Requests for new oral antibiotic prescriptions in children within 2 days: a Norwegian population-based study

Requests for new oral antibiotic prescriptions in children within 2 days: a Norwegian... Abstract Background Children commonly refuse to take antibiotics, which may induce parents to request new antibiotic prescriptions with different pharmaceutical characteristics. Objectives To investigate prescription changes for children 0–12 years receiving oral liquid or solid antibiotic formulations and to explore the relationships between prescription changes and characteristics related to the child, prescriber and antibiotic. Methods A population-based registry study based on data from the Norwegian Prescription Database (NorPD) from 2004 to 2016. Antibiotic prescription changes were defined as the dispensing of subsequent antibiotics with different pharmaceutical characteristics to the same child within 2 days after initial prescriptions. Data were analysed using multivariable logistic regression and generalized estimating equations. Results Requests for new prescriptions followed 3.0% of 2 691 483 initial antibiotic prescriptions for children. Young children who received solid formulations (10.9%) and certain poor-tasting antibiotics (8.6%) had the highest proportions of new prescriptions. Penicillin V was most commonly changed, while macrolides/lincosamides dominated subsequent prescriptions. In order of magnitude, the characteristics associated with requests for new prescriptions were the children’s ages, poor taste and concentration of liquids, size and shape of solids, prescribers born in recent decades, and girl patients. Reimbursed prescriptions and scored solids were associated with fewer requests. Conclusions While only 3% of the antibiotic prescriptions were changed, the preference of broad-spectrum over narrow-spectrum antibiotics for young children in this study mirrors international prescription patterns. Avoiding the costs of children’s refusal and consequent changes may thus be a motivation for choosing more preferred antibiotics. Anti-bacterial agents, child, preschool child, dosage form, prescriptions Introduction Antibiotics are the most commonly prescribed medicines for children in Europe (1). Worldwide, the prescription of antibiotics per child-year is highest in children 5 years and younger (0.5–3.4) and lowest in children 6–12 years (0.2–0.8) (2). Administering antibiotics to children can be challenging, and French parents reported in a survey that their child spat out at least one dose of antibiotics in 22% of the cases (3). In a recent qualitative study, parents said they battled with unwilling children and used several strategies to administer unpalatable antibiotics (4). If unable to get the child to take the medicine, parents sometimes went to the trouble of requesting a new antibiotic prescription (4,5). Such requests represent situations of negative interaction between children and parents and may reduce children’s well-being through treatment delay. Children are also at risk of increased side effects from second-line antibiotics (6). Parents spend time and money on unused antibiotics that later may be administered inappropriately (7), and health-care resources may be wasted in the form of extra time and effort by the prescriber and pharmacy. To better understand the magnitude and nature of this problem in clinical practice, studies exploring changes in antibiotic prescriptions are needed. In a previous Danish study, 5% of <30 000 prescriptions were followed by a new prescription within 2 days for children 0–5 years (8), and a similar study found that penicillin V was changed 3.7 times more often than amoxicillin (9). The authors concluded that this could be caused by differences in palatability and found support for this in previous taste tests (10). In addition to taste, a survey of adolescents and parents of children with chronic diseases in Great Britain showed that formulation factors such as size, shape and volume as well as child’s age were correlated with children’s refusal of medicine (11). Prescriber characteristics may also be associated with use of medicines, as prescription patterns change based on a prescriber’s experience (12,13). Identifying factors related to changed prescriptions can be used to discover trends and population preferences and can be used to cause awareness and design interventions. To some extent, this can be explored in clinical practice using data from entire populations provided by national registers, such as the Norwegian Prescription Database (NorPD) (14). The aim of this study was therefore to investigate prescriptions of oral liquid and solid antibiotic formulations changed within 2 days to antibiotics with different characteristics in children 0–12 years of age in Norway during the period from 2004 to 2016. Furthermore, associations between prescription changes and child, prescriber and antibiotic characteristics were investigated separately for solid and liquid antibiotics. Methods Study design and data source This is a population-based registry study based on data on all prescriptions of oral systemic antibiotics dispensed to children from 2004 to 2016 in the NorPD. Children aged 0–12 were included to explore changes of antibiotic prescriptions across age intervals when both liquid and solid formulations were common (15). The NorPD contains information for all prescription medicines, reimbursed or not, dispensed from Norwegian pharmacies since 1st January 2004 to all individual patients living outside institutions (14). Setting In Norway, systemic antibiotics are available by prescription only, and a physician must be contacted to obtain a new prescription. In the community setting, antibiotics are predominantly dispensed from pharmacies to patients. Exceptions are antibiotics dispensed directly to the patient from out-of-hours primary health care centres that stock a small quantity of medications for use when pharmacies are closed (16). Antibiotics are fully paid for by the child’s parents, except for children with severe/chronic conditions (e.g. immunodeficiency, cancer, or chronic urinary tract infections), whose antibiotic prescriptions are reimbursed. Reimbursed prescriptions accounted for 3.5%–5.4% of the antibiotics prescribed for children below 12 years of age in 2012 (2). Inclusion criteria All systemic oral antibiotic prescriptions classified according to the Anatomical Therapeutic Chemical (ATC) Classification System as ATC-code J01 were included with the exception of the antiseptic methenamine (ATC-code J01XX05). Changed antibiotic prescriptions Changed antibiotic prescriptions were defined as initial prescriptions that were followed by subsequent prescriptions with a different type of antibiotic or pharmaceutical characteristic (e.g. taste, size, shape, or strength/concentration) dispensed to the same child within 2 days. This period was chosen, as changes within the first 2 days were most likely caused by challenges related to the administration of antibiotics rather than lack of clinical effect (17). Prescription change served as the dependent variable and was categorized as either ‘yes’ or ‘no’. Characteristics Medication characteristics Formulations were classified as liquid (mixtures, drops, powder, and dispersible tablets) or solid (tablets and capsules). The shapes of solid formulations were categorized as a capsule, an oval/oblong or round tablet. Scored tablets with indented lines that ease splitting were an independent category. To compare the size of solids of different shapes, the cross-sectional area was computed using the measurement of width (w) and length (l) and the geometric formula (l − w)w + π (w/2)2. The sizes were categorized into four categories: small <20 mm2 (area of a 5-mm round tablet), medium 20–<79 mm2 (area of 10-mm round tablet), large 79–124 mm2 (area of size 1 capsule) or extra-large >124 mm2 . Information regarding the size, shape and scoring of the solids was obtained from the Scandinavian medicinal formularies (18–20), from pillbox (21), or directly from the pharmaceutical manufacturer via personal contact. For generic medications, no longer manufactured, size information was unavailable (1.7% of the prescriptions for solid antibiotics). These were assigned to the same size category as the original matching formulation (tablet or capsule). Antibiotics were grouped according to the ATC system and their overall prescription frequency: Penicillin V (ATC-code J01CE02), macrolides/lincosamides (ATC-code J01F), amoxicillin (ATC-code J01CA04) and others. Poor-tasting liquids included dicloxacillin, clindamycin, trimethoprim, co-amoxicillin and penicillin V, whose scores on taste tests were so low that the likelihood for rejection by children was a concern (10,22,23). Drops were included as a separate variable, as the concentration of antibiotic liquids is believed to influence their use in children (24). Child characteristics Both gender and age were included. Age was grouped as infants (0–1 years), toddlers (2–3 years), preschool children (4–5 years), school children (6–9 years) and pre-teens (10–12 years). Prescriber characteristics Prescribers were classified according to age, specialization and annual prescribing frequency. Age was defined by decade of birth. Specialization was categorized as general practitioner (GP) specialist, paediatrician, other specialist or no specialization. GP specialists have previously shown different antibiotic prescription patterns than non-GP specialists (25), which may influence antibiotic prescription changes. The annual prescribing frequency was grouped into quartiles due to a highly skewed distribution. Statistical analysis Logistic regression was used to assess the relationship between the antibiotic prescription changes and the characteristics of the child, prescriber and antibiotic. As antibiotic prescriptions could be changed several times for the same child, we used generalized estimating equations nested by children to account for possible correlations. Antibiotic prescription changes over time were analysed using univariable models, including the prescription year. Two multivariable models, including children and prescriber characteristics and either formulation characteristics (Model 1) or antibiotic groups (Model 2), were analysed separately for liquid and solid initial formulations due to the collinearity between formulation characteristics and antibiotic groups. Infants were references for liquids and pre-teens for solids due to their common use in these groups. The results from the univariable models were reported as odds ratios (OR) with a 95% confidence interval (95% CI), while multivariable models were reported as adjusted odds ratios (adjOR) with a 95% CI. P value of <0.01 was considered statistically significant. Several sensitivity analyses were performed to assess the robustness of the findings. First, antibiotic change was extended to 3 days after the initial prescription. Second, analyses were performed to reduce the contribution from children with more than four prescriptions per year per child (4% of all prescriptions) and from missing data by excluding prescriptions in 2004 [the year with the most missing patient IDs (26)] and children below 1 year of age, as there may have been a delay in receiving a national ID number. In addition, as Furadantin® is registered as a tablet but may be dispersed before administration, a sensitivity analysis was performed categorizing it as a liquid. The analyses were carried out using Stata version 13.1 (StataCorp, College Station, TX). Results The overall dataset consisted of 2 691 483 initial prescriptions of systemic antibiotics that were dispensed to children 0–12 years between 2004 and 2016 in Norway. Of these, 21 701 prescriptions were followed by new prescriptions on the same day (Day 0), 35 703 on Day 1 and 22 697 on Day 2, totaling 80 101 changed prescriptions (3.0%). Multiple prescriptions dispensed on the same day were excluded from the analyses as the lack of dispensing order did not allow us to identify the initial and changed antibiotic (1.6%, n = 43 769 prescriptions in 21 701 changes). Changes on Day 1–2 were therefore used for the analyses. The remaining dataset consisted of 2 670 754 initial prescriptions (1 976 238, 74% liquid and 694 516, 26% solid) dispensed to 861 991 children. The initial prescriptions were issued by 29 901 prescribers, and 41% (12 277) of these prescribers changed one or more prescriptions over the 13-year study period. Proportions and trends of antibiotic changes on Day 1–2 On Day 1–2, 58 400 (2.2%) prescriptions were changed, of which 42 434 (2.2%) were liquid and 15 966 (2.4%) were solid. The same prescriber issued both the initial and subsequent prescriptions in 45.9% of the cases. The proportion of prescription changes increased over time for solids but not liquids (10-year OR: 1.3 for solids and 1.0 for liquids) (Fig. 1a). Figure 1. View largeDownload slide Proportion of antibiotic prescription changes on Day 1–2 (%) for solid and liquid formulations for (a) year 2004–16 and (b) age 0–12 years for 2.6 million prescriptions of oral antibiotics from the Norwegian Prescription Database. Figure 1. View largeDownload slide Proportion of antibiotic prescription changes on Day 1–2 (%) for solid and liquid formulations for (a) year 2004–16 and (b) age 0–12 years for 2.6 million prescriptions of oral antibiotics from the Norwegian Prescription Database. Children below the age of 7 had a higher proportion of changes following prescription of solids, whereas children above 7 years had a higher proportion of changes following liquids. Two-year-old children had the highest proportion of changes following both solids (10.9%) and liquids (2.7%) (Fig. 1b). Among individual oral antibiotics with at least 5000 prescriptions, amoxicillin had the lowest proportion of changes for both liquids (0.8%) and solids (1.0%) (Table 1). The highest proportion of liquid prescription changes were for dicloxacillin (8.6%) and penicillin V drops (4.9%), and for solids, it was penicillin V (4.7%). Table 1. Top five individual liquid and solid antibiotics with the highest and lowest proportions of antibiotic change for prescriptions of oral antibiotics from the Norwegian Prescription Database between 2004 and 2016 Antibiotic Formulationa Initial prescriptions (n) Antibiotic change (%) Tasteb/sizea Brand name Liquids most commonly changed Dicloxacillin Suspension 8740 8.6 Poor Diclocil® 12.5 mg/ml Penicillin V Drops/solution 19 378 4.9 Poor Weifapenin® 250 mg/ml Penicillin V Drops/solution 174 336 4.0 Poor Apocillin® 250 mg/ml Penicillin V Solution 170 714 3.5 Poor Weifapenin® 50 mg/ml Penicillin V Solution 434 782 3.0 Poor Apocillin® 50 mg/ml Liquids most seldom changed Amoxicillin Solution 222 439 0.8 Not poor Imacillin® 50 mg/ml Amoxicillin Solution 180 306 0.8 Not poor Imacillin® 100 mg/ml Cefalexin Suspension 38 194 0.8 Not poor Keflex® 50 mg/ml Amoxicillin Suspension 7617 0.9 Not poor Amoxicillin® 100 mg/ml Azitromycin Suspension 61 249 1.0 Not poor Azitromax® 40 mg/ml Solids most commonly changed Penicillin V Oval/scored 29 985 4.7 Medium Apocillin® 165 mg Erythromycin Oval 11 592 4.0 Extra-large Abboticin® ES 500 mg Erythromycin Capsule 68 709 3.8 Large Ery-Max® 250 mg Dicloxacillin Capsule 37 147 3.3 Large Diclocil® 250 mg Pivmecillinam Round 23 494 3.3 Medium Penomax® 200 mg Solids most seldom changed Amoxicillin Round/scored 5982 1.0 Medium Imacillin® 250 mg Cefalexin Oval/scored 5207 1.2 Large Keflex® 500 mg Amoxicillin Capsule 10 534 1.2 Large Amoxicillin®Mylan 250 mg Azitromycin Oval/scored 9962 1.3 Extra-large Azitromax® 500 mg Trimethoprim Round/scored 11 272 1.3 Medium Trimetoprim®Orion 100 mg Antibiotic Formulationa Initial prescriptions (n) Antibiotic change (%) Tasteb/sizea Brand name Liquids most commonly changed Dicloxacillin Suspension 8740 8.6 Poor Diclocil® 12.5 mg/ml Penicillin V Drops/solution 19 378 4.9 Poor Weifapenin® 250 mg/ml Penicillin V Drops/solution 174 336 4.0 Poor Apocillin® 250 mg/ml Penicillin V Solution 170 714 3.5 Poor Weifapenin® 50 mg/ml Penicillin V Solution 434 782 3.0 Poor Apocillin® 50 mg/ml Liquids most seldom changed Amoxicillin Solution 222 439 0.8 Not poor Imacillin® 50 mg/ml Amoxicillin Solution 180 306 0.8 Not poor Imacillin® 100 mg/ml Cefalexin Suspension 38 194 0.8 Not poor Keflex® 50 mg/ml Amoxicillin Suspension 7617 0.9 Not poor Amoxicillin® 100 mg/ml Azitromycin Suspension 61 249 1.0 Not poor Azitromax® 40 mg/ml Solids most commonly changed Penicillin V Oval/scored 29 985 4.7 Medium Apocillin® 165 mg Erythromycin Oval 11 592 4.0 Extra-large Abboticin® ES 500 mg Erythromycin Capsule 68 709 3.8 Large Ery-Max® 250 mg Dicloxacillin Capsule 37 147 3.3 Large Diclocil® 250 mg Pivmecillinam Round 23 494 3.3 Medium Penomax® 200 mg Solids most seldom changed Amoxicillin Round/scored 5982 1.0 Medium Imacillin® 250 mg Cefalexin Oval/scored 5207 1.2 Large Keflex® 500 mg Amoxicillin Capsule 10 534 1.2 Large Amoxicillin®Mylan 250 mg Azitromycin Oval/scored 9962 1.3 Extra-large Azitromax® 500 mg Trimethoprim Round/scored 11 272 1.3 Medium Trimetoprim®Orion 100 mg Only antibiotics with >5000 initial prescriptions included. aFormulation and size (medium: 20–<79 mm2, large: 79–124 mm2, extra-large: >124 mm2) based on information mainly from Scandinavian formularies (18–20). bTaste according to taste test references by Steele et al. (10,22,23), where poor taste equals a score of 4 or less on a 10-point scale. View Large Table 1. Top five individual liquid and solid antibiotics with the highest and lowest proportions of antibiotic change for prescriptions of oral antibiotics from the Norwegian Prescription Database between 2004 and 2016 Antibiotic Formulationa Initial prescriptions (n) Antibiotic change (%) Tasteb/sizea Brand name Liquids most commonly changed Dicloxacillin Suspension 8740 8.6 Poor Diclocil® 12.5 mg/ml Penicillin V