Video Abstract
To assess the effectiveness and safety of delayed antibiotic prescription (DAP) compared to immediate antibiotic prescription (IAP) and no antibiotic prescription (NAP) in children with uncomplicated respiratory infections.
Randomized clinical trial comparing 3 antibiotic prescription strategies. The participants were children with acute uncomplicated respiratory infections attended to in 39 primary care centers. Children were randomly assigned into prescription arms as follows: (1) DAP, (2) IAP, or (3) NAP. Primary outcomes were symptom duration and severity. Secondary outcomes were antibiotic use, parental satisfaction, parental beliefs, additional primary care visits, and complications at 30 days.
In total, 436 children were included in the analysis. The mean (SD) duration of severe symptoms was 10.1 (6.3) for IAP, 10.9 (8.5) for NAP, and 12.4 (8.4) for DAP (P = .539), although the differences were not statistically significant. The median (interquartile range) of the greatest severity for any symptom was similar for the 3 arms (median [interquartile range] score of 3 [2–4]; P = .619). Antibiotic use was significantly higher for IAP (n = 142 [96%]) compared to DAP (n = 37 [25.3%]) and NAP (n = 17 [12.0%]) (P < .001). Complications, additional visits to primary care, and satisfaction were similar for all strategies. Gastrointestinal adverse effects were higher for IAP.
There was no statistically significant difference in symptom duration or severity in children with uncomplicated respiratory infections who received DAP compared to NAP or IAP strategies; however, DAP reduced antibiotic use and gastrointestinal adverse effects.
Delayed antibiotic prescription (DAP) in primary care settings optimizes antibiotic use in adults with acute uncomplicated respiratory infections in high-income–economy countries, such as those in southern Europe, with higher rates of antibiotic use.
The current study is the largest ever conducted on DAP for children and is the first study of DAP in a pediatric population in a southern Europe country with a high rate of antibiotic use.
Respiratory tract infections (RTIs) are a major reason for medical visits in pediatrics.1 Most RTIs are self-limiting, and antibiotics hardly alter the course of the condition,2–4 yet antibiotics are frequently prescribed for these conditions.5,6 Antibiotic prescription for RTIs in children is especially considered to be inappropriately high.7,8 The fact that antibiotics are overused is the main reason why resistance to antimicrobial agents has developed9 to the point of becoming a threat to public health.10 Use of antibiotics places patients at risk for adverse effects11 and enhances beliefs to consult for similar episodes.12
In primary care, diagnostic methods are often limited, leading to uncertain diagnoses and unclear cases of antibiotic prescription. Antibiotics are also prescribed because of the concern to avoid complications13 or to meet parental expectations when symptoms persist.14 Delayed antibiotic prescription (DAP) has been used in primary care when there are reasonable doubts about the need for immediate antibiotic prescription (IAP), which is what happens with some RTIs, conjunctivitis,15 and urinary tract infections.16 Some clinical practice guidelines recommend DAP when in doubt that antibiotics may be necessary.17
DAP consists of prescribing an antibiotic to take only if the patient’s condition worsens or fails to improve a few days after a medical visit. The latest Cochrane systematic review comparing DAP, IAP, and no antibiotic prescription (NAP) in adults and children reported no differences in most symptoms or in complications, whereas antibiotic intake was considerably lower for DAP compared to IAP for similar patient satisfaction levels. Reconsultation rates were also similar for the DAP and IAP strategies.18
Randomized clinical trials used to assess DAP for RTIs in children have been conducted for acute otitis media19–21 and pharyngitis.22,23 For the otitis media trials, duration of otalgia was slightly shorter19 and antibiotic use was lower for DAP compared to IAP.19,20 No differences were observed in otalgia frequency,20 pain severity, distress, or school absenteeism.19 As for the pharyngitis trials, only in a single study22 was the severity of symptoms significantly higher in children allocated to DAP compared to IAP. In both the otitis19–21 and pharyngitis22,23 studies, children randomly assigned to IAP experienced more adverse effects.
There is scant evidence about the use of DAP in children, with studies conducted only in the United States,20,21,23 England,19 and Jordan.22 The effects of a DAP strategy in high-income–economy countries with higher rates of antibiotic use, such as those in southern Europe,24 are still unknown. We therefore conducted a randomized clinical trial to assess the effectiveness of DAP compared to IAP and NAP.
Methods
Design
We used a multicenter randomized clinical trial to compare 3 treatment strategies for children with acute uncomplicated RTIs: DAP, IAP, and NAP.
Participants
Patients eligible for inclusion were children aged 2 to 14 years who, with their parent(s), attended a primary care pediatrician’s office with the following conditions: pharyngitis, rhinosinusitis, acute bronchitis, or acute otitis media (Supplemental Information). Children were included if pediatricians had reasonable doubts about the need to prescribe an antibiotic. Pediatricians that had access to rapid streptococcal testing did not include children with pharyngitis but included children with the other 3 infections. Recruitment was conducted in 39 primary care centers in Spain between June 2012 and June 2016. The study was approved by the Clinical Research Ethics Committee of the Institute for Primary Health Care Research Jordi Gol i Gurina, by all other ethics committees involved, and by the Spanish Agency of Medicines and Medical Devices.
Interventions
Children were randomly allocated to one of the DAP, IAP, or NAP arms. Randomization was stratified by pathology and in blocks. Allocation was performed centrally by using an online platform. Children, parents, and health professionals were not blinded.
Parents were advised that regardless of the arm and counting days from the onset of symptoms, their child was likely to feel more or less the same for up to 4 days for acute otitis media, 7 days for pharyngitis, 15 days for rhinosinusitis, and 20 days for acute bronchitis.
For children allocated to DAP, pediatricians handed the antibiotic prescription to parents, recommending them to only consider administering the antibiotic if (1) the child did not start to feel better after 4, 7, 15, or 20 days from symptom onset for acute otitis media, pharyngitis, rhinosinusitis, or acute bronchitis, respectively; (2) the child had a temperature of ≥39°C after 24 hours or a temperature of ≥38°C but <39°C after 48 hours; or (3) the child felt much worse. Parents were told to consider returning to the doctor if they felt it was necessary or if the child felt worse even after taking the antibiotic.
For children allocated to NAP, pediatricians did not prescribe antibiotics. For children allocated to IAP, pediatricians prescribed antibiotics to be taken from the day of the consultation. In both strategies, pediatricians recommended that parents consider returning to the doctor if (1) the child did not start to feel better after 4, 7, 15, or 20 days from symptom onset for acute otitis media, pharyngitis, rhinosinusitis, or acute bronchitis, respectively; (2) the child had a temperature of ≥39°C after 24 hours or a temperature of ≥38°C but <39°C after 48 hours; or (3) the child felt much worse, their condition worsened, or the parent(s) deemed it necessary.
All parents were informed that it was normal for a child to feel slightly worse in the first days after the visit. Each pediatrician decided the antibiotic type to be prescribed for both the DAP and IAP strategies.
Outcomes
Primary efficacy outcomes were severity and duration of acute uncomplicated RTI symptoms over 30 days. Symptom severity was scored by parents on a 7-point Likert scale (0 = no problem to 6 = as bad as it could be). Scoring was as follows: 0 = absence of symptoms, 1 to 2 = mild symptoms, 3 to 4 = moderate symptoms, and 5 to 6 = severe symptoms. Symptom duration was calculated to the point when symptoms disappeared.
