Nationwide survey of the development of drug-resistance in the pediatric field: drug sensitivity of Haemophilus influenzae in Japan

  • Hiroshi SakataEmail author
  • Yoshikiyo Toyonaga
  • Yoshitake Sato
  • Hideaki Hanaki
  • Masato Nonoyama
  • Tomohiro Oishi
  • Keisuke Sunakawa
Original Article


We evaluated the β-lactamase-producing ability and resistance to 20 antibacterial agents of 448 clinically isolated strains of Haemophilus influenzae accumulated from October 2000 to July 2001 (phase 1) and of 376 different strains accumulated from January to June 2004 (phase 2), from institutions that participated in a nationwide Drug-Resistant Pathogen Surveillance Group in Pediatric Infectious Disease. Between phase 1 and phase 2 the proportion of β-lactamase-negative ampicillin (ABPC)-susceptible (BLNAS) strains declined from 62.9% to 34.3%; the proportions of β-lactamase-positive ABPC-resistant (BLPAR) strains were 8.3% and 6.4% in phases 1 and 2, but the proportion of β-lactamase-negative ABPC-resistant (BLNAR) strains increased from 28.8% in phase 1 to 59.3% in phase 2. Comparison of the MIC90 values of the antibacterial agents for H. influenzae in phase 1 and phase 2 showed that cefcapene, cefpodoxime, ceftriaxone, panipenem, and clarithromycin kept the same level, while cefdinir, faropenem, and rokitamycin showed 2-fold to 8-fold decreases. With the exception of the above antibiotics, all of the other antibacterial agents tested showed 2-fold to 4-fold increases. The MIC90 values of the β-lactam drugs for BLNAR were 2-fold to 32-fold higher than the values for BLNAS. The proportion of BLNAR H. influenzae strains rose dramatically over the 3 years between phases 1 and 2. In relation to age, prior administration of antibacterial agents, and attendance at a day nursery as background factors, no significant differences between BLNAS and BLNAR were detected in phase 1. In the phase 2 survey, the proportion of BLNAR strains showed significant differences between children under 3 years and those aged 3 years or more, and there were also significant differences according to whether antibacterial agents, especially β-lactams, had been administered previously. No significant difference was found in resistant bacteria according to whether or not a child had attended a day nursery.

Key words

Pediatric infectious disease Surveillance Haemophilus influenzae Sensitivity Drug resistance 


