Delayed antibiotic prescriptions for respiratory infections

Geoffrey KP Spurling; Chris B Del Mar; Liz Dooley; Justin Clark; Deborah A Askew

doi:10.1002/14651858.CD004417.pub5

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Figure 1

Study flow diagram.

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Figure 2

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

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Figure 3

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

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Analysis 1.1

Comparison 1: Pain: delayed versus immediate antibiotics, Outcome 1: Number of participants with pain on Days 3 to 6

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Analysis 1.2

Comparison 1: Pain: delayed versus immediate antibiotics, Outcome 2: Pain severity on Day 3

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Analysis 1.3

Comparison 1: Pain: delayed versus immediate antibiotics, Outcome 3: Duration of malaise

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Analysis 1.4

Comparison 1: Pain: delayed versus immediate antibiotics, Outcome 4: Duration of pain symptoms

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Analysis 2.1

Comparison 2: Malaise: delayed versus immediate antibiotics, Outcome 1: Number of people with malaise on Day 3

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Analysis 2.2

Comparison 2: Malaise: delayed versus immediate antibiotics, Outcome 2: Malaise severity on Day 3

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Analysis 3.1

Comparison 3: Fever: delayed versus immediate antibiotics, Outcome 1: Fever on Days 3 to 6

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Analysis 3.2

Comparison 3: Fever: delayed versus immediate antibiotics, Outcome 2: Fever severity on Day 3

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Analysis 4.1

Comparison 4: Antibiotic use, Outcome 1: Antibiotic use: delayed versus immediate antibiotics

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Analysis 4.2

Comparison 4: Antibiotic use, Outcome 2: Antibiotic use: delayed versus no antibiotics

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Analysis 5.1

Comparison 5: Patient satisfaction, Outcome 1: Patient satisfaction: delayed versus immediate antibiotics

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Analysis 5.2

Comparison 5: Patient satisfaction, Outcome 2: Patient satisfaction: delayed versus no antibiotics

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Analysis 6.1

Comparison 6: Adverse events, Outcome 1: Vomiting: delayed versus immediate antibiotics

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Analysis 6.2

Comparison 6: Adverse events, Outcome 2: Diarrhoea: delayed versus immediate antibiotics

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Analysis 6.3

Comparison 6: Adverse events, Outcome 3: Rash: delayed versus immediate antibiotics

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Analysis 7.1

Comparison 7: Reconsultation rate, Outcome 1: Reconsultation rate: delayed versus immediate antibiotics

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Summary of findings 1. Delayed antibiotics compared to immediate antibiotics for respiratory infections

Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Delayed antibiotics compared to immediate antibiotics for respiratory infections
Patient or population: respiratory infections Setting: primary care, emergency department, paediatric outpatients Intervention:delayed antibiotics Comparison:immediate antibiotics
Outcomes	*Risk with immediate* antibiotics**	*Risk with delayed* antibiotics**	Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Clinical outcomes assessed with: pain, malaise, fever follow up: range 1 days to 7 days	10 included studies contributing data to this comparison measured clinical outcomes. For the 4 studies including participants with cough or common cold there was no evidence of difference for clinical outcomes. 5 studies included clinical outcome data for the presentation of sore throat, and for most clinical outcomes we found no evidence of difference. 2 studies measured clinical outcomes for participants with acute otitis media with 1 finding no evidence of difference in clinical outcomes, and the other favouring immediate antibiotics for malaise and pain severity on Day 3. There were sufficient outcome data to pool results for some clinical outcome measures. For participants with otitis media and sore throat, results favoured immediate antibiotics over delayed antibiotics for reducing pain and malaise severity on Day 3. For participants with common cold and otitis media, there was no evidence of differences in the number of participants with fever on Days 3 to 6		‐	2419 (10 RCTs)	⊕⊕⊕⊝ MODERATE^a
Antibiotic use: delayed versus immediate antibiotics	930 per 1000	348 per 1000 (286 to 401)	OR 0.04 (0.03 to 0.05)	1963 (7 RCTs)	⊕⊕⊕⊝ MODERATE^a
Patient satisfaction: delayed versus immediate antibiotics	909 per 1000	866 per 1000 (795 to 916)	OR 0.65 (0.39 to 1.10)	1633 (6 RCTs)	⊕⊕⊕⊝ MODERATE^a
Reconsultation rate: delayed versus immediate antibiotics	109 per 1000	113 per 1000 (63 to 196)	OR 1.04 (0.55 to 1.98)	379 (2 RCTs)	⊕⊕⊕⊝ MODERATE^a
Adverse effects of antibiotics (Adverse effects) assessed with: diarrhoea, vomiting, rash follow‐up: range 1 days to 7 days	The outcome of diarrhoea was measured by 4 studies and results favoured delayed antibiotics in 2 studies, and there was no evidence of difference the other 2. The outcome of vomiting was measured by 3 studies with no evidence of difference in 2, and results favouring immediate antibiotics in a third. The results for rash, measured by 2 studies, were sufficiently homogenous to conduct meta‐analysis, and results showed no evidence of difference		‐	1303 (5 RCTs)	⊕⊕⊝⊝ LOW^a,b
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; RR: risk ratio; OR: odds ratio
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.
^aDowngraded 1 level because more than half of studies were not adequately blinded and did not adequately report allocation concealment ^bDowngraded 1 level as results were inconsistent (I² = 93% for vomiting, I² = 72% for diarrhoea, I² = 0% for rash)