Drops/solution 19 378 4.9 Poor Weifapenin® 250 mg/ml Penicillin V Drops/solution 174 336 4.0 Poor Apocillin® 250 mg/ml Penicillin V Solution 170 714 3.5 Poor Weifapenin® 50 mg/ml Penicillin V Solution 434 782 3.0 Poor Apocillin® 50 mg/ml Liquids most seldom changed Amoxicillin Solution 222 439 0.8 Not poor Imacillin® 50 mg/ml Amoxicillin Solution 180 306 0.8 Not poor Imacillin® 100 mg/ml Cefalexin Suspension 38 194 0.8 Not poor Keflex® 50 mg/ml Amoxicillin Suspension 7617 0.9 Not poor Amoxicillin® 100 mg/ml Azitromycin Suspension 61 249 1.0 Not poor Azitromax® 40 mg/ml Solids most commonly changed Penicillin V Oval/scored 29 985 4.7 Medium Apocillin® 165 mg Erythromycin Oval 11 592 4.0 Extra-large Abboticin® ES 500 mg Erythromycin Capsule 68 709 3.8 Large Ery-Max® 250 mg Dicloxacillin Capsule 37 147 3.3 Large Diclocil® 250 mg Pivmecillinam Round 23 494 3.3 Medium Penomax® 200 mg Solids most seldom changed Amoxicillin Round/scored 5982 1.0 Medium Imacillin® 250 mg Cefalexin Oval/scored 5207 1.2 Large Keflex® 500 mg Amoxicillin Capsule 10 534 1.2 Large Amoxicillin®Mylan 250 mg Azitromycin Oval/scored 9962 1.3 Extra-large Azitromax® 500 mg Trimethoprim Round/scored 11 272 1.3 Medium Trimetoprim®Orion 100 mg Antibiotic Formulationa Initial prescriptions (n) Antibiotic change (%) Tasteb/sizea Brand name Liquids most commonly changed Dicloxacillin Suspension 8740 8.6 Poor Diclocil® 12.5 mg/ml Penicillin V Drops/solution 19 378 4.9 Poor Weifapenin® 250 mg/ml Penicillin V Drops/solution 174 336 4.0 Poor Apocillin® 250 mg/ml Penicillin V Solution 170 714 3.5 Poor Weifapenin® 50 mg/ml Penicillin V Solution 434 782 3.0 Poor Apocillin® 50 mg/ml Liquids most seldom changed Amoxicillin Solution 222 439 0.8 Not poor Imacillin® 50 mg/ml Amoxicillin Solution 180 306 0.8 Not poor Imacillin® 100 mg/ml Cefalexin Suspension 38 194 0.8 Not poor Keflex® 50 mg/ml Amoxicillin Suspension 7617 0.9 Not poor Amoxicillin® 100 mg/ml Azitromycin Suspension 61 249 1.0 Not poor Azitromax® 40 mg/ml Solids most commonly changed Penicillin V Oval/scored 29 985 4.7 Medium Apocillin® 165 mg Erythromycin Oval 11 592 4.0 Extra-large Abboticin® ES 500 mg Erythromycin Capsule 68 709 3.8 Large Ery-Max® 250 mg Dicloxacillin Capsule 37 147 3.3 Large Diclocil® 250 mg Pivmecillinam Round 23 494 3.3 Medium Penomax® 200 mg Solids most seldom changed Amoxicillin Round/scored 5982 1.0 Medium Imacillin® 250 mg Cefalexin Oval/scored 5207 1.2 Large Keflex® 500 mg Amoxicillin Capsule 10 534 1.2 Large Amoxicillin®Mylan 250 mg Azitromycin Oval/scored 9962 1.3 Extra-large Azitromax® 500 mg Trimethoprim Round/scored 11 272 1.3 Medium Trimetoprim®Orion 100 mg Only antibiotics with >5000 initial prescriptions included. aFormulation and size (medium: 20–<79 mm2, large: 79–124 mm2, extra-large: >124 mm2) based on information mainly from Scandinavian formularies (18–20). bTaste according to taste test references by Steele et al. (10,22,23), where poor taste equals a score of 4 or less on a 10-point scale. View Large Characteristics associated with requests for new prescriptions following liquid antibiotics In the multivariable models, changes associated with liquid antibiotic prescriptions were (in decreasing magnitude) as follows: antibiotic taste, reimbursed prescriptions, drops, children’s age, prescriber’s birth decade and number of prescriptions issued per year, and gender (Table 2). Table 2. Liquids: characteristics associated with liquid antibiotic formulations that were changed to a prescription with a different antibiotic or pharmaceutical characteristic from the Norwegian Prescription Database between 2004 and 2016 Liquid formulation Characteristics Initial prescriptions (IP), n = 1 976 238 Subsequent prescriptions (% of IP) Univariable OR (95% CI) Model 1: Liquid characteristics Model 2: Antibiotics Multivariable adjOR: (95% CI) Multivariable adjOR: (95% CI) Child  Age group   Infant 0–1 years 623 791 12 561 (2.0) Reference Reference Reference   Toddler 2–3 years 640 816 16 277 (2.5) 1.27 (1.24–1.30) 1.27 (1.24–1.30) 1.26 (1.23–1.29)   Preschool 4–5 years 396 021 7335 (1.9) 0.93 (0.90–0.95) 0.91 (0.88–0.93) 0.89 (0.87–0.92)   School 6–9 years 274 862 5359 (2.0) 0.98 (0.95–1.02) 1.01 (0.97–1.04) 0.99 (0.96–1.02)   Pre-teen 10–12 years 40 748 902 (2.2) 1.13 (1.06–1.22) 1.22 (1.14–1.31) 1.17 (1.09–1.26)  Girl 962 148 20 926 (2.2) 1.03 (1.01–1.05) 1.02 (1.00–1.05) 1.07 (1.05–1.09)  Reimbursed AB 83 825 850 (1.0) 0.46 (0.43–0.50) 0.53 (0.49–0.58) 0.66 (0.61–0.72) Prescriber  Specialist   None 974 765 23 082 (2.4) Reference Reference Reference   GP 815 927 16 405 (2.0) 0.85 (0.83–0.86) 0.97 (0.94–0.99) 0.98 (0.96–1.01)   Paediatrician 98 565 1449 (1.5) 0.65 (0.61–0.69) 0.92 (0.86–0.97) 0.92 (0.87–0.98)   Other 86 981 1498 (1.7) 0.73 (0.69–0.77) 0.92 (0.87–0.97) 0.96 (0.91–1.01)  Birth year   Before 1950 175 637 3215 (1.8) Reference Reference Reference   1950–59 499 770 9300 (1.9) 1.01 (0.97–1.06) 1.02 (0.98–1.06) 1.02 (0.98–1.07)   1960–69 502 622 10 431 (2.1) 1.13 (1.09–1.18) 1.07 (1.03–1.12) 1.08 (1.03–1.13)   1970–79 572 659 13 565 (2.4) 1.29 (1.24–1.35) 1.11 (1.07–1.16) 1.13 (1.08–1.18)   After 1980 224 634 5903 (2.2) 1.44 (1.37–1.50) 1.20 (1.14–1.26) 1.19 (1.13–1.25)  Female prescriber 729 961 16 156 (2.2) 1.05 (1.03–1.07) 0.97 (0.95–0.99) 0.98 (0.96–1.00)  AB prescriptions per year (quartiles)   <23 461 948 10 308 (2.2) Reference Reference Reference   24–42 489 763 11 095 (2.3) 1.01 (0.99–1.04) 1.06 (1.03–1.09) 1.07 (1.04–1.10)   43–73 511 290 10 056 (2.2) 0.97 (0.94–0.99) 1.08 (1.05–1.11) 1.09 (1.06–1.12)   >73 513 237 9975 (1.9) 0.87 (0.84–0.89) 1.04 (1.01–1.07) 1.07 (1.04–1.10) Liquid antibiotic  Poor taste 968 756 29 954 (3.1) 2.60 (2.55–2.66) 2.35 (2.30–2.41)  Drops 194 192 7986 (4.2) 2.17 (2.12–2.23) 1.45 (1.41–1.49)  Antibiotics   Amoxicillin 412 145 3229 (0.8) Reference Reference   Dicloxacillin 8740 756 (8.7) 12.4 (11.4–13.5) 12.3 (11.3–13.4)   Penicillin V 799 380 26 825 (3.4) 4.55 (4.38–4.73) 4.52 (4.35–4.70)   Clarithromycin 55 237 938 (1.7) 2.22 (2.06–2.40) 2.34 (2.17–2.53)   Erythromycin 358 940 6037 (1.7) 2.21 (2.12–2.31) 2.24 (2.14–2.34)   Clindamycin 49 524 821 (1.7) 2.16 (1.99–2.34) 2.20 (2.03–2.39)   Trim-sulpha 79 725 1271 (1.6) 2.09 (1.95–2.24) 2.22 (2.07–2.38)   Trimethoprim 107 010 1475 (1.4) 1.82 (1.70–1.94) 1.93 (1.80–2.06)   Azitromycin 61 249 614 (1.0) 1.31 (1.20–1.44) 1.41 (1.28–1.55)   Cefalexin 38 194 324 (0.9) 1.04 (0.92–1.18) 1.09 (0.96–1.24) Liquid formulation Characteristics Initial prescriptions (IP), n = 1 976 238 Subsequent prescriptions (% of IP) Univariable OR (95% CI) Model 1: Liquid characteristics Model 2: Antibiotics Multivariable adjOR: (95% CI) Multivariable adjOR: (95% CI) Child  Age group   Infant 0–1 years 623 791 12 561 (2.0) Reference Reference Reference   Toddler 2–3 years 640 816 16 277 (2.5) 1.27 (1.24–1.30) 1.27 (1.24–1.30) 1.26 (1.23–1.29)   Preschool 4–5 years 396 021 7335 (1.9) 0.93 (0.90–0.95) 0.91 (0.88–0.93) 0.89 (0.87–0.92)   School 6–9 years 274 862 5359 (2.0) 0.98 (0.95–1.02) 1.01 (0.97–1.04) 0.99 (0.96–1.02)   Pre-teen 10–12 years 40 748 902 (2.2) 1.13 (1.06–1.22) 1.22 (1.14–1.31) 1.17 (1.09–1.26)  Girl 962 148 20 926 (2.2) 1.03 (1.01–1.05) 1.02 (1.00–1.05) 1.07 (1.05–1.09)  Reimbursed AB 83 825 850 (1.0) 0.46 (0.43–0.50) 0.53 (0.49–0.58) 0.66 (0.61–0.72) Prescriber  Specialist   None 974 765 23 082 (2.4) Reference Reference Reference   GP 815 927 16 405 (2.0) 0.85 (0.83–0.86) 0.97 (0.94–0.99) 0.98 (0.96–1.01)   Paediatrician 98 565 1449 (1.5) 0.65 (0.61–0.69) 0.92 (0.86–0.97) 0.92 (0.87–0.98)   Other 86 981 1498 (1.7) 0.73 (0.69–0.77) 0.92 (0.87–0.97) 0.96 (0.91–1.01)  Birth year   Before 1950 175 637 3215 (1.8) Reference Reference Reference   1950–59 499 770 9300 (1.9) 1.01 (0.97–1.06) 1.02 (0.98–1.06) 1.02 (0.98–1.07)   1960–69 502 622 10 431 (2.1) 1.13 (1.09–1.18) 1.07 (1.03–1.12) 1.08 (1.03–1.13)   1970–79 572 659 13 565 (2.4) 1.29 (1.24–1.35) 1.11 (1.07–1.16) 1.13 (1.08–1.18)   After 1980 224 634 5903 (2.2) 1.44 (1.37–1.50) 1.20 (1.14–1.26) 1.19 (1.13–1.25)  Female prescriber 729 961 16 156 (2.2) 1.05 (1.03–1.07) 0.97 (0.95–0.99) 0.98 (0.96–1.00)  AB prescriptions per year (quartiles)   <23 461 948 10 308 (2.2) Reference Reference Reference   24–42 489 763 11 095 (2.3) 1.01 (0.99–1.04) 1.06 (1.03–1.09) 1.07 (1.04–1.10)   43–73 511 290 10 056 (2.2) 0.97 (0.94–0.99) 1.08 (1.05–1.11) 1.09 (1.06–1.12)   >73 513 237 9975 (1.9) 0.87 (0.84–0.89) 1.04 (1.01–1.07) 1.07 (1.04–1.10) Liquid antibiotic  Poor taste 968 756 29 954 (3.1) 2.60 (2.55–2.66) 2.35 (2.30–2.41)  Drops 194 192 7986 (4.2) 2.17 (2.12–2.23) 1.45 (1.41–1.49)  Antibiotics   Amoxicillin 412 145 3229 (0.8) Reference Reference   Dicloxacillin 8740 756 (8.7) 12.4 (11.4–13.5) 12.3 (11.3–13.4)   Penicillin V 799 380 26 825 (3.4) 4.55 (4.38–4.73) 4.52 (4.35–4.70)   Clarithromycin 55 237 938 (1.7) 2.22 (2.06–2.40) 2.34 (2.17–2.53)   Erythromycin 358 940 6037 (1.7) 2.21 (2.12–2.31) 2.24 (2.14–2.34)   Clindamycin 49 524 821 (1.7) 2.16 (1.99–2.34) 2.20 (2.03–2.39)   Trim-sulpha 79 725 1271 (1.6) 2.09 (1.95–2.24) 2.22 (2.07–2.38)   Trimethoprim 107 010 1475 (1.4) 1.82 (1.70–1.94) 1.93 (1.80–2.06)   Azitromycin 61 249 614 (1.0) 1.31 (1.20–1.44) 1.41 (1.28–1.55)   Cefalexin 38 194 324 (0.9) 1.04 (0.92–1.18) 1.09 (0.96–1.24) Multivariable models were also adjusted for the year the AB was dispensed. Only antibiotics with >5000 prescriptions are listed. Bold indicates P < 0.01. AB, antibiotic; adjOR, adjusted odds ratio; CI, confidence interval; OR, odds ratio. View Large Table 2. Liquids: characteristics associated with liquid antibiotic formulations that were changed to a prescription with a different antibiotic or pharmaceutical characteristic from the Norwegian Prescription Database between 2004 and 2016 Liquid formulation Characteristics Initial prescriptions (IP), n = 1 976 238 Subsequent prescriptions (% of IP) Univariable OR (95% CI) Model 1: Liquid characteristics Model 2: Antibiotics Multivariable adjOR: (95% CI) Multivariable adjOR: (95% CI) Child  Age group   Infant 0–1 years 623 791 12 561 (2.0) Reference Reference Reference   Toddler 2–3 years 640 816 16 277 (2.5) 1.27 (1.24–1.30) 1.27 (1.24–1.30) 1.26 (1.23–1.29)   Preschool 4–5 years 396 021 7335 (1.9) 0.93 (0.90–0.95) 0.91 (0.88–0.93) 0.89 (0.87–0.92)   School 6–9 years 274 862 5359 (2.0) 0.98 (0.95–1.02) 1.01 (0.97–1.04) 0.99 (0.96–1.02)   Pre-teen 10–12 years 40 748 902 (2.2) 1.13 (1.06–1.22) 1.22 (1.14–1.31) 1.17 (1.09–1.26)  Girl 962 148 20 926 (2.2) 1.03 (1.01–1.05) 1.02 (1.00–1.05) 1.07 (1.05–1.09)  Reimbursed AB 83 825 850 (1.0) 0.46 (0.43–0.50) 0.53 (0.49–0.58) 0.66 (0.61–0.72) Prescriber  Specialist   None 974 765 23 082 (2.4) Reference Reference Reference   GP 815 927 16 405 (2.0) 0.85 (0.83–0.86) 0.97 (0.94–0.99) 0.98 (0.96–1.01)   Paediatrician 98 565 1449 (1.5) 0.65 (0.61–0.69) 0.92 (0.86–0.97) 0.92 (0.87–0.98)   Other 86 981 1498 (1.7) 0.73 (0.69–0.77) 0.92 (0.87–0.97) 0.96 (0.91–1.01)  Birth year   Before 1950 175 637 3215 (1.8) Reference Reference Reference   1950–59 499 770 9300 (1.9) 1.01 (0.97–1.06) 1.02 (0.98–1.06) 1.02 (0.98–1.07)   1960–69 502 622 10 431 (2.1) 1.13 (1.09–1.18) 1.07 (1.03–1.12) 1.08 (1.03–1.13)   1970–79 572 659 13 565 (2.4) 1.29 (1.24–1.35) 1.11 (1.07–1.16) 1.13 (1.08–1.18)   After 1980 224 634 5903 (2.2) 1.44 (1.37–1.50) 1.20 (1.14–1.26) 1.19 (1.13–1.25)  Female prescriber 729 961 16 156 (2.2) 1.05 (1.03–1.07) 0.97 (0.95–0.99) 0.98 (0.96–1.00)  AB prescriptions per year (quartiles)   <23 461 948 10 308 (2.2) Reference Reference Reference   24–42 489 763 11 095 (2.3) 1.01 (0.99–1.04) 1.06 (1.03–1.09) 1.07 (1.04–1.10)   43–73 511 290 10 056 (2.2) 0.97 (0.94–0.99) 1.08 (1.05–1.11) 1.09 (1.06–1.12)   >73 513 237 9975 (1.9) 0.87 (0.84–0.89) 1.04 (1.01–1.07) 1.07 (1.04–1.10) Liquid antibiotic  Poor taste 968 756 29 954 (3.1) 2.60 (2.55–2.66) 2.35 (2.30–2.41)  Drops 194 192 7986 (4.2) 2.17 (2.12–2.23) 1.45 (1.41–1.49)  Antibiotics   Amoxicillin 412 145 3229 (0.8) Reference Reference   Dicloxacillin 8740 756 (8.7) 12.4 (11.4–13.5) 12.3 (11.3–13.4)   Penicillin V 799 380 26 825 (3.4) 4.55 (4.38–4.73) 4.52 (4.35–4.70)   Clarithromycin 55 237 938 (1.7) 2.22 (2.06–2.40) 2.34 (2.17–2.53)   Erythromycin 358 940 6037 (1.7) 2.21 (2.12–2.31) 2.24 (2.14–2.34)   Clindamycin 49 524 821 (1.7) 2.16 (1.99–2.34) 2.20 (2.03–2.39)   Trim-sulpha 79 725 1271 (1.6) 2.09 (1.95–2.24) 2.22 (2.07–2.38)   Trimethoprim 107 010 1475 (1.4) 1.82 (1.70–1.94) 1.93 (1.80–2.06)   Azitromycin 61 249 614 (1.0) 1.31 (1.20–1.44) 1.41 (1.28–1.55)   Cefalexin 38 194 324 (0.9) 1.04 (0.92–1.18) 1.09 (0.96–1.24) Liquid formulation Characteristics Initial prescriptions (IP), n = 1 976 238 Subsequent prescriptions (% of IP) Univariable OR (95% CI) Model 1: Liquid characteristics Model 2: Antibiotics Multivariable adjOR: (95% CI) Multivariable adjOR: (95% CI) Child  Age group   Infant 0–1 years 623 791 12 561 (2.0) Reference Reference Reference   Toddler 2–3 years 640 816 16 277 (2.5) 1.27 (1.24–1.30) 1.27 (1.24–1.30) 1.26 (1.23–1.29)   Preschool 4–5 years 396 021 7335 (1.9) 0.93 (0.90–0.95) 0.91 (0.88–0.93) 0.89 (0.87–0.92)   School 6–9 years 274 862 5359 (2.0) 0.98 (0.95–1.02) 1.01 (0.97–1.04) 0.99 (0.96–1.02)   Pre-teen 10–12 years 40 748 902 (2.2) 1.13 (1.06–1.22) 1.22 (1.14–1.31) 1.17 (1.09–1.26)  Girl 962 148 20 926 (2.2) 1.03 (1.01–1.05) 1.02 (1.00–1.05) 1.07 (1.05–1.09)  Reimbursed AB 83 825 850 (1.0) 0.46 (0.43–0.50) 0.53 (0.49–0.58) 0.66 (0.61–0.72) Prescriber  Specialist   None 974 765 23 082 (2.4) Reference Reference Reference   GP 815 927 16 405 (2.0) 0.85 (0.83–0.86) 0.97 (0.94–0.99) 0.98 (0.96–1.01)   Paediatrician 98 565 1449 (1.5) 0.65 (0.61–0.69) 0.92 (0.86–0.97) 0.92 (0.87–0.98)   Other 86 981 1498 (1.7) 0.73 (0.69–0.77) 0.92 (0.87–0.97) 0.96 (0.91–1.01)  Birth year   Before 1950 175 637 3215 (1.8) Reference Reference Reference   1950–59 499 770 9300 (1.9) 1.01 (0.97–1.06) 1.02 (0.98–1.06) 1.02 (0.98–1.07)   1960–69 502 622 10 431 (2.1) 1.13 (1.09–1.18) 1.07 (1.03–1.12) 1.08 (1.03–1.13)   1970–79 572 659 13 565 (2.4) 1.29 (1.24–1.35) 1.11 (1.07–1.16) 1.13 (1.08–1.18)   After 1980 224 634 5903 (2.2) 1.44 (1.37–1.50) 1.20 (1.14–1.26) 1.19 (1.13–1.25)  Female prescriber 729 961 16 156 (2.2) 1.05 (1.03–1.07) 0.97 (0.95–0.99) 0.98 (0.96–1.00)  AB prescriptions per year (quartiles)   <23 461 948 10 308 (2.2) Reference Reference Reference   24–42 489 763 11 095 (2.3) 1.01 (0.99–1.04) 1.06 (1.03–1.09) 1.07 (1.04–1.10)   43–73 511 290 10 056 (2.2) 0.97 (0.94–0.99) 1.08 (1.05–1.11) 1.09 (1.06–1.12)   >73 513 237 9975 (1.9) 0.87 (0.84–0.89) 1.04 (1.01–1.07) 1.07 (1.04–1.10) Liquid antibiotic  Poor taste 968 756 29 954 (3.1) 2.60 (2.55–2.66) 2.35 (2.30–2.41)  Drops 194 192 7986 (4.2) 2.17 (2.12–2.23) 1.45 (1.41–1.49)  Antibiotics   Amoxicillin 412 145 3229 (0.8) Reference Reference   Dicloxacillin 8740 756 (8.7) 12.4 (11.4–13.5) 12.3 (11.3–13.4)   Penicillin V 799 380 26 825 (3.4) 4.55 (4.38–4.73) 4.52 (4.35–4.70)   Clarithromycin 55 237 938 (1.7) 2.22 (2.06–2.40) 2.34 (2.17–2.53)   Erythromycin 358 940 6037 (1.7) 2.21 (2.12–2.31) 2.24 (2.14–2.34)   Clindamycin 49 524 821 (1.7) 2.16 (1.99–2.34) 2.20 (2.03–2.39)   Trim-sulpha 79 725 1271 (1.6) 2.09 (1.95–2.24) 2.22 (2.07–2.38)   Trimethoprim 107 010 1475 (1.4) 1.82 (1.70–1.94) 1.93 (1.80–2.06)   Azitromycin 61 249 614 (1.0) 1.31 (1.20–1.44) 1.41 (1.28–1.55)   Cefalexin 38 194 324 (0.9) 1.04 (0.92–1.18) 1.09 (0.96–1.24) Multivariable models were also adjusted for the year the AB was dispensed. Only antibiotics with >5000 prescriptions are listed. Bold indicates P < 0.01. AB, antibiotic; adjOR, adjusted odds ratio; CI, confidence interval; OR, odds ratio. View Large Compared with infants (0–1 years), prescriptions dispensed to toddlers (2–3 years) had the strongest association with prescription changes (adjOR: 1.3) followed by pre-teens (adjOR: 1.2) (Table 2). Reimbursed prescriptions dispensed to children with a chronic disease were least associated with changes (adjOR: 0.7). Girls had significantly higher odds than boys for prescription changes (adjOR: 1.07). Younger prescribers were more strongly associated with changes compared with those born before 1950 (born after 1980, adjOR: 1.2). The variables most strongly associated with a high number of prescription changes were antibiotics with a poor taste (adjOR: 2.4) and drops (adjOR: 1.5) (Table 2). Characteristics associated with requests for new prescriptions following solid antibiotics The prescriber characteristics associated with solid antibiotic prescription changes were quite similar to the prescriber characteristics of liquid antibiotic prescription changes; however, the difference in the association of changes between age groups was much greater for solids than liquids (Table 3). Table 3. Solids: characteristics associated with solid antibiotic formulations that were changed to a prescription with a different antibiotic or pharmaceutical characteristic from the Norwegian Prescription Database (NorPD) between 2004 and 2016 Solid formulation Characteristics Initial prescriptions (IP) n = 694 516 Re-prescriptions (% of IP) Univariable OR (95% CI) Model 1: Solid characteristics Model 2: Antibiotics Multivariable adjOR: (95% CI) Multivariable adjOR: (95% CI) Child  Age group   Pre-teen 10–12 years 272 388 4156 (1.5) Reference Reference Reference   School 6–9 years 313 042 6046 (1.9) 1.28 (1.23–1.33) 1.40 (1.35–1.46) 1.38 (1.33–1.44)   Preschool 4–5 years 74 159 2856 (3.9) 2.61 (2.49–2.74) 3.06 (2.90–3.22) 3.13 (2.98–3.29)   Toddler 2–3 years 26 107 2275 (8.7) 6.25 (5.92–6.59) 7.86 (7.43–8.33) 8.25 (7.80–8.73)   Infant 0–1 years 8820 633 (7.2) 5.18 (4.74–5.67) 7.87 (7.16–8.66) 8.81 (7.99–9.71)  Girl 380 566 8790 (2.3) 1.01 (0.98–1.05) 1.06 (1.03–1.10) 1.06 (1.03–1.10)  Reimbursed AB 35 778 510 (1.4) 0.62 (0.57–0.68) 0.57 (0.52–0.63) 0.68 (0.61–0.76) Prescriber  Specialist   None (ref) 331 810 7935 (2.4) Reference Reference Reference   GP 306 018 6980 (2.3) 0.95 (0.92–0.99) 1.05 (1.01–1.10) 1.04 (1.00–1.08)   Paediatrician 26 286 524 (2.0) 0.86 (0.79–0.94) 0.96 (0.87–1.06) 