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.

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!

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.

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.

As always, comments on the site are welcomed.

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

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

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

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

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

This comment came in under my entry on the VULCAN trial but I actually covered the question in a post almost exactly a year ago.  I am reprinting my response here for more recent readers who may not have reviewed all of the earlier posts I will also summarize my current thinking at the bottom:

The question of whether or not the patient needed to be off of all antibiotic therapy prior to the culture was always less clearly delineated.  It was almost an empirical belief that if a patient was on antibiotics at the time of the culture then the results would be unreliable.  After all, if a culture is reported as showing “no growth” was this because the specimen was poor, the patient never had osteomyelitis in the first place, or the antibiotics had prevented the organism from growing?

A recent study by Louis Bernard and colleagues out of University Hospital of Geneva Switzerland, and published in the September 6, 2009 issue of the International Journal of Infectious Diseases challenges much of what we currently hold as sacrosanct.  In this non-randomized, prospective trial 141 patient with 154 episodes of osteomyelitis each underwent 4 microbiological samplings.  Sample “A” consisted of 2 consecutive sinus tract cultures with bone contact (“A1” & “A2”) after only local cleansing of the sinus tract with 0.9% saline.  Sample “B” consisted of a surgical bone biopsy through the sinus.  Sample “C” was a surgical biopsy obtained through an uninfected sited, referred to as the “gold standard”.  Their results showed that when both sinus tract cultures “A1 & A2” revealed the same organism the concordance between “A” and gold standard “C” was 96%.  They calculated the sensitivity as 91%, specificity as 86% and accuracy as 90%.  On top of that, they found that the result was not affected depending on whether the patient was on antibiotics prior to the cultures or not.

In their Discussion the authors go out of their way to state that “in no way should these consecutive deep sinus tract specimens replace bone culture in situations where a biopsy can be readily obtained because bone culture remains the gold standard for the microbiological diagnosis of osteomyelitis”.  There are sometimes, however, when a surgical culture is just not practical and that patient has already been started on antibiotic therapy, as the authors call it “clinical reality”.

Since this original post, my thought process has not changed much.  I still believe that, if they have not yet been started, it is best to HOLD antibiotics if at all possible, until after the patient is taken to the OR for deep bone (or, for that matter, soft tissue) cultures. The “real world” gets involved, however, when you admit a patient through the Emergency Dept for the stated diagnosis of “infection” and do not plan on taking the pt to the OR until the next day. Unfortunately, in a case like this, you cannot realistically hold antibiotics or the hospital runs the risk of losing the admission.  If the patient is going to the OR later the same day then I believe in holding the drug unless the pt is sick i.e. metabolically unstable, systemically unwell or septic.

What if the patient has already been started on antibiotics?  Conventional wisdom still calls for the pt to be off antibiotics for at least 48 hours.  I don’t believe there is any evidence to support that thinking.  The Bernard study cited above does give us some hope that it doesn’t matter if the patient is still on antibiotics or not but I would still recommend, again if at all possible, taking the patient off the drugs for as long as it is feasible. Heck, I would go for a week if you can.  There is no magic to 48 hours.  The problem is that if the culture is negative, you don’t know whether it is negative because it is not osteo or if it is negative just because of the antibiotics.  Also, the International Working Group on the Diabetic Foot (www.iwgdf.org) has shown in their diabetic foot osteomyelitis guidelines that the only independent factor leading to a positive response to antibiotic therapy for osteo is bone culture directed antibiotic therapy.  We could really use those deep reliable cultures!

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.