Instead of a formal literature review, I just wanted to post a quick clinical comment on something that came up with a patient I saw on consultation in the hospital about 2 weeks ago.  This 91 y/o female nursing home resident was admitted with a diagnosis of “cellulitis”  of the right foot (of course much of this “cellulitis” resolved with elevation of the leg making it more PAD, than infection, but that is a topic for another time).  As is common practice by some services in our hospital she was started on piperacillin/tazobactam 3.375g q6h and vancomycin 1g q12h. 

When I saw the patient the next morning I noticed that her serum creatinine was 0.9.  I was with a resident and I mentioned to him “Now, this is a problem”.  His response was “How come?  It is totally within normal limits?” You see where I am going with this…you CANNOT depend on the serum creatinine to determine renal function especially in an elderly patient.   Although, I know there are newer, more sophisticated techniques that have been developed, the determination of creatinine clearance using the Cockcroft and Gault equation is an easy and handy way to determine the patient’s renal function for the purpose of antibiotic dosing.  I know it is not easy to remember the equation.  Most practitioners I ask can give me the “(140 – age)” part but that is about it.  Just to refresh memories:

(140-age) x Wt(kg) / 72 x serum Creat all (x 0.85) for a female

I know it is not the easiest thing to remember.  The good news is that…don’t worry, there’s an app for that!  It doesn’t matter if you are on iPhone or Droid you can download a free application, usually bundled with multiple other medical calculators, which makes it easy to just plug in the appropriate numbers.  If you don’t happen to have a smartphone handy, just go to a computer at the nursing station and Google “Cockcroft gault equation” and you will end up with about 31,000 results. Don’t bother fishing through, I like the very first one. 

Back to this patient.  She only weighed 110 lbs.  Upon plugging in the numbers we found her Creatinine clearance to be about 30.  This means she was receiving too much antibiotic.  I changed her pip/tazo to the renal dose of 2.25g g6h, held the vancomycin and ordered it to be restarted after 24 hrs at 750mg q24h.  (In a case like this, linezolid which does not have to be adjusted for renal insufficiency would have been an excellent alternative).

The bottom line of this brief anecdote is to just remind you that, when dosing antibiotics cleared through the kidney, you should be determining creat clearance and not just depending on the serum creatinine.  You may be surprised at the result.

It is a rare study I read that makes me want to literally stop everything else I am doing and write a blog post about it.  It is a dreary, gray Sunday morning and I was just catching up on some backlogged journal reading when I picked up the August 2010 issue of Antimicrobial Agents and Chemotherapy.  I came across a paper out of the University of Antioquia in Medellin, Columbia by Omar Vesga and colleagues entitled “Generic Vancomycin Products Fail in vivo despite Being Pharmaceutical Equivalents of the Innovator” (PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/20547818) .  Regular readers of this blog and the Handbook, and those who have attended my lectures, know that I have not been particularly kind to vancomycin given significant failure rates reported in numerous studies. This study might explain why there are so many failures.

Vancomycin was first developed by Eli Lilly after it was discovered as a fermentation product of Amycolatopsis orientalis found in a sample of dirt sent to Lilly from Borneo in 1955.  Early formulations had significant impurities which, along with lending the product a brown color, hence leading to its’ early moniker “Mississippi Mud”, also was felt to lead to significant adverse events.  Lilly eventually found ways to highly purify the product to the relatively safe drug we know today.  Apparently, those extra steps were kept secret until they were finally sold as recently as 2005.  I clearly remember a Lilly sales rep calling on me 20 some years ago when the drug first went generic.  He pulled out a vial of the newly generic vancomycin and it was sandy brown in color.  He then pulled out a vial of the brand named Vancocin and it was, indeed, Lilly white…pun intended.  His point was simply, “Doc, which would you rather have going into your patients’ vein?”  Of course, hospital formularies being the way they were/are we really did not have a choice as to which we wanted to use. 

