Katzung & Trevor's Pharmacology Examination and Board Review, 9th Edition

Chapter 44. Chloramphenicol, Tetracyclines, Macrolides, Clindamycin, Streptogramins, & Linezolid

Chloramphenicol, Tetracyclines, Macrolides, Clindamycin, Streptogramins, & Linezolid: Introduction

The antimicrobial drugs reviewed in this chapter selectively inhibit bacterial protein synthesis. The mechanisms of protein synthesis in microorganisms are not identical to those of mammalian cells. Bacteria have 70S ribosomes, whereas mammalian cells have 80S ribosomes. Differences exist in ribosomal subunits and in the chemical composition and functional specificities of component nucleic acids and proteins. Such differences form the basis for the selective toxicity of these drugs against microorganisms without causing major effects on protein synthesis in mammalian cells.

Inhibitors of Microbial Protein Synthesis

Drugs that inhibit protein synthesis vary considerably in terms of chemical structures and their spectrum of antimicrobial activity. Chloramphenicol, tetracyclines, and the aminoglycosides (see Chapter 45) were the first inhibitors of bacterial protein synthesis to be discovered. Because they had a broad spectrum of antibacterial activity and were thought to have low toxicities, they were overused. Many once highly susceptible bacterial species have become resistant, and most of these drugs are now used for more selected targets. Erythromycin, an older macrolide antibiotic, has a narrower spectrum of action but continues to be active against several important pathogens. Azithromycin and clarithromycin, semisynthetic macrolides, have some distinctive properties compared with erythromycin, as does clindamycin. Newer inhibitors of microbial protein synthesis, which include streptogramins, linezolid, telithromycin, and tigecycline (a tetracycline analog) have activity against certain bacteria that have developed resistance to older antibiotics.

Mechanisms of Action

Most of the antibiotics reviewed in this chapter are bacteriostatic inhibitors of protein synthesis acting at the ribosomal level (Figure 44-1). With the exception of tetracyclines, the binding sites for these antibiotics are on the 50S ribosomal subunit. Chloramphenicol inhibits transpeptidation (catalyzed by peptidyl transferase) by blocking the binding of the aminoacyl moiety of the charged transfer RNA (tRNA) molecule to the acceptor site on the ribosome-messenger (mRNA) complex. Thus, the peptide at the donor site cannot be transferred to its amino acid acceptor. Macrolides, telithromycin, and clindamycin, which share a common binding site on the 50S ribosome, also block transpeptidation. Tetracyclines bind to the 30S ribosomal subunit preventing binding of amino acid-charged tRNA to the acceptor site of the ribosome-mRNA complex.

FIGURE 44-1

Steps in bacterial protein synthesis and targets of several antibiotics. Amino acids are shown as numbered circles. The 70S ribosomal mRNA complex is shown with its 50S and 30S subunits. In step 1, the charged tRNA unit carrying amino acid 6 binds to the acceptor site on the 70S ribosome. The peptidyl tRNA at the donor site, with amino acids 1 through 5, then binds the growing amino acid chain to amino acid 6 (transpeptidation, step 2). The uncharged tRNA left at the donor site is released (step 3), and the new 6-amino acid chain with its tRNA shifts to the peptidyl site (translocation, step 4). The antibiotic-binding sites are shown schematically as triangles. Chloramphenicol (C) and macrolides (M) bind to the 50S subunit and block transpeptidation (step 2). The tetracyclines (T) bind to the 30S subunit and prevent binding of the incoming charged tRNA unit (step 1).

(Reproduced, with permission, from Katzung BG, editor: Basic & Clinical Pharmacology, 11th ed. McGraw-Hill, 2009: Fig. 44-1.)

Streptogramins are bactericidal for most susceptible organisms. They bind to the 50S ribosomal subunit, constricting the exit channel on the ribosome through which nascent polypeptides are extruded. In addition, tRNA synthetase activity is inhibited, leading to a decrease in free tRNA within the cell. Linezolid is mainly bacteriostatic. The drug binds to a unique site on the 50S ribosome, inhibiting initiation by blocking formation of the tRNA-ribosome-mRNA ternary complex.

