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Epidemiology and evolution of antibiotic resistance of Haemophilus influenzae in children 5 years of age or less in France, 2001–2008: a retrospective database analysis

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Abstract

Trends in the evolution of antimicrobial resistance and mechanisms of resistance of Haemophilus influenzae to β-lactam antibiotics in France were assessed through a retrospective database review. The antimicrobial resistance of 2,206 H. influenzae strains from children aged ≤5 years was studied between 2001 and 2008. Strains were isolated from blood or cerebrospinal fluid (n = 170), bronchial secretions (n = 188), middle ear fluid, and nasopharynx or conjunctiva (n = 1,848). A proportion of 95.1 % (n = 2,097) were non-typeable H. influenzae (NTHi). β-lactamase production was identified in 27.5 % of NTHi isolates (all TEM-1), while β-lactamase-negative ampicillin resistance and β-lactamase-negative amoxicillin–clavulanate resistance among NTHi was 16.9 and 6.4 %, respectively. Over time, a statistically significant decrease in β-lactamase-producing strain prevalence (p < 0.0001) and a statistically significant increase in β-lactamase-negative ampicillin-resistant (BLNAR) strains (p < 0.0001) were observed in NTHi isolates from 2001 to 2008. The largest changes coincided with a campaign to reduce antibiotic use in France. An increasing diversity of amino acid substitution patterns was observed, with the emergence of group III/‘III-like’ patterns linked to high-level resistance. In France, amino acid substitution patterns are increasingly diverse, and strains with high-level antibiotic resistance are emerging. This study highlights the complexity of resistance dynamics within a given country. These results have implications on antibiotic guidelines and illustrate the importance of continued surveillance.

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References

  1. Goossens H, Ferech M, Vander Stichele R, Elseviers M; ESAC Project Group (2005) Outpatient antibiotic use in Europe and association with resistance: a cross-national database study. Lancet 365:579–587

    PubMed  Google Scholar 

  2. Ubukata K, Shibasaki Y, Yamamoto K, Chiba N, Hasegawa K, Takeuchi Y, Sunakawa K, Inoue M, Konno M (2001) Association of amino acid substitutions in penicillin-binding protein 3 with beta-lactam resistance in beta-lactamase-negative ampicillin-resistant Haemophilus influenzae. Antimicrob Agents Chemother 45:1693–1699

    Article  PubMed  CAS  Google Scholar 

  3. Clairoux N, Picard M, Brochu A, Rousseau N, Gourde P, Beauchamp D, Parr TR Jr, Bergeron MG, Malouin F (1992) Molecular basis of the non-beta-lactamase-mediated resistance to beta-lactam antibiotics in strains of Haemophilus influenzae isolated in Canada. Antimicrob Agents Chemother 36:1504–1513

    Article  PubMed  CAS  Google Scholar 

  4. Fluit AC, Florijn A, Verhoef J, Milatovic D (2005) Susceptibility of European beta-lactamase-positive and -negative Haemophilus influenzae isolates from the periods 1997/1998 and 2002/2003. J Antimicrob Chemother 56:133–138

    Article  PubMed  CAS  Google Scholar 

  5. Scriver SR, Walmsley SL, Kau CL, Hoban DJ, Brunton J, McGeer A, Moore TC, Witwicki E (1994) Determination of antimicrobial susceptibilities of Canadian isolates of Haemophilus influenzae and characterization of their beta-lactamases. Canadian Haemophilus Study Group. Antimicrob Agents Chemother 38:1678–1680

    Article  PubMed  CAS  Google Scholar 

  6. Nimmo GR, Bell JM, Collignon PJ; Australian Group for Antimicrobial Resistance (2003) Fifteen years of surveillance by the Australian Group for Antimicrobial Resistance (AGAR). Commun Dis Intell 27:S47–S54

