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
First Generation Cephalosporins
- First-generation cephalosporins are active against streptococci and S. aureus, and certain enteric gram negative rods, though many strains of E. coli, Klebsiella pneumoniae, and others have now acquired resistance.
- They are useful in skin and soft tissue infections in areas where MRSA is uncommon, since these are usually due to S. pyogenes and/or S. aureus (MSSA), and are commonly used as prophylaxis against infection during surgical procedures.
- Cefazolin is the most frequently used parenteral agent, and cephalexin can be considered its PO equivalent.
- These penetrate the CNS poorly.
Second Generation Cephalosporins
- Second-generation cephalosporins have activity against H. influenzae whether or not they produce beta-lactamase, which inactivates aminopenicillins.
- These drugs are may be used in the empiric treatment of community-acquired respiratory tract infections in which either S.pneumoniae or H. influenzae may be a pathogen (e.g. sinusitis, otitis media).
- Second generation cephalosporins also have some activity against a number of Enterobacteriaceae.
- Two structurally related antibiotics (the cephamycins cefoxitin and cefotetan) are included with second-generation cephalosporins.
- Cefoxitin and cefotetan, unlike all other cephalosporins, have activity against anaerobes.
- Overall, second-generation cephalosporins are seldom used, but if you have to learn one, cefuroxime is still used occasionally.
Third Generation Cephalosporins
- Third-generation cephalosporins have markedly increased activity against aerobic gram-negative bacilli, particularly the Enterobacteriaceae, compared to earlier generations.
- They are also highly active against most strains of S. pneumoniae, and are stable to the beta-lactamase that can be produced by H. influenzae and Neisseria spp.
- The most commonly used IV drugs in this class are ceftriaxone and cefotaxime (both of which penetrate well into the CNS).
- Ceftazidime has activity against Pseudomonas aeruginosa. Several oral 3rd-generation cephalosporins exist; cefdinir is an example that can be used for sinopulmonary infections, UTIs, etc.
- An important property of some third-generation cephalosporins (e.g., cefotaxime and ceftriaxone) is that they achieve concentrations in cerebrospinal fluid adequate to be bactericidal against Enterobacteriaceae and the three major bacterial meningeal pathogens (i.e., S. pneumoniae, N. meningitidis, and H. influenzae) but are not active against L. monocytogenes.
- Third-generation cephalosporins are also useful for treating serious infections such as nosocomial pneumonia due to aerobic Gram-negative bacilli.
Fourth Generation Cephalosporins
- Cefepime, a parenteral agent, is the only fourth generation cephalosporin available in the US.
- Cefepime has excellent activity against Enterobacteriaceae and P. aeruginosa, including to strains resistant to other cephalosporins.
- In addition, it has good activity against S. aureus.
- Cefepime has no activity against MRSA, enterococci, Listeria, or anaerobes.
- It penetrates well into the CNS.
Fifth Generation Cephalosporins
•Ceftaroline is a newly developed fifth generation cephalosporin with high affinity for PBP2a, conferring excellent activity against MRSA, unlike all other cephalosporins.