Summary of findings 1. Delayed antibiotics compared to immediate antibiotics for respiratory infections

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Summary of findings 2. Delayed antibiotics compared to No antibiotics for respiratory infections

Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Delayed antibiotics compared to no antibiotics for respiratory infections
Patient or population: respiratory infections Setting: Primary care, emergency department Intervention:delayed antibiotics Comparison:No antibiotics
Outcomes	Risk with no antibiotics	*Risk with delayed* antibiotics**	Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Clinical outcomes (clinical outcomes) assessed with: pain, fever, cough, nasal mucosity, follow‐up: range 1 days to 16 days	4 studies measured clinical outcomes for this comparison. 2 studies recruited participants with sore throat, one study recruited participants with otitis media, and 1 study recruited participants with cough, and for these studies there was no evidence of differences found. 1 study recruited participants with the common cold, and found results favouring delayed antibiotics for pain, fever, and cough duration, but no evidence of difference for nasal mucosity		‐	955 (4 RCTs)	⊕⊕⊕⊝ MODERATE^a
Antibiotic use: delayed versus no antibiotics	137 per 1000	287 per 1000 (201 to 392)	OR 2.55 (1.59 to 4.08)	1241 (4 RCTs)	⊕⊕⊕⊝ MODERATE^a
Patient satisfaction: delayed versus no antibiotics	824 per 1000	875 per 1000 (835 to 906)	OR 1.49 (1.08 to 2.06)	1235 (4 RCTs)	⊕⊕⊕⊝ MODERATE^a
Adverse effects of antibiotics (adverse effects) assessed with: vomiting, diarrhoea, rash, follow‐up: range 1 days to 7 days	2 studies measured adverse effects. 1 recruited participants with sore throat, and 1 with otitis media. Neither study found any difference in adverse effects		‐	566 (2 RCTs)	⊕⊕⊕⊝ MODERATE^a
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; RR: risk ratio; OR: odds ratio
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.
^aDowngraded 1 level for inadequate blinding for all studies, and allocation concealment not adequately reported for more than half of studies

Summary of findings 2. Delayed antibiotics compared to No antibiotics for respiratory infections

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Table 1. TIDieR (Template for Intervention Description and Replication) table

