meningitis, pneumonia, and severe SSTI (eg, necrotizing fasciitis) due to MRSA, vancomycin trough concentrations of 15–20 lg/mL are recommended (B-II). I don’t know why “osteomyelitis” is frequently put in the same category as necrotizing fasciitis.  There are so many varieties of osteo in so many locations; I can’t just classify it this way.  I do not bump my vanco doses/levels for osteo just because it is osteo.

64. For most patients with SSTI who have normal renal function and are not obese, traditional doses of 1 g every 12 h are adequate, and trough monitoring is not required (B-II). THANK YOU, THANK YOU, THANK YOU!!!! Finally, some sense in this vanco dosing madness. That being said, if you look at Table 3, they do NOT repeat this. They go back to the “party line” dosing. 

65. Trough vancomycin monitoring is recommended for serious infections and patients who are morbidly obese, have renal dysfunction (including those receiving dialysis), or have fluctuating volumes of distribution (A-II).

Here is my bottom line about the dosing of vancomycin:  If we really need to bump doses this high, I would say it may be time to forget using vancomycin and start using some of the alternative drugs like linezolid, daptomycin, ceftaroline or telavancin. Vancomycin is not some miracle drug we need to keep as first line therapy and not replace.  There are currently 6 antibiotics FDA approved for cSSTI caused by MRSA.  What are we saving them for?  

I welcome your comments about these new IDSA MRSA guidelines

Overall, this is an excellent piece of work and kudos goes out to lead author Dr. Catherine Liu of UCSF and the committee.  Sitting on an IDSA Guidelines committee, I understand the process.  It could not have been easy to come to consensus particularly in an area of ID that is changing so rapidly and where there is the potential for so much controversy.

Although much of the document pertains to infections other than skin/skin structure and bone/joint I still feel it is important to list those points from the Executive Summary which could have direct impact on a lower extremity infection practice.  With all of the new IDSA Guidelines the required format is “Question, Answer, Evidence Summary”.  I will pick out parts of those that apply to our practice and would ask you please read the entire document for the complete picture.  As you would expect, I will not resist adding my 2 cents! My comments will appear in italics

Question I:  What is the management of skin and soft tissue infections in the era of community-associated MRSA?

1. For a cutaneous abscess I&D is the primary treatment.  For simple abscesses or boils I&D alone is likely to be adequate. I have covered this subject in the past.  The treatment of a CA-MRSA simple (usually defined as <5 cm in diameter) abscess is I&D.  There is essentially no evidence that adjunctive antibiotics are warranted.

2. Antibiotic therapy is recommended for abscesses associated with antibiotic therapy is recommended for abscesses associated with the following conditions: severe or extensive disease (eg, involving multiple sites of infection) or rapid progression in presence of associated cellulitis, signs and symptoms of systemic illness, associated comorbidities or immunosuppression, extremes of age, abscess in an area difficult to drain (eg, face, hand, and genitalia), associated septic phlebitis, and lack of response to incision and drainage alone. This point is valuable in that it actually spells out those conditions where antibiotics should be considered adjunctive to the I&D

3. For outpatients with purulent cellulitis (eg, cellulitis associated with purulent drainage or exudate in the absence of a drainable abscess), empirical therapy for CA-MRSA is recommended pending culture results. Empirical therapy for infection due to beta-hemolytic streptococci is likely to be unnecessary. Five to 10 days of therapy is recommended but should be individualized on the basis of the patient’s clinical response. This is an interesting point in it differentiates “purulent” cellulitis from “nonpurulent” cellulitis (see next point).  Frankly, I am not certain that I have seen that in the past.  Most of what we are seeing in the lower extremity is the purulent variety but, as I write this, I have a patient in the hospital with venous insufficiency and a significant cellulitis of her leg, but with no pus.  Sure enough, cultures of the clear drainage just this morning grew Group B, beta-hemolytic Strep.  (See picture below)

4. For outpatients with nonpurulent cellulitis (eg, cellulitis with no purulent drainage or exudate and no associated abscess), empirical therapy for infection due to b-hemolytic streptococci is recommended. The role of CA-MRSA is unknown. For the patient I just mentioned above, she had been started empirically on vancomycin from the ED, she did not improve to my satisfaction so we added piperacillin/tazobactam and had remarkable improvement within 24 hours. I stopped the vanco. 

