The macrolide antibiotics are those that consist of a large lactone
ring to which sugars are attached. Antibiotics in this group include
erythromycin (Ilotycin, E-mycin, Robimycin),
clarithromycin (Biaxin), azithromycin (Zithromax),
and oleandomycin (Matromycin).
Erythro-mycin and its derivatives (clarithromycin, azithromycin) are the only
macrolides in common use, although the acetylated derivative of oleandomycin
(troleandomycin, TAO) is available
for oral use.
Macrolides bind to the 50S
ribosomal subunit of bacte-ria but not to the 80S mammalian ribosome; this
ac-counts for its selective toxicity. Binding to the ribosome occurs at a site
near peptidyltransferase, with a resultant inhibition of translocation, peptide
bond formation, and release of oligopeptidyl tRNA. However, unlike
chlo-ramphenicol, the macrolides do not inhibit protein syn-thesis by intact
mitochondria, and this suggests that the mitochondrial membrane is not
permeable to erythro-mycin.
The macrolides are effective against
a number of organ-isms, including Mycoplasma
spp., H. influenzae, Strep-tococcus spp.
(including S. pyogenes and S. pneumoniae), staphylococci, gonococci, Legionella
pneumophila, and other Legionella
spp. There has been increasing resist-ance of S. pneumoniae to macrolides worldwide. This is true especially if
the strain is resistant to penicillin. This resistance includes not only
erythromycin but also clar-ithromycin and azithromycin. Approximately 10 to 15%
of S. pneumoniae in the United States
show complete re-sistance to macrolides. Staphylococci resistant to
erythro-mycin are resistant to all macrolides.The hemolytic strep-tococci also
exhibit varying degrees of cross-resistance to the macrolides and to lincomycin
and clindamycin, although the macrolides are chemically unrelated to the last
two agents. There are only minor variations in the antibacterial spectrum of
the newer macrolides. Clarithromycin is very active against H. influenzae, Legionella, and Mycobacterium
avium-intracellulare, whereas azithromycin is superior against Branhamella, Neisseria, and H. influenzae but
less active against my-cobacterial species. Clarithromycin and azithromycin
have significant activity against Mycobacterium
avium complex (MAC), and it is one of the drugs of choice in treating
disseminated MAC. Both azithromycin and clar-ithromycin can be used
prophylactically in HIV and AIDS patients to help prevent disseminated MAC.
The macrolides are absorbed
from the intestinal tract, although the presence of food interferes with
absorption and part of the dose is destroyed because of the relative acid
lability of these antimicrobials. To minimize de-struction and enhance
absorption, erythromycin is ad-ministered as a stearate or oleate salt or is
enteric coated. Because stearate and estolate erythromycins are not acid
labile, the administration of these formulations results in higher blood
levels. The O-methyl substitution of
erythromycin that results in clarithromycin also con-fers acid stability and
better absorption with food.
The macrolides diffuse
readily into tissues and cross placental membranes. CSF levels are about 20% of
plasma levels, while biliary concentrations are about 10 times plasma levels.
Although the serum levels of clar-ithromycin and azithromycin are low, these
antibiotics concentrate in tissue and reach high levels.
Erythromycin and azithromycin
are excreted prima-rily in active form in bile, with only low levels found in
urine. Clarithromycin is metabolized to the biologically active 14-OH
metabolite and is eliminated largely by the kidney. The half-life of
erythromycin is approximately 1.4 hours, whereas the half-life of
clarithromycin is 3 to 7 hours and that of azithromycin approaches 68 hours.
Although erythromycin is a
well-established antibiotic, there are relatively few primary indications for
its use. These indications include the treatment of Mycoplasma pneumoniae infections,
eradication of Corynebacterium
diphtheriae from pharyngeal carriers, the early preparox-ysmal stage of
pertussis, chlamydial infections, and more recently, the treatment of
Legionnaires’ disease, Campylobacter enteritis,
and chlamydial conjunctivitis, and
the prevention of secondary pneumonia in neonates.
Erythromycin is effective in
the treatment and pre-vention of S.
pyogenes and other streptococcal infec-tions, but not those caused by the
more resistant fecal streptococci. Staphylococci are generally susceptible to
erythromycin, so this antibiotic is a suitable alternative drug for the
penicillin-hypersensitive individual. It is a second-line drug for the
treatment of gonorrhea and syphilis. Although erythromycin is popular for the
treat-ment of middle ear and sinus infections, including H. in-fluenzae, possible erythromycin-resistant S. pneumoniae is a concern.
The new macrolides have
similar indications for use as erythromycin but with some additional areas of
po-tential value. Clarithromycin has activity against Toxo-plasma gondii and
Mycobacterium avium-intracellulare, and it has expanded coverage against
untypable H. in-fluenzae strains that
predominate in exacerbations of chronic
bronchitis. Azithromycin has less coverage against these organisms, and because
of its lower peak serum concentrations and prolonged protein binding, it
partitions less well across bronchial membranes. The prolonged half-life and
protein binding and the use of an abbreviated one-time dose of azithromycin
appear to be extremely beneficial in the treatment of sexually transmitted
The incidence of side effects
associated with erythro-mycin therapy is very low. Mild gastrointestinal upset
with nausea, diarrhea, and abdominal pain are reported to occur more commonly
when the propionate and es-tolate salts are used. Rashes are seen infrequently
but may be a part of a general hypersensitivity reaction that includes fever
and eosinophilia. Thrombophlebitis may follow intravenous administration, as
may transient im-pairment of hearing.
Cholestatic hepatitis may
occur when drug therapy lasts longer than 10 days or repeated courses are
pre-scribed. The hepatitis is characterized by fever, enlarged and tender
liver, hyperbilirubinemia, dark urine, eosinophilia, elevated serum bilirubin,
and elevated transaminase 1evels. Hepatitis has been associated with the
estolate salt of erythromycin but not with other for-mulations. Although the
hepatitis usually occurs 10 to 20 days after the initiation of therapy, it can
occur within hours in a patient who has had such a reaction in the past. The
hepatitis is believed to be the result of both a hepatotoxic effect and a
hypersensitivity reac-tion; this latter effect is reversible on withdrawal of
the drug. Erythromycin and derivatives induce hepatic mi-crosomal enzymes and
interfere with the actions of var-ious drugs, including theophylline and