Secondary efficacy outcomes were antibiotic use over 30 days, parental satisfaction and beliefs regarding antibiotic efficacy, and additional unscheduled visits to primary care over 30 days. Parental satisfaction was scored according to a 6-point Likert scale (“extremely satisfied” to “not at all satisfied”). Both the severity and satisfaction scales have been previously validated14,25 and used in other studies.13,14 Beliefs on antibiotic efficacy were evaluated with a 6-point Likert scale (“extremely effective” to ”not at all effective”).13,26 Infection-related complications were recorded for the first 30 days (pneumonia, abscesses, cellulitis, visits to the hospital emergency department, and hospital admissions).
Procedures
Previously trained pediatricians informed parents in a structured manner regarding the condition’s natural course, self-limiting processes, adverse effects, and marginal benefits of antibiotics. Included children ≥12 years of age and all parents signed an informed consent form. Eligible children were randomly assigned into the different arms, and parents were given the corresponding DAP, NAP, or IAP recommendations. In the baseline visit, pediatricians collected data on the children’s health status using a visual analog scale scored from 0 to 100 (0 = worst and 100 = best) and on the severity of their symptoms.
The coordinating center followed-up children by telephoning parents on days 2 and 30 after inclusion, as well as on days 7, 15, and 22 if parents indicated in the previous call that symptoms continued. Data collected in the telephone follow-up were health status, severity and duration of symptoms, use of antibiotics and nonantibiotic medication, and in addition, additional visits to primary care, adverse events, and complications, crosschecked against medical records. Parental satisfaction and belief data were collected only on day 30.
Statistical Analysis
The calculated sample size was 450 children (150 per arm), considering a mean (SD) duration of untreated acute uncomplicated RTI of 12 days.14 A 2-day reduction in duration was considered a clinically relevant outcome adopting a bilateral approach. The sample size of 450 children was calculated to identify this difference with a type I error of 5% (α = .05) and power of 80% (β = .2). GRANMO sample size calculator software was used.27 Although the parents and children could interrupt medication at any point in the study, they were still included in follow-up.
Population characteristics were described by using frequencies and percentages for categorical variables and means and SD for quantitative variables. Pearson’s χ2 test was used to compare patient symptoms at the first visit (frequencies and percentages) for the 3 arms. Symptom duration and symptom severity after the first visit were described by using means (SD) and medians and interquartile range (IQR), respectively. For the 3 arms, for each symptom after the first visit, negative binomial regression was used to compare symptom duration, and logistic regression was used to compare symptom severity. Both regression models were adjusted for prescription strategy and informed antibiotic use, and only children with symptoms lasting a day or more were included. Pearson’s χ2 test was used to compare secondary outcomes (frequencies and percentages) for the 3 arms, considering IAP as the reference category. All analyses were guided by an intention-to-treat approach (children randomly allocated to each prescription strategy were included). Children who were lost to follow-up were assigned the average duration and severity of symptoms of the other children included in the same strategy. Significance was set to 5% (α = .05). All statistical analyses were performed by using Stata software version 13.1 (Stata Corp, College Station, TX).
Results
Trial Population
A total of 436 children, with mean (SD) age 6.3 (3.0) years, were included in the study and the analysis (Fig 1), 226 (51.8%) of whom were girls; 224 (51.4%) had acute otitis media, 146 (33.5%) had pharyngitis, 40 (9.2%) had acute bronchitis, and 26 (6.0%) had rhinosinusitis. Fever and discomfort and/or general pain were the most frequent symptoms for all 4 conditions and were also the severest symptoms at the first visit (mean scores of 3.8 and 3.0, respectively, on the 7-point Likert scale [0–6]). At the first visit, mean (SD) duration of symptoms was reported as 2.5 (4.2) days, whereas mean (SD) health status was scored as 65 (18) (0–100). Most children (n = 395 [90.6%]) had no respiratory comorbidity. One or both parents of 173 (39.7%) children were smokers, and the parents of 227 (52.1%) children had finished tertiary education. Parents mainly indicated that they were moderately worried (n = 213 [48.9%]) or a little worried (n = 145 [33.3%]) at the first visit (Table 1). Symptoms at the first visit were similar for the 3 arms (Table 2).
Flow diagram. The number of participants enrolled, randomly assigned, followed-up, and included in the analysis are shown in the figure.
Flow diagram. The number of participants enrolled, randomly assigned, followed-up, and included in the analysis are shown in the figure.
Patient Baseline Characteristics
| Prescription Strategy | Total (N = 436) | |||
|---|---|---|---|---|
| IAP (n = 148) | DAP (n = 146) | NAP (n = 142) | ||
| Girls | 79 (53.4) | 68 (46.6) | 79 (55.6) | 226 (51.8) |
| Age, y, mean (SD) | 6.4 (3.1) | 6.4 (3.2) | 6.1 (2.8) | 6.3 (3.0) |
| 2–5 | 67 (45.2) | 71 (48.6) | 73 (51.4) | 211 (48.4) |
| 6–10 | 59 (39.9) | 58 (39.7) | 57 (40.1) | 174 (39.9) |
