Macrolides
Macrolide
antibiotics possess a many-membered lactone ring to which are attached one or
more deoxy sugars.
Azithromycin,
clarithromycin, dirithromycin, erythromycin, miocamycin, roxithromycin and
troleandomycin.
Erythromycin
was first isolated in 1952 from Streptomyceserythreus. The other members
of the group are semisyntheticderivatives.
The
macrolides are effective mainly against aerobic gram-positive cocci and
bacilli, and to a lesser extent, against gram-negative organisms such as H. Influenzae, N. meningitidis,
N.gonorrhoeae, Campylobacter species, Pateurella multocida, Mycoplasma
pneumoniae, and Legionella
pneumophila.The macrolide antibiotics act as bacteriostatic agents at low
concentrations, and (less frequently) bactericidal agents at high concentrations.
Though erythromycin base is
adequately absorbed on inges-tion, it is inactivated by gastric acids, and so
it is usually administered as enteric-coated tablets or as capsules containing
enteric-coated pellets. Esters of erythromycin (estolate, stearate, and ethyl
succinate) improve acid stability and facilitate better absorption.
Semi-synthetic macrolides are rapidly absorbed from the GI tract, though food
can considerably delay absorp-tion.
The macrolides are widely
distributed in all tissues and body fluids (except brain and CSF), and can also
cross the placental barrier easily. Excretion is renal as well non-renal.
Macrolides
are bacteriostatic agents which inhibit protein synthesis by binding reversibly
to 50s ribosomal subunits of sensitive micro-organisms.
·
In general, macrolide antibiotics
are considered to have fewer, less severe toxic effects than most other
antimicro- bial agents.
o
Allergic reactions are uncommon
(fever, eosinophilia,and skin eruptions).
o
The most striking side-effect,
especially associated with erytrhromycin estolate is cholestatic hepatitis,
which is probably immune-mediated. Cholestasis is charac- terised by elevated
liver enzymes, fever, abdominal pain, and jaundice. Patients without previous
exposure to erythromycin generally develop symptoms after an average of 16 days
of therapy. Patients who have received the drug previously may develop symptoms
within less than 24 hours, and occasionally after a single dose.
Discontinuation of the drug usually results in resolution of hepatotoxic
effects.
o
Other effects include
gastrointestinal irritation, ototox- icity, and thrombophlebitis (after IV
administration). Candidal oesophagitis and gingival hyperplasia are uncommon
adverse effects of treatment with various macrolides. Large doses of macrolides
are also associ-ated with (reversible) high-frequency sensorineural hearing
loss.
o
Rare instances of acute pancreatitis
have been reported.
o
Exacerbation of myasthenia gravis
may occur infre- quently following erythromycin administration.
o
Interstitial nephritis and
glomerulonephritis have been reported with the administration of erythromycin,
but are uncommon.
o
Rarely, erythromycin has been
reported to cause cardiac arrhythmias (QT prolongation and torsades de
pointes). In general, the risk of arrhythmias is increased when erythromycin is
administered in combination with other drugs that prolong the QT interval.
o
Contact dermatitis, fixed drug
eruptions, toxic pustulo- derma, and toxic epidermal necrolysis are
uncommonside effects which may occur with macrolide use.
·
Acute oral overdoses of macrolide
antibiotics are usually not life-threatening, and comprise mainly
gastrointestinal manifestations. Seizures may occur. Treatment is the same as
for penicillin overdose.
Macrolides
(especially erythromycin) potentiate the effects of astemizole, carbamazepine,
corticosteroids, cyclosporine, digoxin, ergot alkaloids, terfenadine,
theophylline, triazolam, valproate, and warfarin, by interfering with
P450-mediated metabolism of these drugs.
·
Severe toxicity is unusual after ingestion; prehospital
decon-tamination is generally not necessary. Discontinuation of the drug
usually results in the resolution of the toxic effects.
·
Food, milk or an antacid may be administered for treatment
of gastrointestinal distress.
·
CBC, electrolytes, and urinalysis are not generally needed
unless the development of haematological disturbances (rare) or nephritis
(rare) is suspected, or if the patient has experienced prolonged vomiting and
diarrhoea.
·
Monitor ECG, vital signs, and fluid and electrolyte balances
in massive overdoses.
·
Arrhythmias respond to magnesium sulphate, isoproterenol,
phenytoin, or overdrive pacing.
·
Liver enzyme levels may aid in diagnosing or following a
patient with evidence of cholestasis or hepatitis.
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