Use of Antimicrobials and Carriage of Penicillin-Resistant Pneumococci in Children

Use of Antimicrobials and Carriage of Penicillin-Resistant Pneumococci in Children Repeated cross-sectional studies covering 10 years Vilhjalmur Ari Arason PhD Thesis University of Iceland, Faculty of Medicine, Department of Family Medicine October 2006 From Department of Family Medicine, University of Iceland, Primary Healthcare Centre of Solvangur and Healthcare Centre Fjördur, IS-220 Hafnarfjördur, Iceland Use of Antimicrobials and Carriage of Penicillin-Resistant Pneumococci in Children Repeated cross-sectional studies covering 10 years Vilhjalmur Ari Arason Supervisor Johann A. Sigurdsson Co-supervisor Karl G. Kristinsson PhD committee: Thorolfur Gudnason (chair), Directorate of Health, Iceland Johann A. Sigurdsson, University of Iceland Vilhjalmur Rafnsson, University of Iceland Magnus Johannsson, University of Iceland Haraldur Briem, Directorate of Health, Iceland Reykjavík 2006 Vilhjálmur Ari Arason: Use of Antimicrobials and Carriage of Penicillin-resistant Pneumococci in Children. Repeated cross-sectional studies covering 10 years The copyright of this thesis rests with the author and no quotation from it or information derived from it may be published without the prior written consent of the author. Háskólaútgáfan Reykjavík 2006 ©Vilhjálmur Ari Arason e-mail: vilhjalmur.a.arason@fjordur.hg.is Umbrot: Þröstur Haraldsson Prentun og bókband: Leturprent ISBN 9979-70-157-9 ISBN 978-9979-70-157-6 ÁGRIP Notkun sýklalyfja og beratíðni penicillín ónæmra pneumókokka hjá börnum – Endurteknar þversniðsrannsóknir á 10 ára tímabili Vilhjálmur Ari Arason Heimilislæknisfræði, Háskóla Íslands, Heilsugæsla höfuðborgar- svæðisins, Sólvangur og Fjörður, Hafnarfirði, Íslandi. Tilgangur: Að athuga notkun sýklalyfja meðal forskólabarna á Ís- landi og meta hugsanlegt samband slíkrar notkunar við beratíðni penicillín ónæmra pneumókokka í nefkoki þeirra. Efniviður og aðferðir: Upplýsingar voru fengnar hjá foreldrum og úr sjúkraskrám heilsugæslustöðva um sýklalyfjaávísanir 2.612 barna á aldrinum 1-6 ára sem bjuggu á mismunandi stöðum á landinu. Úr þessum hóp voru teknar nefkoksræktanir frá 2.486 börnum. Gerðar voru þrjár þversniðsrannsóknir á sömu svæðum á 10 ára tímabili (I. hluti 1993, II. hluti 1998 og III. hluti 2003). Þátttökuhlutfall var frá 75 til 88%. Einnig var unnið úr upplýsingum apóteka sömu svæða varðandi 22.132 ávísanir á sýklalyf til inntöku (utan spítala) fyrir alla aldurshópa árið 1993 og 15.153 ávísanir árið 1998. Aðal mælibreytur: Tíðni penicillín ónæmra pnemókokka í nefkoki og áhættuþættir berasmits, heildarnotkun sýklalyfja, notkun þeirra vegna bráðrar miðeyrnabólgu (acute otitis media), væntingar foreldra og notkun hljóðhimnuröra. Niðurstöður: • Sýklalyfjaávísunum heimilislækna til barna fækkaði um 1/3 á rannsóknartímabilinu. Munur var á ávísanavenjum lækna milli svæða, sérstaklega varðandi meðferð við bráðri miðeyrna- bólgu. • Fylgni var á milli væntinga foreldra til sýklalyfjanotkunar og ávísana lækna á sýklalyf til barna eftir búsetu. • Yfir 30% barna á Íslandi fá hljóðhimnurör á fyrstu 6 aldursár unum. Á svæðum þar sem sýklalyfjanotkunin var mikil var meiri notkun á breiðvirkum sýklalyfjum borið saman við hin iii svæðin og notkun röra í hljóðhimnur fór vaxandi (upp í 44% allra barna). Á öðrum stöðum, þar sem sýklalyfjanotkunin hafði minnkað, var röranotkunin komin mest niður í 17%. • Sterkt samband var á milli sýklalyfjanokunar einstaklinga og tíðni penicillín ónæmra pneumókokka í nefkoki þeirra. • Fjölónæmir (ónæmir fyrir mörgum tegundum sýklalyfja) og jafnframt penicillín ónæmir pneumókokkar af sermisgerð 6B (með sömu svipgerð og Spain6B-2 stofninn) fundust á svæðun- um. Tíðni þeirra náði vissu hámarki en minnkaði síðan aftur eða að þeir hurfu með öllu á þessu 10 ára tímabili, bæði á svæðum þar sem sýklalyfjanotkunin var mikil og eins þar sem hún var lítil. Ályktanir: Sterkt samband ríkir á milli sýklalyfjanotkunar og tíðni penicillín ónæmra pneumókokka í nefkoki barna. Eftir sýkla- lyfjanotkun er barnið næmara fyrir utanaðkomandi smiti svo sem í leikskólum. Líklegt er að faraldsfræðileg dreifing nýrra ónæmra pneumókokkastofna skýri megin sveiflur í beratíðninni. Hugsanlega er samband á milli (of)notkunar sýklalyfja við bráðri miðeyrnabólgu og endurtekinna eyrnabólgusýkinga síðar meir og ísetningu hljóð- himnuröra. Lykilorð: Sýklalyfjanotkun, lyfjaávísanir, bráð miðeyrnabólga, börn, sýklalyfjaónæmi, penicillín ónæmir pneumókokkar, sermisgerð 6B, útbreiðsla bakteríustofna, Spain6B-2, hjarðarónæmi, hljóðhimnurör, heilsugæsla, heimilislækningar. iv ABSTRACT Use of antimicrobials and carriage of penicillin-resistant pneumococci in children – Repeated cross-sectional studies covering 10 years Vilhjalmur Ari Arason Department of Family Medicine, University of Iceland, Primary Healthcare Centre of Solvangur and