Tetracyclines

The tetracyclines work by interacting with the 30S ribosomal subunit of bacteria, and thus inhibiting protein synthesis. Included in the tetracycline family are tetracycline,

minocycline, and doxycycline. In addition to their antimicrobial effect, all of the tetracyclines are anti-inflammatory agents. They inhibit white blood cell chemotaxis, decrease lipase production by P. acnes, and decrease cytokine production. They also offer anti-inflammatory effects by decreasing the activity of matrix metalloproteinases (MMPs) (67). MMPs degrade several components of the extracellular matrix.

Tetracycline is a first-generation tetracycline. It is often administered at 500 mg twice daily for acne. Tetracycline should not be taken with milk as calcium blocks its absorption in the gut. It therefore must be taken on an empty stomach, one hour prior to or two hours after meals. Tetracycline may also cause gastrointestinal upset in some patients. Patients should also be warned of increased photosensitivity while on tetracycline. Other

photosensitive side effects that may occur while on tetracycline include painful photo­onycholysis and pseudoporphyria. Tetracycline is deposited in areas of calcification. As a result, hyperpigmentation of deciduous and permanent teeth and bone may occur. For this reason, tetracycline should not be used in children under the age of 10 as deposition in the bone epiphyses may halt bone growth. Tetracycline is pregnancy category D since it can be deposited in the fetal bones. Nursing mothers should not be given tetracyclines due to the potential for drug excretion through the breast milk.

Doxycycline is a second generation tetracycline administered at 100 mg twice daily for acne. It is better absorbed from the gastrointestinal tract than tetracycline, and can be taken with food, although maximum absorption occurs when taken 30 minutes prior to a meal. Like tetracycline, it can be deposited in areas of calcification such as the teeth and bones, and therefore cannot be used in children under the age of 10, and is pregnancy category D. Photosensitivity is most common with doxycycline and is dose-dependent. 42% of patients taking a total of 200 mg a day will develop photosensitivity (68).

Doxycycline can also be administered for acne at subantimicrobial doses of 20 mg twice a day. In this manner the doxycycline is given at a low dose so that it has only anti­inflammatory effect, and not an antimicrobial effect. Without an antimicrobial action, there

is no opportunity for antibiotic resistance to arise. Doxycycline is the almost effective of the tetracyclines used at subantimicrobial doses because it is the most potent inhibitor of MMP (69). In a study of 40 acne patients who received doxycycline 20 mg po bid for 6 months, no adverse events such as nausea, vomiting, phototoxicity, or vaginitis were noted (70).

Minocycline is another second generation tetracycline given at 100 mg twice daily. Of the tetracyclines it has the best gastrointestinal absorption. It can be taken with food but is best absorbed 30 minutes prior to a meal. Compared to tetracycline and doxycycline, minocycline has more rapid clinical improvement. It also demonstrates a more persistent reduction of inflammation. In vitro, minocycline has the greatest reduction of P. acnes of all the antibiotics used for acne (65). Minocycline’s superior effects are due to its high lipophilicity, and thus better penetration into the pilosebaceous unit. Minocycline can potentially cause a blue-grey hyperpigmentation, vestibular disturbances, or a hypersensitivity drug reaction (70). Three types of hyperpigmentation can occur. Type I hyperpigmentation occurs in areas of scar tissue. Type II hyperpigmentation occurs on previously normal skin, commonly on the anterior shins. Type III hyperpigmentation has a predilection for sun-exposed areas, and often is a diffuse hyperpigmentation. Since minocycline is highly lipophilic it can easily cross the blood-brain barrier. This may result in vestibular disturbances such as dizziness, vertigo, or ataxia. Rarer side effects of minocycline include drug-induced lupus, serum sickness, hepatic failure, and vasculitis. With the exception of serum sickness (which on average occurs 16 days after starting therapy), these side effects often occur after more than a year of therapy (71).

Benign intracranial hypertension, also known as pseudotumor cerebri, can occur with any of the tetracycline antibiotics, and is an increase in cerebrospinal fluid. This increase in intracranial pressure is seen most frequently with minocycline due to its ability to cross the blood-brain barrier. Pseudotumor cerebri can occur between four weeks and 18 months after starting therapy. Patients will complain of a headache that worsens in the evening, diplopia on lateral gaze, and nausea. Papilledema will be demonstrated by ophthalmologic examination. A lumbar puncture can aid in diagnosis, and also be therapeutic by relieving pressure of excess cerebrospinal fluid.