ATC Class:J01AA

VA Class:AM250

AHFS Class:

• Antibacterials 84:04.04

Generic Name(s):

• Tetracycline Hydrochloride

Tetracyclines are antibiotics and semisynthetic antibiotic derivatives obtained from cultures of Streptomyces.

Skin Infections

Tetracyclines have been used topically for the prevention or treatment of superficial infections of the skin caused by susceptible bacteria. Although minor skin infections and wounds usually heal without treatment, some minor skin wounds do not heal without therapy and it is impossible to determine at the time of injury which wounds will be self-healing. Therefore, some experts believe that, by reducing the number of superficial bacteria, topical anti-infectives are useful for preventing infection in minor skin injuries (e.g., cuts, scrapes, burns). The role, if any, of most topical anti-infectives for the treatment of superficial skin infections has not been fully elucidated, and systemic anti-infective therapy is usually required for the treatment of serious or extensive skin infections such as impetigo. Therefore, self-medication with topical anti-infectives for the treatment of superficial skin infections currently is not recommended. In addition, some clinicians caution that indiscriminate use of topical tetracyclines may result in the emergence of organisms resistant to the drugs.

Acne

Tetracycline hydrochloride100 may be used topically in the treatment of inflammatory acne vulgaris. The drug is not indicated in the treatment of noninflammatory acne. Therapy of acne vulgaris must be individualized and frequently modified depending on the types of acne lesions which predominate and the response to therapy. Topical anti-infectives, including tetracyclines, are generally effective in the treatment of mild to moderate inflammatory acne and are particularly useful in the treatment of mild, papular acne of puberty and early adolescence and papular-pustular acne in adult women. Generally, a decrease in the number of inflammatory lesions occurs in most patients after 2-8 weeks of topical therapy with tetracycline hydrochloride. Maximum benefit may not be seen for up to 12 weeks.

There are no well-controlled studies to date comparing the long-term efficacy and adverse effects of commercially available topical clindamycin, topical erythromycin, and topical tetracyclines (topical tetracycline hydrochloride solutions are no longer commercially available in the US) in the treatment of acne vulgaris. However, many clinicians state that topical clindamycin and topical erythromycin appear to be more effective than topical tetracycline hydrochloride. In one study in patients with mild to moderate inflammatory acne vulgaris, 8 weeks of topical therapy with clindamycin phosphate resulted in a greater reduction in the number of papules and pustules than did 8 weeks of topical therapy with tetracycline hydrochloride. Although the free fatty acid content in sebum and the concentration of P. acnes on the skin surface and within comedones have been used to evaluate the efficacy of anti-infectives in the treatment of acne vulgaris, clinical improvement of acne vulgaris does not necessarily correspond with a decrease in these measurements. When topical anti-infective therapy is indicated, the choice of anti-infective should be based on reported adverse effects for each drug and the clinical response of the patient. Some clinicians have reported that patients who fail to respond to one topical anti-infective frequently respond when another topical anti-infective is substituted. Although it has been suggested that failure to respond to topical anti-infective therapy may result from the development of resistance by P. acnes to the drug being administered, failure to respond to topical anti-infective therapy appears to more frequently result from other factors (e.g., poor patient compliance, emotional or psychological factors, use of comedogenic cosmetic products, the presence of deep nodular or cystic lesions, sinus tract formation.

Controlled studies comparing the long-term efficacy and adverse effects of topical anti-infectives with those of other topical agents (e.g., benzoyl peroxide) in the treatment of inflammatory acne are lacking; however, some clinicians state that topical benzoyl peroxide therapy sometimes results in a more rapid reduction in the number of lesions than does topical anti-infective therapy. In patients with a large number of inflammatory lesions, some clinicians suggest that it might be beneficial to use topical benzoyl peroxide or topical tretinoin in conjunction with a topical anti-infective.

Preliminary studies using topical clindamycin, topical erythromycin, or topical tetracycline hydrochloride indicate that these topical anti-infectives are as effective as oral tetracycline hydrochloride in the treatment of mild to moderate inflammatory acne. Some clinicians recommend that oral anti-infective therapy be used initially in the treatment of moderate to severe inflammatory acne vulgaris since the response to topical therapy may be delayed. A topical anti-infective is then used concomitantly after a few weeks, and the oral anti-infective is slowly discontinued. However, further controlled studies are needed to determine when each route of administration is preferred and when combined topical and oral administration of anti-infectives is indicated in the treatment of inflammatory acne vulgaris. For information on the use of oral tetracyclines in the treatment of acne vulgaris, see Uses in the Tetracyclines General Statement 8:12.24.

For other uses of tetracyclines, see 8:12.24.

Skin Infections

If tetracycline hydrochloride is used for the prevention or treatment of superficial infections of the skin, a small amount of the ointment should be applied to the cleansed affected area 2-3 times daily.

