Protein Synthesis Inhibitors - 50 S ribosome Flashcards Preview

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Flashcards in Protein Synthesis Inhibitors - 50 S ribosome Deck (31):
1

Macrolides

Erythromycin
Clarithromycin
Azithromycin

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Ketolides

Telithromycin

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Erythromycin

Esters absorbed well

Acid labile, poor oral absorption

Activity spectrum: mainly gram + cocci, treponema pallidum

Use in patients with PCN allergy

4

Clarithromycin

T1/2 - 3-4 hr

good intestinal absorption

Activity spectrum - extended gram - and chlamydia, legionella, pneumophilia, moraxella

has active metabolite

5

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

6

Telithromycin

T1/2 = 10 hr

Good intestinal absorption

Activity spectrum - covers MDR S. pneumoniae

has active metabolite

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Organisms macrolide antibiotic active against

gram +: S. aureus (except MRSA), group A, B, C, G streptococcus

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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

9

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

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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

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Organisms intrinsically resistant to macrolides due to decreased permeability of the outer cell envelope

Enterobacteriaceae
Pseudomonas spp
Acinetobacter spp

12

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

13

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

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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

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Category B Macrolides

Erythromycin
Azithromycin

Safest macrocodes in pregnancy

16

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

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Lincosamides

Clindamycin

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Clindamycin properties

similar to erythromycin - site and MOA, mech or resistance, efficacy vs non-enteric gram + cocci

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Antimicrobial spectrum of Clindamycin

anaerobes - primary clinical use
-abdominal anaerobic infections associated with trauma
-bacteroides fragilis

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Main adverse event of clindamycin

pseudomembranous colitis caused by C. diff
-manage with:
-metronidazole
-vancomycin PO

21

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

22

Chloramphenicol

Broad spectrum, activate against gram + and -

Restricted to life-threatening infections where there is no alternative - meningitis infections

23

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

24

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

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Kernicterus related to sulfonamides

Neonatal encephalopathy due to bilirubin displacement and poor bilirubin clearance

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Gray baby syndrome related to chloramphenicol

abdominal distension, D/V, dusky gray color, circulatory collapse and death
-drug concentration dependent
-impaired glucuronidation in neonates
-impaired renal clearance

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Intestinomicina

contains chloramphenicol
people with anemia and other low blood cell counts at greater risk of injury of death from using this anti-diarrheal drug

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MOA of Chloramphenicol

binds to 50S ribosomal subunit, inhibits peptide transferase step of protein synthesis

Bacteriostatic

Enter host cells and impair host mitochondrial protein synthesis which produces toxicity

29

Chloramphenicol Resistance

enzymatic modification by acetyltransferase (CAT)

30

Linezolid

Oxazolidinones

used when organisms are vancomycin resistant

protein synthesis inhibitor

bacteriostatic

High levels are present in lungs

Binds to 50 S ribosomal subunit and interferes with binding to initiation complex

31

Linezolid clearance and toxicity

Non-enzymatic oxidation - not CYP450 substrate, inhibitor or inducer

Renal clearance

Long term use increases ALT, decreases platelets, MAO interaction, peripheral neuropathy