Back to the Vesga study: The investigators studied 3 generic versions of vancomycin vs. the “innovator” product to determine concentrations and clinical efficacy via numerous techniques both in vitro and in an in vivo mouse model.  In my opinion this was an elegantly designed, complex study which used multiple techniques including time-kill curves (TKC), broth microdilution and a neutropenic mouse thigh infection model, along with others, while using different strains of S. aureus.  Their findings were fascinating!  To directly quote the Abstract:

 “Vancomycin generics were virtually undistinguishable from the innovator based on concentrations and potency, protein binding, in vitro antibacterial effect determined by minimal inhibitory or bactericidal concentration and TKC, and serum pharmacokinetics.  Despite such similarities, all generic products failed in vivo to kill S. aureus while the innovator displayed the expected bactericidal efficacy…” (Emphasis added) 

The authors conclude that the current standard of “pharmaceutical equivalence predicting therapeutic equivalence” is not true, at least for vancomycin.  They make it clear that they are not claiming that the tested generics were in any way poor quality.  They certainly met all of the current regulations governing the necessary equivalence to make it to the market.  But this study raises a number of questions:  Is this finding of pharmacologic equivalence not equaling clinical efficacy unique to vancomycin or could it be a factor in other generic antibiotics?  Could the universal use of generic vancomycin in hospital pharmacies account for the increasing clinical failures being seen not only in clinical trials but everyday practice?

Those of you who have read my chapter on MRSA in the 3^rd Edition of the Handbook of Lower Extremity Infections (haven’t you all by now?!) or listened to me lecture about MRSA know that I am less than happy with what I perceive to be the overuse of trimethoprim/sulfamethoxazole (TMP/SMX, Bactrim® or Septra®) used empirically against this bug.  It seems to be first line therapy by just about every Emergency Department, Urgent Care, Primary Physician or anyone else treating skin and skin structure infections. My primary objections, spelled out in detail on pages 332-333 of the book, are based on published reports of adverse events when using this drug.  It is not benign when used in the dosages and durations that may be needed to treat CA-MRSA.  In particular, I have concerns with allergies, renal problems, neurological AEs and drug-drug interactions.  Well, a brand new paper just published in the June 28, 2010 issue of Archives of Internal Medicine by Antoniou, Gomes, Juurlink, et. al. entitled Trimethoprim-Sulfamethoxazole Induced Hyperkalemia in Patients Receiving Inhibitors of the Renin-Angiotensin System gives one more reason for concern.

(Link to PubMed Abstract: http://www.ncbi.nlm.nih.gov/pubmed/20585070) 

This was a population based, nested control study of a population >66 year olds who were receiving Angiotensin Converting Enzyme Inhibitors and various antibiotics.  The numbers were impressive.  This was a 14 year study with 4148 identified admissions involving hyperkalemia.  To quote the Conclusions, it was found that “Compared with amoxicillin, the use of TMP/SMX was associated with a nearly 7 fold increased risk of hyperkalemia-associated hospitalization.  No such risk was found with the use of comparator antibiotics”.

I still believe that if you have a mild CA-MRSA infection or are considering a “step down” from either vancomycin or linezolid, then doxycycline or minocycline is frequently preferable over TMP/SMX for therapy. Sure, I have used TMP/SMX in some cases.  One of the more recent that comes to mind was a patient with CA-MRSA plus Stenotrophomonas maltophilia.  Using TMP/SMX gave me a single agent I could use to cover both bugs.  I don’t want to “trash” TMP/SMX but given all of the data out there on potential problems with it, I would encourage you to chose it with a full understanding of the issues surrounding it and not just because you see others prescribing it so freely and randomly.

There is a small group of us that, when we find an interesting article dealing with infections, we pass them on so we can all be stay up to date.  Some of the journals are fairly obscure and are not in my usual monthly reading so I find this a great way to read articles I wouldn’t normally come across.  Below are three such recent papers, all either still ePub ahead of print or recently published about which I find interesting enough to say a few words.

