Tetracyclines, Macrolides, & Clindamycin

Tetracyclines Toxicity

1. GASTROINTESTINAL DISTURBANCES Effects on the gastrointestinal system range from mild nausea and diarrhea to severe, possibly life-threatening enterocolitis. Disturbances in the normal flora may lead to candidiasis (oral and vaginal) and, more rarely, to bacterial superinfections with S aureus or Clostridium difficile. 2. BONY STRUCTURES AND TEETH Fetal exposure to tetracyclines may lead to tooth enamel dysplasia and irregularities in bone growth. Although usually contraindicated in pregnancy, there may be situations in which the benefit of tetracyclines outweighs the risk. Treatment of younger children may cause enamel dysplasia and crown deformation when permanent teeth appear. 3. HEPATIC TOXICITY High doses of tetracyclines, especially in pregnant patients and those with preexisting hepatic disease, may impair liver function and lead to hepatic necrosis. 4. RENAL TOXICITY One form of renal tubular acidosis, Fanconi's syndrome, has been attributed to the use of outdated tetracyclines. Though not directly nephrotoxic, tetracyclines may exacerbate preexisting renal dysfunction. 5. PHOTOSENSITIVITY Tetracyclines, especially demeclocycline, may cause enhanced skin sensitivity to ultraviolet light. 6. VESTIBULAR TOXICITY Dose-dependent reversible dizziness and vertigo have been reported with doxycycline and minocycline.

Tetracyclines Uses

1. PRIMARY USES Tetracyclines are recommended in the treatment of infections caused by Mycoplasma pneumoniae (in adults), chlamydiae, rickettsiae, vibrios, and some spirochetes. Doxycycline is currently an alternative to macrolides in the initial treatment of community-acquired pneumonia. 2. SECONDARY USES Tetracyclines are alternative drugs in the treatment of syphilis. They are also used in the treatment of respiratory infections caused by susceptible organisms, for prophylaxis against infection in chronic bronchitis, in the treatment of leptospirosis, and in the treatment of acne. 3. SELECTIVE USES Specific tetracyclines are used in the treatment of gastrointestinal ulcers caused by Helicobacter pylori (tetracycline), in Lyme disease (doxycycline), and in the meningococcal carrier state (minocycline). Doxycycline is also used for the prevention of malaria and in the treatment of amebiasis (Chapter 52). Demeclocycline inhibits the renal actions of antidiuretic hormone (ADH) and is used in the management of patients with ADH-secreting tumors (Chapter 15). 4. TIGECYCLINE Unique features of this glycylcycline derivative of minocycline include a broad spectrum of action that includes organisms resistant to standard tetracyclines. The antimicrobial activity of tigecycline includes gram-positive cocci resistant to methicillin (MRSA strains) and vancomycin (VRE strains), beta-lactamase-producing gram-negative bacteria, anaerobes, chlamydiae, and mycobacteria. The drug is formulated only for intravenous use.

Tetracyclines

A. Classification Drugs in this class are broad-spectrum bacteriostatic antibiotics that have only minor differences in their activities against specific organisms. B. Pharmacokinetics Oral absorption is variable, especially for the older drugs, and may be impaired by foods and multivalent cations (calcium, iron, aluminum). Tetracyclines have a wide tissue distribution and cross the placental barrier. All the tetracyclines undergo enterohepatic cycling. Doxycycline is excreted mainly in feces; the other drugs are eliminated primarily in the urine. The half-lives of doxycycline and minocycline are longer than those of other tetracyclines. Tigecycline, formulated only for IV use, is eliminated in the bile and has a half-life of 30-36 h. C. Antibacterial Activity Tetracyclines are broad-spectrum antibiotics with activity against gram-positive and gram-negative bacteria, species of Rickettsia, Chlamydia, Mycoplasma, and some protozoa. However, resistance to most tetracyclines is widespread. Resistance mechanisms include the development of mechanisms (efflux pumps) for active extrusion of tetracyclines and the formation of ribosomal protection proteins that interfere with tetracycline binding. These mechanisms do not confer resistance to tigecycline in most organisms, with the exception of the multidrug efflux pumps of Proteus and Pseudomonas species.

