Why do EUCAST have no systemic breakpoints for Enterobacteriaceae with oral cephalosporins?

There have been multiple questions from clinicians, particularly those working in orthopaedics, who have successfully used oral cephalosporins for prophylaxis and to treat Enterobacteriaceae infections for many years. They ask what has changed and why these agents are now considered inappropriate. In EUCAST rationale documents it is stated that Enterobacteriaceae are inappropriate targets in sites other than uncomplicated urinary tract infection, but there is no further explanation. In early EUCAST discussions oral cephalosporins were originally considered inappropriate for treatment of infections in other sites than the urinary tract infection for several reasons: 1. Comparison of free drug pharmacokinetics with MICs alone indicates that inadequate concentrations are achieved for most agents and are borderline at best (see table). 2. The relevant pharmacodynamic relationship indicative of activity of cephalosporins is T>MIC and the target %fT>MIC is 40-50%. Approximate calculations based on common dosages indicate that activity is inadequate for all agents (see table). It should be emphasized that the figures in the table are based on pharmacokinetic parameter values for the mean of the population. Monte Carlo simulations would show that the %fT>MIC values are even less than those in the table for half the population treated. 3. Evidence of successful clinical use is anecdotal and may be unrelated to specific Enterobacteriaceae isolates, which are rare in orthopaedic infection and often in mixtures 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 for Enterobacteriaceae, EUCAST would be happy to review breakpoints. With regards to prophylaxis, there are no pharmacodynamic correlates but it is conventional to use agents that would be active against the relevant target pathogens in treatment.

EUCASTbreakpointsfororalcephalosporins,16February2012

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Pk and Pd data for oral cephalosporins

Agent Cefadroxil Cefalexin Cefixime Cefpodoxime Ceftibuten Cefuroxime axetil Common dose (mg) 500 x 2 500 x 2 400 x 1 200 x 2 400 x 1 500 x 2 Cmax (mg/L) 16-18 10.0-20.7 2.5 2.1-2.6 15-17 5-9 Protein binding (%) 18-20 10-20 70 21-33 63 30-50 T (h) 1.0-1.9 0.5-1 3.0-4.0 2.1-2.4 2.3 1.1-1.4 ECOFF E. coli (mg/L) 16 16 1 2 1 8 Approx. % fT>MIC 0 0 7 0 37 0

Common doses (dose x number of doses per day), Cmax, protein binding and T are from Antimicrobial 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. The ECOFF is essentially the highest MIC for organisms without a resistance mechanism.

EUCASTbreakpointsfororalcephalosporins,16February2012

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