FDA OTC Topical Antimicrobials — First Aid Antibiotics, Antifungals, and Acne Products

Walk through any drugstore pharmacy aisle and you'll find triple antibiotic ointments for cuts, antifungal creams for athlete's foot, and benzoyl peroxide gels for acne — all sold without a prescription and all regulated as over-the-counter (OTC) drug products under the Federal Food, Drug, and Cosmetic Act. Their legal standing rests on FDA's OTC drug monograph system: binding rules specifying exactly which active ingredients, concentrations, dosage forms, and labeling statements make a topical antimicrobial product Generally Recognized as Safe and Effective (GRASE). 21 CFR Part 333 consolidates the OTC monographs for three categories of topical antimicrobials: first aid antibiotics, topical antifungals, and acne treatment products.

Legal Authority

• 21 U.S.C. § 355 — FDCA § 505: topical antimicrobial drug products (antibiotics, antifungals, acne treatments) are drugs; compliance with 21 CFR Part 333 provides the monograph-based GRASE pathway
• 21 U.S.C. § 321 — FDCA definitions: first aid antibiotic ointments, antifungal creams, and acne products are drugs, not cosmetics
• 21 CFR Part 333 — FDA OTC monograph for first aid antibiotics, topical antifungals, and acne treatment products; specifies GRASE active ingredients, concentrations, dosage forms, labeling requirements, and indications

Key Mechanics

Part 333 covers three distinct OTC therapeutic categories through separate subparts. First aid antibiotics (Subpart C) list bacitracin, neomycin sulfate, and polymyxin B sulfate (and their combinations) as GRASE for prevention of infection in minor cuts, scrapes, and burns. Topical antifungals (Subpart D) list clotrimazole, miconazole nitrate, tolnaftate, and undecylenic acid derivatives as GRASE for athlete's foot, jock itch, and ringworm. Acne products (Subpart E) list benzoyl peroxide (2.5%-10%) and salicylic acid (0.5%-2%) as GRASE for acne treatment. Each subpart specifies required labeling warnings — the neomycin allergy warning for triple antibiotic products, the renal precaution for salicylic acid in acne washes, and the ocular caution for products applied near the eyes.

Current Rule (2026)

What This Rule Does

The OTC monograph for topical antimicrobials defines the universe of legally marketable OTC products for three distinct self-treatable conditions: superficial skin infections from cuts and scrapes (first aid antibiotics), superficial fungal infections like athlete's foot and ringworm (topical antifungals), and acne vulgaris (topical acne products). For each category, Part 333 specifies the permitted active ingredients, the allowable concentration range for each ingredient, the permitted dosage forms, the ingredient combinations that are allowed (and those that are not), and the exact labeling language the product must carry.

A manufacturer whose product meets every Part 333 condition for the relevant subpart — right ingredient, right concentration, right form, right label — may market it without filing an individual New Drug Application (NDA). The CARES Act of 2020 converted these OTC monograph conditions from regulations into administrative orders carrying the same legal force, while giving FDA a faster process to update them. Products that deviate from Part 333 conditions (e.g., a new antibiotic active ingredient not listed, an antifungal at an unlisted concentration) require an approved NDA before marketing.

Key Provisions

Subpart B — First Aid Antibiotic Drug Products (§§ 333.101–333.150)

• § 333.110 — Permitted active ingredients: OTC first aid antibiotic drug products may contain one or more of the following antibiotics in ointment (or cream for some ingredients) form:
  • Bacitracin 500 units/g — a polypeptide antibiotic active against gram-positive organisms; the classic single-ingredient antibiotic ointment ingredient; effective against Staphylococcus aureus and Streptococcus species commonly involved in minor skin infections
  • Bacitracin zinc 500 units/g — the zinc salt of bacitracin; identical activity, used as the zinc form for greater stability in formulations
  • Neomycin sulfate equivalent to 3.5 mg neomycin base per gram — an aminoglycoside antibiotic adding coverage against gram-negative organisms; neomycin contact allergy affects approximately 1-3% of the population, a known limitation addressed in the labeling requirements
  • Polymyxin B sulfate 10,000 units/g — a polypeptide antibiotic with strong gram-negative activity, filling the spectrum gap that bacitracin leaves; not absorbed through intact skin
• § 333.110 — Permitted combinations: the rule explicitly permits the following multi-ingredient combinations under a single GRASE determination:
  • Bacitracin + neomycin sulfate (double antibiotic)
  • Bacitracin + polymyxin B sulfate (double antibiotic)
  • Bacitracin zinc + polymyxin B sulfate (double antibiotic)
  • Bacitracin + neomycin sulfate + polymyxin B sulfate (the classic "triple antibiotic" — Neosporin's active ingredients)
  • Bacitracin zinc + neomycin sulfate + polymyxin B sulfate (triple antibiotic zinc form) Each ingredient in a combination must be within its individual concentration range; the combination represents the most commonly sold format in the U.S. OTC market and provides broad-spectrum coverage against both gram-positive and gram-negative bacteria
• § 333.150 — Labeling: the product must state "first aid antibiotic"; indications must include "helps prevent infection in minor cuts, scrapes, and burns"; warnings must include: do not use in eyes, do not use over large areas, stop use and consult doctor if the condition worsens or does not improve within 1 week, keep out of reach of children; neomycin-containing products must add a warning that some people are allergic to neomycin sulfate and should stop use and consult a doctor if rash or irritation develops; directions must specify cleaning the affected area, applying a small amount one to three times daily, and covering with a sterile bandage if desired

