Delayed antibiotics for respiratory infections
Abstract
Background
Concerns exist regarding antibiotic prescribing for acute respiratory tract infections (ARTIs) owing to adverse reactions, cost and antibacterial resistance. One strategy to reduce antibiotic prescribing is to provide prescriptions but to advise delay in the hope symptoms will resolve first. This is an update of a Cochrane Review originally published in 2007 and updated in 2010.
Objectives
To evaluate the use of delayed antibiotics compared to immediate or no antibiotics as a prescribing strategy for ARTIs. We evaluated clinical outcomes including duration and severity measures for pain, malaise, fever, cough and rhinorrhoea in sore throat, acute otitis media, bronchitis (cough) and the common cold. We also evaluated the outcomes of antibiotic use, patient satisfaction, antibiotic resistance and re‐consultation rates and use of alternative therapies.
Search methods
We searched CENTRAL (The Cochrane Library 2013, Issue 2), which includes the Acute Respiratory Infection Group's Specialised Register; Ovid MEDLINE (January 1966 to February Week 3 2013); Ovid MEDLINE In‐Process & Other Non‐Indexed Citations (28 February 2013); EMBASE (1990 to 2013 Week 08); Science Citation Index ‐ Web of Science (2007 to May 2012) and EBSCO CINAHL (1982 to 28 February 2013).
Selection criteria
Randomised controlled trials (RCTs) involving participants of all ages defined as having an ARTI, where delayed antibiotics were compared to antibiotics used immediately or no antibiotics.
Data collection and analysis
Three review authors independently extracted and collected data. Important adverse effects, including adverse effects of antibiotics and complications of disease, were included as secondary outcomes. We assessed the risk of bias of all included trials. We contacted trial authors to obtain missing information where available.
Main results
Ten studies, with a total of 3157 participants, were included in this review. Heterogeneity of the 10 included studies and their results generally precluded meta‐analysis with patient satisfaction being an exception.
There was no difference between delayed, immediate and no prescribed antibiotics for the clinical outcomes evaluated in cough and common cold. In patients with acute otitis media (AOM) and sore throat immediate antibiotics were more effective than delayed for fever, pain and malaise in some studies. There were only minor differences in adverse effects with no significant difference in complication rates.
Delayed antibiotics resulted in a significant reduction in antibiotic use compared to immediate antibiotics. A strategy of no antibiotics resulted in least antibiotic use.
Patient satisfaction favoured immediate antibiotics over delayed (odds ratio (OR) 0.52; 95% confidence interval (CI) 0.35 to 0.76). Delayed and no antibiotics had similar satisfaction rates with both strategies achieving over 80% satisfaction (OR 1.44; 95% CI 0.99 to 2.10).
There was no difference in re‐consultation rates for immediate and delayed groups.
None of the included studies evaluated antibiotic resistance.
Authors' conclusions
Most clinical outcomes show no difference between strategies. Delay slightly reduces patient satisfaction compared to immediate antibiotics (87% versus 92%) but not compared to none (87% versus 83%). In patients with respiratory infections where clinicians feel it is safe not to prescribe antibiotics immediately, no antibiotics with advice to return if symptoms do not resolve is likely to result in the least antibiotic use, while maintaining similar patient satisfaction and clinical outcomes to delayed antibiotics.
PICOs
Plain language summary
Delayed antibiotics for symptoms and complications of acute respiratory tract infections
Previous reviews indicate that antibiotics have, at best, only modest benefit for acute respiratory tract infections (ARTIs). These benefits need to be balanced against adverse effects, costs and the risk of bacteria becoming resistant to antibiotics. One way for doctors to reduce their use is to prescribe delayed antibiotics (meaning providing the prescription but advising the patient/carer to delay their use in the hope that symptoms resolve first). Delayed prescribing resulted in 32% of patients using antibiotics compared to 93% of patients in the immediate prescription group. However, not prescribing antibiotics at all results in the least antibiotic prescribing (14% of patients used antibiotics).
This review found 10 studies, involving 3157 participants, looking at prescribing strategies for respiratory infections. It was generally not possible to combine results from different studies because of incomplete information from some studies and the different types of patients in each study. There were only three trials comparing the strategies of delayed and no antibiotics.
For most symptoms like fever, pain and malaise, there was no difference between immediate, delayed and no antibiotics. The only differences were small and favoured immediate antibiotics for relieving pain and fever for sore throat and pain and malaise for middle ear infections. There was little difference in adverse effects of antibiotics for the three prescribing strategies and no significant difference in complication rates.
Patient satisfaction was slightly reduced in the delayed antibiotic group (87% satisfied) compared to the immediate antibiotic group (92% satisfied). Satisfaction rates were similar between delayed and no antibiotic groups (83% satisfied).
No included studies evaluated antibiotic resistance.
When doctors feel it is safe not to prescribe antibiotics immediately, prescribing none with advice to return if symptoms do not resolve rather than delaying them will result in lower subsequent antibiotic use, while maintaining similar patient satisfaction and symptom outcomes.
