Id - 4-20 - Pharm - Antibiotics 3 (Inhib Of Prot Synth)

Front 1

Selective toxicity

Back 1

When an agent only harms the invader and is harmless to the host.

based on structural/cellular/biochem differences btwn host and invader(e.g. cell wall agents) or exploiting structural/cellular/biochemical differences as therapeutic targets (inhib prot synth bc ribosomes are different)

Front 2

Ribosomes in prok and euk

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prok - does cell wall synth and is 30s/50s

euk - 40/60

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General feat of prot synth inhibitors

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Broader spec than beta-lactams bc cell walls not always necc but prot synth is for a bacteria

Bacteriostatic (aside from 1 grp) because it affects reproduction rather than integrity.

Selectivity due to ribosome diff btwn prok and euk.

Front 4

Sites of action of prot synth

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30s and 50 - aminoglycosides

30s - tetracyclines

50s - macrolides, clindamycin, linezolid.

Front 5

Discov of aminoglycosides

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foudn something called streptomycin that had activ vs m. tuberculosis but had quick resistance develop and caused deafness in some pts.

Front 6

Gentamicin and tobramicin structure

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aminoglycosides

2 aminoglycosides linked to AMINOCYCLITOL (which is in the middle) by glycosydic bonds

Front 7

streptomycin structure

Back 7

2 aminoglycosides with glycosidic bonds and aminocyclitol is on an end. kinda different compared to gentamicin and tobramicin (also aminoglycosides)

Front 8

aminoglycoside struc

Back 8

most have 3 rings - some have 4

ones with 4 have 2 receptor sites for ribsome

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mechanism of aminoglycosides

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binds to 18s RNA and 23s RNA. results in the wrong base being incorporated (misreads the mRNA), blocking of translocation (30S site) and inhibition of recycling (50S site).

they restrict the movement of ribosomes.

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Pharmacodynamics of aminoglycosides

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bacteriostatic at low concentrations

but unlike other prot synth inhibitors, bacteriocidal asides from that.

cidal bc is diffuses through porin channels of outer membrane (and that is rate limiting and req energy). the drug also induces mutated protein insertion into the PM that enhances uptake of teh drug...

Front 11

resistance of aminoglycosides

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caused by membrane impermeability, mutation of bvinding site, methylation of rRNA and inactivating enzymes (this is the most common way)

Front 12

streptomycin spectrum

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aminoglycoside

mycobacterium TB

Front 13

gentamicin and tobramycin spectrum

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aminoglycoside

aerobic GNRs
synergy with GP adn beta lactams (almost always use these with beta lactams)
anaerobes are resistant.

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Tobramycin spectrum

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aminoglycoside

pseudomonas

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Pharmacokin of aminoglycosides

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parenteral admin (need to do it in hospital)

certain ones can be topical (neomicin)

poorly distrib to tissues and half life is 1.5-4 hours

renal excretion!!! (also important to know this one)

signif post-antibiotic effect for GN aerobes

Front 16

AEs of aminoglycosides

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nephrotoxic (ATN)

ototoxic (auditory and vestibular) - irrev; destruc of sensory cells

rash, BM suppression, muscle weakness are minor ones

Front 17

Post antibiotic effect

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persistent suppression of bac growth after a brief exposure to abx even without host defense mechs.

due to either persistence of drug at target site or irrev inhib of the target

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drugs with post antibiotic effect

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AGs, quinolones, newer macrolides, rifampin.

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concentration dependent killing vs. time dependent killing

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[] - higher [] is more efficient and no benefit of longer exposure (e.g. aminoglycosides, fluoroquinolones, metronidazole)

time - need freq dosing and longer exposure

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Dosing of aminoglycosides

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extended interval dosing (once daily) to reduce toxicity (e.g. nephrotoxicity) and take adv of []-dependent killing. whereas toxicity is both time and []=dependent. iti s also cheaper.

also due to nice post-antibiotic effect on GN aerobes

disadv if extender interval dosing is that efficicacy not completely proven yet and can't be done in pts with renal dysfunc.