Selective toxicity of these protein synthesis inhibitors against microorganisms may be explained by target differences. Chloramphenicol does not bind to the 80S ribosomal RNA of mammalian cells, although it can inhibit the functions of mitochondrial ribosomes, which contain 70S ribosomal RNA. Tetracyclines have little effect on mammalian protein synthesis because an active efflux mechanism prevents their intracellular accumulation.

Chloramphenicol

Classification and Pharmacokinetics

Chloramphenicol has a simple and distinctive structure, and no other antimicrobials have been discovered in this chemical class. It is effective orally as well as parenterally and is widely distributed readily crossing the placental and blood-brain barriers. Chloramphenicol undergoes enterohepatic cycling, and a small fraction of the dose is excreted in the urine unchanged. Most of the drug is inactivated by a hepatic glucuronosyltransferase.

Antimicrobial Activity

Chloramphenicol has a wide spectrum of antimicrobial activity and is usually bacteriostatic. Some strains of Haemophilus influenzae, Neisseria meningitidis, and Bacteroides are highly susceptible, and for these organisms chloramphenicol may be bactericidal. It is not active against Chlamydia species. Resistance to chloramphenicol, which is plasmid-mediated, occurs through the formation of acetyltransferases that inactivate the drug.

Clinical Uses

Because of its toxicity, chloramphenicol has very few uses as a systemic drug. It is a backup drug for severe infections caused by Salmonella species and for the treatment of pneumococcal and meningococcal meningitis in beta-lactam-sensitive persons. Chloramphenicol is sometimes used for rickettsial diseases and for infections caused by anaerobes such as Bacteroides fragilis. The drug is commonly used as a topical antimicrobial agent

Toxicity

Gastrointestinal Disturbances

These conditions may occur from direct irritation and from superinfections, especially candidiasis.

Bone Marrow

Inhibition of red cell maturation leads to a decrease in circulating erythrocytes. This action is dose-dependent and reversible. Aplastic anemia is a rare idiosyncratic reaction (approximately 1 case in 25,000-40,000 patients treated). It is usually irreversible and may be fatal.

Gray Baby Syndrome

This syndrome occurs in infants and is characterized by decreased red blood cells, cyanosis, and cardiovascular collapse. Neonates, especially those who are premature, are deficient in hepatic glucuronosyltransferase and are sensitive to doses of chloramphenicol, which would be tolerated in older infants.

Drug Interactions

Chloramphenicol inhibits hepatic drug-metabolizing enzymes, thus increasing the elimination half-lives of drug including phenytoin, tolbutamide and warfarin.

Tetracyclines

Classification

Drugs in this class are broad-spectrum bacteriostatic antibiotics that have only minor differences in their activities against specific organisms.

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.

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.

Clinical Uses

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.

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.

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).

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.

Toxicity

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.

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 outweigh the risk. Treatment of younger children may cause enamel dysplasia and crown deformation when permanent teeth appear.

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.

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.

Photosensitivity

Tetracyclines, especially demeclocycline, may cause enhanced skin sensitivity to ultraviolet light.

Vestibular Toxicity

Dose-dependent reversible dizziness and vertigo have been reported with doxycycline and minocycline.

Macrolides

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 days), mainly in the urine as unchanged drug.

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.

Clinical 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-day 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.

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.

Telithromycin

Telithromycin is a ketolide structurally related to macrolides. The drug has the same mechanism of action as erythromycin and a similar spectrum of antimicrobial activity. However, some macrolide-resistant strains are susceptible to telithromycin because it binds more tightly to ribosomes and is a poor substrate for bacterial efflux pumps that mediate resistance. The drug can be used in community-acquired pneumonia including infections caused by multidrug-resistant organisms. Telithromycin is given orally once daily and is eliminated in the bile and the urine. The adverse effects of telithromycin include hepatic dysfunction and prolongation of the QTc interval. The drug is an inhibitor of the CYP3A4 drug-metabolizing system.

Clindamycin

Classification and Pharmacokinetics

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.

Clinical Use and 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 jiroveci 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 difficilepseudomembranous colitis.