Author Year	Disease	Participants	Trial outcomes	Materials and procedures for clinicians delivering intervention	Clinicians delivering intervention	How intervention was delivered to participants	Where intervention was delivered	When and how much	Tailoring	Modified during trial?	Checks of fidelity?	Fidelity
Arroll 2002a	Common cold	Any age	Antibiotic use, satisfaction, and symptoms of delayed prescribing	Antibiotic prescription (deemed appropriate by treating GP). Procedure not detailed	15 GPs	Delayed: to fill prescription after 3 days if symptoms not improved Immediate: usual care	1 general practice, New Zealand	Once, at index consultation; delayed group asked to wait 3 days	Participants advised to return to GP if symptoms worsened.	None reported	Not detailed	‐
Chao 2008	Acute otitis media	Children (2 to 12 years)	Antibiotic use	2 forms of discharge instruction sheet provided by clinicians to patients: 1) completion of all: when to return for medical care (after 2 to 3 days); how to use complimentary symptom drugs 2) comparison: as above + prescription to fill if still unwell at 2 to 3 days	14 emergency department physicians	Not detailed	Emergency department of an urban public hospital in the USA	Once, at index consultation	Provided with complimentary optional ibuprofen or paracetamol +/‐ benzocaine otic drops at index consultation	None reported	None	None
De la Poza Abad 2016	Acute uncomplicated respiratory infection	Adults	Symptom duration and severity, antibiotic use, patient satisfaction, patients’ beliefs in antibiotic effectiveness	Physician structured script and patient information sheet about self limiting natural history of respiratory infection, pros and cons of antibiotics used with patients. Antibiotic prescription as indicated	GPs	4 groups of antibiotic prescription use: 1) immediate; 2) delayed, patient‐led prescription; 3) delayed, prescription collection; 4) none. Delayed = 3 days	23 primary care centres in 4 regions in Spain	Once, at index consultation; delayed prescription collection group could collect after 3 days if needed	All advised to return if no improvement or worsening after 5 days (pharyngitis) or 10 days (other infections). Central phone follow‐up if symptoms persisted	None reported	None	None
Dowell 2001	Acute uncomplicated cough	Adults (> 16 years)	Symptom duration, prescription uptake, patient satisfaction, patient enablement subsequent consultation rates	Antibiotic prescription of GP's choice provided or lodged at reception.	48 GPs	Immediate: usual care delayed: collect prescription after 1 week if required (within 2 weeks)	22 general practices in Scotland, UK	Once, at index consultation; delayed prescription group asked to wait 1 week	Nil	None reported	Date scripts collected by delayed group	35% (12/34) waited 7 days as asked; mean wait 6 days (range 1 to 10).
El‐Daher 1991	GABHS	Children (4 to 14 years)	Signs and symptoms, antibody titre, subsequent episodes	Immediate group: supplied with 2 days of penicillin, then 8 days of penicillin on Day 3. delayed group: supplied with 2 days of placebo, then 10 days of penicillin on Day 3	Physician	Immediate: 2 days penicillin, then 8 days penicillin delayed: 2 days placebo, then 10 days penicillin	Paediatric clinics at Jordan University of Science and Technology, Jordan	At index consultation, then re‐examined on Day 3	Paracetamol as needed	None reported	None reported	None reported
Gerber 1990	GABHS pharyngitis	Children / adolescents (2 to 22 years)	Positive follow‐up throat cultures, recurrences, symptomatic recurrences, or new acquisitions	Immediate group: supplied with 10‐day course of dose appropriate penicillin V. Delayed group: instructed to wait 48 hours before commencing 10‐day course of penicillin. Telephone follow‐up 24 hours later in both groups and next 24 hours for delayed group to advise commencement	Not reported (implied treating physicians)	Immediate: usual care delayed: wait 48 hours before commencing penicillin	1 private paediatric practice in the USA	At index consultation and telephone follow‐up 24 and 48 hours afterwards	Further 10‐day courses of penicillin if further GABHS pharyngitis	None reported	Urine sample at Day 9, mailed after drying for analysis	No report of urine sample compliance results