McCarthy NL, et al.  Health care-associated and community associated MRSA infections: A comparison of Definitions.  American Journal of Infection Control, 2010:  This retrospective chart review attempts to determine risk factors for CA-MRSA and HA-MRSA based on two commonly used definitions; the epidemiology of the infection and the phenotypic antibiotic sensitivity without looking at the genotype (i.e. looking for the SCCmecIV gene to determine a USA300 strain).  Not surprisingly, to quote their Conclusion from the Abstract “We found few differences between CA- and HA-MRSA infections regardless of how health care association was found. We believe that the migration of CA-MRSA into health care settings and the recent increasing antibiotic resistance of CA-MRSA strains contribute to the lack of factors associated with HA (vs CA) MRSA.”  One finding I did think was particularly relevant was that CA-MRSA accounted for the overwhelming majority of skin and soft tissue infections (p <.0001).

For the past year or two I have been lecturing and writing that the use of classic “risk factors” to determine HA vs CA was a technique of the past. This was recently driven home to me when I saw 3 patients in the hospital with MSSA, 2 of whom were 80+ years old and lived in long term care facilities while I had a perfectly healthy 30 something with no pertinent medical history whatsoever present with a CA-MRSA.  I still continue to use the phenotypic method of looking at antibiotic susceptibilities, particularly toward Bactrim and tetracyclines since we have not seen much CA-MRSA resistance to these drugs at our facility.  It is becoming clearer that perhaps we will need to do the genetic typing, such as the TEM-PCR I discussed in a recent post to really know what we have.  Of course, it may be a moot point in skin and skin structure infections since, as validated by this report, I don’t remember seeing an HA-MRSA in over 2 years.

Nagoba BS et al. A Simple and effective approach for the treatment of diabetic foot ulcers with different Wagner grades.  International Wound Journal, April 23, 2010:  This is a retrospective case series from India that collected data from 1998 into 2009.  They looked at the application of a 3% citric acid gel preparation onto 115 diabetic foot ulcerations of various Wagner classification severities up to, and not including grades IV and V.  Of interest to me was that they took cultures of all of the wounds and performed broth dilution sensitivities of all the organisms against the citric acid.  They found that in grade I-II ulcerations they had 94%+ healing in 5-34 applications.  They also found that in deeper wounds there was marked decrease in slough and drainage with increases in healthy granulation.  They concluded that citric acid was safe and maybe even promoted granulation tissue while killing the bacteria found on the wounds.   

I find various problems with the design of this study and am not reporting it because I consider it an earth shattering breakthrough.  Rather, I bring it to your attention because, currently, one of the “Holy Grails” of wound healing is to find an safe, effective, affordable topical antimicrobial to, perhaps, assist in wound healing.  Heck, I am still not even convinced that bioburden reduction is all that many claim it is, as I have blogged before, however, we are all programmed to kill bacteria on a wound and maybe this is an option.  It should probably at least be looked at in more detail.

Traunmuller F, et al. Linezolid concentrations in infected soft tissue and bone following repetitive doses in diabetic patients with bacterial foot infections.  International Journal of Antimicrobial Agents, 2010:  This study assayed fluid from interstitial spaced, inflamed subcutaneous adipose tissue and metatarsal bone from patients with inflamed diabetic foot infections who were at steady state condition after 600 mg twice daily dosing of linezolid.  What they found was not particularly surprising; in all tissues linezolid penetrated to a level that was similar, if not slightly higher than what was found in plasma.  To quote their Abstract “We conclude that linezolid administered at 600 mg twice daily may be considered an effective treatment in diabetic patients suffering from bacterial foot infections complicated by osteomyelitis”. 

