Core pharmacology

Class Group

ANTIBIOTIC:
CEPHALOSPORIN

Legacy Cicm Level

Level 1

Introduction

3rd Generation Cephalosporin

Indications Uses

used for the
treatment of infections caused by susceptible Gram-positive and Gram-negative bacteria, including infections of the abdomen, bones and joints, CNS, skin and skin
structures, genito-urinary tract (including gonorrhoea), respiratory tract, gynaecological infections, Lyme disease.

Presentation

White powder for IV-
yellowish solution.
Can precipitate with Ca2+ containing solutions

Mechanism of action

Beta lactam ring binds to multiple penicillin binding proteins (carboxy/endo/ transpeptidase) and
prevents crosslinking of bacterial peptidoglycan
inhibits cell wall synthesis
BROADER SPECTRUM

Bacteria eventually lyse due to ongoing activity of cell wall autolytic enzymes (autolysins and murein hydrolases) while cell wall assembly is arrested

Configuration: Stability against Betalactamases

Onset Peak Duration

1g daily (2g BD for meningitis)

Antimicrobial Spectrum

Bacteriocidal

Active against:
- GP cocci (including pen resistant pneumococcus), sensitive staph
- Extended G-ve cover (aerobes)- enterobacter resistance is rapid
- Inferior anaerobe cover compared to second generation

* ESCAPPMs can induce resistance so treatment failures can occur

Resistance Mechanism

cephalosporinases hydrolyse β-lactam rings.
PBP modification.
Enterobacter: Change in porins – Impermeable.

Adverse Effects Toxicity

highly protein bound and is able to displace bilirubin from albumin binding sites,
causing bilirubin; should be avoided in jaundiced neonates.
Pseudolithiasis or Biliary sludge due to a precipitate of Calcium-ceftriaxone seen occasionally.

Absorption

Well absorbed when given IM
IV/IM
Dose is 1-2g daily or BD
On/dur serum peak in 2-3hrs (IM)

Distribution

Crosses the BBB, improved with inflam

Protein binding

85 – 95% PB
Highly protein bound, non-linear dose response

Volume of distribution

small Vd 0.5L/kg

Metabolism

minimally hepatic

Excretion

excreted mostly unchanged in urine and
bile

Half-life

half life 8 hours enabling daily dosing

Special Points

PK changes in Critical Illness:
----------------

D:
Vd ↑’s in critical illness
loading dose (LD = Vd x desired concentration) may increase
Beta lactams are hydrophobic - Vd less effected than hydrophilic drugs

Protien binding - albumin is generally reduced in critical illness → ↑ Ceftriaxone plasma conc → ↓ dose

M:
minimal change due to lack of metabolism

E:
excreted in urine mostly unchanged → renal impairment will significantly increase elimination half times (dose should not exceed 2gm/day)

Protein binding of ceftriaxone reduces CRRT clearance (nil dose adjustment required)