Setting The Record Straight With Griseofulvin

Griseofulvin is really the first oral agent in America for the treatment of superficial fungal infections. The original formulation of this agent had a low water solubility and a low absorption rate. We recognize that, especially, the ultramicrosize form of griseofulvin has an increased absorption in the GI tract. This helps in getting a higher drug concentration to the target tissues and increased bioavailability. The ultramicrosized formulation is more rapidly, completely, and uniformly absorbed than the original and microsize formulations.
Again, keep in mind that the available data on griseofulvin are less than what you might see for some of the newer antifungal agents. This is simply a reflection of the fact that this is one of the older agents. At that time, not as much research was required before a drug came on to market. It’s something going back in history and seeing what some of the newer antifungal agents have to go through in terms of Phase I, Phase II and Phase III studies. In the last 40 to 45 years, we’ve really come a long way in terms of drug development and the fact that they require a lot more in terms of evidence before any agent is approved.

Understanding How Griseofulvin Works
Dr. Gupta: Griseofulvin is metabolized by the hepatic microsomal system and deposited in keratin precursor cells. The mechanism of action of griseofulvin is well delineated. It inhibits the nucleic acid synthesis, the formation of the intracellular microtubules and has an effect on the mitosis of the fungal cells. It is fungistatic and is similar to the ketoconazole, itraconazole, and fluconazole, all of which are fungistatic. This is in contrast to terbinafine and butenafine, which are fungicidal, as well as ciclopirox.

So for both microsize and ultramicrosize griseofulvin, there is increased absorption when taken with a fatty meal but the ultramicrosize formation makes it less dependent on this requirement.
The pharmacokinetics of griseofulvin has not been relatively well studied compared to some of the more recently discovered antifungal agents. The data suggest that low levels of griseofulvin are present within the skin within a few days of discontinuation of the oral agent.
Griseofulvin is fungistatic against dermatophytes and the species that are more important for us in this discussion would be the Trichophyton species, particularly T. tonsurans in the U.S., and less commonly, Microsporum canis.
We also need to recognize that griseofulvin is not effective against non-dermatophyte molds and yeasts, including the Candida species. This may have more implications when it comes to treating tinea pedis and onychomycosis as opposed to tinea capitis.

Exploring The Current Use Of Griseofulvin
Dr. Gupta: I think the current niche of griseofulvin in 2004 will be tinea capitis but certainly, it can be a useful drug for treating tinea pedis. It can also be used to treat tinea corporis and tinea barbae, which are not as frequent perhaps as tinea pedis, tinea capitis and onychomycosis.
When it comes to onychomycosis, I do not see griseofulvin today as being an agent for toenail infections. Furthermore, griseofulvin would not be expected to be active against Candida species, which are more likely to be the causative agent of fingernail rather than toenail onychomycosis.
Very briefly, I do want to touch upon tinea capitis. I know this will be covered in more detail later. Griseofulvin is mainly used for tinea capitis in North America today. It remains the only FDA approved treatment for tinea capitis and has a good cure rate.
Griseofulvin is certainly a very cost-effective agent for tinea capitis. It is also something that a lot of physicians feel very comfortable using for this condition. The fact that it’s approved, especially when it comes to treating children, creates a much higher comfort level.

Getting back to tinea pedis, there is an older study by Zaias, et. al.1 It shows that certainly ultramicrosize griseofulvin does have a good cure rate and this was in comparison with clotrimazole. It was also fairly decent in terms of relapse rates. I do see a place for ultramicrosize griseofulvin in treating tinea pedis. The study by Zaias revealed a decent cure rate.1
One thing to keep in mind with interdigital tinea pedis is the potential contribution of other organisms, by Candida species perhaps, which may or may not be covered by griseofulvin. I think it certainly merits a re-visit into this field and doing some more recent studies.
In talking about just pure indications in the U.S., you recognize that itraconazole and oral terbinafine are not indicated for tinea pedis, although there’s obviously a fair amount of literature that supports their use. Again, griseofulvin is the one that is indicated.

Taking A Closer Look
At The Safety Profile Of Griseofulvin
Dr. Gupta: I’ve found that I use it mainly for tinea capitis. Over the last 25 years or so, I found it to be a very easy to use drug with very few side effects. There is a safety or comfort level with this drug because it has been used for so long whereas you don’t have as much of a comfort with the newer agents. So I think griseofulvin does have the advantage of being a tried and tested agent with a very good safety profile.
In my opinion, griseofulvin has a relatively favorable drug interaction profile.

Discussing The Perception
Of Safety With Griseofulvin
Dr. Joseph: When I was in school 23 to 25 years ago, griseofulvin was the only oral drug we had for the treatment of onychomycosis or tinea pedis. Frankly, we were taught that the drug was dangerous, that it had no place in being used and that the disease states were not worth treating at the risk of treating them.