Little 1997	Sore throat	≥ 4 years	Duration of symptoms, satisfaction and compliance with and perceived efficacy of antibiotics, time off school or work	Immediate group given 10‐day prescription of dose appropriate penicillin V. Delayed group offered antibiotics but could collect prescription if symptoms not settled within 3 days. GP standard advice sheets provided to participants	25 GPs	3 groups of antibiotic prescriptions: 1) immediate: usual care; 2) no antibiotics; 3) delayed: to collect within 3 days.	11 general practices, England, UK	At index consultation; delayed prescription group within 3 days	Erythromycin if sensitive to penicillin. Analgesics or antipyretics allowed.	None reported	GP documented prescription on sheet. Patient daily diary until symptom‐free and medication finished	GPs’ compliance: immediate: 99%; no ABs: 2%; delayed: 5% left with script AB use: immediate: 99%; no: 13%; delayed: 31%
Little 2001	Acute otitis media	Children (0.5 to 10 years)	Symptom resolution, absence from school or nursery, paracetamol consumption	Immediate group prescribed amoxicillin. Delayed group asked to delay 3 days before using prescription, and then only if necessary. GP used standardised advice sheets specific to each group	42 GPs	Immediate: usual care delayed: wait 3 days to collect prescription	General practices in Scotland, UK	At index consultation; delayed prescription group asked to wait 3 days	Antipyretics were allowed.	None reported	Patient diary	No
Little 2005a	Acute uncomplicated lower respiratory tract infection	≥ 3 years	Symptom duration and severity, antibiotic use, satisfaction, belief in antibiotics	Immediate group: prescription for 10 days amoxicillin. Delayed group: prescription written and left at reception for patient to retrieve if wanted (but advised to wait 14 days). Leaflet groups: 1‐page information leaflet covering natural history of illness, when to seek further help. All groups: statement about analgesics, natural history of illness, and prescribing strategy read out by physicians	37 GPs	6 groups (factorial): 1) no antibiotics, no leaflet; 2) delayed antibiotics, no leaflet; 3) immediate antibiotics, no leaflet; 4) no antibiotics, leaflet; 5) delayed antibiotics and leaflet; 6) immediate antibiotics and leaflet. Delay = 14 days	General practices, England, UK	At index consultation; 14 days for delayed prescription group	Erythromycin if allergic to penicillin. Antipyretics allowed.	None reported	Reported antibiotic use in diary	96% immediate group; 20% delayed group; 16% no ABs group
Pichichero 1987	Sore throat (presumed GABHS)	Children (4 to 18 years)	Symptomatic response, recurrent infections	Drugs supplied directly to patients. Usual care 10‐day course penicillin V. Delayed group provided with placebo for first 3 days, then penicillin	Study nurse	Immediate: usual care delayed: placebo for 3 days then penicillin	Primary care paediatric practice in the USA	At index consultation	Antibiotic (tablet or suspension). Antipyretics were allowed	None reported	Check drug bottles at 3 days and 3 weeks. Test urine at 3 days for antibiotic	Confirmed in 98% cases (drug bottles); no ABs used in placebo group
Spiro 2006	Acute otitis media	Children (0.5 to 12 years)	Antibiotic use, clinical symptoms, adverse outcomes, days off school or work, unscheduled medical visits, parents’ comfort with management	Provision of written prescription for antibiotics valid for 3 days. Wait‐and‐see prescription group given written and verbal instructions to only fill prescription if no improvement or worsening 2 days after emergency room visit	Emergency department clinicians	Immediate: usual care Wait‐and‐see prescription: wait 2 days	Paediatric emergency department in the USA	At index consultation and within 3 days if prescription filled	Ibuprofen and otic drops as needed. Primary care contact if worsening	None reported	Verification of filling of prescription by phone call to designated pharmacies for 28% of the sample	All instances of no filling of prescription confirmed by pharmacies, and 90% confirmation of parent report of prescription filled
ABs: antibiotics GABHS: group A beta‐haemolytic streptococcus GP: general practitioner

