Antibacteral Agents 2 - Cell Wall Synthesis Inhibitors Flashcards
3 Stages of Bacterial Wall Synthesis
1) Synthesis and assembly of cell wall subunits occurring in the cytosol
2) Linear polymerization of subunits occurring at cell membrane
3) Cross-linking of peptidoglycan polymers occurring at the cell wall
General Penicillins
- Beta-Lactams
- Bactericidal to growing organisms
- Penicillin Binding Proteins (PBPs) get acylated by penns
- Resistance: via plasmid
- produces beta-lactamases eg penicillinases and cephalosporinases
- Absorption: moderately strong acids, impairs oral absorption > empty stomach
- rapidly absorbed from IM parenteral sites
- Distribution: penetrate into tissues poorly, can enter inflamed tissues or membranes
- Excretion: 90% by tubular kidney secretion; breast milk
Categories of Penicillins
1) Prototype Penicillins
2) Penicillinase-Resistant Penicillins
3) Extended Spectrum Penicillins
2 Prototype Penicillins
*Relatively narrow spectrum of antimicrobial activity
1) Penicillin G: Powerful and inexpensive, hydrolyzed by acid and penicillinase enzyme
- Enterococci > bacteremia
- Neisseria gonorrheae > gonorrhea (though high levels of resistance)
2) Penicllin V: acid resistant, better absorbed than G
Both: Streptococcus pneumoniae > pneumonia, otitis media, sinusitis
3 Penicillinase-Resistant Penicillins
- Nafcillin, Oxacillin, Dicloxacillin
- Not substitutes for pen G except when penicillinase-producing organisms are encountered
- Acid resistance varies
- Eliminated by both renal and hepatic routes
- Narrow spectrum
- Oxacillin: Staphylococcus aureus (MSSA) > cutaneous infection, pneumonia, bacteremia, device associated infections
Extended Spectrum Penicillins
- Increased hydrophilicity allowing penetration through porins of outer membrane of G- organisms
- Ampicillin and amoxicillin: significant additional activity against G- bacilli, acid resistant, NOT resistant to penicillinase,
- Anti-pseudomonal penicillins Ticarcillin & Piperacillin: parenterally; not resistant to penicillinase, effective against Pseudomonas aeruginosa, enterococci, Bacteroides fragilis
- Amp: Enterococcus faecium-faecalis > bacteremia, urinary tract infections
- Amox: Streptococcus pneumoniae > pneumonia, otitis media, sinusitis
- Ampicillin, Amoxicillin +/- Clavulanate:
- E. coli > UTIs, intra-abdominal infections, lower respiratory infections, bacteremias, traveler’s diarrhea
- H. influenza > meningitis, otitis media, sinusitis, community-acquired pneumonia
- Klebsiella > urinary tract infections, intra-abdominal infections, lower respiratory infections, bacteremias
- Pseudomonas aeruginosa > nosocomial infections at any site (urinary tract infections, pneumonia)
β-Lactamase Inhibitors
- Clavulanic Acid, Sulbactam, Tazobactam
- potent, irreversible inhibitors of β-lactamase
- will extend the antibacterial spectrum of the accompanying penicillin only if resistance is due to β-lactamase destruction and the inhibitor is active against that particular β-lactamase
- Clavulanic acid & amoxicillin (Augmentin)
- ticarcillin (Timentin) sulbactam & ampicillin (Unasyn)
- tazobactam & piperacillin (Zosyn)
- Amoxicillin +/- Clavulanate: E. coli, H. influenza, Klebsiella, Pseudomonas
- Piperacillin -Tazobactam & Ticarcillin-Clavulanate: Pseudomonas, Bacteroides fragilis
Vancomycin
*Mechanism: Tricyclic glycopeptide acts by inhibiting cell wall synthesis at stage 2 (linear polymerization)
*Absorption: poor oral, administered IV, except for GI tract indications
*Excretion: renal
*Spectrum: reserved for situations when less toxic agents are ineffective or not tolerated
- Methicillin Resistant Staphylococcus Aureus (MRSA), Staphylococci and streptococci, Enterococci (ampicillin resistant), Clostridium difficile
- meningitis, pneumonia, endocarditis, sepsis
Toxicity: ototoxicity
Daptomycin
*More rapidly bactericidal alternative to vancomycin
*Mechanism: action at bacterial membrane and loss of intracellular ions leading to cell death
*Active against methicillin and vancomycin resistant strains of staphylococci (MRSA and
VRSA) and vancomycin resistant enterococci (VRE)
Cephalosporins
- Beta lactams
- Mechanisms of action, resistance, and pharmacology are similar to those of the penicillins
- Broader spectrum of action vs gram-negative bacteria
- Less susceptibility to penicillinase
- Less cross-reactivity in penicillin sensitive patients
- Absorption: some oral, some parenteral
- Distribution: well into most tissues and fluids
- Excretion: kidneys (require dosage adjust. in renal insufficiency)
- Toxicity: low cross sensitivity w/ pens, superinfection w/ 2nd and 3rd gen (broader spectrum)
Classifications of Cephalosporins
1st generation: Cefazolin, Cephalexin 2nd generation: Cefuroxime 3rd generation: Cefdinir, Ceftriaxone, Ceftazidime 4th generation: Cefepime 5th generation: Ceftaroline
Cephalosporins
1st generation: Cefazolin, Cephalexin
- Effective against G+ cocci, some G- bacilli
- Spectrum like amoxicillin
- More stable to penicillins than many beta lamases
- Prototype: low cost, lower toxicity, penetration
- Greater activity against MSSA than later generations
- Cephalexin: Staph (MSSA), strep, Klebsiella, E. coli
Cephalosporins
2nd generation: Cefuroxime
- Same gram coverage as 1st gen, but more effective for G- (increased spectrum)
- Active against anaerobes
- Ineffective against Pseudomonas
- Spectrum: resistant E. coli, H. influenza (meningitis, otitis media, sinusitis), bacteroides
Cephalosporins
3rd generation: Cefdinir, Ceftriaxone, Ceftazidime
- More expanded G- than 2nd gen
- Moderate antipseudomonal activity
- Spectrum: S. pneumoniae, N. gonorrheae, Pseudomonas aeruginosa, E. coli, Klebsiella
Cephalosporins
4th generation: Cefepime
- Similar to 3rd gen
- More resistant to chromosomal and extended spectrum β-lactamases
- Spectrum: S. pneumoniae, Pseudomonas aeruginosa, E. coli, Klebsiella