Authors' conclusions
Background
Description of the condition
The use of antibiotics for acute respiratory tract infections (ARTIs) is controversial. Empirical evidence suggests that antibiotics have only a modest benefit in acute otitis media (AOM) (Venekamp 2013), pharyngitis (Spinks 2011) and acute bronchitis (Smith 2011) and no effect in the common cold (Arroll 2010). Any benefits have to be weighed up against common adverse reactions (including rash, abdominal pain, diarrhoea and vomiting) and cost (Berman 1997; Niemela 1999). Over‐prescribing may also contribute to community bacterial resistance to antibiotics (Arason 1996; Brook 1998; Verkatesum 1995).
Description of the intervention
There has been interest in strategies to reduce antibiotic prescribing for ARTIs. One of these strategies is to advise patients to 'delay' filling their script and only to fill it if their symptoms persist or deteriorate. Delayed antibiotics are advocated as a means of demonstrating to patients that antibiotics are not always necessary, without making them feel under‐serviced (Arroll 2002b). Two ways of using this strategy have been deployed: giving the patient the antibiotic (with instructions not to use unless there is deterioration); and making the prescription available at the clinic reception (to be picked up in the event of deterioration).
How the intervention might work
Delaying antibiotics may provide a feeling of safety for both patient and clinician should an illness deteriorate. This intervention then provides the safety of having a prescription of antibiotics available, yet an educational way of experiencing whether the illness resolves spontaneously without their use.
A systematic review showed that using delayed antibiotics in ARTIs significantly reduces antibiotic prescribing (Arroll 2003a). The reduction ranges from a risk ratio (RR) of 0.77 (95% confidence interval (CI) 0.73 to 0.81) (Dowell 2001) to RR 0.25 (95% CI 0.19 to 0.34) (Little 1997).
Why it is important to do this review
The delayed antibiotic strategy has also been advocated more recently as a safety net for avoiding rare but important complications of initially uncomplicated ARTIs (Little 2005b). The same authors also advocated delayed antibiotics for reducing antibiotic use, allowing adequate control of symptoms, while providing high levels of patient satisfaction (Little 2005b).
This review asks specifically what effect delayed antibiotics have on clinical outcomes of ARTIs compared to immediate antibiotics and no antibiotics. This review also evaluates the available data on antibiotic use, patient satisfaction and antibiotic resistance for the three prescribing strategies of delayed antibiotics, immediate antibiotics and no antibiotics. This is an update of a Cochrane Review originally published in 2007 (Spurling 2007), with an updated version published in 2010 (Spurling 2010).
Objectives
To evaluate the use of delayed antibiotics compared to immediate or no antibiotics as a prescribing strategy for ARTIs. We aimed to evaluate clinical outcomes including duration and severity measures for pain, malaise, fever, cough and rhinorrhoea in sore throat, AOM, bronchitis (cough) and the common cold. We also aimed to evaluate the outcomes of antibiotic use, patient satisfaction, antibiotic resistance and re‐consultation rates and use of alternative therapies.
Methods
Criteria for considering studies for this review
Types of studies
Randomised controlled trials (RCTs) studying the treatment of ARTIs with delayed antibiotics versus immediate or no antibiotics. Open randomised trials were accepted.
Types of participants
Patients of all ages defined as having ARTIs.
Types of interventions
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'Delayed antibiotic use' was defined as a strategy involving the use of or advice to use antibiotics more than 48 hours after the initial consultation.
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'Immediate antibiotic use' was defined as the immediate use of a prescription of oral antibiotics given at the initial consultation.
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'No antibiotic use' was defined as no prescription of antibiotics at the initial consultation.
Types of outcome measures
Primary outcomes
We compared delayed antibiotics with immediate antibiotics and delayed antibiotics with no antibiotics where data were available.
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Clinical outcomes for sore throat, AOM, bronchitis (cough) and common cold (we included duration and severity measures for the following symptoms: pain, malaise, fever, cough and rhinorrhoea)
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Antibiotic use
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Patient satisfaction (where patient satisfaction is measured on a four to six‐point Likert scale; we defined satisfaction as including both satisfied and very satisfied)
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Antibiotic resistance
Secondary outcomes
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Adverse effects of antibiotics
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Complications of disease
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Re‐consultation
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Use of alternative therapies
Search methods for identification of studies
Electronic searches
For this updated review we searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2013, Issue 2), which includes the Acute Respiratory Infection Group's Specialised Register; Ovid MEDLINE (January 1966 to February Week 3 2013); Ovid MEDLINE In‐Process & Other Non‐Indexed Citations (28 February 2013); EMBASE (1990 to 2013 Week 08); Science Citation Index ‐ Web of Science (2007 to May 2012) and EBSCO CINAHL (1982 to 28 February 2013).
