Broad-spectrum cephalosporins: cefotaxime and ceftriaxone
Cefotaxime and ceftriaxone are broad-spectrum antibiotics with activity against the majority of community-associated Enterobacterales (enteric gram-negative bacilli); they are not active against Pseudomonas aeruginosa. Cefotaxime and ceftriaxone are less active against staphylococci than cefazolin and cefalotin, and are inactive against methicillin-resistant Staphylococcus aureus (MRSA). Although cefotaxime has better intrinsic activity against staphylococci than ceftriaxone, the antistaphylococcal activity of both drugs is dose dependent. Cefotaxime and ceftriaxone do not have clinically useful activity against enterococci.
Some gram-negative bacteria (eg Citrobacter and Enterobacter species) have innate chromosomal resistance in the form of cephalosporinase enzymes. These enzymes may be constitutively expressed (always produced), or be inducible (increased production on exposure), in which case resistance can develop during treatment. Plasmid-mediated extended-spectrum beta-lactamase enzymes (ESBLs) acquired by some gram-negative bacteria (commonly strains of Escherichia coli or Klebsiella pneumoniae) also inactivate cefotaxime and ceftriaxone.
Cefotaxime and ceftriaxone are effective for meningitis because (in the presence of meningeal inflammation) they achieve therapeutic concentrations in the cerebrospinal fluid.
A variety of ceftriaxone doses are recommended in these guidelines depending on potential pathogens, the source of infection and whether the patient is critically ill. A dose of 2 g daily is recommended for most infections, including some for which a 1 g daily dose was previously recommended. Exceptions for which a 1 g daily dose is used include:
- urinary tract infections not associated with sepsis, because ceftriaxone is concentrated in the urinary tract
- infections caused by Haemophilus influenzae, because the concentrations achieved with a 1 g daily dose exceed the H. influenzae minimum inhibitory concentration (MIC) (more than 90% of isolates have an MIC below 0.125 mg/L). However, when empirically treating infections for which Streptococcus pneumoniae is also a potential pathogen (eg pneumonia), a 2 g daily dose is required because S. pneumoniae MICs are rising.
Ceftriaxone pharmacokinetics may be impacted in patients with hypalbuminaemia or in critically unwell patients with augmented renal clearance1. While clinical data are lacking, some pharmacokinetic studies suggest that twice daily dosing (eg 1 g twice daily for adults) may be preferred to daily dosing (with either 1 or 2 g doses) in these patients.
In these guidelines, ceftriaxone is usually preferred to cefotaxime in adults because ceftriaxone requires less frequent dosing. If S. aureus is a likely pathogen, cefotaxime may be recommended as an alternative to ceftriaxone because it has superior intrinsic activity against staphylococci.
There is a risk of harm associated with using ceftriaxone in neonates – it is highly protein bound and can displace bilirubin from albumin, increasing the risk of bilirubin encephalopathy. If using ceftriaxone in neonates, this potential harm must be balanced against the potential benefit of therapy.
To avoid precipitation, do not mix ceftriaxone with calcium-containing intravenous solutions. Ceftriaxone is contraindicated in neonates (up to 28 days old) who are receiving intravenous calcium-containing solutions because this has caused fatalities. In other age groups, ceftriaxone must not be administered simultaneously with intravenous calcium-containing preparations, but can be administered sequentially, provided the infusion lines are thoroughly flushed with a compatible fluid between infusions.