Susceptibility of European beta-lactamase-positive and -negative Haemophilus influenzae isolates from the periods 1997/1998 and 2002/2003

J Antimicrob Chemother. 2005 Jul;56(1):133-8. doi: 10.1093/jac/dki167. Epub 2005 May 25.


Aims: To test prospectively the activity of cefixime and comparators against Haemophilus influenzae from Europe and to compare the susceptibilities of isolates from 1997/1998 with isolates from 2002/2003 paying special attention to the epidemiology of amoxicillin resistance.

Methods: MICs of antibiotics were determined using broth microdilution. For beta-lactamase-negative isolates with reduced susceptibility to amoxicillin, the nucleotide sequence of the penicillin-binding domain of PBP3 was determined.

Results: The prevalence of beta-lactamase-positive isolates in certain countries has reached 38%. During the period 1997/1998, 8.8% of the isolates were beta-lactamase-negative and non-susceptible to amoxicillin (BLNAR). During the period 2002/2003, 9.6% of the isolates were BLNAR. The emergence of the BLNAR phenotype of H. influenzae was demonstrated in all countries with a prevalence ranging from 2% to 20%. The penicillin-binding domain of PBP3 from 30 sequenced isolates showed known amino acid substitutions, although no amino acid changes were observed in two BLNAR isolates. Clonal spread of BLNAR strains was limited or absent in our study. Both beta-lactamase-producing and BLNAR strains of H. influenzae were fully susceptible to cefixime. However, neither beta-lactamase-producing nor BLNAR isolates were fully susceptible to the other cephalosporins tested. All isolates were also fully susceptible to levofloxacin, moxifloxacin, azithromycin and telithromycin.

Conclusions: The prevalence of the BLNAR phenotype in Europe is increasing, but no new amino acid substitutions were detected in the penicillin-binding domain of PBP3. Cefixime remains a useful treatment option for respiratory tract infections, including in areas with increasing resistance problems.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Substitution
  • Binding Sites
  • Cefixime / pharmacology*
  • Drug Resistance, Bacterial
  • Haemophilus influenzae / drug effects*
  • Haemophilus influenzae / enzymology
  • Microbial Sensitivity Tests
  • Penicillin-Binding Proteins / chemistry
  • Penicillin-Binding Proteins / metabolism
  • Time Factors
  • beta-Lactamases / analysis*


  • Penicillin-Binding Proteins
  • Cefixime
  • beta-Lactamases