Macrolides, Ketolides & Streptogramins

Macrolides, Ketolides & Streptogramins

1. Definition, chemistry & class overview

• Macrolides are antibiotics built on a macrocyclic lactone ring to which one or more deoxy sugars are glycosidically attached; the ring size defines the subclass (G&G 14e Ch.60, pp.1182; Katzung 16e Ch.44, pp.859).
  • 14-membered ring: erythromycin, clarithromycin, roxithromycin (and the ketolide telithromycin) (G&G 14e Ch.60, p.1182; KDT 8e Ch.55, p.801).
  • 15-membered ring (an "azalide"): azithromycin — formed by inserting a methyl-substituted nitrogen atom into the lactone ring of erythromycin (G&G 14e Ch.60, p.1182; KDT 8e Ch.55, p.804).
  • 16-membered ring: spiramycin, josamycin (older/natural members) (Katzung 16e Ch.44, p.859; KDT 8e Ch.55, p.805).
• The two sugars on erythromycin are desosamine (an amino sugar) and cladinose (a neutral sugar); the L-cladinose moiety is the structural element removed/replaced to create the ketolides (Katzung 16e Ch.44, p.859, p.861).
• Erythromycin is the prototype, isolated in 1952 by McGuire and coworkers from a strain of Streptomyces erythraeus (now reclassified Saccharopolyspora erythraea) (G&G 14e Ch.60, p.1182; Katzung 16e Ch.44, p.859; KDT 8e Ch.55, p.801).
• Erythromycin is poorly water-soluble (~0.1%), dissolves in organic solvents, is acid-labile, and loses activity rapidly at acid pH / warm temperature — driving the development of acid-stable esters and semisynthetic congeners (Katzung 16e Ch.44, p.859; KDT 8e Ch.55, p.801).
• Clarithromycin differs from erythromycin only by 6-O-methylation of a hydroxyl group, conferring acid stability and improved oral absorption (G&G 14e Ch.60, p.1182; Katzung 16e Ch.44, p.860).
• Class members available in current practice: erythromycin, clarithromycin, azithromycin (the three principal systemic agents), plus roxithromycin and spiramycin (Indian/European practice) and fidaxomicin (a non-systemically-absorbed macrolide reserved for Clostridioides difficile) (G&G 14e Ch.60, p.1182; KDT 8e Ch.55, pp.801–805).
• Ketolides (telithromycin; the investigational cethromycin, solithromycin) are semisynthetic 14-membered-ring derivatives of erythromycin carrying a 3-keto group in place of α-L-cladinose plus a C11–C12 substituted carbamate — modifications that defeat several macrolide-resistance mechanisms (G&G 14e Ch.60, p.1183; Katzung 16e Ch.44, p.861).
• Streptogramins are semisynthetic derivatives of natural products of Streptomyces pristinaespiralis, clinically used as the fixed combination quinupristin (streptogramin B) + dalfopristin (streptogramin A) in a 30:70 ratio (the more-soluble derivatives of pristinamycin IA and IIA) (G&G 14e Ch.60, p.1187; Katzung 16e Ch.44, p.862).