Table 1. TIDieR (Template for Intervention Description and Replication) table

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Table 2. Summary of clinical outcomes: delayed versus immediate antibiotics

Study	Outcome	Delay	Immediate	Favours	Result (95% CI)
Sore throat
Pichichero 1987	Fever severity on Day 3	37.2 (SD 1.2, n = 55)	36.8 (SD 0.6, n = 59)	Immediate antibiotics	MD 0.40 (95% CI 0.05 to 0.75)
	Malaise severity on Day 3	1.3 (SD 1.0, n = 55)	1.1 (SD 0.7, n = 59)	No difference	MD 0.20 (95% CI ‐0.11 to 0.51)
	Pain severity on Day 3	1.6 (SD 1.4, n = 55)	1.3 (SD 1.3, n = 59)	No difference	MD 0.30 (95% CI ‐0.15 to 0.75)
	Compliance	55/55	59/59	No difference	100% in both groups
Gerber 1990	Recurrence rate	‐	‐	No difference	Data not available
Gerber 1990	Compliance	44/50	59/63	Delayed antibiotics	88% in immediate group and 93% in delayed group
El‐Daher 1991	Vomiting	57/118	4/111	Immediate antibiotics	OR 25.00 (95% CI 8.65 to 72.25)
	Pain on Day 3	106/118	42/111	Immediate antibiotics	OR 14.51 (95% CI 7.14 to 29.50)
	Malaise on Day 3	45/118	4/111	Immediate antibiotics	OR 16.49 (95% CI 5.68 to 47.83)
	Fever severity on Day 3	38.0 °C (SD 2.0, n = 118)	37.1 °C (SD 1.0, n = 111)	Immediate antibiotics	SMD 0.58 (95% CI 0.31 to 0.84)
Little 1997	Vomiting	15/179	18/215	No difference	OR 1.00 (95% CI 0.49 to 2.05)
	Diarrhoea	23/179	23/215	No difference	OR 1.23 (95% CI 0.67 to 2.28)
	Rash	11/180	14/215	No difference	OR 0.93 (95% CI 0.41 to 2.11)
	Stomachache	48/180	66/215	No difference	OR 0.82 (95% CI 0.53 to 1.27)
	Fever (> 37.0 °C)	Unavailable	Unavailable	Immediate antibiotics	Data not available
	Pain	Unavailable	Unavailable	No difference	Data not available
	Cough	Unavailable	Unavailable	No difference	Data not available
	Malaise	Unavailable	Unavailable	No difference	Data not available
	Analgesic use	Unavailable	Unavailable	No difference	Data not available
	Time off work	Unavailable	Unavailable	No difference	Data not available
De la Poza Abad 2016	Pain duration (delayed prescription at time of visit)	5.7 days (SD 5.1, n = 45)	4.4 days (SD 2.4, n = 47)	No difference	MD 1.30 (95% CI ‐0.34 to 2.94)
	Pain duration (delayed prescription requiring collection)	7.4 days (SD 6.3, n = 46)	4.4 days (SD 2.4, n = 47)	Immediate antibiotics	MD 3.00 (95% CI ‐1.03 to 4.95)
	Fever duration (delayed prescription at time of visit)	3.1 days (SD 1.8, n = 45)	2.9 days (SD 1.7, n = 47)	No difference	MD ‐0.20 (95% CI ‐0.52 to 0.92)
	Fever duration (delayed prescription requiring collection)	3.4 days (SD 2.4, n = 46)	2.9 days (SD 1.7, n = 47)	No difference	MD 0.50 (95% CI ‐0.35 to 1.35)
	Cough duration (delayed prescription at time of visit)	8.1 days (SD 5.9, n = 45)	8.1 days (SD 5.7, n = 47)	No difference	MD ‐2.50 (95% CI ‐5.52 to 0.52)
	Cough duration (delayed prescription requiring collection)	8.2 days (SD 6.9, n = 46)	8.1 days (SD 5.7, n = 47)	No difference	MD ‐2.40 (95% CI ‐5.59 to 0.79)
	Nasal mucosity duration (delayed prescription at time of visit)	7.2 days (SD 4.3, n = 45)	5.4 days (SD 3.9, n = 47)	Immediate antibiotics	MD ‐1.80 (95% CI 0.12 to 3.48)
	Nasal mucosity duration (delayed prescription requiring collection)	9.7 days (SD 8.3, n = 46)	8.9 days (SD 6.5, n = 46)	Immediate antibiotics	MD 4.30 (95% CI 1.65 to 6.95)
Acute otitis media
Little 2001	Diarrhoea	14/150	25/135	Delayed antibiotics	OR 0.45 (95% CI 0.22 to 0.91)
	Rash	8/150	6/135	No difference	OR 1.21 (95% CI 0.41 to 2.58)
	Participants with pain on Day 3	28/111	15/101	No difference	OR 1.93 (95% CI 0.96 to 3.88)
	Participants with pain on Day 7	3/111	0/101	No difference	OR 6.55 (95% CI 0.33 to 128.35)
	Participants with malaise on Day 3	45/150	19/135	Immediate antibiotics	OR 2.62 (95% CI 1.44 to 4.76)
	Malaise severity Day 3	0.8 (SD 1.7, n = 150)	0.4 (SD 1.0, n = 134)	Immediate antibiotics	MD 0.43 (95% CI 0.11 to 0.75)
	Malaise severity on Day 7	2.2 (SD 2.0, n = 150)	1.5 (SD 1.2, n = 135)	No difference	MD 0.01 (95% CI ‐0.11 to 0.13)
	Pain severity on Day 3	2.6 (SD 2.1, n = 111)	1.8 (SD 1.4, n = 102)	Immediate antibiotics	MD 0.75 (95% CI 0.26 to 1.24)
	Pain severity on Day 7	1.17 (SD 0.75, n = 111)	1.05 (SD 0.38, n = 101)	No difference	MD 0.12 (95% CI ‐0.04 to 0.28)
