ONYCHOMYCOSIS – What Are We Teaching?

November 3rd, 2014 by Warren S. Joseph DPM FIDSA

I have been doing LOTS of talks on onychomycosis over the past few months. The vast majority of these have been CME lectures where I spend significantly more time reviewing the background information of onycho than talking about new drug therapies.  What has amazed me since I first started speaking on this topic over 25 years ago is the lack of understanding of the science behind this INFECTION.  Yes, you read that correctly…onychomycosis is an INFECTION and should be treated with anti-INFECTIVES.  We don’t think twice about treating a bacterial infection with an antibiotic, why don’t we feel as strongly about treating a fungal infection with an antifungal?  This has been my introductory statement in every lecture I give about this disease since I first became interested in this topic and my feeling has not waivered about it.

Perhaps I will expand upon that concept in a future post but for this entry, I want to talk about the total lack of understanding/interest in learning about onycho exhibited by our next generation of this profession; our students and residents. Many students and residents have been attending some of these CME lectures. I don’t know that they are necessarily there to hear my talk or rather it is just a diversion between the “more interesting” surgical topics that are being presented at the same meetings.  Their lack of knowledge about onychomycosis, however, was driven home to me recently while I was speaking at the PRESENT Residency Summit in Teaneck, NJ.

At this well attended seminar I was in front of close to 200 podiatric residents. I started my talk by polling the audience asking how many of them could recite for me the Lauge Hansen Classification of ankle fractures.  As you could imagine, every single resident raised their hand.  I then asked how many could recite the Zaias Classification of onychomycosis**…NOT A SINGLE HAND was raised!  My comment to them was: “Let me get this straight.  Everyone one of you can recite a classification system for a condition that 1/3 of  you may see twice a year but NONE of you can recite the classification system used in every scientific paper written about a condition you will see 20-30 times a day!”

I believe that this is an indictment of our educational system. This lack of knowledge is not necessarily the fault of the residents/students.  They are just learning what has been preached to them as being “important” by their school faculty residency directors and attendings.  Onychomycosis is something to be palliated (debrided, trimmed, ground, etc) and then discharged and reappointed for 60+ days, not treated as the potentially important infection that it is.  I am afraid that more is being taught about how to properly code onychomycosis than any science behind it. (There are, of course, notable faculty members who really believe in teaching this information as something critically important)  We need to start concentrating on the cognitive, medical aspects of podiatric medicine as well as, if not even more than surgical technique.  Being as common a condition as it is, I see no better place to start that new paradigm of podiatric education than in teaching about onychomycosis.

**In 1972, Nardo Zaias, MD, one of the “Godfathers” of onychomycosis in the dermatology world, developed the classification system that is still used today (with some minor modifications) identifying 4 types: Distal Subungual (DSO), White Superficial (WSO), Proximal Subungual (PSO) and Candidal onychomycosis

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Literature Update – Antimicrobial Agents and Chemotherapy, Sept, 2011

September 7th, 2011 by Warren S. Joseph DPM FIDSA

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

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

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

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

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

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

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

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THE 80% SOLUTION (With apologies to Sir Arthur Conan Doyle)

February 24th, 2011 by Warren S. Joseph DPM FIDSA

This Tuesday, February 22, I was quoted in a very fair and balanced article in the Wall Street Journal by Science Reporter Laura Johannes dealing with laser treatment of onychomycosis.

During my interview with Ms. Johannes I bemoaned the lack of published evidence, not only for laser therapy of onychomycosis, but for any of the recently promoted treatments, either device or solution.  I questioned the ubiquity of the claims of 70-80% efficacy that seem rampant and asked her, as I now ask you: What does it mean to you if I say a product is “80% effective”?  Think about that.  Does it mean that 80% of the treated toenails became 100% cured? Or that 80% of patients treated were satisfied? Or, did 80% of toenails reach some undefined clinical endpoint? None of this is ever spelled out.  Let me share with you some claims right from onychomycosis promotions I have seen recently:

Right in the article in the WSJ there is a quote from a Dr. Khoury using the Nomir laser who states “My patients and I are very happy with it”  and it goes on to state that Dr. Khoury “..says it works in about 80% of his patients”

Also in the article it mentions how PinPointe supplied the WSJ with a summary of unpublished (my emphasis) data claiming “71.4% of patients experienced continuous improvement over a year…”

In a “testimonial” (the HIGHEST level of medical evidence, I am sure) on a Formula 3 topical solution brochure a podiatrist from Nebraska states “I would estimate 80-90% success rate”

In an advertisement for Fungasil solution seen in a doctor’s office recently it claims “50-80% cure rate within one year”

Speaking to a sales representative at the Cool Touch Laser booth during the recent Desert Foot meeting “The efficacy is 79.8%”

From a direct mailing of a local podiatrist using laser therapy: 88% Effective, Proven Clinical Results.

