Macrolides
Macrolides are a group of bacteriostatic drugs with a wide spectrum of activity. The name macrolide refers to their large (13–16 carbon) ring structure (Figure 1). Azithromycin, erythromycin, and clarithromycin are the main macrolides in clinical use. Azithromycin is used to treat genital tract infections caused by Chlamydia trachomatis and respiratory tract infections caused by Legionella, Mycoplasma, Chlamydia pneumoniae, and S. pneumoniae. Erythromycin has a similar spectrum of activity but has a shorter half-life and so must be taken more frequently and has more adverse effects, especially on the gastrointestinal tract. Clarithromycin is used primarily in the treatment of Helicobacter infections and to treat and prevent Mycobacterium avium-intracellulare infections. An important adverse effect of clarithromycin is prolongation of the QT interval, which may increase the risk of cardiac death.
Macrolides inhibit bacterial protein synthesis by binding to the 50S ribosomal subunit and blocking translocation. They pre vent the release of the uncharged tRNA after it has transferred its amino acid to the growing peptide chain. The donor site remains occupied, a new tRNA cannot attach, and protein synthesis stops.
Telithromycin (Ketek) is the first clinically useful member of the ketolide group of antibiotics which is similar to the macrolides in general structure and mode of action but is sufficiently different chemically such that organisms resistant to macrolides may be sensitive to telithromycin. It has a wide spectrum of activity against a variety of gram-positive and gram-negative bacteria (including macrolide-resistant pneumococci) and is used to treat community-acquired pneumonia, bronchitis, and sinusitis. It is no longer regularly available in the United States.
Clindamycin
The most useful clinical activity of this bacteriostatic drug is against anaerobes, both gram-positive bacteria such as Clostridium perfringens and gram-negative bacteria such as B. fragilis.
Clindamycin binds to the 50S subunit and blocks peptide bond formation by an undetermined mechanism. Its specificity for bacteria arises from its inability to bind to the 60S subunit of human ribosomes.
The most important side effect of clindamycin is pseudo membranous colitis, which, in fact, can occur with virtually any antibiotic, whether taken orally or parenterally. The pathogenesis of this potentially severe complication is suppression of the normal flora of the bowel by the drug and overgrowth of a drug-resistant strain of C. difficile. The organism secretes an exotoxin that produces the pseudomembrane in the colon and severe, often bloody diarrhea.
Linezolid
Linezolid is useful for the treatment of VRE, MRSA and S. epidermidis, and penicillin-resistant pneumococci. It is bacteriostatic against enterococci and staphylococci but bactericidal against pneumococci.
Linezolid binds to the 23S rRNA in the 50S subunit and inhibits protein synthesis, but the precise mechanism is unknown. It appears to block some early step (initiation) in ribosome formation. Tedizolid is a second-generation drug in the same class as linezolid but is approximately 10 times more effective. It is used for the treatment of skin and soft tissue infections caused by a similar range of bacteria as linezolid and has a similar mechanism of action.
Chloramphenicol
Chloramphenicol is no longer regularly prescribed in the United States because of its rare but real risk of aplastic anemia. The drug is active against a broad range of organisms, including gram-positive and gram-negative bacteria (including anaerobes). It is bacteriostatic against certain organisms, such as Salmonella typhi, but has bactericidal activity against the three important encapsulated organisms that cause meningitis: H. influenzae, S. pneumoniae, and N. meningitidis.
Chloramphenicol inhibits protein synthesis by binding to the 50S ribosomal subunit and blocking the action of peptidyl transferase; this prevents the synthesis of new peptide bonds. It inhibits bacterial protein synthesis selectively because it binds to the catalytic site of the transferase in the 50S bacterial ribosomal subunit but not to the transferase in the 60S human ribosomal subunit. Chloramphenicol inhibits protein synthesis in the mitochondria of human cells to some extent, since mitochondria have a 50S subunit (mitochondria are thought to have evolved from bacteria). This inhibition may be the cause of the dose-dependent toxicity of chloramphenicol to bone marrow.
Chloramphenicol is a comparatively simple molecule with a nitrobenzene nucleus (Figure 1). Nitrobenzene is a bone marrow depressant and is likely to be involved in the hematologic problems reported with this drug. Chloramphenicol causes two types of bone marrow toxicity. One is a dose-dependent suppression, which is more likely to occur in patients receiving high doses for long periods and is reversible when administration of the drug is stopped. The other is aplastic anemia caused by an idiosyncratic reaction to the drug. This reaction is not dose-dependent, can occur weeks after administration of the drug has been stopped, and is not reversible. Fortunately, this reaction is rare, occurring in about 1 in 30,000 patients.
Fig1. Chloramphenicol
One specific toxic manifestation of chloramphenicol is “gray baby” syndrome, in which the infant’s skin appears gray, and vomiting and shock occur. This is due to reduced glucuronyl transferase activity in infants. This enzyme detoxifies chloramphenicol. The decreased activity in infants results in toxic concentrations of chloramphenicol.
Streptogramins
A combination of two streptogramins, quinupristin and dalfopristin (Synercid), is used for the treatment of bloodstream infections caused by vancomycin-resistant Enterococcus faecium (but not vancomycin-resistant Enterococcus faecalis). It is no longer readily available in the United States. It is also approved for use in infections caused by Streptococcus pyogenes, penicillin-resistant S. pneumoniae, MRSA, and methicillin resistant S. epidermidis.
Streptogramins cause premature release of the growing peptide chain from the 50S ribosomal subunit. The structure and mode of action of streptogramins are different from all other drugs that inhibit protein synthesis, and there is no cross resistance between streptogramins and these other drugs.
Retapamulin
Retapamulin (Altabax) is the first clinically available member of a new class of antibiotics called pleuromutilins. These drugs inhibit bacterial protein synthesis by binding to the 23S RNA of the 50S subunit and blocking attachment of the donor tRNA. Retapamulin is a topical antibiotic used in the treatment of skin infections, such as impetigo, caused by S. pyogenes and methicillin- sensitive S. aureus. In 2019, lefamulin (Xenleta), a second pleuromulin, was approved for the treatment of community acquired bacterial pneumonia in adults.
