4/9 Antibacterials I/II: Cell Wall Agents Flashcards
what does Penicillin, Cephalosporin, Monobactam, Carbapenem have in common? What confers each specificity?
common structure: ß lactam ringspecificity
Penicillin, Cephalosporin, Monobactam, Carbapenem all have a common function:
Antimicrobial agents that work by inhibiting cell wall synthesis
in general, how are Penicillin, Cephalosporin, Monobactam, Carbapenem inactivated?
ß lactamase enzymes - cleave the ß-lactam ring (essential for activity)
Why do carbapenems additional stability (more resistant to ß lactamases) over the rest of the drugs?
the H next to the keto group is oriented ABOVE the plane, and this configuration seems to stabilize the molecule, and make it more resistant to ß-lactamases (others: below)
What type of hypersensitivity reaction does penicillin usually cause?What type of physical manifestations?
IgE Type I Hypersensitivity(rash, hives, angioedema, anaphylaxis).
If one is severely allergic to penicillin, what other drugs are they likely to be allergic too as well?
Cephalosporin, Monobactam, Carbapenem
Which one is the safest to use if if the patient had a mild allergic reaction? Why?
monobactam, since it looks the least like penicillin (it doesn’t have the second ring) and is least likely to trigger IgE compared to the other ones
Structure of penicillin?
all contain Ring A (thiazolidine ring) attached to Ring B (ß-lactam ring)
MoA of penicillin?
bind covalently to Penicillin-binding proteins (PBP’s) at the active site, thereby interfering with the transpeptidase reaction, a reaction that is critical in bacterial cell wall synthesis”bactericidal”
how does resistance develop against penicillin?
1) Inactivation by ß-lactamase
2) Modification of target PBP
3) Impaired penetration of the cell (ex: ∆ porin channel)
4) Presence of a new efflux pump
how does MRSA develop?
Modification of target PBP
What drugs are in the Benzopenicillin class?
Penicillin G
Penicillin V
sensitivity of penicillin G to ß lactamases?
sensitive
How is Penicillin G administered?
parenteral (poor oral bioavailability)
- Procaine suspn (IM); duration 1-2 days
- Benzathine suspn (IV); duration 1-4 wks; great for kids
How is Penicillin V administered?
PO; very stable in stomach acid
Penicillins are effective in treating these bugs
- Gram (+)
- strep. pneumo
- S. pyogenes
- Actinomyces
- GNC
- N. meningitides
- Spirochetes (T. pallidum)
what bugs are resistant to penicillin?
Staph (>85%)
Pneumococcus (10-30%)
bowel anaerobes
gonorrhea (Pen G)
most GNR’s
Contraindications of penicillin?
Pen-allergic patients
Side Effects of penicillins?
1) drug allergy especially rash, anaphylaxis
2) anemia (binds to RBC and induces hemolysis)
3) Seizures following high doses
Drug interactions with penicillins?
- synergy with gentamicin against staph and enterococcus
- probenecid inhibits renal active tubular secretion
What situations would warrant penicillin treatment?
- Streptococcal pharyngitis and skin infections
- Pneumonia
- Meningitis
- Endocarditis - if organism is sensitive
- Dental infection (by microaerophilic streptococcus)
- Syphilis
- Prevent rheumatic fever (GrpA ß hemolytic strep complication)
Drugs in the Aminopenicillins class?
Ampicillin
Amoxicillin
sensitivity of aminopenicillins to ß lactamases?
sensitive (its nearly identical to penicillin)
mechanism of action of aminopenicillins?
binds PBP’s and inhibits the assembly of the bacterial cell wall, bactericidal
How is ampicillin different than amoxicillin?
Ampicillin - PO or IV
Amoxicillin - PO (higher oral bioavailability) - newer version of ampicillin with slightly wider spectrum of action; less likely to cause diarrhea
what bugs are sensitive to aminopenicillins?
extended spectrum of action
- Haemophilus influenza
- E. coli
- Listeria monocytogenes
- Proteus mirabilis
- Salmonella
- Shigella
- Enterococcus
Amp HELPSS to kill enterococci
What bugs are resistant to aminopenicillins?
- most staph
- some pneumococcus (>30%)
- some H. flu
- bowel anaerobes
- some GNRs
SE of aminopenicillins?