We all know that linezolid is not FDA indicated for the treatment of osteomyelitis.  In fact, NO antibiotic marketed in the past 10-12 years has been indicated for osteo, not because they don’t work but because the FDA has not developed “Guidance for Industry” on how to perform an osteomyelitis study.  I have also never been a believer in the concept of “bone penetration” as being an important indicator of osteo efficacy.  They techniques have never been standardized and really, to my mind, penetration numbers mean nothing. That all being said, at least this paper gives those of you who remain stuck on the concept of bone penetration evidence that linezolid does get into, not only bone but also frankly infected diabetic foot tissues.  This is not unlike data published by Gary Stein, PharmD and recently reviewed in the Jan/Feb 2010 issue of the Journal of the American Podiatric Medical Association (Nicolau DP, Stein GE. Therapeutic options for diabetic foot infections: A review with an emphasis on tissue penetration characteristics)

I will be in Columbus, OH for the Region IV (Ohio) meeting to lecture on June 3, 2010.  I have been given the “Learning Lunch” spot from 12:00 to 1:30 and plan on covering a broad range of lower extremity infectious diseases topics including MRSA, antibiotic therapy for osteomyelitis and diabetic foot infections.

Prior to my session, I will be in the Exhibit Hall from 9:30 – 11:30 at the Data Trace Booth to sign copies of the Handbook, talk about this blog and just answer questions anyone might have about treating infections.

I hope to see folks there!

I just returned from a lecture trip to Turkey where I had the privilege of giving 5 talks, one in the Mediterranean resort city of Antalya at a nationwide Hospital Infection Congress and 4 to the faculties at various medical universities throughout the country. Before getting into details about specifics dealing with lower extremity infections I first wanted to say that, if you have never visited, and this was my first time, Turkey is an unbelievable country with warm, welcoming people, incredible history, scenery and great food.   Istanbul, a bustling metropolis of over 12 million people, has to be one of the great cities of Europe. 

A Diabetic Foot Infection in Malatya, Turkey

In preparation for my talks I was asked to concentrate on the importance of a team approach to amputation prevention. Having just returned from DFCON I was up to date with the latest published data and reports from around the world about the successes that true amputation prevention teams have achieved in reducing the rates of “major” amputation. I have always found it amazing, if not a bit troubling, that smaller, less developed nations can codify a network of diabetic foot centers throughout their countries more than we have accomplished here in the United States. Even Pakistan and Kosovo, as discussed at this year’s DFCON, are able to reduce amputation rates by starting these centers. Turkey has made some progress towards the goal of developing amputation prevention teams.  Just last year Yesil, et al from Dokuz Eylul University Medical Center in Izmir (a facility, unfortunately, I did not have a chance to visit) reported a reduction of major amputations after starting such a team. (Yesil S. et.al. Exp Clin Endocrinol Diabetes, 2009).  In Istanbul I was honored to meet Dr. N. Saltoglu at Cerrahpasa Medical School, Istanbul University, when I gave one of my lectures to their Infectious Diseases faculty.  Dr. Saltoglu has just recently started a multidisciplinary diabetic foot team at this large institution of >1800 beds.  They are already beginning to see positive outcomes. 

During my trip I also lectured to the infectious disease faculties at Universities in the cities of Malatya and Kayseri both in the Eastern Provinces of the country.  They were very interested in the concept of starting comprehensive diabetic foot teams but were stymied by much the same turf battles and, dare I say, ego issues that we find here in the US.  Patients are treated by their local primary physicians for protracted periods before being sent to the hospital specialists.  Once admitted they are shuttled between various services including endocrinology, vascular surgery, orthopedic surgery and internal medicine with each passing the patient off to another service once their particular part of the job is completed with little coordination of effort.  The ID physicians, in particular, play a very primary role in the treatment of DFI and expressed frustration that, by the time they see the patient, it is often very late in the progression of the disease and they are dealing with infections that have received multiple, often inadequate antibiotics and now present with multi drug resistant pathogens.  The universal regret, oft expressed at DFCON, about the patient being seen too late in the progression of the disease was repeated time and time again.  It just goes to show that you can travel 5000 miles from home to a totally different culture, yet some issues are universal! 

A few other thoughts and interesting findings about lower extremity infections in Turkey:

1.  MRSA is not the problem we have here.  In fact, in most hospitals the rates have been decreasing the past 5 years.  Furthermore, they do not differentiate MRSA into HA- vs. CA- strains. The common thinking is that CA-MRSA is not a widespread problem and they just do not worry about it.  This is a huge difference from here where I need to treat everybody as if they have CA-MRSA until proven otherwise. 