In the original version of this review MEDLINE was searched using the following keywords and MeSH terms in conjunction with the highly sensitive search strategy designed by The Cochrane Collaboration for identifying randomised controlled trials (Dickersin 1994). For this update we applied no trial filters. We used the MEDLINE search strategy to search CENTRAL (Appendix 1) and adapted this to search EMBASE (Appendix 2) and CINAHL (Appendix 3).
Ovid MEDLINE
1 exp Respiratory Tract Infections/ (114895)
2 (upper respiratory tract infection$ or urti).mp. (2482)
3 exp Otitis Media/ (8289)
4 otitis media.mp. (10100)
5 exp Pharyngitis/ (4870)
6 pharyngitis.mp. (3733)
7 exp Tonsillitis/ (2065)
8 tonsillitis.mp. (2423)
9 exp Common Cold/ (1492)
10 common cold.mp. (2207)
11 exp Bronchitis/ (8275)
12 bronchitis.mp. (8027)
13 exp Sinusitis/ (8071)
14 sinusitis.mp. (10465)
15 sore throat$.mp. (2080)
16 or/1‐15 (133707)
17 exp Anti‐Bacterial Agents/ (215537)
18 antibiotic$.mp. (127408)
19 or/17‐18 (278179)
20 (delay$ adj15 prescri$).mp. (474)
21 and/16,19‐20 (55)
There were no language or date of publication restrictions in any of the electronic database searches.
Searching other resources
We scanned abstracts from the search results to identify trials that loosely met the inclusion criteria. We checked references of all relevant retrieved trials to identify any other articles.
Data collection and analysis
Selection of studies
In the original publication of this review, we scanned abstracts from the initial search results to identify trials that loosely met the inclusion criteria. We checked references of all relevant retrieved trials to identify any other articles. Three review authors (RFo, LD, CDM) independently reviewed the full‐text articles of the retrieved trials.
In the 2010 update, one further study was found to meet the inclusion criteria (Chao 2008) and two review authors (LD, CDM) independently assessed the methodological quality of the new included study that met the inclusion criteria at that time (Chao 2008).
Similarly, in this updated review (2013), three authors (RFo, GS, RFa) scanned abstracts from the updated searches to identify trials that met the inclusion criteria, checking the references of all retrieved trials to identify other articles. Three review authors (LD, CDM, RFa) independently reviewed the full‐text articles of the retrieved trials and applied the inclusion criteria.
We identified two papers, Little 2006 and Moore 2009, as reporting longer‐term outcomes from previously included studies (Little 2001; Little 2005a).
Data extraction and management
In the initial publication of this review, three review authors (RFo, LD and CDM) independently extracted data for each study trial to be included. We extracted data in a blinded manner (that is, without the knowledge of the study results, the names of the authors, institutions or journal of publication). We extracted additional data from graphs of the published articles of El‐Daher 1991 and Pichichero 1987 on fever severity and symptom scores.
In this most recent update (2013), two review authors (LD, CDM) independently extracted data from the two new included papers. We contacted the authors of Little 2006 to obtain original data for the outcomes of earache at three months and one year that had been reported as odds ratios (ORs) in the published trial. The complete data were unavailable and there was some inconsistency between what was provided and the published numbers. These results have been included in the text of this review, in the form of the published ORs.
Assessment of risk of bias in included studies
In the first publication of this review three review authors (RFo, LD, CDM) independently assessed the quality of each of the study trials that met the inclusion criteria. We resolved disagreements by consensus. Assessment was blinded (that is, without the knowledge of the study results, the names of the authors, institutions or journal of publication).
We rated the quality of each eligible RCT according to the 'Risk of bias' tool available in RevMan 5.2 and criteria set out in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We assessed methodological quality under the headings of allocation, blinding, incomplete outcome data, selective reporting and other potential sources of bias.
Two review authors (LD, CDM) independently assessed the methodological quality of the trial included in the 2010 update.
We resolved disagreements by discussion.
Measures of treatment effect
We analysed data using RevMan 5.2. We expressed continuous data comparisons using mean differences (MD) where there was one study or standardised MD where more than one study used different measurement scales. We expressed dichotomous data using odds ratios (OR). We pooled data into clinical outcomes where multiple trial results for the same clinical presentation existed and there was no heterogeneity.
Unit of analysis issues
The units of analysis for each outcome are the individual research participants.
Dealing with missing data
Six studies included an intention‐to‐treat (ITT) analysis. Three other studies described their minimal drop‐out rates. One study (El‐Daher 1991) did not discuss the drop‐out rate, though it was small.
Assessment of heterogeneity
We did not undertake a meta‐analysis for most clinical outcomes owing to multiple analyses with only one or two study results. We pooled results where satisfactorily low I2 statistic and non‐significant Chi2 test results were found. We did not undertake a meta‐analysis for antibiotic use owing to the heterogeneity of the included study results, likely owing to different antibiotic indications for different clinical presentations.
Assessment of reporting biases
Two studies collected data on clinical outcomes yet did not report them in detail (Dowell 2001; Gerber 1990). In both cases, the studies reported that there was no difference between control and intervention groups.
