Macrolides and ketolides Flashcards
macrolides
Erythromycin, Azithromycin, Clarithromycin
ketolides
Telithromycin
macrolide chemistry
Erythromycin is a natural macrolide derived from Streptomyces erythreus that contains a 14-membered macrocyclic lactone ring.
Clarithromycin is a semisynthetic macrolide structurally derived from erythromycin. Clarithromycin is also a 14-membered ring, synthesized by substituting a methoxy group for the C-6 hydroxyl group of erythromycin. This structural change improves oral bioavailability (by increasing acid stability), provides enhanced antibacterial activity, enhances tissue penetration, and prolongs the elimination half-life.
Azithromycin is also a semisynthetic derivative of erythromycin in which an amino group is inserted into the erythromycin ring at position 9a. Azithromycin is a 15*-membered ring, and is technically considered an azalide**. These structural changes improves oral bioavailability (by increasing acid stability), improves antibacterial activity (especially against Gram-negative aerobes like H. influenzae), enhances tissue penetration, and prolongs the elimination half-life.
macrolides MOA
Macrolide antibiotics interfere with microbial protein synthesis (translocation steps) at the ribosomal level. The macrolides reversibly bind 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.*
Macrolides typically display bacteriostatic activity; however, they may display bactericidal activity when present at high concentrations against very susceptible organisms (Streptococcus pneumoniae, Streptococcus pyogenes).
macrolides MOR
Active efflux – mef gene encodes for an efflux pump that pumps the macrolide out of the bacteria; usually confers low-level resistance to the macrolides (macrolide therapy may still be used in some cases); accounts for the majority (70 to 80%) of macrolide-resistant S. pneumoniae in the US.
Alteration in the binding site – methylation of the macrolide 50S binding site coded for by the 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 (such as clindamycin and Synercid); accounts for the majority of macrolide-resistant S. pneumoniae in Europe.
Cross-resistance is usually observed among the macrolides.
macrolide spectrum of activity
The macrolides are primarily bacteriostatic, but may display bactericidal activity in certain situations or against specific organisms. When bactericidal, they typically display time- dependent activity; however, in some situations, azithromycin may display concentration-dependent activity (AUC/MIC correlates with efficacy).
Gram-positive aerobes (C > E > A)
-Group and Viridans streptococci
-S. pneumoniae (overall covers ∼ 65 to 70% of strains; primarily active against PSSP; poor activity against PISP and PRSP)
-Methicillin–susceptible S. aureus (MSSA – mild to moderate infections only)
-Bacillus spp, Corynebacterium spp.
Gram-negative aerobes (A > C > E) – NOT the Enterobacteriaceae*
-Haemophilus influenzae (not erythromycin)
-Moraxella catarrhalis
-Neisseria spp.
Other Organisms* (Azithro and Clarithro are better for Legionella and Mycoplasma)
-Legionella pneumophila**
-Mycoplasma* pneumoniae
-Chlamydophila* pneumoniae and Chlamydia* trachomatis
-Treponema pallidum (Syphilis)
-Campylobacter jejuni
-Borrelia burgdorferi (Lyme disease)
-Bordetella pertussis, Brucella, Pasteurella, Ureaplasma*, Actinomyces
-Mycobacterium avium complex** (Azithro and Clarithro)
-Other atypical mycobacteria - Clarithromycin
Anaerobes – activity against anaerobes “above the diaphragm”
macrolides absorption
Erythromycin – variable absorption (F = 15 to 45%) depending on the formulation; food decreases the absorption of all preparations except the estolate form
-Erythromycin base* is acid labile and subject to destruction by gastric acid; various preparations of erythromycin base are available with an acid-resistant coating (enteric coated) to delay destruction until it reaches the small bowel where it is absorbed
-Erythromycin esters and ester salts** (stearate, estolate, ethyl succinate) – are more acid stable and better absorbed
Clarithromycin – is acid stable and well absorbed from the GI tract (regardless of the presence of food**); oral bioavailability is 52 to 55% with peak concentrations occurring at 3 hours
Azithromycin – is acid stable; oral bioavailability approaches 37% with peak concentrations occurring at 2 to 3 hours; food does not affect the absorption of the tablets or suspension
