Term
| What are 3 generic structural features of cephalosporins? (How does each compare to penicillin?) |
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Definition
1. B-lactam ring (same as penicillin)
2. Six-membered ring containing sulfur fused to B-lactam ring (vs. penicillin's 5-membered thioazole ring)
3. Two variable R-groups (penicillins have one)
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Term
| Are cephalosporins bactericidal or bacteriostatic? |
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Definition
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Term
| How do cephalosporins work? |
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Definition
Like all B-lactams, they inhibit transpeptidase, a PBP that cross-links peptidoglycans in the cell wall of Gram+ bacteria. Specifically, they mimic the structure of dimerized alanine, which transpeptidase links to a lysine of a neighboring peptidoglycan. Once the bacterial cell wall is compromised, an autolytic program is activates and the bacterium lyses.
Note: the penultimate alanine is linked to the neighboring lysine; the last alanine falls off.
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Term
| What are three mechanisms of resistance to cephalosporins? Which are most clinically significant? |
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Definition
1. β-lactamases cleave the B-lactam ring (MOST clinically important)
2. Mutant PBPs have lowered affinity for cephalosporin (also important)
3. Efflux (pumping out) of drug from target cell (not so important)
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Term
| How are cephalosporins administered? |
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Definition
1st, 2nd, and 3rd generation: oral, IM, and IV
4th generation: IV only.
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Term
| Cefoxtaxime has a shorter half-life and lower max concentration in the blood than ceftraixone, but a higher max concentration in the CSF (both are 3rd gen). How is the possible? |
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Definition
Half-life in blood is not the same as half-life in CSF; ceftriaxone has a longer half-life in CSF than cefotaxime. |
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Term
| Why wouldn't you use 1st or 2nd generation cephalosporins to treat meningitis? |
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Definition
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Term
| How are cephalosporins metabolized/excreted? |
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Definition
Minimal metabolism. Cephalosporins are mostly excreted renally. Some are eliminated hepatically (preferable for patients with renal insufficiency). |
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Term
What are advantages of 1st generation cephalosporins?
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Definition
Good activity against Gram+ bacteria (only moderate against Gram-). |
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Term
What are clinical uses of 1st generation cephalosporins?
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Definition
Uncomplicated streptococcal and staphylococcal infection. |
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Term
What are advantages of 2nd generation cephalosporins?
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Definition
Increased activity against Gram- organisms relative to 1st generation. |
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Term
| What are clinical uses of 2nd generation cephalosporins? |
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Definition
Gram+ organisms (not as good as 1st gen)
Some Gram- organisms: E. Coli, Klebsiella, Proteus
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Term
| What are advantages of 3rd generation cephalosporins? (Ceftriaxone) |
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Definition
1. Excellent activity against Gram- organisms. (Not so good for Gram+.)
2. More resistant to B-lactamases (vs. 1st and 2nd gen)
Note: B-lactamase is still the most clinically important mechanism of resistance against 3rd generation cephalosporins)
3. Therapeutic distribution to CSF (vs. 1st and 2nd gen)
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Term
| What are clinical uses of 3rd generation cephalosporins? |
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Definition
S. pneumoniae (Gram+, but B-lactamase makes it resistant to 1st/2nd generation)
Nisseria (bacterial meningitis and gonorrhea)
P. aeruginosa
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Term
What are advantages of 4th generation cephalosporins?
(Cefapime)
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Definition
1. Broad spectrum: Good activity against both Gram+ and Gram-
2. More resistant to B-lactamases (vs. 1st and 2nd gen)
Note: B-lactamase is still the most clinically important mechanism of resistance against 3rd generation cephalosporins)
3. Improved penetration in Gram- bacteria due to positive charge
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Term
What are clinical uses of 4th generation cephalosporins?
(Cefapime)
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Definition
P. aeruginosa
Neutropenic fever
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Term
| Cephalosporins follow a sort of 'spectrum' through generations 1-3. Describe this spectrum of activity and resistance. |
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Definition
1st generation: Good Gram+ activity (at expense of Gram- activity) and high susceptibility to B-lactamase.
2nd generation: Middle ground activity; Susceptible to B-lactamase.
3rd generation: Good Gram- activity (at expense of Gram positive activity) and high B-lactamase resistance
*4th generation has it all*
[image]
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Term
| Only some Gram- bacteria sensitive to B-lactams. What are 3 factors that influence Gram- sensitivity to penicillins or cephalosporins? |
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Definition
Gram- sensitivity depends upon:
1. Ability of drug to penetrate cell wall
2. Drug sensitivity to B-lactamases, which often surround peptidoglycans in cell wall
3. Affinity for target enzyme (PBP)
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Term
| What are some adverse effects of cephalosporins? |
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Definition
1. Related to route of administration (GI upset for oral, injection site pain for IM, phlebitis for IV)
2. Kidney damage at high doses for patients with pre-existing renal disease, or if given in conjunction with other nephrotoxic drugs
3. Hypersensitivity (rash, anaphylaxis)
Note: 5-10% of patients with anaphylactic reaction to penicillin will also have anaphylactic reaction to cephalosporins.
*4. Cefotetan (methyltiotetrazole ring): causes bleeding disorders (interferes with vit K-dependent clotting factors) and disulfiram-like alcohol toxicity (interferes with alcohol metabolism)
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Term
| If a patient has an anaphylactic response to penicillin, can we treat with a cephalosporin? |
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Definition
NO!!!! 5-10% of these patients will also have an anaphylactic response to cephalosporins. |
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