    PubMed  Google Scholar 

  7. Dabernat H, Seguy M, Faucon G, Delmas C (2007) Epidemiology of Haemophilus influenzae strains collected in 2004 in France and in vitro assessment of their susceptibility to antibiotics. Med Mal Infect 37:320–324

    Article  PubMed  CAS  Google Scholar 

  8. García-Cobos S, Campos J, Cercenado E, Román F, Lázaro E, Pérez-Vázquez M, de Abajo F, Oteo J (2008) Antibiotic resistance in Haemophilus influenzae decreased, except for beta-lactamase-negative amoxicillin-resistant isolates, in parallel with community antibiotic consumption in Spain from 1997 to 2007. Antimicrob Agents Chemother 52:2760–2766

    Article  PubMed  Google Scholar 

  9. Heilmann KP, Rice CL, Miller AL, Miller NJ, Beekmann SE, Pfaller MA, Richter SS, Doern GV (2005) Decreasing prevalence of beta-lactamase production among respiratory tract isolates of Haemophilus influenzae in the United States. Antimicrob Agents Chemother 49:2561–2564

    Article  PubMed  CAS  Google Scholar 

  10. Jones ME, Karlowsky JA, Blosser-Middleton R, Critchley IA, Thornsberry C, Sahm DF (2002) Apparent plateau in beta-lactamase production among clinical isolates of Haemophilus influenzae and Moraxella catarrhalis in the United States: results from the LIBRA Surveillance initiative. Int J Antimicrob Agents 19:119–123

    Article  PubMed  CAS  Google Scholar 

  11. García-Cobos S, Campos J, Lázaro E, Román F, Cercenado E, García-Rey C, Pérez-Vázquez M, Oteo J, de Abajo F (2007) Ampicillin-resistant non-beta-lactamase-producing Haemophilus influenzae in Spain: recent emergence of clonal isolates with increased resistance to cefotaxime and cefixime. Antimicrob Agents Chemother 51:2564–2573

    Article  PubMed  Google Scholar 

  12. Karlowsky JA, Critchley IA, Blosser-Middleton RS, Karginova EA, Jones ME, Thornsberry C, Sahm DF (2002) Antimicrobial surveillance of Haemophilus influenzae in the United States during 2000–2001 leads to detection of clonal dissemination of a beta-lactamase-negative and ampicillin-resistant strain. J Clin Microbiol 40(3):1063–1066

    Article  PubMed  CAS  Google Scholar 

  13. Ito M, Hotomi M, Maruyama Y, Hatano M, Sugimoto H, Yoshizaki T, Yamanaka N (2010) Clonal spread of β-lactamase-producing amoxicillin–clavulanate-resistant (BLPACR) strains of non-typeable Haemophilus influenzae among young children attending a day care in Japan. Int J Pediatr Otorhinolaryngol 74:901–906

    Article  PubMed  Google Scholar 

  14. Sanbongi Y, Suzuki T, Osaki Y, Senju N, Ida T, Ubukata K (2006) Molecular evolution of beta-lactam-resistant Haemophilus influenzae: 9-year surveillance of penicillin-binding protein 3 mutations in isolates from Japan. Antimicrob Agents Chemother 50:2487–2492

    Article  PubMed  CAS  Google Scholar 

  15. Hasegawa K, Yamamoto K, Chiba N, Kobayashi R, Nagai K, Jacobs MR, Appelbaum PC, Sunakawa K, Ubukata K (2003) Diversity of ampicillin-resistance genes in Haemophilus influenzae in Japan and the United States. Microb Drug Resist 9:39–46

    Article  PubMed  CAS  Google Scholar 

  16. Murray PR (1995) Manual of clinical microbiology, 6th edn. ASM Press, Washington DC

    Google Scholar 

  17. Falla TJ, Crook DW, Brophy LN, Maskell D, Kroll JS, Moxon ER (1994) PCR for capsular typing of Haemophilus influenzae. J Clin Microbiol 32:2382–2386