I think we have to put this issue to rest because as Dr. Gupta discussed, there are only minimal drug interactions and a good safety profile. In regard to the penicillin allergy issue, quite interestingly, you showed the structure, but there’s no beta lactam ring. I recently gave a lecture and somebody asked me the question about whether there’s cross reactivity with patients who are penicillin allergic. There is this perception, perhaps more so in podiatric medicine than in dermatology, that this is not a drug that should be used. Does anybody else have any thoughts on this?
Dr. Shin: When I was in training as a pediatric resident, every time we thought about putting someone on griseofulvin, we were always taught to monitor the CBC and LFTs. It was just automatic. However, my approach has changed over the years. We’ve used it so much in pediatric dermatology because the medication has been around for over 50 years. We realize that we’ve checked all those bloods and rarely have changes. At this point, I don’t even check a CBC or LFTs unless a patient is on a high dose of 25 to 30 mg/kg/day for an extended period of time, greater than three months. Prior to that, I don’t even check it at all. I’d be interested to hear your experience, whether you do monitor.
Dr. Joseph: How about baselines? Do you get baselines?
Dr. Shin: In a healthy child I do not.

Dr. Spielfogel: As far as bloodwork goes, I’m not doing any bloodwork when I put a patient on ultramicrosize griseofulvin for tinea pedis as opposed to when I put somebody on terbinafine or itraconazole for onychomycosis. Then I’ll do a baseline and follow-up bloodwork. I really think it’s up to the discretion of the doctor if he or she wants to do bloodwork but it’s not necessary unless there is a medical indication. It’s a safe drug. The studies have shown that there’s no risk of any kind of hepatic injury.2,3 I have been prescribing the drug a lot and have not had any problems.
Dr. Blass: I’m doing LFTs in less than 5 percent of the people I’m putting on ultramicrosize griseofulvin and I select them based on their medical history. If the patient has many years of heavy alcoholism, I’ll look. I’ve also started lately to look at people who are in professions that exposed them to blood contamination before the days of bloodborne safety regulations. For people who worked in ambulances 20 years ago, I might run a liver function test.
As far as CBCs, I’ve had no problem. I’ve never really had to use the drug for more than two months. As far as penicillin allergy is concerned, what I’ve started doing is sort of dividing patients into two different categories. For patients who have a rash that bothers them a little bit, I’ll give them half a tablet and say, “If nothing happens, take the other half.” I’ll start them with a sample and I have yet to find a penicillin reaction to the drug at all. Of course, I grew up in the days when we used griseofulvin to treat onychomycosis. Back then, we used it for six months and ran blood tests every 30 days. Even then, you didn’t see a huge amount of problems with it.

Addressing Safety Concerns Of Other Physicians And Patients
Dr. Gupta: I think a good history is essential when we talk about the potential for hepatitis, even in younger kids. One should check for barbiturates and potential drug interactions, even though these are few. I think the data has showed that it’s fairly safe, whether you use it for four weeks, six weeks or eight weeks.

Dr. Joseph: I think everybody at this table would agree that history is probably the single most important point. The patients sometimes don’t give us the best history. We also tend to forget about things like the HMG co-reductase inhibitors and the statins. A lot of people are on statins and we know that statins do have their effects on liver function and can elevate liver function tests (LFTs). This is just something else to be aware of not even so much for drug interactions but in gauging previous hepatic toxicity before using any of the antifungals.
Dr. Blass: That’s where I get the major resistance from the primary care physician. He says his patient is on a statin and he doesn’t want to challenge the patient’s liver with a second drug. Well, I don’t think he really has an understanding of what a really neat organ the liver is. Different drugs use different cytochrome P-450 enzymes to be metabolized. It’s only when two drugs compete for metabolism that you could run into an interaction.
Dr. Joseph: Any other points to make on the safety issues here?
Dr. Shin: I have one more comment concerning the use of griseofulvin in the treatment of tinea capitis. When I have a high suspicion that a patient does have tinea capitis, I’m going to start him or her on griseofulvin right away and then tell the parents that the medication has been around for many years, it has an excellent safety profile and they really don’t have anything to lose. I tell them they can only gain from starting treatment right away. Some people want to wait for a positive culture before treating, but I think that it’s just worth nipping it because of the drug’s safety profile and efficacy.

Fungistatic Versus Fungicidal:
Does It Make A Difference?
Dr. Joseph: I think the whole positive culture issue is a great point and I do want to come back to that a little later. I would like to pose a pharmacokinetic question: What about fungistatic versus fungicidal? This is something that’s been debated for all the different drugs. Does it really play that much of a role? Does it really make that much of a difference that, say, griseofulvin is fungistatic versus something like terbinafine which is fungicidal?
Griseofulvin doesn’t have the so-called reservoir effect that we see with some of the newer oral antifungals in that the levels can be down within 24 or 48 hours. If you’re treating tinea capitis or tinea pedis — especially with tinea pedis in which you may need a month or so for the skin to slough — do you need to maintain the drug levels? I don’t know how quickly the skin sloughs on the scalp. However, knowing that the fungus is in the stratum corneum, do we need to maintain drug levels throughout the course of a full cycle in order to ensure that the inhibited organism is no longer present as opposed to a dead organism that we know is just going to slough off anyway?
Dr. Spielfogel: As far as -static and -cidal, it really doesn’t make a difference to me. I just want a good clinical response.

