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FUNGAL NAIL INFECTIONS

Onychomycosis (also known as "dermatophytic onychomycosis,"[1] "ringworm of the nail,"[1] and "tinea unguium"[1]) means fungal infection of the nail.[2] It is the most common disease of the nails and constitutes about a half of all nail abnormalities.[3]
This condition may affect toenails or fingernails, but toenail infections are particularly common. The prevalence of onychomycosis is about 6-8% in the adult population.[4]

Classification
There are four classic types of onychomycosis:[5]:305
Distal subungual onychomycosis is the most common form of tinea unguium, and is usually caused by Trichophyton rubrum, which invades the nail bed and the underside of the nail plate.

White superficial onychomycosis (WSO) is caused by fungal invasion of the superficial layers of the nail plate to form "white islands" on the plate. It accounts for only 10 percent of onychomycosis cases. In some cases, WSO is a misdiagnosis of "keratin granulations" which are not a fungus, but a reaction to nail polish that can cause the nails to have a chalky white appearance. A laboratory test should be performed to confirm.[6]

Proximal subungual onychomycosis is fungal penetration of the newly formed nail plate through the proximal nail fold. It is the least common form of tinea unguium in healthy people, but is found more commonly when the patient is immunocompromised.

Candidal onychomycosis is Candida species invasion of the fingernails, usually occurring in persons who frequently immerse their hands in water. This normally requires the prior damage of the nail by infection or trauma. 

Signs and symptoms

The nail plate can have a thickened, yellow, or cloudy appearance. The nails can become rough and crumbly, or can separate from the nail bed. There is usually no pain or other bodily symptoms, unless the disease is severe.^[7]

Dermatophytids are fungus-free skin lesions that sometimes form as a result of a fungus infection in another part of the body. This could take the form of a rash or itch in an area of the body that is not infected with the fungus. Dermatophytids can be thought of as an allergic reaction to the fungus.

Patients with onychomycosis may experience significant psychosocial problems due to the appearance of the nail. This is particularly increased when fingernails are affected.^[8]

Onychomycosis

Onychomycosis due to Trychophyton rubrum, right and left great toe.

Onycomycosis of the right thumb. Notice how some of the tip of the thumb nail itself is being removed, while the root of the fungus is not visible, as it is embedded into the nail bed. The fungus grew from the nail bed itself and attached itself over the nail of the thumb.

 Causes

The causative pathogens of onychomycosis include dermatophytes, Candida, and nondermatophytic molds. Dermatophytes are the fungi most commonly responsible for onychomycosis in the temperate western countries; while Candida and nondermatophytic molds are more frequently involved in the tropics and subtropics with a hot and humid climate.^[9]

Dermatophytes

Trichophyton rubrum is the most common dermatophyte involved in onychomycosis. Other dermatophytes that may be involved are T. interdigitale, Epidermophyton floccosum, T. violaceum, Microsporum gypseum, T. tonsurans, T. soudanense (considered by some to be an African variant of T. rubrum rather than a full-fledged separate species) and the cattle ringworm fungus T. verrucosum. A common outdated name that may still be reported by medical laboratories is Trichophyton mentagrophytes for T. interdigitale. The name T. mentagrophytes is now restricted to the agent of favus skin infection of the mouse; though this fungus may be transmitted from mice and their danders to humans, it generally infects skin and not nails.

 Other

Other causative pathogens include Candida and nondermatophytic molds, in particular members of the mold generation Scytalidium (name recently changed to Neoscytalidium), Scopulariopsis, and Aspergillus. Candida spp. mainly cause fingernail onychomycosis in people whose hands are often submerged in water. Scytalidium mainly affects people in the tropics, though it persists if they later move to areas of lichen planus, contact dermatitis, trauma, nail bed tumor or yellow nail syndrome, laboratory confirmation may be necessary. The three main approaches are potassium hydroxide smear, culture and histology. This involves microscopic examination and culture of nail scrapings or clippings. Recent results indicate the most sensitive diagnostic approaches are direct smear combined with histological examination,^[10] and nail plate biopsy using periodic acid-Schiff stain.^[11] To reliably identify nondermatophyte molds, several samples may be necessary.^[12]

 Treatment

Treatment of onychomycosis is challenging because the infection is embedded within the nail and is difficult to reach. As a result, full removal of symptoms is very slow and may take a year or more.