Data synthesis
Most of the data in this review are reported as a narrative synthesis describing outcome measures. As indicated previously, we pooled results where satisfactorily low I2 statistic and non‐significant Chi2 test results were found. We undertook a meta‐analysis for the outcomes of fever for sore throat and patient satisfaction.
Subgroup analysis and investigation of heterogeneity
Subgroup analyses were considered for all outcomes and included year of publication, clinical presentation, differences in the intervention and risk of bias.
We describe in the results section the two subgroup analyses that showed differences in outcomes. We explored heterogeneity of antibiotic use in delayed antibiotic arms further with analysis of different methods of the delay strategy. We explored heterogeneity of patients satisfaction further with respect to blinding of outcome assessor and patient.
Results
Description of studies
Results of the search
Searches conducted for this review have resulted in 244 articles being identified by electronic searching; 28 were retrieved for more detailed evaluation and 17 studies have been formally evaluated.
Five studies were excluded and are described in the Excluded studies section. Two studies identified in this 2013 update reported longer‐term outcomes from previously included studies (Little 2006; Moore 2009) and while their data have been added to this review, they are considered part of the original included studies.
Ten trials were eligible for inclusion. They included 1159 participants in their delayed antibiotic arm, with 1067 participants in the immediate antibiotic arm of nine trials and 465 participants in the no antibiotic arm of three trials.
In this most recent update (2013), following removal of duplicated studies, searches resulted in the identification of 77 articles (out of the 244 previously mentioned). Five articles were retrieved for further evaluation (out of 28). Three studies were excluded (out of a total of five) because they were not randomised. The remaining two reported longer‐term outcomes from previously included studies (Little 2006; Moore 2009) and while their data have been added to this review, they are considered part of the original included studies. Therefore, there are no more included studies as a result of this 2013 update.
Included studies
Nine trials compared immediate antibiotics with delayed antibiotics. Four of these trials investigated acute pharyngitis/sore throat; two with AOM; two with cough and one dealt with the common cold. Early studies of sore throat (El‐Daher 1991; Gerber 1990; Pichichero 1987) were designed as efficacy trials to identify the rate of relapse of group A beta‐haemolytic streptococcus (GABHS) throat in immediate versus delayed antibiotic groups. Subsequent trials (Arroll 2002a; Dowell 2001; Little 1997; Little 2001; Spiro 2006) comparing delayed antibiotics and immediate antibiotics were conducted with a view to evaluate the use of delayed antibiotics to reduce the use of antibiotics for upper respiratory tract infections (RTIs).
Three studies compared the prescribing strategy of no antibiotics with delayed antibiotics (Chao 2008; Little 1997; Little 2005a). These three trials investigated the presentations of sore throat (Little 1997), cough (Little 2005a) and AOM (Chao 2008). This last trial (Chao 2008) also asked patients in the no antibiotic arm to return if their symptoms had not resolved.
Excluded studies
Since the first publication of this review, five trials have been excluded. One because it used a before‐and‐after study design (Cates 1999) and four because they were not randomised.
Risk of bias in included studies
Summaries of the bias in included studies are provided in Figure 1 and Figure 2.
Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies.
Methodological quality summary: review authors' judgements about each methodological quality item for each included study.
Allocation
Eight included studies were adequately randomised using random number tables or computer‐generated randomisation. In two studies the method of randomisation was not described (El‐Daher 1991; Little 1997). Only four trials described adequate allocation concealment using opaque envelopes (Arroll 2002a; Little 2001; Little 2005a; Spiro 2006)
Blinding
Three studies attempted to blind the patient and the doctor without mentioning the outcome assessor (Arroll 2002a; El‐Daher 1991; Pichichero 1987). In one study patients were told only that they would be given one of two sets of instructions about taking antibiotics for their colds. Participants read an information sheet and then completed a consent form. Thus, patients were blinded to what the other group would take (Arroll 2002a). Two studies used placebo tablets to blind patients (El‐Daher 1991; Pichichero 1987). Seven studies attempted to blind some or all aspects of the study; that is, the patients, the doctor and the outcome assessor. For four studies (Chao 2008; Dowell 2001; Little 2005a; Spiro 2006), the outcomes assessor was blinded but not the patient or the care giver. For the remaining three studies no blinding was undertaken (Gerber 1990; Little 1997; Little 2001).
Incomplete outcome data
Only one trial (El‐Daher 1991) had incomplete outcome data and did not adequately address it.
Selective reporting
Only one trial (Gerber 1990) reported collecting important information (in this case related to clinical outcomes) without fully reporting it.
Other potential sources of bias
No other sources of bias were identified.