5. For empirical coverage of CA-MRSA in outpatients with SSTI, oral antibiotic options include the following: clindamycin, trimethoprim-sulfamethoxazole (TMP-SMX), a tetracycline (doxycycline or minocycline), and linezolid. If coverage for both beta-hemolytic streptococci and CA-MRSA is desired, options include the following: clindamycin alone or TMP-SMX or a tetracycline in combination with a beta-lactam (eg, amoxicillin) or linezolid alone. This point really just lists the oral antibiotic choices we knew we had all along.  I would direct you to the documents “evidence summary” to see how little actual data there is backing any of this though.  Furthermore, I am not as enamored with TMP/SMX as the recommendations in these Guidelines and tend to prefer using doxycycline or minocycline.

6. The use of rifampin as a single agent or as adjunctive therapy for the treatment of SSTI is not recommended. I agree and do not use rifampin.  As you will see in the osteomyelitis and prosthetic joint section these guidelines are very “pro” rifampin despite what I feel is a lack of any significant evidence.

7. For hospitalized patients with complicated SSTI (cSSTI; defined as patients with deeper soft-tissue infections, surgical/traumatic wound infection, major abscesses, cellulitis, and infected ulcers and burns), in addition to surgical debridement and broad-spectrum antibiotics, empirical therapy for MRSA should be considered pending culture data. This point it BIG!  They are recommending pretty much ALL patients admitted with cSSTI, which would translate into almost all admitted patients, be started on anti-MRSA therapy.  There is no leeway given for local/regional variations in incidence.  Sure, most of us have been doing this but, frankly, in the past 6 months to a year, most of our admitted patients are NOT growing MRSA at this point.  I have actually started going back to escalation (no MRSA empiric coverage) therapy in some cases. 

Given the importance of this document I would rather break down the discussion into shorter, hopefully more easily digestible portions.  Above I covered the first section on Skin and skin structure infections.  I also want to comment on the bone and joint recommendations which include osteomyelitis, septic arthritis and implant related infections along with my favorite part (see my previous postings on the topic) the recommendations for vancomycin dosing and monitoring.  Stay tuned…

Non-purulent cellulitis casued by Group B beta-hemolytic strep, not MRSA

My question is: Does one need to prescribe antibiotics after I+Ding an abscess? I use to work at a county hospital in Oakland, California  where there was a high MRSA rate. At that time (2005), we were being taught not it is unneccessary to prescribe antibiotics after I+Ding an abscess, other than to practice defensive medicine. But, is it necessary to prescribe antibiotic in your opinion after an abscess I+D? I am talking about a classic abscess, not a cellulitis of any form.

This is an excellent question that allows me to go off in two directions.  First, to directly answer Dr. McLeod’s question, NO, the evidence is fairly strong that I&D of an abscess of <5cm in diameter without concomitant antibiotic therapy is considered adequate and appropriate therapy for an MRSA abscess.  For one of the first studies that really showed this, and the one that was probably quoted by the folks with whom you worked in 2005, I direct you to the 2004 paper by Lee et.al in the Pediatric Infectious Disease Journal (PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/14872177)

The 2^nd direction or “tangent” I want to explore with this entry has more to do with the follow up of this type of patient, or for that matter any infection patient.  The question is “How long do you need to continue antibiotic therapy?”

A few years ago I was sitting in on a lecture at the annual meeting of the Infectious Diseases Society of America.  Unfortunately, I can’t remember the speaker in order to give appropriate credit but what has stuck with me ever since is the concept he proposed: Why do we continue to routinely give 10-14 day prescriptions of antibiotics when the infection may be clinically cured in 2-3 days? Rather we should consider the concept of giving the patient antibiotics until clinically better and then for only another 2-3 days an idea that can be called “Better Plus 2”. 

