Page 834 - Basic _ Clinical Pharmacology ( PDFDrive )

820 SECTION VIII Chemotherapeutic Drugs

of erythromycin ethylsuccinate is 0.4–0.8 g every 6 hours. Oral AZITHROMYCIN
erythromycin base (1 g) is sometimes combined with oral neo-
mycin or kanamycin for preoperative preparation of the colon. Azithromycin, a 15-atom lactone macrolide ring compound, is
The intravenous dosage of erythromycin lactobionate is 0.5–1.0 g derived from erythromycin by addition of a methylated nitrogen
every 6 hours for adults and 15–20 mg/kg/d divided every 6 hours into the lactone ring. Its spectrum of activity, mechanism of action,
for children. The higher dosage is recommended when treating and clinical uses are similar to those of clarithromycin. Azithromy-
pneumonia caused by L pneumophila. cin is active against M avium complex and T gondii. Azithromycin
is slightly less active than erythromycin and clarithromycin against
Adverse Reactions staphylococci and streptococci and slightly more active against
H influenzae. Azithromycin is highly active against Chlamydia sp.
Anorexia, nausea, vomiting, and diarrhea are common. Gastro-
intestinal intolerance, which is due to a direct stimulation of gut Azithromycin differs from erythromycin and clarithromy-
motility, is the most common reason for selecting an alternative to cin mainly in pharmacokinetic properties. A 500-mg dose of
erythromycin. This side effect may actually be desirable in some azithromycin produces relatively low serum concentrations of
circumstances, leading to the off-label use of erythromycin to treat approximately 0.4 mcg/mL. However, azithromycin penetrates
patients with gastroparesis. into most tissues (except cerebrospinal fluid) and phagocytic
Erythromycins, particularly the older estolate formulation, can cells extremely well, with tissue concentrations exceeding serum
produce acute cholestatic hepatitis (fever, jaundice, impaired liver concentrations by 10- to 100-fold. The drug is slowly released
function), probably as a hypersensitivity reaction. Most patients from tissues (tissue half-life of 2–4 days) to produce an elimina-
recover from this, but hepatitis recurs if the drug is readministered. tion half-life approaching 3 days. These unique properties permit
Other allergic reactions include fever, eosinophilia, and rashes. once-daily dosing and shortening of the duration of treatment in
Erythromycin metabolites inhibit cytochrome P450 enzymes many cases. For example, a single 1-g dose of azithromycin is as
and, thus increase the serum concentrations of numerous drugs, effective as a 7-day course of doxycycline for chlamydial cervicitis
including theophylline, warfarin, cyclosporine, and methylpred- and urethritis. Azithromycin, as a 500-mg loading dose, followed
nisolone. Erythromycin increases serum concentrations of oral by a 250-mg single daily dose for the next 4 days, is commonly
digoxin by increasing its bioavailability. used alone or in combination with a beta-lactam antibiotic to treat
community-acquired pneumonia.
Azithromycin is rapidly absorbed and well tolerated orally. Alumi-
CLARITHROMYCIN num and magnesium antacids do not alter bioavailability but delay
absorption and reduce peak serum concentrations. Because it has a
Clarithromycin is derived from erythromycin by addition of a 15-member (not 14-member) lactone ring, azithromycin does not
methyl group and has improved acid stability and oral absorption inactivate cytochrome P450 enzymes and, therefore, is free of the
compared with erythromycin. Its mechanism of action is the same drug interactions that occur with erythromycin and clarithromycin.
as that of erythromycin. Clarithromycin and erythromycin are Macrolide antibiotics prolong the electrocardiographic QT
similar with respect to antibacterial activity except that clarithro- interval due to an effect on potassium ion channels. Prolongation
mycin is more active against Mycobacterium avium complex (see of the QT interval can lead to the torsades de pointes arrhythmia.
Chapter 47). Clarithromycin also has activity against Mycobacte- Recent studies have suggested that azithromycin may be associated
rium leprae, Toxoplasma gondii, and H influenzae. Erythromycin- with a small increased risk of cardiac death.
resistant streptococci and staphylococci are also resistant to
clarithromycin.
A 500-mg dose of clarithromycin produces serum concen- FIDAXOMICIN
trations of 2–3 mcg/mL. The longer half-life of clarithromycin
(6 hours) compared with erythromycin permits twice-daily Fidaxomicin, a minimally absorbed macrolide used to treat
dosing. The recommended dosage is 250–500 mg twice daily or Clostridium difficile infections, is discussed in Chapter 50.
1000 mg of the extended-release formulation once daily. Clar-
ithromycin penetrates most tissues well, with concentrations equal
to or exceeding serum concentrations. KETOLIDES
Clarithromycin is metabolized in the liver and is partially
eliminated in the urine. The major metabolite, 14-hydroxyclar- Ketolides are semisynthetic, 14-membered-ring macrolides, dif-
ithromycin, also has antibacterial activity and is eliminated in the fering from erythromycin by substitution of a 3-keto group for
urine. Dosage reduction (eg, a 500-mg loading dose, then 250 mg the neutral sugar l-cladinose. Telithromycin is approved for
once or twice daily) is recommended for patients with creatinine limited clinical use. It is active in vitro against Streptococcus pyo-
clearances less than 30 mL/min. Clarithromycin has drug interac- genes, S pneumoniae, S aureus, H influenzae, Moraxella catarrhalis,
tions similar to those described for erythromycin. Mycoplasma sp, L pneumophila, Chlamydia sp, H pylori, Neisseria
The advantages of clarithromycin compared with erythromy- gonorrhoeae, B fragilis, T gondii, and certain nontuberculous
cin are lower incidence of gastrointestinal intolerance and less mycobacteria. Many macrolide-resistant strains are susceptible to
frequent dosing. ketolides because the structural modification of these compounds