1.00 (0.91–1.11)   Other 30 402 527 (1.7) 0.73 (0.66–0.79) 0.84 (0.77–0.92) 0.90 (0.82–0.99)  Birth year   Before 1950 67 823 1291 (1.9) Reference Reference Reference   1950–59 192 050 4023 (2.1) 1.10 (1.03–1.17) 1.02 (0.96–1.09) 1.02 (0.96–1.09)   1960–69 172 782 3912 (2.3) 1.19 (1.12–1.27) 1.09 (1.02–1.16) 1.08 (1.01–1.15)   1970–79 184 484 4549 (2.5) 1.30 (1.22–1.38) 1.16 (1.09–1.25) 1.15 (1.08–1.24)   After 1980 77 011 2186 (2.8) 1.49 (1.39–1.60) 1.26 (1.16–1.37) 1.25 (1.15–1.36)  Female prescriber 240 884 5660 (2.3) 1.04 (1.00–1.07) 0.98 (0.95–1.02) 0.97 (0.94–1.01)  AB Prescriptions per year (quart)   <23 208 436 4587 (2.2) Reference Reference Reference   24–42 174 434 4139 (2.4) 1.08 (1.04–1.13) 1.10 (1.05–1.15) 1.08 (1.04–1.13)   43–73 166 187 3965 (2.4) 1.09 (1.04–1.14) 1.15 (1.10–1.20) 1.13 (1.08–1.19)   >73 145 459 3275 (2.3) 1.03 (0.98–1.08) 1.14 (1.08–1.19) 1.13 (1.07–1.18) Solid antibiotic  Shape   Round 137 849 3023 (2.2) Reference Reference   Oval 399 566 8090 (2.0) 0.91 (0.88–0.95) 1.32 (1.25–1.39)   Capsule 157 101 4853 (3.1) 1.40 (1.34–1.47) 1.50 (1.41–1.60)  Scored 418 047 7849 (1.9) 0.63 (0.62–0.66) 0.64 (0.60–0.67)  Size   20–<79 mm2 360 892 7898 (2.2) Reference Reference   79–124 mm2 281 419 6887 (2.4) 1.12 (1.08–1.16) 1.06 (1.00–1.11)   >124 mm2 52 205 1181 (2.3) 1.04 (0.97–1.10) 1.19 (1.10–1.28)  Antibiotic   Amoxicillin 26 429 321 (1.2) Reference Reference   Erythromycin 80 309 3102 (3.9) 3.25 (2.90–3.65) 3.92 (3.49–4.42)   Dicloxacillin 55 097 1644 (3.0) 2.50 (2.22–2.82) 2.22 (1.96–2.51)   Clarithromycin 8971 169 (1.9) 1.56 (1.29–1.88) 2.10 (1.74–2.54)   Pivmecillinam 56 993 1780 (3.1) 2.63 (2.33–2.96) 1.83 (1.62–2.08)   Clindamycin 17 996 384 (2.1) 1.76 (1.52–2.05) 1.76 (1.51–2.05)   Penicillin V 355 262 7142 (2.0) 1.67 (1.49–1.87) 1.50 (1.34–1.68)   Azitromycin 9969 134 (1.3) 1.12 (0.91–1.37) 1.34 (1.09–1.64)   Doxycycline 5000 65 (1.3) 1.06 (0.81–1.38) 1.33 (1.01–1.75)   Trim-sulpha 14 964 210 (1.4) 1.18 (0.99–1.41) 1.26 (1.05–1.51)   Trimethoprim 22 510 305 (1.4) 1.13 (0.97–1.32) 1.17 (0.99–1.37)   Cefalexin 6 064 71 (1.2) 0.97 (0.75–1.26) 1.11 (0.86–1.44)   Nitrofurantoin 24 499 435 (1.8) 1.49 (1.28–1.72) 0.61 (0.52–0.72) Solid formulation Characteristics Initial prescriptions (IP) n = 694 516 Re-prescriptions (% of IP) Univariable OR (95% CI) Model 1: Solid characteristics Model 2: Antibiotics Multivariable adjOR: (95% CI) Multivariable adjOR: (95% CI) Child  Age group   Pre-teen 10–12 years 272 388 4156 (1.5) Reference Reference Reference   School 6–9 years 313 042 6046 (1.9) 1.28 (1.23–1.33) 1.40 (1.35–1.46) 1.38 (1.33–1.44)   Preschool 4–5 years 74 159 2856 (3.9) 2.61 (2.49–2.74) 3.06 (2.90–3.22) 3.13 (2.98–3.29)   Toddler 2–3 years 26 107 2275 (8.7) 6.25 (5.92–6.59) 7.86 (7.43–8.33) 8.25 (7.80–8.73)   Infant 0–1 years 8820 633 (7.2) 5.18 (4.74–5.67) 7.87 (7.16–8.66) 8.81 (7.99–9.71)  Girl 380 566 8790 (2.3) 1.01 (0.98–1.05) 1.06 (1.03–1.10) 1.06 (1.03–1.10)  Reimbursed AB 35 778 510 (1.4) 0.62 (0.57–0.68) 0.57 (0.52–0.63) 0.68 (0.61–0.76) Prescriber  Specialist   None (ref) 331 810 7935 (2.4) Reference Reference Reference   GP 306 018 6980 (2.3) 0.95 (0.92–0.99) 1.05 (1.01–1.10) 1.04 (1.00–1.08)   Paediatrician 26 286 524 (2.0) 0.86 (0.79–0.94) 0.96 (0.87–1.06) 1.00 (0.91–1.11)   Other 30 402 527 (1.7) 0.73 (0.66–0.79) 0.84 (0.77–0.92) 0.90 (0.82–0.99)  Birth year   Before 1950 67 823 1291 (1.9) Reference Reference Reference   1950–59 192 050 4023 (2.1) 1.10 (1.03–1.17) 1.02 (0.96–1.09) 1.02 (0.96–1.09)   1960–69 172 782 3912 (2.3) 1.19 (1.12–1.27) 1.09 (1.02–1.16) 1.08 (1.01–1.15)   1970–79 184 484 4549 (2.5) 1.30 (1.22–1.38) 1.16 (1.09–1.25) 1.15 (1.08–1.24)   After 1980 77 011 2186 (2.8) 1.49 (1.39–1.60) 1.26 (1.16–1.37) 1.25 (1.15–1.36)  Female prescriber 240 884 5660 (2.3) 1.04 (1.00–1.07) 0.98 (0.95–1.02) 0.97 (0.94–1.01)  AB Prescriptions per year (quart)   <23 208 436 4587 (2.2) Reference Reference Reference   24–42 174 434 4139 (2.4) 1.08 (1.04–1.13) 1.10 (1.05–1.15) 1.08 (1.04–1.13)   43–73 166 187 3965 (2.4) 1.09 (1.04–1.14) 1.15 (1.10–1.20) 1.13 (1.08–1.19)   >73 145 459 3275 (2.3) 1.03 (0.98–1.08) 1.14 (1.08–1.19) 1.13 (1.07–1.18) Solid antibiotic  Shape   Round 137 849 3023 (2.2) Reference Reference   Oval 399 566 8090 (2.0) 0.91 (0.88–0.95) 1.32 (1.25–1.39)   Capsule 157 101 4853 (3.1) 1.40 (1.34–1.47) 1.50 (1.41–1.60)  Scored 418 047 7849 (1.9) 0.63 (0.62–0.66) 0.64 (0.60–0.67)  Size   20–<79 mm2 360 892 7898 (2.2) Reference Reference   79–124 mm2 281 419 6887 (2.4) 1.12 (1.08–1.16) 1.06 (1.00–1.11)   >124 mm2 52 205 1181 (2.3) 1.04 (0.97–1.10) 1.19 (1.10–1.28)  Antibiotic   Amoxicillin 26 429 321 (1.2) Reference Reference   Erythromycin 80 309 3102 (3.9) 3.25 (2.90–3.65) 3.92 (3.49–4.42)   Dicloxacillin 55 097 1644 (3.0) 2.50 (2.22–2.82) 2.22 (1.96–2.51)   Clarithromycin 8971 169 (1.9) 1.56 (1.29–1.88) 2.10 (1.74–2.54)   Pivmecillinam 56 993 1780 (3.1) 2.63 (2.33–2.96) 1.83 (1.62–2.08)   Clindamycin 17 996 384 (2.1) 1.76 (1.52–2.05) 1.76 (1.51–2.05)   Penicillin V 355 262 7142 (2.0) 1.67 (1.49–1.87) 1.50 (1.34–1.68)   Azitromycin 9969 134 (1.3) 1.12 (0.91–1.37) 1.34 (1.09–1.64)   Doxycycline 5000 65 (1.3) 1.06 (0.81–1.38) 1.33 (1.01–1.75)   Trim-sulpha 14 964 210 (1.4) 1.18 (0.99–1.41) 1.26 (1.05–1.51)   Trimethoprim 22 510 305 (1.4) 1.13 (0.97–1.32) 1.17 (0.99–1.37)   Cefalexin 6 064 71 (1.2) 0.97 (0.75–1.26) 1.11 (0.86–1.44)   Nitrofurantoin 24 499 435 (1.8) 1.49 (1.28–1.72) 0.61 (0.52–0.72) Multivariable models were also adjusted for the year the AB was dispensed. Only antibiotics with >5000 prescriptions are listed. Bold indicates P < 0.01. AB, antibiotic; adjOR, adjusted odds ratio; CI, confidence interval; OR, odds ratio. View Large Table 3. Solids: characteristics associated with solid antibiotic formulations that were changed to a prescription with a different antibiotic or pharmaceutical characteristic from the Norwegian Prescription Database (NorPD) between 2004 and 2016 Solid formulation Characteristics Initial prescriptions (IP) n = 694 516 Re-prescriptions (% of IP) Univariable OR (95% CI) Model 1: Solid characteristics Model 2: Antibiotics Multivariable adjOR: (95% CI) Multivariable adjOR: (95% CI) Child  Age group   Pre-teen 10–12 years 272 388 4156 (1.5) Reference Reference Reference   School 6–9 years 313 042 6046 (1.9) 1.28 (1.23–1.33) 1.40 (1.35–1.46) 1.38 (1.33–1.44)   Preschool 4–5 years 74 159 2856 (3.9) 2.61 (2.49–2.74) 3.06 (2.90–3.22) 3.13 (2.98–3.29)   Toddler 2–3 years 26 107 2275 (8.7) 6.25 (5.92–6.59) 7.86 (7.43–8.33) 8.25 (7.80–8.73)   Infant 0–1 years 8820 633 (7.2) 5.18 (4.74–5.67) 7.87 (7.16–8.66) 8.81 (7.99–9.71)  Girl 380 566 8790 (2.3) 1.01 (0.98–1.05) 1.06 (1.03–1.10) 1.06 (1.03–1.10)  Reimbursed AB 35 778 510 (1.4) 0.62 (0.57–0.68) 0.57 (0.52–0.63) 0.68 (0.61–0.76) Prescriber  Specialist   None (ref) 331 810 7935 (2.4) Reference Reference Reference   GP 306 018 6980 (2.3) 0.95 (0.92–0.99) 1.05 (1.01–1.10) 1.04 (1.00–1.08)   Paediatrician 26 286 524 (2.0) 0.86 (0.79–0.94) 0.96 (0.87–1.06) 1.00 (0.91–1.11)   Other 30 402 527 (1.7) 0.73 (0.66–0.79) 0.84 (0.77–0.92) 0.90 (0.82–0.99)  Birth year   Before 1950 67 823 1291 (1.9) Reference Reference Reference   1950–59 192 050 4023 (2.1) 1.10 (1.03–1.17) 1.02 (0.96–1.09) 1.02 (0.96–1.09)   1960–69 172 782 3912 (2.3) 1.19 (1.12–1.27) 1.09 (1.02–1.16) 1.08 (1.01–1.15)   1970–79 184 484 4549 (2.5) 1.30 (1.22–1.38) 1.16 (1.09–1.25) 1.15 (1.08–1.24)   After 1980 77 011 2186 (2.8) 1.49 (1.39–1.60) 1.26 (1.16–1.37) 1.25 (1.15–1.36)  Female prescriber 240 884 5660 (2.3) 1.04 (1.00–1.07) 0.98 (0.95–1.02) 0.97 (0.94–1.01)  AB Prescriptions per year (quart)   <23 208 436 4587 (2.2) Reference Reference Reference   24–42 174 434 4139 (2.4) 1.08 (1.04–1.13) 1.10 (1.05–1.15) 1.08 (1.04–1.13)   43–73 166 187 3965 (2.4) 1.09 (1.04–1.14) 1.15 (1.10–1.20) 1.13 (1.08–1.19)   >73 145 459 3275 (2.3) 1.03 (0.98–1.08) 1.14 (1.08–1.19) 1.13 (1.07–1.18) Solid antibiotic  Shape   Round 137 849 3023 (2.2) Reference Reference   Oval 399 566 8090 (2.0) 0.91 (0.88–0.95) 1.32 (1.25–1.39)   Capsule 157 101 4853 (3.1) 1.40 (1.34–1.47) 1.50 (1.41–1.60)  Scored 418 047 7849 (1.9) 0.63 (0.62–0.66) 0.64 (0.60–0.67)  Size   20–<79 mm2 360 892 7898 (2.2) Reference Reference   79–124 mm2 281 419 6887 (2.4) 1.12 (1.08–1.16) 1.06 (1.00–1.11)   >124 mm2 52 205 1181 (2.3) 1.04 (0.97–1.10) 1.19 (1.10–1.28)  Antibiotic   Amoxicillin 26 429 321 (1.2) Reference Reference   Erythromycin 80 309 3102 (3.9) 3.25 (2.90–3.65) 3.92 (3.49–4.42)   Dicloxacillin 55 097 1644 (3.0) 2.50 (2.22–2.82) 2.22 (1.96–2.51)   Clarithromycin 8971 169 (1.9) 1.56 (1.29–1.88) 2.10 (1.74–2.54)   Pivmecillinam 56 993 1780 (3.1) 2.63 (2.33–2.96) 1.83 (1.62–2.08)   Clindamycin 17 996 384 (2.1) 1.76 (1.52–2.05) 1.76 (1.51–2.05)   Penicillin V 355 262 7142 (2.0) 1.67 (1.49–1.87) 1.50 (1.34–1.68)   Azitromycin 9969 134 (1.3) 1.12 (0.91–1.37) 1.34 (1.09–1.64)   Doxycycline 5000 65 (1.3) 1.06 (0.81–1.38) 1.33 (1.01–1.75)   Trim-sulpha 14 964 210 (1.4) 1.18 (0.99–1.41) 1.26 (1.05–1.51)   Trimethoprim 22 510 305 (1.4) 1.13 (0.97–1.32) 1.17 (0.99–1.37)   Cefalexin 6 064 71 (1.2) 0.97 (0.75–1.26) 1.11 (0.86–1.44)   Nitrofurantoin 24 499 435 (1.8) 1.49 (1.28–1.72) 0.61 (0.52–0.72) Solid formulation Characteristics Initial prescriptions (IP) n = 694 516 Re-prescriptions (% of IP) Univariable OR (95% CI) Model 1: Solid characteristics Model 2: Antibiotics Multivariable adjOR: (95% CI) Multivariable adjOR: (95% CI) Child  Age group   Pre-teen 10–12 years 272 388 4156 (1.5) Reference Reference Reference   School 6–9 years 313 042 6046 (1.9) 1.28 (1.23–1.33) 1.40 (1.35–1.46) 1.38 (1.33–1.44)   Preschool 4–5 years 74 159 2856 (3.9) 2.61 (2.49–2.74) 3.06 (2.90–3.22) 3.13 (2.98–3.29)   Toddler 2–3 years 26 107 2275 (8.7) 6.25 (5.92–6.59) 7.86 (7.43–8.33) 8.25 (7.80–8.73)   Infant 0–1 years 8820 633 (7.2) 5.18 (4.74–5.67) 7.87 (7.16–8.66) 8.81 (7.99–9.71)  Girl 380 566 8790 (2.3) 1.01 (0.98–1.05) 1.06 (1.03–1.10) 1.06 (1.03–1.10)  Reimbursed AB 35 778 510 (1.4) 0.62 (0.57–0.68) 0.57 (0.52–0.63) 0.68 (0.61–0.76) Prescriber  Specialist   None (ref) 331 810 7935 (2.4) Reference Reference Reference   GP 306 018 6980 (2.3) 0.95 (0.92–0.99) 1.05 (1.01–1.10) 1.04 (1.00–1.08)   Paediatrician 26 286 524 (2.0) 0.86 (0.79–0.94) 0.96 (0.87–1.06) 1.00 (0.91–1.11)   Other 30 402 527 (1.7) 0.73 (0.66–0.79) 0.84 (0.77–0.92) 0.90 (0.82–0.99)  Birth year   Before 1950 67 823 1291 (1.9) Reference Reference Reference   1950–59 192 050 4023 (2.1) 1.10 (1.03–1.17) 1.02 (0.96–1.09) 1.02 (0.96–1.09)   1960–69 172 782 3912 (2.3) 1.19 (1.12–1.27) 1.09 (1.02–1.16) 1.08 (1.01–1.15)   1970–79 184 484 4549 (2.5) 1.30 (1.22–1.38) 1.16 (1.09–1.25) 1.15 (1.08–1.24)   After 1980 77 011 2186 (2.8) 1.49 (1.39–1.60) 1.26 (1.16–1.37) 1.25 (1.15–1.36)  Female prescriber 240 884 5660 (2.3) 1.04 (1.00–1.07) 0.98 (0.95–1.02) 0.97 (0.94–1.01)  AB Prescriptions per year (quart)   <23 208 436 4587 (2.2) Reference Reference Reference   24–42 174 434 4139 (2.4) 1.08 (1.04–1.13) 1.10 (1.05–1.15) 1.08 (1.04–1.13)   43–73 166 187 3965 (2.4) 1.09 (1.04–1.14) 1.15 (1.10–1.20) 1.13 (1.08–1.19)   >73 145 459 3275 (2.3) 1.03 (0.98–1.08) 1.14 (1.08–1.19) 1.13 (1.07–1.18) Solid antibiotic  Shape   Round 137 849 3023 (2.2) Reference Reference   Oval 399 566 8090 (2.0) 0.91 (0.88–0.95) 1.32 (1.25–1.39)   Capsule 157 101 4853 (3.1) 1.40 (1.34–1.47) 1.50 (1.41–1.60)  Scored 418 047 7849 (1.9) 0.63 (0.62–0.66) 0.64 (0.60–0.67)  Size   20–<79 mm2 360 892 7898 (2.2) Reference Reference   79–124 mm2 281 419 6887 (2.4) 1.12 (1.08–1.16) 1.06 (1.00–1.11)   >124 mm2 52 205 1181 (2.3) 1.04 (0.97–1.10) 1.19 (1.10–1.28)  Antibiotic   Amoxicillin 26 429 321 (1.2) Reference Reference   Erythromycin 80 309 3102 (3.9) 3.25 (2.90–3.65) 3.92 (3.49–4.42)   Dicloxacillin 55 097 1644 (3.0) 2.50 (2.22–2.82) 2.22 (1.96–2.51)   Clarithromycin 8971 169 (1.9) 1.56 (1.29–1.88) 2.10 (1.74–2.54)   Pivmecillinam 56 993 1780 (3.1) 2.63 (2.33–2.96) 1.83 (1.62–2.08)   Clindamycin 17 996 384 (2.1) 1.76 (1.52–2.05) 1.76 (1.51–2.05)   Penicillin V 355 262 7142 (2.0) 1.67 (1.49–1.87) 1.50 (1.34–1.68)   Azitromycin 9969 134 (1.3) 1.12 (0.91–1.37) 1.34 (1.09–1.64)   Doxycycline 5000 65 (1.3) 1.06 (0.81–1.38) 1.33 (1.01–1.75)   Trim-sulpha 14 964 210 (1.4) 1.18 (0.99–1.41) 1.26 (1.05–1.51)   Trimethoprim 22 510 305 (1.4) 1.13 (0.97–1.32) 1.17 (0.99–1.37)   Cefalexin 6 064 71 (1.2) 0.97 (0.75–1.26) 1.11 (0.86–1.44)   Nitrofurantoin 24 499 435 (1.8) 1.49 (1.28–1.72) 0.61 (0.52–0.72) Multivariable models were also adjusted for the year the AB was dispensed. Only antibiotics with >5000 prescriptions are listed. Bold indicates P < 0.01. AB, antibiotic; adjOR, adjusted odds ratio; CI, confidence interval; OR, odds ratio. View Large Children below 4 years had almost eight times higher odds than pre-teens for changing a solid prescription. Prescriptions for both capsules and oval tablets were more strongly associated with prescription changes than round tablets (adjOR: 1.5 and 1.3, respectively), while scored tablets had a lower association (adjOR:0.6). There was also an influence of size, with extra-large solids having a stronger association with prescription changes (adjOR: 1.2) (Table 3). Initial and subsequent antibiotic prescriptions Of the initial prescriptions that were changed, penicillin V comprised the majority (58%) while amoxicillin was least commonly changed (6%) (Table 4). The macrolide/lincosamide group comprised most of the sequential prescriptions (36%). Of the initial macrolide/lincosamide antibiotics that were changed, 43% were followed by a subsequent prescription of a penicillin (penicillin V or amoxicillin). Table 4. Initial oral solid and liquid antibiotics and subsequent prescriptions with different antibiotics or pharmaceutical characteristics (e.g. taste, size, shape, or strength/concentration) from the Norwegian Prescription Database between 2004 and 2016 Initial prescription Subsequent prescription Penicillin V Macro/linco Amoxicillin Other Form Antibiotic Form (n) Solid (6509) Liquid (10 707) Solid (4039) Liquid (16 946) Solid (790) Liquid (10 512) Solid (4062) Liquid (4835) Solid Liquid PenV, 58% (33 967) Solid (7142) 2.3% (164) 42.5% (3038) 20.6% (1468) 15.5% (1108) 2.7% (196) 9.5% (677) 5.5% (395) 1.3% (96) 31.1% (2223) 68.9% (4919) Liquid (26 825) 17.9% (4813) 18.2% (4873) 0.8% (226) 34.0% (9151) 0.3% (76) 24.6% (6601) 0.5% (131) 3.6% (954) 19.6% (5246) 80.4% (21 579) Macro/linco, 21% (12 235) Solid (3789) 17.7% (669) 3.6% (136) 17.4% (661) 34.1% (1291) 5.8% (220) 3.8% (144) 15.8% (600) 1.8% (68) 56.7% (2150) 43.3% (1639) Liquid (8446) 6.7% (570) 19.6% (1652) 15.3% (1294) 24.3% (2056) 0.9% (72) 20.7% (1749) 2.9% (242) 9.6% (811) 25.8% (2178) 74.2% (6268) Amoxicillin, 6% (3550) Solid (321) 8.4% (27) 2.5% (8) 28.7% (92) 10.9% (35) 9.3% (30) 20.9% (67) 16.8% (54) 2.5% (8) 63.2% (203) 36.8% (118) Liquid (3229) 3.2% (103) 13.4% (434) 1.3% (42) 53.4% (1725) 3.4% (109) 4.6% (149) 4.1% (133) 16.5% (534) 12.0% (387) 88.0 % (2842) Other, 15% (8648) Solid (4714) 2.1% (100) 4.7% (223) 4.8% (228) 19.6% (926) 1.4% (66) 8.7% (408) 21.6% (1020) 37.0% (1743) 30.0% (1414) 70.0% (3300) Liquid (3934) 1.6% (63) 8.7% (343) 0.7% (28) 16.6% (654) 0.5% (21) 18.2% (717) 37.8% (1487) 15.8% (621) 40.6% (1599) 59.4% (2335) All formulations Total (58 400) Total penV 29.5% (17 216) Total macro/linco 35.9% (20 985) Total amoxicillin 19.4% (11 302) Total other 15.2% (8897) 26.4% (15 400) 73.6% (43 000) Initial prescription Subsequent prescription Penicillin V Macro/linco Amoxicillin Other Form Antibiotic Form (n) Solid (6509) Liquid (10 707) Solid (4039) Liquid (16 946) Solid (790) Liquid (10 512) Solid (4062) Liquid (4835) Solid Liquid PenV, 58% (33 967) Solid (7142) 2.3% (164) 42.5% (3038) 20.6% (1468) 15.5% (1108) 2.7% (196) 9.5% (677) 5.5% (395) 1.3% (96) 31.1% (2223) 68.9% (4919) Liquid (26 825) 17.9% (4813) 18.2% (4873) 0.8% (226) 34.0% (9151) 0.3% (76) 24.6% (6601) 0.5% (131) 3.6% (954) 19.6% (5246) 80.4% (21 579) Macro/linco, 21% (12 235) Solid (3789) 17.7% (669) 3.6% (136) 17.4% (661) 34.1% (1291) 5.8% (220) 3.8% (144) 15.8% (600) 1.8% (68) 56.7% (2150) 43.3% (1639) Liquid (8446) 6.7% (570) 19.6% (1652) 15.3% (1294) 24.3% (2056) 0.9% (72) 20.7% (1749) 2.9% (242) 9.6% (811) 25.8% (2178) 74.2% (6268) Amoxicillin, 6% (3550) Solid (321) 8.4% (27) 2.5% (8) 28.7% (92) 10.9% (35) 9.3% (30) 20.9% (67) 16.8% (54) 2.5% (8) 63.2% (203) 36.8% (118) Liquid (3229) 3.2% (103) 13.4% (434) 1.3% (42) 53.4% (1725) 3.4% (109) 4.6% (149) 4.1% (133) 16.5% (534) 12.0% (387) 88.0 % (2842) Other, 15% (8648) Solid (4714) 2.1% (100) 4.7% (223) 4.8% (228) 19.6% (926) 1.4% (66) 8.7% (408) 21.6% (1020) 37.0% (1743) 30.0% (1414) 70.0% (3300) Liquid (3934) 1.6% (63) 8.7% (343) 0.7% (28) 16.6% (654) 0.5% (21) 18.2% (717) 37.8% (1487) 15.8% (621) 40.6% (1599) 59.4% (2335) All formulations Total (58 400) Total penV 29.5% (17 216) Total macro/linco 35.9% (20 985) Total amoxicillin 19.4% (11 302) Total other 15.2% (8897) 26.4% (15 400) 73.6% (43 000) PenV, penicillin V; Macro/linco, macrolides/lincosamides. View Large Table 4. Initial oral solid and liquid antibiotics and subsequent prescriptions with different antibiotics or pharmaceutical characteristics (e.g. taste, size, shape, or strength/concentration) from the Norwegian Prescription Database between 2004 and 2016 Initial prescription Subsequent prescription Penicillin V Macro/linco Amoxicillin Other Form Antibiotic Form (n) Solid (6509) Liquid (10 707) Solid (4039) Liquid (16 946) Solid (790) Liquid (10 512) Solid (4062) Liquid (4835) Solid Liquid PenV, 58% (33 967) Solid (7142) 2.3% (164) 42.5% (3038) 20.6% (1468) 15.5% (1108) 2.7% (196) 9.5% (677) 5.5% (395) 1.3% (96) 31.1% (2223) 68.9% (4919) Liquid (26 825) 17.9% (4813) 18.2% (4873) 0.8% (226) 34.0% (9151) 0.3% (76) 24.6% (6601) 0.5% (131) 3.6% (954) 19.6% (5246) 80.4% (21 579) Macro/linco, 21% (12 235) Solid (3789) 17.7% (669) 3.6% (136) 17.4% (661) 34.1% (1291) 5.8% (220) 3.8% (144) 15.8% (600) 1.8% (68) 56.7% (2150) 43.3% (1639) Liquid (8446) 6.7% (570) 19.6% (1652) 