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Publisher's version (útgefin grein), Background: Antimicrobial resistance is a growing global health threat. To preserve the effectiveness of antimicrobials, it is important to reduce demand for antimicrobials. Objectives: The objective of the study was to screen the existing peer-reviewed literature to identify articles that addressed the potential impact of influenza or Pneumococcus vaccination on antibiotic usage. Data sources: PubMed, Embase Study eligibility criteria: Clinical studies where antimicrobial prescribing was assessed in both vaccinated and unvaccinated populations. Participants and interventions: All patient populations were included (infants, children, adults and elderly), where the effects of the intervention (vaccination) was assessed Results: We identified unique 3638 publications, of which 26 were judged to be of sufficiently high quality to allow the calculation of the potential impact of vaccination. Of these studies 23/26 found a significant reduction in antibiotic use by at least one of the parameters assessed. Limitations: Different measures used to define anti-microbial use, studies typically focus on specific risk groups and most studies are from high-income countries. Conclusions and implications of key findings: Despite the limitations of the review, the evidence indicates that improved coverage with existing vaccines may significantly reduce antimicrobial demand. This suggests it may be a valuable tool for antimicrobial stewardship.Key messages While vaccines against a number of pathogens have been studied for their ability to reduce antimicrobial use, currently only vaccination against influenza or pneumococcus has generated sufficient data for analysis Vaccination against either influenza or pneumococcus significantly reduced overall antimicrobial prescribing rates, both in vaccinated individuals and at a population level Maintaining and expanding vaccination coverage thus appears to be a key tool for antimicrobial stewardship., GlaxoSmithKline Biologicals S.A. funded the independent assessment by Pallas and all costs related to the development of this review article, but did not provide payment to the authors.

Publisher's version (útgefin grein), Objectives: The aim of the present superiority study was to determine the effect of systemic antibiotics primarily on patient-reported outcome measures (PROMs) and post-surgical complications in patients undergoing oral implant therapy with simultaneous guided bone regeneration (GBR). Materials and Methods: A total of 236 medically and periodontally healthy patients received oral implants with simultaneous GBR at seven centres. Pre-operative antibiotics of 2 g amoxicillin were prescribed to the test group 1 hr prior to surgery and 500 mg thrice daily on days 1–3 after surgery. The control group was given a placebo. Group allocation was performed randomly. Primary outcome variables were PROMs recorded as visual analogue scale scores assessed on days 1–7 and 14 on pain, swelling, haematoma and bleeding. Post-operative complications as secondary outcome variables were examined at 1, 2, 4 and 12 weeks from surgery. Chi-square tests and repeated measures of analysis of variance (ANOVA) were performed for statistical evaluation. Results: No statistically significant differences (p >.05) between the two groups were detected for the evaluated PROMs. The same was noted with respect to post-surgical complications. Four implants were lost—three in the test group and one in the control group. Conclusion: In this trial, systemic antibiotics did not provide additional benefits to PROMs, nor the prevention of post-surgical complications in medically and periodontally healthy patients undergoing oral implant therapy with simultaneous GBR. However, further studies with larger sample sizes are still required to support the clinical outcomes of this study., This study has been supported by a research grant of the ITI Foundation (ITI Grant‐No: No. 962_2013). Further, we want to thank the Geistlich AG, Wolhusen, Switzerland, for providing bone substitutes and collagen membranes (Bio‐Oss® and Bio‐Gide®); Medochemie Limassol, Cyprus, for providing the study medication; and the Straumann AG (Basel, Switzerland) for granting a 50% discount on all the implant materials used in the presented study. The co‐operation of the staff of the centres involved in the study is highly appreciated: (1) Peking University, School of Stomatology, Beijing PR China (2) Medical University Graz, University Clinic of Dental Medicine & Oral Health, Department of Oral Surgery and Orthodontics, Graz Austria (3) Griffith University, Gold Coast, School of Dentistry and Oral Health, Queensland, Australia (4) The University of Hong Kong, Faculty of Dentistry, Hong Kong SAR PR China (5) University of Iceland, Faculty of Odontology, Reykjavik, Iceland (6) Shanghai Jiao Tong University, Shanghai Ninth People's Hospital, Department of Implant Dentistry, Shanghai PR China (7) National Dental Centre Singapore, Singapore

