Glycopeptides: Parental Drugs

Vancomycin

1.)  Narrow spectrum

2.)  G+ ONLY--can't penetrate OM

3.)  No activity against pseudomonas, anaerobic, mycobacteria, or spirochetes (-).

4.) Act by complexing the un-crossed-linked peptide strands also blocking transpeptidation

Synergism

effectiveness of the drugs together is greater than that of either drug alone

(beta lactams-->penicillins)

Pen G or V

1.) narrow spectrum

2.) active againist streptococci & few gram -

3.)IM (V=po)

(beta lactam-->penicillins)

Nafacillin

1.) narrow spectrum

2.) active against beta lactamase-producing staph

3.) considered penicillinase-resistant PCN

4.) combat bacteria that have developed resistance to penicillin-G.

(beta lactams-->penicillin)

amoxicillin

1.) broad spectrum

2.) active against most gram - & some gram +

3.) lower potency against staphlococci

(beta lactam-->penicillin)

piperacillin

1.) anti-pseudomonal penicillins

2.) active against klebsiella, enterobacter,   pseudomonas MDR-GNS

3.) includes experienced resistant microbes

Tetracyclines

Doxycycline

1.) block binding of incoming tRNA to A site

2.) selectivity works against bacterial ribosomes not eukaryotes due to structural differences in 16S vs. 18S rRNA

3.) reversible action--bacteriostatic activity

Tetracyclines-->Doxycycline

4.) broad spectrum

5.) both gram +/-

6.) no activity against pseudomonas or anaerobic

7.) no synergestic

8.) works against wall-less & intracellular

Macrolides

1.) erythromycin

2.) clarithromycin

3.) azithromycin

Macrolide uses

1.) broad spectrum

2.) gram +

3.) no activity against pseudomonas, anaerobic

4.) no synergistic activity w/other agent

5.) works against wall-less & intracellular

6.) zithromax works against mycobacteria via MAC

Gram Positive rods

streptococci

staphylococci

Gram Negative cocci

1.) gonococcus

2.) meningooccus

'Natural Penicillin' Action

• (ex) pen G & V
• target of action=final stage of cw synthesis
• mimic D-ala end of peptide; bind to PBP located inside bacterial cw
• irreversible inhibit transpeptidase activity & cross-linking of cw
• activate autolysin by interfering w/autolysin inhibitor (bactericidal action)

Penicillin drug resistance

• common sttreptococcus pneumoniae, neisseria gonorrhoeae
• prod. of drug inactivating enzyme: organisms that prod. beta lactamase are resistant to PCN
• PCN resistant= streptococcus pneumoniae occur by change of target site by mutation in coding gene for primary PBP

Pencillinase resistant penicillins

 action

• (ex) nafcillin
• target of action=final stage of cw synthesis
• mimic D-ala end of peptide; bind to PBP located inside bacterial cw
• irreversible inhibit transpeptidase activity & cross-linking of cw
• activate autolysin by interfering w/autolysin inhibitor (bactericidal action)

Broad spectrum penicillins

action

• (ex) amoxicillin
• target of action=final stage of cw synthesis
• mimic D-ala end of peptide; bind to PBP located inside bacterial cw
• irreversible inhibit transpeptidase activity & cross-linking of cw
• activate autolysin by interfering w/autolysin inhibitor (bactericidal action)

Penicillinase-resistant penicillins

 resistance

• new bacterial protein with peptidase activity, but low affinity for these drugs
• new target--> lower drug affinity

Broad spectrum resistance

(amoxicillin)

• common; altered target--inactivation
• mutations in genes encoding PBPs lead to resistance
• some that produce beta lactamase resistant to these drugs

Extended spectrum penicillins

action

• (ex) piperacillin
• target of action=final stage of cw synthesis
• mimic D-ala end of peptide; bind to PBP located inside bacterial cw
• irreversible inhibit transpeptidase activity & cross-linking of cw
• activate autolysin by interfering w/autolysin inhibitor (bactericidal action)

extended spectrum penicillins

 resistance

• uncommon--susceptible to beta lactamase produced by some resistant bacteria

cephalosporins 1st generation

action

• (ex) cefazolin
• • target of action=final stage of cw synthesis
  • mimic D-ala end of peptide; bind to PBP located inside bacterial cw
  • irreversible inhibit transpeptidase activity & cross-linking of cw
  • activate autolysin by interfering w/autolysin inhibitor (bactericidal action)

Cephalosporins 1st generation

resistance

• common; altered target--inactivation
• mutations in genes encoding PBPs lead to resistance
• some that produce beta lactamase resistant to these drugs