Effects of interventions
For most outcomes meta‐analyses were not possible: some studies did not describe their data in sufficient detail and others were too heterogeneous to safely allow meta‐analysis. Therefore, few forest plots have more than one study. Table 1 summarises the statistical outcomes available for each study. However, for patient satisfaction, data were available and homogenous, so pooled results using a random‐effects model are presented. For sore throat, two trials with minimal heterogeneity have been pooled for the outcome of fever severity on day three.
| Study | Outcome | Favours | Result (with 95% CI) | Notes |
| Sore throat | ||||
| Outcomes in this table are the result of a comparison between delayed and immediate antibiotics unless otherwise specified | ||||
| Pichichero 1987 | Fever severity on day 3 | SMD 0.40 (0.05 to 0.75) | ||
| Malaise severity on day 3 | No difference | MD 0.20 (‐0.11 to 0.51) | ||
| Pain severity on day 3 | No difference | MD 0.30 (‐0.15 to 0.75) | ||
| Compliance | No difference | 100% in both groups | ||
| Gerber 1990 | Recurrence rate | No difference | ||
| Compliance | Delayed antibiotics | 88% in immediate group and 93% in the delayed group | ||
| El Daher 1991 | Vomiting | Immediate antibiotics | OR 25.00 (8.65 to 72.25) | |
| Pain on day 3 | Immediate antibiotics | OR 14.51 (7.14 to 29.50) | ||
| Malaise on day 3 | Immediate antibiotics | OR 16.49 (5.68 to 47.83) | ||
| Fever severity on day 3 | Immediate antibiotics | SMD 0.58 (0.31 to 0.84) | ||
| Compliance | ||||
| Little 1997 | Vomiting | No difference | OR 1.00 (0.49 to 2.05) | |
| Diarrhoea | No difference | OR 1.23 (0.67 to 2.28) | ||
| Rash | No difference | OR 0.93 (0.41 to 2.11) | ||
| Stomach ache | No difference | OR 0.82 (0.53 to 1.27) | ||
| Fever (> 37.0 ºC) | Immediate antibiotics | |||
| Sore throat | No difference | |||
| Cough | No difference | |||
| Malaise | No difference | |||
| Analgesic use | No difference | |||
| Time off work | No difference | |||
| AOM | ||||
| Little 2001 | Diarrhoea | Delayed antibiotics | OR 0.45 (0.22 to 0.91) | |
| Rash | No difference | OR 1.21 (0.41 to 2.58) | ||
| Patients with pain on day 3 | No difference | OR 1.93 (0.96 to 3.88) | ||
| Patients with pain on day 7 | No difference | OR 6.55 (0.33 to 128.35) | ||
| Patients with malaise on day 3 | Immediate antibiotics | OR 2.62 (1.44 to 4.76) | ||
| Malaise severity day 3 | Immediate antibiotics | MD 0.43 (0.11 to 0.75) | ||
| Malaise severity on day 7 | No difference | MD 0.01 (‐0.11 to 0.13) | ||
| Pain severity on day 3 | Immediate antibiotics | MD 0.75 (0.26 to 1.24) | ||
| Pain severity on day 7 | No difference | MD 0.12 (‐0.04 to 0.28) | ||
| Paracetamol consumption | Immediate antibiotics | MD 0.59 (0.25 to 0.93) | ||
| Last day of crying | Immediate antibiotics | MD 0.69 (0.31 to 1.07) | ||
| Little 2001 (published in Little 2006) | Episodes of earache in the 3 months since randomisation | No difference | OR 0.89 (0.48 to 1.65) | |
| Episodes of earache over 1 year | No difference | OR 1.03 (0.6 to 1.78) | ||
| Spiro 2006 | Fever day 4 to 6 | No difference | OR 0.88 (0.53 to 1.47) | |
| Vomiting | No difference | OR 1.01 (0.47 to 2.16) | ||
| Diarrhoea | Delayed antibiotics | OR 0.27 (0.13 to 0.58) | ||
| Chao 2008 | Fever day 3 | No difference | OR 1.45 (0.50 to 4.24) | |
| Pain day 3 | No difference | OR 0.64 (0.29 to 1.38) | ||
| Cough | ||||
| Dowell 2001 | Clinical outcomes | No difference | ||
| Little 2005a | All clinical outcomes | No difference | ||
| Common cold | ||||
| Arroll 2002 | Patients with fever on day 3 | No difference | OR 0.75 (0.22 to 2.6) | |
| Patients with fever on day 7 | No difference | OR 0.68 (0.15 to 3.17) | ||
| Patients with diarrhoea | No difference | OR 0.79 (0.53 to 1.19) | ||
| Patients with pain on day 3 | No difference | OR 1.47 (0.58 to 3.77) | ||
| Patients with pain on day 7 | No difference | OR 0.31 (0.03 to 3.03) | ||
| Patients with cough on day 3 | No difference | OR 0.90 (0.37 to 2.18) | ||
| Patients with cough on day 7 | No difference | OR 0.72 (0.32 to 1.58) | ||
| Fever severity day 3 | No difference | MD ‐0.24 (‐0.48 to 0.00) | ||
| Fever severity on day 7 | Delayed antibiotics | MD ‐0.32 (‐0.57 to ‐0.07) | Mean temperature for both < 37 ºC | |
| Antibiotic use | ||||
| Sore throat | ||||
| Little 1997 | Antibiotic use (none versus delayed) | No antibiotics (least antibiotic use) | OR 3.18 (1.85 to 5.46) | |
