CHAPTER 218

TOPICAL ANTIBIOTICS
Mark W. Bonner
Paul M. Benson
William D. James

Topical antibiotics play an important role in the management of many common dermatologic
conditions (Table 218-1). They are prescribed most often by dermatologists for the management
of mild to moderate acne vulgaris or as adjunctive treatment with oral agents. For localized
superficial infections, such as impetigo, the use of a topical agent (e.g., mupirocin) may
eliminate the need for oral antibiotics and the accompanying problems of compliance,
gastrointestinal side effects, and potential drug interactions. Topical antibiotics are still
frequently prescribed as prophylactic agents after minor surgery or cosmetic procedures
(chemical peel or laser resurfacing) to reduce the risk of postoperative wound infection and to
speed wound healing. The use of topical antibiotics for prophylaxis after such minor procedures
has been proven to be unnecessary and incurs risk of inducing allergy. Petrolatum is
recommended for use after clean surgical procedures.

TOPICAL
ANTIBIOTICS
Topical antibiotics are useful in the treatment of acne and rosacea.
Use in impetigo may obviate the need for oral antibiotics.
Use of topical antibiotics to prevent wound infection after clean surgical procedures is
unnecessary.

AGENTS USED IN THE TOPICAL lREATMENT OF ACNE AND ROSACEA

The efficacy of topical antibiotics for the treatment of acne vulgaris and rosacea may be due to
their direct antibiotic effect, but many of the topical antibiotics exhibit anti-inflammatory
properties by suppressing neutrophil chemotactic factor or by other mechanisms. There are
concerns about the use of topical antibiotics in the treatment of acne vulgaris because of the
increasing levels of antibiotic resistance to common topicals. Combining the antimicrobial
benzoyl peroxide with antibiotics reduces the development of antibiotic resistance.

TABLE 218-1
Topical Antibiotics
FORM MECHANISM OF
NAME SOURCE BACTERIA
AVAILABLE ACTION
Bacitracin Bacillus subtilis O Cell wall inhibitor Gr+
Polymyxin B B.polymyxa O Detergent Gr-
Gramicidin O Ion channel Gr+
Pseudomonas
Mupirocin O Transfer RNA inhibitor Gr+
Fluorescens
Streptomyces
Neomycin O 30S ribosome inhibition Gr-
Fradiae
Tetracycline Semisyntheticb O,S 30S ribosome inhibition Gr
Meclocycline Semisyntheticc C 30S ribosome inhibition Gr
Streptococcus
Erythromycin S, G, P.O 50S ribosome inhibition Gr
erythreus
Clindamycin Semisynthetic S,G,L 50S ribosome inhibition
Chloramphenicol S. venezuelaed C 50S ribosome inhibition
Fusidic acid NA Interferes with EF-G
Silver
Synthetic C
sulfadiazine
Mafenide acetate Synthetic C Enzyme inhibition Gr
Nitrofurazone Synthetic C,S Enzyme inhibition Gr
Metronidazole Synthetic G,C Electrochemical Anaerobes
Broad
Clioquinol Synthetic C,O Unknown
spectrum
Azelaic acid Synthetic C,G Protein synthesis inhibition Gr+
C=cream; EF-G =elongation factor G; G=gel; Gr + =Gram-positive; Gr - =Gram-negative; Gr
=Gram-positive or -negative; L=lotion; NA=not available in the United States; O=ointment;
P=pledget; S=solusion.
a
Bacteria refers to bacteria usually susceptible to antibiotic.
b
Semisynthetic from chlortetracycline, fermented from some species of Streptomyces.
C
Semisynthetic from tetracycline.
d
Now completely synthesized.

Erythromycin
Erythromycin belongs to the group of macrolide antibiotics and is active against both Gram
positive cocci and Gram-negative bacilli. It is used princi pally as a topical agent in the treatment
of acne. Erythromycin binds to the bacterial 50S ribosome and blocks translocation of the
peptidyl-transfer RNA (tRNA) molecule from the acceptor to the donor site, interfering with the
formation of the polypeptide chain and inhibiting protein synthesis. In addition to its antibacterial
properties, erythromycin has anti-inflammatory activity. Erythromycin is available as a 1.5
percent to 2.0 percent solution, gel, pledgets, and ointment as a single agent. It is also available
in combination with benzoyl peroxide.

Clindamycin
Clindamycin is a semisynthetic lincosamide antibiotic that is derived from lincomycin. The
mechanism of action is very similar to that of erythromycin, with binding to the 50S ribosome
and suppression of bacterial protein synthesis. Clindamycin is used topically as a 1 percent gel,
solution, suspension (lotion), and foam primarily for the treatment of acne. It is also available as
a combination with benzoyl peroxide, which may slow the development of antibiotic resistance
to clindamycin. Pseudomembranous colitis rarely has been reported to occur with the topical use
of clindamycin.2

Metronidazole
Metronidazole, a topical nitroimidazole, is currently available as a 0.75 percent gel, cream, or
lotion and as a 1 percent cream or gel for the topical treatment of rosacea. In the lower strength,
it is applied twice daily, and in the higher strength, it is used once daily. Orally, metronidazole
has broad-spectrum activity against many protozoal organisms and anaerobes.

