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
what are the 4th generation parenteral and oral cephalopsorin drugs?
PARENTERAL
1. cefepime
how are cephalosporins classified?
cephalosporins are classified into generations based on their activity
later generations generally become more effective against Gram (-) bacteria due to an increasing number of polar groups (also become zwitterions)
later generations are often the broadest spectrum and are reserved against penicillin resistant infections to prevent the spread of cephalosporin resistant bacteria
which cephalosporin can cross the blood brain carrier? what’s it used to treat?
Ceftazidime (3rd gen)
it can can cross the blood brain barrier so it’s used to treat meningitis
what are the characteristics of first generation cephalosprins?
they have a stronger antimicrobial action on G+ bacteria than the other generations, but action on G- bacteria is relatively poor
what do first generation cephalosporins not work on?
they are NOT effective against Pseudomonas
what are first generation cephalosporins used to treat?
they are chiefly used in treating infection of the penicillinase-producing aurococcus (S. aureus) and as surgical prophylaxis
most commonly used 1st Gen is Cephalexin
what are the characterisitcs of cefazolin?
parenteral 1st generatio cephalosporin drug
is cleared by glomerular filtration and is highly protein bound
consequently, it has a relatively long plasma half-life (~2hrs)
does not penetrate CNS and can not be used to treat meningitis
what are the characteristics of second generation cephalosporins?
action of this generation on G+ bacteria is the same or a little less than that of the first generation
but their antimicrobial action on G- bacteria is increased
what is Cefotetan used to treat?
parenteral 2nd generation cephalosporin drug
most effective against anaerobes such as B. fragilis
what do 2nd generation cephalosporin drugs not work on?
ineffective against Pseudomonas aeruginosa
what is cefuroxime used for?
oral 2nd generation cephalosporin
it’s the only second-generation drug that crosses the blood-brain barrier well enough to be used for the treatment of meningitis, especially H. influenzae meningitis
Cefuroxime has enhanced activity against H. influenzae and M. catarrhalis respiratory infections, including B-lactamase expressing strains
what are the characteristics of 3rd generation cephalosporins?
the broadest spectrums of all cephalosporins
high activity against G- bacteria
high resistance to β-lactamases
the best penetration into the CSF
what are 3rd generation cephalosporins mainly used for?
they are chiefly used in infections of the urethral or biliary tract with the drug-resistant strains and Pseudomonas
what is ceftazidime used for?
parenteral 3rd generation cephalosporin drug
best activity of all cephalosporins against Pseudomonas (plus aminoglycoside for pseudomonal meningitis)
what is cefoperazone used for?
3rd generation cephalosporin drug
it’s eliminated (70%) in the bile, and is thus very useful in patients with renal failure
what is ceftriaxone used for?
parenteral 3rd generation cephalosporin drug
drug of choice for treatment of gonorrhea
also effective against many other gram - pathogens
cleared by biliary excretion; relatively long plasma t1/2 (8 hours)
what is cefdinir used for?
oral 3rd generation cephalosporin drug
caused by b-lactamase producing organisms
what are the characteristics of cefepime?
parenteral 4th generation cephalosporin drug
stable to hydrolysis by plasmid-encoded B-lactamases
unlike other cephalosporins, poor inducer of chromosomal B-lactamases, and some extended-spectrum plasmid encoded B-lactamases
also relatively resistant to most of these B-lactamases
NOT stable to some extended spectrum b-lactamases (e.g., TEM-3)
what other drug complication would indicate that you shouldn’t use caphalosporin?
there is an approximately 10% incidence of cross-hypersensitivity between penicillins and cephalosporins
cephalosporins are generally too risky for use in patients who have had an anaphylactic episode with a penicillin
what is an adverse effects of cephalosporin?
- nephrotoxicity
first-generation cephalosporins have certain nephrotoxicity
second-generation have slight nephrotoxicity
third and fourth generations have almost no nephrotoxicity
what is an adverse effect of cefotetan?