| Antibiotic use (delayed versus immediate) | Delayed antibiotics (less than immediate) | OR 0.00 (0.00 to 0.02) | ||
| AOM | ||||
| Little 2001 | Antibiotic use | Delayed antibiotics | OR 0.05 (0.02 to 0.08) | |
| Spiro 2006 | Antibiotic use | Delayed antibiotics | OR 0.09 (0.05 to 0.17) | |
| Chao 2008 | Antibiotic use | No antibiotics | OR 4.06 (2.01 to 8.19) | |
| Cough | ||||
| Dowell 2001 | Antibiotic use | Delayed antibiotics | OR 0.00 (0.00 to 0.07) | |
| Little 2005 | Antibiotic use (none versus delayed) | No difference | OR 1.30 (0.77 to 2.21) | |
| Little 2005 | Antibiotic use (delayed versus immediate) | Delayed antibiotics | OR 0.01 (0.00 to 0.02) | |
| Common cold | ||||
| Arroll 2002 | Antibiotic use | Delayed antibiotics | OR 0.20 (0.09 to 0.44) | |
| Patient satisfaction | ||||
| Sore throat | ||||
| Little 1997 | Patient satisfaction (none versus delayed) | No difference | OR 1.49 (0.70 to 3.19) | |
| Patient satisfaction (delayed versus immediate) | No difference | OR 0.61 (0.25 to 1.49) | ||
| AOM | ||||
| Little 2001 | Patient satisfaction (immediate versus delayed) | Immediate antibiotics | OR 0.32 (0.16 to 0.65) | |
| Chao 2008 | Patient satisfaction (delayed versus none) | No difference | OR 2.00 (0.65 to 6.18) | |
| Cough | ||||
| Dowell 2001 | Patient satisfaction | Immediate antibiotics | OR 0.19 (0.01 to 4.01) | |
| Little 2005 | Patient satisfaction (none versus delayed) | No difference | OR 1.34 (0.84 to 2.14) | |
| Little 2005 | Patient satisfaction (delayed versus immediate) | Immediate antibiotics | OR 0.58 (0.34 to 0.97) | |
| Common cold | ||||
| Arroll 2002 | Patient satisfaction | No difference | OR 1.47 (0.32 to 6.85) | |
| Secondary outcomes | ||||
| Sore throat | ||||
| Pichichero 1987 | Re‐consultation rate | No difference | OR 0.83 (0.30 to 2.29) | |
| AOM | ||||
| Spiro 2006 | Re‐consultation rate | No difference | OR 1.21 (0.52 to 2.81) | |
| LRTI | ||||
| Little 2005a (published in Moore 2009) | Re‐consultation in the year following the index consultation (excluding the first month after consultation) | No difference | IRR 0.81 (0.51 to 1.28) |
AOM: acute otitis media
CI: confidence interval
IRR: incident rate ratio
LRTI: lower respiratory tract infection
MD: mean difference
OR: odds ratio
SMD: standardised mean difference
Results are outlined under the headings of clinical outcomes, antibiotic use and patient satisfaction in order to reflect the important clinical considerations relevant to the strategy of prescribing delayed antibiotics. The strategy of delayed antibiotics is compared to the strategies of immediate antibiotics and no antibiotics, depending on the available data. For each illness category there is at least one RCT (for example, common cold) with a maximum of four (sore throat). Given the low numbers of trials for each illness category, conclusions for illness categories need to be treated with caution. The multiplicity of comparisons for the clinical outcomes stratified by illness, makes a type I error more likely. However, clinical outcomes are stratified by illness owing to known differences in the effect of antibiotics on different types of respiratory infections. Antibiotic use and patient satisfaction data have been presented without this stratification as they are less likely to be affected by illness type and to show more clearly the effect of prescribing strategies.
Clinical outcomes
See Table 1.
Sore throat
Four included studies examined sore throat (El‐Daher 1991; Gerber 1990; Little 1997; Pichichero 1987).
Delayed antibiotics versus immediate antibiotics
Pain was reduced on day three in the immediate antibiotic group compared to delayed antibiotics in one study (Analysis 1.1). Pain was not significantly different between delayed and immediate antibiotic groups in three studies (Gerber 1990; Little 1997; Pichichero 1987).
Malaise was reduced on day three in the immediate antibiotic group compared to delayed antibiotics in one study (Analysis 2.1) and no difference was found in the other study measuring this outcome (Analysis 2.2).
Fever severity on day three was reduced with immediate antibiotics compared to delayed antibiotics in two studies (pooled results odds ratio (OR) 0.53; 95% confidence interval (CI) 0.31 to 0.74) (Analysis 3.1). The number of days with fever was reduced in the immediate antibiotic group of Little 1997 and there was no difference found in the fourth study (Gerber 1990).