Macrolides

A. Classification and Pharmacokinetics The macrolide antibiotics (erythromycin, azithromycin, and clarithromycin) are large cyclic lactone ring structures with attached sugars. The drugs have good oral bioavailability, but azithromycin absorption is impeded by food. Macrolides distribute to most body tissues, but azithromycin is unique in that the levels achieved in tissues and in phagocytes are considerably higher than those in the plasma. The elimination of erythromycin (via biliary excretion) and clarithromycin (via hepatic metabolism and urinary excretion of intact drug) is fairly rapid (half-lives of 2 and 6 h, respectively). Azithromycin is eliminated slowly (half-life 2-4 d), mainly in the urine as unchanged drug. B. Antibacterial Activity Erythromycin has activity against many species of Campylobacter, Chlamydia, Mycoplasma, Legionella, gram-positive cocci, and some gram-negative organisms. The spectra of activity of azithromycin and clarithromycin are similar but include greater activity against species of Chlamydia, Mycobacterium avium complex, and Toxoplasma. Azithromycin is also effective in gonorrhea, as an alternative to ceftriaxone and in syphilis, as an alternative to penicillin G. Resistance to the macrolides in gram-positive organisms involves efflux pump mechanisms and the production of a methylase that adds a methyl group to the ribosomal binding site. Cross-resistance between individual macrolides is complete. In the case of methylase-producing microbial strains, there is partial cross-resistance with other drugs that bind to the same ribosomal site as macrolides, including clindamycin and streptogramins. Resistance in Enterobacteriaceae is the result of formation of drug-metabolizing esterases.

Macrolides Toxicity

Adverse effects, especially with erythromycin, include gastrointestinal irritation (common) via stimulation of motolin receptors, skin rashes, and eosinophilia. A hypersensitivity-based acute cholestatic hepatitis may occur with erythromycin estolate. Hepatitis is rare in children, but there is an increased risk with erythromycin estolate in the pregnant patient. Erythromycin inhibits several forms of hepatic cytochrome P450 and can increase the plasma levels of many drugs, including anticoagulants, carbamazepine, cisapride, digoxin, and theophylline. Similar drug interactions have also occurred with clarithromycin. The lactone ring structure of azithromycin is slightly different from that of other macrolides, and drug interactions are uncommon because azithromycin does not inhibit hepatic cytochrome P450.

Clindamycin

Clindamycin inhibits bacterial protein synthesis via a mechanism similar to that of the macrolides, although it is not chemically related. Mechanisms of resistance include methylation of the binding site on the 50S ribosomal subunit and enzymatic inactivation. Gram-negative aerobes are intrinsically resistant because of poor penetration of clindamycin through the outer membrane. Cross-resistance between clindamycin and macrolides is common. Good tissue penetration occurs after oral absorption. Clindamycin undergoes hepatic metabolism, and both intact drug and metabolites are eliminated by biliary and renal excretion.

Macrolides Uses

Erythromycin is effective in the treatment of infections caused by M pneumoniae, Corynebacterium, Campylobacter jejuni, Chlamydia trachomatis, Chlamydophila pneumoniae, Legionella pneumophila, Ureaplasma urealyticum, and Bordetella pertussis. The drug is also active against gram-positive cocci (but not penicillin-resistant Streptococcus pneumoniae [PRSP] strains) and beta-lactamase-producing staphylococci (but not methicillin-resistant S aureus [MRSA] strains). Azithromycin has a similar spectrum of activity but is more active against H influenzae, Moraxella catarrhalis, and Neisseria. Because of its long half-life, a single dose of azithromycin is effective in the treatment of urogenital infections caused by C trachomatis, and a 4-d course of treatment has been effective in community-acquired pneumonia. Clarithromycin has almost the same spectrum of antimicrobial activity and clinical uses as erythromycin. The drug is also used for prophylaxis against and treatment of M avium complex and as a component of drug regimens for ulcers caused by H pylori. Fidaxomicin is a narrow-spectrum macrolide antibiotic that inhibits protein synthesis and is selectively active against gram-positive aerobes and anaerobes. Given orally, systemic absorption is minimal. Fidaxomicin has proved to be as effective as vancomycin for the treatment of C difficile colitis, possibly with lower relapse rate.

Clindamycin Toxicity

The main use of clindamycin is in the treatment of severe infections caused by certain anaerobes such as Bacteroides. Clindamycin has been used as a backup drug against gram-positive cocci (it is active against community-acquired strains of methicillin-resistant S aureus) and is recommended for prophylaxis of endocarditis in valvular disease patients who are allergic to penicillin. The drug is also active against Pneumocystis jirovecii and is used in combination with pyrimethamine for AIDS-related toxoplasmosis. The toxicity of clindamycin includes gastrointestinal irritation, skin rashes, neutropenia, hepatic dysfunction, and possible superinfections such as C difficile pseudomembranous colitis.