Think about this…you automatically give someone a 7, 10, 14 day Rx for an antibiotic.  What do you tell them as you hand them the script?  “Make sure you take it until it is all finished”.  Heck, it even says it right on the bottle the patient receives from the pharmacy!  WHY?  Because we have been taught that is the way to prevent resistance development. Now, let’s look at the patient proposed by Dr. McLeod above.  You I&D that abscess AND give antibiotics for 10 days solely because this is what you have been taught or you want to practice defensive medicine, or whatever reason.  You see the patient back on Day 3 and the wound looks great.  The abscess and any surrounding cellulitis are gone BUT the patient still has 7 days of antibiotic to go; an antibiotic that is not medically necessary because the patient is clinically cured.  Think about it; how do we develop antibiotic resistance?  By giving an antibiotic when it isn’t necessary!  Is this a greater risk than stopping the antibiotic too early, I would venture an opinion that, yes, it is.

As you know from reading my posts, I am a believer in backing up what I write about with literature/science. Before writing this entry I tried to find some substantiation for this concept in the literature.  On my cursory PubMed search nothing came up. It may or may not be out there and I just could not find it.  If anyone is familiar with support for this concept please let me know. It is just one of those ideas that make perfect sense to me.  There is nothing of which I am aware supporting the routine use of 10-14 days of antibiotics, at least in skin and skin structure infections, so why should Better Plus 2 be any less valid or legitimate? I wanted to throw this out for you to ponder the next time you write that rote duration on your antibiotic Rx.

The whole idea of this blog is to be interactive.  I want to hear others’ thoughts and ideas!  This is what will make it intellectually stimulating and fun for me and, hopefully, valuable to those monitoring the site

To this end I would like to start a “What Would You Do?” entry.  I will ask a clinical question or two, maybe present a case, and ask you for feedback on what you would do in this situation.  Give me your thought processes that lead you to your position.  Then, in a subsequent post I will review the responses and give you my approach along with any pertinent clinical evidence I have to back it up.

Let’s start with this; a recent very well done study was published on dental procedures and prosthetic joint infections (I will not give you the reference yet. That will hold until the answers come in) that may alter the way we look at antibiotic prohylaxis in these situations.  So, here are the questions/clinical scenarios I have for you:

1.  You placed a prosthetic joint into a patient’s foot.  Or, let’s even expand it out since there aren’t as many joints being placed anymore, you placed some hardware into a patient’s foot while doing surgery on that foot.  Let’s say the surgery was 18 months ago.  The patient calls you because she is going to the dentist for some dental hygiene and to have a crown placed on a tooth.  DO YOU, OR DON’T YOU, RECOMMEND ANTIBIOTIC PROPHYLAXIS FOR THIS PATIENT BEFORE THE DENTAL WORK?

2.  A patient comes to see you for the chief complaint of a bunion.  You discuss surgical correction.  After the patient agrees to have the surgery scheduled she informs you that she had a prosthetic knee implanted 18 months ago.  DO YOU PLACE THE PATIENT ON PROPHYLACTIC ANTIBIOTICS TO PREVENT A PROSTHETIC JOINT INFECTION FOLLOWING YOUR FOOT SURGERY?

OK, have at it.  There are really no right or wrong answers (or, maybe there are…it depends on the answers I get).  Once I receive some input I will give you my thoughts on the subject and give a summary of this recent study to which I referred above.