  1. 1.
    Hasegawa K, Chiba N, Kobayashi R, Murayama SY, Iwata S, Sunakawa K, et al. Rapidly increasing prevalence of β-lactamasenonproducing, ampicillin-resistant Haemophilus influenzae type b in patients with meningitis. Antimicrob Agents Chemother 2004;48:1509–1514.CrossRefPubMedGoogle Scholar
  2. 2.
    Hasegawa K, Kobayashi R, Takada E, Ono A, Chiba N, Morozumi M, et al. 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;57:1077–1082.CrossRefPubMedGoogle Scholar
  3. 3.
    Japanese Society of Chemotherapy. Committee for Revision of MIC Determination Method: Revision of minimal inhibitory concentration (MIC) determination method. Chemotherapy 1981;29:76–79.Google Scholar
  4. 4.
    National Committee for Clinical Laboratory Standards. MIC testing supplemental tables. NCCLS Document M100-S13 (M7). Wayne, Pennsylvania: National Committee for Clinical Laboratory Standards; 2003.Google Scholar
  5. 5.
    Clements DA. Haemophilus influenzae type b. In: Gershon AA, Hotez PJ, Katz SL, editors. Krugman’s infectious diseases of children. 11th ed. Philadelphia: Mosby; 2004. p. 239–257.Google Scholar
  6. 6.
    Heath PT, McVernon J. The UK Hib vaccine experience. Arch Dis Child 2002;86:396–399.CrossRefPubMedGoogle Scholar
  7. 7.
    Jacobs MR, Felmingham D, Appelbaum PC, Gruneberg RN. The Alexander Project 1998–2000: susceptibility of pathogens isolated from community-acquired respiratory tract infection to commonly used antimicrobial agents. J Antimicrob Chemother 2003;52:229–246.CrossRefPubMedGoogle Scholar
  8. 8.
    Heilmann KP, Rice CL, Miller AL, Miller NJ, Beekmann SE, Pfaller MA, et al. Decreasing prevalence of beta-lactamase production among respiratory tract isolates of Haemophilus influenzae in the United States. Antimicrob Agents Chemother 2005;49:2561–2564.CrossRefPubMedGoogle Scholar
  9. 9.
    Sakata H. Bactericidal activities of parenteral antibiotics and genotype of penicillin-binding protein in Streptococcus pneumoniae and Haemophilus influenzae isolated from children’s blood. J Infect Chemother 2006;12:338–342.CrossRefPubMedGoogle Scholar
  10. 10.
    Matsumoto A, Hosoya M, Katayose M, Murai H, Kawasaki Y, Sato K, et al. Antimicrobial resistance in Streptococcus pneumoniae and Haemophilus influenzae isolated from nasopharynxi in children. Kansenshogaku Zasshi 78:482–489.Google Scholar
  11. 11.
    Endo H, Kayama Y, Kawamura K, Sato N, Shimoda H, Ubukata K, et al. Bacterial strains isolated from upper pharynx of young children suffering from acute respiratory tract infections. J J Pediatr Soc 2002;106:472–481.Google Scholar
  12. 12.
    Uno Y. Surveillance based on molecular epidemiology for Streptococcus pneumoniae isolated from the nasopharynx in pediatric patients with acute otitis media. JPN J Chemotherapy; 52:68–74.Google Scholar
  13. 13.
    Uno Y. Surveillance based on molecular epidemiology of Haemophilus influenzae isolated from the nasopharynx of pediatric patients with acute otitis media. JPN J Chemotherapy; 52:163–168.Google Scholar
  14. 14.
    Ito M, Shirai A, Sakunaka K, Tsukatani T, Shibuya K, Yoshizaki T, et al. Rate of isolation of nasopharyngeal penicillin-resistant Streptococcus pneumoniae from 18-month-old infants. Oto-Rhino-Laryngology Tokyo 2000;43:540–546.Google Scholar
  15. 15.
    Ito M, Furukawa M. Survey of the rate of isolation of Haemophilus influenzae in the general population. Journal of Japan Society for Infectious Diseases in Otolaryngology 2002;20:94–97.Google Scholar
  16. 16.
    Felmingham D, Reinert RR, Hirakata Y, Rodloff A. Increasing prevalence of antimicrobial resistance among isolates of Streptococcus pneumoniae from the PROTEKT surveillance study, and comparative in vitro activity of the ketolide, telithromycin. J Antimicrob Chemother 2002;50(Suppl S1):25–37.PubMedGoogle Scholar
  17. 17.
    Hoban D, Felmingham D. The PROTEKT surveillance study: antimicrobial susceptibility of Haemophilus influenzae and Moraxella catarrhalis from community-acquired respiratory tract infections. J Antimicrob Chemother 2002;50(Suppl):49–59.PubMedGoogle Scholar
  18. 18.
    Ubukata K, Chiba N, Kobayashi R, Hasegawa K, Konno M. Surveillance based on molecular epidemiology for Haemophilus influenzae isolates between 1998 and 2000 in Japan. Results of clinical isolates of Streptococcus pneumoniae, etc., collected by the Community-Acquired Bacterial Infections Working Group. Japanese Journal of Chemotherapy 2002;50:794–804.Google Scholar
  19. 19.
    Ubukata K, Kobayashi R, Chiba N, Hasegawa K, Konno M. Surveillance based on molecular epidemiology for Streptococcus pneumoniae isolates between 1998 and 2000 in Japan. Results of clinical isolates collected by the Community-Acquired Bacterial Infections Working Group. JPN J Chemotherapy 2003;51:60–70.Google Scholar

Copyright information

© Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases 2009

Authors and Affiliations

  • Hiroshi Sakata
    • 1
    Email author
  • Yoshikiyo Toyonaga
    • 2
  • Yoshitake Sato
    • 3
  • Hideaki Hanaki
    • 4
  • Masato Nonoyama
    • 5
  • Tomohiro Oishi
    • 6
  • Keisuke Sunakawa
    • 4
  1. 1.Asahikawa Kosei HospitalHokkaidoJapan
  2. 2.Sekishinkai Sayama HospitalSaitamaJapan
  3. 3.Fuji Heavy Industries Health Insurance Society General Ota HospitalGunmaJapan
  4. 4.The Kitasato InstituteTokyoJapan
  5. 5.Ebina General HospitalKanagawaJapan
  6. 6.Niigata Prefectural Shibata HospitalNiigataJapan

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