| 11–14 | 22 (14.9) | 17 (11.7) | 12 (8.4) | 51 (11.7) |
| Wt, kg, mean (SD) | 25.8 (11.6) | 26.1 (12.1) | 24.0 (10.0) | 25.3 (11.3) |
| Parental education | ||||
| Primary or less | 7 (4.7) | 3 (2.1) | 7 (4.9) | 17 (3.9) |
| Secondary | 66 (44.6) | 65 (44.5) | 61 (43.0) | 192 (44.0) |
| Tertiary | 75 (50.7) | 78 (53.4) | 74 (52.1) | 227 (52.1) |
| Respiratory comorbidity | 16 (10.8) | 14 (9.6) | 11 (7.8) | 41 (9.4) |
| Pulmonary disease | 13 (8.8) | 13 (8.9) | 7 (4.9) | 33 (7.6) |
| Smoker parents | 60 (40.5) | 57 (39.0) | 56 (39.4) | 173 (39.7) |
| Respiratory tract infection | ||||
| Rhinosinusitis | 9 (6.1) | 9 (6.1) | 8 (5.6) | 26 (6.0) |
| Pharyngitis | 48 (32.4) | 49 (33.6) | 49 (34.5) | 146 (33.5) |
| Acute bronchitis | 14 (9.5) | 13 (8.9) | 13 (9.2) | 40 (9.2) |
| Acute otitis media | 77 (52.0) | 75 (51.4) | 72 (50.7) | 224 (51.4) |
| Symptom severity score, mean (SD)a | ||||
| Fever | 3.7 (2.0) | 3.7 (1.6) | 4.1 (1.7) | 3.8 (1.8) |
| Discomfort and/or general pain | 3.1 (1.3) | 3.0 (1.1) | 3.0 (1.3) | 3.0 (1.2) |
| Cough | 2.1 (1.9) | 2.4 (1.9) | 2.5 (2.1) | 2.3 (1.9) |
| Difficulty sleeping | 2.6 (1.8) | 2.8 (1.8) | 3.1 (1.8) | 2.8 (1.8) |
| Everyday routine disruptions | 2.8 (1.4) | 2.7 (1.3) | 2.9 (1.3) | 2.8 (1.4) |
| Irritability | 2.6 (1.6) | 2.6 (1.5) | 2.6 (1.6) | 2.6 (1.6) |
| Symptom duration previsit, d, mean (SD) | 2.5 (3.1) | 2.8 (5.8) | 2.2 (3.2) | 2.5 (4.2) |
| General health status score, mean (SD)b | 66 (19) | 65 (17) | 64 (19) | 65 (18) |
| Feverish | 32 (36.8) | 28 (33.3) | 19 (26.0) | 79 (32.4) |
| Fever ≥38°C lasting ≥24 h | 51 (34.5) | 54 (37.0) | 62 (43.7) | 167 (38.3) |
| Parental worry level | ||||
| Not at all or only slightly worried | 17 (11.5) | 25 (17.1) | 17 (12.0) | 59 (13.5) |
| A little worried | 52 (35.1) | 46 (31.5) | 47 (33.1) | 145 (33.3) |
| Moderately worried | 69 (46.6) | 71 (48.6) | 73 (51.4) | 213 (48.9) |
| Very or extremely worried | 10 (6.8) | 4 (2.7) | 5 (3.5) | 19 (4.4) |
| Prescription Strategy | Total (N = 436) | |||
|---|---|---|---|---|
| IAP (n = 148) | DAP (n = 146) | NAP (n = 142) | ||
| Girls | 79 (53.4) | 68 (46.6) | 79 (55.6) | 226 (51.8) |
| Age, y, mean (SD) | 6.4 (3.1) | 6.4 (3.2) | 6.1 (2.8) | 6.3 (3.0) |
| 2–5 | 67 (45.2) | 71 (48.6) | 73 (51.4) | 211 (48.4) |
| 6–10 | 59 (39.9) | 58 (39.7) | 57 (40.1) | 174 (39.9) |
| 11–14 | 22 (14.9) | 17 (11.7) | 12 (8.4) | 51 (11.7) |
| Wt, kg, mean (SD) | 25.8 (11.6) | 26.1 (12.1) | 24.0 (10.0) | 25.3 (11.3) |
| Parental education | ||||
| Primary or less | 7 (4.7) | 3 (2.1) | 7 (4.9) | 17 (3.9) |
| Secondary | 66 (44.6) | 65 (44.5) | 61 (43.0) | 192 (44.0) |
| Tertiary | 75 (50.7) | 78 (53.4) | 74 (52.1) | 227 (52.1) |
| Respiratory comorbidity | 16 (10.8) | 14 (9.6) | 11 (7.8) | 41 (9.4) |
| Pulmonary disease | 13 (8.8) | 13 (8.9) | 7 (4.9) | 33 (7.6) |
| Smoker parents | 60 (40.5) | 57 (39.0) | 56 (39.4) | 173 (39.7) |
| Respiratory tract infection | ||||
| Rhinosinusitis | 9 (6.1) | 9 (6.1) | 8 (5.6) | 26 (6.0) |
| Pharyngitis | 48 (32.4) | 49 (33.6) | 49 (34.5) | 146 (33.5) |
| Acute bronchitis | 14 (9.5) | 13 (8.9) | 13 (9.2) | 40 (9.2) |
| Acute otitis media | 77 (52.0) | 75 (51.4) | 72 (50.7) | 224 (51.4) |
| Symptom severity score, mean (SD)a | ||||
| Fever | 3.7 (2.0) | 3.7 (1.6) | 4.1 (1.7) | 3.8 (1.8) |
| Discomfort and/or general pain | 3.1 (1.3) | 3.0 (1.1) | 3.0 (1.3) | 3.0 (1.2) |
| Cough | 2.1 (1.9) | 2.4 (1.9) | 2.5 (2.1) | 2.3 (1.9) |
| Difficulty sleeping | 2.6 (1.8) | 2.8 (1.8) | 3.1 (1.8) | 2.8 (1.8) |
| Everyday routine disruptions | 2.8 (1.4) | 2.7 (1.3) | 2.9 (1.3) | 2.8 (1.4) |
| Irritability | 2.6 (1.6) | 2.6 (1.5) | 2.6 (1.6) | 2.6 (1.6) |
| Symptom duration previsit, d, mean (SD) | 2.5 (3.1) | 2.8 (5.8) | 2.2 (3.2) | 2.5 (4.2) |
| General health status score, mean (SD)b | 66 (19) | 65 (17) | 64 (19) | 65 (18) |
| Feverish | 32 (36.8) | 28 (33.3) | 19 (26.0) | 79 (32.4) |
| Fever ≥38°C lasting ≥24 h | 51 (34.5) | 54 (37.0) | 62 (43.7) | 167 (38.3) |
| Parental worry level | ||||
| Not at all or only slightly worried | 17 (11.5) | 25 (17.1) | 17 (12.0) | 59 (13.5) |
| A little worried | 52 (35.1) | 46 (31.5) | 47 (33.1) | 145 (33.3) |
| Moderately worried | 69 (46.6) | 71 (48.6) | 73 (51.4) | 213 (48.9) |
| Very or extremely worried | 10 (6.8) | 4 (2.7) | 5 (3.5) | 19 (4.4) |
Data are reported as frequencies and percentages except where otherwise indicated.
Symptoms, scored on a Likert scale from 0 (no problems) to 6 (as bad as it could be), are those common to the 4 studied pathologies.
Scored at first visit on a visual analog scale from 0 (worst health status) to 100 (best health status).
Patient Symptoms at the First Visit
| Prescription Strategy | Total (N = 436), n (%) | |||
|---|---|---|---|---|
| IAP (n = 148), n (%) | DAP (n = 146), n (%) | NAP (n = 142), n (%) | ||
| Moderate symptoms (3 or 4)a | 120 (81.1) | 115 (78.8) | 117 (82.4) | 352 (80.7) |
| Severe symptoms (5 or 6)a | 71 (48.0) | 70 (48.0) | 75 (52.8) | 216 (49.5) |
| Common symptomsb | ||||
| Everyday routine disruptions | 128 (96.2) | 126 (98.4) | 125 (98.4) | 379 (97.7) |
| Irritability | 100 (91.7) | 98 (92.5) | 97 (91.5) | 295 (91.9) |
| Pharyngitis symptoms | ||||
| Fever | 41 (89.1) | 45 (100.0) | 42 (97.7) | 128 (95.5) |
| Headache | 33 (86.8) | 29 (96.7) | 23 (74.2) | 85 (85.9) |
| Sore throat | 46 (95.8) | 47 (97.9) | 47 (100.0) | 140 (97.9) |
| Difficulty swallowing | 43 (91.5) | 43 (93.5) | 43 (95.6) | 129 (93.5) |
| Acute otitis media symptoms | ||||
| Earache | 76 (100.0) | 70 (97.2) | 71 (100.0) | 217 (99.1) |
| Rhinosinusitis and acute bronchitis symptoms | ||||