macrolide distribution
All 3 macrolides extensively distribute into tissues** (except for the CSF*) and cells** (including macrophages and neutrophils). Both clarithromycin and azithromycin achieve substantially higher tissue concentrations in relationship to serum concentrations; achieve minimal serum concentrations so that they may be ineffective for bacteremia**. Both clarithromycin and azithromycin achieve higher intracellular concentrations than erythromycin
macrolide elimination
Erythromycin
-Excreted primarily in the bile with some demethylation in the liver by CYP450 enzymes; 2 to 15% of a dose is excreted in the urine
-Half-life = 1.4 hours, but may be prolonged up to 5 hours in patients with renal failure (but NO dosage adjustment is necessary)
Clarithromycin
-Extensively metabolized in the liver by the CYP450 enzymes** (8 metabolites, with one active metabolite); 18% of the parent drug and all of its metabolites are excreted in the urine
-Elimination half-life = 3 to 7 hours in normal renal function and is markedly prolonged in the presence of renal insufficiency so that dosage adjustment is necessary in patients with a CrCl under 30 ml/min*
Azithromycin
-Biliary excretion, predominantly as unchanged drug into the feces
-Elimination half-life = 68 hours due to extensive tissue sequestration and binding (tissue half-life estimated at 4 days)
*NONE of the macrolides are removed during hemodialysis or peritoneal dialysis
clinical uses of macrolides
RTIs, uncomlicated skin and soft tissue infections, STDs, mycobacterium avium comlex infections (MAC), other (Campylobacter jejuni infections, Helicobacter pylori (in combination)), Macrolides are alternative antibiotics for the treatment of the following mild to moderate infections in penicillin-allergic patients***: Group A streptococcal upper respiratory infections, Prophylaxis of bacterial endocarditis, Syphilis and gonorrhea, Superficial minor staphylococci infection, Rheumatic fever prophylaxis
macrolides in RTIs
Pharyngitis, Tonsillitis, Otitis Media, Sinusitis – alternative in penicillin-allergic patients
Acute Exacerbations of Chronic Bronchitis – azithromycin and clarithromycin are best if H. influenzae is suspected
Community Acquired Pneumonia - especially for **atypical coverage; monotherapy for outpatients or combined with a β-lactam (e.g., ceftriaxone) for inpatients
Other – Pertussis, C. diphtheriae
macrolides in STDs
A single 1-gram dose of azithromycin is used for the treatment of nongonococcal urethritis or cervicitis due to Chlamydia trachomatis
macrolides and MAC
Mycobacterium avium Complex Infections (MAC) – clarithromycin (500 to 1000 mg every 12 hours) as part of a combination regimen with ethambutol and/or rifabutin for treatment; azithromycin alone for prophylaxis (1200 mg weekly)
macrolide adverse reactions
Gastrointestinal - epigastric distress, abdominal pain, nausea, vomiting, and diarrhea – most common*** (in up to 33% of patients) with oral administration of erythromycin** (may also occur with IV); less common with clarithromycin and azithromycin (10%) Cholestatic hepatitis (rare) - most often seen in adult patients who receive > 1 to 2 weeks of erythromycin estolate therapy Thrombophlebitis and infusion site irritation (IV erythromycin and azithromycin) - erythromycin lactobionate and gluceptate or azithromycin can cause thrombophlebitis, which can be partially avoided by diluting the dose in at least 250 ml of intravenous fluid and infusing slowly over 60 minutes into a large vein Allergic reactions (rash, fever, eosinophilia) Ototoxicity - rare; has been reported in patients with renal insufficiency who are receiving high intravenous doses of erythromycin (≥4 gm/day) QT prolongation Exacerbation/worsening of symptoms of myasthenia gravis
macrolide drug interactions
Both erythromycin* and clarithromycin* are inhibitors of the cytochrome P450** (3A4 and 2C9) 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
Azithromycin does NOT inhibit the cytochrome P450 enzyme system, and is NOT thought to be associated with the drug-drug interactions*** listed above. However, hypoprothrombinemia has been reported during post-marketing surveillance in patient stabilized on warfarin - ? if due to presence of infection rather than the azithromycin. FDA recommends careful monitoring of PT/INR.