 Pharmacological

Most treatments are either systemic antifungal medications, such as terbinafine and itraconazole, or topical, such as nail paints containing ciclopirox or amorolfine. There is also evidence for combining systemic and topical treatments.^[13]

For superficial white onychomycosis, systemic rather than topical antifungal therapy is advised.^[14]

Other methods include oral medication, such as: itraconazole (Sporanox), fluconazole (Diflucan), or terbinafine (Lamisil). These medications permit the nail to grow infection-free, gradually replacing the infected part of one’s nail. These medications must be consumed for six to twelve weeks, but the final result will not be seen until the nail fully grows out. However, it may take four months or longer to eliminate an infection, depending on the severity of the infection, as well as the rate at which one’s nails grow. Future infections are likely to occur, principally if one continues to expose the nails to warm and/or moist conditions. Drawbacks of this method include side effects, such as headache, upset stomach, skin rashes, or allergic reactions to ingredients in the medication. Other side effects (of a more serious nature) include: liver damage and heart failure.^[15]

 Relative effectiveness of treatments

Amorolfine is currently the most effective topical treatment for onychomycosis, but is not approved in the United States or Canada. Amorolfine 5% nail lacquer in once-weekly or twice-weekly applications has been shown in well designed, placebo-controlled studies to be between 60% and 71% effective in treating toenail onychomycosis; complete cure rates three months after stopping treatment (after six months of treatment) is estimated to be between 38% and 46%.

Itraconazole is effective for oral treatment of onychomycosis. Pulse dosing (escalating drug levels early in the dosing interval followed by a prolonged dose-free period) is 61% to 75% effective in providing a complete cure.

In July 2007, a meta-study reported on clinical trials for topical treatments of fungal nail infections. The study included six randomised, controlled trials dating up to March 2005.^[16] The main findings are:

• There is some evidence ciclopiroxolamine and butenafine are both effective, but both need to be applied daily for prolonged periods (at least 1 year).
• There is evidence topical ciclopiroxolamine has poor cure rates, and that amorolfine might be substantially more effective.
• Further research into the effectiveness of antifungal agents for nail infections is required.

A 2002 study compared the efficacy and safety of terbinafine in comparison to placebo, itraconazole and griseofulvin in treating fungal infections of the nails.^[17] The main findings were for reduced fungus, terbinafine was found to be significantly better than itraconazole and griseofulvin, and terbinafine was better tolerated than itraconazole.

• A small study in 2004 showed ciclopirox nail paint was more effective when combined with topical urea cream.^[18]
• A study of 504 patients in 2007 found aggressive debridement of the nail, combined with oral terbinafine, significantly reduced symptom frequency over terbinafine alone.^[19]
• A 2007 randomised clinical trial with 249 patients showed a combination of amorolfine nail lacquer and oral terbinafine enhanced clinical efficacy and is more cost-effective than terbinafine alone.^[20]

 Drug pipeline

Most drug development activities are focused on the discovery of new antifungals and novel delivery methods to promote access of existing antifungal drugs into the infected nail plate. Active clinical trials investigating onychomycosis:^[21]

 Phase III

• A medicinal nail lacquer, MycoVa from Apricus Biosciences,^[22] contains terbinafine as the active ingredient and a permeation enhancer DDAIP which facilitates the delivery of the drug into the nail bed where the fungus resides.^[23][24]
• A comparison of delivery methods for itraconzole^[25]
• Safety and tolerability of topical terbinafine^[26]
• Laser-based treatments^[27]
• Topical IDP-108^[28]
• Bifonazole cream application after nail ablation with urea paste^[29]

 Phase II

• A topical treatment, AN-2690, is being developed by Schering-Plough Corp and Anacor Pharmaceuticals. It is active against Trichophyton species.^[30]
• Posaconazole, taken orally.^[31]
• A topical treatment, NB-002, is being developed by NanoBio Corporation.^[25] It has completed Phase II trials.^[32]

 Drug-free treatments

Nd:YAG lasers are being used for treatment of toenail fungus. These lasers target the fungus while leaving surrounding nail and tissue undamaged Published research has shown an effectiveness between 70 and 80%, and in many cases, a single treatment is sufficient This treatment is safe and has no side effects, since the laser is applied directly to the infection.

A Noveon-type laser, already in use by physicians for some types of cataract surgery, is used by some podiatrists, although the only scientific study on its efficacy, while showing positive results, included far too few test subjects for the laser to be proven generally effective.^[33]

The Ontario Osteopathic and Alternative Medicine Association in Ontario, Canada, have developed a laser-based method, "LAFT", which is claimed to have a 96% success rate based on "hundreds of treatments given".^[34] However, no scientific studies seem to have been performed and the website promoting the treatment has shown to contain biased and false information on the efficacy of conventional treatments.

