Respiratory: Ab 2

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Inhibitors of Cell Wall Synthesis

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beta lactams, vancomycin

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PTG Structure

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alternating NAM and NAG sugar backbone (glycosidic bonds) w/ pentapeptide linked to each NAM. Strength derived from crosslinking btw adj peptides.

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PBP's

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act together to link PTG monomers to make chains and to crosslink chains. popular drug target.

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beta lactams

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penicillins, carbapenems, cephalosporins

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beta lactam mechanism

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mimic D-Ala-D-Ala terminus to inhibit PBP-catalyzed transpeptidation

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high molecular mass PBP

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essential for cell viability; involved in cell elongation, maintenance of cell shape

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low molecular mass PBP

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nonessential; hydrolyze crosslinks, involved in PTG remodeling

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effectiveness of beta lactams is based on

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affinity for one of the essential PBP's; ability of the AB to reach the PBP in the periplasm of gram neg bacteria (intrinsic resistance of an org)

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extrinsic resistance of an organism

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presence or absence of resistance mechanisms: beta lactamase, change in membrane permeability, efflux pump, PBP mutation

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Beta Lactamases

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can be chromosomally or plasmid-mediated; catalyze rapid hydrolysis of acyl-enzyme complex, inactivating beta lactam.

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gram positive beta lactamases

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excreted into media; become dilluted, have higher affinity for AB

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gram negative beta lactamases

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retained in periplasm; less affinity for AB but effective b/c they are confined to a small space

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beta lactamase-producing SA

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can still be treated w/ beta lactam that is resistant to beta lactamase. Oxacillin, nafcillin, 2nd/3rd generation cephalosporins and carbapanems

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extended spectrum beta lactamases

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new nosocomial strains able to hydrolyze previously resistant AB. big health threat

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Changes to OM permeability

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porins can acquire mutations that constrict channel, decrease AB permeation. Can cause significant resistance when combined w/ beta lactam

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Efflux pumps

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Use Na/proton/ATP hydrolysis gradient to pump drug out.

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Changes to PBP's

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decreased rate of inactivation by AB; evolved by recombinant DNA.

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Penicillin-Resistant Strep Pneumo

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mutations in all of the essential PBP's; resistant to other AB types, too. Treat w/ vancomycin, Linezolid or streptogramins

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MIC determined by

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the essential PBP w/ the highest rate of acetylation. To become resistant, the organism must change that PBP first

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MRSA

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acquires a new PBP from an animal pathogen w/ very low rate of acetylation w/ all beta lactams.

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treating MRSA

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no beta lactams; can use vancomycin, linezolid or streptogramins

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CA-MRSA

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incidence is increasing and many carry genes for Panto-Valentine Leukocidin, a cytotoxin that causes necrotizing hemorrhagic pneumonia

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Penicillin G and V

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useful for gram positives; NESS; Neisseria, Enterococci, Strep Pneumo, The Syph

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Penicillinase-resistant penicillins

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methicillin, oxacillin, dicloxacillin, nafcillin; Used for staph aureus - not MRSA

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oral amoxicillin and ampicillin

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have wider gram negative coverage, due to their more hydrophillic properties. Used for LUSH: Listeria, UTI, Strep Pneumo (otitis media, RTI), hemophilus

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Uses for Ticarcillin, Pipericillin, Mezlocillin (almost always combined with an aminoglycoside

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tough to treat gram negs like Klebsiella, Serratia

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Aztreonam

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only useful for gram neg; doesn't cause allergic rxns

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carbapenems

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imipenem and meropenem; broadest spectrum of activity, only used for serious infections

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beta lactamase inhibitors

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bind and inhibit beta lactamase; have poor AB activity alone. Ex: Augmentin (amoxicillin + clavulanate)

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Clavulanic acid mechanism

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react w/ beta lactamase to form acyl-enzyme complex. Leads to irreversible inhibition of beta lactamase

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Cephalosporins - 1st gen

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mostly active vs gram pos; Cephalexin, oral

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Cephalexin uses

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CA skin infections

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2nd gen cephalosporins

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less gram pos activ, more gram neg. Cefuroxime

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Cefuroxime uses

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CA pneumonia due to hemophilus or klebsiella

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3rd gen cephalosporins

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most used; treat gram neg and have good permeability of meninges. Ceftriaxone, Cefotaxime.

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Ceftriaxone, Cefotaxime uses

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gram negative meningitis, best treatment for gonorrhea

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beta lactam pharmacokinetics

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distribute widely in body; not metabolized; excreted in urine. Cetriaxone has longest half life

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penicillin toxicity

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least tox of all AB (mammals don't have cell wall); most common is hypersensitivity rxn.

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cephalosporin toxicity

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hypersensitivity is most common; pt w/ mild penicillin allergy may tolerate this class. Any hx of anaphylaxis is a contraindication. bleeding disorders, N/V w/ alcohol, risk of superinfection w/ 2nd/3rd gen.

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Vancomycin

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bactericidal for gram positive; doesn't readily penetrate gram neg OM.

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vancomycin mech

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tightly binds d-ala-d-ala and prevents glycan polymerization and cross linking.

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vancomycin uses

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MRSA, E faecium and faecalis, pen-resis strep pneumo, pseudomembranous colitis from C Diff.

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Vancomycin tox

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nephrotoxicity, red man syndrome

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vancomycin resistance

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Often seen in Enterococcus Faecium. Plasmid mediated, inducible.

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resistance mechanism

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replacement of terminal d-ala with d-lac (no longer binds vancomycin but still uses PBPs

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Vancomycin Intermediate Staph Aureus VISA

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following prolonged exposure (25d-18w)- thickening of cell wall, trapping of vancomycin limiting access to cytoplasm

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Vancomycin Resistant Staph Aureus VRSA

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obtained VanA via transposon and associated genes by horizontal transfer; still rare and susceptible to other antibiotics

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vancomycin route of administration

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IV unless treating C diff (oral)