Azelaic Acid
Azelaic acid is a dicarboxylic acid found in food (whole-grain cereals and animal products).
There is a normal human plasma level (20 to 80 ng/mi); topical application does not significantly
alter this level. The mechanism of action is thought to be normalization of the keratinization
process (decreased thickness of the stratum corneum, decreased number and size of eratohyaline
granules, and decreased amount of filaggrin). There are reports of in vitro activity against
Propionibacterium acnes and Staphylococcus epidermidis, which may be due to protein
synthesis nhibition. In aerobic microorganisms, there is inhibition of oxidoreductive enzymes
(such as tyrosinase, mitochondrial enzymes of the respiratory chain, 5ex-reductase, and DNA
polymerases). In anaerobic bacteria, there is disruption of glycolysis. Azelaic acid is used
principally in the treatment of acne vulgaris and rosacea, although there are some advocates for
its use in the treatment of hyperpigmentation (such as melasma for which it was initially
developed). However, the U.S. Food and Drug Administration has not approved the drug for this
indication. Azelaic acid is available as a 15 percent gel or 20 percent cream preparation.

Sulfonamides (Sulfacetamide)
Sulfacetamide is a topical sulfonamide used in the treatment of rosacea and acne. The
antibacterial mechanism of action for most sulfonamides is competition with para-aminobenzoic
acid (pABA) during the synthesis of folic acid. The mechanism of action for topical treatment of
rosacea is not understood at this time. Sulfacetamide is available as a 10 percent lotion and in
combination with 5 percent sulfur in a gel, cream, suspension, cleanser, cloths,
and mask.

AGENTS USED FOR THE TOPICAL THERAPY OF SUPERFICIAL BACTERIAL

INFECTIONS AND BURNS
Localized impetigo, superficial dirty abrasions, and secondarily infected chronic dermatoses are
commonly treated with topical antibiotics. However, widespread impetigo, infection of the lower
extremities, or disease occurring in immunocompromised individuals should be treated with
systemic antibiotics to reduce the risk of serious complications. Topical antibiotics are still at
times used following minor surgical procedures. The result of a large study comparing bacitracin
and petrolatum in more than 1200 minor surgical procedures demonstrated that bacitracin did not
statistically decrease the already low rate of infection. Several patients were, however, shown to
be allergic to bacitracin. Petrolatum proved to be cheaper, of equal efficacy and to have fewer
side effects than bacitracin.3 When clean wounds are made during minor surgery, there is no need
to use antibacterial ointment to aid in healing or prevent infection. Because burns produce a
fertile ground for life-threatening secondary infection, prophylactic topical
therapy is often used.

Mupirocin
Mupirocin, which was formerly known as pseudomonic acid A, is a topical antibiotic agent
derived from Pseudomonas (luorescens.The drug reversibly binds to isoleucyl- tRNA synthetase
and inhibits bacterial protein synthesis. The activity of mupirocin is limited to Gram-positive
bacteria, especially staphylococci and most streptococci. Its activity is enhanced in an acid pH
environment (5.5), which is the normal pH of the skin. Mupirocin is somewhat temperature-
sensitive, and thus loses efficacy if exposed to high temperatures. Mupirocin ointment 2 percent
is applied three times daily and is principally indicated for the treatment of localized impetigo
caused by S. aureus and Streptococcus pyogenes. One study in the Tennessee Veterans' Affairs
Hospital demonstrated that prolonged use of mupirocin ointment to control methicillin-resistant
S. aureus (MRSA) carriage, especially in bedridden patients with decubitus ulcers, led to
significant resistance.4 Furthermore, Japanese researchers found that low serum concentrations of
mupirocin are achieved after intranasal application and postulated that this might explain the
selection of mupirocin-resistant strains of 5 aureus.s A small pilot study using intranasal
application of a combination antibiotic ointment containing bacitracin, polymyxin B, and
gramicidin successfully decolonized 80 percent (9 out of 11) of MRSA-positive patients who
remained clear after a mean follow-up of 2 months. All cases of mupirocin-sensitive MRSA
were eradicated, whereas. only three of five cases of mupirocinresistant were eliminated.6 New
formulations that involve the use of the calcium salt of mupirocin (the calcium salt aids in
chemical stability in the intranasal preparation) are available for intranasal use as a 2 percent
ointment and a 2 percent topical cream.
Bacitracin
Bacitracin is a topical polypeptide antibiotic originally isolated from the Tracy-I strain of
Bacillus subtilis. Bacitracin is a cyclic polypeptide with multiple components (A, B, and C).
Bacitracin A is the major component of commercial products and is often used as the zinc salt.
Bacitracin interferes with bacterial cell wall synthesis by binding to and inhibiting the
dephosphorylation of a membranebound lipid pyrophosphate. It is active against Gram-positive
cocci such as staphylococci and streptococci. Most Gram-negative organisms and yeast are
resistant to the drug. It is available as bacitracin ointment and as zinc bacitracin, with 400 to 500
units per gram. Topical bacitracin is effective for the treatment of superficial bacterial infections
of the skin such as impetigo, furunculosis, and pyodermas. It is often combined with polymyxin
B and neomycin as a triple antibiotic ointment applied several times daily for the treatment of
secondarily infected eczematous dermatitis such as atopic dermatitis, nummular dermatitis, or
stasis dermatitis. Unfortunately, the topical application of bacitracin carries with it the risk of
allergic contact sensitization and, rarely, anaphylactic shock.7

Polymyxin B
Polymyxin B is a topical antibiotic derived from a spore-forming soil aerobe B. polymyxa.
Polymyxin B is a mixture of polymyxin BI and B2, which are both cyclic polypeptides. They
function as cationic detergents that interact strongly with bacterial cell wall membrane
phospholipids, thus disrupting the integrity of the cell membrane. Polymyxin B is active against
a wide range of Gram-negative organisms, including P. aeruginosa, Enrerobaaer, and
Escherichia coli. Polymyxin B is available in ointment form (5000 to 10,000 units per gram) in
combination with bacitracin or as triple antibiotic ointment with bacitracin and neomycin. It
should be applied one to three times a day.

