Macrolides

Question 1

What are the macrolides?

Answer 1

erythromycin, azithromycin, clarithromycin

Question 2

Explain the differences in chemical structure between erythromycin, azithromycin, and clarithromycin.

Answer 2

2. Erythromycin contains a 14-membered macrocyclic lactone ring.
3. Clarithromycin is also a 14-memebred ring, synthesized by substituting a methoxy group for the C-6 hydroxyl group of erythromycin. This improves oral bioavailability (by increasing acid stability), provides enhanced antibacterial activity, enhances tissue penetration, and prolongs the elimination half-life.
4. Azithromycin: an amino group is inserted into the erythromycin ring at position 9a. It is a 15-membered ring and is technically considered an azalide. This improves oral bioavailability, improves antibacterial activity, enhances tissue penetration, and prolongs the elimination half-life.

Question 3

Explain the clinical advantages of clarithromycin and azithromycin over erythromycin.

Answer 3

1. Both clarithromycin and azithromycin have structural modifications to improve tissue penetration, enhance the spectrum activity, improve tolerability, and improve pharmacologic characteristics (less acid labile, longer elimination half-lives).

Question 4

Describe the mechanism of action of the macrolide antibiotics.

Answer 4

1. MOA: Interfere with microbial protein synthesis (translocation steps) at the ribosomal level. Reversibly binds to the 50S ribosomal subunit to induce dissociation of peptidyl transfer RNA from the ribosome during the elongation phase so that protein synthesis is suppressed, and bacterial growth is inhibited. Display bacteriostatic activity, may be bactericidal against streptococcus.

Question 5

Describe the mechanisms by which bacteria develop resistance to these antibiotics.

Answer 5

1. Active efflux: mef gene encodes for efflux pump that pumps macrolide out of bacteria (away from ribosomal binding site); confers low-level resistance to the macrolides (macrolide therapy may still be used in some cases).
2. Alteration in binding site: methylation of the macrolide 50S binding site coded for by erm (erythromycin ribosomal methylase) gene, which leads to low affinity binding of macrolides; confers high-level resistance to all macrolides AND other antibiotics that bind to the 50S ribosome.
3. Cross resistance is usually observed among the macrolides.

Question 6

Describe the general differences in spectrum of activity between the macrolides, with special emphasis on their activity against atypical bacteria.

Answer 6

1. Primarily bacteriostatic, but when bactericidal, display time-dependent activity.
2. Gram-positive aerobes: C > E > A; PSSP, MSSA
3. Gram-negative aerobes: A > C > E; NOT the Enterobacteriaceae – haemophilus influenzae, Moraxella catarrhalis, Neisseria spp.
4. Use FQs or macrolide to cover our atypical bacteria. Legionella pneumophila, mycobacterium avium complex.
5. Anaerobes: activity against anaerobes above the diaphragm.

Question 7

Macrolide distribution

Answer 7

All 3 extensively distribute into tissues (EXCEPT for the CSF) and cells. Clarithromycin and azithromycin achieve minimal serum concentrations so that they may be ineffective for bacteremia.

Question 8

Macrolide absorption

Answer 8

1. erythromycin – food decreases the absorption, erythromycin base is acid labile and subject to destruction by gastric acid, use enteric coated to delay destruction; erythromycin esters and ester salts (stearate, estolate, ethyl succinate) are more acid stable and better absorbed.
2. Clarithromycin: acid stable and well absorbed regardless of food.
3. Azithromycin: acid stable. Food has not affect.

Question 9

Macrolide half-life

Answer 9

Azithromycin has longest half-life of 68 hours due to extensive tissue sequestration and binding.

Question 10

Macrolide route of excretion

Answer 10

1. Erythromycin excreted in bile by CYP450 enzymes.
2. Clarithromycin metabolized in liver by CYP450 enzymes.
3. Azithromycin: biliary excretion.

Question 11

Macrolide necessity of dosage adjustment in renal insufficiency/removal by hemodialysis

Answer 11

only in clarithromycin – dosage adjustment in patients with a CrCl < 30 ml/min. NONE are removed during hemodialysis or peritoneal dialysis (because they’re so large).

Question 12

What are the main indications of the macrolides?

Answer 12

1. Respiratory tract infections: community acquired pneumonia – especially for atypical coverage, monotherapy for outpatients or combined with a beta-lactam (ceftriaxone) for inpatients.
2. Sexually transmitted diseases: single 1 gram dose of azithromycin for nongonococcal urethritis or cervicitis due to chlamydia trachomatis.
3. Mycobacterium avium complex infections.
4. As alternative antibiotics for mild-moderate infections in penicillin-allergic patients.

Question 13

What are the major AEs of macrolides?

Answer 13

1. Gastrointestinal: most common with oral administration of erythromycin; less common with clarithromycin and azithromycin.
2. Thrombophlebitis and infusion site irritation
3. QTc prolongation: caution in patients with hypokalemia/magnesemia, preexisting QT prolongation, h/o torsades, on other QT prolongating drugs.

Question 14

What measures can be employed to alleviate the gastrointestinal distress or phlebitis that may be encountered with erythromycin therapy?

Answer 14

Thrombophlebitis: can be partially avoided by diluting the dose in at least 250 ml of IV fluid and infusing slowly over 60 minutes into a large vein.
GI: switch to clarithromycin or azithromycin

Question 15

List the major drug interactions associated with the macrolides and understand the difference between the macrolides in terms of their propensity to cause drug interactions.

Answer 15

1. Both erythromycin and clarithromycin are inhibitors or CYP450 enzyme system. Concomitant administration may increase the serum concentrations of the following drugs (and potentially lead to toxicity): theophylline, carbamazepine, valproate, cyclosporine, digoxin, phenytoin, warfarin.
2. Azithromycin does NOT inhibit the CYP450 enzyme system and is NOT thought to be associated with the drug-drug interactions above. Hypoprothrombinemia has been reported in patients on warfarin – careful monitoring of PT/INR.