ICL 2.28: Antibiotics III Flashcards Preview

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Flashcards in ICL 2.28: Antibiotics III Deck (63)
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1
Q

what do β-lactamases do?

A

these enzymes hydrolyze the β-lactam ring, deactivating the drug, but are not covalently bound to the drug as PBPs are

2
Q

where are β-lactamases found?

A

they are especially prevalent in Gram (-) bacteria

3
Q

how many classes of β-lactamases are there? how do they work?

A

A,C,D = catalyze the reaction using a serine residue

B class = uses metallo- β-lactamases to catalyze the reaction using zinc

4
Q

what two categories of β-lactamases are there?

A
  1. chromosomal borne

expression of chromosomal b-lactamases can be induced by β-lactam antibiotics

  1. plasmid borne

plasmids bearing β-lactamases can be transmitted across bacterial species

5
Q

what is the most commonly encountered β-lactamase in gram - bacteria?

A

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

6
Q

what are the classes of β-lactamases?

A
  1. penicillinases
  2. cephalosporinases/carbapenemases
  3. extended spectrum β-lactamase
7
Q

what are penicillinases?

A

β-lactamase that only hydrolyze β-lactam ring in penicillins

8
Q

what are cephalosporinases/carbapenemases?

A

B-lactamases that preferentially cleave these β-lactams

9
Q

what are extended spectrum β-lactamases?

A

β-lactamases that cleave penicillins, cephalosporins, and sometimes also carbapenems

10
Q

what are the 3 β-lactamases inhibitor drugs available?

A
  1. clavulanate
  2. sulbactam
  3. tazobactam

these are the 3 currently clinically available β-lactamases inhibitors which are combined with β-lactam antibiotics

11
Q

what do β-lactamases inhibitors do?

A

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

12
Q

what is Unasyn?

A

β-Lactam/inhibitor combination:

ampicillin + sulbactam

ampicillin is an aminopenicillin

13
Q

what is augmentin?

A

β-Lactam/inhibitor combination:

amoxicillin + clavulanate

amoxicillin is an aminopenicillin

14
Q

what is zosyn?

A

β-Lactam/inhibitor combination:

piperacillin + tazobactam

piperacillin is a ureidopenicillin extended-spectrum penicillin

15
Q

what is timentin?

A

β-Lactam/inhibitor combination:

ticarcillin + clavulanate

ticarcillin is carboxypenicillin extended-spectrum penicillin

16
Q

how do β-Lactam/inhibitor combinations work?

A

the companion penicillin, not the β-lactamase inhibitor, determines the antibacterial spectrum of the combination

17
Q

what is the structure of cephalosporins?

A

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

18
Q

structure of cephalosporins

A

slide 15

19
Q

what happens when you make substitutions at cephalosporin ring position 7?

A

substitutions at cephalosporin ring position 7 affect spectrum and stability to β-lactamases

20
Q

what happens when you make substitutions at cephalosporin ring position 3?

A

substitutions at ring position 3 influence the pharmacokinetic profile and toxicity

21
Q

what does an additional CD3O- attached to ring position 7 do to cephalosporins?

A

cephamycins that have an additional CH3O- attached to ring position 7

they are even more resistant to β-lactamases

22
Q

what is the mechanism behind cephalosporins?

A

the acetoxy group (or other R group) will leave when the drug acylates the PBP

23
Q

what are the 1st generation parenteral and oral cephalopsorin drugs?

A

PARENTERAL

  1. cefazolin
  2. cephalothin

ORAL
1. cephalexin

24
Q

what are the 2nd generation parenteral and oral cephalopsorin drugs?

A

PERENTERAL
1. cefotetan

ORAL
1. cefprozil

  1. cefuroxime-axetil
25
Q

what are the 3rd generation parenteral and oral cephalopsorin drugs?

A

PARENTERAL
1. cefotaxime

  1. ceftazidime
  2. ceftriaxone

ORAL
1. cefdinir

26
Q

what are the 4th generation parenteral and oral cephalopsorin drugs?

