Bacteriostatic inhibitors of protein synthesis: tetracyclines, macrolides, and others
Tetracyclines
The tetracyclines are broad-spectrum antibiotics. In the United States, four tetracyclines are available for systemic therapy. All four—tetracycline, demeclocycline, doxycycline, and minocycline—are similar in structure, antimicrobial actions, and adverse effects. Principal differences among them are pharmacokinetic. Because the similarities among these drugs are more pronounced than their differences, we will discuss the tetracyclines as a group, rather than focusing on a prototype. Unique properties of individual tetracyclines are indicated as appropriate.
Mechanism of action
The tetracyclines suppress bacterial growth by inhibiting protein synthesis. These drugs bind to the 30S ribosomal subunit, and thereby inhibit binding of transfer RNA to the messenger RNA–ribosome complex.* As a result, addition of amino acids to the growing peptide chain is prevented. At the concentrations achieved clinically, the tetracyclines are bacteriostatic.
Therapeutic uses
Treatment of infectious diseases.
Extensive use of tetracyclines has resulted in increasing bacterial resistance. Because of resistance, and because antibiotics with greater selectivity and less toxicity are now available, use of tetracyclines has declined. Today, tetracyclines are rarely drugs of first choice. Disorders for which they are first-line drugs include (1) rickettsial diseases (eg, Rocky Mountain spotted fever, typhus fever, Q fever); (2) infections caused by Chlamydia trachomatis (trachoma, lymphogranuloma venereum, urethritis, cervicitis); (3) brucellosis; (4) cholera; (5) pneumonia caused by Mycoplasma pneumoniae; (6) Lyme disease; (7) anthrax; and (8) gastric infection with H. pylori.
Treatment of acne.
Tetracyclines are used topically and orally for severe acne vulgaris. Beneficial effects derive from suppressing the growth and metabolic activity of Propionibacterium acnes, an organism that secretes inflammatory chemicals. Oral doses for acne are relatively low. As a result, adverse effects are minimal. Acne is discussed at length in Chapter 105 (Drugs for the Skin).
Peptic ulcer disease.
Helicobacter pylori, a bacterium that lives in the stomach, is a major contributing factor to peptic ulcer disease. Tetracyclines, in combination with metronidazole and bismuth subsalicylate, are a treatment of choice for eradicating this bug. The role of H. pylori in ulcer formation is discussed in Chapter 78 (Drugs for Peptic Ulcer Disease).
Periodontal disease.
Two tetracyclines—doxycycline and minocycline—are used for periodontal disease. Doxycycline is used orally and topically, whereas minocycline is used only topically.
Topical minocycline [Arestin] and doxycycline [Atridox] are employed as adjuncts to scaling and root planing. The objective is to reduce pocket depth and bleeding in adults with periodontitis. Benefits derive from suppressing bacterial growth. Both products are applied directly to the site of periodontal disease.
Pharmacokinetics
Individual tetracyclines differ significantly in their pharmacokinetic properties. Of particular significance are differences in half-life and route of elimination. Also important is the degree to which food decreases absorption. The pharmacokinetic properties of individual tetracyclines are summarized in Table 86–1.
TABLE 86–1
Pharmacokinetic Properties of the Tetracyclines
Percent of Oral Dose Absorbed* | Effect of Food on Absorption | Route of Elimination | Half-Life | ||||
Class | Drug | Lipid Solubility | Normal (hr) | Anuric (hr) | |||
Short Acting | Tetracycline | Low | 60–80 | Large decrease | Renal | 8 | 57–108† |
Intermediate Acting | Demeclocycline | Moderate | 60–80 | Large decrease | Renal | 12 | 40–60† |
Long Acting | Doxycycline | High | 90–100 | Small decrease | Hepatic | 18 | 17–30 |
Minocycline | High | 90–100 | No change | Hepatic | 16 | 11–23 |
*Percent absorbed when taken on an empty stomach.
†Do not use in patients with renal impairment because the drug could accumulate to toxic levels.
Duration of action.
The tetracyclines can be divided into three groups: short acting, intermediate acting, and long acting (see Table 86–1). These differences are related to differences in lipid solubility: The only short-acting tetracycline (tetracycline) has relatively low lipid solubility, whereas the long-acting agents (doxycycline, minocycline) have relatively high lipid solubility.
Absorption.
All of the tetracyclines are orally effective, although the extent of absorption differs among individual agents (see Table 86–1). Absorption of three agents—tetracycline, demeclocycline, and doxycycline—is reduced by food, whereas absorption of minocycline is not.
Elimination.
Tetracyclines are eliminated by the kidneys and liver. All tetracyclines are excreted by the liver into the bile. After the bile enters the intestine, most tetracyclines are reabsorbed.
