Bacteriostatic inhibitors of protein synthesis: tetracyclines, macrolides, and others

All of the drugs discussed in this chapter inhibit bacterial protein synthesis. However, unlike the aminoglycosides, which are bactericidal, the drugs considered here are largely bacteriostatic. That is, they suppress bacterial growth and replication but do not produce outright kill. In general, the drugs presented here are second-line agents, used primarily for infections resistant to first-line agents.

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.

Selective toxicity of the tetracyclines results from their poor ability to cross mammalian cell membranes. In order to influence protein synthesis, tetracyclines must first gain access to the cell interior. These drugs enter bacteria by way of an energy-dependent transport system. Mammalian cells lack this transport system, and hence do not actively accumulate the drug. Consequently, although tetracyclines are inherently capable of inhibiting protein synthesis in mammalian cells, their levels within host cells remain too low to be harmful.

Therapeutic uses

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	Percent of Oral Dose Absorbed*	Effect of Food on Absorption	Route of Elimination	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.

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.

The tetracyclines form insoluble chelates with calcium, iron, magnesium, aluminum, and zinc. The result is decreased absorption. Accordingly, tetracyclines should not be administered together with (1) calcium supplements, (2) milk products (because they contain calcium), (3) iron supplements, (4) magnesium-containing laxatives, and (5) most antacids (because they contain magnesium, aluminum, or both).

Distribution.

Tetracyclines are widely distributed to most tissues and body fluids. However, penetration to the cerebrospinal fluid (CSF) is poor, and hence levels in the CSF are too low to treat meningeal infections. Tetracyclines readily cross the placenta and enter the fetal circulation.

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.

Long-acting tetracyclines are eliminated by the liver, primarily as metabolites. Because these agents are excreted by the liver, their half-lives are unaffected by kidney dysfunction. Accordingly, the long-acting agents (doxycycline and minocycline) are drugs of choice for tetracycline-responsive infections in patients with 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.

Suprainfection of the bowel with staphylococci or with Clostridium difficile produces severe diarrhea and can be life threatening. The infection caused by C. difficile is known as C. difficile–associated diarrhea (CDAD), also known as antibiotic-associated pseudomembranous colitis (AAPMC). Patients should notify the prescriber if significant diarrhea occurs, so that the possibility of bacterial suprainfection can be evaluated. If a diagnosis of suprainfection with staphylococci or C. difficile is made, tetracyclines should be discontinued immediately. Treatment of CDAD consists of oral vancomycin or metronidazole plus vigorous fluid and electrolyte replacement.

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.

Photosensitivity.

All tetracyclines can increase the sensitivity of the skin to ultraviolet light. The most common result is exaggerated sunburn. Advise patients to avoid prolonged exposure to sunlight, wear protective clothing, and apply a sunscreen to exposed skin.

Other adverse effects.

Vestibular toxicity—manifesting as dizziness, lightheadedness, and unsteadiness—has occurred with minocycline. Rarely, tetracyclines have produced pseudotumor cerebri (a benign elevation in intracranial pressure). In a few patients, demeclocycline has produced nephrogenic diabetes insipidus, a syndrome characterized by thirst, increased frequency of urination, and unusual weakness or tiredness. Because of their irritant properties, tetracyclines can cause pain at sites of IM injection and thrombophlebitis when administered intravenously.

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	Usual Dosing Interval (hr)	Adult (mg)	Pediatric (mg/kg)^a
Short Acting	Tetracycline	generic only	PO	6	1000–2000	25–50
			IV^b	12	500–1000	10–20
			IM^c	12	300	15–25
Intermediate Acting	Demeclocycline	Declomycin	PO	12	600	6–12
Long Acting	Doxycycline	Vibramycin, others	PO	24	100^d	2.2^e
			IV^b	24	100–200^f	2.2–4.4^g
	Minocycline	Minocin, others	PO	12	200^h	4ⁱ
			IV^b	12	200^h	4ⁱ