A

PARENTERAL

1. cefepime

27
Q

how are cephalosporins classified?

A

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

28
Q

which cephalosporin can cross the blood brain carrier? what’s it used to treat?

A

Ceftazidime (3rd gen)

it can can cross the blood brain barrier so it’s used to treat meningitis

29
Q

what are the characteristics of first generation cephalosprins?

A

they have a stronger antimicrobial action on G+ bacteria than the other generations, but action on G- bacteria is relatively poor

30
Q

what do first generation cephalosporins not work on?

A

they are NOT effective against Pseudomonas

31
Q

what are first generation cephalosporins used to treat?

A

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

32
Q

what are the characterisitcs of cefazolin?

A

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

33
Q

what are the characteristics of second generation cephalosporins?

A

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

34
Q

what is Cefotetan used to treat?

A

parenteral 2nd generation cephalosporin drug

most effective against anaerobes such as B. fragilis

35
Q

what do 2nd generation cephalosporin drugs not work on?

A

ineffective against Pseudomonas aeruginosa

36
Q

what is cefuroxime used for?

A

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

37
Q

what are the characteristics of 3rd generation cephalosporins?

A

the broadest spectrums of all cephalosporins

high activity against G- bacteria

high resistance to β-lactamases

the best penetration into the CSF

38
Q

what are 3rd generation cephalosporins mainly used for?

A

they are chiefly used in infections of the urethral or biliary tract with the drug-resistant strains and Pseudomonas

39
Q

what is ceftazidime used for?

A

parenteral 3rd generation cephalosporin drug

best activity of all cephalosporins against Pseudomonas (plus aminoglycoside for pseudomonal meningitis)

40
Q

what is cefoperazone used for?

A

3rd generation cephalosporin drug

it’s eliminated (70%) in the bile, and is thus very useful in patients with renal failure

41
Q

what is ceftriaxone used for?

A

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)

42
Q

what is cefdinir used for?

A

oral 3rd generation cephalosporin drug

caused by b-lactamase producing organisms

43
Q

what are the characteristics of cefepime?

A

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)

44
Q

what other drug complication would indicate that you shouldn’t use caphalosporin?

A

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

45
Q

what is an adverse effects of cephalosporin?

A
  1. nephrotoxicity

first-generation cephalosporins have certain nephrotoxicity

second-generation have slight nephrotoxicity

third and fourth generations have almost no nephrotoxicity

46
Q

what is an adverse effect of cefotetan?

A
  1. delayed blood clotting because of low prothrombin levels in blood
  2. alcohol intolerance
47
Q

what are carbapenems?

A

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

48
Q

what is thienamycin?

A

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

49
Q

how is thienamycin made?

A

due to its highly unstable nature this drug and its derivatives are created through synthesis, not bacterial fermentation

50
Q

what do you have to give with thienamycin and why?

A

due to its rapid degradation by the renal peptidase, it is treated with cilastatin

51
Q

which carbapenems are better than thienamycin?

A

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

52
Q

what is Cilastatin?

A

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)

53
Q

what is the most adverse effect of imipenem-cilastatin?

A

CNS toxicity

there is decreased consciousness and myoclonic jerking

this may result from cilastatin inhibition of imipenem transport out of the CSF

54
Q

what is meropenem?

A

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

55
Q

what is the only clinically useful monobactam?

A

aztreonam

56
Q

how does aztreonam work?

A

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)

57
Q

which agents are primarily used as B-lactam substitutes?

A
  1. spectinomycin
  2. vancomycin
  3. daptomycin
58
Q

what is spectinomycin?

A

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

59
Q

what is vacomycin?

A

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

60
Q

what is the MOA of vancomycin?

A

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

61
Q

what are the adverse effects of vancomycin?

A
  1. ototoxic = deafness
  2. nephrotoxic = blood and protein in urine
  3. thrombophlebitis = clots in bloodstream
  4. hypotensioni & “red man” syndrome because the drug releases hsitamine
62
Q

what is daptomycin?

A

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

63
Q

what are the adverse effects of daptomycin?

A

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