15.3% (1294) 24.3% (2056) 0.9% (72) 20.7% (1749) 2.9% (242) 9.6% (811) 25.8% (2178) 74.2% (6268) Amoxicillin, 6% (3550) Solid (321) 8.4% (27) 2.5% (8) 28.7% (92) 10.9% (35) 9.3% (30) 20.9% (67) 16.8% (54) 2.5% (8) 63.2% (203) 36.8% (118) Liquid (3229) 3.2% (103) 13.4% (434) 1.3% (42) 53.4% (1725) 3.4% (109) 4.6% (149) 4.1% (133) 16.5% (534) 12.0% (387) 88.0 % (2842) Other, 15% (8648) Solid (4714) 2.1% (100) 4.7% (223) 4.8% (228) 19.6% (926) 1.4% (66) 8.7% (408) 21.6% (1020) 37.0% (1743) 30.0% (1414) 70.0% (3300) Liquid (3934) 1.6% (63) 8.7% (343) 0.7% (28) 16.6% (654) 0.5% (21) 18.2% (717) 37.8% (1487) 15.8% (621) 40.6% (1599) 59.4% (2335) All formulations Total (58 400) Total penV 29.5% (17 216) Total macro/linco 35.9% (20 985) Total amoxicillin 19.4% (11 302) Total other 15.2% (8897) 26.4% (15 400) 73.6% (43 000) Initial prescription Subsequent prescription Penicillin V Macro/linco Amoxicillin Other Form Antibiotic Form (n) Solid (6509) Liquid (10 707) Solid (4039) Liquid (16 946) Solid (790) Liquid (10 512) Solid (4062) Liquid (4835) Solid Liquid PenV, 58% (33 967) Solid (7142) 2.3% (164) 42.5% (3038) 20.6% (1468) 15.5% (1108) 2.7% (196) 9.5% (677) 5.5% (395) 1.3% (96) 31.1% (2223) 68.9% (4919) Liquid (26 825) 17.9% (4813) 18.2% (4873) 0.8% (226) 34.0% (9151) 0.3% (76) 24.6% (6601) 0.5% (131) 3.6% (954) 19.6% (5246) 80.4% (21 579) Macro/linco, 21% (12 235) Solid (3789) 17.7% (669) 3.6% (136) 17.4% (661) 34.1% (1291) 5.8% (220) 3.8% (144) 15.8% (600) 1.8% (68) 56.7% (2150) 43.3% (1639) Liquid (8446) 6.7% (570) 19.6% (1652) 15.3% (1294) 24.3% (2056) 0.9% (72) 20.7% (1749) 2.9% (242) 9.6% (811) 25.8% (2178) 74.2% (6268) Amoxicillin, 6% (3550) Solid (321) 8.4% (27) 2.5% (8) 28.7% (92) 10.9% (35) 9.3% (30) 20.9% (67) 16.8% (54) 2.5% (8) 63.2% (203) 36.8% (118) Liquid (3229) 3.2% (103) 13.4% (434) 1.3% (42) 53.4% (1725) 3.4% (109) 4.6% (149) 4.1% (133) 16.5% (534) 12.0% (387) 88.0 % (2842) Other, 15% (8648) Solid (4714) 2.1% (100) 4.7% (223) 4.8% (228) 19.6% (926) 1.4% (66) 8.7% (408) 21.6% (1020) 37.0% (1743) 30.0% (1414) 70.0% (3300) Liquid (3934) 1.6% (63) 8.7% (343) 0.7% (28) 16.6% (654) 0.5% (21) 18.2% (717) 37.8% (1487) 15.8% (621) 40.6% (1599) 59.4% (2335) All formulations Total (58 400) Total penV 29.5% (17 216) Total macro/linco 35.9% (20 985) Total amoxicillin 19.4% (11 302) Total other 15.2% (8897) 26.4% (15 400) 73.6% (43 000) PenV, penicillin V; Macro/linco, macrolides/lincosamides. View Large The sensitivity analyses negligibly changed the results of the multivariable regressions (results not shown). Discussion Summary of the main findings Requests for new prescriptions followed 3.0% of 2 691 483 initial antibiotic prescriptions for children. Young children who received solid formulations (10.9%) and certain poor-tasting antibiotics (8.6%) had the highest proportions of new prescriptions. Penicillin V was most commonly changed, while macrolides/lincosamides dominated subsequent prescriptions. In order of magnitude, the characteristics associated with requests for new prescriptions were as follows: the children’s ages (solids), poor taste and concentration of liquids, size and shape of solids, prescribers born in recent decades, and girl patients. Reimbursed prescriptions and scored solids were associated with fewer requests. Comparison with existing literature Changed antibiotic prescriptions represent situations of parents in great distress, unable to get their child to take the medicine prescribed to get well (4). In addition, changes from narrow- to broad-spectrum antibiotics may increase children’s short-term risk of side effects (6), and change of intestinal microbiome may result in future sequelae (27), furthering this distress. Changes also take parents’ time away from the sick child to contact the prescriber and pharmacy and increase treatment costs for extra antibiotic courses. Surprisingly, girls experienced more prescription changes than boys, which is not explained by significant body size differences (28). Boys were generally more positive than girls towards taking oral formulations of different types and sizes in a recent study, indicating possible gender differences (29). Giving toddlers medicine may be extra difficult, as their proportion of change was higher than other age groups. This may be related to the increased use of broad-spectrum antibiotics in this age group, putting them at risk of antibiotic resistance (30). One explanation may be that prescribers choose more acceptable medicines to save time, as 41% of our prescribers had issued a new prescription (25). Prescribers born in recent decades changed more prescriptions, which may have contributed to the increase in prescription changes over the last 13 years. This effect remained after adjusting for type of antibiotics and warrants further exploration. Poor-tasting liquid antibiotics had 2.4 times higher odds of being changed than better-tasting liquids. This corresponds with findings that taste is a key characteristic associated with children’s refusal of medicines (31,32) and indicates that prescription changes can be used to identify antibiotics that are challenging for children to use. Changed prescriptions most likely underestimate administration challenges (4) and may contribute to the difference found in chronic children who were 3.8 times more likely to refuse poor-tasting medicines at least once (11). Taste may also explain why poor-tasting liquid penicillin V was most frequently replaced by better-tasting liquid amoxicillin and erythromycin, and even solid penicillin V that is easier to taste mask (33). Changes between liquid concentrations were seen for all the antibiotic groups. Concentrated liquids had 1.5 times greater odds of being changed, indicating that the advantage of having a smaller volume may not compensate for the stronger taste. The opposite was found in a study of children with chronic disease, although this was believed to be caused by an age factor (24). There is little consensus in the literature regarding which size and shape solids to prescribe at different ages, but recent studies have shown that preschool children can swallow and even prefer mini tablets of 2–3 mm (34,35). There is a large discrepancy, though, between clinical studies and the availability of solids for clinical use (36). The two smallest solids in the dataset were 11 × 5 mm and 9 × 6.5 mm, which in a recent review would not be considered appropriate for children under 13 years (37). This is in keeping with the results in this study where younger children had stronger association with solid formulation changes, and medium and scored tablets had lower independent associations. Children can be taught to swallow solids (38), which may explain why this study showed that prescriptions reimbursed for children with a serious or chronic disease had lower odds for prescription changes. Capsules had 1.5 times higher odds of prescription changes than round tablets, and erythromycin capsules were changed most frequently. This lack of preference for capsules may be explained by their large size and a misconception of being made from plastic (29). Erythromycin capsules, however, contain granules that can be sprinkled on food, making them easier to swallow (39), although this may not be known. Changes from penicillin V tablets to erythromycin were also seen (Table 4), which may indicate that opening the capsules may be known by some. Strengths and limitations of the study The strength of this study is the inclusion of prescriptions from the entire Norwegian paediatric population over a 13-year period. The two main limitations are lack of information regarding (i) the reason for requesting a new prescription and (ii) type and severity of infections. The prevalence of allergies and adverse effects is unknown and could contribute an overestimation of changes due to administration challenges. Though uncommon, more than one antibiotic could also have been prescribed on the same day intentionally, thus overestimating changes. Changes due to therapeutic failure could also overestimate the results, although the finding that more prescriptions were changed on Day 1 than on Day 2 indicates that this is unlikely to be a key factor. Conclusion and implication Changed prescriptions have costs for the involved children, their families and the health-care system in general. Narrow-spectrum antibiotics were changed more often than broad-spectrum antibiotics, indicating that costs related to children’s refusal and consequent antibiotic changes may contribute to the increased prescription rates of broad-spectrum antibiotics observed for young children in general. Advocating the development of more user-friendly formulations for children can therefore contribute to a more appropriate use of antibiotics in the paediatric population. Declaration Funding: this study was funded by a grant from the Liaison Committee between the Central Norway Regional Health Authority and Norwegian University of Science and Technology (NTNU). Ethical approval: the study was approved by the Regional Committee for Medical and Health Research Ethics, Central Region, ref 2014/1743, and the Norwegian Prescription Database, ref 17/10581. Patient and prescriber personal identification numbers were pseudonymized by NorPD, allowing individual children’s prescriptions to be tracked over time without exposing their identities. The data were handled and stored anonymously. Conflict of interest: none. Acknowledgements The authors would like to thank Eva Skovlund for support with the statistical analyses. References 1. Sturkenboom MC , Verhamme KM , Nicolosi A , et al. Drug use in children: cohort study in three European countries . BMJ 2008 ; 337 : a2245 . Google Scholar CrossRef Search ADS PubMed 2. Youngster I , Avorn J , Belleudi V , et al. Antibiotic use in children—a cross-national analysis of 6 countries . J Pediatr 2017 ; 182 : 239 – 244.e1 . Google Scholar CrossRef Search ADS PubMed 3. Cohen R , de La Rocque F , Lecuyer A , et al. Study of the acceptability of antibiotic syrups, suspensions, and oral solutions prescribed to pediatric outpatients . Eur J Pediatr 2009 ; 168 : 851 – 7 . Google Scholar CrossRef Search ADS PubMed 4. Bergene EH , Rø TB , Steinsbekk A . Strategies parents use to give children oral medicine: a qualitative study of online discussion forums . Scand J Prim Health Care 2017 ; 35 : 221 – 8 . Google Scholar CrossRef Search ADS PubMed 5. Brookes-Howell L , Wood F , Verheij T , et al. Trust, openness and continuity of care influence acceptance of antibiotics for children with respiratory tract infections: a four country qualitative study . Fam Pract 2014 ; 31 : 102 – 10 . Google Scholar CrossRef Search ADS PubMed 6. Turck D , Bernet JP , Marx J , et al. Incidence and risk factors of oral antibiotic-associated diarrhea in an outpatient pediatric population . J Pediatr Gastroenterol Nutr 2003 ; 37 : 22 – 6 . Google Scholar CrossRef Search ADS PubMed 7. Grigoryan L , Burgerhof JG , Haaijer-Ruskamp FM , et al. ; SAR group . Is self-medication with antibiotics in Europe driven by prescribed use ? J Antimicrob Chemother 2007 ; 59 : 152 – 6 . Google Scholar CrossRef Search ADS PubMed 8. Thrane N , Olesen C , Schonheyder HC , Sorensen HT . Multiple prescriptions of antibiotics for children aged 0 to 5 years in relation to type of antibiotic . J Antimicrob Chemother 1999 ; 44 : 839 – 42 . Google Scholar CrossRef Search ADS PubMed 9. Pottegård A , Hallas J . Children prefer bottled amoxicillin . Ugeskr Laeger 2010 ; 172 : 3468 – 70 . Google Scholar PubMed 10. Steele RW , Estrada B , Begue RE , Mirza A , Travillion DA , Thomas MP . A double-blind taste comparison of pediatric antibiotic suspensions . Clin Pediatr (Phila) 1997 ; 36 : 193 – 9 . Google Scholar CrossRef Search ADS PubMed 11. Venables R , Batchelor H , Hodson J , et al. Determination of formulation factors that affect oral medicines acceptability in a domiciliary paediatric population . Int J Pharm 2015 ; 480 : 55 – 62 . Google Scholar CrossRef Search ADS PubMed 12. Tell D , Engström S , Mölstad S . Adherence to guidelines on antibiotic treatment for respiratory tract infections in various categories of physicians: a retrospective cross-sectional study of data from electronic patient records . BMJ Open 2015 ; 5 : e008096 . Google Scholar CrossRef Search ADS PubMed 13. Gjelstad S , Dalen I , Lindbaek M . GPs’ antibiotic prescription patterns for respiratory tract infections–still room for improvement . Scand J Prim Health Care 2009 ; 27 : 208 – 15 . Google Scholar CrossRef Search ADS PubMed 14. Furu K . Establishment of the nationwide norwegian prescription database (NorPD)–new opportunities for research in pharmacoepidemiology in Norway . Norsk Epidemiologi 2008 ; 18 : 129 – 36 . 15. Schirm E , Tobi H , de Vries TW , Choonara I , De Jong-van den Berg LT . Lack of appropriate formulations of medicines for children in the community . Acta Paediatr 2003 ; 92 : 1486 – 9 . Google Scholar CrossRef Search ADS PubMed 16. Rebnord IK , Thue G , Hunskår S . Equipment for diagnostics, laboratory analyses and treatment in out-of-hours services . Tidsskr Nor Laegeforen 2009 ; 129 : 987 – 90 . Google Scholar CrossRef Search ADS PubMed 17. Sanchez Garcia M . Early antibiotic treatment failure . Int J Antimicrob Agents 2009 ; 34 ( suppl 3 ): S14 – 9 . Google Scholar CrossRef Search ADS PubMed 18. Felleskatalogen . https://www.felleskatalogen.no/medisin/ (accessed 27 April 2018) 19. FASS . http://www.fass.se/LIF/ (accessed 27 April 2018) . 20. Pro.medicin.dk . http://pro.medicin.dk/ (accessed 27 April 2018) . 21. Pillbox . https://pillbox.nlm.nih.gov/ (accessed 27 April 2018) . 22. Steele RW , Russo TM , Thomas MP . Adherence issues related to the selection of antistaphylococcal or antifungal antibiotic suspensions for children . Clin Pediatr (Phila) 2006 ; 45 : 245 – 50 . Google Scholar CrossRef Search ADS PubMed 23. Steele RW , Thomas MP , Bégué RE . Compliance issues related to the selection of antibiotic suspensions for children . Pediatr Infect Dis J 2001 ; 20 : 1 – 5 . Google Scholar CrossRef Search ADS PubMed 24. Rouse C , Mistry P , Rayner O , et al. A mixed methods study of the administration of flucloxacillin oral liquid; identifying strategies to overcome administration issues of medicines with poor palatability . Int J Pharm Pract 2017 ; 25 : 326 – 34 . Google Scholar CrossRef Search ADS PubMed 25. Gjelstad S , Straand J , Dalen I , Fetveit A , Strøm H , Lindbæk M . Do general practitioners’ consultation rates influence their prescribing patterns of antibiotics for acute respiratory tract infections ? J Antimicrob Chemother 2011 ; 66 : 2425 – 33 . Google Scholar CrossRef Search ADS PubMed 26. Berg C , Blix HS , Fenne O , et al. Norwegian Prescription Database 2010–2014, in Statistics . Oslo : Norwegian Institute of Public Health , 2015 . 27. Korpela K , Salonen A , Virta LJ , et al. Intestinal microbiome is related to lifetime antibiotic use in Finnish pre-school children . Nat Commun 2016 ; 7 : 10410 . Google Scholar CrossRef Search ADS PubMed 28. Júlíusson PB , Roelants M , Eide GE , et al. Growth references for Norwegian children . Tidsskr Nor Laegeforen 2009 ; 129 : 281 – 6 . Google Scholar CrossRef Search ADS PubMed 29. Ranmal SR , Cram A , Tuleu C . Age-appropriate and acceptable paediatric dosage forms: insights into end-user perceptions, preferences and practices from the Children’s Acceptability of oral formulations (CALF) study . Int J Pharm 2016 ; 514 : 296 – 307 . Google Scholar CrossRef Search ADS PubMed 30. Holstiege J , Schink T , Molokhia M , et al. Systemic antibiotic prescribing to paediatric outpatients in 5 European countries: a population-based cohort study . BMC Pediatr 2014 ; 14 : 174 . Google Scholar CrossRef Search ADS PubMed 31. European Medicines Agency. Guideline on pharmaceutical development of medicines for paediatric use EMA/CHMP/QWP/805880/2012. London: European Medicines Agency, 2013. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2013/07/WC500147002.pdf (accessed 25 April 2018) . 32. Davies EH , Tuleu C . Medicines for children: a matter of taste . J Pediatr 2008 ; 153 : 599 – 604, 604.e1–2 . Google Scholar CrossRef Search ADS PubMed 33. Walsh J , Cram A , Woertz K , et al. ; European Formulation Initiative . Playing hide and seek with poorly tasting paediatric medicines: do not forget the excipients . Adv Drug Deliv Rev 2014 ; 73 : 14 – 33 . Google Scholar CrossRef Search ADS PubMed 34. van Riet-Nales DA , Ferreira JA , Schobben AF , et al. Methods of administering oral formulations and child acceptability . Int J Pharm 2015 ; 491 : 261 – 7 . Google Scholar CrossRef Search ADS PubMed 35. Drumond N , van Riet-Nales DA , Karapinar-Çarkit F , Stegemann S . Patients’ appropriateness, acceptability, usability and preferences for pharmaceutical preparations: results from a literature review on clinical evidence . Int J Pharm 2017 ; 521 : 294 – 305 . Google Scholar CrossRef Search ADS PubMed 36. Jacobsen L , Riley K , Lee B , Bradford K , Jhaveri R . Tablet/capsule size variation among the most commonly prescribed medications for children in the USA: retrospective review and firsthand pharmacy audit . Paediatr Drugs 2016 ; 18 : 65 – 73 . Google Scholar CrossRef Search ADS PubMed 37. Mistry P , Batchelor H ; SPaeDD-UK project (Smart Paediatric Drug Development—UK) . Evidence of acceptability of oral paediatric medicines: a review . J Pharm Pharmacol 2017 ; 69 : 361 – 76 . Google Scholar CrossRef Search ADS PubMed 38. Meltzer EO , Welch MJ , Ostrom NK . Pill swallowing ability and training in children 6 to 11 years of age . Clin Pediatr (Phila) 2006 ; 45 : 725 – 33 . Google Scholar CrossRef Search ADS PubMed 39. Nunn T , Williams J . Formulation of medicines for children . Br J Clin Pharmacol 2005 ; 59 : 674 – 6 . Google Scholar CrossRef Search ADS PubMed © The Author(s) 2018. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Family Practice Oxford University Press

