Page 833 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 44 Tetracyclines, Macrolides, Clindamycin, Chloramphenicol, Streptogramins, & Oxazolidinones 819

a 14-atom lactone ring, was obtained in 1952 from Streptomyces Resistance to erythromycin is usually plasmid-encoded. Three
erythreus, now called Saccharopolyspora erythraea. Clarithromycin general mechanisms have been identified: (1) reduced perme-
and azithromycin are semisynthetic derivatives of erythromycin. ability of the cell membrane or active efflux; (2) production
(by Enterobacteriaceae) of esterases that hydrolyze macrolides;
Macrolide O and (3) modification of the ribosomal binding site (so-called
ring ribosomal protection) by chromosomal mutation or by a mac-
R 1 R 1
rolide-inducible or constitutive methylase. Efflux and methylase
OH production are the most important resistance mechanisms in
R 2 O R 1 Gram-positive organisms. Cross-resistance is complete between
R 1 6 OH
R 1 R erythromycin and the other macrolides. Constitutive methylase
O 1
O O C H production also confers resistance to structurally unrelated but
2 5
mechanistically similar compounds such as clindamycin and strep-
N(R )
1 2
Desosamine togramin B (so-called macrolide-lincosamide-streptogramin, or
O O
OH MLS-type B, resistance), which share the same ribosomal binding
O R 1 site. Because nonmacrolides are poor inducers of the methylase,
HO R 1 strains expressing an inducible methylase will appear susceptible
OR 1
Cladinose in vitro. However, constitutive mutants that are resistant can be
R 1 selected out and emerge during therapy with clindamycin.
Erythromycin (R = CH , R = H)
2
3
1
Clarithromycin (R , R = CH ) Pharmacokinetics
1
3
2
Erythromycin base is destroyed by stomach acid and must be
ERYTHROMYCIN administered with enteric coating. Food interferes with absorp-
tion. The stearate and ethylsuccinate formulations are fairly acid-
Chemistry resistant and somewhat better absorbed. A 500-mg intravenous
dose of erythromycin lactobionate produces serum concentrations
The general structure of erythromycin is shown with the mac- of 10 mcg/mL 1 hour after dosing. The serum half-life is approxi-
rolide ring and the sugars desosamine and cladinose. It is poorly mately 1.5 hours normally and 5 hours in patients with anuria.
soluble in water (0.1%) but dissolves readily in organic solvents. Adjustment for renal failure is not necessary. Erythromycin is
Solutions are fairly stable at 4°C but lose activity rapidly at 20°C not removed by dialysis. Large amounts of an administered dose
and at acid pH. Erythromycins are usually dispensed as various are excreted in the bile, and only 5% is excreted in the urine.
esters and salts. Absorbed drug is distributed widely except to the brain and cere-
brospinal fluid. Erythromycin is taken up by polymorphonuclear
Mechanism of Action & Antimicrobial leukocytes and macrophages. It traverses the placenta and reaches
Activity the fetus.
The antibacterial action of erythromycin and other macrolides Clinical Uses
may be inhibitory or bactericidal, particularly at higher concentra-
tions, for susceptible organisms. Activity is enhanced at alkaline Erythromycin is a traditional drug of choice in corynebacterial
pH. Inhibition of protein synthesis occurs via binding to the 50S infections (diphtheria, corynebacterial sepsis, erythrasma) and
ribosomal RNA. The binding site is near the peptidyltransferase in respiratory, neonatal, ocular, or genital chlamydial infections.
center, and peptide chain elongation (ie, transpeptidation) is While it was used in treatment of community-acquired pneu-
prevented by blocking of the polypeptide exit tunnel. As a result, monia because its spectrum of activity includes pneumococcus,
peptidyl-tRNA is dissociated from the ribosome. Erythromy- M pneumoniae, and L pneumophila, newer macrolides are better
cin also inhibits the formation of the 50S ribosomal subunit tolerated and more commonly selected. Macrolide resistance is
(Figure 44–1). increasing in pneumococci and M pneumoniae. Erythromycin had
Erythromycin is active against susceptible strains of Gram-pos- also been useful as a penicillin substitute in penicillin-allergic indi-
itive organisms, especially pneumococci, streptococci, staphylo- viduals with infections caused by staphylococci and streptococci.
cocci, and corynebacteria. Mycoplasma pneumoniae, L pneumophila, Emergence of erythromycin resistance in staphylococci and in
Chlamydia trachomatis, Chlamydophila psittaci, Chlamydophila strains of group A streptococci has made macrolides less attractive
pneumoniae, H pylori, Listeria monocytogenes, and certain myco- as first-line agents for treatment of pharyngitis and skin and soft
bacteria (Mycobacterium kansasii, Mycobacterium scrofulaceum) tissue infections. Erythromycin has been studied as prophylaxis
also are susceptible. Gram-negative organisms such as Neisseria sp, against endocarditis during dental procedures in individuals with
Bordetella pertussis, Bartonella henselae, and Bartonella quintana as valvular heart disease, but clindamycin, which is better tolerated,
well as some Rickettsia species, Treponema pallidum, and Campylo- has largely replaced it.
bacter species are susceptible. Haemophilus influenzae is somewhat The oral dosage of erythromycin base or stearate is
less susceptible. 0.25–0.5 g every 6 hours (for children, 40 mg/kg/d). The dosage