Carbapenems
- Beta-lactam ring fused to a carbon containing penem ring = carbapenem
- Broadest spectrum of all available antibiotics
- Gram pos (not MRSA or Enterococcus)
- Gram neg (including Pseudomonas*) *not ertapenam
- Anaerobes
• Active in presence of many beta-lactamases
-including ESBL, Amp-C, others
• Resistance mediated by carbapenemases
-KPC, NDM, others
• Better penetration in gram neg via porins to periplasmic space
Carbapenems - Imipenem
– Hydrolyzed in kidney by human beta-lactamase to nephrotoxic metabolite
– Combination with cilastatin (specific inhibitor of dehydropeptidase I)
– Increased risk ofseizures (GABA receptor inhibition)
Carbapenems - Meropenem
• Most frequently used
Carbapenems - Ertapenem
•Does not cover Pseudomonas
Carbapenems - Susceptible
- Streptococci
- MSSA
- Gram-negative rods
- Pseudomonas: susceptible
- Anaerobes
- (Listeria)
Carbapenems - Resistant
- MRSA
- Enterococci
- Atypicals
- Spirochetes
Monobactams
- Monobactam = monocyclic beta-lactam
- Aztreonam
- IV and inhaled use only
- No significant crossallergenicity with other betalactams
- Spectrum: aerobic gram negatives (including Pseudomonas) only
Vancomycin
Vancomycin Pharmacokinetics
• Pharmacokinetics
– Not absorbed from the GI tract
– CSF +/- , high dosesrequired
– Adverse Effects: “Red man” syndrome can be mistaken for allergy. Due to histamine release during rapid infusion
– Nephrotoxicity
– Excreted unchanged through kidney by glomerular filtration; must adjust dose with renal insufficiency
• Clinical Use
– MRSA and other gram positive organisms resistant to beta-lactams
– Serious infection and beta-lactam allergy
– Oral therapy of C. difficile colitis
Daptomycin
- Cyclic lipopeptide with high molecular weight (1620 g/mol)
- Active only against gram positive organisms
– Active against streptococci, Staphylococci (including MRSA), enterococci (including VRE).
• Mechanism of action
– Binds to bacterial cell membrane via calcium-dependent insertion of its lipid tail
– Forms a channel that causes efflux of potassium and depolarization of the cell membrane.
• Pharmacokinetics
– Penetrates poorly (volume of distribution 0.1 L/kg)
– Inactivated by pulmonary surfactant—not effective for pneumonia
• Adverse reactions
– Myopathy and rhabdomyolysis (increased risk with statins)
• Expensive
– $22,000 for a 4 week course
Overview of Staphylococcus aureus beta lactam resistance.
- Resistance to penicillin G is mediated by a beta-lactamase that hydrolyzes the betalactam ring. At present, fewer than 5 percent S. aureus isolates remain sensitive to penicillin.
- Resistance to anti-staphylococcal penicillins is occurring with increasing frequency. S. aureus resistant to anti-staphylococcal penicillins are termed methicillin resistant S. aureus or MRSA.
- This resistance is mediated by production a new PBP (PBP2a, encoded by the mecA gene) that has reduced affinity for beta-lactam antibiotics.
- Methicillin resistant S. aureus are also resistant to all beta-lactam antibiotics except for 5th-generation cephalosporins, which have increased binding affinity for PBP2a.
- MRSA are sensitive to the glycopeptide antibiotic vancomycin; but over the past decade, there have been reports of S. aureus with intermediate resistance to vancomycin.
- Cases of vancomycin resistant S. aureus (VRSA) have been reported! Obviously, the possibility of an increase in vancomycin resistant strains of S. aureus is of great concern, but has not become a significant problem to date.
Vancomycin Resistance
•The most common mechanism of vancomycin resistance is by expression of vanA.
-The vanA resistance genes are carried on a transposable element that encodes several enzymes responsible for the vancomycin resistance.
•The D-Ala-D-Ala terminus of the peptidoglycan pentapeptide of resistant enterococci is converted to D-Ala-D-lactate.
-Affinity of vancomycin for binding the D-Ala-D-lactate terminus is 1000-fold less than for D-Ala-D-Ala, resulting in resistance.
•Enterococcus faecium and Enterococcus faecalis strains resistant to vancomycin have emerged as a major clinical problem in recent years (~15% of enterococcal strains isolated in intensive care units demonstrate vancomycin resistance).
-Vancomycin-resistant enterococci (VRE) may also be resistant to other classes of antibiotics, rendering infections caused by them medically incurable.
- S. aureus strains with intermediate resistance to vancomycin do not harbor the vanA gene, but rather can arise via selection following serial exposure to vancomycin.
- In contrast, vancomycin resistant S. aureus (VRSA) derive their resistance from acquisition of the vanA element from enterococci.
