Protein Synthesis Inhibitors - 50 S ribosome Flashcards
Macrolides
Erythromycin
Clarithromycin
Azithromycin
Ketolides
Telithromycin
Erythromycin
Esters absorbed well
Acid labile, poor oral absorption
Activity spectrum: mainly gram + cocci, treponema pallidum
Use in patients with PCN allergy
Clarithromycin
T1/2 - 3-4 hr
good intestinal absorption
Activity spectrum - extended gram - and chlamydia, legionella, pneumophilia, moraxella
has active metabolite
Azithromycin
T1/2 = 40 hr
Good intestinal absorption
Activity spectrum - same + more gram -
Drug of choice for legionnaire’s disease
Has active metabolite, least drug-drug interactions
Telithromycin
T1/2 = 10 hr
Good intestinal absorption
Activity spectrum - covers MDR S. pneumoniae
has active metabolite
Organisms macrolide antibiotic active against
gram +: S. aureus (except MRSA), group A, B, C, G streptococcus
Major indications of macrolines/ketolides in CAP
S. pneumoniae
Hemophilus spp
Moraxella catarrhalis
Atypical:
Legionella pneumophila
Chlamydiphila pneumonia
Mycoplasma
Distribute into and concentrate in body tissues and phagocytic cells where concentrations are greater than in plasma
MOA of macrolides and ketolides
irreversible bind 50 S subunit of bacterial ribosomes
bacteriostatic
Inhibit translocation step of protein synthesis –> inhibition of bacterial protein synthesis
Mechanisms of resistance to Macrolides
Methylation of ribosome
-Methylases encoded by erythromycin ribosome methylase genes (ERM-A, -B, -C…) alter macrolide binding to ribosome –> high level of resistance
Macrolide efflux pumps - mef E genes, pump macrolides out of cytosol –> mid-level resistance
Organisms intrinsically resistant to macrolides due to decreased permeability of the outer cell envelope
Enterobacteriaceae
Pseudomonas spp
Acinetobacter spp
Adverse Effects and clinical complications of macrolides and ketolides
GI: N/V/D
Hepatotoxicity - rare, serious
- cholestatic jaundice - erythromycin astrolabe (hypersensitivity)
- fatal hepatotoxicity - telithromycin
Cardiac - QTc interval prolongation - rare, serious
Drug-Drug: CYP3A interaction
Reversible hearing loss
QT interval prolongation with macrolides and telithromycin
intrinsic arrhythmogenic capability via blockade of the Ikr channel - inward rectifying K+ channel
Prolonged cardiac depolarization - prolonged QT interval - increases risk for torsades de pointes arrhythmias
Erythromycin>clarithromycin and azithromycin
Erythromycin with CYP3A4 inhibitors
Erythromycin alone associated with 2 fold risk of sudden cardiac death
5 fold increase if taking CYP3A4 - elevates circulating erythromycin levels
Category B Macrolides
Erythromycin
Azithromycin
Safest macrocodes in pregnancy
Macrocodes and CYP450 drug-drug interactions
Erythromycin and clarithromycin interact with inhibition of hepatic CYP3A enzymes
Azithromycin minimal effects on hepatic enzymes and fewer documented drug interactions
Lincosamides
Clindamycin
Clindamycin properties
similar to erythromycin - site and MOA, mech or resistance, efficacy vs non-enteric gram + cocci
Antimicrobial spectrum of Clindamycin
anaerobes - primary clinical use
- abdominal anaerobic infections associated with trauma
- bacteroides fragilis
Main adverse event of clindamycin
pseudomembranous colitis caused by C. diff
- manage with:
- metronidazole
- vancomycin PO
Management of toxin production of MRSA
MRSA harbor Panton-Valentine leukocidin (PVL) toxin
Alpha-toxin and SEB - (S. aureus enterotoxin B) - higher in CA-MRSA than hospital acquired MRSA
-community acquired more virulent
Use Clindamycin or Linezolid, do not increase toxins
Chloramphenicol
Broad spectrum, activate against gram + and -
Restricted to life-threatening infections where there is no alternative - meningitis infections
Lethal toxicities of Chloramphenicol
Aplastic anemia - idiosyncratic, life-threatening, occur after stopped. Pt with G6PD deficiency
Gray Baby Syndrome - developmental origins, penetrates human cells and disrupt mitochondrial protein synthesis
- Abdominal distension, D/V, dusky gray color
- circulatory collapse and death
- drug concentration dependent - impaired glucuronidation in neonates and impaired renal clearance
Development of clearance enzymes in neonates
Sulfating - day 5 Acetylation day 20 Glomerular filtration day 30 Glucuronidation - day 60 Conjugation day 90 - glucose, GSH Tubular secretion - day 180