- delayed blood clotting because of low prothrombin levels in blood
- alcohol intolerance
what are carbapenems?
carbapenems are a potent class of β-lactams which attack a wide range of PBPs, have low toxicity, and are much more resistant to β-lactamases than the penicillins or cephalosporins
what is thienamycin?
carbapenem
one of the most broad spectrum antibiotics ever discovered
it uses import porins unavailable to other β-lactams to enter Gram (-) bacteria
no cross-resistance with other b-lactams, and they are not recognized well by bacterial b-lactamases
how is thienamycin made?
due to its highly unstable nature this drug and its derivatives are created through synthesis, not bacterial fermentation
what do you have to give with thienamycin and why?
due to its rapid degradation by the renal peptidase, it is treated with cilastatin
which carbapenems are better than thienamycin?
modifications of Thienamycin have produced superior carbapenems called Meropenem and Ertapenem
they are not degraded by renal peptidase and do not have the side effects of Imipenem
what is Cilastatin?
Cilastatin inhibits renal dehydropeptidase-1, an enzyme that inactivates imipenem
Cilastatin also helps prevent kidney toxicity of imipenem by blocking its active uptake and accumulation by renal tubule cells
that’s why you give cilastatin with imipenem (thienamycin)
what is the most adverse effect of imipenem-cilastatin?
CNS toxicity
there is decreased consciousness and myoclonic jerking
this may result from cilastatin inhibition of imipenem transport out of the CSF
what is meropenem?
antimicrobial spectrum is broad, like imipenem
but it’s not hydrolyzed by dehydropeptidase-1
so there’s decreased incidence of CNS toxicity compared with imipenem/cilastatin
what is the only clinically useful monobactam?
aztreonam
how does aztreonam work?
it’s a monobactam
while it resembles the other β-lactam antibiotics and targets the PBP of bacteria, its mechanism of action is significantly different
it binds to PBP-3 which is ONLY present in aerobic Gram negative bacteria!!!!
it’s is highly effective in treating Gram (-) bacteria and is resistant to many β-lactamases and and does not induce expression of chromosomal b-lactamases
if chromosomal B-lactamases have been induced by other B-lactams, they will bind aztreonam and prevent it from binding to PBP-3
little risk of cross-allergy with penicillins or cephalosporins (except ceftazidime)
which agents are primarily used as B-lactam substitutes?
- spectinomycin
- vancomycin
- daptomycin
what is spectinomycin?
B-lactam substitue
its sole use is for treatment of penicillin-resistant gonococcal infections or gonococcal infections in penicillin-allergic patients
does not penetrate the CNS
low toxicity: nausea, chills, fever, dizziness
what is vacomycin?
B-lactam substitute
used for treatment of meth.-resistant Staph. aureus (MRSA)
it’s also the backup drug for C. difficile pseudomembranous colitis
but little activity vs Gm- bacilli
what is the MOA of vancomycin?
it’s not a B-lactam!!
Vancomycins bind to the two terminal amino acids of the monomer’s pentapeptide (D-Ala-D-Ala)
this binding prevents the transpeptidase enzymes from forming the peptide cross-links between the rows and layers of peptidoglycan
what are the adverse effects of vancomycin?
- ototoxic = deafness
- nephrotoxic = blood and protein in urine
- thrombophlebitis = clots in bloodstream
- hypotensioni & “red man” syndrome because the drug releases hsitamine
what is daptomycin?
B-lactam substitute
a cyclic lipopeptide antibiotic
inserts in cell membrane and causes rapid depolarization
indicated for skin and skin structure infections
also indicated for Staph. aureus bacteremia and endocarditis
NOT effective for respiratory infections because daptomycin is inactivated by lung surfactant
what are the adverse effects of daptomycin?
significant muscle damage and muscle cell death = rhabdomyolysis
so you need to monitor patients for muscle pain/weakness
there can also be paresthesia at high doses = sensation of tingling, burning, pricking, or numbness of a person’s skin with no apparent long-term physical effect
