Antibacterial Pharmacology: Macrolides Flashcards
Attributes of Macrolides
- Macrolides have a similar antibacterial spectrum to beta-lactams, specifically penicillin
- They are also effective against anaerobes and some atypical bacteria (including mycoplasma), and readily enter lung cells → good for treating lung infections bc good absorption of drug in tissue
- Somewhat acid stable; commonly administered orally, and distributed to most tissues (especially the lung, not the CNS)
- Generic names usually end in “-thromycin”; difficult to differentiate from AG nomenclature
Macrolides: - Erythromycin
- Clarithromycin
- Azithromycin
What is macrolides mechanism of action?
- Macrolides bind to the 23S rRNA of the 50S subunit in bacterial ribosomes
- Inhibit protein synthesis; bacteriostatic
What are the types of macrolides?
Further divided by spectrum of activity:
- Narrow spectrum (Erythromycin)
- Extended spectrum (gram negative: Azithromycin)
- Azithromycin and clarithromycin (gram +) are semi-synthesized derivated of naturally occuring erythromycin
Attributes of macrolide erythromycin (the OG)
- Spectrum of activity: Similar to amoxicillin, with the addition of some atypical pathogens (Chlamydia, Mycoplasma, Rickettsia)
- Great for gram-positive streptococci and staphylococci and can be used in place of amoxicillin in patients with penicillin allergy
- Not good against Enterobacteriaceae, unlike amoxicillin
- Important uses:
- Some intracellular pathogens
- Respiratory infections
Attributes of macrolide Azithromycin (newer macrolide_
Attributes:
- Spectrum of activity: More effective against Gram negative aerobes (still has effectiveness against members of other classes)
- Very long half-lives (up to 90h) – can be administered 1x per day or less often, compared to 4x/d for erythromycin
- Commonly used for community-acquired bacterial pneumonia
- Can be used to treat chlamydia in pregnant women (unlike tetracyclines, which can impact bone development in the fetus - can cross placenta and get into fetus)
Macrolides pharmacokinetics
- Penetrate cells better than most drug classes
- Macrolides concentrate in the lung and lung macrophages (up to 70x plasma concentration) – excellent for treating lung disease
- FYI: Also exhibit anti-inflammatory effects (inhibit neutrophil migration, function, and leukotriene synthesis)
- Erythromycin has a very short half life (<2hr) compared to the newer macrolides
- Erythromycin (not good → dont want this), but not azithromycin (therefore safer option) inhibits CYP450 enzymes
Macrolides resistance
- Best studied mechanism: Target modification through horizontal gene transfer of erm gene (methylation of the 23S rRNA binding site)
- Some bacteria can also acquire macrolide efflux pump genes (mef genes) that decrease intracellular concentration of macrolides
adverse reactions of macrolides
- One of the safest classes of antibacterial drugs!
- Tissue irritation is the main adverse effect
- Tissue irritation: Causes substantial pain on IM injection
- GI intolerance represents the most frequent reason for discontinuing oral erythromycin
- Directly stimulates gut motility and can cause nausea, vomiting, diarrhea, and sometimes anorexia; effect highly variable from patient to patient
- Azithromycin followed by clarithromycin are much easier on the gut -“directed” dosing - Drug interactions (erythromycin only) due to CYP450 inhibition
Scenario: A young boy falls from a tree, sustaining a soft-tissue wound of his upper arm, which becomes swollen and painful due to an anaerobic bacterial infection.The boy does not have any drug allergies. Based on what we have discussed in this course,
choose the one drug from the choices below that would & be most appropriate for treating this infection. Assume that systemic (i.e. enteral or parenteral; not topical) administration will be necessary for several days.
Chloramphenicol (think of it as own AMD class) is an almost ideal antimicrobial why?
An almost ideal antimicrobial:
- Broad spectrum
- Generally very safe
- Distributes to all tissues except prostate;
penetrates cornea extremely well
- Oral, topical, and injectable forms
But…
- Can cause fatal aplastic anemia in humans
Chloramphenicol mechanism of action
- similar to macrolide
- chloramphenicol bind to the 23S rRNA of the 50S subunit in
bacterial ribosomes - Inhibit protein synthesis; bacteriostatic
Chloramphenicol adverse effects
- Rare: Only ~1/50,000 people are susceptible to fatal aplastic
anemia if administered chloramphenicol - Genetic predisposition (similar to malignant hyperthermia)
- Not dose-related; irreversible
- Drug is banned for use in food animals (documented fatalities in humans after consumption)
- Risk of fatal aplastic anemia appears to be highest with oral administration and lower with topical use
- Risk of reversible bone marrow suppression with every patient