Publisher's version (útgefin grein), Resistance to macrolide antibiotics is a global concern in the treatment of Streptococcus pyogenes (group A Streptococcus [GAS]) infections. In Iceland, since the detection of the first macrolide-resistant isolate in 1998, three epidemic waves of macrolide-resistant GAS infections have occurred, with peaks in 1999, 2004, and 2008. We conducted whole-genome sequencing of all 1,575 available GAS macrolide-resistant clinical isolates of all infection types collected at the national reference laboratory in Reykjavik, Iceland, from 1998 to 2016. Among 1,515 erythromycin-resistant isolates, 90.3% were of only three emm types, emm4 (n = 713), emm6 (n = 324), and emm12 (n = 332), with each being predominant in a distinct epidemic peak. The antibiotic efflux pump genes, mef(A) and msr(D), were present on chimeric mobile genetic elements in 99.3% of the macrolide-resistant isolates of these emm types. Of note, in addition to macrolide resistance, virtually all emm12 isolates had a single amino acid substitution in penicillin-binding protein PBP2X that conferred a 2-fold increased penicillin G and ampicillin MIC among the isolates tested. We conclude that each of the three large epidemic peaks of macrolide-resistant GAS infections occurring in Iceland since 1998 was caused by the emergence and clonal expansion of progenitor strains, with macrolide resistance being conferred predominantly by inducible Mef(A) and Msr(D) drug efflux pumps. The occurrence of emm12 strains with macrolide resistance and decreased beta-lactam susceptibility was unexpected and is of public health concern., This study was supported in part by the Fondren Foundation, Houston Methodist Hospital and Research Institute, and National Institutes of Health grants AI139369 and AI146771 (to J.M.M.).

Background Since the introduction of pneumococcal conjugate vaccines, vaccine type pneumococcal carriage and disease has decreased world-wide. The aim was to monitor changes in the nasopharyngeal carriage of pneumococci, the distribution of serotypes and antimicrobial resistance in children before and after initiation of the 10-valent pneumococcal vaccination in 2011, in a previously unvaccinated population. Methods Repeated cross-sectional study at 15 day-care centres in greater Reykjavik area. Nasopharyngeal swabs were collected yearly in March from 2009 to 2015. The swabs were selectively cultured for pneumococci, which were serotyped using latex agglutination and/or PCR and antimicrobial susceptibility determined. Two independent studies were conducted. In study 1, on total impact, isolates from children aged, Funding for this study was provided by GlaxoSmithKline Biologicals SA and a grant was received from the Landspitali University Hospital Research Fund. GlaxoSmithKline Biologicals SA was provided the opportunity to review a draft version of this manuscript but the authors are solely responsible for final content and interpretation. The authors received no financial support or other form of compensation related to the development of the manuscript.