Delayed antibiotics versus no antibiotics
One study examining sore throat compared the prescribing strategy of delayed antibiotics with no antibiotics (Little 1997). This study found no difference in any clinical outcome between these two prescribing strategies.
Complications
Data on complications of sore throat such as rheumatic fever, post‐streptococcal glomerulonephritis and peri‐tonsillar abscess were not reported in any of the four studies looking at sore throat for the three prescribing strategies of immediate, delayed and no antibiotics.
Acute otitis media (AOM)
Three included trials examined AOM (Chao 2008; Little 2001; Spiro 2006).
Delayed antibiotics versus immediate antibiotics
Pain and malaise were greater using delayed antibiotics compared to immediate antibiotics in one study measuring these outcomes on day three (Analysis 4.1). One study examined clinical outcomes on days four to six and found no difference (Analysis 5.1).
Other proxies for malaise outcomes reported by Little 2001 included last day of crying, which favoured the immediate antibiotic group by approximately 16 hours in children with AOM (0.69 days; 95% CI 0.31 to 0.07). In the same study, just over half a spoon of paracetamol a day less was used in the immediate antibiotic group (0.59; 95% CI 0.25 to 0.93). On day one there were no significant differences between immediate and delayed antibiotic groups in symptom outcome measures and by day seven there was no difference between immediate and delayed antibiotic groups (Little 2001).
Further analysis of earache from one trial (Little 2001) found the delayed prescribing strategy did not significantly increase risk of earache at three months (OR 0.89; 95% CI 0.48 to 1.65) or one year (OR 1.03; 95% CI 0.60 to 1.78) (Little 2006).
Delayed antibiotics versus no antibiotics
Only one study compared delayed antibiotics with no antibiotics with no significant difference for pain or fever on day three (Analysis 8.1; Analysis 9.1). This trial also advised participants in the no antibiotic arm to re‐present in two to three days if symptoms did not resolve.
Complications
Data on complications of AOM such as mastoiditis, rheumatic fever and post‐streptococcal glomerulonephritis were not reported in any of the three studies looking at AOM for the prescribing strategies of immediate and delayed antibiotics. However, Spiro 2006 and Chao 2008 noted that there were no serious adverse events for participants in the study.
Bronchitis (cough)
Two studies examined the prescribing strategies of immediate versus delayed antibiotics for the clinical presentation of cough (Dowell 2001; Little 2005a) and neither found any difference in clinical outcomes, including fever and cough.
Complications
Little 2005a also looked at delayed antibiotics versus no antibiotics and found no difference in clinical outcomes between the two prescribing strategies. One patient in the no antibiotic group (out of 273) of this study developed pneumonia and recovered with antibiotics in hospital.
Dowell 2001 did not report on complications in the immediate and delayed antibiotic groups.
Common cold
One study looked at immediate antibiotics versus delayed antibiotics (Arroll 2002a) and found no difference between the two prescribing strategies for the clinical outcomes of fever, cough, pain and malaise (Analysis 10.1; Analysis 11.4; Analysis 12.1).
Antibiotic use
See Table 1.
Delayed antibiotics
The three studies included in this systematic review published prior to 1992 examined the concern that immediate antibiotics for streptococcal pharyngitis might impair the body's immune response and predispose the patient to a relapse of pharyngitis. Compliance in both immediate and delayed antibiotic groups was close to 100%. Six of the included studies published after 1992 were conducted to evaluate the role of delayed antibiotics as a way of reducing antibiotic use for respiratory infections compared to immediate antibiotics. All six studies found that antibiotic use was significantly reduced in the delayed antibiotic group compared to the immediate antibiotic group. There were significant differences in the way antibiotics were delayed which may have resulted in the marked heterogeneity of this result. Of the seven studies published after 1991, four had the delayed script kept at reception to be picked up (Dowell 2001; Little 1997; Little 2001; Little 2005a) and in three, the script was issued to patients with instructions to delay (Arroll 2002a; Chao 2008; Spiro 2006). For the delayed arms of the four studies where the script was left at reception, antibiotics were used in 28% of cases (173/618) compared with antibiotics being used in 40% of cases (122/305) where antibiotics were issued to patients with instructions to delay.
Overall, the seven trials post 1992 providing a delayed antibiotic arm found 295 prescriptions filled out of 923 participants (32.0%).
Immediate antibiotics
Six trials published post 1992 provided immediate antibiotic arms examining this outcome resulting in 790 participants filling prescriptions out of 847 participants (93.3%) (Analysis 13.1).
No antibiotics
Three studies compared delayed antibiotics with no antibiotics. Little 1997 found that there was less antibiotic use with the no antibiotic strategy compared to delayed antibiotics. Little 2005a found no differences. Chao 2008 is the most recent and only study conducted comparing delayed antibiotics only with no antibiotics and also found that fewer antibiotics were prescribed in the no antibiotic group (Analysis 15.1).
Overall, 65 patients filled scripts out of 466 participants (13.9%).
Patient satisfaction
See Table 1.
