Protein Synthesis Inhibitors Ii

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Most protein inhibitors are...

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bacteriostatic --> rely on good immune system to clear --> not good for immunocompromised

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Erythromycin - MOA

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Macrolide

Useful alternative for penicillin G; gram (-)

Binds L-15 protein of 50s --> dissociates peptidyl tRNA from ribosome and blocks its translocation from A --> P site

Premature release of polypeptide

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Erythromycin - resistance

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Methylation of 23s RNA (MLS - part of 50s) --> disrupts drug binding

MLS phenotype - site where three drugs (macrolides, lincosamides, streptogamin B) bind; can have resistance here

Resistance - inducible or constitutive production of ERM genes (erythromycin methylase)

Inducible - macrolides induce ERM expression

Constitutive - natural ERM expression; MLS cross-resistance

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Erythromycin - physiological disposition

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Gastric acid destruction - enteric coated

Food interferes

Metabolites inhibit cytP450 --> potentiated drug effects

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Erythromycin - adverse effects

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GI (nausea, vomitting, diarrhea) --> direct stimulation of gut motility (motilin receptors)

Used postoperatively to promote peristalsis

Liver toxicity - acute cholestatic hepatitis

Hypersensitivity

Ototoxicity (reversible - high IV doses)

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Clarithromycin

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Macrolide; useful penicillin alternative for gram +

similar to erythromycin but more active against M. avium

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Clarithromycin - physiologic disposition

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more acid-stable

hepatic metabolism renal excretion --> dose reduce w/ disease

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Clarithromycin - adverse effects

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Ototoxicity (reversible)

Teratogenic (avoid in pregnancy)

Drug-drug interactions

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Azithromycin

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Macrolide; spectrum similar to clarithromycin

MOA - same as erythromycin

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Azithromycin - physiologic disposition

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High tissue concentrations --> 3 day half-life

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Azithromycin - adverse effects

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Food/antacid decrease absorption

No drug-drug interactions

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Telithromycin

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Erythromycin derivative - can use in resistant organisms

Liver metabolism --> drug interactions

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Telithromycin - adverse effects

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GI
Vision (higher in women >40)
Myasthenia gravis (worsens)
Hepatic dysfunction
QT prolongation

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Clindamycin

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Lincosamide (L in MLS)

gram + aerobes, gram -/+ anaerobes

Indicated - serious infections of anaerobic Bacteroides; mixed anaerobic infections

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Clindamycin - MOA

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same as erythromycin (binds 50s, inhibits translocation of tRNA --> p site --> inhibits protein synthesis

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Clindamycin - resistance

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Only constitutive ERM strains are resistant (clind doesn't induce)

NOT a substrate for macrolide efflux pumps

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Clindamycin - physiologic disposition

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Oral/parenteral

Hepatic metabolism - dose adjust w/ hepatic disease

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Clindamycin - adverse effects

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Pseudomembranous colitis - secretes necrotizing toxin --> potentially fatal)

GI, rash

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Pseudomembranous colitis due to C. difficile - TX

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Oral metronidazole

Oral vancomycin

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Metronidazole - indications, MOA

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Anerobic infections, pseudomembranous colitis (C. difficile)

Anaerobic conditions - bacterial nitroreductase forms radical products

Resistance w/ lower levels nitroreductase

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Metronidazole - physiologic disposition

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Gets into CNS

Liver metabolism, renal excretion - dose adjust w/ disease

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Metronidazole - drug/drug interactions

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Liver metabolism --> metabolite inhibits aldehyde dehydrogenase --> nausea/vomiting w/ ethanol (disulfiram-like rxn)

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Metronidazole - adverse effects

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dry mouth, metallic taste
Dark red/brown urine
CNS - vertigo, paresthesias, dizziness

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Vancomycin

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Only gram + --> inhibits cell wall synthesis (inhibits peptidoglycan synthetase)

Useful for MRSA, alternative for C. difficile associated pseudomembranous collitis

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Drugs for vancomycin resistance

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Streptogramins - protein synthesis inhibitors

Linezolid - protein synthesis inhibitors

Daptomycin - membrane depolarizer

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Streptogamins

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Reversibly bind 50s, block peptidyl transferase --> prevent translocation to P site = inhibit elongation/protein synthesis

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Linezolid

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Useful for vancomycin resistance

MOA - bind 23sRNA unique site (not MLS) --> prevent formation of functional 70s complex --> inhibits protein synthesis

No dose adjust for renal dysfunction

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Linezolid - adverse reactions

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Myelosuppression (anemia, leukopenia, thrombocytopenia)

Not for phenylketonurics

Peripheral/optic neuropathy

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Linezolid - drug interactions

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Inhibits MOA (hypertension if taken w/ tyramine rich food)

Caution w/ pseudoephedrine, SSRIs, tyramine foods

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Daptomycin

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For skin infections...NOT pneumonia

MOA - forms pores --> release of ions --> depolarization --> loss of ion balance --> cell death

Give IV, dose adjust for renal dysfunction

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Daptomycin - adverse effects

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GI
High doses increase creatine phosphokinase --> muscle weakness/discomfort

Stop statins?