Topical Aminoglycosides
(Neomycin and Gentamicin)
The aminoglycosides are an important group of antibiotics used both topically and systemically
for the treatment of infections caused by Gram-negative bacilli. Aminoglycosides exert their
bactericidal effects by binding to the 30S ribosomal subunit and interfering with protein
synthesis. Neomycin sulfate, the aminoglycoside most often used topically, is a fermentation
product of Streptomyces fradiae. Commercial neomycin is a mixture of neomycin Band C,
whereas framycetin, used in Canada and some European countries, is pure neomycin B.8
Neomycin sulfate has activity against aerobic Gram-negative bacteria and is used most
commonly for prophylaxis against infection in superficial abrasions, cuts, and burns. It is
available in ointment form (3.5 mg/g) and is also packaged in combination with other antibiotics
such as bacitracin, polymyxin, and gramicidin. Other agents, such as lidocaine, pramoxine, or
hydrocortisone, also are available in combination with neomycin. Neomycin is not recommended
by many dermatologists because it is responsible for a large number of cases of allergic contact
dermatitis. The prevalence of contact dermatitis is high, with 6 percent to 8 percent of patients
undergoing patch testing being positive.9 Neomycin sulfate (20 percent) in petrolatum is used to
assess for contact allergy. Gentamicin sulfate is derived as a fermentation product from
Micromonospora purpurea. It is avai1able as a topical 0.1 percent cream or ointment. It is used
by some dermatologic surgeons when operating on the ear, especially in diabetic or other
immunocompromised patients, to provide prophylaxis against malignant otitis externa due to P.
aeruginosa. The ophthalmic formulation is useful in caring for operative wounds in the
periorbital area.

Sulfonamides (Silver Sulfadiazine and Mafenide Acetate)

The sulfonamides are structurally similar to PABA and compete with it during the synthesis of
folic acid. Sulfonamides are used to treat acne vulgaris, acne rosacea, and burns. Silver
sulfadiazine is thought to release silver slowly and exerts its effect on the bacterial cell walls and
membranes. The mechanism of action of mafenide is not the typical sulfonamide mechanism of
action because PABA does not antagonize its performance. Mafenide acetate, if used over large
areas of skin, has the potential to cause metabolic acidosis, and it can cause intense pain on
topical administration. Both agents are broad-spectrum antibacterials useful in the treatment of
burns. Candida superinfection may be a problem with mafenide cream.

Nitrofurazone
Nitrofurazone (Furacin) is a nitrofuran derivative used for the treatment of bum patients. The
mechanism of action involves the inhibition of bacterial enzymes involved in the aerobic and
anaerobic degradation of glucose and pyruvate. Nitrofurazone is available as a 0.2 percent cream,
solution, or soluble dressing, and its spectrum of activity includes staphylococci, streptococci, E.
coli, Clostridium perfingens, and Proteus sp.

MISCELLANEOUS AGENTS

Gramicidin
Gramicidin is a topical antibiotic derived from B. brevis. The gramicidins are linear peptides that
form stationary ion channels in susceptible bacteria. The antibiotic activity of gramicidin is
restricted to Gram-positive bacteria.

Chloramphenicol
Chloramphenicol is available in the United States with use limited to the treatment of minor
bacterial skin infections. The mechanism of action is similar to that of erythromycin and
clindamycin, with inhibition of the 50S ribosome blocking translocation of peptidyl tRNA from
the acceptor to the donor site. Chloramphenicol is available as a 1 percent cream. It is used
infrequently because fatal aplastic anemia or dose-related bone marrow suppression has been
reported following topical exposure.10

Clioquinol
Clioquinol (also known as iodoch/orhydroxyquin) is a broad-spectrum antibacteria/antifungal
topical that is currently indicated for the treatment of inflammatory skin disorders and tinea pedis
and has been used for minor bacterial infections. It is a synthetic hydroxyquinoline whose
mechanism of action is unknown. The disadvantages of clioquinol include discoloration of
clothing, skin, hair, and nails and the potential to cause irritation. Clioquinol may interfere with
thyroid function determination because the iodine moiety interferes with tests that rely on iodine
uptake (this effect can last for up to 3 months after application). However, clioquinol does not
interfere with testing
for T3 or T4.
REFERENCES
1. Esterly NB et al: The effect of antimicrobial agents on leukocyte chemotaxis. Invest
DermatoI70:51, 1978
2. Clindamycin (topical), in Drug Il1formatiol1 for the Health Care Professiol1al (USPDI).
Englewood, CO, Micromedex, 2000, p 930
3. Smack DP et al: Infection and allergy incidence in ambulatory surgery patients using
white petrolatum versus bacitracin ointment.]AMA 276:972, 1996
4. Vasquez JE et al: The epidemiology of mupirocin resistance among methicillin- resistant
Staphylococcus aureus at a Veteran's Affairs hospital. Infect Control Hosp Epidemiol 21
:459, 2000
5. Watanabe H et al: low concentrations of mupirocin in pharynx following intranasal
application may contribute to mupirocin resistance in methicillin resistant Staphylococcus
aureus. ] C/in Microbiol 39:3775, 2001
6. Fung S et al: The utility of Polysporin ointment in the eradication of methicillin-resistant
Staphylococcus aureus colonization: A pilot study. Infect Control Hosp Epidemiol
21:653,2000
7. Farley M et al: Bacitracin anaphylaxis. Am] Contact Dermatitis 6:28, 1995
8. Budavari S: The Merck Index, 12th ed. Whitehouse Station, NJ, Merck & Co, 1996,
p1108
9. Marks JG, Deleo VA: Standard allergens, in Contact and Occupational Dermatology, St.
louis, MO, Mosby Year Book, 1992 p 59
10. Chloramphenicol (topical), in Drug Information for the Health Care Professional (USP
DI). Englewood, CO, Micromedex, 2000, p 795
 CHAPTER 2 1 9

Topical Antifungal Agents

Whitney A. High
James E. Fitzpatrick

TOPICAL ANTIFUNGAL AGENTS

Preferred treatment for superficial fungal infection of limited extent.
Low cost, low incidence of drug interactions, few side effects and complications, ease of
use.
Use systemic agent when superficial fungal infection affects large surface area, involves
terminal hair or nails, or is resistant to topical management.
Topical antifungal classes: Imidazoies, allylamines, benzylamines, polyenes.
Ciclopirox olamine: Unique topical antifungal with broad-spectrum activity, variety of
indications.
Side effects: Irritant dermatitis, allergic contact dermatitis, urticarial reactions.
Combination agents (antifungal and steroid):
Watch for side effects due to glucocorticoids.
Combination agents: Higher rate of treatment failure, disease relapse.