2.  There are different antibiotics.  Whereas we use so much vancomycin for our MRSA in-patient soft tissue infections, their drug of first choice is teicoplanin.  This is another glycopeptides that, although widely used in other parts of the world, never received its US approval.  Like vancomycin, teicoplanin presents its own set of problems with dosing including having to give adequate loading dose, measuring troughs and the potential for liver toxicity. There may also be “MIC Creep” issues with MRSA and teicoplanin.  Another unique antibiotics is cefoperazone/sulbactam a β-lactamase inhibitor combination I remember reading about 20 years ago when it was thought that it might be brought into the US.  Other drugs are the same including piperacillin/tazobactam, ertapenem and imipenem. 

3.  ESBLs are a major problem.  Whereas we are just now beginning to see extended spectrum β-lactamase (ESBL) producing gram negative rods here in our US diabetic foot infections, Turkey has had them for years.  In fact, there are enzymes found in Turkey that you would be hard pressed to find anywhere else in the world.   Surveillance surveys have found gram negative resistance rates to cephalosporins and even quinolones in the 50-60% range.  It is felt that some of this may be caused by the long term, inadequate antibiotic therapy that is often started by primary physicians or even pharmacists before the patient is seen by the ID specialists.  And, of course, the universal overuse of the flouroquinolones is thought to contribute.   

4.  Acinetobacter, especially multi-drug resistant strains, is a problem.  I found this particularly interesting given the well documented outbreak of Acinetobacter infections that has been reported in our troops returning from the current Middle Eastern conflict.  When in some of these Eastern sections of Turkey one is not far from Iraq and Syria.  Perhaps there is something in the environment or the locale that propagates this organism.

With Dr. Bayindir, Director of Infectious Diseases, University Hospital, Malatya, Turkey

(My thanks to David Armstrong, DPM, PhD for bringing this press release to my attention)

TaiGen Announces Nemonoxacin (TG-873870) Once-A-Day Oral Dosing in Diabetic Foot Infection Met Primary Endpoints

According to its manufacturer TaiGen, nemonoxacin, a novel, non-fluorinated quinolone has shown promising results in a single armed, multinational, proof of concept Phase II clinical trial against diabetic foot infections (DFI). What is unique about this drug is that, unlike other currently available quinolones, nemonoxacin has activity against MRSA and vancomycin resistant gram positive organisms.  Those who have heard me lecture know that I have not been a huge fan of quinolones in the treatment of gram positive infections since, especially earlier generation drugs such as ciprofloxacin could, and often did, cause rapid development of resistance in these organisms.  In fact, a number of quinolones have been implicated in potentiating MRSA development.  Seeing a new agent in this class with this broadened gram positive coverage is really interesting and has potential to be an important therapeutic advance.

The use of quinolones in the treatment of DFI has an interesting history.  The first antibiotic ever officially labeled by the FDA for the treatment of “complicated skin and skin structure infections including diabetic foot infections” was a quinolone…trovafloxacin (Trovan®, Pfizer).  Unfortunately, the drug, having been granted the most indications of any new antibiotic at the time of release, 14, was heavily marketed and possibly over utilized.  A number of deaths resulted, although there has been question about the agent’s role in those deaths, and the drug was essentially pulled from the market (although it was technically still available it had extreme restrictions placed on its use by the FDA). Trovan was unique in that it was extremely broad spectrum including activity against many common gram-positives, gram-negatives, and even anaerobes. So, its spectrum of activity was extremely promising for use in DFI.  Few other quinolones that have been developed share the broad spectrum that Trovan possessed.   A number of other broad spectrum, anti-anaerobic quinolones looked to show promise in the treatment of DFI but were never pursued. Gemifloxacin received indications only for respiratory infections. Gatifloxacin was marketed for skin and skin structure infections but was pulled from the market when it was found to cause problems with glucose homeostasis.  Moxifloxacin has a spectrum of activity very similar to Trovan and should be useful in DFI.  It does have an indication for complicated skin and skin structure infections, is given orally and once daily.  However, it has not received a DFI indication.  A number of years ago a DFI trial was started but, from what I understand, was stopped mid stream.  I am not privy to the reasons the trial was halted and development for this indication stalled.  The drug has recently been acquired my Merck in its merger with Schering Plough.  Merck has a long history of DFI drug development so it will be interesting to see if anything comes of this.