| Breathlessness | 16 (80.0) | 16 (88.9) | 14 (77.8) | 46 (82.1) |
| Chest noises breathing | 15 (93.8) | 10 (83.3) | 14 (93.3) | 39 (90.7) |
| Pharyngitis and acute bronchitis symptoms | ||||
| Cough | 38 (74.5) | 35 (79.6) | 31 (75.6) | 104 (76.5) |
| Rhinosinusitis, pharyngitis, and acute bronchitis symptoms | ||||
| Discomfort and/or general pain | 68 (98.6) | 69 (100.0) | 66 (100.0) | 203 (99.5) |
| Nasal mucus | 46 (82.1) | 51 (89.5) | 46 (86.8) | 143 (86.1) |
| Difficulty sleeping | 45 (90.0) | 47 (87.0) | 42 (87.5) | 134 (88.2) |
| Prescription Strategy | Total (N = 436), n (%) | |||
|---|---|---|---|---|
| IAP (n = 148), n (%) | DAP (n = 146), n (%) | NAP (n = 142), n (%) | ||
| Moderate symptoms (3 or 4)a | 120 (81.1) | 115 (78.8) | 117 (82.4) | 352 (80.7) |
| Severe symptoms (5 or 6)a | 71 (48.0) | 70 (48.0) | 75 (52.8) | 216 (49.5) |
| Common symptomsb | ||||
| Everyday routine disruptions | 128 (96.2) | 126 (98.4) | 125 (98.4) | 379 (97.7) |
| Irritability | 100 (91.7) | 98 (92.5) | 97 (91.5) | 295 (91.9) |
| Pharyngitis symptoms | ||||
| Fever | 41 (89.1) | 45 (100.0) | 42 (97.7) | 128 (95.5) |
| Headache | 33 (86.8) | 29 (96.7) | 23 (74.2) | 85 (85.9) |
| Sore throat | 46 (95.8) | 47 (97.9) | 47 (100.0) | 140 (97.9) |
| Difficulty swallowing | 43 (91.5) | 43 (93.5) | 43 (95.6) | 129 (93.5) |
| Acute otitis media symptoms | ||||
| Earache | 76 (100.0) | 70 (97.2) | 71 (100.0) | 217 (99.1) |
| Rhinosinusitis and acute bronchitis symptoms | ||||
| Breathlessness | 16 (80.0) | 16 (88.9) | 14 (77.8) | 46 (82.1) |
| Chest noises breathing | 15 (93.8) | 10 (83.3) | 14 (93.3) | 39 (90.7) |
| Pharyngitis and acute bronchitis symptoms | ||||
| Cough | 38 (74.5) | 35 (79.6) | 31 (75.6) | 104 (76.5) |
| Rhinosinusitis, pharyngitis, and acute bronchitis symptoms | ||||
| Discomfort and/or general pain | 68 (98.6) | 69 (100.0) | 66 (100.0) | 203 (99.5) |
| Nasal mucus | 46 (82.1) | 51 (89.5) | 46 (86.8) | 143 (86.1) |
| Difficulty sleeping | 45 (90.0) | 47 (87.0) | 42 (87.5) | 134 (88.2) |
Statistical significance was calculated per symptom by using Pearson’s χ2 test.
Symptoms are scored on a Likert scale from 0 (no problems) to 6 (as bad as it could be).
Symptoms common to the 4 studied pathologies.
Primary Outcomes
Duration in days of any symptom until disappearance was similar for the 3 arms. Mean (SD) duration in days of any symptom until disappearance was DAP 8.3 (7.7) versus IAP 8.3 (7.8) (P = .968) and NAP 7.9 (9.3) versus IAP 8.3 (7.8) (P = .593) (Poverall = 0.888). Mean (SD) duration in days of severe symptoms was DAP 12.4 (8.4) versus IAP 10.1 (6.3) (P = .247) and NAP 10.9 (8.5) versus IAP 10.1 (6.3) (P = .682) (Poverall = 0.539). Mean (SD) duration in days of moderate symptoms was DAP 11.7 (8.7) versus IAP 10.2 (7.5) (P = .257) and NAP 10.0 (8.4) versus IAP 10.2 (7.5) (P = .869) (Poverall = 0.435). Regarding the symptoms common to all 4 conditions, namely, everyday routine disruptions and irritability, mean (SD) duration was similar for the 3 arms (P = .837 and P = .965, respectively) (Table 3).
Duration in Days of Patient Symptoms After the First Visit
| Prescription Strategy | Total (N = 436) | ||||||
|---|---|---|---|---|---|---|---|
| IAP (n = 148) | DAP (n = 146) | NAP (n = 142) | |||||
| Mean (SD) | Mean (SD) | Pa | Mean (SD) | Pa | Mean (SD) | Overall P | |
| Any symptom to disappearance | 8.3 (7.8) | 8.3 (7.7) | .968 | 7.9 (9.3) | .593 | 8.1 (8.2) | .888 |
| Moderate symptoms (3 or 4)b | 10.2 (7.5) | 11.7 (8.7) | .257 | 10.0 (8.4) | .869 | 10.7 (8.2) | .435 |
| Severe symptoms (5 or 6)b | 10.1 (6.3) | 12.4 (8.4) | .247 | 10.9 (8.5) | .682 | 11.3 (7.9) | .539 |
| Common symptomsc | |||||||
| Everyday routine disruptions | 4.2 (3.8) | 4.5 (4.0) | .848 | 4.8 (5.1) | .488 | 4.6 (4.4) | .837 |
| Irritability | 4.6 (4.3) | 4.7 (4.1) | .767 | 4.9 (5.6) | .794 | 4.9 (4.7) | .965 |
| Pharyngitis symptoms | |||||||
| Fever | 3.6 (2.2) | 4.0 (5.2) | .534 | 4.2 (5.3) | .400 | 3.9 (4.5) | .824 |
| Headache | 5.8 (8.7) | 5.5 (7.0) | .867 | 3.3 (3.0)d,e | .052 | 5.1 (7.0) | .080 |
| Sore throat | 5.2 (4.7) | 5.0 (4.1) | .824 | 5.5 (6.2) | .741 | 5.2 (5.0) | .907 |
| Difficulty swallowing | 4.9 (4.8) | 4.7 (3.8) | .812 | 5.0 (5.2) | .952 | 4.9 (4.6) | .970 |
| Acute otitis media symptoms | |||||||
| Earache | 5.1 (5.3) | 4.4 (3.9) | .239 | 5.2 (6.3) | .893 | 4.9 (5.2) | .567 |
| Rhinosinusitis and acute bronchitis symptoms | |||||||
| Breathlessness | 7.5 (6.5) | 10.2 (9.8) | .321 | 11.6 (11.1) | .169 | 9.7 (9.3) | .175 |
| Chest noises breathing | 6.2 (4.1) | 5.3 (5.2) | .694 | 10.6 (16.0)e | .111 | 7.6 (10.5) | .101 |
| Pharyngitis and acute bronchitis symptoms | |||||||
| Cough | 7.9 (4.4) | 9.5 (7.1) | .295 | 8.0 (6.6) | .948 | 8.5 (6.0) | .527 |
| Rhinosinusitis, pharyngitis, and acute bronchitis symptoms | |||||||
| Discomfort and/or general pain | 7.9 (8.2) | 6.6 (6.7) | .222 | 5.6 (5.2)d | .023 | 6.7 (6.8) | .022 |
| Nasal mucus | 10.3 (9.0) | 10.5 (8.9) | .811 | 8.3 (7.5) | .260 | 9.6 (8.5) | .444 |
| Difficulty sleeping | 5.8 (7.4) | 5.2 (5.2) | .546 | 5.5 (5.6) | .745 | 5.5 (6.1) | .890 |
| Prescription Strategy | Total (N = 436) | ||||||
|---|---|---|---|---|---|---|---|
| IAP (n = 148) | DAP (n = 146) | NAP (n = 142) | |||||
| Mean (SD) | Mean (SD) | Pa | Mean (SD) | Pa | Mean (SD) | Overall P | |
| Any symptom to disappearance | 8.3 (7.8) | 8.3 (7.7) | .968 | 7.9 (9.3) | .593 | 8.1 (8.2) | .888 |
| Moderate symptoms (3 or 4)b | 10.2 (7.5) | 11.7 (8.7) | .257 | 10.0 (8.4) | .869 | 10.7 (8.2) | .435 |
| Severe symptoms (5 or 6)b | 10.1 (6.3) | 12.4 (8.4) | .247 | 10.9 (8.5) | .682 | 11.3 (7.9) | .539 |