When Patient Communication
Can Bolster Compliance
Dr. Blass: I think, in some cases, clinical outcomes are more of a patient compliance and patient communication issue. You may start a patient on a drug like griseofulvin and all the symptoms are gone in two weeks. That is because the symptoms aren’t coming from the existence of the fungus, they are coming from the growth of the fungus. You may stop the fungus from growing, but fungus is probably one of the most resistant organisms in the world. As somebody once said, “If we blow ourselves off the planet, the first thing out of the rubble will be a cockroach and he will have a tinea infection.”
However, you explain to the patient that just because he or she feels better, it doesn’t mean the organism is gone. You’ve got to tell patients to finish the drug. If you don’t take the time to explain it to the patient, then it leads to the patient perception of “Well, it went away but it came right back. I got a new one.” No, you didn’t get a new one, you got the same one right back. That’s why you tell patients to finish the bottle. Now, with virtually every prescription I write, I ask the patient to bring the medication to the next office visit. I’ll say that I want to make sure the pharmacist filled the prescription properly. This is an out and out fabrication. What I really want to see is did they fill it and are the right number of tablets gone from that bottle? Are they taking it properly?

Dr. Joseph: That’s a great idea. It’s a great idea not only for treatment of tinea pedis, but for anything, antibiotics in particular.
Dr. Shin: I agree with the compliance issue, especially for the treatment of tinea capitis in children, because our treatment period is much longer. Since the dermatophyte is present within the hair shaft, deep in the follicle, a minimum of six to eight weeks of treatment is required. It is of utmost importance to explain to the family that the child must receive continuous therapy for this duration.

References:

1. Zaias N, Battistini F, Gomez-Urcuyo F, et. al. Cutis 1978;22:197-199.

2. Garcia Rodriguez LA, Duque AA, et. al. A cohort study on the risk of acute liver injury among users of ketoconazole and other antifungal drugs. Br J Clin Pharm 1999;48:847-852.

3. Chien, Rong-Nan, et. al. Hepatic injury during ketoconazole therapy in patients with onychomycosis: a controlled cohort study. Hepatology January 1997 103-107.

4. Roujeau JC, Sigurgeirsson B, et. al. Is dermatomycosis of the foot (onychomycosis/tinea pedis) a risk factor in the development of bactericidal cellulitis of the leg? A case-control study. 2003 AAD poster presentation.

5. Gupta AK, Humke S. The prevalence and management of onychomycosis in diabetic patients. Eur J Dermatol 2000;10:379-384. Reference ID: 25

6. Eady EA, Jove JH. Staphylococcus aureus. Curr Opin Infect Dis 16:103-124, 2003.

7. Personal communication with Harvey Lemont, DPM.

8. Leyden JJ. Progression of interdigital infections from simplex to complex. J Am Acad Dermatol 1993 May; 28 (5 Pt 1):S7-S11.

9. Gentles JC, Evans EG. Foot infections in swimming baths. Br Med J 1973 Aug. 4: 3(5874): 260-2.

10. Handbook of Nonprescription Drugs. 12th ed.

11. American Podiatric Medical Association Department of Public Relations 2000 Survey of Attitudes Toward Foot Care.

12. Pharmacy Times, June 2002, OTC Supplement 2002.

13. IMS Health.

14. Bioavailability of Microsized and Ultramicrosized Griseofulvin Products in Man. J Pharmacol and Biopharmacol 1980;8(4):347-362.

15. Kidawa AS. A comparison of Gris-PEG and Fulvicin-U/F in the treatment of tinea pedis. 1981;71:323-327.

16. Ghannom M, et. al. J Am Acad Dermatol 2003;48:189-93.

17. Lobato MN, et. al. Pediatrics 1997;4:551-4.

18. Elewski BE. Tinea capitis: a current perspective. J Am Acad Dermatol 2000;42:1-20.

19. Mackenzie DWR. Hairbrush diagnosis: in detection and eradication of non-fluorescent scalp ringworm. Br Med J1963;ii:363-5.

20. Williams JV, et. al. Pediatrics 1995;96:265-7.

21. Pomerantz AJ, et. al. Arch Pediatr Adolesc Med 1999;153:483-486.

22. Babel DE, Baughman SA. J Am Acad Dermatol 1989;21:1209-12.

23. Martinez-Roig A. Pediatr Infect Dis J 1988;7:37-40.

24. Bennett ML, et. al. Pediatr Dermatol 2000;17(4):304-309.

25. Friedlander SF, et. al. Pediatrics 2002;109(4):602-607.

26. Physicians Desk Reference.

27. Gupta AK, et. al. Efficacy and safety of itraconazole use in children. Dermatol Clin 21 (2003) 521-25.

28. Elewski BE. Int J Dermatol 1997;36:537-41.

29. Gupta AK, et. al. Br J Dermatol 1999;141:304-306.

30. Allen HB. Pediatrics 1982;69:81-83.

31. Greer DL. Intl J Dermatol 2000;39:302-4.

32. Sharma V, et. al. Arch Pediatr Adolesc Med 2001;7:818-821.