Acne Vulgaris

For the topical treatment of acne vulgaris, a tetracycline hydrochloride topical solution (a topical solution of tetracycline hydrochloride is no longer commercially available in the US) has been applied to the cleansed affected area each morning and evening.100 Ointments containing tetracyclines should not be used for the treatment of acne vulgaris. Prolonged therapy (several months or years) may be necessary for the treatment of acne vulgaris. Therapy is usually continued for as long as a satisfactory response is obtained and no severe or intolerable toxicity occurs.

Adverse Effects

Tetracyclines appear to have a low order of toxicity and a low index of sensitization when applied topically to the skin. Dermatitis and associated symptomatology have been reported rarely with topical application.

Areas of skin treated with topical preparations containing tetracyclines will fluoresce under ultraviolet light, and patients should be advised that this effect occurs.

Precautions and Contraindications

Topical use of tetracyclines may result in overgrowth of nonsusceptible organisms including fungi. Gram-negative folliculitis has been reported rarely following topical use of tetracycline hydrochloride in the treatment of acne vulgaris. If superinfection or suprainfection occurs during tetracycline therapy, the drugs should be discontinued and appropriate therapy instituted.

Topical preparations containing tetracyclines are for external use only and should not be used near the eyes, nose, or mouth100,101 or applied over large areas of the body. Patients considering self-medication with a topical anti-infective for deep or puncture wounds, animal bites, or serious burns should be advised to first consult a physician. Patients using topical preparations containing tetracyclines for the prevention of infection in minor skin injuries (e.g., cuts, scrapes, burns) should be advised to discontinue the topical anti-infective preparation and consult a physician if the condition persists or worsens; topical tetracycline preparations should not be used for longer than 1 week unless directed by a physician.

The manufacturers state that topical preparations containing tetracyclines should be used with caution in patients with hepatic or renal impairment.101 Although hepatotoxicity and renal effects have been reported with systemic use of tetracyclines (see the Tetracyclines General Statement 8:12.24), these effects have not been reported to date with topical use of the drugs.

Tetracycline topical preparations are contraindicated in patients hypersensitive to tetracyclines or any ingredients in the formulations.100,101 Cross-allergenicity among the tetracyclines has been demonstrated, and the possibility that patients who become sensitized to one topical tetracycline may also be sensitive to other topical and/or systemic tetracyclines should be considered.

Pediatric Precautions

Serious dental and skeletal effects have occurred following systemic use of tetracyclines in children younger than 8 years of age. (See Cautions in the Tetracyclines General Statement 8:12.24.) Although these effects have not been reported to date following topical application of tetracyclines and are unlikely because of the low doses used topically, the possibility that these effects could occur should be considered if the drugs are used topically in children younger than 8 years of age. The manufacturer states that safety and efficacy of Topicycline^® in children younger than 11 years of age have not been established.

Pregnancy, Fertility, and Lactation

Pregnancy

Reproduction studies in rats and rabbits using subcutaneous or topical tetracycline have not revealed evidence of harm to the fetus. There are no adequate or well-controlled studies to date using tetracyclines in pregnant women,100,101 and topical preparations containing the drugs should be used in pregnant women only when the possible benefits outweigh the potential risks.

Fertility

Reproduction studies in rats and rabbits using subcutaneous or topical tetracycline have not revealed evidence of impaired fertility.

Lactation

Although it is not known whether tetracyclines are distributed into milk following topical application,100,101 the drugs are distributed into milk following systemic administration. Therefore, topical preparations containing tetracyclines probably should not be used in nursing women.

Mechanism of Action

Tetracyclines are usually bacteriostatic in action, but may be bactericidal in high concentrations or against highly susceptible organisms.

Tetracyclines appear to inhibit protein synthesis in susceptible organisms primarily by reversibly binding to 30S ribosomal subunits, thereby inhibiting binding of aminoacyl transfer-RNA to those ribosomes. In addition, tetracyclines appear to reversibly bind to 50S ribosomal subunits. There is preliminary evidence that tetracyclines also alter cytoplasmic membranes of susceptible organisms resulting in leakage of nucleotides and other intracellular components from the cell. At high concentrations, tetracyclines also inhibit mammalian protein synthesis.