Ceftaroline now becomes the 6^th antibiotic FDA approved for the treatment of cSSSI caused by MRSA.  It is the first cephalosporin with this indication which is both good and bad.  It is good because it seems to have a typical cephalosporin safety profile, which is to say, very safe with only a few adverse events noted in the trials and nothing untoward was found.  Most clinicians are really comfortable with this class of antibiotic.  It is also broad spectrum including gram negatives but without Pseudomonas.  Most of the other anti-MRSA drugs, with the exception of tigecycline, are pretty limited to gram positive cocci.  The downside is that cephalosporins are not the “golden child” they once were.  I know that my personal use has declined significantly.  The greatest problem is that these drugs can lead to an increasing incidence of some of the new multi drug resistant gram negative rods including E. coli, P. mirablis and Klebsiella that produce “extended spectrum beta-lactamase” (ESBL) or Klebsiella pneumonae carbapenemase (KPC).  Although usually found in sick patients in the ICU, I have started to see these cropping up in lower extremity infections.  Heck, even Katie Couric did a piece on these new “Superbugs” on her evening news show.

The bottom line is that ceftaroline (Teflaro) should be a welcome new addition to treat mixed infections including those containing MRSA.  Where it will pan out to treat lower extremity infections, and in particular DFI, and the attention Forest pays to those of us treating these infections, remains up in the air.

While all of the hoopla surrounded ceftobiprole, another drug was pretty quietly making its way through the clinical trial process; ceftaroline.  Ceftaroline is being developed by Cerexa Inc., a wholly owned subsidiary of New York’s Forest Pharmaceuticals under license from Takeda in Japan.  This month has proven to be an important one for this antibiotic.  In the September 15 issue of Clinical Infectious Diseases the results of their cSSSI trial, named the CANVAS study have been published (PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/20695801) and on September 8, the Anti-infective Drug Advisory Panel of the FDA gave the drug a very positive endorsement for 2 indications including cSSSI.

The CANVAS trials were two identical, phase 3, international, multicenter, randomized, double blind studies which compared IV ceftaroline (600mg q12h) to the combination of vancomycin + aztreonam for cSSSI.  Inclusion criteria pretty much followed the FDA’s Guidance for cSSSI.  Unfortunately, diabetic foot ulcers were excluded! That being said, almost a full 50% of all infections in both groups occurred in the lower extremity.  (NOTE to Cerexa…how about a diabetic foot infection trial? We desperately need more drugs with that indication!)  1378 patients received study drug with 693 in the ceftaroline group and 685 in the comparator with demographics being similar in both. As expected, S. aureus was the most common pathogen with MRSA found in 40% of the ceftaroline group and 34% of the comparator group.

I would direct the reader to the full paper for all of the different efficacy measures.  Suffice it to say that results were similar in all measured endpoints including the clinically evaluable group (91.6% ceftaroline vs. 92.7% comparator) as were the rates of adverse reactions and discontinuations, all really pretty low, in the single digits.   One other point of interest is that although ceftaroline is not effective, in vitro, against Pseudomonas aeruginosa, the clinical cure rates when this organism was found in combination with others was still very high.  Again, this brings up the issue I have addressed many times, as to the relative lack of importance of this bug as a primary pathogen.

As for the news about the FDA, a press release put out by the company and found from many sources, including Medscape reported that the Advisory Panel enthusiastically and unanimously voted (18-0 for the cSSSI indication) to support the drugs application for approval.  It has frequently been repeated that the FDA itself does not have to follow the Panel’s recommendation but it almost always does.  Especially when it was as positive as this.  The bottom line is that I think we will see a new option for the IV treatment of cSSSI caused by mixed infections including MRSA in the next few months.  It will be interesting to see the impact this has on the marketplace since many people have a very high comfort level with cephalosporins.  Furthermore, this drug can be used for mixed gram positive and gram negative infections.  One major downside is the obvious lack of coverage of ESBL and KPC producing gram negatives.  These are becoming an issue in cSSSI.

Reference:

Corey GR, Wilcox M, Talbot GH, Friedland HD, Baculik T, Witherell GW, Critchley I, Das AF, Thye D. Integrated analysis of CANVAS 1 and 2: phase 3, multicenter, randomized, double-blind studies to evaluate the safety and efficacy of ceftaroline versus vancomycin plus aztreonam in complicated skin and skin-structure infection. Clin Infect Dis. 2010 Sep 15;51(6):641-50.