    PubMed  CAS  Google Scholar 

  18. Dabernat H, Delmas C, Seguy M, Pelissier R, Faucon G, Bennamani S, Pasquier C (2002) Diversity of beta-lactam resistance-conferring amino acid substitutions in penicillin-binding protein 3 of Haemophilus influenzae. Antimicrob Agents Chemother 46:2208–2218

    Article  PubMed  CAS  Google Scholar 

  19. Comité de l’Antibiogramme de la Société Française de Microbiologie. Société Française de Microbiologie. http://www.sfm-microbiologie.org. [cited 2010 Nov 27]

  20. European Committee on Antimicrobial Susceptibility Testing (EUCAST). European Society of Clinical Microbiology and Infectious Diseases. http://www.eucast.org/. [cited 2010 Nov 27]

  21. Ladhani S, Slack MPE, Heath PT, von Gottberg A, Chandra M, Ramsay ME; European Union Invasive Bacterial Infection Surveillance participants (2010) Invasive Haemophilus influenzae Disease, Europe, 1996–2006. Emerging Infect Dis 16:455–463

    Article  PubMed  Google Scholar 

  22. Markowitz SM (1980) Isolation of an ampicillin-resistant, non-beta-lactamase-producing strain of Haemophilus influenzae. Antimicrob Agents Chemother 17:80–83

    Article  PubMed  CAS  Google Scholar 

  23. Dabernat H, Delmas C (1998) Activité du Centre National de Référence des Haemophilus influenzae, années 1996–1997: le déclin du type b [Activity of the French H. influenzae National Reference Center, 1996–1997: years of decline of type b]. Med Mal Infect 28:940–946

    Article  Google Scholar 

  24. Gazagne L, Delmas C, Bingen E, Dabernat H (1998) Molecular epidemiology of ampicillin-resistant non-beta-lactamase-producing Haemophilus influenzae. J Clin Microbiol 36:3629–3635

    PubMed  CAS  Google Scholar 

  25. Sevillano D, Giménez M-J, Cercenado E, Cafini F, Gené A, Alou L, Marco F, Martínez-Martínez L, Coronel P, Aguilar L (2009) Genotypic versus phenotypic characterization, with respect to beta-lactam susceptibility, of Haemophilus influenzae isolates exhibiting decreased susceptibility to beta-lactam resistance markers. Antimicrob Agents Chemother 53:267–270

    Article  PubMed  CAS  Google Scholar 

  26. Barbosa AR, Giufrè M, Cerquetti M, Bajanca-Lavado MP (2011) Polymorphism in ftsI gene and {beta}-lactam susceptibility in Portuguese Haemophilus influenzae strains: clonal dissemination of beta-lactamase-positive isolates with decreased susceptibility to amoxicillin/clavulanic acid. J Antimicrob Chemother 66:788–796

    Article  PubMed  CAS  Google Scholar 

  27. Jansen WTM, Verel A, Beitsma M, Verhoef J, Milatovic D (2006) Longitudinal European surveillance study of antibiotic resistance of Haemophilus influenzae. J Antimicrob Chemother 58:873–877

    Article  PubMed  CAS  Google Scholar 

  28. Sabuncu E, David J, Bernède-Bauduin C, Pépin S, Leroy M, Boëlle PY, Watier L, Guillemot D (2009) Significant reduction of antibiotic use in the community after a nationwide campaign in France, 2002–2007. PLoS Med 6:e1000084

    Article  PubMed  Google Scholar 

  29. Kempf M, Baraduc R, Bonnabau H, Brun M, Chabanon G, Chardon H, Croizé J, Demachy MC, Donnio PY, Dupont P, Fosse T, Gibel L, Gravet A, Grignon B, Hadou T, Hamdad F, Joly-Guillou ML, Koeck JL, Maugein J, Péchinot A, Ploy MC, Raymond J, Ros A, Roussel-Delvallez M, Segonds C, Vergnaud M, Vernet-Garnier V, Lepoutre A, Gutmann L, Varon E, Lanotte P (2011) Epidemiology and antimicrobial resistance of Streptococcus pneumoniae in France in 2007: data from the Pneumococcus Surveillance Network. Microb Drug Resist 17:31–36