Streptogramins

Quinupristin-dalfopristin, a combination of 2 streptogramins, is bactericidal (see prior discussion of mechanism of action) and has a duration of antibacterial activity longer than the half-lives of the 2 compounds (postantibiotic effects). Antibacterial activity includes penicillin-resistant pneumococci, methicillin-resistant (MRSA) and vancomycin-resistant staphylococci (VRSA), and resistant E faecium; E faecalis is intrinsically resistant via an efflux transport system. Administered intravenously, the combination product may cause pain and an arthralgia-myalgia syndrome. Streptogramins are potent inhibitors of CYP3A4 and increase plasma levels of many drugs, including astemizole, cisapride, cyclosporine, diazepam, nonnucleoside reverse transcriptase inhibitors, and warfarin.

Linezolid

The first of a novel class of antibiotics (oxazolidinones), linezolid is active against drug-resistant gram-positive cocci, including strains resistant to penicillins (eg, MRSA, PRSP) and vancomycin (eg, VRE). The drug is also active against L monocytogenes and corynebacteria. Linezolid binds to a unique site located on the 23S ribosomal RNA of the 50S ribosomal subunit, and there is currently no cross-resistance with other protein synthesis inhibitors. Resistance (rare to date) involves a decreased affinity of linezolid for its binding site. Linezolid is available in both oral and parenteral formulations and should be reserved for treatment of infections caused by multidrug-resistant gram-positive bacteria. The drug is metabolized by the liver and has an elimination half-life of 4-6 h. Thrombocytopenia and neutropenia occur, most commonly in immunosuppressed patients. Linezolid has been implicated in the serotonin syndrome when used in patients taking selective serotonin reuptake inhibitors (SSRIs).

Checklist

When you complete this chapter, you should be able to:

 Explain (1 sentence per drug class) how these agents inhibit bacterial protein synthesis.

 Identify the primary mechanisms of resistance to each of these drug classes.

 Name the most important agents in each drug class, and list 3 clinical uses of each.

 Recall distinctive pharmacokinetic features of the major drugs.

 List the characteristic toxic effects of the major drugs in each class.

Drug Summary Table: Tetracyclines, Macrolides, & Other Protein Synthesis Inhibitors

Subclass Mechanism of Action Activity & Clinical Uses Pharmacokinetics & Interactions Toxicities Tetracyclines Tetracycline Doxycycline Minocycline Tigecycline Bind 30S ribosomal subunit-bacteriostatic; tigecycline has broadest spectrum and resistance is less common Infections due to chlamydiae, mycoplasma, rickettsiae, spirochetes, and H pylori; treatment of acne (low dose) Oral, IV; renal and biliary clearance Doxycycline mainly gastrointestinal (GI) elimination and long half-life GI upsets, deposition in developing bones and teeth, photosensitivity, superinfection Macrolides Erythromycin Azithromycin Clarithromycin Telithromycin Bind to 50S ribosomal subunit;bacteriostatic; least resistance to telithromycin Community-acquired pneumonia, pertussis, corynebacteria, and chlamydial infections Oral; IV for erythromycin, azithromycin Hepatic clearance, azithromycin long half-life (>40 h) GI upsets, hepatic dysfunction; QT elongation;CYP450 inhibition (not azithromycin) LincosamideClindamycin Bind to 50S ribosomal subunit; bacteriostatic Skin, soft tissue, and anaerobic infections Oral, IV; hepatic clearance GI upsets; C difficile colitis Streptogramins Quinupristin-dalfopristin Binds to 50s ribosomal subunit; bactericidal Staphylococcal infections, vancomycin-resistant E faecium IV; renal clearance Infusion-related arthralgia and myalgia; CYP450 inhibition Chloramphenicol Binds to 50S ribsosomal subunit; bacteriostatic Wide spectrum, but mainly backup Oral, IV; hepatic clearance, short half-life Dose-related anemia; gray baby syndrome Oxazolidinone Linezolid Binds to 23S RNA of 50S subunit; bacteriostatic Activity includes MRSA, PRSP,and VRE strains Oral, IV; hepatic clearance Dose-related anemia, neuropathy,optic neuritis; serotonin syndrome with SSRIs

MRSA, methicillin-resistant staphylococci; PRSP, penicillin-resistant pneumococci; SSRIs, selective serotonin reuptake inhibitors; VRE, vancomycin-resistant enterococci.



If you find an error or have any questions, please email us at admin@doctorlib.info. Thank you!