	Paracetamol consumption	2.3 spoons	1.7 spoons	Immediate antibiotics	MD 0.59 (95% CI 0.25 to 0.93)
	Last day of crying	2.2 days	1.5 days	Immediate antibiotics	MD 0.69 (95% CI 0.31 to 1.07)
Little 2006	Episodes of earache in the 3 months since randomisation	Unavailable	Unavailable	No difference	OR 0.89 (95% CI 0.48 to 1.65)
Little 2006	Episodes of earache over 1 year	Unavailable	Unavailable	No difference	OR 1.03 (95% CI 0.60 to 1.78)
Spiro 2006	Pain day 4 to 6	85/132	89/133	No difference	OR 0.89 (95% CI 0.54 to 1.48)
	Fever day 4 to 6	42/132	46/133	No difference	OR 0.88 (95% CI 0.53 to 1.47)
	Vomiting	15/132	15/133	No difference	OR 1.01 (95% CI 0.47 to 2.16)
	Diarrhoea	10/132	31/133	Delayed antibiotics	OR 0.27 (95% CI 0.13 to 0.58)
Cough
Dowell 2001	Clinical outcomes	Unavailable	Unavailable	No difference	Data not available
Little 2005a	Clinical outcomes	Unavailable	Unavailable	No difference	Data not available
De la Poza Abad 2016	Pain duration (delayed prescription at time of visit)	11.0 days (SD 8.0, n = 32)	10.5 days (SD 8.0, n = 32)	No difference	MD 0.50 (95% CI ‐0.34 to 4.42)
	Pain duration (delayed prescription requiring collection)	8.9 days (SD 6.9, n = 32)	10.5 days (SD 8.0, n = 32)	No difference	MD ‐1.60 (95% CI ‐5.26 to 2.06)
	Fever duration (delayed prescription at time of visit)	5.6 days (SD 5.9, n = 32)	4.1 days (SD 5.7, n = 32)	No difference	MD 1.50 (95% CI ‐1.34 to 4.34)
	Fever duration (delayed prescription requiring collection)	4.7 days (SD 4.6, n = 32)	4.1 days (SD 5.7, n = 32)	No difference	MD 0.60 (95% CI ‐1.94 to 3.14)
	Cough duration (delayed prescription at time of visit)	15.6 days (SD 8.8, n = 32)	13.0 days (SD 7.0, n = 32)	No difference	MD 2.60 (95% CI ‐1.30 to 6.50)
	Cough duration (delayed prescription requiring collection)	12 days (SD 5.6, n = 32)	13.0 days (SD 7.0, n = 32)	No difference	MD ‐1.00 (95% CI ‐4.11 to 2.11)
Common cold
Arroll 2002a	Participants with fever on Day 3	5/67	6/62	No difference	OR 0.75 (95% CI 0.22 to 2.6)
	Participants with fever on Day 7	3/67	4/62	No difference	OR 0.68 (95% CI 0.15 to 3.17)
	Participants with diarrhoea	11/67	12/62	No difference	OR 0.79 (95% CI 0.53 to 1.19)
	Participants with pain on Day 3	13/61	9/58	No difference	OR 1.47 (95% CI 0.58 to 3.77)
	Participants with pain on Day 7	1/61	3/58	No difference	OR 0.31 (95% CI 0.03 to 3.03)
	Participants with cough on Day 3	54/67	51/62	No difference	OR 0.90 (95% CI 0.37 to 2.18)
	Participants with cough on Day 7	41/61	43/58	No difference	OR 0.72 (95% CI 0.32 to 1.58)
	Fever severity on Day 3	36.2 °C (SD 0.7, n = 61)	36.4 °C (SD 0.6, n = 58)	No difference	MD ‐0.24 (95% CI ‐0.48 to 0.00)
	Fever severity on Day 7	36.0 °C (SD 0.8, n = 59)	36.3 °C (SD 0.6, n = 60)	Delayed antibiotics	MD ‐0.32 (95% CI ‐0.57 to ‐0.07)
De la Poza Abad 2016	Pain duration (delayed prescription at time of visit)	8.4 days (SD 8.2, n = 29)	6.7 days (SD 4.5, n = 20)	No difference	MD 1.70 (95% CI ‐1.88 to 5.28)
	Pain duration (delayed prescription requiring collection)	10.1 days (SD 7.5, n = 20)	6.7 days (SD 4.5, n = 20)	No difference	MD 3.40 (95% CI ‐0.43 to 7.23)
	Fever duration (delayed prescription at time of visit)	3.0 days (SD 1.2, n = 29)	5.3 days (SD 6.2, n = 20)	No difference	MD ‐2.30 (95% CI ‐5.05 to 0.45)
	Fever duration (delayed prescription requiring collection)	4.2 days (SD 3.0, n = 20)	5.3 days (SD 6.2, n = 20)	No difference	MD ‐1.10 (95% CI ‐4.12 to 1.92)
	Cough duration (delayed prescription at time of visit)	8.3 days (SD 5.2, n = 29)	7.6 days (SD 5.6, n = 20)	No difference	MD ‐0.70 (95% CI ‐2.40 to 3.80)
	Cough duration (delayed prescription requiring collection)	6.4 days (SD 4.6, n = 20)	7.6 days (SD 5.6, n = 20)	No difference	MD ‐1.20 (95% CI ‐4.38 to 1.98)
	Nasal mucosity duration (delayed prescription at time of visit)	15.2 days (SD 9.7, n = 29)	13.0 days (SD 8.8, n = 20)	No difference	MD 2.20 (95% CI ‐3.03 to 7.43)
	Nasal mucosity duration (delayed prescription requiring collection)	10.7 days (SD 7.2, n = 20)	13.0 days (SD 8.8, n = 20)	No difference	MD ‐2.30 (95% CI ‐7.28 to 2.68)
CI: confidence interval MD: mean difference OR: odds ratio SD: standard deviation SMD: standardised mean difference

