Macrolide Anti Flashcards
Generations of All antimicrobials
General Background macrolides
Which portion of the drug is responsible for Causing SEs?
Which portion is key for interactions?
Predominantly used for the treatment of? and some?
Hgih concentrations in?
Key structural features?
- Cladinose- GI effects
- Desosamine- Interaction with target
- Used for gram (+) strains, but also some gram (-)
- levels in bronchial tree
- 14-member ring lactone and basic amino groups
Macrolide static or cidal?
- Static blocks peptide escape tunnel
Macrolide MOA?
key binding sites?
Erythromycin
Bacterio___
Inhibits?
Binds to?
Binding dose?
Incompletely formed?
- Static
- Inhibits bacterial protein biosynth
- Binds rRNA bases in 23SrRNA of the 50S bacterial ribosome
- Binding of macrolide in the groove blocks the exit route for growing peptide
- Incompletley formed peptides (di or tri) dissociate
ERM resistance
Resistance (MLSb cross resistance)
Major:
Moderate:
Common clinically in?
Genes for methylation
- Extends to drugs with overlapping binding sites (lincosamides, Streptogrammin B)
- Major ERM enzymes that methylate - loss of key H-binding interactions
- Moderate: Mutation in A2058–>G reduction in binding
- Genes can be encoded on plasmids and chromosomes —>spreading gene
- Staph, Strep, atypicals (no cell wall)
Less common Erythromycin modes of resistance
- Resistance due to export or poor uptake (gram -) known, but less common
- Resistance due to lactone hydrolysis, efflux, or phophorylation are rare
- R- Factor mediated self-methylation of A2503 residue of ribosome
- prevents macrolide binding
- Extends to clindamycin, chloramphenicol, pleuromutilin, streptogramin A, Linezolid
Stability and ADME/DMPK for Erythromycin
Interactions
Major usage: Upper respiratory infections (also consider spectrum) Desosamine causes high concentration in bronchials
Minor: GI/motility/ prokinetic effect (cladinose)
CYP3A4 interaction lead to arrhythmias
Instability of erythromycins to acid (stomach)
What is the fix for this?
spiroketal formation in the presence of acid is an inactive metabolite of erythromycin, this also causes GI cramps
Enteric coating gets the drug to the small intestine
Erythromycin salts and esters
Erythromycin products with better water solubility
Gluceptate salt (IV)
Lactrobionate (IV)
Clarithromycin
Whats changed and what does this mean?
Drug is linked with?
C6-OMe
Increased acid stability and less GI cramping, more lipophilic
Increased CV risk
Azithromycin
Presently?
Improved?
And?
- Drug of choice
- Improved PK AUC/MIC- Lower acid sensitivity, rapid absorption from GI: better serum levels than Ery, longer t1/2, CYP interactions less, high levels in respiratory, significant PAE
- PD- Broader spectrum (good vs gram +, enhanced against gram (-)
- Recently linked with prolonged QT interval and cardia arrhythmias
WHats bugs cause respiratory infections
- Streptococcus pneumonia
- Haemophilus influezae
- Moraxella catarrhalis
- Atypical (no cell wall)
Common forms of Erythromycin
Telithromycin
Ketolide?
Heterocylic group does what?
Change where?
What interferes with cholinergic system?
Interactions?
Approved for tx of?
Major SEs?
Cethromycin
Trials for?
Quinolones: addition what?
But Doesnt interact with?
C6?
Spectrum
Solithromycin
Ketolide?
Heterocyclic group does what?
C6?
Spectrum?
Lincosamides
Lincomycin
Static or Cidal?
Structurally different to macrolide but?
General Properties of Lincosamides?
LIncomycin—> Clindamycin