| Common symptomsc | |||||||
| Everyday routine disruptions | 4.2 (3.8) | 4.5 (4.0) | .848 | 4.8 (5.1) | .488 | 4.6 (4.4) | .837 |
| Irritability | 4.6 (4.3) | 4.7 (4.1) | .767 | 4.9 (5.6) | .794 | 4.9 (4.7) | .965 |
| Pharyngitis symptoms | |||||||
| Fever | 3.6 (2.2) | 4.0 (5.2) | .534 | 4.2 (5.3) | .400 | 3.9 (4.5) | .824 |
| Headache | 5.8 (8.7) | 5.5 (7.0) | .867 | 3.3 (3.0)d,e | .052 | 5.1 (7.0) | .080 |
| Sore throat | 5.2 (4.7) | 5.0 (4.1) | .824 | 5.5 (6.2) | .741 | 5.2 (5.0) | .907 |
| Difficulty swallowing | 4.9 (4.8) | 4.7 (3.8) | .812 | 5.0 (5.2) | .952 | 4.9 (4.6) | .970 |
| Acute otitis media symptoms | |||||||
| Earache | 5.1 (5.3) | 4.4 (3.9) | .239 | 5.2 (6.3) | .893 | 4.9 (5.2) | .567 |
| Rhinosinusitis and acute bronchitis symptoms | |||||||
| Breathlessness | 7.5 (6.5) | 10.2 (9.8) | .321 | 11.6 (11.1) | .169 | 9.7 (9.3) | .175 |
| Chest noises breathing | 6.2 (4.1) | 5.3 (5.2) | .694 | 10.6 (16.0)e | .111 | 7.6 (10.5) | .101 |
| Pharyngitis and acute bronchitis symptoms | |||||||
| Cough | 7.9 (4.4) | 9.5 (7.1) | .295 | 8.0 (6.6) | .948 | 8.5 (6.0) | .527 |
| Rhinosinusitis, pharyngitis, and acute bronchitis symptoms | |||||||
| Discomfort and/or general pain | 7.9 (8.2) | 6.6 (6.7) | .222 | 5.6 (5.2)d | .023 | 6.7 (6.8) | .022 |
| Nasal mucus | 10.3 (9.0) | 10.5 (8.9) | .811 | 8.3 (7.5) | .260 | 9.6 (8.5) | .444 |
| Difficulty sleeping | 5.8 (7.4) | 5.2 (5.2) | .546 | 5.5 (5.6) | .745 | 5.5 (6.1) | .890 |
Only patients who had symptoms for 1 d or more were included. Statistical significance was calculated by adjusting a negative binomial regression model per symptom, with the number of days with the symptom as the dependent variable and prescription strategy and antibiotic use as independent variables.
IAP is the reference category.
Symptoms are scored on a Likert scale from 0 (no problems) to 6 (as bad as it could be).
Symptoms common to the 4 studied pathologies.
P < .05 compared to IAP.
P < .10 compared to DAP.
The greatest severity for any symptom on the 7-point Likert scale was similar for the 3 arms, for a median (IQR) score of 3 (2–4). Severity of both common symptoms and specific symptoms was broadly similar for all 3 arms, with significant differences only between DAP and IAP in 2 of 13 symptoms (sore throat and cough), between IAP and NAP in 2 of 13 symptoms (fever and discomfort and/or general pain), and between DAP and NAP in 1 of 13 symptoms (fever) (Table 4).
Severity Scores for Patient Symptoms After the First Visit
| Prescription Strategy | Total | ||||
|---|---|---|---|---|---|
| IAP, median (IQR) | DAP, median (IQR) | NAP, median (IQR) | Total, median (IQR) | Overall P | |
| Maximum severity of any symptoma | 3 (2–4) | 3 (2–4) | 3 (2–4) | 3 (2–4) | .619 |
| Common symptomsb | |||||
| Everyday routine disruptions | 2 (1–3) | 2 (2–3) | 2 (2–3) | 2 (2–3) | .740 |
| Irritability | 2 (1–3) | 2 (2–3) | 2 (1–3) | 2 (2–3) | .556 |
| Pharyngitis symptoms | |||||
| Fever | 2 (1–3) | 2 (2–3) | 3 (2–4)c,d | 2 (2–3) | .090 |
| Headache | 2 (1–4) | 3 (2–3) | 3 (3–4) | 3 (2–4) | .926 |
| Sore throat | 3 (2–3) | 3 (2–5)c | 3 (2–4) | 3 (2–4) | .044 |
| Difficulty swallowing | 2 (2–3) | 3 (2–4) | 2 (2–4) | 3 (2–4) | .141 |
| Acute otitis media symptoms | |||||
| Earache | 2 (1–3) | 2 (1–3) | 2 (2–3) | 2 (1–3) | .543 |
| Rhinosinusitis and acute bronchitis symptoms | |||||
| Breathlessness | 3 (2–3) | 3 (2–3) | 2 (2–3) | 3 (2–3) | .822 |
| Chest noises on breathing | 2 (1–2) | 2 (2–3) | 2 (2–3) | 2 (1–2) | .113 |
| Pharyngitis and acute bronchitis symptoms | |||||
| Cough | 2 (2–3) | 3 (2–3)c | 2 (1–3) | 2 (2–3) | .097 |
| Rhinosinusitis, pharyngitis, and acute bronchitis | |||||
| Discomfort and/or general pain | 2 (1–3) | 2 (2–3) | 3 (2–3)c | 2 (2–3) | .145 |
| Nasal mucus | 2 (1–3) | 2 (2–3) | 3 (2–3) | 3 (2–3) | .682 |
| Difficulty sleeping | 2 (1–3) | 2 (2–3) | 2 (2–4) | 2 (2–3) | .769 |
| Prescription Strategy | Total | ||||
|---|---|---|---|---|---|
| IAP, median (IQR) | DAP, median (IQR) | NAP, median (IQR) | Total, median (IQR) | Overall P | |
| Maximum severity of any symptoma | 3 (2–4) | 3 (2–4) | 3 (2–4) | 3 (2–4) | .619 |
| Common symptomsb | |||||
| Everyday routine disruptions | 2 (1–3) | 2 (2–3) | 2 (2–3) | 2 (2–3) | .740 |
| Irritability | 2 (1–3) | 2 (2–3) | 2 (1–3) | 2 (2–3) | .556 |
| Pharyngitis symptoms | |||||
| Fever | 2 (1–3) | 2 (2–3) | 3 (2–4)c,d | 2 (2–3) | .090 |
| Headache | 2 (1–4) | 3 (2–3) | 3 (3–4) | 3 (2–4) | .926 |
| Sore throat | 3 (2–3) | 3 (2–5)c | 3 (2–4) | 3 (2–4) | .044 |
| Difficulty swallowing | 2 (2–3) | 3 (2–4) | 2 (2–4) | 3 (2–4) | .141 |
| Acute otitis media symptoms | |||||
| Earache | 2 (1–3) | 2 (1–3) | 2 (2–3) | 2 (1–3) | .543 |
| Rhinosinusitis and acute bronchitis symptoms | |||||
| Breathlessness | 3 (2–3) | 3 (2–3) | 2 (2–3) | 3 (2–3) | .822 |
| Chest noises on breathing | 2 (1–2) | 2 (2–3) | 2 (2–3) | 2 (1–2) | .113 |
| Pharyngitis and acute bronchitis symptoms | |||||
| Cough | 2 (2–3) | 3 (2–3)c | 2 (1–3) | 2 (2–3) | .097 |
| Rhinosinusitis, pharyngitis, and acute bronchitis | |||||
| Discomfort and/or general pain | 2 (1–3) | 2 (2–3) | 3 (2–3)c | 2 (2–3) | .145 |
| Nasal mucus | 2 (1–3) | 2 (2–3) | 3 (2–3) | 3 (2–3) | .682 |
| Difficulty sleeping | 2 (1–3) | 2 (2–3) | 2 (2–4) | 2 (2–3) | .769 |
The medians and IQRs for symptom severity were calculated for symptoms lasting >1 consecutive day during the 30-d follow-up. Statistical significance was calculated by adjusting an ordered logistic regression model per symptom, with severity as the dependent variable and prescription strategy and antibiotic use as independent variables.