If I read a paper of a randomized, controlled clinical trial on an antibiotic therapy and there is a result showing 90% success, it is clearly spelled out as to what the endpoint was.  It may have been 90% microbiologic cure (defined as negative culture) or 90% clinical cure (no residual clinical evidence of infection), etc.  Even in the onychomycosis literature, when proper studies were performed on terbinafine, itraconazole or ciclopirox lacquer, you could read the studies and KNOW exactly what the endpoint was, be it mycologic cure, complete cure or something in-between. This is what is lacking in many of these claims.  I find it hard to believe they all can be so incredibly close in efficacy and, frankly how they can be…so effective!  I think we will all agree that the “gold standard” in the treatment of onychomycosis is oral terbinafine, followed closely by oral itraconazole.  Yet, if you actually look at the FDA approved CLINICAL CURE numbers (clearly defined in the criteria as mycologic cure plus 100% normal nail appearance at the end of the study) terbinafine only had a 38% cure rate and itraconazole, only 14%.  Has medical science advanced so rapidly in the past 10-15 years that now we can double that success rate?

So, why is 70-80% used as the claimed efficacy rates for all of these various promotions against onychomycosis.  I guess some may be based in clinical trials, published or not.  Some of these efficacies may be absolutely true…I just don’t know since, other than the published Nomir study, I haven’t seen any data, my point in the WSJ.  Maybe docs and companies feel that they need to claim 70-80% to feel comfortable selling a treatment or a product to a patient.  I welcome your thoughts.

Posted in Onychomycosis | 2 Comments »

Consumer Reports and Onychomycosis

June 1st, 2010 by Warren S. Joseph DPM FIDSA

In the July 2010 issue of Consumer Reports there is a short (less than one page) “5-Minute Consult” article from the magazine’s chief medical advisor Marvin Lipman, MD entitled “Treating Toenail Fungus”. Overall, I think it is a well written and accurate piece that gives consumers some valuable information.  I do, however, find a few points on which Dr. Lipman and I would not totally agree.

1.  The article starts out by talking about all of the attention and “millions of dollars” spent each year for drug company marketing of onychomycosis in a “futile” attempt to treat the condition.  Apparently, Dr. Lipman has not been watching for direct-to-consumer (DTC) ads on TV, looking for journal advertisement about onycho products or seeing Pharma reps in his office.  If he did, he would know that there is not, nor has there been for about 2-3 years, ANY money spent on onychomycosis product advertisements at all!  All 3 FDA approved products are currently generic and no money is spent on marketing them.  I would also take exception to his classification of the treatment as “futile”.  Both clinical trials, and clinical experience showed terbinafine and itraconazole to be rather effective agents.  Even if they do not work all of the time, their use is far from futile. 

2.  Dr. Lipman states that the treatment is “only occasionally medically necessary” except to prevent secondary bacterial infection particularly in diabetic patients and the immunocompromised. Despite many studies showing quality of life issues and other medical complications of onycho, the entire “cosmetic vs. medically necessary” argument has been going on for years, mainly perpetuated by the insurance companies who used it as an excuse to not pay for the drug.   It is interesting that, now that the drugs are generic and inexpensive, suddenly there seems to be little trouble getting them covered.  I guess the generic forms are medically necessary while the name brands were not. 

3.  His comments on the “do it yourself” Internet market for onychomycosis products is right on target.  Although some are capable of killing fungus few if any have been subject to randomized controlled trials.  This also goes for most of those products being sold by our colleagues out of their offices. (Anecdotal testimony perpetuated by representative, i.e. “According to Drs. Smith and Jones, it works 90% of the time” does NOT equal medical evidence!)

4. Dr. Lipman’s discussion on prescription options is also mostly correct.  I would challenge his comment that a “3-month course of treatment can run up to several hundreds of dollars not including doctor’s visits and cost of tests”.  Now that these drugs are generic we are all familiar with the $4 Rx of terbinafine that many of our patients are now able to receive from discount pharmacies.  In fact, oral therapy of onychomycosis is actually quite inexpensive. The downside to his is that it has stymied any new oral therapy development since few Pharma companies want to develop a new, expensive drug to challenge such inexpensive therapy.

5. My final comment is in regard to his comment that a single laser treatment, “usually by a podiatrist, may be effective nearly 90% of the time but at around $1200 a pop”.  I find it quite interesting that Dr. Lipman is critical of prescription orals and topical and all of the anecdotal remedies holding them up to scrutiny for their lack of clinical evidence yet he mentions a 90% success rate with lasers. I need to point out that NONE of the lasers have been proven to work anywhere near the 90% mark with a single treatment and only one, the Noveon system, has any published data whatsoever.  (For full disclosure, I have been a consultant to both Nomir and Patholase).  The Noveon data just published last week by Adam Landsman, DPM, PhD and colleagues in the May/June issue of the Journal of the American Podiatric Medical Association used 4 treatments and evaluated at 180 days.  They found that 85% of the nails were improved as judged by an independent, blinded expert panel. Patholase has just completed their prospective study on the PinPointe system but it has not yet been published.