To date, there are several lasers seeking approval and one that has been cleared by the Food and Drug Administration.^[35]

 Natural remedies

As with many diseases, there are also some scientifically unverified folk or alternative medicine remedies.

• Australian tea tree oil^[36][37] has been tested, but there is insufficient information to make recommendations for its use for onychomycosis.^[38]
• Grapefruit seed extract as a natural antimicrobial is not demonstrated. Its effectiveness is scientifically unverified. Multiple studies indicate the universal antimicrobial activity is due to contamination with synthetic preservatives that were unlikely to be made from the seeds of the grapefruit.^{[39][40][41][42][43]}
• Thymol, an ingredient common in mouthwashes and medicated chest rub ointments, has been shown to have a potential to be effective against the fungus that commonly infects toenails.^[44]
• Snakeroot leaf extract has, in studies, shown ability to treat superficial onychomycosis, although the results show it is less effective, and equal to conventional drugs ciclopirox and ketaconazole, respectively.^[45][46]

 See also

• Athlete's foot
• Nail disease
• List of tinea infections
• List of cutaneous conditions

 References

1. ^ ^{a b c} Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. p. 1135. ISBN 1-4160-2999-0.
2. ^ onychomycosis at Dorland's Medical Dictionary
3. ^ Szepietowski JC, Salomon J (2007). "Do fungi play a role in psoriatic nails?". Mycoses 50 (6): 437–42. doi:10.1111/j.1439-0507.2007.01405.x. PMID 17944702.
4. ^ "Impact 07 - Dermatology" (PDF). Bay Bio. 2007. Retrieved 2007-06-13.
5. ^ James, William D.; Berger, Timothy G.; et al. (2006). Andrews' Diseases of the Skin: clinical Dermatology. Saunders Elsevier. ISBN 0-7216-2921-0.
6. ^ "AAPA". Cmecorner.com. Retrieved 2010-08-05.
7. ^ Onychomycosis at eMedicine
8. ^ Szepietowski JC, Reich A (September 2008). "Stigmatisation in onychomycosis patients: a population-based study". Mycoses 52: 343. doi:10.1111/j.1439-0507.2008.01618.x. PMID 18793262.
9. ^ Chi CC, Wang SH, Chou MC (2005). "The causative pathogens of onychomycosis in southern Taiwan". Mycoses 48 (6): 413–20. doi:10.1111/j.1439-0507.2005.01152.x. PMID 16262878.
10. ^ Karimzadegan-Nia M; Mir-Amin-Mohammadi A; Bouzari N, Firooz A (2007). "Comparison of direct smear, culture and histology for the diagnosis of onychomycosis". Australas. J. Dermatol. 48 (1): 18–21. doi:10.1111/j.1440-0960.2007.00320.x. PMID 17222296.
11. ^ Weinberg JM; Koestenblatt EK; Tutrone WD; Tishler HR; Najarian L (2003). "Comparison of diagnostic methods in the evaluation of onychomycosis". J. Am. Acad. Dermatol. 49 (2): 193–7. doi:10.1067/S0190-9622(03)01480-4. PMID 12894064.
12. ^ PubMed
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15. ^ http://www.mayoclinic.com/health/nail-fungus/DS00084/DSECTION=treatments-and-drugs
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17. ^ Haugh M, Helou S, Boissel JP, Cribier BJ (2002). "Terbinafine in fungal infections of the nails: a meta-analysis of randomized clinical trials". Br. J. Dermatol. 147 (1): 118–21. doi:10.1046/j.1365-2133.2002.04825.x. PMID 12100193.
18. ^ Mitchel L. Zoler (April 1, 2004). "Boosts drug entry into nails: urea, ciclopirox combo tested for onychomycosis.(Focus on Skin Disorders)". Internal Medical News. p. 69.
19. ^ Potter LP, Mathias SD, Raut M, Kianifard F, Landsman A, Tavakkol A (2007). "The impact of aggressive debridement used as an adjunct therapy with terbinafine on perceptions of patients undergoing treatment for toenail onychomycosis". The Journal of dermatological treatment 18 (1): 46–52. doi:10.1080/09546630600965004. PMID 17373090.