- drug allergy especially rash, anaphylaxis
- seizures following high doses
- antibiotic-associated colitis
Contraindications of aminopenicillins?
Pen-allergic patients
drug interactions with aminopenicillins?
- synergy with gentamicin against enterococcus
- probenecid inhibits renal active tubular secretion of ampicillin
- ampicillin may inhibit tubular secretion of MTX
indications for aminopenicillins?
- otitis media
- neonatal sepsis
- Lyme disease (early)
- simple UTI’s (GNRs, such as E. coli, klebsiella, enterobacter, proteus)
- meningitis with sensitive pathogens
- URI
- endocarditis w. sensitive pathogens
What are examples of “semi-synthetic” penicillins?
- Nafcillin
- Dicloxacillin
- Oxacillin
- Methicillin - original
sensitivity of nafcillin to ß lactmases?
more resistant to ß lactamases (have more complex side chains; more stable)
MoA of nafcillin?
binds PBP’s and inhibits the assembly of the bacterial cell wall, bactericidal
There are various types of semi-synthetic penicillins. How would you use them clinically?
nafcillin or oxacillin - IV; serious infections with MSSA
dicloxacillin - PO; less severe infections
bugs sensitive to nafcillin?
Same as penicillin, but narrow spectrum
- S. aureus (except MRSA, resistant due to altered PBP target site)
“use naf for staph”
bugs resistant to nafcillin or within the same class?
- MRSA (usually bc they have a different PBP)
- pneumococcus
- oral/bowel anaerobes
- GNR (most)
contraindications for semi-synthetic pencillins?
Pen-allergic patients
SE of semi-synthetic penicillins (ie nafcillin)?
- drug allergy HSR
- neprotoxic - allergic interstitial nephritis
- Methicillin – highly nephrotoxic (causes allergic interstitial nephritis) and resistant to ß-lactamase; not used anymore
drug interactions with nafcillin?
- synergy with gentamicin against enterococcus
- probenecid inhibits renal active tubular secretion
indications for nafcillin or semi-synthetic pencillins within the same class?
Staph aureus infections, especially if pathogen is sensitive (in skin, soft tissue, bone, lung, endocarditis)
Drugs in the Anti-Pseudomonas class?
- Piperacillin
- Carbenicillin
- Ticarcillin
Piperacillin - sensitivity to ß lactamases?
sensitive
MoA of Piperacillin?
binds PBP’s and inhibits the assembly of the bacterial cell wall, bactericidal
What is one thing that you have to consider when dosing Piperacillin and Carbenicillin?
resistance w. monotherapy; given in combination therapy with gentamycin or tobramycin to decrease resistance
How is Piperacillin and Carbenicillin administered?
- Piperacillin - IV
- Carbenicillin - PO
bugs sensitive to Piperacillin and Carbenicillin?
Same as penicillin, but with extended spectrum
- Pseudomonas
- GNR
bugs resistant to Piperacillin and Carbenicillin?
- GPC
- Anaerobes
- Enterococcus
- pneumococcus
- most S. aureus
- increasing # of resistant pseudomonas and GNRs
contraindications of anti-pseudomonal agents??
Pen-allergic patients
SE of Piperacillin and Carbenicillin?
- drug allergy especially rash, anaphylaxis
- antibiotic-associated colitis
drug interactions of Piperacillin and Carbenicillin?
- synergy with gentamicin against Pseudomonas
- probenecid inhibits renal active tubular secretion of Piperacillin
- Piperacillin may inhibit tubular secretion of MTX
indications for Piperacillin and Carbenicillin?
- Pseudomonas infections (usually given in combination with gentamycin or tobramycin for synergy)
- Carbenicillin – used treat non-life threatning infections (ie UTI) caused by Pseudomonas)
- intra-abdominal infections (mixed GNR, anaerobes, and enterococcus)
- nosocomial pneumonia (because often caused by GNR in the ICU)
What are some ß-lactamase inhibitors that are manufactured with penicillins?
Clavulanic acid, sulbactam, and tazobactam
How do ß-lactamase inhibitors work?
resemble ß lactam molecules and prevents cleavage of ß lactam rings, but have very weak antimicrobial activity themselves
thus they are added to amoxicillin or ampicillin or pipercillin, whose “range” is extended by the inhibitor