Superficial fungal infections, including dermatophytoses, candidiasis, and pityriasis versicolor,

are most often restricted to the epidermis. In treating these infections, the chnician must select
between topical or systemic management. Factors guiding management include, but are not
limited to, the:
extent and severity of the infection,
site of involvement,
co-morbid conditions or potential drug interactions, if any,
anticipated efficacy of treatment,
cost and access to medication, and
ease of use.
 Patients with limited fungal infections confined to glabrous skin are usually best treated with
topical agents. Conversely, those with extensive or recalcitrant disease, or with involvement of
terminal hair or nails, may be better suited for systemic management. In some cases, either
treatment option may be reasonably chosen.
Treatment with topical antifungal therapy enjoys several advantages over systemic
management, including:
fewer side effects,
fewer drug interactions,
localization of treatment, and
generally lower cost.

Numerous topical antifungal medications are available (Table 219-1). For the most part,
specific antifungal agents have replaced non-specific topical treatments, such as keratolytics
(salicylic acid) or antiseptics (gentian violet or Castellani's paint), which were once the
cornerstones of management.
The "ideal" topical antifungal is easily defined (Table 219-2), yet no one current topical agent
possesses all of these properties. Despite Widespread availability, few topical antifungal agents
have been directly compared with one another in clinical trials. Studies sponsored by the
manufacturer often compare just the active agent to the vehicle. Extrapolation between studies is
further complicated due to differences in study design, duration of therapy, site of infection,
selection methodology, or treatment endpoint.
Most topical antifungals belong to one of three classes: (1) imidazoles, (2) allylamines and
benzylamines, and (3) polyenes. Some agents do not fit well into this schema and are discussed
separately.

IMIDAZOLES
Imidazoles represent a broad class of antifungal medications. Certain of these, such as
clotrimazole, have been around for decades, while others, such as sertaconazole, have only
become available recently.
Mechanism of Action
lmidazoles impede synthesis of a component of the fungal cell wall through inhibition of
lanosterol 14a-demethylase, a cytochrome P450 dependent enzyme, which converts lanosterol to
ergosterol.1 Depletion of ergosterol results in membrane instability and hyperpermeability, which
are changes incompatible with growth and survival of the fungus. lmidazoles are considered
fungistatic. Although all possess the same mechanism of action, in vitro studies demonstrate that
not all dermatophytes are uniformly susceptible to an imidazole at an equivalent concentration,
and this may explain some treatment fail ures.2-4 Currently, there is no uniform reference method
for susceptibility testing of dermatophytes. Topical imidazoles possess anti-inflammatory
activity via inhibition of neutrophil chemotaxis, calmodulin activity, synthesis of leukotrienes
and prostaglandins, and histamine release from mast cells.5-7 Some agents, such as ketoconazole,
yield anti-inflammatory effects equivalent to 1 percent hydrocortisone. a Topical imidazoles also
demonstrate limited antibacterial properties, particularly with respect to Gram-positive
organisms.9.10

TABLE 219-1
Topical Antifungal Agents Commonly Used in Dermatology
GENERIC TRADE PREGNANCY
FORMULATION Rx/OTC
NAME(S) NAME(S) CLASS
Imidazoles
Clotrimazole Cruex (Rx) 1% cream, C Rx and OTC
DesenexAF 10tion,lozenges/troches,
Lotrimin powder, C Rx and OTC
Lotrimin AF spray solution, solution
Mycelex
Econazole Spectazole 1% Ecostatin C Rx only
cream C Ax
only
Ketoconazole Nizoral 1%and 2% cream and C Rx and OTC
Nizoral AD shampoo
Miconazole Micatin 2% cream, lotion, C OTC
 Micozole powder, spray powder,
Monistat-Derm spray solution
Zeasorb AF
Oxiconazole Derimine 1% cream, lotion B Rx
Mytungar
Oceral
Oceral GB
Okinazole
Oxistat
Oxizole
Sertaconazole Ertaczo 2% cream C Rx
Sulconazole Exelderm 1% cream, solution C Rx
Sulcosyn
Allylamine
Naftifine Naftin 1%cream, gel B Rx
Terbinafine Lamisil 1% cream, spray B Rx
LamisilAT solution, solution
Benzylamines
Butenafine Mentax 1% cream B Rx
Polyenes
Nystatin Bio-Statin 100,000 Ulg cream, C Rx
Mycostatin lozenge/troche,
Nystop ointment, powder,
Pedi-Dri solution
Other topical
antifungals
Ciclopirox Loprox 0.77% cream or lotion, B Rx
olamine Penlac 1%shampoo or solution
8% nail lacquer
Tolnaftate Equate (Wal- 1% cream, powder, N/A OTC
 Mart) spray powder, spray
Tinactin solution, solution
Undecylenic Desenexb 20% cream, 10% N/A OTC
acid Cruex (OTC)c penetrating foam, 10%-
20% powder, 20%
spray powder
Combination
agents
Clotrimazole- Lotrisone 1% clotrimazole and N/A Rx
betamethasone 0.05% betamethasone
dipropionate dipropionate
dipropionate in cream
or lotion
Nystatin- Mycolog-II 100,000 U/g nystatin N/A Rx
triamcinolone Mytrex and 0.1%triamcinolone
acetonide Quenalog acetonide

