Antibiotic use and bacterial complications following upper respiratory tract infections: a population based study

Disclosure: the authors have nothing to disclose Thomas Cars, pharmacist1, Irene Eriksson, pharmacist1, 2, Anna Granath, ENT surgeon3, Björn Wettermark1, 2, associate professor in pharmacoepidemiology, Jenny Hellman, pharmacist4, Christer Norman, general practicioner4, Anders Ternhag, consultant in infectious diseases2, 4 1 Department of Healthcare Development, Public Healthcare Services Committee, Stockholm County Council, Stockholm, Sweden 2 Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden 3 Department of Clinical Science, Intervention and Technology, Karolinska Institutet and Ear, Nose and Throat Clinic Karolinska University Hospital, Stockholm, Sweden 4 Public Health Agency of Sweden, Solna, Sweden Disclosure: the authors have nothing to disclose

Objectives Method for continuous monitoring of incidence of upper respiratory tract infections (URTIs), antibiotic use and frequency of complications due to concerns on safety of restrictive antibiotic guidelines (AOM, tonsillitis, sinusitis) (MIRA- measures and indicators of good rationales in antibiotic use) Ecologic and prospective cohort study

Setting Primary care, outpatient specialist and inpatient care in Stockholm County, Sweden (2.2 million catchment area, approximately 23% of Swedish population) Collection and analyses of administrative healthcare data on consultations, diagnoses and dispensed prescription medicines from January, 2006, to January, 2016.

Main outcome measures Ecological study: 10 year trend analyses of incidence of URTIs, bacterial infections/complications and respiratory antibiotic use Prospective cohort study: Incidence of bacterial complications following URTIs in antibiotic-exposed and non-exposed patients.

Antibiotic exposure to respratory tract antibiotics Exposed  prescription dispensed within the episode Not exposed  no prescription, or the first antibiotic prescription dispensed on the same day as a recorded bacterial complication

Prospective cohort study: PPPP Prospective cohort study: Outpatients with diagnosis acute otitis media, tonsillitis, sinusitis or acute upper respiratory tract infections of multiple and unspecified sites AOM Stratification 4 sub-cohorts Tonsillitis Acute sinusitis Combination Sinusitis + URTI Unspecified (children mainly)

Definition of episode Complication/ mastoiditis Closes episode Dispensation Respiratory tract antibiotic Recorded AOM diagnosis Recorded AOM diagnosis Index date Recorded AOM diagnosis Recorded AOM diagnosis Index date ≥ 30 days Episode of AOM New episode of AOM

Exclusion criteria Episodes with the first diagnosis recorded in inpatient setting Episodes with incomplete data follow up Episodes with primary infection and complication recorded the first day

Databases The regional healthcare data warehouse of Stockholm County (VAL) and the Swedish Prescribed Drug Register. VAL: comprehensive administrative healthcare data for all Stockholm County residents (encrypted data)

Demographics and prescribed antibiotics From VAL : demographic data (age, gender), diagnoses (ICD-10) in primary care, outpatient specialist- and inpatient care , consultation dates , hospital admission and discharge dates, migration and death records. From the Swedish Prescribed Drug Register data on dispensed antibiotics (ATC codes)

Results ecological study Total utilization (for all URTIs) of respiratory tract antibiotics decreased by 32% (12<10 DDD/1000 inhabitants/day) (p<0.0001) Proportion of patients treated with antibiotics for AOM declined from 88% to 81% No increased trend for mastoiditis (p=0.0933) was observed.

Results ecological study No increased trend for mastoiditis (p=0.0933) was observed. Decline in number of diagnosed AOM episodes, meningitis and complicated sinusitis in children (ethmoidal origin, periorbital cellulitis)

Results AOM cohort study 82 582 individuals diagnosed with AOM without prescription of antibiotics (16%), and 435 362 individuals were treated with antibiotics (84%) No difference in risk for mastoiditis or meningitis for the non-exposed group 19 cases of mastoiditis and 5 cases of meningitis: AOM index date=recorded complication date

No antibiotic treatment Treated with antibiotics No of patients No of complications Risk per 10000 Mastoiditis after acute otitis media 0-4 45 473 6 1.32 243 141 23 0.95 5-14 21 294 3 1.41 88 741 13 1.46 15-64 12 676 1 0.79 93 582 9 0.96 65+ 2 412 - 7 809 1.28 Total1 81 864 10 1.22 4 33 273 46 1.06 Meningitis after acute otitis media 45 476 2 0.44 243 151 0.04 21 292 0.47 88 746 93 581 1.39 7 804 4 5.13 81 865 0.49 433 286 18 0.42

Conclusions Severe bacterial complications related to URTIs, including mastoiditis and meningitis in relation to AOM, were infrequent (less than 1.5/10 000 episodes Restrictive use of antibiotics for common URTIs  no increase of severe bacterial complications Many complications occur at the index date implying aggressive course of infections