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PHL 424
Antimicrobials
4th Lecture
By
Abdelkader Ashour, Ph.D.
Phone: 4677212
Email: [email protected]
Inhibitors of bacterial protein synthesis,
Macrolides
 The macrolides are a group of closely related
compounds characterized by a macrocyclic lactone ring
to which deoxy sugars are attached
 The prototype drug, erythromycin was obtained in 1952
from Streptomyces erythreus
 It was the first of these drugs to find clinical application,
both as a drug of first choice and as an alternative to
penicillin in individuals who are allergic to penicillin
 The newer members, clarithromycin, azithromycin &
telithromycin are semisynthetic derivatives of
erythromycin
 Telithromycin is the first ketolide antimicrobial agent that
has been approved and is now in clinical use
 Ketolides and macrolides have very similar antimicrobial
coverage. However, the ketolides are active against many
macrolide resistant G+ve strains
 The structural modifications in these drugs aimed at:



improved acid stability
Enhanced absorption & tissue penetration
broadened the spectrum of activity
Inhibitors of bacterial protein synthesis,
Macrolides, contd.
 MOA:
 Macrolides are bacteriostatic agents that
inhibit protein synthesis by binding
reversibly to 50S ribosomal subunits of
sensitive microorganisms
 They then inhibit the translocation step
wherein a newly synthesized peptidyl
tRNA molecule moves from the A site on
the ribosome to the P site
 They may also interfere at other steps,
such as transpeptidation
 This leads to inhibition of bacterial protein
synthesis
 Generally considered to be bacteriostatic.
They may be bactericidal at higher doses
 Their binding site is either identical or in
close proximity to that for clindamycin and
chloramphenicol
Macrolides
and
clindamycin
Inhibitors of bacterial protein synthesis,
Macrolides
 Antimicrobial actions:
 Erythromycin usually is bacteriostatic, but may be bactericidal in high concentrations
against very susceptible organisms
G+ve bacteria accumulate about 100 times more erythromycin than do G-ve
bacteria
It is most active in vitro against aerobic G+ve cocci and bacilli
Erythromycin is inactive against most aerobic enteric G-ve bacilli. It has modest
activity in vitro against other G-ve organisms (e.g., H. influenzae, N. meningitidis and
N. gonorrhoeae)
 Clarithromycin is slightly more potent than erythromycin against sensitive strains of
streptococci and staphylococci
 Azithromycin is less active than erythromycin against G+ve organisms and slightly
more active than either erythromycin or clarithromycin against H. influenzae and N.
gonorrhoeae
 Azithromycin and clarithromycin are activity against some protozoa (e.g.,
Toxoplasma gondii and Plasmodium spp.). Clarithromycin has good activity against
Mycobacterium leprae
Inhibitors of bacterial protein synthesis,
Macrolides, contd.
 Resistance mechanisms: Resistance to macrolides usually results from one of four
mechanisms:
1. The inability of the organism to take up the antibiotic or the presence of an efflux
pump, both of which limit the amount of intracellular drug
2. Ribosomal protection by inducible or constitutive production of methylase enzymes
which modify the ribosomal target and decrease drug binding
 This results in decreased affinity of the 50S ribosomal subunit for the antibiotic
3. Macrolide hydrolysis by esterases
4. Chromosomal mutations that alter 50S ribosomal protein
 Because the mechanisms producing resistance to erythromycin affect all
macrolides, cross-resistance among them is complete
Inhibitors of bacterial protein synthesis,
Macrolides, contd.
 Pharmacokinetics
 Erythromycin base is incompletely but adequately absorbed from the upper small
intestine. Because it is inactivated by gastric acid, the drug is administered with
enteric coating that dissolves in the duodenum, or as an ester (Clarithromycin,
azithromycin, and telithromycin are stable to stomach acid and are readily absorbed)
 Food, which increases gastric acidity, may delay absorption erythromycin (and
azithromycin but can increase that of clarithromycin)
 Erythromycin diffuses readily into intracellular fluids, achieving antibacterial activity in
essentially all sites except the brain and CSF
 Erythromycin (and telithromycin) are extensively metabolized and are known to inhibit
the oxidation of a number of drugs through their interaction with the cytochrome P450
system
 Interference with the metabolism of drugs such as theophylline and carbamazepine
has been reported
 Large amounts of an administered dose are excreted in the bile and lost in feces, and
only 5% is excreted in the urine. Partial reabsorption occurs through the enterohepatic
circulation
Inhibitors of bacterial protein synthesis,
Macrolides, contd.
 Pharmacokinetics, contd.:
 Clarithromycin is absorbed rapidly from the GIT after oral administration, but 1st-pass
metabolism reduces its bioavailability to ~ 50%. It may be given with or without food
 The extended-release form, typically given once-daily as a 1-g dose, should be
administered with food to improve bioavailability
 It distributes widely and achieve high intracellular concentrations equal to or
exceeding serum concentrations throughout the body
 Clarithromycin and its metabolites are eliminated by renal and nonrenal mechanisms.
It is metabolized in the liver to several metabolites, the active 14-hydroxy metabolite
being the most significant. It is recommended that the dosage of this drug be adjusted
in patients with compromised renal function
 Azithromycin's unique pharmacokinetic properties include extensive tissue
distribution and high drug concentrations within cells, resulting in much greater
concentrations of drugs in tissue compared to simultaneous serum concentrations
 Tissue fibroblasts act as the natural reservoir for the drug in vivo
 The drug is slowly released from tissues (tissue half-life of 2–4 days) to produce an
elimination half-life approaching 3 days. These unique properties permit once-daily
dosing and shortening of the duration of treatment in many cases
 It undergoes some hepatic metabolism to inactive metabolites, but biliary excretion is
the major route of elimination. Only 12% of drug is excreted unchanged in the urine
Inhibitors of bacterial protein synthesis,
Macrolides, contd.
 Therapeutic Uses:
 Erythromycin is the drug of choice for treating persons with B. pertussis disease
and for postexposure prophylaxis of household members and close contacts
 Erythromycin is very effective in corynebacterial infections
 Erythromycin is useful as a penicillin substitute in penicillin-allergic individuals
with infections caused by streptococci or pneumococci
 Chlamydial infections can be treated effectively with any of the macrolides