Do yourselves a favor and find the piece since you know that your patients are going to be questioning you about it!   

Ulceration under a mycotic nail in a patient with diabetes

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Region IV Book Signing

May 25th, 2010 by Warren S. Joseph DPM FIDSA

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!

Posted in Antibiotics, Book, Diabetic Foot, Infections, MRSA, Onychomycosis, Osteomyelitis | 2 Comments »

Lasers and Onychomycosis

January 26th, 2010 by Warren S. Joseph DPM FIDSA

One of our readers recently sent the blog the following comment:

“Anything new to add to comments in book about laser treatment of fungal nails?  In my area there are ads for DPMs offering this $1000 per treatment!  My question is; does it work?”

Up to this point I have been tacitly avoiding this topic waiting for all of the chips to fall into place.  I guess it is time to, at least give my initial thoughts.  I will start by disclosing that I was a member of the original Patholase/PinPointe Advisory Board although I am currently not working with that company and I am a current Advisory Board member for Nomir. Being under a non-disclosure agreement with both I must therefore be very careful to only give background information that is in the public domain and give only MY OPINION based on the information in the public domain so as not to let slip any confidential information that I may have picked up along the way.  This is another reason I have not written about this topic.     

Although there may be more than two commercial products to mention, I will limit my discussion to the two best known, the PinPointe Laser from Patholase and the Noveon Laser from Nomir.  These are totally different devices that use different forms of laser energy. As I write this NEITHER is FDA approved specifically for the treatment of onychomycosis although both have a device clearance for general podiatric and dermatologic use.  Interestingly, if you actually look for the specifics of that general definition, onychomycosis is not included.

To this point each company has taken very different marketing approaches.  PinPointe, despite not having the FDA approval, has been aggressively marketing the device to podiatrists based on their general usage clearance.  Up to this point, their publically available data supporting the use of the device for onychomycosis has been limited to a small number of patients originally treated pre-marketing and by early adapters of the device.  This data is not from a prospective, IRB approved, randomized controlled trial. To their credit, a quick search on www.clinicaltrials.gov under the term “onychomycosis” does reveal that they are currently engaged in such a clinical trial.  They also continue to collect retrospective data from current users.  To the best of my knowledge they have published no studies based on their clinical data or their technology. 

Nomir has taken the path of performing an initial three IRB approved, prospective clinical trials and has submitted their pivotal trial to the FDA in an attempt to receive an onychomycosis indication.  Their technology, using a dual wavelength (870 & 930 nm) near infrared (IR) laser light to cause photoinactivation of  both fungus and bacteria, including T. rubrum and MRSA, at physiologic temperatures, has been shown to be successful in vitro and in vivo, and was recently published by its developer Dr. Eric Bornstein http://www.nomirmedical.com/products/publications.htm in the Nov/Dec 2009 issue of Photochemistry and Photobiology.  They have also submitted the preliminary results of their pivotal clinical data for the treatment of onychomycosis which has been accepted for publication in a peer reviewed, indexed journal.  Although they have signed up podiatrists to be trained on the device, it has not yet been made commercially available. 

Enough background…to answer the question that initiated this discourse, I guess I would have to say that, yes, given the data I have seen, these two laser therapies do, in fact, show positive results in the treatment of onychomycosis.  Will they work in every patient with nail fungus?  Of course not!  Even oral terbinafine only had a 38% total cure rate in its clinical trials.  Which brings up another question…do they work even as well as the oral agents?  Frankly, no one can say at this point without seeing the results of the same type of well designed, controlled trials that those drugs went through.  I will say this much for certain, there is no risk of systemic toxicity with the lasers as there is with the oral drugs, no matter how rare.  Is the treatment worth $1000?  That is something that only an individual patient can answer.  I hear through the proverbial grapevine that there has been no shortage of folks willing to pay that or similar amounts for the treatment.  Heck, there are scores of physicians specializing in cosmetic treatments, some without rigidly controlled and studied FDA approved data, that have done quite well promoting their services.

Until more information is available on which definitive statements can be made, I would have to advise each of my readers to use their own moral and ethical compass in determining what is appropriate for their patients and their practice.   I would really appreciate any comments you may have if you are currently using a laser on either your own patient experience or if you have seen patients treated by other docs and their satisfaction level.

Posted in Onychomycosis | 1 Comment »

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