NlA =not applicable; OTC =over-the-counter agent; Rx =prescription agent.

a
Varying pregnancy class depends on form; majority of forms are Category C.
b
Some forms of Desenex contain other agents, such as tolnaflate, clotrimazole, miconazole, or
terbinafine.
c
Some forms of Cruex contain miconazole

TABLE 219-2
Properties of an Ideal Topical
Antifungal Agent
Broad spectrum of action
Fungicidal at therapeutic concentration
Absence of resistance within the targeted fungi
Keratinophilic with penetration of the cornified envelope without systemic absorption
Nonirritating and hypo-allergenic
 Possess anti-inflammatory properties
Once-per-day application (or less)
Short duration of therapy for cure
Availability in multiple formulations (cream, solution, etc.) and sizes
Inexpensive

TABLE 219-3
Indications for the Use of
Topicallmidazoles
Dermatophytoses
Tinea pedis/tinea manum
Tinea cruris
Tinea corporis
Tinea faciei (the unbearded face)
Pityriasis versicolor
Mucocutaneous candidiasisa
Cutaneous candidiasis
Vulvovaginal candidiasisb
Oral candidiasis (thrushf
Perteche
Seborrheic dermatitisd

a
Oxiconazole and sulconazole have relatively weaker activity against candida.
b
Clotrimazole, econazole, miconazole, tercenazole, and tioconazole are available as vaginal
preparations.
c
Clotrimazole-dissolving troches are used for oral thrush.
d
Ketocenazole is used for seborrheic dermatitis.
Pharmacokinetics
Topical antifungals are designed expressly for treating superficial fungal infections.
Consequently, all marketed imidazoles demonstrate excellent penetration of the stratum corneum
with strong keratinophilic behavior. Sulconazole may be detected in the stratum corneum up to
96 hours after application. 11 Similarly, sertaconazole, the newest of all marketed imidazoles,
has a half-life within the stratum corneum of more than 60 hours12 Because of this high affinity
for keratin, systemic absorption of imidazoles is low, with urinary excretion usually in the range
of 0.3 percent to 1.0 percent of the applied dose. Even when applied to inflamed skin, absorption
of imidazoles does not usually exceed 4 percent of the applied dose. Again, sulconazole is
unique in that percutaneous absorption in the range of 8 percent to 11 percent of the applied dose
exceeds that of all other imidazoles.11

Indications
Indications for topical imidazole use are detailed in Table 219-3. Because of inherent
antibacterial activity, some topical imidazoles have demonstrated modest efficacy in treating
erythrasma, impetigo, and ecthyma. Because there are more potent antibacterial agents, this is
nOI a preferred indication for imidazole use.8,13,14 Cure rates for superficial fungal infection
treated with imidazoles are variable and often depend upon study design. For example, topical
miconazole has demonstrated a 63 percent to 100 percent cure rate, depending upon the study
quoted. A thorough review of the literature provides no compelling evidence that significant
differences in cure or relapse exist among the various topi cal imidazoles; however, other
considerations may dictate selection of a particular imidazole. Topical imidazoles are available
as a cream or lotion. Although lotions are better suited for use over large areas or upon hair-
bearing skin, limited studies suggest a cream may be marginally more effective. In studies
performed by the manufacturer, oxiconazole cream yielded a clinical and mycologic cure in
52 percent of tinea pedis cases while the lotion yielded the same cure in just 41 percent of cases.
Additionally, the potential for irritancy must be considered. In one study of topical clotrimazole
for treatment of tinea cruris, erosive reactions developed in four of 27 patients while sulconazole
did not cause any erosions in the same population. IS Similarly, in a second study, severe irritant
reactions were reported with miconazole use but not with sulconazole use.16 Until formal studies
of irritancy are performed we often recommend use of sulconazole in sensitive areas such as the
groin. Finally, ease of use may be a factor to consider, as some imidazoles are specifically
approved for once-daily dosing (see Dosing Regimen).

Dosing Regimen
Topical imidazoles are available in a multitude of forms (see Table 219-1). Econazole,
ketoconazole, and oxiconazole are approved for once-daily dosing but twice-daily dosing is
recommended for the remainder. Nevertheless, although twice-daily dosing is recommended Eor
sulconazole, a study comparing oncedaily to twice-daily dosing in tinea corporis and tinea cruris
reported an identical rate of cure.IS This might have been predicted based upon the 60-hour
halflife within the stratum comeum.12 Application of all topical antifungals, including
imidazoles, should include normal skin for a radius of 2 em beyond the affected area. Duration
oE treatment with imidazoles has varied. In general, tinea corpori and tinea cruris require
treatment for approximately 2 weeks, whereas tinea pedis may require treatment for up to 4
weeksY Treatment should be continued for at least 1 week after all symptoms have abated.18