Quinolone have been perhaps the most abused class of antibiotic.  They have been massively overused because of their perceived broad spectrum and safety.  However, a significant number of these drugs have been pulled from the market for toxicities.  I mentioned 2 above, trovafloxacin and gatifloxacin.  There have been others.  Be aware of problems ranging from liver and renal toxicity to neurotoxicity and photosensitivity.  Last but not least, in the past few years they have received the dreaded FDA “Black Box” warning for the role they can play in tendon ruptures, particularly of the Achilles tendon.  Please use these antibiotics prudently when indicated.

Two studies published in the January 7, 2010 issue of the New England Journal of Medicine have received a tremendous amount of play in the popular press.  One paper out of Baylor in Houston looked at comparing chlorhexidine + alcohol vs. povidone iodine as a preoperative surgical prep.  In a total of 849 subjects in the ITT analysis they found that the surgical site infection rate was significantly lower with the chlorhexidine + alcohol than it was with the old “standby” povidone iodine (9.5% v. 16.1% P=0.004) Here is a link to that abstract http://content.nejm.org/cgi/content/short/362/1/18.

The second study, out of the Netherlands, explored the issue of decolonization in nasal carriers of S. aureus.  http://content.nejm.org/cgi/content/short/362/1/9.  A total of 6771 patients were screened on admission using PCR for rapid identification of the Staph.  1270 swabs were positive, 808 underwent a surgical procedure.  The patients were all treated with mupirocin nasal ointment and chlorhexidine soap vs. a placebo.  The rate of S. aureus infection was 3.4% in the treated group vs. 7.7% in the placebo group.    Interestingly, ALL were methicillin susceptible (MSSA) so the study may, or may not be able to be extrapolated to MRSA carriage.

Hospital acquired infections, particularly surgical site infections cause a tremendous amount of morbidity and mortality not to mention costing billions of dollars to treat.  The monetary situation is complicated by CMS guidelines that may not pay a hospital for treatment of any nosocomial infection.  Therefore, new and improved techniques for minimizing these infections are being studied.  Some of what is done today for infection prevention in the surgical suite has not changed much in decades i.e. the use of the povidone iodine prep.  I remember doing those back when I was a surgical resident in the early 1980s!  Chlorhexidine is by no means a new product.  In fact, it may be older than povidone iodine.  A quick PubMed search finds papers going back to the 1960s.  More recently, the combination of chlorhexidine with alcohol has shown to be a better antiseptic with longer activity than chlorhexidine alone.  This is true not only for prepping the patient but also as a hand prep for the physician.  This recent study just shows us that as new high level evidence becomes available, we may have to change some very ingrained thoughts and practices.

As for the nasal carriage paper, I find that interesting and not unexpected.  What needs to be looked at is carriage of MRSA and surgical site infections.  There are some papers out there and I do discuss them in the book.  This is a more involved topic for another post. 

Telavancin (Vibativ – Theravance/Astellas) is a novel lipoglycopeptide, related to vancomycin, that has been recently approved by the FDA for the treatment of complicated skin and skin structure infections (cSSSI) caused by MRSA.  Telavancin now joins the ranks of vancomycin, linezolid, daptomycin and tigecycline as being the only 5 antibiotics with this approval.  An excellent review of this drug was published by Saravolatz, Stein and Johnson in the December 15, 2009 issue of Clinical Infectious Diseases.  Here is a link to the Abstract: http://www.journals.uchicago.edu/doi/abs/10.1086/648438 .  I highly recommend anyone interested in this drug to search out this complete article and familiarize yourself with it.