Symptoms are scored on a Likert scale from 0 (no problems) to 6 (as bad as it could be).
Symptoms common to the 4 studied pathologies.
P < .05 compared to IAP.
P < .10 compared to DAP.
Secondary Outcomes
Antibiotics were taken in the IAP arm by 142 (96.0%) children compared with 17 (12.0%) children in the NAP arm (P < .001) and 37 (25.3%) children in the DAP arm (P < .001). Of the 17 children in the NAP arm who took antibiotics, only 7 of these attended an unscheduled visit to primary care, and the mean duration between randomization and antibiotic prescription was 2 days. There were no significant differences in antibiotic treatment duration (P = .316) nor in the type of antibiotic (P = .108) for the 3 arms. Nonantibiotic medication use was similar for DAP (n = 136 [93.2%]) and NAP (n = 136 [95.8%]) and higher than for IAP (n = 108 [73.0%]) (P < .001). Belief that antibiotics were very or extremely effective was higher for parents of children in the IAP arm than in the other arms (IAP n = 106 [81.6%] versus DAP n = 38 [42.2%] versus NAP n = 23 [29.1%]; P < .001). Gastrointestinal adverse effects were lower in the DAP and NAP arms compared to the IAP arm (P = .037). There were no differences between arms in complications (P = .813) or unscheduled visits to primary care (P = .895), and satisfaction was similarly high for the 3 arms (P = .389). There were 5 complications: perforated eardrum and hospitalization due to dehydration (1 child each) and 3 unscheduled visits to the hospital (Table 5).
Secondary Outcomes
| Prescription Strategy | Total | ||||||
|---|---|---|---|---|---|---|---|
| IAP | DAP | NAP | |||||
| n = 148 | n = 146 | Pa | n = 142 | Pa | N = 436 | Overall P | |
| Antibiotic used | 142 (96.0) | 37 (25.3) | <.001 | 17 (12.0) | <.001 | 196 (45.0) | <.001 |
| Antibiotic duration, d, mean (SD) | 7.9 (2.0) | 8.4 (2.3) | .181 | 7.5 (2.7) | .613 | 7.9 (2.1) | .316 |
| Type of antibiotic | .475 | .092 | .108 | ||||
| Amoxicillin | 106 (74.7) | 30 (81.1) | 9 (52.9) | 145 (74.0) | |||
| Azithromycin | 11 (7.8) | 2 (5.4) | 2 (11.8) | 15 (7.7) | |||
| Amoxicillin-clavulanate | 9 (6.3) | 4 (10.8) | 1 (5.9) | 14 (7.1) | |||
| Phenoxymethylpenicillin (penicillin V) | 7 (4.9) | 1 (2.7) | 1 (5.9) | 9 (4.6) | |||
| Otherb | 9 (6.3) | 0 (0.0) | 4 (23.5) | 13 (6.6) | |||
| Nonantibiotic medication | 108 (73.0) | 136 (93.2) | <.001 | 136 (95.8) | <.001 | 380 (87.2) | <.001 |
| Unscheduled primary care visits | 16 (10.8) | 15 (10.3) | .881 | 17 (12.0) | .756 | 48 (11.0) | .895 |
| Health status score, mean (SD)c | 97 (8) | 97 (8) | .555 | 97 (9) | .929 | 97 (8) | .762 |
| Gastrointestinal adverse effects | 13 (8.8) | 5 (3.4) | .064 | 4 (2.8) | .040 | 22 (5.1) | .037 |
| Complications | 2 (1.4) | 1 (0.7) | .577 | 2 (1.4) | .967 | 5 (1.2) | .813 |
| Parental satisfaction | .352 | .373 | .389 | ||||
| Not at all or slightly satisfied | 2 (1.4) | 1 (0.7) | 0 (0.0) | 3 (0.7) | |||
| Little or moderately satisfied | 10 (7.0) | 5 (3.6) | 10 (7.2) | 25 (5.9) | |||
| Very or extremely satisfied | 130 (91.2) | 135 (95.7) | 129 (92.8) | 394 (93.4) | |||
| Belief in antibiotic effectiveness | <.001 | <.001 | <.001 | ||||
| Not at all or slightly effective | 3 (2.3) | 8 (8.9) | 9 (11.4) | 20 (6.7) | |||
| Little or moderately effective | 21 (16.1) | 44 (48.9) | 47 (59.5) | 112 (37.4) | |||
| Very or extremely effective | 106 (81.6) | 38 (42.2) | 23 (29.1) | 167 (55.9) | |||
| Prescription Strategy | Total | ||||||
|---|---|---|---|---|---|---|---|
| IAP | DAP | NAP | |||||
| n = 148 | n = 146 | Pa | n = 142 | Pa | N = 436 | Overall P | |
| Antibiotic used | 142 (96.0) | 37 (25.3) | <.001 | 17 (12.0) | <.001 | 196 (45.0) | <.001 |
| Antibiotic duration, d, mean (SD) | 7.9 (2.0) | 8.4 (2.3) | .181 | 7.5 (2.7) | .613 | 7.9 (2.1) | .316 |
| Type of antibiotic | .475 | .092 | .108 | ||||
| Amoxicillin | 106 (74.7) | 30 (81.1) | 9 (52.9) | 145 (74.0) | |||
| Azithromycin | 11 (7.8) | 2 (5.4) | 2 (11.8) | 15 (7.7) | |||
| Amoxicillin-clavulanate | 9 (6.3) | 4 (10.8) | 1 (5.9) | 14 (7.1) | |||
| Phenoxymethylpenicillin (penicillin V) | 7 (4.9) | 1 (2.7) | 1 (5.9) | 9 (4.6) | |||
| Otherb | 9 (6.3) | 0 (0.0) | 4 (23.5) | 13 (6.6) | |||
| Nonantibiotic medication | 108 (73.0) | 136 (93.2) | <.001 | 136 (95.8) | <.001 | 380 (87.2) | <.001 |
| Unscheduled primary care visits | 16 (10.8) | 15 (10.3) | .881 | 17 (12.0) | .756 | 48 (11.0) | .895 |
| Health status score, mean (SD)c | 97 (8) | 97 (8) | .555 | 97 (9) | .929 | 97 (8) | .762 |
| Gastrointestinal adverse effects | 13 (8.8) | 5 (3.4) | .064 | 4 (2.8) | .040 | 22 (5.1) | .037 |
| Complications | 2 (1.4) | 1 (0.7) | .577 | 2 (1.4) | .967 | 5 (1.2) | .813 |
| Parental satisfaction | .352 | .373 | .389 | ||||
| Not at all or slightly satisfied | 2 (1.4) | 1 (0.7) | 0 (0.0) | 3 (0.7) | |||
| Little or moderately satisfied | 10 (7.0) | 5 (3.6) | 10 (7.2) | 25 (5.9) | |||
| Very or extremely satisfied | 130 (91.2) | 135 (95.7) | 129 (92.8) | 394 (93.4) | |||
| Belief in antibiotic effectiveness | <.001 | <.001 | <.001 | ||||
| Not at all or slightly effective | 3 (2.3) | 8 (8.9) | 9 (11.4) | 20 (6.7) | |||
| Little or moderately effective | 21 (16.1) | 44 (48.9) | 47 (59.5) | 112 (37.4) | |||
| Very or extremely effective | 106 (81.6) | 38 (42.2) | 23 (29.1) | 167 (55.9) | |||
Data are reported as frequencies and percentages except where otherwise indicated.
