Antibiotics: Cell Wall Synthesis Inhibitors Flashcards
Beta Lactam Antibiotics
• Beta-lactam antibiotics
- Structure: all contain a four member nitrogen-containing beta lactam ring
- Interfere with transpeptidase reaction in bacterial cell wall synthesis
Beta Lactam Antibiotic MOA
- All beta-lactam antibiotics inhibit bacterial growth by interfering with a specific step in bacterial cell wall synthesis.
- The cell wall is a rigid outer layer that completely surrounds the cytoplasmic membrane.
- The cell wall is composed of a complex cross-linked polymer, peptidoglycan, consisting of polysaccharides and polypeptides.
- The polysaccharide contains alternating amino sugars, Nacetylglucosamine (NAM) and N-acetylmuramic acid (NAG) with an amino acid peptide linked to the Nacetyl-muramic acid.
- This peptide terminates in Dalanyl-D-alanine (D-Ala-D-Ala).
- Transpeptidases (often termed penicillin-binding proteins [PBPs]) in bacteria catalyze the reaction that removes the terminal alanine to form a crosslink with a nearby peptide, which gives cell wall its structural rigidity.
- Betalactam antibiotics are structural analogs of the natural substrate and are covalently bound by the transpeptidase (PBP) at the active site.
- After a beta-lactam antibiotic has attached to the PBP, the transpeptidation reaction is inhibited, and peptidoglycan synthesis is blocked.
- Beta-lactam antibiotics are bactericidal.
Resistance
(1) Beta-lactamase production
(2) Alteration in PBPs
(3) Exclusion of antibiotic
Resistance - Beta lactamase production
•Beta-lactamase production is the most common mechanism of resistance.
-More than 100 different beta-lactamases have been identified.
- Some beta-lactamases, such as those produced by Staphylococcus aureus, Haemophilus species, and E. coli are relatively narrow in substrate specificity and will hydrolyze penicillins but not cephalosporins.
- Other beta-lactamases, such as those produced by Pseudomonas aeruginosa and Enterobacter species have a much broader spectrum of activity and will hydrolyze both cephalosporins and penicillins.
Resistance - ALteration in PBPs
- Alteration in PBPs is responsible for methicillin resistance in staphylococci (MRSA) and penicillin resistance in pneumococci.
- These resistant organisms produce PBPs that have low affinity for binding beta-lactam antibiotics, and as a result they are not inhibited except at high drug concentrations, which may exceed what is clinically achievable.
Resistance - Exclusion by antibiotic
- Exclusion of antibiotic by impaired penetration of antibiotic, which occurs only in gram negative species, is due to impermeability of the outer membrane that is present in gram negative but not in gram-positive bacteria.
- Beta-lactam antibiotics cross the outer membrane and enter gram-negative organisms via outer membrane protein channels (porins).
- Absence of the proper channel or down-regulation of its production can prevent or greatly reduce drug entry into the cell.
- Some organisms produce efflux pumps to effectively actively transport antibiotics outside of the outer membrane.
Adverse Reactions
- Rare, but significant mortality
- Type I hypersensitivity: IgE mediated
- Other types of hypersensitivity responsible for rash, fever, serum sickness, etc.
- Drug/allergy history is critical
Beta Lactams
- Penicillins
- Cephalosporins
- Carbapenems
- Monobactams
Penicillans
– Standard penicillins
– Aminopenicillins
– Anti-staphylococcal penicillins
– Anti-pseudomonal penicillins
Standard Penicillins
- Gram + that do not produce beta lactamase
- Penicillin G
-Crystalline (IV) and benzathine (IM)
•Penicillin V
-Well absorbed (PO)
• Pharmacokinetics
- Distribution: all tissues, good CNS penetration
- Elimination: primarily renal excretion
•Adverse Reactions
- Common: rash, diarrhea
- Rare: lowers seizure threshold
Aminopenicillins
- Ampicillin (IV) and amoxicillin (PO)
- Compared to penicillin…
- Similar gram positive coverage
- Covers some gram negatives (e.g. H. influenzae, E. coli, Salmonella spp.)
- No anaerobic coverage
• Pharmacokinetics
- Absorption: amoxicillin well absorbed
- Distribution: all body sites, including CSF
• Adverse Reactions
- Diarrhea, GI upset
- Rash: mono (65-100%), CLL (90%), allopurinol (15%)
Aminopenicillins Clinical Use
- Streptococci: GAS, GBS, S. pneumoniae (some), viridans Strep
- Staphylococci: <5% susceptible due to beta lactamase
- Enterococci: E. faecalis
- Listeria: treatment of choice
- Gram negatives:
- Enhanced activity compared to penicillin
- H. influenzae
- Some E. coli, Shigella, Salmonella
- Anaerobes: no activity
- Atypicals: no activity
- Spirochetes: active (but penicillin is favored)
Anti-Staphylococcal Penicillins
- ~95% of S. aureus isolates resistant to penicillin G (beta lactamase)
- Stable to Staph beta-lactamase
-Methicillin, Nafcillin, Oxacillin (IV); Dicloxacillin (PO)
• Resistance: altered penicillin binding protein (MRSA)
- PBP2a, encoded by mecA
• Pharmacokinetics:
- Dicloxacillin well absorbed
- Nafcillin hepatic elimination
- Penetrate CNS
• Adverse Effects
- GI
- Rash
- Occasional: hepatotoxicity (nafcillin), cytopenias
• Clinical use: MSSA, but not MRSA
Anti-Pseudomonal Penicillins
• Extended spectrum aminopenicillins
– Same spectrum of activity with additional activity vs. gram neg bacilli including Pseudomonas aeruginosa
– Like aminopenicillins
- not stable against Staph betalactamase
– Piperacillin
Beta-lactamase Inhibitors
• Contain beta-lactam ring - inhibits bacterial beta- lactamases of:
- S. aureus
- H. influenzae
- Some Enterobacteriaceae
- B. fragilis and other anaerobes
• No clinically useful activity alone
- used in combination with beta- lactam antibiotic
Beta-lactamase Inhibitors Combinations
• With aminopenicillins:
- Amoxicillin/clavulanate (Augmentin)
- Ampicillin/sulbactam (Unasyn)
•With anti-pseudomonal penicillins:
- Piperacillin/tazobactam (Zosyn)
Cephalosporins
- Generations: 1st - 5th
- All cover Strep spp, MSSA, E. coli
- As generations ascend:
- Similar gram positive coverage
- Better gram negative coverage
- Ceftazidime (3rd) and cefepime (4th) cover Pseudomonas
- Ceftaroline (5th) covers MRSA, Enterococci
Cephalosprins Adverse Reactions
• Adverse Reactions:
- ~10% cross-allergenicity with penicillins; avoid in patients with IgE mediated PCN allergy (anaphylaxis)
- GI upset, rash
- Occasional: bone marrow suppression (any), cholestasis (ceftriaxone)
• Pharmacokinetics:
- CSF penetration: cefotaxime, ceftriaxone (3rd gen.) and cefepime (4th)
- No CNS penetration: 1st gen
- Most renally excreted
- Ceftriaxone excreted in bile