Download Macrolids

Macrolides
Macrolides
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The macrolides are a group of closely related
compounds characterized by a macrocyclic lactone ring
(usually containing 14 or 16 atoms) to which deoxy
sugars are attached.
The prototype drug, erythromycin, which consists of two
sugar moieties attached to a 14-atom lactone ring, was
obtained in 1952 from Streptomyces erythreus.
Clarithromycin and azithromycin are semisynthetic
derivatives of erythromycin.
Macrolid Antibiotics
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The antibacterial action of erythromycin may be
inhibitory or bactericidal, depending on the drug
concentration at the site of action.
Activity is enhanced at alkaline pH.
Inhibition of protein synthesis occurs via binding
to the 50S ribosomal RNA, which blocks the
aminoacyl translocation reaction and formation
of initiation complexes.
Macrolid Antibiotics
Resistance
Resistance to erythromycin is usually plasmid-encoded.
 Three mechanisms have been identified:
(1) reduced permeability of the cell membrane or active efflux;
(2) production (by Enterobacteriaceae) of esterases that hydrolyze
macrolides; and
(3) modification of the ribosomal binding site (so-called ribosomal
protection) by chromosomal mutation or by a macrolide-inducible or
constitutive methylase.
 Efflux and methylase production are by far the most important
resistance mechanisms in gram-positive organisms.
 Cross-resistance is complete between erythromycin and the other
macrolides.
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Macrolid Antibiotics
Erythromycin
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(prototype)
Antimicrobial spectrum
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Gram-positive organisms
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Pneumococci
Streptococci
Staphylococci
Corynebacteria
Mycoplasma
Legionella
Chlamydia trachomatis
Chlamydia psittachi
Helicobacter
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Listeria
 Gram-negative organisms
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Rickettsia
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Neisseria species
Bordatella pertusis
Bartonella henselae
Bartonella quintana
Treponema pallidum
Campylobacter species
Clinical Use
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Eerythromycin is the drug of choice in;
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corynebacterial infections (diphtheria, corynebacterial sepsis, erythrasma); in
respiratory,
 neonatal, ocular, or genital chlamydial infections; and
 in treatment of community-acquired pneumonia because its spectrum of activity
includes pneumococcus, mycoplasma, and legionella.
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Erythromycin is also useful as a penicillin substitute in penicillin-allergic
individuals with infections caused by staphylococci (assuming that the
isolate is susceptible), streptococci, or pneumococci.
Emergence of erythromycin resistance in strains of group A streptococci
and pneumococci (penicillin-resistant pneumococci in particular) has made
macrolides less attractive as first-line agents for treatment of pharyngitis,
skin and soft tissue infections, and pneumonia.
Erythromycin has been recommended as prophylaxis against endocarditis
during dental procedures in individuals with valvular heart disease, although
clindamycin, which is better tolerated, has largely replaced it.
Although erythromycin estolate is the best-absorbed salt, it imposes the
greatest risk of adverse reactions. Therefore, the stearate or succinate salt
may be preferred.
Adverse Reactions
A. GASTROINTESTINAL EFFECTS
Anorexia, nausea, vomiting, and diarrhea occasionally accompany oral
administration. Gastrointestinal intolerance, which is due to a direct
stimulation of gut motility, is the most common reason for discontinuing
erythromycin and substituting another antibiotic.
B. LIVER TOXICITY
Erythromycins, particularly the estolate, can produce acute cholestatic
hepatitis (fever, jaundice, impaired liver function), probably as a
hypersensitivity reaction. Most patients recover from this, but hepatitis
recurs if the drug is readministered. Other allergic reactions include fever,
eosinophilia, and rashes.
C. DRUG INTERACTIONS
Erythromycin metabolites can inhibit cytochrome P450 enzymes and thus
increase the serum concentrations of numerous drugs, including
theophylline, oral anticoagulants, cyclosporine, and methylprednisolone.
Erythromycin increases serum concentrations of oral digoxin by increasing
its bioavailability.
Other Macrolides
Clarithromycin
 Azithromycin
 Roxithromycin
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Clarithromycin
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Clarithromycin is derived from erythromycin by addition of a methyl
group and has improved acid stability and oral absorption compared
with erythromycin.
Its mechanism of action is the same as that of erythromycin.
Clarithromycin and erythromycin are virtually identical with respect
to antibacterial activity except that clarithromycin is more active
against Mycobacterium avium complex.
Clarithromycin also has activity against M leprae and Toxoplasma
gondii.
Erythromycin-resistant streptococci and staphylococci are also
resistant to clarithromycin.
Clarithromycin
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The longer half-life of clarithromycin (6 hours) compared with erythromycin permits
twice-daily dosing.
The recommended dosage is 250-500 mg twice daily or 1000 mg of the extended
release formulation once daily.
Clarithromycin penetrates most tissues well, with concentrations equal to or
exceeding serum concentrations.
Clarithromycin is metabolized in the liver.
The major metabolite is 14-hydroxyclarithromycin, which also has antibacterial
activity.
A portion of active drug and this major metabolite is eliminated in the urine, and
dosage reduction (eg, a 500-mg loading dose, then 250 mg once or twice daily) is
recommended for patients with creatinine clearances less than 30 mL/min.
Clarithromycin has drug interactions similar to erythromycin (can inhibit cytochrome
P450 enzymes).
The advantages of clarithromycin compared with erythromycin are lower incidence of
gastrointestinal intolerance and less frequent dosing.
Except for the specific organisms noted above, the two drugs are otherwise
therapeutically very similar, and the choice of one over the other usually turns out to
be cost and tolerability.
Azithromycin
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Azithromycin, a 15-atom lactone macrolide ring compound, is derived from
erythromycin by addition of a methylated nitrogen into the lactone ring.
Its spectrum of activity and clinical uses are virtually identical to those of
clarithromycin.
Azithromycin is active against M avium complex and T gondii.
Azithromycin is slightly less active than erythromycin and clarithromycin against
staphylococci and streptococci and slightly more active against H influenzae.
Azithromycin is highly active against chlamydia.
Azithromycin differs from erythromycin and clarithromycin mainly in pharmacokinetic
properties.
A 500-mg dose of azithromycin produces relatively low serum concentrations of
approximately 0.4 mcg/mL.
However, azithromycin penetrates into most tissues (except cerebrospinal fluid) and
phagocytic cells extremely well, with tissue concentrations exceeding serum
concentrations by 10- to 100-fold. The drug is slowly released from tissues (tissue
half-life of 2-4 days) to produce an elimination half-life approaching 3 days.
Azithromycin
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These unique properties permit once-daily dosing and shortening of the
duration of treatment in many cases.
For example, a single 1-g dose of azithromycin is as effective as a 7-day
course of doxycycline for chlamydial cervicitis and urethritis.
Community-acquired pneumonia can be treated with azithromycin given as
a 500-mg loading dose, followed by a 250-mg single daily dose for the next
4 days.
Azithromycin is rapidly absorbed and well tolerated orally.
It should be administered 1 hour before or 2 hours after meals.
Aluminum and magnesium antacids do not alter bioavailability but delay
absorption and reduce peak serum concentrations.
Because it has a 15-member (not 14-member) lactone ring, azithromycin
does not inactivate cytochrome P450 enzymes and therefore is free of the
drug interactions that occur with erythromycin and clarithromycin.
Roxithromycin
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Similar to clarithromycin and erythromycin.