Ultimate elimination of short- and intermediate-acting tetracyclines—tetracycline and demeclocycline—is in the urine, largely as the unchanged drug (see Table 86–1). Because these agents undergo renal elimination, they can accumulate to toxic levels if the kidneys fail. Consequently, tetracycline and demeclocycline should not be given to patients with significant renal impairment.
Adverse effects
Gastrointestinal irritation.
Tetracyclines irritate the GI tract. As a result, oral therapy is frequently associated with epigastric burning, cramps, nausea, vomiting, and diarrhea. These reactions can be reduced by giving tetracyclines with meals—although food may decrease absorption. Occasionally, tetracyclines cause esophageal ulceration. Risk can be minimized by avoiding dosing at bedtime. Because diarrhea may result from suprainfection of the bowel (in addition to nonspecific irritation), it is important that the cause of diarrhea be determined.
Effects on bones and teeth.
Tetracyclines bind to calcium in developing teeth, resulting in yellow or brown discoloration; hypoplasia of the enamel may also occur. The intensity of tooth discoloration is related to the total cumulative dose: Staining is darker with prolonged and repeated treatment. When taken after the fourth month of gestation, tetracyclines can cause staining of deciduous teeth of the infant. However, use during pregnancy will not affect permanent teeth. Discoloration of permanent teeth occurs when tetracyclines are taken by patients ages 4 months to 8 years, the interval during which tooth enamel is being formed. Accordingly, these drugs should be avoided by children under 8 years old. The risk of tooth discoloration with doxycycline may be less than with other tetracyclines.
Tetracyclines can suppress long-bone growth in premature infants. This effect is reversible upon discontinuation of treatment.
Suprainfection.
As discussed in Chapter 83, a suprainfection is an overgrowth with drug-resistant microbes, which occurs secondary to suppression of drug-sensitive organisms. Because the tetracyclines are broad-spectrum agents, and therefore can decrease viability of a wide variety of microbes, the risk of suprainfection is greater than with antibiotics that have a more narrow spectrum.
Overgrowth with fungi (commonly Candida albicans) may occur in the mouth, pharynx, vagina, and bowel. Symptoms include vaginal or anal itching; inflammatory lesions of the anogenital region; and a black, furry appearance of the tongue. Suprainfection with Candida can be managed by discontinuing tetracyclines. When this is not possible, antifungal therapy is indicated.
Hepatotoxicity.
Tetracyclines can cause fatty infiltration of the liver. Hepatotoxicity manifests clinically as lethargy and jaundice. Rarely, the condition progresses to massive liver failure. Liver damage is most likely when tetracyclines are administered intravenously in high doses (greater than 2 gm/day). Pregnant and postpartum women with kidney disease are at especially high risk.
Renal toxicity.
Tetracyclines may exacerbate renal impairment in patients with pre-existing kidney disease. Because tetracycline and demeclocycline are eliminated by the kidneys, these agents should not be given to patients with renal impairment. If a patient with renal impairment requires a tetracycline, either doxycycline or minocycline should be used, since these drugs are eliminated primarily by the liver.
Drug and food interactions
As noted, tetracyclines can form nonabsorbable chelates with certain metal ions (calcium, iron, magnesium, aluminum, zinc). Substances that contain these ions include milk products, calcium supplements, iron supplements, magnesium-containing laxatives, and most antacids. If a tetracycline is administered with these agents, its absorption will be decreased. To minimize interference with absorption, tetracyclines should be administered at least 1 hour before or 2 hours after ingestion of chelating agents.
Dosage and administration
Administration.
For systemic therapy, tetracyclines may be administered orally, intravenously, and by IM injection. Oral administration is preferred, and all tetracyclines are available in oral formulations. As a rule, oral tetracyclines should be taken on an empty stomach (1 hour before meals or 2 hours after) and with a full glass of water. An interval of at least 2 hours should separate tetracycline ingestion and ingestion of products that can chelate these drugs (eg, milk, calcium or iron supplements, antacids). Three tetracyclines can be given IV (Table 86–2), but this route should be employed only when oral therapy cannot be tolerated or has proved inadequate. Intramuscular injection is extremely painful and used rarely.