During pregnancy, erythromycin is recommended as first-line therapy for
chlamydial urogenital infections
 A macrolide or tetracycline is the drug of choice for mycoplasma infections
 Clarithromycin 500 mg, in combination with omeprazole, 20 mg, and amoxicillin,
1 g, each administered twice daily for 10 to 14 days, is effective for treatment of
peptic ulcer disease caused by H. pylori
 Penicillin is the drug of choice for the prophylaxis of recurrences of rheumatic
fever. Erythromycin is an effective alternative for individuals who are allergic to
penicillin
Inhibitors of bacterial protein synthesis,
Macrolides, contd.
 Side effects:
 Serious untoward effects are rarely caused by erythromycin. Among the allergic
reactions observed are fever, eosinophilia and skin eruptions, which may occur
alone or in combination; each disappears shortly after therapy is stopped
 Cholestatic hepatitis is the most striking side effect (fever, jaundice, impaired liver
function), probably as a hypersensitivity reaction
 Anorexia, nausea, vomiting, and diarrhea occasionally accompany oral
administration (due to a direct stimulation of gut motility)
 Epigastric distress is common for erythromycin. Clarithromycin and azithromycin
seem to be better tolerated by the patient
 Ototoxicity: Transient deafness has been associated with erythromycin, especially at
high dosages
 Drug interactions:
 Erythromycin and clarithromycin can inhibit cytochrome P450 enzymes and thus
increase the serum concentrations of numerous drugs, including theophylline,
warfarin, cyclosporine, corticosteroids and digoxin
 This can lead to toxic accumulations of these drugs

Azithromycin appears to be free of these drug interactions
Inhibitors of bacterial protein synthesis,
Macrolides, contd.
 Contraindications:
 Patients with hepatic dysfunction should be treated cautiously with erythromycin,
telithromycin, or azithromycin, because these drugs accumulate in the liver. Similar
situation with patients who are renally compromised
 Telithromycin has the potential to prolong the QTc interval in some patients.
Therefore, it should be avoided in patients with congenital prolongation of the QTc
interval and in those patients with proarrhythmic conditions