Table 2. Summary of clinical outcomes: delayed versus immediate antibiotics

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Table 3. Summary of clinical outcomes: delayed versus no antibiotics

Study	Outcome	*Delay*	No antibiotics	Favours	Result (with 95% CI)
Sore throat
De la Poza Abad 2016	Pain duration (delayed prescription at time of visit)	5.7 days (SD 5.1, n = 45)	7.8 days (SD 6.0, n = 46)	No difference	MD ‐2.10 (95% CI ‐4.39 to 0.19)
	Pain duration (delayed prescription requiring collection)	7.4 days (SD 6.3, n = 46)	7.8 days (SD 6.0, n = 46)	No difference	MD ‐0.40 (95% CI ‐2.91 to 2.11)
	Fever duration (delayed prescription at time of visit)	3.1 days (SD 1.8, n = 45)	3.2 days (SD 2.5, n = 46)	No difference	MD 0.10 (95% CI 0.99 to 0.79)
	Fever duration (delayed prescription requiring collection)	3.4 days (SD 2.4, n = 46)	3.2 days (SD 2.5, n = 46)	No difference	MD 0.20 (95% CI ‐0.80 to 1.20)
	Cough duration (delayed prescription at time of visit)	8.1 days (SD 5.9, n = 45)	10.6 days (SD 8.6, n = 46)	No difference	MD 0.0 (95% CI ‐2.37 to 2.37)
	Cough duration (delayed prescription requiring collection)	8.2 days (SD 6.9, n = 46)	10.6 days (SD 8.6, n = 46)	No difference	MD 0.10 (95% CI ‐2.48 to 2.68)
	Nasal mucosity duration (delayed prescription at time of visit)	7.2 days (SD 4.3, n = 45)	8.9 days (SD 6.5, n = 45)	No difference	MD ‐1.70 (95% CI ‐3.96 to 0.56)
	Nasal mucosity duration (delayed prescription requiring collection)	9.7 days (SD 8.3, n = 46)	8.9 days (SD 6.5, n = 46)	No difference	MD 0.80 (95% CI ‐2.25 to 3.85)
Little 2005a	Clinical outcomes	Unavailable	Unavailable	No difference	Unavailable
Acute otitis media
Chao 2008	Fever day 3	18/106	8/100	No difference	OR 1.45 (95% CI 0.50 to 4.24)
Chao 2008	Pain day 3	26/106	29/100	No difference	OR 0.64 (95% CI 0.29 to 1.38)
Cough
De la Poza Abad 2016	Pain duration (delayed prescription at time of visit versus no antibiotics)	11 days (SD 8.0, n = 32)	12.2 days (SD 8.0, n = 32)	No difference	MD ‐1.20 (95% CI ‐5.07 to 2.67)
	Pain duration (delayed prescription requiring collection versus no antibiotics)	8.9 days (SD 6.9, n = 32)	12.2 days (SD 7.8, n = 32)	No difference	MD ‐3.30 (95% CI ‐6.91 to 0.31)
	Fever duration (delayed prescription at time of visit versus no antibiotics)	5.6 days (SD 5.9, n = 32	7.2 days (SD 7.9, n = 32)	No difference	MD ‐1.60 (95% CI ‐8.82 to 5.62)
	Fever duration (delayed prescription requiring collection versus no antibiotics)	4.7 days (SD 4.6, n = 32)	7.2 days (SD 7.9, n = 32)	No difference	MD ‐2.50 (95% CI ‐5.67 to 0.67)
	Cough duration (delayed prescription at time of visit versus no antibiotics)	15.6 days (SD 8.8, n = 32)	15.1 days (SD 7.6, n = 32)	No difference	MD ‐0.50 (95% CI ‐3.53 to 4.53)
	Cough duration (delayed prescription requiring collection versus no antibiotics)	12.0 days (SD 5.6, n = 32)	15.1 days (SD 7.6, n = 32)	No difference	MD ‐3.10 (95% CI ‐6.37 to 0.17)
Common cold
De la Poza Abad 2016	Pain duration (delayed prescription at time of visit versus no antibiotics)	8.4 days (SD 8.2, n = 29)	13.7 days (SD 6.7, n = 19)	Delayed antibiotics	MD ‐5.30 (95% CI ‐9.54 to ‐1.06)
	Pain duration (delayed prescription requiring collection versus no antibiotics)	10.1 days (SD 7.5, n = 20)	13.7 days (SD 6.7, n = 19)	No difference	MD ‐3.60 (95% CI ‐8.06 to 0.86)
	Fever duration (delayed prescription at time of visit versus no antibiotics)	3.0 days (SD 1.2, n = 29)	9.0 days (SD 8.9, n = 19)	Delayed antibiotics	MD ‐6.00 (95% CI ‐10.03 to ‐1.97)
	Fever duration (delayed prescription requiring collection versus no antibiotics)	4.2 days (SD 3, n = 20)	9.0 days (SD 8.9, n = 19)	Delayed antibiotics	MD ‐4.80 (95% CI ‐9.01 to ‐0.59)
	Cough duration (delayed prescription at time of visit versus no antibiotics)	8.3 days (SD 5.2, n = 29)	11.7 days (SD 6.4, n = 19)	No difference	MD ‐3.40 (95% CI ‐6.84 to 0.04)
	Cough duration (delayed prescription requiring collection versus no antibiotics)	6.4 days (SD 4.6, n = 20)	11.7 days (SD 6.4, n = 19)	Delayed antibiotics	MD ‐5.30 (95% CI ‐8.81 to ‐1.79)
	Nasal mucosity duration (delayed prescription at time of visit versus no antibiotics)	15.2 days (SD 9.7, n = 29)	15.2 days (SD 7.5, n = 19)	No difference	MD ‐0.0 (95% CI ‐4.88 to 4.88)
	Nasal mucosity (delayed prescription requiring collection versus no antibiotics)	10.7 days (SD 7.2, n = 20)	15.2 days (SD 7.5, n = 19)	No difference	MD ‐4.50 (95% CI ‐9.12 to 0.12)
CI: confidence interval MD: mean difference OR: odds ratio SD: standard deviation