20. ^ Baran R, Sigurgeirsson B, Berker DD, et al. (2007). "A multicentre, randomized, controlled study of the efficacy, safety and cost-effectiveness of a combination therapy with amorolfine nail lacquer and oral terbinafine compared with oral terbinafine alone for the treatment of onychomycosis with matrix involvement". British Journal of Dermatology 157 (1): 149. doi:10.1111/j.1365-2133.2007.07974.x. PMID 17553051.
21. ^ clinicaltrials.gov
22. ^ ClinicalTrials.gov NCT00459537
23. ^ "Apricus Biosciences Announces Expanded European Patent Coverage For MycoVa(TM) For Nail Fungus". The Street. Retrieved 2011-03-14.
24. ^ NEXMED Medicines of the Future
25. ^ ^{a b} ClinicalTrials.gov NCT00356915
26. ^ ClinicalTrials.gov NCT00443820 and ClinicalTrials.gov NCT00443898
27. ^ ClinicalTrials.gov NCT00935649 and ClinicalTrials.gov NCT00776464
28. ^ ClinicalTrials.gov NCT01008033
29. ^ ClinicalTrials.gov NCT00781820
30. ^ Barak O, Loo DS (2007). "AN-2690, a novel antifungal for the topical treatment of onychomycosis". Curr Opin Investig Drugs 8 (8): 662–8. PMID 17668368.
31. ^ ClinicalTrials.gov NCT00491764
32. ^ NanoBio - Onychomycosis
33. ^ Landsman, Adam S.; et al. (2010). "Treatment of mild, moderate, and severe onychomycosis using 870- and 930-nm light exposure". Journal of the American Podiatric Medical Association 100 (3): 166–177.
34. ^ "LAFT".^{[unreliable source]}
35. ^ Cathy Becker, Jonann Brady (April 9, 2009). "Promising New Treatment for Fungus-Free Feet". ABC news. Retrieved 2009-11-06.
36. ^ Buck DS, Nidorf DM, Addino JG (1994). "Comparison of two topical preparations for the treatment of onychomycosis: Melaleuca alternifolia (tea tree) oil and clotrimazole". J Fam Pract 38 (6): 601–5. PMID 8195735.
37. ^ Nenoff P, Haustein UF, Brandt W (1996). "Antifungal activity of the essential oil of Melaleuca alternifolia (tea tree oil) against pathogenic fungi in vitro". Skin Pharmacol. 9 (6): 388–94. doi:10.1159/000211450. PMID 9055360.
38. ^ "Tea tree oil (Melaleuca alternifolia)". Drugs & Supplements. Mayo Clinic. May 1, 2006. Retrieved 2008-01-29.
39. ^ von Woedtke T, Schlüter B, Pflegel P, Lindequist U, Jülich WD (1999). "Aspects of the antimicrobial efficacy of grapefruit seed extract and its relation to preservative substances contained". Pharmazie 54 (6): 452–6. PMID 10399191.
40. ^ Sakamoto S, Sato K, Maitani T, Yamada T (1996). [Analysis "of components in natural food additive "grapefruit seed extract" by HPLC and LC/MS"] (in Japanese). Eisei Shikenjo hokoku. Bulletin of National Institute of Hygienic Sciences (114): 38–42. PMID 9037863.
41. ^ Takeoka G, Dao L, Wong RY, Lundin R, Mahoney N (2001). "Identification of benzethonium chloride in commercial grapefruit seed extracts". J. Agric. Food Chem. 49 (7): 3316–20. doi:10.1021/jf010222w. PMID 11453769.
42. ^ Takeoka GR, Dao LT, Wong RY, Harden LA (2005). "Identification of benzalkonium chloride in commercial grapefruit seed extracts". J. Agric. Food Chem. 53 (19): 7630–6. doi:10.1021/jf0514064. PMID 16159196.
43. ^ Ganzera M, Aberham A, Stuppner H (2006). "Development and validation of an HPLC/UV/MS method for simultaneous determination of 18 preservatives in grapefruit seed extract". J. Agric. Food Chem. 54 (11): 3768–72. doi:10.1021/jf060543d. PMID 16719494.
44. ^ Ramsewak RS, et al. In vitro antagonistic activity of monoterpenes and their mixtures against 'toe nail fungus' pathogens. Phytother Res. 2003 Apr;17(4):376-9.
45. ^ PMID 19683043 
46. ^ PMID 18671197
47. Wikipedia, Onchomycoses

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