LEC 34 Antimicrobials II Flashcards
How do polymyxins (colistin = polymixin E) work?
- destroys the cell membrane
- most active against Gram-negative bc of the presence of the outer membrane
- low levels of resistance
- active against non-growing cells
- HIGHLY toxic and destroys eukaryotic cell membranes also –> NOT USED OFTEN
- Generally topical use only; systemic use restricted to tx of serious gram negative infxns
Why has colistin been used more in recent years?
d/t the appearance of panresistant bacteria (Pseudomonas, Klebsiella, and Acinetobacter spp)
However, resistance appearing d/t enzyme that modifies lipid A
How does Daptomycin (Cubicin) work?
- Active against GRAM POSITIVE (including MRSA)
- Exact MOA unknown - binds cytoplasmic membrane resulting in depolarization and disrupts cellular functions (Bactericidal)
- Not active against gram-negative - can’t pass OM
- Not active in the lungs - ie not useful for pneumonia
What two classes of drugs are cell wall inhibitors?
- Beta Lactams
- Glycopeptides
What is the largest class of cell wall inhibiting abx?
Beta-lactams
What are the classes of beta-lactams?
- Penicillins
- Cephalosporins
- Carbapenems
- Monobactams
What is the defining structure of a beta-lactam?
a four membered ring
How do beta-lactams function?
- target penicillin-binding proteins (PBPs) and inhibit transglycosylation and transpeptidation of cell wall
- impairs wall remodelling (disrupts cell division)
- induces autolysins (cell lysis)
- Bactericidal, but only against growing cells
What structure is characteristic of beta lactams?
a 4 membered ring
How is the beta lactam function considered bactericidal?
- Impairs wall remodeling - disrupts cell division
- Induces autolysins - cell lysis
Bactericidal, but ONLY AGAINST GROWING CELLS
Do beta lactams work on gram negatives?
Yes, but it depends on whether it can pass the porins.
Much more effective for gram positive
What is a form of resistance to beta lactams?
Production of beta lactamases - degrades 4 membered ring
Generally plasmid encoded
How have drug developers overcome this resistance issue of beta lactamases?
They started making beta lactamase inhibitors that are generally given in combo with the beta lactam
Suicide inhibitors of beta lactamases
What are some of the beta-lactam/beta-lactamase inhibitor drugs?
- Ampicillin + sulbactam = Unasyn
- Amoxicillin + clavulanate = Augmentin
- Ticarcillin + clavulanate = Timentin
- Piperacillin + tazobactam = Zosyn
What is Pseudomonas aeruginosa?
Gram negative bacillus that has developed pan resistance
other pan resistance: Acinetobacter and Klebsiella
How do you treat Pseudomonas aeruginosa infxn?
High dose aminoglycoside (tobramycin) + Extended spectrum penicillin/beta-lactamase inhibitor (ticaricillin-clavulanate or piperacillin-tazobactam)
What do you know about Penicillin G?
- Acid sensitive
- Poorly absorbed orally
What is better about Penicillin V vs G?
- Acid Stable
- Better absorbed - allows oral dosing
- Lead to production of better penicillins - amoxicillin & ampicillin
Which drug is absorbed better: Amoxicillin or Ampicillin?
Amoxicillin (95%)
Ampicillin -> 40%
Early penicillins were most effective against what kind of bacteria?
Gram positive or negative?
Gram-Positive
Mods were made to increase gram neg coverage and decrease resistance
Aminopenicillins (amox & amp) have increased activity against what?
Gram-Negatives
Carboxypenicillins (carbenicillin & Ticaricillin) and Ureidopenicillins (piperacillin) have what kind of spectrum?
- Increased gram neg spectrum
- more resistant to beta lactamases
What are the semi-synthetic beta lactams and what advantage do they confer?
- Methicillin - acid sens.; not given oral
- Oxacillin/Nafcillin - acid stable; absorbed from GI tract
Both are beta lactamase resistant
How does methicillin resistance occur?
- PBP2A is encoded by the gene mecA on the chromosome
- PBP2A has a lower affinity for beta lactams
First generation cephalosporins (cefazolin, cephalothin) have what kind of spectrum?
Narrow spectrum - mostly Gram positive
Second generation cephalosporins (cefaclor, cefonicid) have what kind of spectrum?
Expanded spectrum - Better Gram negative coverage and some anaerobes
Third generation cephalosporins (cefotaxime, ceftriaxone) have what kind of spectrum?
Broad spectrum - Even better gram negative coverage, but at the expense of gram positives
Fourth generation cephalosporins (cefepime) have what kind of spectrum?
Extended spectrum - Broad spec, relatively resistant to beta lactamases
What is the 5th generation cephalosporin that binds PBP2A and is therefore active against MRSA?
Ceftaroline
formulated as a prodrug
What is the spectrum of carbapenems?
- Gram positive cocci but not MRSA or VRE
- Does however include very problematic gram negs: Klebsiella, Enterobacter, Pseudomonas, Acinetobacter
also includes anaerobe: Bacteroides fragilis
How does carbapenem resistance occur?
- Production of carbapenemase (most common)
- Also inactivated by the human renal enzyme dehydropeptidase
- Efflux pumps
- Porin change/loss
Which carbapenem is not dehydropeptidase sensitive?
Meropenem
Imipenem/Cilastatin combo can avoid the dehydropeptidase because why?
Cilastatin is a peptidase inhibitor
What is the MOA for glycopeptides (vancomycin)?
Bind irreversibly to terminal alanines in pentapeptide chain required for cross-linking
Important drugs for Gram +, ESPECIALLY MRSA
How does vancomycin resistance occur?
- Intrinsic: can’t pass Gram neg outer membrane
- Acquired: Substitution of terminal D-alanine with D-lactate
Acquisition of Tn1546
What is GISA/VISA?
- Staph aureus with reduced susceptibility but not full blown resistance
- Thick cell wall - overproduction of terminal alanines so the drug binds at outer surface of cell wall and has trouble penetrating
Vancomycin is normally an IV drug, but can be used orally to treat what infection?
C. difficle
What other two drugs treat C. difficile infections other than vancomycin?
- Metronidazole
- Fidaxomicin
What do you know about Bacitracin?
Cell wall inhibitor used topically and often combined with a polymixin to increase the spectrum of activity
What do you know about Fosfomycin?
Cell wall inhibitor used as a single dose tx for UTIs
What do you know about Cycloserine and Isoniazid?
Important anti-mycobacterial agents
