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EUCAST breakpoints for oral cephalosporins, 16 February 2012 Page 1 of 2

Why do EUCAST have no systemic breakpoints forEnterobacteriaceae with oral cephalosporins?

There have been multiple questions from clinicians, particularly those working inorthopaedics, who have successfully used oral cephalosporins for prophylaxis andto treat Enterobacteriaceae infections for many years. They ask what has changedand why these agents are now considered inappropriate.

In EUCAST rationale documents it is stated that Enterobacteriaceae areinappropriate targets in sites other than uncomplicated urinary tract infection, but

there is no further explanation. In early EUCAST discussions oral cephalosporinswere originally considered inappropriate for treatment of infections in other sites thanthe urinary tract infection for several reasons:

1. Comparison of free drug pharmacokinetics with MICs alone indicates thatinadequate concentrations are achieved for most agents and are borderline at best(see table).

2. The relevant pharmacodynamic relationship indicative of activity of cephalosporinsis T>MIC and the target %fT>MIC is 40-50%. Approximate calculations based oncommon dosages indicate that activity is inadequate for all agents (see table). Itshould be emphasized that the figures in the table are based on pharmacokineticparameter values for the mean of the population. Monte Carlo simulations wouldshow that the %fT>MIC values are even less than those in the table for half thepopulation treated.

3. Evidence of successful clinical use is anecdotal and may be unrelated to specificEnterobacteriaceae isolates, which are rare in orthopaedic infection and often inmixtures of organisms both from bone and other sites.

4. Oral cephalosporins have mostly been used as follow-up therapy after

successful parenteral treatment in hospital.

If there is evidence for oral cephalosporins relating MIC to outcome forEnterobacteriaceae, EUCAST would be happy to review breakpoints.

With regards to prophylaxis, there are no pharmacodynamic correlates but it isconventional to use agents that would be active against the relevant targetpathogens in treatment.

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EUCAST breakpoints for oral cephalosporins, 16 February 2012 Page 2 of 2

Pk and Pd data for oral cephalosporins

AgentCommondose (mg)

Cmax(mg/L)

Proteinbinding

(%)T(h)

ECOFFE. coli(mg/L)

Approx. %fT>MIC

Cefadroxil 500 x 2 16-18 18-20 1.0-1.9 16 0

Cefalexin 500 x 2 10.0-20.7 10-20 0.5-1 16 0

Cefixime 400 x 1 2.5 70 3.0-4.0 1 7

Cefpodoxime 200 x 2 2.1-2.6 21-33 2.1-2.4 2 0

Ceftibuten 400 x 1 15-17 63 2.3 1 37

Cefuroximeaxetil

500 x 2 5-9 30-50 1.1-1.4 8 0

Common doses (dose x number of doses per day), Cmax, protein binding and T are fromAntimicrobial Agents (2005, Ed Bryskier) and Antibiotic and Chemotherapy (2010, Ed. Finch et al).

MICs are based on the epidemiological cut-off values (ECOFFs) from the EUCAST MIC website. TheECOFF is essentially the highest MIC for organisms without a resistance mechanism.