Tetracycline, like other systemic antibiotics, significantly decreases the percentage of free fatty acids in the skin, decreases the population of acnes, and inhibits leukocyte chemotaxis. Unlike other antibiotics, tetracycline concentrates in cells of inflamed skin more that in normal skin. Tetracycline also reduces the production of keratin in sebaceous follicles and inhabits phagocytosis as well as complement activation by the alternate pathway. Tetracycline is considered to be the systemic antibiotic of choice for acne because of its beneficial actions, relatively low cost, and low incidence of side effects despite long-term use. A 250 to 500 mg dose of tetracycline can be administered once of twice a day, but a time interval of one to two hours should lapse before ingestion of antacids, iron compounds, and dairy products.

Other systematic antibiotics proven to be effective for acne include; erythromycin, clindamycin, cotrimoxazole, doxycyclkine, and minocycline. The use of oral clindamycin for acne is limited due to the perceived increased risk of pseudomembranous colitis. Some clinicians believe erythromycin might have a safer adverse effect profile compared to tetracycline and yet provide similar efficacy. In reflectory cases, minocycline and doxycycline may penetrate into tissue and sebaceous follicles better because of their lipophilicity. Disadvantages with the use of minocycline include a high incidence of vestibular toxity and discoloration of skin and teeth. Cotrimoxazole may also be effective in some cases of tetracycline resistant acne, however, it should be reserved for refractory cases to minimize development of bacterial resistance.