e1-05: Tetracycline Group

The tetracyclines are a group of medications with common basic chemical structures, antimicrobial activity, and pharmacologic properties.

Tetracyclines are inhibitors of protein synthesis and are bacteriostatic for many gram-positive and gram-negative bacteria. They strongly inhibit the growth of mycoplasmas, rickettsiae, chlamydiae, spirochetes, and some protozoa (eg, amoebas, malaria). Their antipneumococcal activity approaches that of the macrolides, and almost all H influenzae are inhibited. Tetracyclines also have some activity against some vancomycin-resistant enterococci (VRE). Doxycycline and minocycline are potential options for treatment of S aureus infections, including some methicillin-resistant strains. Tetracycline-resistant staphylococci often retain susceptibility to doxycycline and minocycline, and doxycycline-resistant S aureus can still be susceptible to minocycline. Tetracyclines have little utility in the treatment of gram-negative aerobic infection. However, minocycline is reliable in its activity against S maltophilia and multidrug-resistant Acinetobacter. Receipt of doxycycline in combination with ceftriaxone in the treatment of community-acquired pneumonia has been associated with a reduction in the rate of associated antibacterial C difficile disease. The antibacterial activity of doxycycline against C difficile is likely the mechanism of action for this finding.

Oral bioavailability varies depending on the medication. Absorption is impaired by dairy products, aluminum hydroxide gels (antacids), and chelation with divalent cations, eg, Ca²⁺ or Fe²⁺. Chelation is less problematic with doxycycline and minocycline when compared with tetracycline. However, doses of all tetracyclines should be staggered at least 2 hours before or after receipt of multivalent cations. Oral bioavailability is moderate with tetracycline and highest with doxycycline and minocycline (95% or more). Lipid solubility of minocycline and doxycycline accounts for their penetration into the cerebrospinal fluid, prostate, tears, and saliva.

Tetracyclines are primarily metabolized in the liver and excreted in bile. Doxycycline requires no dosage adjustment in kidney disease; in contrast, other tetracyclines should be avoided or given in reduced dosage.

For patients unable to take oral medication, some tetracyclines (doxycycline, minocycline) are formulated for parenteral administration in doses similar to the oral preparations.

Tetracyclines are medications of choice for infections with Chlamydia, Chlamydophila, Mycoplasma, Rickettsia, Ehrlichia, and Vibrio organisms and for some spirochetal infections. Sexually transmitted diseases in which chlamydiae often play a role—endocervicitis, urethritis, proctitis, and epididymitis—should be treated with doxycycline for 7–14 days. Pelvic inflammatory disease is often treated with doxycycline plus cefoxitin or cefotetan. Other chlamydial infections (psittacosis, lymphogranuloma venereum, trachoma) and sexually transmitted diseases (granuloma inguinale) also respond to doxycycline. Other uses include treatment of acne, respiratory infections, Lyme disease and relapsing fever, brucellosis, glanders, tularemia (often in combination with streptomycin), cholera, mycoplasmal pneumonia, actinomycosis, nocardiosis, malaria, infections caused by M marinum and Pasteurella species (typically after an animal bite), and as malaria prophylaxis (including multidrug-resistant P falciparum). They also have been used in combination with other medications for amebiasis, falciparum malaria, and recurrent ulcers due to H pylori. With its modest activity against pneumococci (same or better than macrolides) and reliable coverage of H influenzae, Chlamydophila, Legionella, and Mycoplasma organisms, doxycycline should be considered as a potential empiric monotherapy in mild cases of community-acquired pneumonia or in combination with beta-lactams for patients with community-acquired pneumonia and comorbidities. Doxycycline and minocycline are options in the treatment of community-onset skin and soft tissue infection due to methicillin-resistant S aureus. As discussed previously, minocycline and doxycycline are superior to tetracycline in the treatment of methicillin-resistant S aureus; doxycycline-resistant isolates are often still inhibited by minocycline. Minocycline is equally as efficacious as doxycycline for the therapy of nongonococcal urethritis and cervicitis.

Adverse Effects

A. Allergy

Hypersensitivity reactions with fever or skin rashes are uncommon.

B. Gastrointestinal Side Effects

Diarrhea, nausea, and anorexia are common. Tetracycline administration, particularly doxycycline and minocycline, should be avoided at bedtime due to the risk of esophageal erosion.

C. Bones and Teeth

Tetracyclines are bound to calcium deposited in growing bones and teeth, causing fluorescence, discoloration, enamel dysplasia, deformity, or growth inhibition. Therefore, tetracyclines should not be given to pregnant women, nursing women, or children under 8 years of age. The warning regarding dental staining with tetracyclines and children has existed for decades. However, children treated with doxycycline for suspected Rocky Mountain spotted fever have been found to have no dental staining, enamel hypoplasia, or tooth color differences. Consequently, certain children can likely receive doxycycline if other options are less favorable.

D. Liver Damage

Tetracyclines can impair hepatic function or even cause liver necrosis, particularly in the presence of preexisting liver disease.

E. Other

All tetracyclines may induce photosensitization, especially in fair-skinned individuals. Minocycline induces vestibular reactions (dizziness, vertigo, nausea, vomiting), with a frequency of 35–70% associated with doses of 200 mg daily.