IAP is the reference category.
Antibiotics prescribed to <5 patients: cefuroxime, benzathine benzylpenicillin (benzathine penicillin G), and combinations (amoxicillin with cefuroxime, amoxicillin with phenoxymethylpenicillin [penicillin V]).
Scored on a visual analog scale from 0 (worst health status) to 100 (best health status).
Discussion
We report findings for DAP compared to IAP and NAP strategies for children with uncomplicated RTIs as explored in this trial of DAP in children. To our knowledge, this is the largest such study conducted to date. Moderate and severe symptom durations for DAP were slightly greater than for IAP and NAP, although differences were not statistically significant. The greatest severity for any symptom was similar for the 3 arms. Antibiotic use was significantly lower in the DAP and NAP arms than in the IAP arm, and nonantibiotic medication was significantly higher in the DAP and NAP arms. Complications, unscheduled visits to primary care, and emergency hospital visits were similar for all 3 strategies, and likewise, satisfaction was high for all 3 strategies. The IAP arm experienced more gastrointestinal adverse effects than the DAP and NAP arms.
Our findings coincide for the most part with the findings of the 2017 Cochrane review18 on DAP for RTIs, which reported similar symptom durations and no difference in complications for the 3 strategies and lower antibiotic use for DAP and NAP strategies. However, low use of antibiotics observed in clinical trials should be viewed with caution because the study participants receive structured advice and so are more motivated.28 In terms of satisfaction, this was high and similar for the 3 arms in our study, contrasting with the Cochrane review,18 which reported higher satisfaction for IAP than for DAP and NAP. In our study, we found a significant reduction in gastrointestinal adverse events for DAP and NAP compared to IAP, corroborating previous studies in which authors have evaluated DAP for RTIs in children.19,20
Our findings are broadly similar to those of a previous trial in an adult population in Spain conducted by our group.26 In that study, moderate and severe symptom durations were higher for DAP than for IAP but lower than for NAP, whereas in our study in children, symptom duration was slightly greater for DAP than for either IAP or NAP. As for antibiotic use, findings for DAP in children were more favorable than in adults: 32.6% of adults compared with 25.3% of children allocated to DAP took antibiotics. The lower use of antibiotics in our pediatrics study compared to our adult study may be related to 2 factors: greater concern of parents about the adverse effects of antibiotics and more medical consultations for milder episodes. Parents have been reported to be cautious about using antibiotics for RTIs in children on the basis of concerns about adverse effects29 and past experiences,30 whereas adults tended not to recall serious consequences of antibiotic treatment.30 As for medical consultations, parents visited the doctor on behalf of children 3.5 days sooner than adults, and milder episodes led to a higher proportion of doctor visits on behalf of children (the median value of the highest severity score [any symptom] was 2 points lower for children than for adults). The reasons for an earlier medical visit may be fears of the condition worsening or major complications in children or differences in perceptions of the antibiotic risk/benefit equation.30
Our findings need to be considered in relation to some limitations. A first main limitation was the open-label design of the study, with outcomes reported by children.31 However, to reduce the possible placebo effect caused by the open-label nature of the study, all the children received structured information about respiratory diseases and the use of nonantibiotic medication. The second limitation was related to the inferred results for acute bronchitis and rhinosinusitis, as 85% of the included children had acute media otitis or pharyngitis. Nevertheless, strengths of the study are its pragmatic design and the fact that it is the largest ever conducted on DAP for children in southern Europe, in a country with a high rate of antibiotic use.
DAP is an efficacious and safe strategy for reducing inappropriate antibiotic treatment of uncomplicated RTIs in children when the doctor has reasonable doubts regarding the indication. DAP is therefore a useful tool for addressing the public health issue of bacterial resistance.10 However, NAP remains the recommended strategy when it is clear that antibiotics are not indicated like in most cases of acute bronchitis.32
We suggest that the results of this study will enable recommendations to be made for DAP for specific RTIs in children given that as yet there are no guidelines that draw distinctions according to age groups.33 There is a need, however, for further studies in which authors explore patient profiles for which DAP would be not appropriate, as well as studies in which authors assess DAP-related educational interventions for physicians and parents and children with acute uncomplicated RTIs.34
Conclusions
In this randomized clinical trial of antibiotic treatment strategies for acute, uncomplicated RTIs in children, there was no statistically significant difference in symptom duration or severity who received DAP compared to NAP and IAP strategies. DAP compared to IAP led to greatly reduced antibiotic use and fewer gastrointestinal adverse effects associated with antibiotic intake.