Subpart C — Topical Antifungal Drug Products (§§ 333.201–333.250)

• § 333.210 — Permitted active ingredients: OTC topical antifungals address dermatophyte infections (athlete's foot, ringworm, jock itch) and, for some ingredients, Candida (yeast) infections. Permitted active ingredients and concentrations:
  • Clioquinol 3 percent — an antimicrobial with both antifungal and antibacterial activity; also covers some secondary bacterial infection; used in athlete's foot and related conditions
  • Haloprogin 1 percent — a synthetic antifungal targeting dermatophytes; effective for tinea pedis, tinea cruris, and tinea corporis
  • Miconazole nitrate 2 percent — an azole antifungal that inhibits ergosterol synthesis in fungal cell membranes; among the most widely used OTC antifungal active ingredients; effective against dermatophytes and Candida albicans; available as cream, spray powder, and powder
  • Povidone-iodine 10 percent — a broad-spectrum antimicrobial with antifungal properties; the 10% concentration is the OTC-approved strength; broader antimicrobial spectrum than dedicated antifungals but with some skin irritation potential
  • Tolnaftate 1 percent — a thiocarbamate antifungal specifically targeting dermatophytes by inhibiting fungal squalene epoxidase; does not cover Candida; long track record in OTC use for athlete's foot; available as cream, powder, spray powder, and solution
  • Undecylenic acid and its salts (total undecylenate) 10 to 25 percent — a fatty acid with antifungal activity; used mainly as powder formulations; lower clinical efficacy than azoles or allylamines but with good safety profile; often combined with zinc undecylenate
• § 333.210 — Professional labeling for Candida indications: clioquinol and miconazole nitrate products may include labeling for Candida albicans infections (cutaneous candidiasis) in addition to dermatophyte infections, but only in "professional labeling" directed to healthcare providers — the consumer-facing label addresses only the dermatophyte indications; this distinction reflects FDA's view that Candida skin infections require more clinical evaluation before self-diagnosis is reliable
• § 333.250 — Labeling: products for athlete's foot must state "cures athlete's foot (tinea pedis)"; for ringworm, "cures ringworm (tinea corporis)"; for jock itch, "relieves itching, scaling, burning, and discomfort which accompany jock itch (tinea cruris)"; warnings include: do not use on children under 2 without doctor advice, for athlete's foot and ringworm: if condition persists beyond 4 weeks, consult a doctor; for jock itch: if condition persists beyond 2 weeks, consult a doctor; keep out of reach of children; for externaluse only

Subpart D — Topical Acne Drug Products (§§ 333.301–333.350)

• § 333.310 — Permitted active ingredients: OTC acne products address acne vulgaris through several distinct mechanisms — keratolysis, antibacterial activity against Cutibacterium acnes (formerly Propionibacterium acnes), and sebum reduction. Permitted active ingredients:
  • Benzoyl peroxide 2.5 to 10 percent — the most clinically effective OTC acne active ingredient; works by releasing free radicals that kill C. acnes bacteria (no clinically significant resistance has developed because the mechanism is non-antibiotic); also has mild keratolytic and comedolytic activity; available as gels, creams, lotions, and washes; the 2.5% concentration is as effective as 10% for antibacterial activity with less irritation; concentrations above 10% are not permitted OTC
  • Resorcinol 2 percent — a phenolic compound with keratolytic activity that helps break down blackheads and whiteheads; may only be used in OTC acne products in combination with sulfur at the concentrations specified below — resorcinol alone is not permitted as a standalone OTC acne active ingredient
  • Resorcinol monoacetate 3 percent — the acetate ester of resorcinol; same restriction applies: must be combined with sulfur
  • Salicylic acid 0.5 to 2 percent — a beta-hydroxy acid (BHA) that promotes skin cell shedding and unclogs pores by penetrating into the pore opening; reduces comedones (blackheads and whiteheads) by exfoliating inside the follicle; the primary alternative to benzoyl peroxide for OTC acne; available as cleansers, toners, pads, gels, and creams; best for non-inflammatory acne (comedones) but less effective than benzoyl peroxide for inflammatory papules and pustules
  • Sulfur 3 to 8 percent — a keratolytic ingredient with weak antibacterial activity; used alone or in combination with resorcinol; less effective than benzoyl peroxide but with a different mechanism useful as an adjunct
• § 333.310 — Permitted combinations: the rule permits:
  • Resorcinol 2% + sulfur 3–8% (combination must use both within these ranges)
  • Resorcinol monoacetate 3% + sulfur 3–8% Combinations other than these (e.g., benzoyl peroxide + salicylic acid in a single product) are not covered by the OTC monograph and would require NDA approval
• § 333.350 — Labeling: products must state "for the treatment of acne" or "helps treat acne"; indications must identify the product as treating "acne, pimples, blemishes, blackheads, or whiteheads" (permitted terms vary by ingredient); warnings include: when using benzoyl peroxide, avoid unnecessary sun exposure and use sunscreen when outdoors, avoid contact with hair and dyed fabrics (benzoyl peroxide bleaches); for salicylic acid: do not use in children under 2; directions must specify how often to apply and the maximum use period