    Article  PubMed  Google Scholar 

  30. Murphy TF, Brauer AL, Sethi S, Kilian M, Cai X, Lesse AJ (2007) Haemophilus haemolyticus: a human respiratory tract commensal to be distinguished from Haemophilus influenzae. J Infect Dis 195:81–89

    Article  PubMed  CAS  Google Scholar 

  31. McCrea KW, Xie J, LaCross N, Patel M, Mukundan D, Murphy TF, Marrs CF, Gilsdorf JR (2008) Relationships of nontypeable Haemophilus influenzae strains to hemolytic and nonhemolytic Haemophilus haemolyticus strains. J Clin Microbiol 46:406–416

    Article  PubMed  Google Scholar 

  32. Dabernat H, Plisson-Sauné MA, Delmas C, Séguy M, Faucon G, Pélissier R, Carsenti H, Pradier C, Roussel-Delvallez M, Leroy J, Dupont MJ, De Bels F, Dellamonica P (2003) Haemophilus influenzae carriage in children attending French day care centers: a molecular epidemiological study. J Clin Microbiol 41:1664–1672

    Article  PubMed  CAS  Google Scholar 

  33. Watanabe H, Hoshino K, Sugita R, Asoh N, Watanabe K, Oishi K, Nagatake T (2004) Possible high rate of transmission of nontypeable Haemophilus influenzae, including beta-lactamase-negative ampicillin-resistant strains, between children and their parents. J Clin Microbiol 42:362–365

    Article  PubMed  Google Scholar 

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Acknowledgments

The statistical analysis was done by Aurélie Le Plain, Alice Raillard, and Sabrina Collas de Souza from 4Clinics. The authors thank Sylvia Taylor for her contribution to the study design and analysis plan, coordination of the statistical analysis, and review of the manuscript; Linda Hanssens for the manuscript initiation and review, and support for its realization; and Dr. Joanne Wolter (independent medical writer funded by GSK), Veronique Mouton, and Barbara Pelgrims for their assistance in the preparation of the manuscript. The authors thank their colleagues for their participation in the national network for the surveillance of Haemophilus influenzae infections and their contribution to the activity of the Centre National de Référence des Haemophilus influenzae, and the technicians of the Laboratory for their excellent technical assistance.

Transparency declaration

GSK Biologicals paid for all costs associated with the development and the publishing of the present manuscript. The corresponding author had full access to the data and final responsibility for submission of the publication.

Pr. Dabernat has received an institutional grant from GSK Biologicals for this study. He has received consulting fees, support for travel to scientific meetings, and payment for writing/reviewing the manuscript from GSK Biologicals. Pr. Dabernat declares that he participated in a GSK working group on strategies for vaccination against non-typeable Haemophilus influenzae in the past 3 years. Dr. Delmas has no conflict of interest.

Authorship contribution

Both authors contributed equally to this study.

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Authors and Affiliations

  1. Faculté de Médecine, Laboratoire de Bactériologie, Toulouse, France

    H. Dabernat & C. Delmas

  2. Laboratoire AMIS—Anthropologie Moléculaire et Imagerie de Synthèse, UMR 5288 CNRS/Université Paul Sabatier, 37 allées Jules Guesde, 31000, Toulouse, France

    H. Dabernat

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Correspondence to H. Dabernat.

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Dabernat, H., Delmas, C. Epidemiology and evolution of antibiotic resistance of Haemophilus influenzae in children 5 years of age or less in France, 2001–2008: a retrospective database analysis. Eur J Clin Microbiol Infect Dis 31, 2745–2753 (2012). https://doi.org/10.1007/s10096-012-1623-9

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