Acknowledgments
Members of the DAP Pediatrics Group are as follows: Catalonia, Spain: Gemma Mas-Dalmau, Pablo Alonso-Coello, Laura Muñoz Hurtado, Ignasi Gich Saladich, Lorena Martínez Villamizar (Iberoamerican Cochrane Center Biomedical Research Institute Sant Pau, Barcelona), Mariam de la Poza Abad (Dr Carles Ribas Primary Care Center, Barcelona), Laura Muñoz Ortiz (Agència de Qualitat i Avaluació Sanitàries de Catalunya, Barcelona), Carmen Villanueva López, Natividad Herrero Torres (Centro de Salud Manso, Barcelona), Ma Pilar Cortés Viana (Centro de Salud Maragall, Barcelona), Carme Palasí Bargalló, Maria Amor Peix Galito (Centro de Salud Sardenya, Barcelona), Francesca Camps Serra, Rosa Mené Bergara (Centro de Salud Río de Janeiro, Barcelona), Paloma Ramírez Álvarez (Centro de Salud Sants, Barcelona), and Marisa Pietrafesa Barreiro (Centro de Salud Bordeta-Magòria, Barcelona); Madrid, Spain: Oscar Espinazo Ramos, Josefa Manuel Enguidanos (Centro de Salud Las Matas, Las Rozas de Madrid), Ana Isabel Pérez Hernández (Centro de Salud Torrelodones, Torrelodones), Pilar Ortiz Ros, Virgina del Rey Márquez (Centro de Salud Dos de Mayo, Móstoles), Lucía Barahona Rondón (Centro de Salud Valleaguado, Coslada) María Rosario Benítez Rubio, Ana Ma Valero Marugán (Centro de Salud Miraflores, Alcobendas), María Laura Casado Sánchez (Centro de Salud San Blas, Parla), and Ángeles de Pando Bravo (Centro de Salud Villanueva de la Cañada, Villanueva de la Cañada); Basque Country, Spain: Pedro Gorrotxategi Gorrotxategi (Centro de Salud Pasai San Pedro, Pasaia), María Encarnación Gonzalo Alonso (Centro de Salud Ugao-Miraballes, Ugao-Miraballes y Centro de Salud Arrigorriaga, Arrigorriaga), Tatiana Menéndez Bada (Centro de Salud Iruña de Oka, Nanclares de la Oka), Miren Arrate Bengoa Gorosabel (Centro de Salud Bergara, Bergara), Carmen Callén Blecua (Centro de Salud Bidebieta, San Sebastián), Inés Hernández Salvador (Centro de Salud Alango, Getxo), and Irene Ozcoidi Erro (Centro de Salud Amara Berri, San Sebastián); Asturias, Spain: Emma Argüelles Prendes (Centro de Salud Ribadesella, Ribadesella); Castilla la Mancha, Spain: Javier Eduardo Blanco González (Centro de Salud El Casar de Talamanca, El Casar); Castilla y León, Spain: Carmelo Gutiérrez Abad (Centro de Salud Las Huelgas, Burgos) and Marta Esther Vázquez Fernández (Centro de Salud Arturo Eyries, Valladolid); and Galicia, Spain: Teresa Valls Duran (Centro de Salud Val Miñor, Nigrán). United Kingdom: Paul Little (Aldermoor Health Centre, Southampton). Gemma Mas-Dalmau is a doctoral candidate at Universitat Autònoma de Barcelona (Department of Pediatrics, Obstetrics, and Gynecology and Preventive Medicine and Public Health), Barcelona, Spain. Pablo Alonso-Coello is a researcher included in the CERCA Programme of the Generalitat de Catalunya.
We thank the parents and children included in the study for their participation. We also thank Cristina Puchol Sánchez for help with data collection and Victoria Leo Rosas and Ailish Maher for help translating the article into English.
Dr Alonso-Coello conceptualized and designed the study, contributed to drafting of the manuscript, obtained funding, made administrative, technical, and material support, conducted study supervision and had full access to all the data in the study, and assumed responsibility for the integrity of the data and the accuracy of the data analysis; Ms Mas-Dalmau conceptualized and designed the study, contributed to drafting of the manuscript, made administrative, technical, and material support, and conducted study supervision; Drs Villanueva López and Gorrotxategi Gorrotxategi conceptualized and designed the study, conducted the acquisition and interpretation of data, and critically reviewed the manuscript for important intellectual content; Ms Argüelles Prendes, Mr Espinazo Ramos, Ms Valls Duran, Ms Gonzalo Alonso, Dr Cortés Viana, Ms Menéndez Bada, Dr Vázquez Fernández, and Ms Pérez Hernández conducted the acquisition and interpretation of data and critically reviewed the manuscript for important intellectual content; Dr de la Poza Abad conceptualized and designed the study, obtained funding, conducted the interpretation of data, and critically reviewed the manuscript for important intellectual content; Ms Muñoz Ortiz conducted the statistical analysis and critically reviewed the manuscript for important intellectual content; Dr Little conceptualized and designed the study and critically reviewed the manuscript for important intellectual content; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.
Deidentified individual participant data, the study protocol, the statistical analysis plan, and the informed consent form will be made available after publication. The data will be made available to researchers who provide a methodologically sound proposal for use. Proposals should be submitted to the corresponding author.
This trial has been registered at www.clinicaltrials.gov (identifier NCT01800747).
FUNDING: Funded by Instituto de Salud Carlos III under a 2016 grant call (Acción Estratégica en Salud 2013–2016: Programa de Investigación Orientada a los Retos de la Sociedad) within the framework of the Spanish National Plan for Scientific and Technical Research and Innovation 2013–2016 (dossier PI11/02192) cofunded by the European Union through the European Regional Development Fund and with the support of the Spanish Ministry of Health, Social Services, and Equality (reference EC11-339).
Comments
RE:
The diagnostic criteria used in our trial was modified criteria from previous studies (Little 2001) that was revised in accordance with the Spanish Association of Pediatricians criteria.
In relation to rapid Streptococcus testing, in the publication we specify that if paediatricians had access to this test children were not eligible for participation. In Spain there are still a considerable number of centers that do not offer this diagnostic test. Children that according to symptoms/signs were considered by physicians as likely to present a group A streptococcal infection were also not eligible for participating in the trial. Physicians included children with pharyngitis that they were unclear about the best course of action. These children could receive any of the three options. This is consistent with clinical practice as some clinicians may choose antibiotics to avoid potential pharyngitis complications.
- Mas-Dalmau G, Villanueva López C, Gorrotxategi Gorrotxategi P, Argüelles Prendes E, Espinazo Ramos O, Valls Duran T, Gonzalo Alonso ME, Cortés Viana MP, Menéndez Bada T, Vázquez Fernández ME, Pérez Hernández AI, Muñoz Ortiz L, Little P, de la Poza Abad M, Alonso-Coello P; DAP PEDIATRICS GROUP*. Delayed Antibiotic Prescription for Children With Respiratory Infections: A Randomized Trial. Pediatrics. 2021 Mar;147(3):e20201323.
- Little P, Gould C, Williamson I, Moore M, Warner G, Dunleavey J. Pragmatic randomised controlled trial of two prescribing strategies for childhood acute otitis media. BMJ. 2001;322(7282):336-342.
RE: G Mas-Dalmau et al, Delayed Antibiotic Prescription for Children With Respiratory Infections
Mas-Dalmau and colleagues report on an issue of enduring interest to primary care pediatricians, i.e. a pragmatic and effective approach to the judicious use of antimicrobial in ambulatory settings. Of particular interest is their finding that patients in the delayed antibiotic and no-antibiotic use groups expressed attitudes toward the use of these agents that is more often concordant with our goal of limiting non-indicated antimicrobials for self-limited infections. (A corollary conclusion is consistent with everyday experience. Practitioners who prescribe non-indicated antibiotics predispose families to the opposite attitude, thus feeding a vicious cycle of over-use.)
I am concerned, however, by the authors' omission of explicit diagnostic criteria for patients with acute otitis media and rhinosinusitis. In interpreting the outcomes data, it would be helpful to know if these conformed to AAP guidelines for the diagnosis of these conditions. Further, no mention is made about laboratory testing to exclude S. pyogenes infection for the subset of patients with "pharyngitis." A large body of data indicate that antimicrobial therapy reduces the duration of symptoms for streptococcal pharyngitis only modestly, but that penicillin is indicated nonetheless for the prevention of acute rheumatic fever.
RE: G Mas-Dalmau et al, Delayed Antibiotic Prescription for Children With Respiratory Infections
I am concerned, however, by the authors' omission of explicit diagnostic criteria for patients with acute otitis media and rhinosinusitis. In interpreting the outcomes data, it would be helpful to know if these conformed to AAP guidelines for the diagnosis of these conditions. Further, no mention is made about laboratory testing to exclude S. pyogenes infection for the subset of patients with ""pharyngitis."" A large body of data indicate that antimicrobial therapy reduces the duration of symptoms for streptococcal pharyngitis only modestly, but that penicillin is indicated nonetheless for the prevention of acute rheumatic fever.