Requests for new oral antibiotic prescriptions in children within 2 days: a Norwegian population-based study

Loading next page...
 
/lp/ou_press/requests-for-new-oral-antibiotic-prescriptions-in-children-within-2-VrtukC0rZF
Publisher
Oxford University Press
Copyright
© The Author(s) 2018. Published by Oxford University Press.
ISSN
0263-2136
eISSN
1460-2229
D.O.I.
10.1093/fampra/cmy033
Publisher site
See Article on Publisher Site

Abstract

Abstract Background Children commonly refuse to take antibiotics, which may induce parents to request new antibiotic prescriptions with different pharmaceutical characteristics. Objectives To investigate prescription changes for children 0–12 years receiving oral liquid or solid antibiotic formulations and to explore the relationships between prescription changes and characteristics related to the child, prescriber and antibiotic. Methods A population-based registry study based on data from the Norwegian Prescription Database (NorPD) from 2004 to 2016. Antibiotic prescription changes were defined as the dispensing of subsequent antibiotics with different pharmaceutical characteristics to the same child within 2 days after initial prescriptions. Data were analysed using multivariable logistic regression and generalized estimating equations. Results Requests for new prescriptions followed 3.0% of 2 691 483 initial antibiotic prescriptions for children. Young children who received solid formulations (10.9%) and certain poor-tasting antibiotics (8.6%) had the highest proportions of new prescriptions. Penicillin V was most commonly changed, while macrolides/lincosamides dominated subsequent prescriptions. In order of magnitude, the characteristics associated with requests for new prescriptions were the children’s ages, poor taste and concentration of liquids, size and shape of solids, prescribers born in recent decades, and girl patients. Reimbursed prescriptions and scored solids were associated with fewer requests. Conclusions While only 3% of the antibiotic prescriptions were changed, the preference of broad-spectrum over narrow-spectrum antibiotics for young children in this study mirrors international prescription patterns. Avoiding the costs of children’s refusal and consequent changes may thus be a motivation for choosing more preferred antibiotics. Anti-bacterial agents, child, preschool child, dosage form, prescriptions Introduction Antibiotics are the most commonly prescribed medicines for children in Europe (1). Worldwide, the prescription of antibiotics per child-year is highest in children 5 years and younger (0.5–3.4) and lowest in children 6–12 years (0.2–0.8) (2). Administering antibiotics to children can be challenging, and French parents reported in a survey that their child spat out at least one dose of antibiotics in 22% of the cases (3). In a recent qualitative study, parents said they battled with unwilling children and used several strategies to administer unpalatable antibiotics (4). If unable to get the child to take the medicine, parents sometimes went to the trouble of requesting a new antibiotic prescription (4,5). Such requests represent situations of negative interaction between children and parents and may reduce children’s well-being through treatment delay. Children are also at risk of increased side effects from second-line antibiotics (6). Parents spend time and money on unused antibiotics that later may be administered inappropriately (7), and health-care resources may be wasted in the form of extra time and effort by the prescriber and pharmacy. To better understand the magnitude and nature of this problem in clinical practice, studies exploring changes in antibiotic prescriptions are needed. In a previous Danish study, 5% of <30 000 prescriptions were followed by a new prescription within 2 days for children 0–5 years (8), and a similar study found that penicillin V was changed 3.7 times more often than amoxicillin (9). The authors concluded that this could be caused by differences in palatability and found support for this in previous taste tests (10). In addition to taste, a survey of adolescents and parents of children with chronic diseases in Great Britain showed that formulation factors such as size, shape and volume as well as child’s age were correlated with children’s refusal of medicine (11). Prescriber characteristics may also be associated with use of medicines, as prescription patterns change based on a prescriber’s experience (12,13). Identifying factors related to changed prescriptions can be used to discover trends and population preferences and can be used to cause awareness and design interventions. To some extent, this can be explored in clinical practice using data from entire populations provided by national registers, such as the Norwegian Prescription Database (NorPD) (14). The aim of this study was therefore to investigate prescriptions of oral liquid and solid antibiotic formulations changed within 2 days to antibiotics with different characteristics in children 0–12 years of age in Norway during the period from 2004 to 2016. Furthermore, associations between prescription changes and child, prescriber and antibiotic characteristics were investigated separately for solid and liquid antibiotics. Methods Study design and data source This is a population-based registry study based on data on all prescriptions of oral systemic antibiotics dispensed to children from 2004 to 2016 in the NorPD. Children aged 0–12 were included to explore changes of antibiotic prescriptions across age intervals when both liquid and solid formulations were common (15). The NorPD contains information for all prescription medicines, reimbursed or not, dispensed from Norwegian pharmacies since 1st January 2004 to all individual patients living outside institutions (14). Setting In Norway, systemic antibiotics are available by prescription only, and a physician must be contacted to obtain a new prescription. In the community setting, antibiotics are predominantly dispensed from pharmacies to patients. Exceptions are antibiotics dispensed directly to the patient from out-of-hours primary health care centres that stock a small quantity of medications for use when pharmacies are closed (16). Antibiotics are fully paid for by the child’s parents, except for children with severe/chronic conditions (e.g. immunodeficiency, cancer, or chronic urinary tract infections), whose antibiotic prescriptions are reimbursed. Reimbursed prescriptions accounted for 3.5%–5.4% of the antibiotics prescribed for children below 12 years of age in 2012 (2). Inclusion criteria All systemic oral antibiotic prescriptions classified according to the Anatomical Therapeutic Chemical (ATC) Classification System as ATC-code J01 were included with the exception of the antiseptic methenamine (ATC-code J01XX05). Changed antibiotic prescriptions Changed antibiotic prescriptions were defined as initial prescriptions that were followed by subsequent prescriptions with a different type of antibiotic or pharmaceutical characteristic (e.g. taste, size, shape, or strength/concentration) dispensed to the same child within 2 days. This period was chosen, as changes within the first 2 days were most likely caused by challenges related to the administration of antibiotics rather than lack of clinical effect (17). Prescription change served as the dependent variable and was categorized as either ‘yes’ or ‘no’. Characteristics Medication characteristics Formulations were classified as liquid (mixtures, drops, powder, and dispersible tablets) or solid (tablets and capsules). The shapes of solid formulations were categorized as a capsule, an oval/oblong or round tablet. Scored tablets with indented lines that ease splitting were an independent category. To compare the size of solids of different shapes, the cross-sectional area was computed using the measurement of width (w) and length (l) and the geometric formula (l − w)w + π (w/2)2. The sizes were categorized into four categories: small <20 mm2 (area of a 5-mm round tablet), medium 20–<79 mm2 (area of 10-mm round tablet), large 79–124 mm2 (area of size 1 capsule) or extra-large >124 mm2 . Information regarding the size, shape and scoring of the solids was obtained from the Scandinavian medicinal formularies (18–20), from pillbox (21), or directly from the pharmaceutical manufacturer via personal contact. For generic medications, no longer manufactured, size information was unavailable (1.7% of the prescriptions for solid antibiotics). These were assigned to the same size category as the original matching formulation (tablet or capsule). Antibiotics were grouped according to the ATC system and their overall prescription frequency: Penicillin V (ATC-code J01CE02), macrolides/lincosamides (ATC-code J01F), amoxicillin (ATC-code J01CA04) and others. Poor-tasting liquids included dicloxacillin, clindamycin, trimethoprim, co-amoxicillin and penicillin V, whose scores on taste tests were so low that the likelihood for rejection by children was a concern (10,22,23). Drops were included as a separate variable, as the concentration of antibiotic liquids is believed to influence their use in children (24). Child characteristics Both gender and age were included. Age was grouped as infants (0–1 years), toddlers (2–3 years), preschool children (4–5 years), school children (6–9 years) and pre-teens (10–12 years). Prescriber characteristics Prescribers were classified according to age, specialization and annual prescribing frequency. Age was defined by decade of birth. Specialization was categorized as general practitioner (GP) specialist, paediatrician, other specialist or no specialization. GP specialists have previously shown different antibiotic prescription patterns than non-GP specialists (25), which may influence antibiotic prescription changes. The annual prescribing frequency was grouped into quartiles due to a highly skewed distribution. Statistical analysis Logistic regression was used to assess the relationship between the antibiotic prescription changes and the characteristics of the child, prescriber and antibiotic. As antibiotic prescriptions could be changed several times for the same child, we used generalized estimating equations nested by children to account for possible correlations. Antibiotic prescription changes over time were analysed using univariable models, including the prescription year. Two multivariable models, including children and prescriber characteristics and either formulation characteristics (Model 1) or antibiotic groups (Model 2), were analysed separately for liquid and solid initial formulations due to the collinearity between formulation characteristics and antibiotic groups. Infants were references for liquids and pre-teens for solids due to their common use in these groups. The results from the univariable models were reported as odds ratios (OR) with a 95% confidence interval (95% CI), while multivariable models were reported as adjusted odds ratios (adjOR) with a 95% CI. P value of <0.01 was considered statistically significant. Several sensitivity analyses were performed to assess the robustness of the findings. First, antibiotic change was extended to 3 days after the initial prescription. Second, analyses were performed to reduce the contribution from children with more than four prescriptions per year per child (4% of all prescriptions) and from missing data by excluding prescriptions in 2004 [the year with the most missing patient IDs (26)] and children below 1 year of age, as there may have been a delay in receiving a national ID number. In addition, as Furadantin® is registered as a tablet but may be dispersed before administration, a sensitivity analysis was performed categorizing it as a liquid. The analyses were carried out using Stata version 13.1 (StataCorp, College Station, TX). Results The overall dataset consisted of 2 691 483 initial prescriptions of systemic antibiotics that were dispensed to children 0–12 years between 2004 and 2016 in Norway. Of these, 21 701 prescriptions were followed by new prescriptions on the same day (Day 0), 35 703 on Day 1 and 22 697 on Day 2, totaling 80 101 changed prescriptions (3.0%). Multiple prescriptions dispensed on the same day were excluded from the analyses as the lack of dispensing order did not allow us to identify the initial and changed antibiotic (1.6%, n = 43 769 prescriptions in 21 701 changes). Changes on Day 1–2 were therefore used for the analyses. The remaining dataset consisted of 2 670 754 initial prescriptions (1 976 238, 74% liquid and 694 516, 26% solid) dispensed to 861 991 children. The initial prescriptions were issued by 29 901 prescribers, and 41% (12 277) of these prescribers changed one or more prescriptions over the 13-year study period. Proportions and trends of antibiotic changes on Day 1–2 On Day 1–2, 58 400 (2.2%) prescriptions were changed, of which 42 434 (2.2%) were liquid and 15 966 (2.4%) were solid. The same prescriber issued both the initial and subsequent prescriptions in 45.9% of the cases. The proportion of prescription changes increased over time for solids but not liquids (10-year OR: 1.3 for solids and 1.0 for liquids) (Fig. 1a). Figure 1. View largeDownload slide Proportion of antibiotic prescription changes on Day 1–2 (%) for solid and liquid formulations for (a) year 2004–16 and (b) age 0–12 years for 2.6 million prescriptions of oral antibiotics from the Norwegian Prescription Database. Figure 1. View largeDownload slide Proportion of antibiotic prescription changes on Day 1–2 (%) for solid and liquid formulations for (a) year 2004–16 and (b) age 0–12 years for 2.6 million prescriptions of oral antibiotics from the Norwegian Prescription Database. Children below the age of 7 had a higher proportion of changes following prescription of solids, whereas children above 7 years had a higher proportion of changes following liquids. Two-year-old children had the highest proportion of changes following both solids (10.9%) and liquids (2.7%) (Fig. 1b). Among individual oral antibiotics with at least 5000 prescriptions, amoxicillin had the lowest proportion of changes for both liquids (0.8%) and solids (1.0%) (Table 1). The highest proportion of liquid prescription changes were for dicloxacillin (8.6%) and penicillin V drops (4.9%), and for solids, it was penicillin V (4.7%). Table 1. Top five individual liquid and solid antibiotics with the highest and lowest proportions of antibiotic change for prescriptions of oral antibiotics from the Norwegian Prescription Database between 2004 and 2016 Antibiotic Formulationa Initial prescriptions (n) Antibiotic change (%) Tasteb/sizea Brand name Liquids most commonly changed Dicloxacillin Suspension 8740 8.6 Poor Diclocil® 12.5 mg/ml Penicillin V Drops/solution 19 378 4.9 Poor Weifapenin® 250 mg/ml Penicillin V Drops/solution 174 336 4.0 Poor Apocillin® 250 mg/ml Penicillin V Solution 170 714 3.5 Poor Weifapenin® 50 mg/ml Penicillin V Solution 434 782 3.0 Poor Apocillin® 50 mg/ml Liquids most seldom changed Amoxicillin Solution 222 439 0.8 Not poor Imacillin® 50 mg/ml Amoxicillin Solution 180 306 0.8 Not poor Imacillin® 100 mg/ml Cefalexin Suspension 38 194 0.8 Not poor Keflex® 50 mg/ml Amoxicillin Suspension 7617 0.9 Not poor Amoxicillin® 100 mg/ml Azitromycin Suspension 61 249 1.0 Not poor Azitromax® 40 mg/ml Solids most commonly changed Penicillin V Oval/scored 29 985 4.7 Medium Apocillin® 165 mg Erythromycin Oval 11 592 4.0 Extra-large Abboticin® ES 500 mg Erythromycin Capsule 68 709 3.8 Large Ery-Max® 250 mg Dicloxacillin Capsule 37 147 3.3 Large Diclocil® 250 mg Pivmecillinam Round 23 494 3.3 Medium Penomax® 200 mg Solids most seldom changed Amoxicillin Round/scored 5982 1.0 Medium Imacillin® 250 mg Cefalexin Oval/scored 5207 1.2 Large Keflex® 500 mg Amoxicillin Capsule 10 534 1.2 Large Amoxicillin®Mylan 250 mg Azitromycin Oval/scored 9962 1.3 Extra-large Azitromax® 500 mg Trimethoprim Round/scored 11 272 1.3 Medium Trimetoprim®Orion 100 mg Antibiotic Formulationa Initial prescriptions (n) Antibiotic change (%) Tasteb/sizea Brand name Liquids most commonly changed Dicloxacillin Suspension 8740 8.6 Poor Diclocil® 12.5 mg/ml Penicillin V Drops/solution 19 378 4.9 Poor Weifapenin® 250 mg/ml Penicillin V Drops/solution 174 336 4.0 Poor Apocillin® 250 mg/ml Penicillin V Solution 170 714 3.5 Poor Weifapenin® 50 mg/ml Penicillin V Solution 434 782 3.0 Poor Apocillin® 50 mg/ml Liquids most seldom changed Amoxicillin Solution 222 439 0.8 Not poor Imacillin® 50 mg/ml Amoxicillin Solution 180 306 0.8 Not poor Imacillin® 100 mg/ml Cefalexin Suspension 38 194 0.8 Not poor Keflex® 50 mg/ml Amoxicillin Suspension 7617 0.9 Not poor Amoxicillin® 100 mg/ml Azitromycin Suspension 61 249 1.0 Not poor Azitromax® 40 mg/ml Solids most commonly changed Penicillin V Oval/scored 29 985 4.7 Medium Apocillin® 165 mg Erythromycin Oval 11 592 4.0 Extra-large Abboticin® ES 500 mg Erythromycin Capsule 68 709 3.8 Large Ery-Max® 250 mg Dicloxacillin Capsule 37 147 3.3 Large Diclocil® 250 mg Pivmecillinam Round 23 494 3.3 Medium Penomax® 200 mg Solids most seldom changed Amoxicillin Round/scored 5982 1.0 Medium Imacillin® 250 mg Cefalexin Oval/scored 5207 1.2 Large Keflex® 500 mg Amoxicillin Capsule 10 534 1.2 Large Amoxicillin®Mylan 250 mg Azitromycin Oval/scored 9962 1.3 Extra-large Azitromax® 500 mg Trimethoprim Round/scored 11 272 1.3 Medium Trimetoprim®Orion 100 mg Only antibiotics with >5000 initial prescriptions included. aFormulation and size (medium: 20–<79 mm2, large: 79–124 mm2, extra-large: >124 mm2) based on information mainly from Scandinavian formularies (18–20). bTaste according to taste test references by Steele et al. (10,22,23), where poor taste equals a score of 4 or less on a 10-point scale. View Large Table 1. Top five individual liquid and solid antibiotics with the highest and lowest proportions of antibiotic change for prescriptions of oral antibiotics from the Norwegian Prescription Database between 2004 and 2016 Antibiotic Formulationa Initial prescriptions (n) Antibiotic change (%) Tasteb/sizea Brand name Liquids most commonly changed Dicloxacillin Suspension 8740 8.6 Poor Diclocil® 12.5 mg/ml Penicillin V Drops/solution 19 378 4.9 Poor Weifapenin® 250 mg/ml Penicillin V Drops/solution 174 336 4.0 Poor Apocillin® 250 mg/ml Penicillin V Solution 170 714 