The exact mechanisms by which tetracyclines reduce lesions of acne vulgaris have not been fully elucidated; however, the effect appears to be partly the result of the antibacterial activity of the drugs. Following topical application to the skin of a 0.22% solution of tetracycline hydrochloride in a vehicle containing n-decyl methyl sulfoxide (Topicycline^®; no longer commercially available in the US), the drug inhibits the growth of susceptible organisms (principally Propionibacterium acnes ) on the surface of the skin and reduces the concentration of free fatty acids in sebum. The reduction in free fatty acids in sebum may be an indirect result of the inhibition of lipase-producing organisms which convert triglycerides into free fatty acids or may be a direct result of interference with lipase production in these organisms. Free fatty acids are comedogenic and are believed to be a possible cause of the inflammatory lesions (e.g., papules, pustules, nodules, cysts) of acne. However, other mechanisms also appear to be involved because clinical improvement of acne vulgaris with topical tetracyclines does not necessarily correspond with a reduction in the bacterial flora of the skin or a decrease in the free fatty acid content of sebum. In one study, tetracycline hydrochloride did not inhibit the growth of P. acnes within open comedones following topical application of a 1% solution of the drug in a pyrollidone vehicle (a vehicle which presumably enhances penetration); however, topical application of a 1% solution of clindamycin as the phosphate in the same vehicle did inhibit these organisms within open comedones.

In an in vivo study, topical application of a 5% solution of tetracycline hydrochloride suppressed the local inflammatory response (e.g., erythema, pustules) to patch tests of 40% potassium iodide. Tetracycline hydrochloride also inhibited leukocyte chemotaxis in an in vitro study. It has been hypothesized that these effects could be other mechanisms by which tetracycline suppresses the inflammatory lesions of acne vulgaris.

Spectrum

Tetracyclines have a broad spectrum of activity and are active against most Rickettsia, Chlamydia, Mycoplasma, spirochetes, and many aerobic and anaerobic gram-negative and gram-positive bacteria. The drugs are inactive against fungi and viruses.

In vitro, tetracycline concentrations of 0.1-5 mcg/mL inhibit most susceptible strains of Actinomyces, Clostridium, Chlamydia trachomatis, Enterobacter aerogenes, Escherichia coli, Haemophilus, Klebsiella, Mycoplasma, Neisseria, and Propionibacterium acnes.

Many factors such as inoculum size, pH, and test media can influence results of in vitro susceptibility tests of tetracyclines. When the Kirby-Bauer disk-diffusion procedure is used for in vitro testing, a tetracycline class disk containing 30 mg of tetracycline hydrochloride may be used to test susceptibility to tetracycline.

Resistance

Many strains of E. aerogenes, E. coli, and Klebsiella are resistant to tetracyclines. Although the drugs are active against some strains of staphylococci, streptococci, and pneumococci, tetracycline resistance has been reported in these organisms with increasing frequency. Nearly all strains of Proteus and Pseudomonas aeruginosa are resistant to tetracyclines.

Resistance to tetracyclines may be natural or acquired. Resistance is usually caused by decreased permeability of the cell surface which occurs as the result of mutation or the presence of an inducible, plasmid-mediated resistance factor which is acquired via conjugation. Plasmid-mediated resistance can be transferred between organisms of the same or different species, and resistance to other tetracyclines and several other anti-infectives (e.g., aminoglycosides, chloramphenicol, sulfonamides) may be transferred on the same plasmid.

Pharmacokinetics

Following topical application to the skin of a 2% hydroalcoholic solution of tetracycline hydrochloride, the drug does not appear to be absorbed into the stratum corneum or pilosebaceous apparatus. However, when a 0.22% solution of tetracycline hydrochloride in a vehicle containing n-decyl methyl sulfoxide (Topicycline^®; no longer commercially available in the US) has been applied topically to the skin, the drug penetrated the pilosebaceous apparatus and adjacent tissues. Twice daily topical application to the skin of the 0.22% solution has resulted in serum concentrations of tetracycline of 0.1 mcg/mL or less.

There is no published information on the absorption of tetracycline hydrochloride following topical application to the skin of ointment containing the drug.

Chemistry and Stability

Chemistry

Tetracyclines are antibiotics and semisynthetic antibiotic derivatives obtained from cultures of Streptomyces. Tetracycline is derived from S. aureofaciens or produced semisynthetically from oxytetracycline, which is derived from S. rimosus . Tetracycline is commercially available for topical use as the hydrochloride salt.100

Tetracycline hydrochloride occurs as yellow, crystalline powder. Tetracycline hydrochloride is odorless and moderately hygroscopic and is soluble in water and slightly soluble in alcohol. Tetracycline hydrochloride exhibits a brilliant, yellow fluorescence under ultraviolet light.

Stability

Topical preparations containing tetracyclines should generally be stored at 15-30°C.100 The drugs are stable in air, but darken on exposure to sunlight in moist air.

Only references cited for selected revisions after 1984 are available electronically.

100. Roberts Laboratories. Topicycline^® (tetracycline hydrochloride) for topical solution prescribing information, dated 1991 May. In: Physicians' desk reference. 48th ed. Montvale, NJ: Medical Economics Company Inc; 1994:1884.

101. Ortho-McNeil Pharmaceutical. Meclan^® (meclocycline sulfosalicylate) cream 1% prescribing information. In: Physicians' desk reference. 48th ed. Montvale, NJ: Medical Economics Company Inc; 1994:1710.