How It Affects You

If you manufacture OTC topical antimicrobial products: your formulation must exactly match the applicable Part 333 subpart conditions. The concentration ranges are binding — a benzoyl peroxide product at 11% is not covered by the monograph and requires an approved NDA. Permitted combinations are enumerated: a benzoyl peroxide + salicylic acid combination product (common in the market) is not GRASE under Part 333 and requires its own NDA or NDA supplement. Under the CARES Act OTC reform, FDA can update these conditions through administrative orders; check FDA's OTC Monograph Order webpage for updates. All products must also comply with Drug Facts labeling format (21 CFR Part 201).

If you are treating a minor skin infection: for minor cuts, scrapes, and burns, the triple antibiotic combination (bacitracin + neomycin + polymyxin B) provides the broadest OTC antibacterial coverage, but approximately 1-3% of people have a neomycin contact allergy — if you've had a reaction to antibiotic ointments before, a bacitracin-only or bacitracin + polymyxin B product avoids neomycin. For athlete's foot, miconazole nitrate 2% and tolnaftate 1% are clinically comparable for dermatophyte infections, but only miconazole covers Candida — if you're diabetic or immunocompromised with persistent foot infection, see a provider because Candida and bacterial superinfection are more common in those populations.

If you are managing acne: benzoyl peroxide is the most effective OTC ingredient for inflammatory acne (red papules and pustules) because it kills C. acnes bacteria; 2.5% is as effective as 10% with less irritation, making it a good starting point. Salicylic acid works better for comedonal acne (blackheads and whiteheads) by unclogging pores. Both are available in OTC products. The combination benzoyl peroxide + salicylic acid products sold OTC are not covered by the Part 333 monograph — they are marketed under their own NDAs or as cosmetics with drug claims — check the Drug Facts label to confirm the product's regulatory status.

If you are a pharmacist or healthcare provider: OTC first aid antibiotics are appropriate for minor wounds but should not be used on large areas or for more than 1 week — persistent or expanding redness, warmth, or streaking suggests spreading cellulitis requiring systemic antibiotics. Neomycin allergy is often mistaken for a wound infection because the delayed hypersensitivity reaction (reddening, weeping) mimics cellulitis — patch testing clarifies this. For acne, OTC benzoyl peroxide is first-line for mild-to-moderate inflammatory acne; topical retinoids and topical or oral antibiotics (prescription) are added when OTC treatment is insufficient.

Statutory Authority

This rule implements:

• 21 U.S.C. § 355 — New drug approval requirements (OTC monograph products are exempt from individual NDA review when meeting monograph conditions)
• 21 U.S.C. § 321(p) — Definition of "new drug" and the GRASE standard
• 21 U.S.C. § 352 — Misbranding provisions (products not meeting monograph labeling requirements are misbranded)
• 21 U.S.C. §§ 360fff–360fff-8 — OTC Drug Monograph Reform (CARES Act of 2020, Title III): converted OTC monograph conditions into administrative orders; authorized expedited FDA order process for adding, removing, or modifying monograph conditions

Recent Rulemakings

• CARES Act of 2020 (Pub. L. 116-136, Title III) — OTC Drug Monograph Reform: enacted administrative order mechanism; existing Part 333 conditions deemed final orders under the new framework
• 85 FR 16,326 (March 2020) — FDA proposed rule on safety and effectiveness of consumer antiseptic products (a related 21 CFR Part 310 rulemaking) finding insufficient safety data for several antiseptic active ingredients; that rulemaking does not affect Part 333's antibiotic or antifungal monographs but illustrates FDA's ongoing review of OTC topical drug products under the CARES Act framework
• 81 FR 61,106 (September 2016) — FDA final rule deferring action on triclosan and other antiseptic active ingredients pending additional safety data; underscores that ingredients not listed in Part 333 require NDA-level evidence even if long used in OTC products

Pending Action