ICL 2.28: Antibiotics III Flashcards
what do β-lactamases do?
these enzymes hydrolyze the β-lactam ring, deactivating the drug, but are not covalently bound to the drug as PBPs are
where are β-lactamases found?
they are especially prevalent in Gram (-) bacteria
how many classes of β-lactamases are there? how do they work?
A,C,D = catalyze the reaction using a serine residue
B class = uses metallo- β-lactamases to catalyze the reaction using zinc
what two categories of β-lactamases are there?
- chromosomal borne
expression of chromosomal b-lactamases can be induced by β-lactam antibiotics
- plasmid borne
plasmids bearing β-lactamases can be transmitted across bacterial species
what is the most commonly encountered β-lactamase in gram - bacteria?
TEM-1
it’s a plasmid-mediated β-lactamase
up to 90% of ampicillin resistance in E. coli is due to the production of TEM-1
what are the classes of β-lactamases?
- penicillinases
- cephalosporinases/carbapenemases
- extended spectrum β-lactamase
what are penicillinases?
β-lactamase that only hydrolyze β-lactam ring in penicillins
what are cephalosporinases/carbapenemases?
B-lactamases that preferentially cleave these β-lactams
what are extended spectrum β-lactamases?
β-lactamases that cleave penicillins, cephalosporins, and sometimes also carbapenems
what are the 3 β-lactamases inhibitor drugs available?
- clavulanate
- sulbactam
- tazobactam
these are the 3 currently clinically available β-lactamases inhibitors which are combined with β-lactam antibiotics
what do β-lactamases inhibitors do?
they bind irreversibly to β-lactamases but do not have good activity against PBPs
their rings are modified to break open after acylating the β-lactamase enzyme
so they inactivate bacterial β-lactamases and are used to enhance the antibacterial actions of β-lactamases antibiotics
but they only have weak antibacterial actions…
they inhibit many but not all bacterial β-lactamases and can protect hydrolyzable penicillins from inactivation by the enzymes
they are only available in fixed combination with specific penicillins
what is Unasyn?
β-Lactam/inhibitor combination:
ampicillin + sulbactam
ampicillin is an aminopenicillin
what is augmentin?
β-Lactam/inhibitor combination:
amoxicillin + clavulanate
amoxicillin is an aminopenicillin
what is zosyn?
β-Lactam/inhibitor combination:
piperacillin + tazobactam
piperacillin is a ureidopenicillin extended-spectrum penicillin
what is timentin?
β-Lactam/inhibitor combination:
ticarcillin + clavulanate
ticarcillin is carboxypenicillin extended-spectrum penicillin
how do β-Lactam/inhibitor combinations work?
the companion penicillin, not the β-lactamase inhibitor, determines the antibacterial spectrum of the combination
what is the structure of cephalosporins?
cephalosporins are similar to penicillins but have a 6 member dihydrothiazine ring instead of a 5 member thiazolidine ring
unlike penicillin, cephalosporins have two side chains which can be easily modified
cephalosporins are also more difficult for β-lactamases to hydrolyze
structure of cephalosporins
slide 15
what happens when you make substitutions at cephalosporin ring position 7?
substitutions at cephalosporin ring position 7 affect spectrum and stability to β-lactamases
what happens when you make substitutions at cephalosporin ring position 3?
substitutions at ring position 3 influence the pharmacokinetic profile and toxicity
what does an additional CD3O- attached to ring position 7 do to cephalosporins?
cephamycins that have an additional CH3O- attached to ring position 7
they are even more resistant to β-lactamases
what is the mechanism behind cephalosporins?
the acetoxy group (or other R group) will leave when the drug acylates the PBP
what are the 1st generation parenteral and oral cephalopsorin drugs?
PARENTERAL
- cefazolin
- cephalothin
ORAL
1. cephalexin
what are the 2nd generation parenteral and oral cephalopsorin drugs?
PERENTERAL
1. cefotetan
ORAL
1. cefprozil
- cefuroxime-axetil
what are the 3rd generation parenteral and oral cephalopsorin drugs?
PARENTERAL
1. cefotaxime
- ceftazidime
- ceftriaxone
ORAL
1. cefdinir