3.5 Poor Weifapenin® 50 mg/ml Penicillin V Solution 434 782 3.0 Poor Apocillin® 50 mg/ml Liquids most seldom changed Amoxicillin Solution 222 439 0.8 Not poor Imacillin® 50 mg/ml Amoxicillin Solution 180 306 0.8 Not poor Imacillin® 100 mg/ml Cefalexin Suspension 38 194 0.8 Not poor Keflex® 50 mg/ml Amoxicillin Suspension 7617 0.9 Not poor Amoxicillin® 100 mg/ml Azitromycin Suspension 61 249 1.0 Not poor Azitromax® 40 mg/ml Solids most commonly changed Penicillin V Oval/scored 29 985 4.7 Medium Apocillin® 165 mg Erythromycin Oval 11 592 4.0 Extra-large Abboticin® ES 500 mg Erythromycin Capsule 68 709 3.8 Large Ery-Max® 250 mg Dicloxacillin Capsule 37 147 3.3 Large Diclocil® 250 mg Pivmecillinam Round 23 494 3.3 Medium Penomax® 200 mg Solids most seldom changed Amoxicillin Round/scored 5982 1.0 Medium Imacillin® 250 mg Cefalexin Oval/scored 5207 1.2 Large Keflex® 500 mg Amoxicillin Capsule 10 534 1.2 Large Amoxicillin®Mylan 250 mg Azitromycin Oval/scored 9962 1.3 Extra-large Azitromax® 500 mg Trimethoprim Round/scored 11 272 1.3 Medium Trimetoprim®Orion 100 mg Antibiotic Formulationa Initial prescriptions (n) Antibiotic change (%) Tasteb/sizea Brand name Liquids most commonly changed Dicloxacillin Suspension 8740 8.6 Poor Diclocil® 12.5 mg/ml Penicillin V Drops/solution 19 378 4.9 Poor Weifapenin® 250 mg/ml Penicillin V Drops/solution 174 336 4.0 Poor Apocillin® 250 mg/ml Penicillin V Solution 170 714 3.5 Poor Weifapenin® 50 mg/ml Penicillin V Solution 434 782 3.0 Poor Apocillin® 50 mg/ml Liquids most seldom changed Amoxicillin Solution 222 439 0.8 Not poor Imacillin® 50 mg/ml Amoxicillin Solution 180 306 0.8 Not poor Imacillin® 100 mg/ml Cefalexin Suspension 38 194 0.8 Not poor Keflex® 50 mg/ml Amoxicillin Suspension 7617 0.9 Not poor Amoxicillin® 100 mg/ml Azitromycin Suspension 61 249 1.0 Not poor Azitromax® 40 mg/ml Solids most commonly changed Penicillin V Oval/scored 29 985 4.7 Medium Apocillin® 165 mg Erythromycin Oval 11 592 4.0 Extra-large Abboticin® ES 500 mg Erythromycin Capsule 68 709 3.8 Large Ery-Max® 250 mg Dicloxacillin Capsule 37 147 3.3 Large Diclocil® 250 mg Pivmecillinam Round 23 494 3.3 Medium Penomax® 200 mg Solids most seldom changed Amoxicillin Round/scored 5982 1.0 Medium Imacillin® 250 mg Cefalexin Oval/scored 5207 1.2 Large Keflex® 500 mg Amoxicillin Capsule 10 534 1.2 Large Amoxicillin®Mylan 250 mg Azitromycin Oval/scored 9962 1.3 Extra-large Azitromax® 500 mg Trimethoprim Round/scored 11 272 1.3 Medium Trimetoprim®Orion 100 mg Only antibiotics with >5000 initial prescriptions included. aFormulation and size (medium: 20–<79 mm2, large: 79–124 mm2, extra-large: >124 mm2) based on information mainly from Scandinavian formularies (18–20). bTaste according to taste test references by Steele et al. (10,22,23), where poor taste equals a score of 4 or less on a 10-point scale. View Large Characteristics associated with requests for new prescriptions following liquid antibiotics In the multivariable models, changes associated with liquid antibiotic prescriptions were (in decreasing magnitude) as follows: antibiotic taste, reimbursed prescriptions, drops, children’s age, prescriber’s birth decade and number of prescriptions issued per year, and gender (Table 2). Table 2. Liquids: characteristics associated with liquid antibiotic formulations that were changed to a prescription with a different antibiotic or pharmaceutical characteristic from the Norwegian Prescription Database between 2004 and 2016 Liquid formulation Characteristics Initial prescriptions (IP), n = 1 976 238 Subsequent prescriptions (% of IP) Univariable OR (95% CI) Model 1: Liquid characteristics Model 2: Antibiotics Multivariable adjOR: (95% CI) Multivariable adjOR: (95% CI) Child  Age group   Infant 0–1 years 623 791 12 561 (2.0) Reference Reference Reference   Toddler 2–3 years 640 816 16 277 (2.5) 1.27 (1.24–1.30) 1.27 (1.24–1.30) 1.26 (1.23–1.29)   Preschool 4–5 years 396 021 7335 (1.9) 0.93 (0.90–0.95) 0.91 (0.88–0.93) 0.89 (0.87–0.92)   School 6–9 years 274 862 5359 (2.0) 0.98 (0.95–1.02) 1.01 (0.97–1.04) 0.99 (0.96–1.02)   Pre-teen 10–12 years 40 748 902 (2.2) 1.13 (1.06–1.22) 1.22 (1.14–1.31) 1.17 (1.09–1.26)  Girl 962 148 20 926 (2.2) 1.03 (1.01–1.05) 1.02 (1.00–1.05) 1.07 (1.05–1.09)  Reimbursed AB 83 825 850 (1.0) 0.46 (0.43–0.50) 0.53 (0.49–0.58) 0.66 (0.61–0.72) Prescriber  Specialist   None 974 765 23 082 (2.4) Reference Reference Reference   GP 815 927 16 405 (2.0) 0.85 (0.83–0.86) 0.97 (0.94–0.99) 0.98 (0.96–1.01)   Paediatrician 98 565 1449 (1.5) 0.65 (0.61–0.69) 0.92 (0.86–0.97) 0.92 (0.87–0.98)   Other 86 981 1498 (1.7) 0.73 (0.69–0.77) 0.92 (0.87–0.97) 0.96 (0.91–1.01)  Birth year   Before 1950 175 637 3215 (1.8) Reference Reference Reference   1950–59 499 770 9300 (1.9) 1.01 (0.97–1.06) 1.02 (0.98–1.06) 1.02 (0.98–1.07)   1960–69 502 622 10 431 (2.1) 1.13 (1.09–1.18) 1.07 (1.03–1.12) 1.08 (1.03–1.13)   1970–79 572 659 13 565 (2.4) 1.29 (1.24–1.35) 1.11 (1.07–1.16) 1.13 (1.08–1.18)   After 1980 224 634 5903 (2.2) 1.44 (1.37–1.50) 1.20 (1.14–1.26) 1.19 (1.13–1.25)  Female prescriber 729 961 16 156 (2.2) 1.05 (1.03–1.07) 0.97 (0.95–0.99) 0.98 (0.96–1.00)  AB prescriptions per year (quartiles)   <23 461 948 10 308 (2.2) Reference Reference Reference   24–42 489 763 11 095 (2.3) 1.01 (0.99–1.04) 1.06 (1.03–1.09) 1.07 (1.04–1.10)   43–73 511 290 10 056 (2.2) 0.97 (0.94–0.99) 1.08 (1.05–1.11) 1.09 (1.06–1.12)   >73 513 237 9975 (1.9) 0.87 (0.84–0.89) 1.04 (1.01–1.07) 1.07 (1.04–1.10) Liquid antibiotic  Poor taste 968 756 29 954 (3.1) 2.60 (2.55–2.66) 2.35 (2.30–2.41)  Drops 194 192 7986 (4.2) 2.17 (2.12–2.23) 1.45 (1.41–1.49)  Antibiotics   Amoxicillin 412 145 3229 (0.8) Reference Reference   Dicloxacillin 8740 756 (8.7) 12.4 (11.4–13.5) 12.3 (11.3–13.4)   Penicillin V 799 380 26 825 (3.4) 4.55 (4.38–4.73) 4.52 (4.35–4.70)   Clarithromycin 55 237 938 (1.7) 2.22 (2.06–2.40) 2.34 (2.17–2.53)   Erythromycin 358 940 6037 (1.7) 2.21 (2.12–2.31) 2.24 (2.14–2.34)   Clindamycin 49 524 821 (1.7) 2.16 (1.99–2.34) 2.20 (2.03–2.39)   Trim-sulpha 79 725 1271 (1.6) 2.09 (1.95–2.24) 2.22 (2.07–2.38)   Trimethoprim 107 010 1475 (1.4) 1.82 (1.70–1.94) 1.93 (1.80–2.06)   Azitromycin 61 249 614 (1.0) 1.31 (1.20–1.44) 1.41 (1.28–1.55)   Cefalexin 38 194 324 (0.9) 1.04 (0.92–1.18) 1.09 (0.96–1.24) Liquid formulation Characteristics Initial prescriptions (IP), n = 1 976 238 Subsequent prescriptions (% of IP) Univariable OR (95% CI) Model 1: Liquid characteristics Model 2: Antibiotics Multivariable adjOR: (95% CI) Multivariable adjOR: (95% CI) Child  Age group   Infant 0–1 years 623 791 12 561 (2.0) Reference Reference Reference   Toddler 2–3 years 640 816 16 277 (2.5) 1.27 (1.24–1.30) 1.27 (1.24–1.30) 1.26 (1.23–1.29)   Preschool 4–5 years 396 021 7335 (1.9) 0.93 (0.90–0.95) 0.91 (0.88–0.93) 0.89 (0.87–0.92)   School 6–9 years 274 862 5359 (2.0) 0.98 (0.95–1.02) 1.01 (0.97–1.04) 0.99 (0.96–1.02)   Pre-teen 10–12 years 40 748 902 (2.2) 1.13 (1.06–1.22) 1.22 (1.14–1.31) 1.17 (1.09–1.26)  Girl 962 148 20 926 (2.2) 1.03 (1.01–1.05) 1.02 (1.00–1.05) 1.07 (1.05–1.09)  Reimbursed AB 83 825 850 (1.0) 0.46 (0.43–0.50) 0.53 (0.49–0.58) 0.66 (0.61–0.72) Prescriber  Specialist   None 974 765 23 082 (2.4) Reference Reference Reference   GP 815 927 16 405 (2.0) 0.85 (0.83–0.86) 0.97 (0.94–0.99) 0.98 (0.96–1.01)   Paediatrician 98 565 1449 (1.5) 0.65 (0.61–0.69) 0.92 (0.86–0.97) 0.92 (0.87–0.98)   Other 86 981 1498 (1.7) 0.73 (0.69–0.77) 0.92 (0.87–0.97) 0.96 (0.91–1.01)  Birth year   Before 1950 175 637 3215 (1.8) Reference Reference Reference   1950–59 499 770 9300 (1.9) 1.01 (0.97–1.06) 1.02 (0.98–1.06) 1.02 (0.98–1.07)   1960–69 502 622 10 431 (2.1) 1.13 (1.09–1.18) 1.07 (1.03–1.12) 1.08 (1.03–1.13)   1970–79 572 659 13 565 (2.4) 1.29 (1.24–1.35) 1.11 (1.07–1.16) 1.13 (1.08–1.18)   After 1980 224 634 5903 (2.2) 1.44 (1.37–1.50) 1.20 (1.14–1.26) 1.19 (1.13–1.25)  Female prescriber 729 961 16 156 (2.2) 1.05 (1.03–1.07) 0.97 (0.95–0.99) 0.98 (0.96–1.00)  AB prescriptions per year (quartiles)   <23 461 948 10 308 (2.2) Reference Reference Reference   24–42 489 763 11 095 (2.3) 1.01 (0.99–1.04) 1.06 (1.03–1.09) 1.07 (1.04–1.10)   43–73 511 290 10 056 (2.2) 0.97 (0.94–0.99) 1.08 (1.05–1.11) 1.09 (1.06–1.12)   >73 513 237 9975 (1.9) 0.87 (0.84–0.89) 1.04 (1.01–1.07) 1.07 (1.04–1.10) Liquid antibiotic  Poor taste 968 756 29 954 (3.1) 2.60 (2.55–2.66) 2.35 (2.30–2.41)  Drops 194 192 7986 (4.2) 2.17 (2.12–2.23) 1.45 (1.41–1.49)  Antibiotics   Amoxicillin 412 145 3229 (0.8) Reference Reference   Dicloxacillin 8740 756 (8.7) 12.4 (11.4–13.5) 12.3 (11.3–13.4)   Penicillin V 799 380 26 825 (3.4) 4.55 (4.38–4.73) 4.52 (4.35–4.70)   Clarithromycin 55 237 938 (1.7) 2.22 (2.06–2.40) 2.34 (2.17–2.53)   Erythromycin 358 940 6037 (1.7) 2.21 (2.12–2.31) 2.24 (2.14–2.34)   Clindamycin 49 524 821 (1.7) 2.16 (1.99–2.34) 2.20 (2.03–2.39)   Trim-sulpha 79 725 1271 (1.6) 2.09 (1.95–2.24) 2.22 (2.07–2.38)   Trimethoprim 107 010 1475 (1.4) 1.82 (1.70–1.94) 1.93 (1.80–2.06)   Azitromycin 61 249 614 (1.0) 1.31 (1.20–1.44) 1.41 (1.28–1.55)   Cefalexin 38 194 324 (0.9) 1.04 (0.92–1.18) 1.09 (0.96–1.24) Multivariable models were also adjusted for the year the AB was dispensed. Only antibiotics with >5000 prescriptions are listed. Bold indicates P < 0.01. AB, antibiotic; adjOR, adjusted odds ratio; CI, confidence interval; OR, odds ratio. View Large Table 2. Liquids: characteristics associated with liquid antibiotic formulations that were changed to a prescription with a different antibiotic or pharmaceutical characteristic from the Norwegian Prescription Database between 2004 and 2016 Liquid formulation Characteristics Initial prescriptions (IP), n = 1 976 238 Subsequent prescriptions (% of IP) Univariable OR (95% CI) Model 1: Liquid characteristics Model 2: Antibiotics Multivariable adjOR: (95% CI) Multivariable adjOR: (95% CI) Child  Age group   Infant 0–1 years 623 791 12 561 (2.0) Reference Reference Reference   Toddler 2–3 years 640 816 16 277 (2.5) 1.27 (1.24–1.30) 1.27 (1.24–1.30) 1.26 (1.23–1.29)   Preschool 4–5 years 396 021 7335 (1.9) 0.93 (0.90–0.95) 0.91 (0.88–0.93) 0.89 (0.87–0.92)   School 6–9 years 274 862 5359 (2.0) 0.98 (0.95–1.02) 1.01 (0.97–1.04) 0.99 (0.96–1.02)   Pre-teen 10–12 years 40 748 902 (2.2) 1.13 (1.06–1.22) 1.22 (1.14–1.31) 1.17 (1.09–1.26)  Girl 962 148 20 926 (2.2) 1.03 (1.01–1.05) 1.02 (1.00–1.05) 1.07 (1.05–1.09)  Reimbursed AB 83 825 850 (1.0) 0.46 (0.43–0.50) 0.53 (0.49–0.58) 0.66 (0.61–0.72) Prescriber  Specialist   None 974 765 23 082 (2.4) Reference Reference Reference   GP 815 927 16 405 (2.0) 0.85 (0.83–0.86) 0.97 (0.94–0.99) 0.98 (0.96–1.01)   Paediatrician 98 565 1449 (1.5) 0.65 (0.61–0.69) 0.92 (0.86–0.97) 0.92 (0.87–0.98)   Other 86 981 1498 (1.7) 0.73 (0.69–0.77) 0.92 (0.87–0.97) 0.96 (0.91–1.01)  Birth year   Before 1950 175 637 3215 (1.8) Reference Reference Reference   1950–59 499 770 9300 (1.9) 1.01 (0.97–1.06) 1.02 (0.98–1.06) 1.02 (0.98–1.07)   1960–69 502 622 10 431 (2.1) 1.13 (1.09–1.18) 1.07 (1.03–1.12) 1.08 (1.03–1.13)   1970–79 572 659 13 565 (2.4) 1.29 (1.24–1.35) 1.11 (1.07–1.16) 1.13 (1.08–1.18)   After 1980 224 634 5903 (2.2) 1.44 (1.37–1.50) 1.20 (1.14–1.26) 1.19 (1.13–1.25)  Female prescriber 729 961 16 156 (2.2) 1.05 (1.03–1.07) 0.97 (0.95–0.99) 0.98 (0.96–1.00)  AB prescriptions per year (quartiles)   <23 461 948 10 308 (2.2) Reference Reference Reference   24–42 489 763 11 095 (2.3) 1.01 (0.99–1.04) 1.06 (1.03–1.09) 1.07 (1.04–1.10)   43–73 511 290 10 056 (2.2) 0.97 (0.94–0.99) 1.08 (1.05–1.11) 1.09 (1.06–1.12)   >73 513 237 9975 (1.9) 0.87 (0.84–0.89) 1.04 (1.01–1.07) 1.07 (1.04–1.10) Liquid antibiotic  Poor taste 968 756 29 954 (3.1) 2.60 (2.55–2.66) 2.35 (2.30–2.41)  Drops 194 192 7986 (4.2) 2.17 (2.12–2.23) 1.45 (1.41–1.49)  Antibiotics   Amoxicillin 412 145 3229 (0.8) Reference Reference   Dicloxacillin 8740 756 (8.7) 12.4 (11.4–13.5) 12.3 (11.3–13.4)   Penicillin V 799 380 26 825 (3.4) 4.55 (4.38–4.73) 4.52 (4.35–4.70)   Clarithromycin 55 237 938 (1.7) 2.22 (2.06–2.40) 2.34 (2.17–2.53)   Erythromycin 358 940 6037 (1.7) 2.21 (2.12–2.31) 2.24 (2.14–2.34)   Clindamycin 49 524 821 (1.7) 2.16 (1.99–2.34) 2.20 (2.03–2.39)   Trim-sulpha 79 725 1271 (1.6) 2.09 (1.95–2.24) 2.22 (2.07–2.38)   Trimethoprim 107 010 1475 (1.4) 1.82 (1.70–1.94) 1.93 (1.80–2.06)   Azitromycin 61 249 614 (1.0) 1.31 (1.20–1.44) 1.41 (1.28–1.55)   Cefalexin 38 194 324 (0.9) 1.04 (0.92–1.18) 1.09 (0.96–1.24) Liquid formulation Characteristics Initial prescriptions (IP), n = 1 976 238 Subsequent prescriptions (% of IP) Univariable OR (95% CI) Model 1: Liquid characteristics Model 2: Antibiotics Multivariable adjOR: (95% CI) Multivariable adjOR: (95% CI) Child  Age group   Infant 0–1 years 623 791 12 561 (2.0) Reference Reference Reference   Toddler 2–3 years 640 816 16 277 (2.5) 1.27 (1.24–1.30) 1.27 (1.24–1.30) 1.26 (1.23–1.29)   Preschool 4–5 years 396 021 7335 (1.9) 0.93 (0.90–0.95) 0.91 (0.88–0.93) 0.89 (0.87–0.92)   School 6–9 years 274 862 5359 (2.0) 0.98 (0.95–1.02) 1.01 (0.97–1.04) 0.99 (0.96–1.02)   Pre-teen 10–12 years 40 748 902 (2.2) 1.13 (1.06–1.22) 1.22 (1.14–1.31) 1.17 (1.09–1.26)  Girl 962 148 20 926 (2.2) 1.03 (1.01–1.05) 1.02 (1.00–1.05) 1.07 (1.05–1.09)  Reimbursed AB 83 825 850 (1.0) 0.46 (0.43–0.50) 0.53 (0.49–0.58) 0.66 (0.61–0.72) Prescriber  Specialist   None 974 765 23 082 (2.4) Reference Reference Reference   GP 815 927 16 405 (2.0) 0.85 (0.83–0.86) 0.97 (0.94–0.99) 0.98 (0.96–1.01)   Paediatrician 98 565 1449 (1.5) 0.65 (0.61–0.69) 0.92 (0.86–0.97) 0.92 (0.87–0.98)   Other 86 981 1498 (1.7) 0.73 (0.69–0.77) 0.92 (0.87–0.97) 0.96 (0.91–1.01)  Birth year   Before 1950 175 637 3215 (1.8) Reference Reference Reference   1950–59 499 770 9300 (1.9) 1.01 (0.97–1.06) 1.02 (0.98–1.06) 1.02 (0.98–1.07)   1960–69 502 622 10 431 (2.1) 1.13 (1.09–1.18) 1.07 (1.03–1.12) 1.08 (1.03–1.13)   1970–79 572 659 13 565 (2.4) 1.29 (1.24–1.35) 1.11 (1.07–1.16) 1.13 (1.08–1.18)   After 1980 224 634 5903 (2.2) 1.44 (1.37–1.50) 1.20 (1.14–1.26) 1.19 (1.13–1.25)  Female prescriber 729 961 16 156 (2.2) 1.05 (1.03–1.07) 0.97 (0.95–0.99) 0.98 (0.96–1.00)  AB prescriptions per year (quartiles)   <23 461 948 10 308 (2.2) Reference Reference Reference   24–42 489 763 11 095 (2.3) 1.01 (0.99–1.04) 1.06 (1.03–1.09) 1.07 (1.04–1.10)   43–73 511 290 10 056 (2.2) 0.97 (0.94–0.99) 1.08 (1.05–1.11) 1.09 (1.06–1.12)   >73 513 237 9975 (1.9) 0.87 (0.84–0.89) 1.04 (1.01–1.07) 1.07 (1.04–1.10) Liquid antibiotic  Poor taste 968 756 29 954 (3.1) 2.60 (2.55–2.66) 2.35 (2.30–2.41)  Drops 194 192 7986 (4.2) 2.17 (2.12–2.23) 1.45 (1.41–1.49)  Antibiotics   Amoxicillin 412 145 3229 (0.8) Reference Reference   Dicloxacillin 8740 756 (8.7) 12.4 (11.4–13.5) 12.3 (11.3–13.4)   Penicillin V 799 380 26 825 (3.4) 4.55 (4.38–4.73) 4.52 (4.35–4.70)   Clarithromycin 55 237 938 (1.7) 2.22 (2.06–2.40) 2.34 (2.17–2.53)   Erythromycin 358 940 6037 (1.7) 2.21 (2.12–2.31) 2.24 (2.14–2.34)   Clindamycin 49 524 821 (1.7) 2.16 (1.99–2.34) 2.20 (2.03–2.39)   Trim-sulpha 79 725 1271 (1.6) 2.09 (1.95–2.24) 2.22 (2.07–2.38)   Trimethoprim 107 010 1475 (1.4) 1.82 (1.70–1.94) 1.93 (1.80–2.06)   Azitromycin 61 249 614 (1.0) 1.31 (1.20–1.44) 1.41 (1.28–1.55)   Cefalexin 38 194 324 (0.9) 1.04 (0.92–1.18) 1.09 (0.96–1.24) Multivariable models were also adjusted for the year the AB was dispensed. Only antibiotics with >5000 prescriptions are listed. Bold indicates P < 0.01. AB, antibiotic; adjOR, adjusted odds ratio; CI, confidence interval; OR, odds ratio. View Large Compared with infants (0–1 years), prescriptions dispensed to toddlers (2–3 years) had the strongest association with prescription changes (adjOR: 1.3) followed by pre-teens (adjOR: 1.2) (Table 2). Reimbursed prescriptions dispensed to children with a chronic disease were least associated with changes (adjOR: 0.7). Girls had significantly higher odds than boys for prescription changes (adjOR: 1.07). Younger prescribers were more strongly associated with changes compared with those born before 1950 (born after 1980, adjOR: 1.2). The variables most strongly associated with a high number of prescription changes were antibiotics with a poor taste (adjOR: 2.4) and drops (adjOR: 1.5) (Table 2). Characteristics associated with requests for new prescriptions following solid antibiotics The prescriber characteristics associated with solid antibiotic prescription changes were quite similar to the prescriber characteristics of liquid antibiotic prescription changes; however, the difference in the association of changes between age groups was much greater for solids than liquids (Table 3). Table 3. Solids: characteristics associated with solid antibiotic formulations that were changed to a prescription with a different antibiotic or pharmaceutical characteristic from the Norwegian Prescription Database (NorPD) between 2004 and 2016 Solid formulation Characteristics Initial prescriptions (IP) n = 694 516 Re-prescriptions (% of IP) Univariable OR (95% CI) Model 1: Solid characteristics Model 2: Antibiotics Multivariable adjOR: (95% CI) Multivariable adjOR: (95% CI) Child  Age group   Pre-teen 10–12 years 272 388 4156 (1.5) Reference Reference Reference   School 6–9 years 313 042 6046 (1.9) 1.28 (1.23–1.33) 1.40 (1.35–1.46) 1.38 (1.33–1.44)   Preschool 4–5 years 74 159 2856 (3.9) 2.61 (2.49–2.74) 3.06 (2.90–3.22) 3.13 (2.98–3.29)   Toddler 2–3 years 26 107 2275 (8.7) 6.25 (5.92–6.59) 7.86 (7.43–8.33) 8.25 (7.80–8.73)   Infant 0–1 years 8820 633 (7.2) 5.18 (4.74–5.67) 7.87 (7.16–8.66) 8.81 (7.99–9.71)  Girl 380 566 8790 (2.3) 1.01 (0.98–1.05) 1.06 (1.03–1.10) 1.06 (1.03–1.10)  Reimbursed AB 35 778 510 (1.4) 0.62 (0.57–0.68) 0.57 (0.52–0.63) 0.68 (0.61–0.76) Prescriber  Specialist   None (ref) 331 810 7935 (2.4) Reference Reference Reference   GP 306 018 6980 (2.3) 0.95 (0.92–0.99) 1.05 (1.01–1.10) 1.04 (1.00–1.08)   Paediatrician 26 286 524 (2.0) 0.86 (0.79–0.94) 0.96 (0.87–1.06) 1.00 (0.91–1.11)   Other 30 402 527 (1.7) 0.73 (0.66–0.79) 0.84 (0.77–0.92) 0.90 (0.82–0.99)  Birth year   Before 1950 67 823 1291 (1.9) Reference Reference Reference   1950–59 192 050 4023 (2.1) 1.10 (1.03–1.17) 1.02 (0.96–1.09) 1.02 (0.96–1.09)   1960–69 172 782 3912 (2.3) 1.19 (1.12–1.27) 1.09 (1.02–1.16) 1.08 (1.01–1.15)   1970–79 184 484 4549 (2.5) 1.30 (1.22–1.38) 1.16 (1.09–1.25) 1.15 (1.08–1.24)   After 1980 77 011 2186 (2.8) 1.49 (1.39–1.60) 1.26 (1.16–1.37) 1.25 (1.15–1.36)  Female prescriber 240 884 5660 (2.3) 1.04 (1.00–1.07) 