Fjordur, IS-220 Hafnarfjordur, Iceland. Objectives: The overall aim of this thesis was to analyse the use of antimicrobials in pre-school children in Iceland and the connection between such use and the carriage of penicillin-nonsusceptible pneumococci (PNSP). Study populations and methods: Prescription data and medical histories from 2,612 children, aged 1 to 6 years, living in different geographically welldefined study areas in Iceland, and nasopharyngeal specimens from 2,486 children were analysed in three cross- sectional studies covering 10 years (Phase I 1993, II 1998, and III 2003). Participation varied from 75% to 88%. Annual analysis of oral antimicrobial sales/prescriptions for whole communities (hospital use excluded) were based on 22,132 prescriptions in 1993, and 15,153 in 1998. Main outcome measures: The prevalence and risk factors for nasopharyngeal carriage of PNSP, total antimicrobial use, antimicrobial use for acute otitis media (AOM), parental expectations and tympanostomy tube placements. Results: • Antimicrobial prescription rates among GPs diminished by about 1/3 over the study period. Prescription habits varied greatly between communites especially because of AOM. • Parents’ expectations of antimicrobial prescriptions were associated with the antimicrobial prescription rate in each area. • The cumulative prevalence of tympanostomy tube placement among pre-school children is high in Iceland (over 30%). In v areas where the prescription rate was high, broad-spectrum antimicrobials were prescribed relatively more often than in other areas, and the tympanostomy tube placement rate was increasing (up to 44% of all children). In other areas, tympanostomy tube rate among children deceased (down to 17%) at the same time as antimicrobial use for AOM diminished. • There was a strong association between antimicrobial use on the individual level and the nasopharyngeal carriage of PNSP. • PNSP, multiresistant, serotype 6B (phenotypically identical to the Spain6B-2 clone) appeared and disappeared over a 10-year period, in communities with both high and low antimicrobial use. Conclusions: There is a strong association between antimicrobial use for individual children and the nasopharyngeal carriage of PNSP. Pneumococcus is acquired from other children, usually in day-care settings and PNSP selectively colonised when receiving antimicrobials. Spread of novel resistant clones appears to be the main reason for marked changes in pneumococcal resistance rates in individual communities over time. Antimicrobial drug (over)use for AOM my be associated with future episodes of AOM and tympanostomy tube placements. Key words: antimicrobial use, drug prescription, acute otitis media, children, antimicrobial resistance, penicillin-nonsusceptible pneumococci, clonal spread, Spain6B-2, herd immunity, tympanostomy tube placement, primary healthcare, general practice. vi ACKNOWLEDGEMENTS I wish to express my sincere gratitude to all those who have made this thesis possible. I especially want to thank: My supervisor Professor Jóhann Ágúst Sigurðsson, head of De- partment of Family Medicine, University of Iceland. Without his experience, enthusiasm, positive and encouraging attitude and patience, this thesis may never have come true. Our long co-operation has developed into a good friendship. My other co-authors, Professor Karl G. Kristinsson, Dr. Sigurður Guðmundsson, Helga Erlendsdóttir, Guðrún Stefánsdóttir, Aðal- steinn Gunnlaugsson, Dr. Linn Getz and Professor Sigvard Mölstad for valuable expertise and co-operation in the research. Professor emeritus Calle Bengtsson former head of the Depart- ment of Primary Healthcare, Gothenburg for his generous support and enthusiasm in beginning writing the thesis. My colleagues and others at the Fjordur Healthcentre and Solvang- ur Healthcentre Hafnarfjordur for encouragement and help with my patients. Special thanks to all the children who participated in the study, their parents, the general practitioners who assisted in the study areas and to the staff of the Department of Clinical Microbiology, Landspitali University Hospital. Last but not least, my wife Ingibjörg Ásgeirsdóttir for supporting me so unselfishly and tolerating me all the time I have spent working in this research last 15 years. Also my children, Ásgeir Snær and his wife Eyrún, Jóhanna and her boyfriend Hördur, Ásta and my grand- children Steinn Andri, Hjördís María, Ingibjörg Svana and Emilía for their patience and encouragement. This study was mainly supported by the Icelandic College of Family Physicians. It was also granted by The Research Fund of the University of Iceland, and the Research Fund of the Landspitali University Hospi- tal, Reykjavik. vii CONTENTS ÁGRIP .......................................................................................

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