Risks and Precautions

Risks associated with the use of topical imidazoles include those inherent to all topical
medications (Table 219-4). Additionally, clotrimazole is marketed in combination with the
topical glucocorticoid, betamethasone dipropionate. It was assumed that the addition of the
steroid would more rapidly relieve inflammation, scaling, and pruritus. Early studies
demonstrated the combination was indeed more effective than clotrimazole alone in alleviating
symptoms.19,20 However, betamethasone dipropionate is a potent topical steroid and, soon after
release of the combination product, striae and other cutaneous side effects from the steroid
component were reported.21 Longer-term studies also reported a higher relapse rate (36 percent)
with use of combination product.22,23 This combination product may comprise 50 percent or
more of antifungal prescriptions by primary care providers, compared to less than 7 percent
among dermatologists.24 It is likely that overuse by non-specialists occurs because of the
mistaken assumption either that the steroid agent is mild, or that the combination will be a "better
choice" when the differential diagnosis is unresolved.25 The U.S. Food and Drug Administration
has twice revised the product warnings for clotrimazole-betamethasone dipropionate,
discouraging use on thin skin, for prolonged periods, or when the diagnosis is in doubt.
TABLE 219-4
Adverse Reactions to Topical Antifungals
Irritant contact dermatitis (worsened by occlusion)
Allergic contact dermatitis (to active agent or more likely to other ingredients/preservatives)
Urticarial reactions (rare)
Inappropriate treatment due to misdiagnosis (more likely with over-the-counter agents)

Complications
Use of topical imidazoles is associated with few complications. Because of low systemic
absorption, drug interactions with topical imidazoles are extremely rare. Nevertheless, in a single
study, increased serum tacrolimus levels were observed in renal transplant recipients who used
clotrimazole troches for mucocutaneous candidiasis.26 For this reason, use of nystatin may be
preferred when treating thrush in transplant patients using tacrolimus. Concerns of resistance
must also be considered. Resistance of Calldida albican to clotrimazole has been described in
human immunodeficiency virus-positive patients with mucocutaneous candidiasis.27 Low levels
of in vitro resistance of various Calldida sp. to other topical imidazoles has also been
documented.28 Often, this resistance is associated with resistance to oral fluconazole.

ALLYLAMINES AND BENZVLAMINES

Allylarnines and benzylamines are closely related compounds. Currently, two topical allylamines
and a single topical benzylamine are marketed (see Table 219-1).

Mechanism of Action
Allylamines and benzylamines share a common mechanism of action. These agents impede
synthesis of ergosterol through inhibition of squalene epoxidase, an enzyme that converts
squalene to squalene oxide.29 Depletion of ergosterol results in membrane instability and
hyperpermeability. Allylamines and benzylamines are considered fungicidal because the
accumulation of intracellular squalene leads directly to cell death. The clinical significance of
this cidal action is unclear. Unlike imidazoles, the activity of allylarnines and benzylarnines is
independent of the cytochrome P450 enzyme system. When compared to naftifine, terbinafine
demonstrates a 10- to 100-fold increased potency in vitro, although this does not appear to be
relevant in clinical use. Like imidazoles, allylamines and benzylamines demonstrate anti-
inlammatory activity.S.30 Naftifine inhibits adhesion of polymorphonuclear cells to
endothelium, interrupts chemotaxis, and inhibits the 5-lipoxygenase proint lammatory
pathway.31,32 It is assumed that terbinafine and butenafine yield anti-inflammatory effects
through similar mechanisms. Allylamines and benzylamines also demonstrate limited
antibacterial properties. In fact, a recent study showed lowered minimum inhibitory
concentrations for bacteria as well as fungi when terbinafine was used in combination with
benzoyl peroxide.33

Pharmacokinetics
Allylamines and benzylamines are highly lipid soluble and efficiently penetrate the stratum
corneum, where they may persist for extended durations.34 Butenafine has been detected within
the stratum corneum at minimum inhibitory concentration for at least 72 hours after
application,3s and terbinafine may persist at a similar level for up to 7 days after application.36
Systemic absorption of these agents is quite low, with typical urinary excretion in the range of 3
percent to 5 percent of the applied dose, an amount considered biologically and clinically
insignificant.36

Indications
Indications for the use of topical allylamines and topical benzylamines are detailed in Table 219-
5. Despite antibacterial properties, terbinafine has proven inferior to mupirocin for treatment of
impetigo,37 and a traditional antibacterial agent should be used instead. Similarly, although
allylamines and benzylamines do demonstrate activity against dimorphic fungi involved in
systemic infection such as Sporothrix schenckii, Blastomyces dermatitidis, and Histoplasmosis
capsulatunI, topical therapy is inappropriate in this situation. Limited evidence suggests that
topical allylamines or benzylamines may be preferred over topical imidazoles for certain
dermatophyte infections. Repeated trials for tinea pedis indicate that 1 week of topical
terbinafine is as effective as 4 weeks of topical imidazoles, with cure resulting in 53 percent to
95 percent of cases.38-41 Use of this abbreviated treatment with terbinafine has been confirmed
in trials using the active agent versus vehicle alone.42 In some instances, resolution of tinea pedis
using terbinafine has occurred with as few as three doses.43 Currently a 30-g tube of terbinafine is
three times more expensive than a 30-g tube of clotrimazole.44 Considering the frequency of
application, the amount of medication required, the likelihood of patient compliance and ease of
use, and the rapidity of results, some experts recommend topical terbinafine over topical
imidazoles for tinea pedis.45,46 Nevertheless, using the same data, other experts have
recommended initial use of less expensive imidazole therapy with reservation of allylamines and
benzylamines for treatment failure.47 A consensus has not yet been achieved. Finally, topical
allylamines and benzylamines are effective against Candida or PityrosponJm sp. However, given
the relative cost of these agents compared to cheaper, equally reliable, and specifically approved
agents, such as imidazoles, polyenes, ciclopiroxamine, and over-thecounter selenium sulfide,
there is no compelling reason to turn away from these more affordable options.

Dosing Regimen
Topical allylamines and benzylamines are available in a number of forms (see Table 219-1).
Each agent has a slightly different dosing regimen based upon the formulation and the location
and severity of infection (Table 219-6). Risks and Precautions Risks associated with use of
topical allylamines and benzylamines are those inherent to all topical medicaments (see Table
219-3).

