This study of 213 recruited patients not only looked at wound healing differences between silver containing dressings and non-silver low adherence dressings in the treatment of VLU but also the cost effectiveness of the two.  The primary measure was complete ulcer healing at 12 weeks with secondary measures being; time to healing, quality of life and the aforementioned cost-effectiveness.  Although I do have some issues with the study design including the leeway given in dressing selection, compression definition and number of visits, I do find the results interesting. 

As one might reasonably expect given the paucity of good evidence on the effectiveness of silver dressings as a class, the VULCAN study found that there were no significant differences between dressings in the number of ulcers healed at 12 weeks (59.6% silver, 56.7% non-sliver) nor to median time to healing. As could also be expected, silver dressings cost significantly more to use ($46.60 vs. $8.70 as converted from the reported £).  The authors concluded that “There was no evidence to support the routine use of silver-donating dressings beneath compression for venous ulcerations”. 

This finding won’t surprise anyone who has heard me lecture on “Differentiating infected from non-infected wounds” as I did at the APMA meeting, who has read the chapter on Diabetic Foot Infections in the 3^rd Edition (specifically page 120), or has read my blog post from March 3, 2010 entitled “Bioburden and Wound Healing”.  Silver dressings are everywhere.  Just about every wound healing product line includes a number of silver donating products in every imaginable format.  Yet, there is little to no evidence to support that they are of any benefit in wound healing or preventing wound infection.  This revelation first came to me upon reading the Cochrane Collaborative systematic review of the literature on silver dressings which, like the VULCAN trial, found little evidence to support their routine use.  This does not mean I don’t use them.  Like most clinicians, if I see a heavily colonized wound I am seemingly genetically programmed to reduce the bioburden and kill the bugs. 

What I am saying is that we should be practicing evidenced based medicine and not costing our patients or the health care system dollars that none of us can afford to spend on a therapy without solid science behind it.  So, next time a sales rep comes to speak to you about their latest and greatest silver product, ask for scientific proof, not some pretty “before and after” pictures, that it contributes to wound healing.  Unfortunately, I doubt you will get much.  These products are all approved by the FDA as 510k medical devices.  Therefore, there is little clinical science necessary to get them approved.   

REFERENCES

Lipsky BA, Holroyd KJ, Zasloff M. Topical versus systemic antimicrobial therapy for treating mildly infected diabetic foot ulcers: a randomized, controlled, double-blinded, multicenter trial of pexiganan cream. Clin Infect Dis.  2008;47:1537-45.

Michaels JA, Campbell B, King B, Palfreyman SJ, Shackley P, Stevenson M. Randomized controlled trial and cost-effectiveness analysis of silver-donating antimicrobial dressings for venous leg ulcers (VULCAN trial). Br J Surg. 2009;96:1147-56.

 Vermeulen H, van Hattem JM, Storm-Versloot MN, Ubbink DT. Topical silver for treating infected wounds. Cochrane Database Syst Rev. 2007 Jan 24;(1):CD005486

(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.

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)

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!

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

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.

1. Does the use of a topical antimicrobial decrease the wound of bioburden?

2. By decreasing the wound of bioburden do we hasten wound healing?

3. By decreasing the wound of bioburden do we prevent colonized wounds from becoming clinically infected?

Surprisingly, really none of these questions have been answered to my satisfaction. For this particular discussion I will concentrate on question #2. An interesting study entitled “Bacterial burden and wound outcomes as influenced by negative pressure wound therapy” with just published in the February 2010 issue of Wounds by Boone, Braitman, Gentics, et.al out of St. Luke’s – Roosevelt Hospital in New York City. In this small pilot study using a porcine wound model infected wounds were created using a combination of bacteria including Pseudomonas, Staphylococcus and Bacteroides, and then treated with V.A.C. therapy using either regular or silver impregnated foam along with a moist wound dressing control. Both quantitative and semi-quantitative bacterial cultures were performed. To quote the Abstract “The wounds continue to show gross and microscopic improvement when treated with standard NPWT and NPWT with silver compared to moist wound care controls. However, the bacterial burden in all wounds continued to increase and broaden to include local skin flora, which had been absent immediately after wounding.” The authors concluded that the improvement in healing of the wounds could not be explained by a change in their bacterial burden.

The results of this study are actually similar to some of the earlier work performed using the V.A.C. Wounds healed more rapidly when the device was applied yet, almost paradoxically, the bioburden of the healing wounds seemed to increase rather than decrease as the wounds continued to heal. This certainly seems counterintuitive to the entire concept that the bacteria are somehow inhibiting wound healing. Maybe this all points to the ancient concept of “laudable pus”!  Of course many factors must be considered. Probably more important than the number of bacteria is which types of bacteria are actually present. Certainly there is a difference in pathogenicity of some bacteria over others. Also of interest in this study is that the silver impregnated foam did not decrease the bioburden any more than the standard foam (question #1 anybody?)

Please do not take that to mean that I am somehow “dissing” all antimicrobial wound products.  I certainly use them and will continue to in the foreseeable future.  The bottom line to this entire discussion is that, although we are programmed to feel that somehow all bacteria in wounds are detrimental, perhaps the presence is not always necessary to eliminate. Before we jump on any bandwagon promoting the “latest and greatest” in antimicrobial wound therapies perhaps we should step back and ask the three critical questions I posed above. By prodding industry to produce high levels of evidence-based medicine it can only improve our overall treatment of these difficult patient problems.

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. 

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.

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