Term
| What are the 3 macrolides? |
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Definition
Erythromyicn
Clarithromycin
Azithromycin
(Ery-, Clari-, Azithromycin)
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Term
| What is the core structure of a macrolide? |
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Definition
Macrolactone ring
Erythromicin (original)
Clarithromycin (-OCH3 instead of -OH)
Azithromycin (N in macrolactone ring)
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Term
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Definition
They inhibit the 50S bacterial ribosomal subunit, preventing elongation and release of peptide.
Note: Human ribosomal subunits are 40S and 60S, which accounts for macrolide selectively for bacteria.
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Term
| What are the general targets of macrolides? |
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Definition
Gram+ organisms (some streptococcal and staphylococcal infections - alternative to penicillin)
Some intracellular organisms
- some Chlamydia, M. pneumoniae, Legionella
- Mycobacterium avium (clarithromycin and azithromycin only)
Note: macrolides cannot penetrate Gram- bacteria
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Term
| Are macrolides bactericidal or bacteriostatic? |
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Definition
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Term
| What are important mechanisms of resistance to macrolides? |
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Definition
1. (Major) MLS resistance: Methylation of the 50S ribosomal subunit decreases macrolide binding.
Note: MLS = Macrolide-Lincosamide-Streptogramin. This mechanisms has cross-resistance with clindamycin (a lincosamide), streptogramins.
2. (Major) M resistance: Efflux of macrolide
Note: Sharp rise in ZPak (azithromycin) prescriptions has led to more M resistance, espectially in children.
Note: Single resistance has stabilized but double resistance is rising now (MLS + M)
3. (Minor) Destruction of erythromycin (unimportant)
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Term
| What are major differences between the macrolides? |
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Definition
Acid stability: Clarithromycin and azithromycin are more acid-stable than erythromycin, which needs to be coated to survive the stomach.
Half-life: Azithromycin has a long half life - 35-40hrs!! More than 10X t1/2 of erythromycin (1.6hr) and clarithromycin (2.6hr).
Note: Very popular due to shortened course (5 days)
Targets: clarithromycin and azithromycin are active against Mycobaterium avium.
Adverse Effects:
- Erythromycin (estolate form) causes cholestatic hepatitis (hypersensitivity rxn)
- Clarithromycin and azithromycin cause less GI toxicity
- Azithromycin causes less inhibition of P450
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Term
| What is the major adverse effect of macrolides? |
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Definition
Inhibit cytochrome P450 CYP3A4, which metabolizes 50% of the drugs people take.
Note: Inhibition by azithromycin is less than erythromycin, clarythromycin
Note: Huge consequences for drug interactions (they don't get metabolized, --> overdose). E.g., terfenadine was a safe OTC antihistamine, which caused fatal cardiac arrhythmias when combined with macrolides. Now, the metabolized (active) form is given directly, aka Allegra.
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Term
| What are some adverse effects of erythromycin in particular? |
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Definition
1. Significant GI toxicity
Note: So problematic that 1/3 of patients refuse to take erythromycin again
2. Cholestatic Hepatitis: hypersensitivity reaction to erythromycin estolate form
-- fever, abdominal pain, eosinophilia
-- increased bilirubin/jaundice
-- onset 10-20 days after initiation of therapy
Note: estolate helps erthromycin get through acidic stomach intact
3. Transient deafness at high doses (reverses after finishing treatment course)
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Term
| Where in the body are macrolides absorbed? |
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Definition
Small intestine; this is why they need to survive the acidic stomach (erythromycin must be coated).
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Term
| What is the distribution of macrolides in the body? |
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Definition
Once in the bloodstream (absorbed via small intestine), widely diffuses into tissues but not CSF. |
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Term
| How are macrolides excreted? |
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Definition
Primarily in bile. Some excreted unchanged in urine. |
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Term
| How are macrolides metabolized? |
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Definition
Concentrated in liver; some demethylation. |
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