title: Cephalosporin MIC creep among gonococci: time for a pharmacodynamic rethink?
abstract: BACKGROUND
  Gonorrhoea has been among the easiest infections to cure with antibiotics. Nevertheless, emerging resistance has driven repeated treatment shifts. Decreased cephalosporin susceptibility is now being reported. We examined cephalosporin MIC trends for Neisseria gonorrhoeae in the UK and undertook pharmacodynamic analyses to predict efficacy against strains with raised MICs.
  
  
  METHODS
  Neisseria gonorrhoeae isolates were collected annually in a structured surveillance from 26 genitourinary medicine clinics in England and Wales. MICs were determined by agar dilution and confirmed by Etests. Pharmacodynamic modelling was performed for cefixime and ceftriaxone with Monte Carlo simulations.
  
  
  RESULTS
  There was a progressive emergence of small numbers of gonococci with cephalosporin MICs of 0.125-0.25 mg/L; these were not seen before 2005 but, for ceftriaxone and cefixime, respectively, accounted for 0.4% (95% confidence interval 0.2%-1.1%) and 2.8% (1.6%-4.8%) of the 1253 isolates collected in 2008; such MICs are 16-64 times the modal values for the species. Pharmacodynamic analysis was complicated by evidence that cephalosporins need a longer period with the free drug level above MIC than the 7-10 h required for penicillin G; nevertheless, pharmacodynamic analyses predict that failures with the standard 400 mg cefixime po and 250 mg ceftriaxone im regimens become likely around the present MIC maxima.
  
  
  CONCLUSIONS
  Gonococci with ceftriaxone and cefixime MICs of 0.125-0.25 mg/L are accumulating in the UK. These MICs lie on the edge of likely responsiveness to current regimens, which need review. Possible responses include: (i) higher cephalosporin doses; (ii) multidose cephalosporin regimens; (iii) multidrug regimens; (iv) microbiologically directed treatment; or, in the future, (v) drug cycling. The practicalities of these approaches are discussed.
authors.affiliation: Health Protection Agency Centre for Infections, 61 Colindale Avenue, London NW9 5EQ, UK.
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Chisholm
authors.forename: Johan W
authors.initials: JW
authors.lastname: Mouton
authors.forename: David A
authors.initials: DA
authors.lastname: Lewis
authors.forename: Tom
authors.initials: T
authors.lastname: Nichols
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Ison
authors.forename: David M
authors.initials: DM
authors.lastname: Livermore
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D002511:Cephalosporins / Q000494:pharmacology*; D004739:England; D005260:Female; D006069:Gonorrhea / Q000382:microbiology*; D006801:Humans; D008297:Male; D008826:Microbial Sensitivity Tests; D009344:Neisseria gonorrhoeae / Q000187:drug effects* / Q000302:isolation & purification; D013997:Time Factors; D014852:Wales
chemical_list: D000900:Anti-Bacterial Agents; D002511:Cephalosporins