High prevalence of type b beta-lactamase-non-producing ampicillin-resistant Haemophilus influenzae in meningitis: the situation in Japan where Hib vaccine has not been introduced

J Antimicrob Chemother. 2006 Jun;57(6):1077-82. doi: 10.1093/jac/dkl142. Epub 2006 Apr 14.


Objectives: To study yearly changes in resistance and to identify ftsI mutations in beta-lactamase-non-producing ampicillin-resistant (BLNAR) and TEM-1 beta-lactamase-producing amoxicillin/clavulanic acid-resistant (BLPACR) isolates of Haemophilus influenzae from patients with meningitis.

Methods: Between January 2000 and December 2004, we received 621 isolates of H. influenzae from 285 member institutions of the Nationwide Surveillance Study Group for Bacterial Meningitis. All isolates were analysed by PCR to identify resistance genes and tested for susceptibility to beta-lactams. The ftsI gene was sequenced in all BLNAR and BLPACR isolates.

Results: All but four isolates were of serotype b. The isolates could be divided into six classes, namely beta-lactamase-non-producing ampicillin-susceptible (25.0%), TEM-1 beta-lactamase-producing ampicillin-resistant (11.0%), beta-lactamase-non-producing low-level ampicillin-resistant with N526K or R517H substitution in the ftsI gene (30.4%), BLNAR with an S385T substitution together with either N526K or R517H substitution in ftsI (22.2%), BLPACR-I with either a N526K or R517H substitution in ftsI (9.5%) and BLPACR-II with an S385T substitution together with either a N526K or R517H substitution in ftsI (1.9%). The prevalence of BLNAR has increased rapidly, from 5.8% in 2000 to 34.5% in 2004. All BLNAR and BLPACR-II strains were classified into nine subgroups on the basis of substitution patterns in the ftsI gene. The MICs of cephalosporin antibiotics for H. influenzae transformants into which the ftsI genes from BLNAR strains of each of the nine subgroups were introduced increased to varying degrees depending on the mutations.

Conclusions: The results suggest that introduction of H. influenzae type b (Hib) vaccination into infants and children is necessary for the prevention of severe Hib infections in Japan.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Substitution
  • Ampicillin Resistance / genetics*
  • Anti-Bacterial Agents / pharmacology
  • Child, Preschool
  • DNA, Bacterial / analysis
  • DNA, Bacterial / chemistry
  • DNA, Bacterial / genetics
  • Gene Transfer, Horizontal
  • Genes, Bacterial
  • Haemophilus influenzae type b / drug effects*
  • Haemophilus influenzae type b / enzymology
  • Haemophilus influenzae type b / genetics
  • Haemophilus influenzae type b / isolation & purification
  • Humans
  • Infant
  • Japan
  • Meningitis, Haemophilus / microbiology*
  • Microbial Sensitivity Tests
  • Mutation
  • Mutation, Missense
  • Penicillin-Binding Proteins / genetics
  • Polymerase Chain Reaction
  • Sequence Analysis, DNA
  • Transformation, Bacterial
  • beta-Lactamases / analysis*
  • beta-Lactams / pharmacology


  • Anti-Bacterial Agents
  • DNA, Bacterial
  • Penicillin-Binding Proteins
  • beta-Lactams
  • beta-Lactamases
  • beta-lactamase TEM-1