TABLE 86–2
Tetracyclines: Routes of Administration, Dosing Interval, and Dosage
Usual Dosing Interval (hr) | Total Daily Dose | |||||
Class | Drug | Trade Names | Route | Adult (mg) | Pediatric (mg/kg)a | |
Short Acting | Tetracycline | generic only | PO | 6 | 1000–2000 | 25–50 |
IVb | 12 | 500–1000 | 10–20 | |||
IMc | 12 | 300 | 15–25 | |||
Intermediate Acting | Demeclocycline | Declomycin | PO | 12 | 600 | 6–12 |
Long Acting | Doxycycline | Vibramycin, others | PO | 24 | 100d | 2.2e |
IVb | 24 | 100–200f | 2.2–4.4g | |||
Minocycline | Minocin, others | PO | 12 | 200h | 4i | |
IVb | 12 | 200h | 4i |
aDoses presented are for children over the age of 8 years. Use in children below this age may cause permanent staining of teeth.
bThe intravenous route is used only if oral therapy cannot be tolerated or is inadequate.
cIntramuscular injection is extremely painful and used only rarely.
dFirst-day regimen is 100 mg initially, followed by 100 mg 12 hours later.
eFirst-day regimen is 2.2 mg/kg initially, followed by 2.2 mg/kg 12 hours later.
fFirst-day regimen is 200 mg in one or two slow infusions (1 to 4 hours).
gFirst-day regimen is 4.4 mg/kg in one or two slow infusions (1 to 4 hours).
hFirst-day regimen is 200 mg initially, followed by 100 mg 12 hours later.
iFirst-day regimen is 4 mg/kg initially, followed by 2 mg/kg 12 hours later.
In addition to their systemic use, two agents—doxycycline and minocycline—are available in formulations for topical therapy of periodontal disease (see above).
Summary of major precautions
Two tetracyclines—tetracycline and demeclocycline—are eliminated primarily in the urine, and hence will accumulate to toxic levels in patients with kidney disease. Accordingly, patients with kidney disease should not use these drugs.
Tetracyclines can cause discoloration of deciduous and permanent teeth. Tooth discoloration can be avoided by withholding these drugs from pregnant women and from children under 8 years of age.
Diarrhea may indicate a potentially life-threatening suprainfection of the bowel. Advise patients to notify the prescriber if diarrhea occurs.
High-dose IV therapy has been associated with severe liver damage, particularly in pregnant and postpartum women with kidney disease. As a rule, these women should not receive tetracyclines.
Macrolides
The macrolides are broad-spectrum antibiotics that inhibit bacterial protein synthesis. Why are they called macrolides? Because they are big. Erythromycin is the oldest member of the family. The newer macrolides—azithromycin and clarithromycin—are derivatives of erythromycin.
Erythromycin
Erythromycin has a relatively broad antimicrobial spectrum and is a preferred or alternative treatment for a number of infections. The drug is one of our safest antibiotics and will serve as our prototype for the macrolide family.
Mechanism of action
Antibacterial effects result from inhibition of protein synthesis: Erythromycin binds to the 50S ribosomal subunit and thereby blocks addition of new amino acids to the growing peptide chain. The drug is usually bacteriostatic, but can be bactericidal against highly susceptible organisms, or when present in high concentration. Erythromycin is selectively toxic to bacteria because ribosomes in the cytoplasm of mammalian cells do not bind the drug. Also, in contrast to chloramphenicol (see below), erythromycin cannot cross the mitochondrial membrane, and therefore does not inhibit protein synthesis in host mitochondria.
Antimicrobial spectrum
Erythromycin has an antibacterial spectrum similar to that of penicillin. The drug is active against most gram-positive bacteria as well as some gram-negative bacteria. Bacterial sensitivity is determined in large part by the ability of erythromycin to gain access to the cell interior.
Therapeutic uses
Erythromycin is a commonly used antibiotic. The drug is a treatment of first choice for several infections and may be used as an alternative to penicillin G in patients with penicillin allergy.
Erythromycin is a preferred treatment for pneumonia caused by Legionella pneumophila (legionnaires’ disease).
Erythromycin is considered the drug of first choice for individuals infected with Bordetella pertussis, the causative agent of whooping cough. Because symptoms are caused by a toxin produced by B. pertussis, erythromycin does little to alter the course of the disease. However, by eliminating B. pertussis from the nasopharynx, treatment does lower infectivity.
Corynebacterium diphtheriae is highly sensitive to erythromycin. Accordingly, erythromycin is the treatment of choice for acute diphtheria and eliminating the diphtheria carrier state.
Several infections respond equally well to erythromycin and tetracyclines. Both are drugs of first choice for certain chlamydial infections (urethritis, cervicitis) and for pneumonia caused by M. pneumoniae.
Erythromycin may be employed as an alternative to penicillin G in patients with penicillin allergy. The drug is used most frequently as a substitute for penicillin to treat respiratory tract infections caused by Streptococcus pneumoniae and by group A Streptococcus pyogenes. Erythromycin can also be employed as an alternative to penicillin for preventing recurrences of rheumatic fever and bacterial endocarditis.

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