Cephalosporins

Question 1

Structure

Answer 1

B-lactam ring + 6-membered dihydrothiazine ring

Greater stability against B-lactamase

Cephamycin contain methoxy at C-7–>activity for anaerobes

Question 2

MOA

Answer 2

Inhibit cell wall synthesis by inhibiting PBP located in bacterial cell wall (transpeptidase)

Except Cefiderocol–>siderophore (trojan horse)

Bactericidal–> time-dependent (T>MIC)

Question 3

Spectrum of Activity

Answer 3

1st generation: Most active against Gram (+) aerobes + good activity vs Gram (-) aerobes

1st–>2nd–>3rd–>4th
Lose Gram (+) activity, increase Gram (-) activity
Increased B-lactamase resistance (stability)

Question 4

Pharmacokinetics

Answer 4

Absorption: degraded by gastric acid
- lower concentrations of PO vc IV–>PO only for mild-moderate infections
- food decreases absorption of cefaclor and lorcarbef

Distribution: widely distributed into tissues and fluids
- CSF concentrations achieved ONLY with parenteral Cefuroxime with inflamed meninges and parenteral 3rd/4th generation

Elimination: eliminated unchanged in the kidneys
-dose adjustments in renal insufficiency
-Ceftriaxone (biliary) and Cefoperazone (liver): NO DOSE ADJUSTMENTS

T1/2 < 2 hours EXCEPT CEFTRIAXONE t1/2=8 hours

Question 5

Production of B-lactamase enzymes

Answer 5

B-lactamase: hydrolyzes B-lactam ring inactivating antibiotics

Production:
Gram (+): Penicillin-resistant Staphylococcus aureus
Gram (-): H. influenza, Moraxella, Neisseria, E. coli, klebsiella, Enterobacter
Gram (-) anaerobes: Bacteroides fragilis

B-lactamase Resistant:
3rd/4th generation cephalosporins
Cefiderocol (ESBL, AMPC, Carbapenemases)
Cephalosporin-B lactamase inhibitor combination

B-lactamase inducer:
Ceftazidime + Enterobacter

Question 6

PBP alterations

Answer 6

Leads to decreased binding affinity

Penicillin-resistant Streptococcus pneumoniae (PRSP)
-Chromosomally mediated mutation that codes for PBP
-Except Cefiderocol and Combos

Methicillin-resistant Staphylococcus aureus (MRSA)
-PBP–>PBP2A
-Except Ceftaroline

Question 7

Decreased penetration due to alterations in outer membrane porins

Question 8

1st generation

Answer 8

Best activity against Gram (+)

Cefazolin: parenteral
Cephalexin: oral

Spectrum: MSSA–> DOC
Little activity against gram (-): PEK

Question 9

2nd generation–>cephamycin, carbacephems

Answer 9

Slightly less activity against Gram (+) aerobes + more Gram (-) aerobes

Cefuroxime, Cefprozil, Cefoxitin

Spectrum:
-MSSA
-HENPEK
-BDA: ONLY cephamycins (cefoxitin, cefotetan, cefmetazole)

Question 10

3rd generation

Answer 10

Less activity against Gram (+) aerobes + greater for Gram (-) aerobes

Ceftriaxone and Cefotaxime retain best activity against Gram (+)

Ceftriaxone
Ceftazidime
Cefpodoxime

Spectrum:
- PRSP–> ONLY Ceftriaxone and cefotaxime
-MSSA
-Pseudomonas aeruginosa–> ONLY ceftazidime and cefoperazone

Question 11

4th generation

Answer 11

Weak inducer of AmpC, stable against B-lactamase

Cefepime

Spectrum:
-PRSP
-MSSA
-Pseudomonas aeruginosa

Question 12

5th generation

Answer 12

MRSA activity

Ceftaroline

Spectrum:
-PRSP
-MSSA
-MRSA–> 4th line

Question 13

Miscellaneous

Answer 13

Active against most resistant enzymes

Cefiderocol

Spectrum:
-Pseudomonas aeruginosa
- AmpC, KPC, NDM, VIM, OXA-48, some ESBL

Question 14

Cephalosporin + B-lactamase inhibitor combination

Answer 14

Stability for B-lactamase

Ceftolozane-Tazobactam
Ceftazidime-Avibactam

Spectrum:
-Pseudomonas aeruginosa
- Zerbaxa (more active): AmpC, some ESBL
-Avycaz AmpC, some ESBL, KPC, OXA

Question 15

Adverse Effects

Answer 15

• Hypersensitivity:
  Cross-reactivity is estimated to be 1 to 5%; first generation cephalosporins (except cefazolin because it has a unique R1 side chain) demonstrate the highest risk (up to 10%)
• Hypoprothrombinemia
• Disulfiram reaction (avoid alcohol)
  Cephalorsporins with the NMTT side chain are cefamandole, cefotetan, cefmetazole, cefoperazone, and moxalactam
• Hematologic: leukopenia, neutropenia, thrombocytopenia
  primarly with prolonged therapy > 2 weeks

GI:
Biliary sludging: ceftriaxone
Pseudomembranous colitis