Complications
omplications occurring with use of topical allylamines or benzylamines are few.

TABLE 219-5
Indications for the Use ofTopical
Allylamines and Benzylamines
Dermatophytoses
Tinea pedis/tinea manum
Tinea cruris
Tinea corporis
Tinea faciei (the unbearded face)
Pityriasis versicolor"
a
Although butenafine is approved by the U.S. Food and Drug Administration for use in pityriasis
versicolor. the availability of numerous. more cost-effective remedies limits use in this clinical
situation.

POLYENES
Polyenes were among the first agents discovered to possess specific antifungal properties. The
two major topical polyene antifungals are nystatin and amphotericin B. Only topical nystatin is
actively marketed in the United States (see Table 219-1).

TABLE 219-6
Recommended Use of Topical Allylamines and Benzylamines
Recommendation
Agent Frequency of Application Duration of Aplication
Naftifine Cream-once daily General instructions for use 2
Gel-twice daily wk beyond resolution of
sypmtoms
Terbinafine Tinea pedis (interdigital)- At least 1wk
twice daily At least 2 wk
Tinea pedis (plantar)-twice At least 1wk, up to 4 wk
daily
Tinea elsewhere-once or twice
daily
Butenafine Tinea pedis-once to twice At least 1wk if twice daily,
daily and at
least 4 wk if once daily
Tinea elsewhere-once daily At least 2 wk
Pityriasis versicolor-once At least 2 wk
dailya
a
Although butenafine is approved by the U.S. Food and Drug Administration for use in pityriasis
versicolor, the
availability of numerous, more cost-effective remedies limits use in this clinical situation.
Mechanism of Action
Like all polyenes, nystatin binds irreversibly to membrane sterols present in susceptible species
of Candida.48 The polyene molecules demonstrate a higher affinity for fungal sterols, including
ergosterol, than for human sterols, yielding imperfect selective toxicity. This irreversible binding
alters membrane permeability, causing leakage of essential intracellular omponents and fungal
death. In low concentrations, nystatin is fungistatic, but at high concentrations it may be
fungicida1. 49

Pharmacokinetics
Nystatin is insoluble in water and is not absorbed from intact skin, the gastrointestinal tract, or
the vagina.50

Indications
Topical nystatin is used to treat mucocutaneous candidiasis caused by C. albicans, and other
susceptible species such as C. parapsilosis, C. krusei, and C. tropicalis. Repeated studies have
demonstrated that topical imidazoles are more effective than nystatin in treating vulvovaginal
candidiasis, and use of nystatin for this indication has diminished in recent years.51,52 Nystatin is
not effective against dermatophytes or Pityrosporumj and hence, it is not indicated for treatment
of tinea or pityriasis versicolor.

Dosing Regimen
Nystatin is available as a powder, cream, ointment, suspension, and pastille. To treat oral
candidiasis (thrush), the suspension or pastille is used four to five times daily, usually for 2
weeks. To treat cutaneous infection, the powder, cream, and ointment are used twice daily for
approximately 2 weeks.

Risks and Precautions

Risks associated with use of topical nystatin are those inherent to all topical medicaments (see
Table 219-3). A significant number of cases of allergic contact dermatitis attributed to nystatin
alone have been reported. These reactions have been reported with topical and oral use.53,54
Anaphylaxis has been described with use of nystatin-containing vaginal suppositories but the
reaction was attributed to ingredients other than nystatin.55 A combination agent consisting of
nystatin and triamcinolone acetonide is widely marketed. The addition of triamcinolone may
provide additional benefit over nystatin alone during the first few days of treatment when
inflammation is maximaI.56 After this initial period, the manufacturer recommends a transition to
nystatin alone or to other topical antifungal agents. Although triamcinolone acetonide is only a
mid-potency agent, cutaneous sequelae, including striae, skin atrophy, and steroid-induced acne,
have been reported.57 Because candidiasis often involves thin and fragile skin, such as that of the
intertriginous areas, the risk of damage is likely potentiated. Finally, many of the combined
formulations contained, or may still contain, ethy-lenediamine, a sensiti.zer that may cause
allergic contact dermatitis.58 As with clotrimazole-betamethasone dipropionate, the combination
agent of nystatin triamcinolone acetonide is more often prescribed by non-dermatologists.

Complications
Complications with topical polyenes are few. Nystatin resistance may be encountered in some
Candida Sp.59,60 This resistance may either be seen in wild strains (primary-type) or it may be
induced during therapy (secondary-type). Although C. albicans maintains a low rate of
spontaneous resistance to nystatin,61 particularly in comparison to resistance to imidazoles,62
other species, such as C. tropicalis, C. guilliermondi, C krusei, and C. stellatoides, rapidly
acquire resistance upon exposure to nystatin.

OTHER AGENTS
Some topical antifungals, such as ciclopirox olamine, tolnaftate, and undecylenic acid, do not fit
well into the major classes and are instead discussed separately.

Ciclopirox Olamine
Ciclopirox olamine is a hydroxypyridone antifungal agent with a unique structure and mode of
action.

