Tetracyclines alter the normal gastrointestinal flora, with suppression of susceptible coliform organisms and overgrowth of Pseudomonas, Proteus, staphylococci, resistant coliforms, clostridia, and Candida. This can result in intestinal functional disturbances, anal pruritus, vaginal or oral candidiasis, or Clostridium difficile– associated colitis. However, the risk of C difficile colitis may be lower with tetracyclines than with other antibiotics.
B. Bony Structures and Teeth
Tetracyclines are readily bound to calcium deposited in newly formed bone or teeth in young children. When a tetracycline is given during pregnancy, it can be deposited in the fetal teeth, leading to fluorescence, discoloration, and enamel dysplasia. It can also be deposited in bone, where it may cause deformity or growth inhibition. Because of these effects, tetracyclines are generally avoided in pregnancy. If the drug is given for long periods to children younger than 8 years, similar changes can result.
C. Other Toxicities
Tetracyclines can impair hepatic function, especially during pregnancy, in patients with preexisting liver disease, and when high doses are given intravenously. Hepatic necrosis has been reported with daily doses of 4 g or more intravenously. Renal tubular acidosis and Fanconi syndrome have been attributed to the administration of outdated tetracycline preparations. Tetracyclines given along with diuretics may cause nephrotoxicity. Tetracycline and minocycline may accumulate to toxic levels in patients with impaired kidney function. Intravenous injection can lead to venous thrombosis. Intramuscular injection produces painful local irritation and should be avoided. Systemically administered tetracyclines commonly induce sensitivity to sunlight or ultraviolet light, particularly in fair-skinned persons. Dizziness, vertigo, and tinnitus have been noted, particularly with high doses or prolonged administration of minocycline. These symptoms may also occur with higher doses of doxycycline.
The macrolides are a group of closely related compounds characterized by a macrocyclic lactone ring (usually containing 14 or 16 atoms) to which deoxy sugars are attached. The prototype drug, erythromycin, which consists of two sugar moieties attached to a 14-atom lactone ring, was obtained in 1952 from Streptomyces erythreus, now called Saccharopolyspora erythraea. Clarithromycin and azithromycin are semisynthetic derivatives of erythromycin.
Erythromycin (R1 = CH3, R2 = H) Clarithromycin (R1, R2 = CH3)
The general structure of erythromycin is shown with the macrolide ring and the sugars desosamine and cladinose. It is poorly soluble in water (0.1%) but dissolves readily in organic solvents. Solutions are fairly stable at 4°C but lose activity rapidly at 20°C and at acid pH. Erythromycins are usually dispensed as various esters and salts.
Mechanism of Action & Antimicrobial Activity
The antibacterial action of erythromycin and other macrolides may be inhibitory or bactericidal, particularly at higher concentrations, for susceptible organisms. Activity is enhanced at alkaline pH. Inhibition of protein synthesis occurs via binding to the 50S ribosomal RNA. The binding site is near the peptidyltransferase center, and peptide chain elongation (ie, transpeptidation) is prevented by blocking of the polypeptide exit tunnel. As a result, peptidyl-tRNA is dissociated from the ribosome. Erythromycin also inhibits the formation of the 50S ribosomal subunit (Figure 44–1).