Publisher's version (útgefin grein). Publisher’s Note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations., Background: Antimicrobial resistance is a public-health threat and antimicrobial consumption is the main contributor. The ten-valent pneumococcal conjugate vaccine (PHiD-CV10) was introduced into the Icelandic vaccination program in 2011. The aim was to estimate the vaccine impact of PHiD-CV10 on outpatient antimicrobial prescriptions in children. Methods: Eleven Icelandic birth-cohorts (2005–2015) were followed from birth until three years of age or to the end of the study period (December 31, 2016). Birth-cohorts were grouped as vaccine non-eligible (VNEC, 2005–2010) or vaccine eligible (VEC, 2011–2015). Data on primary care visits for respiratory infections and antimicrobial prescriptions were extracted from two national registers. Using national identification numbers, prescriptions were linked to physician visits if filled within three days of the visit. Incidence rates and incidence rate ratios between VNEC and VEC were calculated. An Andersen-Gill model was used to model the individual level data, accounting for repeated events and censoring. Vaccine impact was calculated as (1 – Hazard Ratio) × 100%. Results: Included were 53,510 children who contributed 151,992 person-years of follow-up and filled 231,660 antimicrobial prescriptions. The incidence rate was significantly lower in the VEC compared to the VNEC, 144.5 and 157.2 prescriptions per 100 person-years respectively (IRR 0.92, 95%CI 0.91–0.93). Children in VEC were more likely to have filled zero (IRR 1.16 (95%CI 1.10–1.23) and 1–4 (IRR 1.08 95%CI 1.06–1.11) prescriptions compared to children in VNEC. The vaccine impact of PHiD-CV10 against all-cause antimicrobial prescriptions was 5.8% (95%CI 1.6–9.8%).When only considering acute otitis media-associated prescriptions, the vaccine impact was 21.8% (95%CI 11.5–30.9%). Conclusion: The introduction of PHiD-CV10 lead to reduced antimicrobial use in children, mainly by reducing acute otitis media episodes. This intervention therefore reduces both disease burden and could slow the spread of antimicrobial resistance., An investigator-initiated study funded by GlaxoSmithKline Biologicals SA. Additionally, a grant was received from the Landspitali University Hospital Research Fund. GlaxoSmithKline Biologicals SA was provided the opportunity to review a draft version of this manuscript, but the authors are solely responsible for final content and interpretation. The authors received no financial support or other form of compensation related to the development of the manuscript.

Background Information on pneumococcal serotype distribution before vaccination is a prerequisite for evaluation of vaccine effect. The aim was to investigate the prevalence of pneumococcal serotypes isolated from middle ear (ME), lower respiratory tract (LRT) and from invasive disease (IPD) in Iceland prior to implementation of ten-valent pneumococcal Haemophilus influenzae protein D conjugate vaccine (PHiD-CV-10) into the infant vaccination program (April 2011). Methods and findings All isolates cultured 2007–2011 from ME, LRT and IPD identified as pneumococci were serotyped and tested for susceptibility at the Clinical Microbiology Department, Landspitali University Hospital that serves approximately 85% of the Icelandic population. Pneumococcal isolates were 1711 and 1616 (94.4%) were available for serotyping and included. Isolates belonging to PHiD-CV10 serotypes (VTs) were 1052 (65.1%). Isolates from ME were 879 (54.4%), with 639 (72.7%) from 0–1 year old patients and 651 of VTs (74%). Isolates from LRT were 564 (34.9%), with 292 (51.8%) from ≥65 years old patients, and 300 (53.2%) of VTs. IPD isolates were 173 (10.7%), although more evenly distributed according to age than isolates from the other sites most were from adults and the youngest age group,101 (58.4%) isolates were of VTs. The most common serotype was 19F, 583 (36.1%). Its prevalence was highest in ME, 400 (45.5%), 172 (30.5%) in LRT and 11 isolates (6.4%), in IPD. Penicillin non-susceptible isolates were 651 (40.3%), mainly belonging to VTs, 611 (93.9%), including 535 (82.2%) of 19F. Conclusions Multiresistant isolates of serotype 19F were highly prevalent, especially from ME of young children but also from LRT of adults. Serotype 14 was the most common serotype in IPD. The rate of VTs was high and almost all PNSP were of VTs. There was great difference in vaccine coverage between sampling sites, also reflecting difference in vaccine coverage by age groups., The Landspitali University Hospital Research Fund grant.

Neðst á síðunni er hægt að nálgast ritgerðina í heild sinni með því að smella á hlekkinn View/Open 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 crosssectional 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 vi 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. Tilgangur: Að athuga notkun sýklalyfja meðal forskólabarna á Íslandi 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 miðeyrnabólgu. • 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 aldursárunum. Á svæðum þar sem sýklalyfjanotkunin var mikil var meiri notkun á breiðvirkum sýklalyfjum borið saman við hin iv 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 svæðunum. 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 sýklalyfjanotkun 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 hljóðhimnuröra