Front 21

aminoglycoside mnemonic

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MEAN GNATS (GENTAMICIN, neomycin, amikacin, TOBRAMYCIN, STREPTOMYCIN) canNOT (nephrotoxicity, ototoxicity and teratogen) kill anaerobes.

ineffective against anaerobes bc drug needs O2 for bacteria to take it up

Front 22

Tetracycline mechanism

Back 22

binds to 30s and blocks amino-acyl-tRNA binding.

Front 23

resistance of tetracyclines

Back 23

efflux pumps and poor permeability.

less binding to 30s.

inactiv by enzymes

rarely used in teh US due to resistance.

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pharmacodynamics and spectrum of tetracyclin

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bacteriostatic

spectrum - GP and aerobes are resistant.
e coli, some anaerobes, mycoplasma, chlamydia, legionella, rickettsia (Rocky mtn spotted fever)

outpt preferred to in hospital.

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pharmacokin of tetracyclines

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abs in gut but poorly with food or chelators present.

good tissue and CSF penetration

doxycycline - hepatic metab
tetracycline - renal elim.

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AEs of tetracyclines

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GI intol, hepatotoxic, skin photosens.

never use in pregnancy, neonates, or children. get deposits in teeth and bone.

never use in renal failure.

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Macrolides

Back 27

Need to know clarithromycin, erythromycin and azithromycin

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Mech of macrolides

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binds and blocks polypeptide release channel on 50S. This blocks translocation.

Front 29

Resistance of macrolides

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Modified 23S rRNA binding site on 50S subunit of ribosome (either chromosomal mutation or induction of methylase)

also efflux or reduced perm

and production of esterase (by enteriobacteriaceae)

Front 30

Pharmacodynamics of macrolides

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erythromycin - bacteriostatic but cidal in certain conditions

clarithromycin and azithromycin - static; less resistance to these.

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spectrum of erythromycin

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GPC, mycoplasma, legionella, chlamydia. Can be used in penicillin allergics

use in resp tract infections

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spectrum of clarithromycin and azithromycin

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GPC, mycoplasma, legionella, chlamydia. Can be used in penicillin allergics (all the same as erythromycin so far)

also h influenza and mycobacteria.

use in resp tract infections

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pharmacokin of macrolides

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well abs from GI tract.
widely distributed

1/2 life clarithromycin - 3-7 hours
erythro - 1.4 hours
azithro - 68 hours

hepatic metab.
clarithromycin and erythromicin inhibits hepatic CYP3A

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AEs of macrolides

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GI upset, skin rash, ototoxic (espec in elderly), drug interactions (CYP3A inhibition). rarely hepatitis

erythromycin - cholestatic jaundice.

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clindamycin mech

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binds to 50s on a 23s rRNA binding site and interferes with peptide bond formation. (partial overlap in binding site with macrolides)

mutual interference is co-rx with macrolides

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resistance of clindamycin

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same as macrolides

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pharmacodyn and spectrum of clindamycin

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bacteriostatic and narrow spectrum

GPC (staph and strep), oral and bowerl anaerobes (1/2 of bacillus fragilus)

often for deep seated infections (e.g. intraabdom) in combo with aminoglycosides

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pharmacokin of clindamycin

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well abs for GI tract, good tissue penetration (large Vd). [] is intracellular.

1/2 life - 2-2.5 hours

hepatic metab.

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AEs of clindamycin

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hypersensitivity - skin rashes
GI intol and pseudomembranous colitis (C. difficile - saying that is looks similar to the c diff pseudomembranes?)

hepatotoxic hepatitis

BM suppression laeding to less WBCs.

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Oxazolidinones mech of action

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Linezolid is the one to learn - binds to 23s rRNA of 50S to block translocation

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resistance of linezolid

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mutation of 23S and there is no cross-resistance with other drug classes

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pharmacodyn and spectrum of linezolid

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wide range of GP organisms are susceptible.
static against staph and enterococci
cidal against most strep

to tx VRE, VRSA, MRSA

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pharmacokin of linezolid

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IV and oral (100% bioavail)
half life is 5 hours (2x a day dosing)
renal (30%) and hepatic (65%) clearance

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AEs of linezolid

Back 44

hematologic - leukopenia/thrombo and aplastic anemia
GI intol
biochcem hepatitis.