MECHANISM OF ACTION
Unlike most other topical antifungals, ciclopirox olamine does not interfere with sterol
synthesis.63 Instead, it interrupts active membrane transport of essential cellular precusors,
particularly trivalent cations.64 Ultimately, this diSrupts cellular function, leading to demise of
the fungus. If concentrations of the drug are high enough, the membrane integrity of the fungus
may actually be impaired.
Ciclopirox olamine also has inherent anti-inflammatory activity exerted through
inhibition of prostaglandin and leukotriene synthesis within polymorphonuclear cells.65 Broad-
spectrum antibacterial properties have also been attributed to ciclopirox olamine. In one study,
topical ciclopirox olamine had broader coverage against Gram-positive and Gram-negative
organisms than did topical irnidazoles or topical allylamines.66

PHARMACOKINETICS
When applied to the skin, ciclopirox olamine remains in high concentration within the epidermis
and upper dermis. Ciclopirox olamine penetrates keratin easily, with cadaveric skin
demonstrating concentrations in the epidermis that were 10 to 15 times the minimum inhibitory
concentration for a sensitive species.65 This ability to penetrate keratin recommends use for
onychomycosis, as the drug is also capable of penetrating the nail plate material.67 Studies of
drug metabolism have demonstrated that, with typical use, approximately 10 percent of the
administered dose is excreted in the urine.68

INDICATIONS
Ciclopirox olamine is indicated for the treatment of dermatophytoses and onychomycosis,
candidiasis, pityriasis versicolor, seborrheic dermatitis, and even cutaneous infections with
unusual saprophytes.69 In tinea pedis, amycologic cure rate of up to 85 percent has been
observed, and in seborrheic dermatitis, a significantly larger percentage of users had > 75 percent
improvement with 2 weeks of use than those using the shampoo vehicle alone.70,7l Although
treatment with ciclopirox olamine for tinea pedis and seborrheic dermatitis has yielded results on
par with other modalities, use in onychomycosis has met with more modest success. Often, an
assessment of efficacy depends upon whether a mycologic cure (culturenegative) or clinical cure
(a disease-free nail) defines success.72 Although a disease-free nail is often the patient's true goal,
ciclopirox olamine achieved such a response in just 5.5 percent ta 8.5 percent of those treated
with a standard 48-week course.72,73 Two recent trials demonstrated increased efficacy when
using oral terbinafine in combination with topical ciclopirox olamine, as opposed to oral
terbinafine alone.74,75 Debate regarding the use of ciclopirox olamine as an independent or
adjunct treatment for onychomycosis is ongoing.

DOSING REGIMEN
Ciclopirox olamine is available in a wide range of forms (see Table 219-1). Cutaneous
candidiasis, dermatophytoses, and pityriasis versicolor should be treated twice daily for 2 weeks
to 1 month, but treatment for tinea pediS should continue 1 month or longer. When using
ciclopirox shampoo for seborrheic dermatitis, treatment may occur twice weekly for an indefinite
duration. Improvement is generally noted in 2 to 4 weeks. Finally, in treating onychomycosis, the
nail lacquer is applied daily to the nail and hyponychium for 48 weeks and excess medication is
removed weekly with alcohol.

RISKS AND PRECAUTIONS

Risks associated with use of topical ciclopirox olamine are those inherent to all topical
medicaments (see Table 219-3). Allergic contact dermatitis has been reported only rarely, and
ciclopirox olamine is considered a weak sensitizer.76 In patients with an allergic reaction to
ciclopirox, imidazoles may be used with relative safety because of a markedly different chemical
structure.

COMPLICATIONS
Serious complications with topical ciclopirox olamine are few.

Older Agents
Tolnaftate and undecylenic acid are older agents now available only in over-thecounter products
(see Table 219-1). Repeated studies have now demonstrated that they are approximately equal in
efficacy,77,78 and that both are less efficacious than topical imidazoles, allylamines,
benzylamines, and ciclopirox olamine. Additionally, tolnaftate is ineffective for treating
candidiasis. Topical tolnaftate and topical undecylenic acid share the same risks and precautions
inherent to all topical medications (see Table 219-3). Additionally, topical forms of undecylenic
acid may yield an unpleasant "fishy smell" that further discourages use. Because both agents are
considered less efficacious than imidazoles, monitaring for treatment failure is indicated when
using these medications.

TOLNAFTATE
UNDECYLENIC ACID

CONCLUSIONS
Because of relatively low cost, acceptable efficacy, ease of use, and low potential for side
effects, complications, or drug interactions, topical antifungals are preferred for most superficial
fungal infections of limited extent. Alternatively, use of a systemic agent is justified when a
superficial fungal infection covers a large surface area, involves terminal hair or nails, or has
proven recalcitrant to prior topical management. Imidazoles provide a reasonable balance of
efficacy and affordability and are indicated for treatment of dermatophytoses, mucocutaneous
candidiasis, and pityriasis versicolor. Despite higher cost, allylamines and benzylamines may be
advantageous in some cases of tinea pediS, due to shorter treatment courses. Ciclopirox olamine
is a topical antifungal with a unique mechanism of action and a broad range of indications.
Topical nystatin is useful in treating mucocutaneous candidiasis, but is ineffective for
dermatophyte infections. Use of tolnaftate and undecylenic acid is decreasing due to lower
efficacy compared with other available agents.

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The full reference list for all chapters is available at www.digm7.com.
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17. Gupta AK et al: An overview of topical antifungal therapy in dermatomycoses. A North
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18. Weinstein A, Berman B: Topical treatment of common superficial tinea infections. Am Fam
Ph"siciall 65:2095, 2002
24. Greenberg Hi et aI: Clotrimazole/betamethasone diproprionate: A review of costs and
complications in the treatment of common cutaneous fungal infections. Pedialr Denllalof 19:78,
2002
47. Crawford F et al: Topical treatments for fungal infections of the skin and nails of the foot.
Cochralle Database yst ReV' 2:CD001434, 2000
65. Gupta AK, Plott T: Ciclopirox: A broadspectrum antifungal with antibacterial and anti-
inflammatory properties. fll/ J Dermatol 43:3, 2004
74. Avner 5, Nir N, Henri T: Combination of oral terbinafine and topical ciclopirox compared to
oral terbinafine for the treatment of onychomycosis. } Dermatolog Treat 16:327, 2005