Cephalosporin 2nd generation

action

• (ex) cefuroxime
• target of action=final stage of cw synthesis
• mimic D-ala end of peptide; bind to PBP located inside bacterial cw
• irreversible inhibit transpeptidase activity & cross-linking of cw
• activate autolysin by interfering w/autolysin inhibitor (bactericidal action)

Cephalosporin 2nd generation

resistance (cefuroxime)

• common--altered target (PBPs)
• inactivation of drug by beta lactamases
• reduced uptake of drugs into gram - bacteria

cephalosporins 3rd generation

action

• (ex) ceftazidine & ceftriaxone
target of action=final stage of cw synthesis
mimic D-ala end of peptide; bind to PBP located inside bacterial cw
irreversible inhibit transpeptidase activity & cross-linking of cw
activate autolysin by interfering w/autolysin inhibitor (bactericidal action

cephaloporins 3rd generation

• uncommon--altered target (PBPs)
• inactivation of drug by beta lactamases
• reduced uptake of drugs into gram - bacteria

cephalosporins 4th generation

action

• (ex) cefepime
• • target of action=final stage of cw synthesis
  • mimic D-ala end of peptide; bind to PBP located inside bacterial cw
  • irreversible inhibit transpeptidase activity & cross-linking of cw
  • activate autolysin by interfering w/autolysin inhibitor (bactericidal action)

Glycopeptide inhibitors

action

• (ex) vancomycin
• inhibition of cw synthesis by complexing w/D-alanyl-D-alanine, shielding it from transpeptidation rxn
• cross links are not made in growing cell wall

sulfonamide action

• targets nucleic acid syn

• analogs of PABA

• competitive inhibitors of dihydropteric acid synthase

• FYI: PABA is intermediate in folic acid syn. needed by bacteria to survive--sulfonamide resemble PABA so they bind instead in folic acid biosynthetic pathway & blocks the production of vital folic acid for bacteria

Glycopeptide inhibitor

resistance

• uncommon, but seen in enterococcus faecium w/resistance gene

Aminoglycosides Action

• (ex) streptomycin, gentamicin, tobramycin
• targets protein synthesis--30S subunit
• inhibits initiation & elongation of translation by misreading
• acceptor 30S binds inappropriately activated tRNAs=amino acid sub=nonfunctional proteins
• concentration dependent

aminoglycosides resistance

• common: drug inactivation by enzymatic modification
• involving transferase enzymes
• altered target
• reduced uptake of drug across OM

Tetracycline Action

• (ex) doxycycline
• targets protein synthesis--30S
• reversibly inhibit elongation of protein syn. by binding to acceptor site of amino acyl tRNAs @ 30S

Tetracycline resistance

• common--decreased drug accessibility by upregulation of efflux pumps
• FYI: efflux pumps removes drugs outside the cell

Macrolides Action

• (ex) erythromycin, azithromycin, clarithromycin
• targets protein syn. 50S
• bind to 23S rRNA of 50S
• block translocation & release of tRNA after peptide bond formation

Macrolides Resistance

• altered target
• 23S rRNA in 50S is altered by methylation of adenine nucleotides in RNA
• methylase is plasmid mediated
• cross resistance to lincosamides

Lincosamide Action

• (ex) clindamycin 
• targets protein syn. 50S
• bind to 23S rRNA of 50S
• block translocation & release of tRNA after peptide bond formation

Lincosamide Resistance

• enzymatic modification, altered ribosomal binding sites
• cross resistance to macrolides

Fluoroquinolones action

• (ex) levofloxacin, ciprofloxacin
• targets nucleic acid syn
• drugs bind to DNA gyrase (topII)
• enzyme facilitates DNA unwinding by making dbl-stranded breaks
• drugs inhibit DNA replication

Fluoroquinolones resistance

• resistance occurs by target alteration--alteration of DNA gyrase
• decreased drug accessibility (efflux pump)
• don't achieve inhibitory concentration in cells

Rifampin action

• targets RNA synthesis

• binds to beta subunit of core enzyme--DNA-dependent RNA polymerase

Rifampin resistance

• common--resistance occurs easily via pt mutation on beta subunit encoding region

Oxazolidinones action

• (ex) linezolid 
• targets protein syn. 50S
• newer agents bind to 50S ribosome @ 30S
• inhibits initation of protein syn

Bacitracin action

• inhibits dephosphorylation of lipid carrier
• inhibits teichoic acid syn
• topical antibiotic
• effective against mostly gram +