Without going into too much detail (which may infringe on copyright?), I would like to point out a few important take home messages that I got out of this paper and from my review of other literature on the subject. First some of the positives:

1.  The usual dose is 10mg/kg q24h.  Thus, we have the ease of a once daily dosing

2.  The drug is consistently bactericidal against most S. aureus.   Various reviews have shown that this probably has little impact in the treatment of cSSSI and may be more important in blood stream infections for which this drug is not approved.

3.  It is effective against MSSA, MRSA, VISA and hVISA.  It is also effective against daptomycin and linezolid resistant strains.  It does not have activity against the most common strains of VRE.

4.  Unlike vancomycin, there is no call to monitor serum trough levels

5.  In two pivotal cSSSI clinical trials it was found to be “non inferior” (FDA speak) to vancomycin. 63% of the S. aureus strains were MRSA making it the largest number of MRSA patients in a cSSSI study to date.

Now some downsides:

 1.  It is primarily excreted through the kidneys so significant dosage modification must be made in cases of renal insufficiency. The recommendations are the full 10 mg/kg q24h if the creatinine clearance is >50 mL/min, 7.5 mg/kg if 30-50 and 10 mg/kg q48h if the clearance is <30.

2.  Chronic, infected diabetic foot ulcerations were specifically excluded from the two pivotal trials!  I don’t see this drug receiving the coveted “…including diabetic foot infections” approval anytime soon.

3.  Although the overall safety looked comparable to vancomycin there were higher rates of some significant adverse events including altered taste, nausea and vomiting along with an increase in renal events.  On the other hand, vancomycin had higher rates of infusion reactions

4.  The drug has received a black box warning for fetal risk.

So what is the bottom line?  I agree with the authors of this review that we need new novel antibiotics to combat MRSA especially given all of the increasing reports of vancomycin MIC creep and treatment failures.  Many of the drugs that looked promising earlier in their development have either been slowed considerably (ceftobiprole) or stopped totally (oritavancin, iclaprim) so the once fertile pipeline is looking a bit thin.  Telavancin gives us one more drug to add to that relatively short list of alternatives to vanco especially with organisms that have developed resistance (although extremely rare) to those other antibiotics.  At this early point in its history, I am somewhat concerned about its lack of diabetic foot infection data and its increase in adverse events compared to vanco.  The black box may also impact some potential patients.  Given that we have other vanco alternatives with years of clinical experience, including diabetic foot data, and well known safety profiles I may feel more comfortable seeing more clinical data and published AE experiences before jumping in with both feet.

Some interesting news just came out yesterday.  It looks like J&J’s new anti-MRSA cephalosporin, ceftobiprole has been, once again, turned back by the FDA. See the story here:

http://money.cnn.com/news/newsfeeds/articles/marketwire/0572888.htm

Many of us had pretty high hopes for this antibiotic as it was to be the first cephalosporin active against MRSA.  Although it is IV only, the idea of having a new MRSA agent that was in a class of drugs well liked and trusted by most, was appealing.  It is also broad spectrum against a wide range of other Gram positive and Gram negative organisms. J&J even performed a clinical trial specifically looking at diabetic foot infections with promising results thus hoping to become only the 4^th antibiotic (after linezolid, ertapenem and piperacillin/tazobactam) with that specific FDA indication.  The drug was initially submitted for approval way back in 2007.  The FDA sent an Approvable Letter questioning conduct at some of the study sites.  The action taken yesterday by the Agency now seems to totally question the viability of the two pivotal trials.  This may mean that entirely new studies would have to be completed thus delaying this drug for years more.  It will be interesting to continue to watch this.

In the meantime, all is not lost for anti-MRSA cephalosporins.  The drug most thought would be the late-comer to this party, ceftaroline, seems to be moving ahead.  I will keep you all informed as I hear anything new.

I wish all of my readers a healthy, happy and prosperous, New Year