Table 3. Summary of clinical outcomes: delayed versus no antibiotics

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Comparison 1. Pain: delayed versus immediate antibiotics

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 Number of participants with pain on Days 3 to 6 Show forest plot	4		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

1.2 Pain severity on Day 3 Show forest plot	2	327	Std. Mean Difference (IV, Fixed, 95% CI)	0.35 [0.13, 0.57]

1.3 Duration of malaise Show forest plot	1	294	Mean Difference (IV, Random, 95% CI)	0.10 [‐0.86, 1.06]

1.4 Duration of pain symptoms Show forest plot	1	588	Mean Difference (IV, Random, 95% CI)	‐0.44 [‐1.17, 0.29]

1.4.1 Pharyngitis	1	294	Mean Difference (IV, Random, 95% CI)	‐0.20 [‐1.21, 0.81]
1.4.2 Acute otitis media	1	294	Mean Difference (IV, Random, 95% CI)	‐0.70 [‐1.76, 0.36]

Comparison 1. Pain: delayed versus immediate antibiotics

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Comparison 2. Malaise: delayed versus immediate antibiotics

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
2.1 Number of people with malaise on Day 3 Show forest plot	2		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

2.2 Malaise severity on Day 3 Show forest plot	2	398	Std. Mean Difference (IV, Fixed, 95% CI)	0.29 [0.09, 0.48]

Comparison 2. Malaise: delayed versus immediate antibiotics

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Comparison 3. Fever: delayed versus immediate antibiotics

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
3.1 Fever on Days 3 to 6 Show forest plot	2	394	Odds Ratio (M‐H, Fixed, 95% CI)	0.86 [0.54, 1.38]

3.2 Fever severity on Day 3 Show forest plot	3		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

Comparison 3. Fever: delayed versus immediate antibiotics

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Comparison 4. Antibiotic use

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
4.1 Antibiotic use: delayed versus immediate antibiotics Show forest plot	8	2257	Odds Ratio (M‐H, Fixed, 95% CI)	0.03 [0.02, 0.04]

4.1.1 Antibiotic use: delayed (prescription at time of visit) versus immediate antibiotics	4	841	Odds Ratio (M‐H, Fixed, 95% CI)	0.06 [0.04, 0.09]
4.1.2 Antibiotic use: delayed (prescription collection) versus immediate antibiotics	5	1416	Odds Ratio (M‐H, Fixed, 95% CI)	0.02 [0.01, 0.03]
4.2 Antibiotic use: delayed versus no antibiotics Show forest plot	4	1241	Odds Ratio (M‐H, Random, 95% CI)	2.55 [1.59, 4.08]

4.2.1 Antibiotic use: delayed (prescription at time of visit) versus no antibiotics	2	353	Odds Ratio (M‐H, Random, 95% CI)	3.84 [2.18, 6.76]
4.2.2 Antibiotic use: delayed (prescription collection) versus no antibiotics	3	888	Odds Ratio (M‐H, Random, 95% CI)	2.05 [1.11, 3.80]

Comparison 4. Antibiotic use

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Comparison 5. Patient satisfaction

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
5.1 Patient satisfaction: delayed versus immediate antibiotics Show forest plot	7	1927	Odds Ratio (M‐H, Random, 95% CI)	0.77 [0.45, 1.29]

5.2 Patient satisfaction: delayed versus no antibiotics Show forest plot	4	1235	Odds Ratio (M‐H, Random, 95% CI)	1.49 [1.08, 2.06]

Comparison 5. Patient satisfaction

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Comparison 6. Adverse events

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
6.1 Vomiting: delayed versus immediate antibiotics Show forest plot	3		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected

6.2 Diarrhoea: delayed versus immediate antibiotics Show forest plot	4		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

6.3 Rash: delayed versus immediate antibiotics Show forest plot	2	680	Odds Ratio (M‐H, Fixed, 95% CI)	1.03 [0.54, 1.97]

Comparison 6. Adverse events

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Comparison 7. Reconsultation rate

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
7.1 Reconsultation rate: delayed versus immediate antibiotics Show forest plot	2	379	Odds Ratio (M‐H, Fixed, 95% CI)	1.04 [0.55, 1.98]

Comparison 7. Reconsultation rate

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