0.98 (0.95–1.02) 0.97 (0.94–1.01)  AB Prescriptions per year (quart)   <23 208 436 4587 (2.2) Reference Reference Reference   24–42 174 434 4139 (2.4) 1.08 (1.04–1.13) 1.10 (1.05–1.15) 1.08 (1.04–1.13)   43–73 166 187 3965 (2.4) 1.09 (1.04–1.14) 1.15 (1.10–1.20) 1.13 (1.08–1.19)   >73 145 459 3275 (2.3) 1.03 (0.98–1.08) 1.14 (1.08–1.19) 1.13 (1.07–1.18) Solid antibiotic  Shape   Round 137 849 3023 (2.2) Reference Reference   Oval 399 566 8090 (2.0) 0.91 (0.88–0.95) 1.32 (1.25–1.39)   Capsule 157 101 4853 (3.1) 1.40 (1.34–1.47) 1.50 (1.41–1.60)  Scored 418 047 7849 (1.9) 0.63 (0.62–0.66) 0.64 (0.60–0.67)  Size   20–<79 mm2 360 892 7898 (2.2) Reference Reference   79–124 mm2 281 419 6887 (2.4) 1.12 (1.08–1.16) 1.06 (1.00–1.11)   >124 mm2 52 205 1181 (2.3) 1.04 (0.97–1.10) 1.19 (1.10–1.28)  Antibiotic   Amoxicillin 26 429 321 (1.2) Reference Reference   Erythromycin 80 309 3102 (3.9) 3.25 (2.90–3.65) 3.92 (3.49–4.42)   Dicloxacillin 55 097 1644 (3.0) 2.50 (2.22–2.82) 2.22 (1.96–2.51)   Clarithromycin 8971 169 (1.9) 1.56 (1.29–1.88) 2.10 (1.74–2.54)   Pivmecillinam 56 993 1780 (3.1) 2.63 (2.33–2.96) 1.83 (1.62–2.08)   Clindamycin 17 996 384 (2.1) 1.76 (1.52–2.05) 1.76 (1.51–2.05)   Penicillin V 355 262 7142 (2.0) 1.67 (1.49–1.87) 1.50 (1.34–1.68)   Azitromycin 9969 134 (1.3) 1.12 (0.91–1.37) 1.34 (1.09–1.64)   Doxycycline 5000 65 (1.3) 1.06 (0.81–1.38) 1.33 (1.01–1.75)   Trim-sulpha 14 964 210 (1.4) 1.18 (0.99–1.41) 1.26 (1.05–1.51)   Trimethoprim 22 510 305 (1.4) 1.13 (0.97–1.32) 1.17 (0.99–1.37)   Cefalexin 6 064 71 (1.2) 0.97 (0.75–1.26) 1.11 (0.86–1.44)   Nitrofurantoin 24 499 435 (1.8) 1.49 (1.28–1.72) 0.61 (0.52–0.72) Solid formulation Characteristics Initial prescriptions (IP) n = 694 516 Re-prescriptions (% of IP) Univariable OR (95% CI) Model 1: Solid characteristics Model 2: Antibiotics Multivariable adjOR: (95% CI) Multivariable adjOR: (95% CI) Child  Age group   Pre-teen 10–12 years 272 388 4156 (1.5) Reference Reference Reference   School 6–9 years 313 042 6046 (1.9) 1.28 (1.23–1.33) 1.40 (1.35–1.46) 1.38 (1.33–1.44)   Preschool 4–5 years 74 159 2856 (3.9) 2.61 (2.49–2.74) 3.06 (2.90–3.22) 3.13 (2.98–3.29)   Toddler 2–3 years 26 107 2275 (8.7) 6.25 (5.92–6.59) 7.86 (7.43–8.33) 8.25 (7.80–8.73)   Infant 0–1 years 8820 633 (7.2) 5.18 (4.74–5.67) 7.87 (7.16–8.66) 8.81 (7.99–9.71)  Girl 380 566 8790 (2.3) 1.01 (0.98–1.05) 1.06 (1.03–1.10) 1.06 (1.03–1.10)  Reimbursed AB 35 778 510 (1.4) 0.62 (0.57–0.68) 0.57 (0.52–0.63) 0.68 (0.61–0.76) Prescriber  Specialist   None (ref) 331 810 7935 (2.4) Reference Reference Reference   GP 306 018 6980 (2.3) 0.95 (0.92–0.99) 1.05 (1.01–1.10) 1.04 (1.00–1.08)   Paediatrician 26 286 524 (2.0) 0.86 (0.79–0.94) 0.96 (0.87–1.06) 1.00 (0.91–1.11)   Other 30 402 527 (1.7) 0.73 (0.66–0.79) 0.84 (0.77–0.92) 0.90 (0.82–0.99)  Birth year   Before 1950 67 823 1291 (1.9) Reference Reference Reference   1950–59 192 050 4023 (2.1) 1.10 (1.03–1.17) 1.02 (0.96–1.09) 1.02 (0.96–1.09)   1960–69 172 782 3912 (2.3) 1.19 (1.12–1.27) 1.09 (1.02–1.16) 1.08 (1.01–1.15)   1970–79 184 484 4549 (2.5) 1.30 (1.22–1.38) 1.16 (1.09–1.25) 1.15 (1.08–1.24)   After 1980 77 011 2186 (2.8) 1.49 (1.39–1.60) 1.26 (1.16–1.37) 1.25 (1.15–1.36)  Female prescriber 240 884 5660 (2.3) 1.04 (1.00–1.07) 0.98 (0.95–1.02) 0.97 (0.94–1.01)  AB Prescriptions per year (quart)   <23 208 436 4587 (2.2) Reference Reference Reference   24–42 174 434 4139 (2.4) 1.08 (1.04–1.13) 1.10 (1.05–1.15) 1.08 (1.04–1.13)   43–73 166 187 3965 (2.4) 1.09 (1.04–1.14) 1.15 (1.10–1.20) 1.13 (1.08–1.19)   >73 145 459 3275 (2.3) 1.03 (0.98–1.08) 1.14 (1.08–1.19) 1.13 (1.07–1.18) Solid antibiotic  Shape   Round 137 849 3023 (2.2) Reference Reference   Oval 399 566 8090 (2.0) 0.91 (0.88–0.95) 1.32 (1.25–1.39)   Capsule 157 101 4853 (3.1) 1.40 (1.34–1.47) 1.50 (1.41–1.60)  Scored 418 047 7849 (1.9) 0.63 (0.62–0.66) 0.64 (0.60–0.67)  Size   20–<79 mm2 360 892 7898 (2.2) Reference Reference   79–124 mm2 281 419 6887 (2.4) 1.12 (1.08–1.16) 1.06 (1.00–1.11)   >124 mm2 52 205 1181 (2.3) 1.04 (0.97–1.10) 1.19 (1.10–1.28)  Antibiotic   Amoxicillin 26 429 321 (1.2) Reference Reference   Erythromycin 80 309 3102 (3.9) 3.25 (2.90–3.65) 3.92 (3.49–4.42)   Dicloxacillin 55 097 1644 (3.0) 2.50 (2.22–2.82) 2.22 (1.96–2.51)   Clarithromycin 8971 169 (1.9) 1.56 (1.29–1.88) 2.10 (1.74–2.54)   Pivmecillinam 56 993 1780 (3.1) 2.63 (2.33–2.96) 1.83 (1.62–2.08)   Clindamycin 17 996 384 (2.1) 1.76 (1.52–2.05) 1.76 (1.51–2.05)   Penicillin V 355 262 7142 (2.0) 1.67 (1.49–1.87) 1.50 (1.34–1.68)   Azitromycin 9969 134 (1.3) 1.12 (0.91–1.37) 1.34 (1.09–1.64)   Doxycycline 5000 65 (1.3) 1.06 (0.81–1.38) 1.33 (1.01–1.75)   Trim-sulpha 14 964 210 (1.4) 1.18 (0.99–1.41) 1.26 (1.05–1.51)   Trimethoprim 22 510 305 (1.4) 1.13 (0.97–1.32) 1.17 (0.99–1.37)   Cefalexin 6 064 71 (1.2) 0.97 (0.75–1.26) 1.11 (0.86–1.44)   Nitrofurantoin 24 499 435 (1.8) 1.49 (1.28–1.72) 0.61 (0.52–0.72) Multivariable models were also adjusted for the year the AB was dispensed. Only antibiotics with >5000 prescriptions are listed. Bold indicates P < 0.01. AB, antibiotic; adjOR, adjusted odds ratio; CI, confidence interval; OR, odds ratio. View Large Table 3. Solids: characteristics associated with solid antibiotic formulations that were changed to a prescription with a different antibiotic or pharmaceutical characteristic from the Norwegian Prescription Database (NorPD) between 2004 and 2016 Solid formulation Characteristics Initial prescriptions (IP) n = 694 516 Re-prescriptions (% of IP) Univariable OR (95% CI) Model 1: Solid characteristics Model 2: Antibiotics Multivariable adjOR: (95% CI) Multivariable adjOR: (95% CI) Child  Age group   Pre-teen 10–12 years 272 388 4156 (1.5) Reference Reference Reference   School 6–9 years 313 042 6046 (1.9) 1.28 (1.23–1.33) 1.40 (1.35–1.46) 1.38 (1.33–1.44)   Preschool 4–5 years 74 159 2856 (3.9) 2.61 (2.49–2.74) 3.06 (2.90–3.22) 3.13 (2.98–3.29)   Toddler 2–3 years 26 107 2275 (8.7) 6.25 (5.92–6.59) 7.86 (7.43–8.33) 8.25 (7.80–8.73)   Infant 0–1 years 8820 633 (7.2) 5.18 (4.74–5.67) 7.87 (7.16–8.66) 8.81 (7.99–9.71)  Girl 380 566 8790 (2.3) 1.01 (0.98–1.05) 1.06 (1.03–1.10) 1.06 (1.03–1.10)  Reimbursed AB 35 778 510 (1.4) 0.62 (0.57–0.68) 0.57 (0.52–0.63) 0.68 (0.61–0.76) Prescriber  Specialist   None (ref) 331 810 7935 (2.4) Reference Reference Reference   GP 306 018 6980 (2.3) 0.95 (0.92–0.99) 1.05 (1.01–1.10) 1.04 (1.00–1.08)   Paediatrician 26 286 524 (2.0) 0.86 (0.79–0.94) 0.96 (0.87–1.06) 1.00 (0.91–1.11)   Other 30 402 527 (1.7) 0.73 (0.66–0.79) 0.84 (0.77–0.92) 0.90 (0.82–0.99)  Birth year   Before 1950 67 823 1291 (1.9) Reference Reference Reference   1950–59 192 050 4023 (2.1) 1.10 (1.03–1.17) 1.02 (0.96–1.09) 1.02 (0.96–1.09)   1960–69 172 782 3912 (2.3) 1.19 (1.12–1.27) 1.09 (1.02–1.16) 1.08 (1.01–1.15)   1970–79 184 484 4549 (2.5) 1.30 (1.22–1.38) 1.16 (1.09–1.25) 1.15 (1.08–1.24)   After 1980 77 011 2186 (2.8) 1.49 (1.39–1.60) 1.26 (1.16–1.37) 1.25 (1.15–1.36)  Female prescriber 240 884 5660 (2.3) 1.04 (1.00–1.07) 0.98 (0.95–1.02) 0.97 (0.94–1.01)  AB Prescriptions per year (quart)   <23 208 436 4587 (2.2) Reference Reference Reference   24–42 174 434 4139 (2.4) 1.08 (1.04–1.13) 1.10 (1.05–1.15) 1.08 (1.04–1.13)   43–73 166 187 3965 (2.4) 1.09 (1.04–1.14) 1.15 (1.10–1.20) 1.13 (1.08–1.19)   >73 145 459 3275 (2.3) 1.03 (0.98–1.08) 1.14 (1.08–1.19) 1.13 (1.07–1.18) Solid antibiotic  Shape   Round 137 849 3023 (2.2) Reference Reference   Oval 399 566 8090 (2.0) 0.91 (0.88–0.95) 1.32 (1.25–1.39)   Capsule 157 101 4853 (3.1) 1.40 (1.34–1.47) 1.50 (1.41–1.60)  Scored 418 047 7849 (1.9) 0.63 (0.62–0.66) 0.64 (0.60–0.67)  Size   20–<79 mm2 360 892 7898 (2.2) Reference Reference   79–124 mm2 281 419 6887 (2.4) 1.12 (1.08–1.16) 1.06 (1.00–1.11)   >124 mm2 52 205 1181 (2.3) 1.04 (0.97–1.10) 1.19 (1.10–1.28)  Antibiotic   Amoxicillin 26 429 321 (1.2) Reference Reference   Erythromycin 80 309 3102 (3.9) 3.25 (2.90–3.65) 3.92 (3.49–4.42)   Dicloxacillin 55 097 1644 (3.0) 2.50 (2.22–2.82) 2.22 (1.96–2.51)   Clarithromycin 8971 169 (1.9) 1.56 (1.29–1.88) 2.10 (1.74–2.54)   Pivmecillinam 56 993 1780 (3.1) 2.63 (2.33–2.96) 1.83 (1.62–2.08)   Clindamycin 17 996 384 (2.1) 1.76 (1.52–2.05) 1.76 (1.51–2.05)   Penicillin V 355 262 7142 (2.0) 1.67 (1.49–1.87) 1.50 (1.34–1.68)   Azitromycin 9969 134 (1.3) 1.12 (0.91–1.37) 1.34 (1.09–1.64)   Doxycycline 5000 65 (1.3) 1.06 (0.81–1.38) 1.33 (1.01–1.75)   Trim-sulpha 14 964 210 (1.4) 1.18 (0.99–1.41) 1.26 (1.05–1.51)   Trimethoprim 22 510 305 (1.4) 1.13 (0.97–1.32) 1.17 (0.99–1.37)   Cefalexin 6 064 71 (1.2) 0.97 (0.75–1.26) 1.11 (0.86–1.44)   Nitrofurantoin 24 499 435 (1.8) 1.49 (1.28–1.72) 0.61 (0.52–0.72) Solid formulation Characteristics Initial prescriptions (IP) n = 694 516 Re-prescriptions (% of IP) Univariable OR (95% CI) Model 1: Solid characteristics Model 2: Antibiotics Multivariable adjOR: (95% CI) Multivariable adjOR: (95% CI) Child  Age group   Pre-teen 10–12 years 272 388 4156 (1.5) Reference Reference Reference   School 6–9 years 313 042 6046 (1.9) 1.28 (1.23–1.33) 1.40 (1.35–1.46) 1.38 (1.33–1.44)   Preschool 4–5 years 74 159 2856 (3.9) 2.61 (2.49–2.74) 3.06 (2.90–3.22) 3.13 (2.98–3.29)   Toddler 2–3 years 26 107 2275 (8.7) 6.25 (5.92–6.59) 7.86 (7.43–8.33) 8.25 (7.80–8.73)   Infant 0–1 years 8820 633 (7.2) 5.18 (4.74–5.67) 7.87 (7.16–8.66) 8.81 (7.99–9.71)  Girl 380 566 8790 (2.3) 1.01 (0.98–1.05) 1.06 (1.03–1.10) 1.06 (1.03–1.10)  Reimbursed AB 35 778 510 (1.4) 0.62 (0.57–0.68) 0.57 (0.52–0.63) 0.68 (0.61–0.76) Prescriber  Specialist   None (ref) 331 810 7935 (2.4) Reference Reference Reference   GP 306 018 6980 (2.3) 0.95 (0.92–0.99) 1.05 (1.01–1.10) 1.04 (1.00–1.08)   Paediatrician 26 286 524 (2.0) 0.86 (0.79–0.94) 0.96 (0.87–1.06) 1.00 (0.91–1.11)   Other 30 402 527 (1.7) 0.73 (0.66–0.79) 0.84 (0.77–0.92) 0.90 (0.82–0.99)  Birth year   Before 1950 67 823 1291 (1.9) Reference Reference Reference   1950–59 192 050 4023 (2.1) 1.10 (1.03–1.17) 1.02 (0.96–1.09) 1.02 (0.96–1.09)   1960–69 172 782 3912 (2.3) 1.19 (1.12–1.27) 1.09 (1.02–1.16) 1.08 (1.01–1.15)   1970–79 184 484 4549 (2.5) 1.30 (1.22–1.38) 1.16 (1.09–1.25) 1.15 (1.08–1.24)   After 1980 77 011 2186 (2.8) 1.49 (1.39–1.60) 1.26 (1.16–1.37) 1.25 (1.15–1.36)  Female prescriber 240 884 5660 (2.3) 1.04 (1.00–1.07) 0.98 (0.95–1.02) 0.97 (0.94–1.01)  AB Prescriptions per year (quart)   <23 208 436 4587 (2.2) Reference Reference Reference   24–42 174 434 4139 (2.4) 1.08 (1.04–1.13) 1.10 (1.05–1.15) 1.08 (1.04–1.13)   43–73 166 187 3965 (2.4) 1.09 (1.04–1.14) 1.15 (1.10–1.20) 1.13 (1.08–1.19)   >73 145 459 3275 (2.3) 1.03 (0.98–1.08) 1.14 (1.08–1.19) 1.13 (1.07–1.18) Solid antibiotic  Shape   Round 137 849 3023 (2.2) Reference Reference   Oval 399 566 8090 (2.0) 0.91 (0.88–0.95) 1.32 (1.25–1.39)   Capsule 157 101 4853 (3.1) 1.40 (1.34–1.47) 1.50 (1.41–1.60)  Scored 418 047 7849 (1.9) 0.63 (0.62–0.66) 0.64 (0.60–0.67)  Size   20–<79 mm2 360 892 7898 (2.2) Reference Reference   79–124 mm2 281 419 6887 (2.4) 1.12 (1.08–1.16) 1.06 (1.00–1.11)   >124 mm2 52 205 1181 (2.3) 1.04 (0.97–1.10) 1.19 (1.10–1.28)  Antibiotic   Amoxicillin 26 429 321 (1.2) Reference Reference   Erythromycin 80 309 3102 (3.9) 3.25 (2.90–3.65) 3.92 (3.49–4.42)   Dicloxacillin 55 097 1644 (3.0) 2.50 (2.22–2.82) 2.22 (1.96–2.51)   Clarithromycin 8971 169 (1.9) 1.56 (1.29–1.88) 2.10 (1.74–2.54)   Pivmecillinam 56 993 1780 (3.1) 2.63 (2.33–2.96) 1.83 (1.62–2.08)   Clindamycin 17 996 384 (2.1) 1.76 (1.52–2.05) 1.76 (1.51–2.05)   Penicillin V 355 262 7142 (2.0) 1.67 (1.49–1.87) 1.50 (1.34–1.68)   Azitromycin 9969 134 (1.3) 1.12 (0.91–1.37) 1.34 (1.09–1.64)   Doxycycline 5000 65 (1.3) 1.06 (0.81–1.38) 1.33 (1.01–1.75)   Trim-sulpha 14 964 210 (1.4) 1.18 (0.99–1.41) 1.26 (1.05–1.51)   Trimethoprim 22 510 305 (1.4) 1.13 (0.97–1.32) 1.17 (0.99–1.37)   Cefalexin 6 064 71 (1.2) 0.97 (0.75–1.26) 1.11 (0.86–1.44)   Nitrofurantoin 24 499 435 (1.8) 1.49 (1.28–1.72) 0.61 (0.52–0.72) Multivariable models were also adjusted for the year the AB was dispensed. Only antibiotics with >5000 prescriptions are listed. Bold indicates P < 0.01. AB, antibiotic; adjOR, adjusted odds ratio; CI, confidence interval; OR, odds ratio. View Large Children below 4 years had almost eight times higher odds than pre-teens for changing a solid prescription. Prescriptions for both capsules and oval tablets were more strongly associated with prescription changes than round tablets (adjOR: 1.5 and 1.3, respectively), while scored tablets had a lower association (adjOR:0.6). There was also an influence of size, with extra-large solids having a stronger association with prescription changes (adjOR: 1.2) (Table 3). Initial and subsequent antibiotic prescriptions Of the initial prescriptions that were changed, penicillin V comprised the majority (58%) while amoxicillin was least commonly changed (6%) (Table 4). The macrolide/lincosamide group comprised most of the sequential prescriptions (36%). Of the initial macrolide/lincosamide antibiotics that were changed, 43% were followed by a subsequent prescription of a penicillin (penicillin V or amoxicillin). Table 4. Initial oral solid and liquid antibiotics and subsequent prescriptions with different antibiotics or pharmaceutical characteristics (e.g. taste, size, shape, or strength/concentration) from the Norwegian Prescription Database between 2004 and 2016 Initial prescription Subsequent prescription Penicillin V Macro/linco Amoxicillin Other Form Antibiotic Form (n) Solid (6509) Liquid (10 707) Solid (4039) Liquid (16 946) Solid (790) Liquid (10 512) Solid (4062) Liquid (4835) Solid Liquid PenV, 58% (33 967) Solid (7142) 2.3% (164) 42.5% (3038) 20.6% (1468) 15.5% (1108) 2.7% (196) 9.5% (677) 5.5% (395) 1.3% (96) 31.1% (2223) 68.9% (4919) Liquid (26 825) 17.9% (4813) 18.2% (4873) 0.8% (226) 34.0% (9151) 0.3% (76) 24.6% (6601) 0.5% (131) 3.6% (954) 19.6% (5246) 80.4% (21 579) Macro/linco, 21% (12 235) Solid (3789) 17.7% (669) 3.6% (136) 17.4% (661) 34.1% (1291) 5.8% (220) 3.8% (144) 15.8% (600) 1.8% (68) 56.7% (2150) 43.3% (1639) Liquid (8446) 6.7% (570) 19.6% (1652) 15.3% (1294) 24.3% (2056) 0.9% (72) 20.7% (1749) 2.9% (242) 9.6% (811) 25.8% (2178) 74.2% (6268) Amoxicillin, 6% (3550) Solid (321) 8.4% (27) 2.5% (8) 28.7% (92) 10.9% (35) 9.3% (30) 20.9% (67) 16.8% (54) 2.5% (8) 63.2% (203) 36.8% (118) Liquid (3229) 3.2% (103) 13.4% (434) 1.3% (42) 53.4% (1725) 3.4% (109) 4.6% (149) 4.1% (133) 16.5% (534) 12.0% (387) 88.0 % (2842) Other, 15% (8648) Solid (4714) 2.1% (100) 4.7% (223) 4.8% (228) 19.6% (926) 1.4% (66) 8.7% (408) 21.6% (1020) 37.0% (1743) 30.0% (1414) 70.0% (3300) Liquid (3934) 1.6% (63) 8.7% (343) 0.7% (28) 16.6% (654) 0.5% (21) 18.2% (717) 37.8% (1487) 15.8% (621) 40.6% (1599) 59.4% (2335) All formulations Total (58 400) Total penV 29.5% (17 216) Total macro/linco 35.9% (20 985) Total amoxicillin 19.4% (11 302) Total other 15.2% (8897) 26.4% (15 400) 73.6% (43 000) Initial prescription Subsequent prescription Penicillin V Macro/linco Amoxicillin Other Form Antibiotic Form (n) Solid (6509) Liquid (10 707) Solid (4039) Liquid (16 946) Solid (790) Liquid (10 512) Solid (4062) Liquid (4835) Solid Liquid PenV, 58% (33 967) Solid (7142) 2.3% (164) 42.5% (3038) 20.6% (1468) 15.5% (1108) 2.7% (196) 9.5% (677) 5.5% (395) 1.3% (96) 31.1% (2223) 68.9% (4919) Liquid (26 825) 17.9% (4813) 18.2% (4873) 0.8% (226) 34.0% (9151) 0.3% (76) 24.6% (6601) 0.5% (131) 3.6% (954) 19.6% (5246) 80.4% (21 579) Macro/linco, 21% (12 235) Solid (3789) 17.7% (669) 3.6% (136) 17.4% (661) 34.1% (1291) 5.8% (220) 3.8% (144) 15.8% (600) 1.8% (68) 56.7% (2150) 43.3% (1639) Liquid (8446) 6.7% (570) 19.6% (1652) 15.3% (1294) 24.3% (2056) 0.9% (72) 20.7% (1749) 2.9% (242) 9.6% (811) 25.8% (2178) 74.2% (6268) Amoxicillin, 6% (3550) Solid (321) 8.4% (27) 2.5% (8) 28.7% (92) 10.9% (35) 9.3% (30) 20.9% (67) 16.8% (54) 2.5% (8) 63.2% (203) 36.8% (118) Liquid (3229) 3.2% (103) 13.4% (434) 1.3% (42) 53.4% (1725) 3.4% (109) 4.6% (149) 4.1% (133) 16.5% (534) 12.0% (387) 88.0 % (2842) Other, 15% (8648) Solid (4714) 2.1% (100) 4.7% (223) 4.8% (228) 19.6% (926) 1.4% (66) 8.7% (408) 21.6% (1020) 37.0% (1743) 30.0% (1414) 70.0% (3300) Liquid (3934) 1.6% (63) 8.7% (343) 0.7% (28) 16.6% (654) 0.5% (21) 18.2% (717) 37.8% (1487) 15.8% (621) 40.6% (1599) 59.4% (2335) All formulations Total (58 400) Total penV 29.5% (17 216) Total macro/linco 35.9% (20 985) Total amoxicillin 19.4% (11 302) Total other 15.2% (8897) 26.4% (15 400) 73.6% (43 000) PenV, penicillin V; Macro/linco, macrolides/lincosamides. View Large Table 4. Initial oral solid and liquid antibiotics and subsequent prescriptions with different antibiotics or pharmaceutical characteristics (e.g. taste, size, shape, or strength/concentration) from the Norwegian Prescription Database between 2004 and 2016 Initial prescription Subsequent prescription Penicillin V Macro/linco Amoxicillin Other Form Antibiotic Form (n) Solid (6509) Liquid (10 707) Solid (4039) Liquid (16 946) Solid (790) Liquid (10 512) Solid (4062) Liquid (4835) Solid Liquid PenV, 58% (33 967) Solid (7142) 2.3% (164) 42.5% (3038) 20.6% (1468) 15.5% (1108) 2.7% (196) 9.5% (677) 5.5% (395) 1.3% (96) 31.1% (2223) 68.9% (4919) Liquid (26 825) 17.9% (4813) 18.2% (4873) 0.8% (226) 34.0% (9151) 0.3% (76) 24.6% (6601) 0.5% (131) 3.6% (954) 19.6% (5246) 80.4% (21 579) Macro/linco, 21% (12 235) Solid (3789) 17.7% (669) 3.6% (136) 17.4% (661) 34.1% (1291) 5.8% (220) 3.8% (144) 15.8% (600) 1.8% (68) 56.7% (2150) 43.3% (1639) Liquid (8446) 6.7% (570) 19.6% (1652) 15.3% (1294) 24.3% (2056) 0.9% (72) 20.7% (1749) 2.9% (242) 9.6% (811) 25.8% (2178) 74.2% (6268) Amoxicillin, 6% (3550) Solid (321) 8.4% (27) 2.5% (8) 28.7% (92) 10.9% (35) 9.3% (30) 20.9% (67) 16.8% (54) 2.5% (8) 63.2% (203) 36.8% (118) Liquid (3229) 3.2% (103) 13.4% (434) 1.3% (42) 53.4% (1725) 3.4% (109) 4.6% (149) 4.1% (133) 16.5% (534) 12.0% (387) 88.0 % (2842) Other, 15% (8648) Solid (4714) 2.1% (100) 4.7% (223) 4.8% (228) 19.6% (926) 1.4% (66) 8.7% (408) 21.6% (1020) 37.0% (1743) 30.0% (1414) 70.0% (3300) Liquid (3934) 1.6% (63) 8.7% (343) 0.7% (28) 16.6% (654) 0.5% (21) 18.2% (717) 37.8% (1487) 15.8% (621) 40.6% (1599) 59.4% (2335) All formulations Total (58 400) Total penV 29.5% (17 216) Total macro/linco 35.9% (20 985) Total amoxicillin 19.4% (11 302) Total other 15.2% (8897) 26.4% (15 400) 73.6% (43 000) Initial prescription Subsequent prescription Penicillin V Macro/linco Amoxicillin Other Form Antibiotic Form (n) Solid (6509) Liquid (10 707) Solid (4039) Liquid (16 946) Solid (790) Liquid (10 512) Solid (4062) Liquid (4835) Solid Liquid PenV, 58% (33 967) Solid (7142) 2.3% (164) 42.5% (3038) 20.6% (1468) 15.5% (1108) 2.7% (196) 9.5% (677) 5.5% (395) 1.3% (96) 31.1% (2223) 68.9% (4919) Liquid (26 825) 17.9% (4813) 18.2% (4873) 0.8% (226) 34.0% (9151) 0.3% (76) 24.6% (6601) 0.5% (131) 3.6% (954) 19.6% (5246) 80.4% (21 579) Macro/linco, 21% (12 235) Solid (3789) 17.7% (669) 3.6% (136) 17.4% (661) 34.1% (1291) 5.8% (220) 3.8% (144) 15.8% (600) 1.8% (68) 56.7% (2150) 43.3% (1639) Liquid (8446) 6.7% (570) 19.6% (1652) 15.3% (1294) 24.3% (2056) 0.9% (72) 20.7% (1749) 2.9% (242) 9.6% (811) 25.8% (2178) 74.2% (6268) Amoxicillin, 6% (3550) Solid (321) 8.4% (27) 2.5% (8) 28.7% (92) 10.9% (35) 9.3% (30) 20.9% (67) 16.8% (54) 2.5% (8) 63.2% (203) 36.8% (118) Liquid (3229) 3.2% (103) 13.4% (434) 1.3% (42) 53.4% (1725) 3.4% (109) 4.6% (149) 4.1% (133) 16.5% (534) 12.0% (387) 88.0 % (2842) Other, 15% (8648) Solid (4714) 2.1% (100) 4.7% (223) 4.8% (228) 19.6% (926) 1.4% (66) 8.7% (408) 21.6% (1020) 37.0% (1743) 30.0% (1414) 70.0% (3300) Liquid (3934) 1.6% (63) 8.7% (343) 0.7% (28) 16.6% (654) 0.5% (21) 18.2% (717) 37.8% (1487) 15.8% (621) 40.6% (1599) 59.4% (2335) All formulations Total (58 400) Total penV 29.5% (17 216) Total macro/linco 35.9% (20 985) Total amoxicillin 19.4% (11 302) Total other 15.2% (8897) 26.4% (15 400) 73.6% (43 000) PenV, penicillin V; Macro/linco, macrolides/lincosamides. View Large The sensitivity analyses negligibly changed the results of the multivariable regressions (results not shown). Discussion Summary of the main findings Requests for new prescriptions followed 3.0% of 2 691 483 initial antibiotic prescriptions for children. Young children who received solid formulations (10.9%) and certain poor-tasting antibiotics (8.6%) had the highest proportions of new prescriptions. Penicillin V was most commonly changed, while macrolides/lincosamides dominated subsequent prescriptions. In order of magnitude, the characteristics associated with requests for new prescriptions were as follows: the children’s ages (solids), poor taste and concentration of liquids, size and shape of solids, prescribers born in recent decades, and girl patients. Reimbursed prescriptions and scored solids were associated with fewer requests. Comparison with existing literature Changed antibiotic prescriptions represent situations of parents in great distress, unable to get their child to take the medicine prescribed to get well (4). In addition, changes from narrow- to broad-spectrum antibiotics may increase children’s short-term risk of side effects (6), and change of intestinal microbiome may result in future sequelae (27), furthering this distress. Changes also take parents’ time away from the sick child to contact the prescriber and pharmacy and increase treatment costs for extra antibiotic courses. Surprisingly, girls experienced more prescription changes than boys, which is not explained by significant body size differences (28). Boys were generally more positive than girls towards taking oral formulations of different types and sizes in a recent study, indicating possible gender differences (29). Giving toddlers medicine may be extra difficult, as their proportion of change was higher than other age groups. This may be related to the increased use of broad-spectrum antibiotics in this age group, putting them at risk of antibiotic resistance (30). One explanation may be that prescribers choose more acceptable medicines to save time, as 41% of our prescribers had issued a new prescription (25). Prescribers born in recent decades changed more prescriptions, which may have contributed to the increase in prescription changes over the last 13 years. This effect remained after adjusting for type of antibiotics and warrants further exploration. Poor-tasting liquid antibiotics had 2.4 times higher odds of being changed than better-tasting liquids. This corresponds with findings that taste is a key characteristic associated with children’s refusal of medicines (31,32) and indicates that prescription changes can be used to identify antibiotics that are challenging for children to use. Changed prescriptions most likely underestimate administration challenges (4) and may contribute to the difference found in chronic children who were 3.8 times more likely to refuse poor-tasting medicines at least once (11). Taste may also explain why poor-tasting liquid penicillin V was most frequently replaced by better-tasting liquid amoxicillin and erythromycin, and even solid penicillin V that is easier to taste mask (33). Changes between liquid concentrations were seen for all the antibiotic groups. Concentrated liquids had 1.5 times greater odds of being changed, indicating that the advantage of having a smaller volume may not compensate for the stronger taste. The opposite was found in a study of children with chronic disease, although this was believed to be caused by an age factor (24). There is little consensus in the literature regarding which size and shape solids to prescribe at different ages, but recent studies have shown that preschool children can swallow and even prefer mini tablets of 2–3 mm (34,35). There is a large discrepancy, though, between clinical studies and the availability of solids for clinical use (36). The two smallest solids in the dataset were 11 × 5 mm and 9 × 6.5 mm, which in a recent review would not be considered appropriate for children under 13 years (37). This is in keeping with the results in this study where younger children had stronger association with solid formulation changes, and medium and scored tablets had lower independent associations. Children can be taught to swallow solids (38), which may explain why this study showed that prescriptions reimbursed for children with a serious or chronic disease had lower odds for prescription changes. Capsules had 1.5 times higher odds of prescription changes than round tablets, and erythromycin capsules were changed most frequently. This lack of preference for capsules may be explained by their large size and a misconception of being made from plastic (29). Erythromycin capsules, however, contain granules that can be sprinkled on food, making them easier to swallow (39), although this may not be known. Changes from penicillin V tablets to erythromycin were also seen (Table 4), which may indicate that opening the capsules may be known by some. Strengths and limitations of the study The strength of this study is the inclusion of prescriptions from the entire Norwegian paediatric population over a 13-year period. The two main limitations are lack of information regarding (i) the reason for requesting a new prescription and (ii) type and severity of infections. The prevalence of allergies and adverse effects is unknown and could contribute an overestimation of changes due to administration challenges. Though uncommon, more than one antibiotic could also have been prescribed on the same day intentionally, thus overestimating changes. Changes due to therapeutic failure could also overestimate the results, although the finding that more prescriptions were changed on Day 1 than on Day 2 indicates that this is unlikely to be a key factor. Conclusion and implication Changed prescriptions have costs for the involved children, their families and the health-care system in general. Narrow-spectrum antibiotics were changed more often than broad-spectrum antibiotics, indicating that costs related to children’s refusal and consequent antibiotic changes may contribute to the increased prescription rates of broad-spectrum antibiotics observed for young children in general. Advocating the development of more user-friendly formulations for children can therefore contribute to a more appropriate use of antibiotics in the paediatric population. Declaration Funding: this study was funded by a grant from the Liaison Committee between the Central Norway Regional Health Authority and Norwegian University of Science and Technology (NTNU). Ethical approval: the study was approved by the Regional Committee for Medical and Health Research Ethics, Central Region, ref 2014/1743, and the Norwegian Prescription Database, ref 17/10581. Patient and prescriber personal identification numbers were pseudonymized by NorPD, allowing individual children’s prescriptions to be tracked over time without exposing their identities. The data were handled and stored anonymously. Conflict of interest: none. Acknowledgements The authors would like to thank Eva Skovlund for support with the statistical analyses. References 1. Sturkenboom MC , Verhamme KM , Nicolosi A , et al. Drug use in children: cohort study in three European countries . BMJ 2008 ; 337 : a2245 . Google Scholar CrossRef Search ADS PubMed 2. Youngster I , Avorn J , Belleudi V , et al. Antibiotic use in children—a cross-national analysis of 6 countries . J Pediatr 2017 ; 182 : 239 – 244.e1 . Google Scholar CrossRef Search ADS PubMed 3. Cohen R , de La Rocque F , Lecuyer A , et al. Study of the acceptability of antibiotic syrups, suspensions, and oral solutions prescribed to pediatric outpatients . Eur J Pediatr 2009 ; 168 : 851 – 7 . Google Scholar CrossRef Search ADS PubMed 4. Bergene EH , Rø TB , Steinsbekk A . Strategies parents use to give children oral medicine: a qualitative study of online discussion forums . Scand J Prim Health Care 2017 ; 35 : 221 – 8 . Google Scholar CrossRef Search ADS PubMed 5. Brookes-Howell L , Wood F , Verheij T , et al. Trust, openness and continuity of care influence acceptance of antibiotics for children with respiratory tract infections: a four country qualitative study . Fam Pract 2014 ; 31 : 102 – 10 . Google Scholar CrossRef Search ADS PubMed 6. Turck D , Bernet JP , Marx J , et al. Incidence and risk factors of oral antibiotic-associated diarrhea in an outpatient pediatric population . J Pediatr Gastroenterol Nutr 2003 ; 37 : 22 – 6 . Google Scholar CrossRef Search ADS PubMed 7. Grigoryan L , Burgerhof JG , Haaijer-Ruskamp FM , et al. ; SAR group . Is self-medication with antibiotics in Europe driven by prescribed use ? J Antimicrob Chemother 2007 ; 59 : 152 – 6 . Google Scholar CrossRef Search ADS PubMed 8. Thrane N , Olesen C , Schonheyder HC , Sorensen HT . Multiple prescriptions of antibiotics for children aged 0 to 5 years in relation to type of antibiotic . J Antimicrob Chemother 1999 ; 44 : 839 – 42 . Google Scholar CrossRef Search ADS PubMed 9. Pottegård A , Hallas J . Children prefer bottled amoxicillin . Ugeskr Laeger 2010 ; 172 : 3468 – 70 . Google Scholar PubMed 10. Steele RW , Estrada B , Begue RE , Mirza A , Travillion DA , Thomas MP . A double-blind taste comparison of pediatric antibiotic suspensions . Clin Pediatr (Phila) 1997 ; 36 : 193 – 9 . Google Scholar CrossRef Search ADS PubMed 11. Venables R , Batchelor H , Hodson J , et al. Determination of formulation factors that affect oral medicines acceptability in a domiciliary paediatric population . Int J Pharm 2015 ; 480 : 55 – 62 . Google Scholar CrossRef Search ADS PubMed 12. Tell D , Engström S , Mölstad S . Adherence to guidelines on antibiotic treatment for respiratory tract infections in various categories of physicians: a retrospective cross-sectional study of data from electronic patient records . BMJ Open 2015 ; 5 : e008096 . Google Scholar CrossRef Search ADS PubMed 13. Gjelstad S , Dalen I , Lindbaek M . GPs’ antibiotic prescription patterns for respiratory tract infections–still room for improvement . Scand J Prim Health Care 2009 ; 27 : 208 – 15 . Google Scholar CrossRef Search ADS PubMed 14. Furu K . Establishment of the nationwide norwegian prescription database (NorPD)–new opportunities for research in pharmacoepidemiology in Norway . Norsk Epidemiologi 2008 ; 18 : 129 – 36 . 15. Schirm E , Tobi H , de Vries TW , Choonara I , De Jong-van den Berg LT . Lack of appropriate formulations of medicines for children in the community . Acta Paediatr 2003 ; 92 : 1486 – 9 . Google Scholar CrossRef Search ADS PubMed 16. Rebnord IK , Thue G , Hunskår S . Equipment for diagnostics, laboratory analyses and treatment in out-of-hours services . Tidsskr Nor Laegeforen 2009 ; 129 : 987 – 90 . Google Scholar CrossRef Search ADS PubMed 17. Sanchez Garcia M . Early antibiotic treatment failure . Int J Antimicrob Agents 2009 ; 34 ( suppl 3 ): S14 – 9 . Google Scholar CrossRef Search ADS PubMed 18. Felleskatalogen . https://www.felleskatalogen.no/medisin/ (accessed 27 April 2018) 19. FASS . http://www.fass.se/LIF/ (accessed 27 April 2018) . 20. Pro.medicin.dk . http://pro.medicin.dk/ (accessed 27 April 2018) . 21. Pillbox . https://pillbox.nlm.nih.gov/ (accessed 27 April 2018) . 22. Steele RW , Russo TM , Thomas MP . Adherence issues related to the selection of antistaphylococcal or antifungal antibiotic suspensions for children . Clin Pediatr (Phila) 2006 ; 45 : 245 – 50 . Google Scholar CrossRef Search ADS PubMed 23. Steele RW , Thomas MP , Bégué RE . Compliance issues related to the selection of antibiotic suspensions for children . Pediatr Infect Dis J 2001 ; 20 : 1 – 5 . Google Scholar CrossRef Search ADS PubMed 24. Rouse C , Mistry P , Rayner O , et al. A mixed methods study of the administration of flucloxacillin oral liquid; identifying strategies to overcome administration issues of medicines with poor palatability . Int J Pharm Pract 2017 ; 25 : 326 – 34 . Google Scholar CrossRef Search ADS PubMed 25. Gjelstad S , Straand J , Dalen I , Fetveit A , Strøm H , Lindbæk M . Do general practitioners’ consultation rates influence their prescribing patterns of antibiotics for acute respiratory tract infections ? J Antimicrob Chemother 2011 ; 66 : 2425 – 33 . Google Scholar CrossRef Search ADS PubMed 26. Berg C , Blix HS , Fenne O , et al. Norwegian Prescription Database 2010–2014, in Statistics . Oslo : Norwegian Institute of Public Health , 2015 . 27. Korpela K , Salonen A , Virta LJ , et al. Intestinal microbiome is related to lifetime antibiotic use in Finnish pre-school children . Nat Commun 2016 ; 7 : 10410 . Google Scholar CrossRef Search ADS PubMed 28. Júlíusson PB , Roelants M , Eide GE , et al. Growth references for Norwegian children . Tidsskr Nor Laegeforen 2009 ; 129 : 281 – 6 . Google Scholar CrossRef Search ADS PubMed 29. Ranmal SR , Cram A , Tuleu C . Age-appropriate and acceptable paediatric dosage forms: insights into end-user perceptions, preferences and practices from the Children’s Acceptability of oral formulations (CALF) study . Int J Pharm 2016 ; 514 : 296 – 307 . Google Scholar CrossRef Search ADS PubMed 30. Holstiege J , Schink T , Molokhia M , et al. Systemic antibiotic prescribing to paediatric outpatients in 5 European countries: a population-based cohort study . BMC Pediatr 2014 ; 14 : 174 . Google Scholar CrossRef Search ADS PubMed 31. European Medicines Agency. Guideline on pharmaceutical development of medicines for paediatric use EMA/CHMP/QWP/805880/2012. London: European Medicines Agency, 2013. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2013/07/WC500147002.pdf (accessed 25 April 2018) . 32. Davies EH , Tuleu C . Medicines for children: a matter of taste . J Pediatr 2008 ; 153 : 599 – 604, 604.e1–2 . Google Scholar CrossRef Search ADS PubMed 33. Walsh J , Cram A , Woertz K , et al. ; European Formulation Initiative . Playing hide and seek with poorly tasting paediatric medicines: do not forget the excipients . Adv Drug Deliv Rev 2014 ; 73 : 14 – 33 . Google Scholar CrossRef Search ADS PubMed 34. van Riet-Nales DA , Ferreira JA , Schobben AF , et al. Methods of administering oral formulations and child acceptability . Int J Pharm 2015 ; 491 : 261 – 7 . Google Scholar CrossRef Search ADS PubMed 35. Drumond N , van Riet-Nales DA , Karapinar-Çarkit F , Stegemann S . Patients’ appropriateness, acceptability, usability and preferences for pharmaceutical preparations: results from a literature review on clinical evidence . Int J Pharm 2017 ; 521 : 294 – 305 . Google Scholar CrossRef Search ADS PubMed 36. Jacobsen L , Riley K , Lee B , Bradford K , Jhaveri R . Tablet/capsule size variation among the most commonly prescribed medications for children in the USA: retrospective review and firsthand pharmacy audit . Paediatr Drugs 2016 ; 18 : 65 – 73 . Google Scholar CrossRef Search ADS PubMed 37. Mistry P , Batchelor H ; SPaeDD-UK project (Smart Paediatric Drug Development—UK) . Evidence of acceptability of oral paediatric medicines: a review . J Pharm Pharmacol 2017 ; 69 : 361 – 76 . Google Scholar CrossRef Search ADS PubMed 38. Meltzer EO , Welch MJ , Ostrom NK . Pill swallowing ability and training in children 6 to 11 years of age . Clin Pediatr (Phila) 2006 ; 45 : 725 – 33 . Google Scholar CrossRef Search ADS PubMed 39. Nunn T , Williams J . Formulation of medicines for children . Br J Clin Pharmacol 2005 ; 59 : 674 – 6 . Google Scholar CrossRef Search ADS PubMed © The Author(s) 2018. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

Journal

Family PracticeOxford University Press

Published: May 9, 2018

There are no references for this article.

You’re reading a free preview. Subscribe to read the entire article.


DeepDyve is your
personal research library

It’s your single place to instantly
discover and read the research
that matters to you.

Enjoy affordable access to
over 18 million articles from more than
15,000 peer-reviewed journals.

All for just $49/month

Explore the DeepDyve Library

Search

Query the DeepDyve database, plus search all of PubMed and Google Scholar seamlessly

Organize

Save any article or search result from DeepDyve, PubMed, and Google Scholar... all in one place.

Access

Get unlimited, online access to over 18 million full-text articles from more than 15,000 scientific journals.

Your journals are on DeepDyve

Read from thousands of the leading scholarly journals from SpringerNature, Elsevier, Wiley-Blackwell, Oxford University Press and more.

All the latest content is available, no embargo periods.

See the journals in your area

DeepDyve

Freelancer

DeepDyve

Pro

Price

FREE

$49/month
$360/year

Save searches from
Google Scholar,
PubMed

Create lists to
organize your research

Export lists, citations

Read DeepDyve articles

Abstract access only

Unlimited access to over
18 million full-text articles

Print

20 pages / month

PDF Discount

20% off