Delayed antibiotics versus immediate antibiotics
Patient satisfaction has been measured in five out of seven studies evaluating the prescribing strategy of delayed antibiotics since 1992 (Arroll 2002a; Dowell 2001; Little 1997; Little 2001; Little 2005a). Two of these studies indicated that study participants were more satisfied with the strategy of immediate antibiotics than delayed antibiotics (Little 2001; Little 2005a). There was no difference found in the other three studies (Arroll 2002a; Dowell 2001; Little 1997). The pooled result for this outcome with these five studies was an odds ratio (OR) of 0.52 (95% CI 0.35 to 0.76) favouring immediate antibiotics. Fixed‐ and random‐effects analyses gave similar results. A breakdown of the trials by blinding gave two trials (Dowell 2001; Little 2005a) which blinded the outcome assessor and one blinded the patient and the doctor (Arroll 2002a) to give an odds ratio for all three studies of 0.62 (95% CI 0.38 to 1.01). The two completely unblinded trials (Little 1997; Little 2001) give an OR of 0.42 (95% CI 0.22 to 0.78). Overall 92% of the participants in the immediate antibiotics arms were satisfied versus 87% in the delayed arms.
Delayed antibiotics versus no antibiotics
Three studies examined patient satisfaction comparing the prescribing strategies of delayed antibiotics and no antibiotics (Chao 2008; Little 1997; Little 2005a). While there was no difference in patient satisfaction for any of these studies, the pooled result for these three studies was an odds ratio of 1.44 (95% CI 0.99 to 2.10) showing no statistically significant difference. Fixed‐ and random‐effects analyses gave similar results. A breakdown of the trials by blinding gave two trials (Chao 2008; Little 2005a) which blinded the outcome assessor to give an odds ratio for these two trials of 1.42 (95% CI 0.92 to 2.19). The one completely unblinded trial (Little 1997) gave an odds ratio of 1.49 (95% CI 0.70 to 3.19). In the delayed antibiotic arm 413 of the participants were satisfied or very satisfied out of 473 participants (87.3%) compared to 387 out of 465 participants in the no antibiotics group (83.2%).
Adverse effects of antibiotics
Adverse effects are considered under different clinical headings owing to differences in antibiotic prescribing recommendations for each condition. This is likely to have contributed to the heterogeneity evident in the forest plots for these outcomes preventing pooling of results. Adverse results are presented graphically for delayed versus immediate antibiotics (Analysis 17.1; Analysis 17.2; Analysis 17.3; Analysis 18.4) and delayed versus no antibiotics (Analysis 18.1; Analysis 18.2; Analysis 18.3; Analysis 18.4).
Sore throat
Delayed antibiotics versus immediate antibiotics
One study (Little 1997) found no difference for diarrhoea, vomiting, rash and stomach ache. El‐Daher 1991 found more vomiting in the delayed group compared to the immediate antibiotics.
Delayed antibiotics versus no antibiotics
One study (Little 1997) found no difference for diarrhoea, vomiting, rash and stomach ache.
AOM
Delayed antibiotics versus immediate antibiotics
Little 2001 and Spiro 2006 found reduced diarrhoea in the delayed antibiotic group. Spiro 2006 did not find any difference between delayed and immediate antibiotics for vomiting and Little 2001 found no difference for the outcome of rash.
Delayed antibiotics versus no antibiotics
There were no adverse events in either group reported by Chao 2008.
Bronchitis (cough)
Delayed antibiotics versus immediate antibiotics
Little 2005a found no difference for adverse effects.
Delayed antibiotics versus no antibiotics
Little 2005a found no difference for adverse effects.
Common cold
Delayed antibiotics versus immediate antibiotics
There was no significant difference between the groups for diarrhoea, a potential adverse effect of antibiotics (Arroll 2002a).
Re‐consultation rates
Re‐consultation rates were the same between delayed and immediate antibiotic groups in two studies (Analysis 19.1). Subsequent consultation rates in the 12 months (excluding the first month) were also the same between delayed and immediate antibiotic groups in one study (Little 2001). Participants with sore throat in one study were more likely to intend to consult again if they received immediate antibiotics compared to delayed antibiotics (Little 1997).
Discussion
Summary of main results
Small differences were found between prescribing strategies for clinical outcomes with immediate antibiotics most likely to show benefit over delayed antibiotics in participants with sore throat and acute otitis media (AOM). All strategies appear to have similar safety with no advantage found for delayed antibiotics over no antibiotics for disease complications. Delay and no antibiotic strategies dramatically reduce the use of antibiotics for acute respiratory tract infections (ARTIs) compared to immediate antibiotics. The least antibiotic use was in the no antibiotic group followed by delay and then immediate. The number needed to treat to prevent one antibiotic prescription using the delay strategy is 1.6 compared to immediate antibiotics. The number needed to treat to prevent one antibiotic prescription using a no antibiotic strategy compared to delay is 5.6. Patient satisfaction was highest in the immediate antibiotic group with 92.2% being satisfied or very satisfied with the consultation. The delay and no groups had similar quite high satisfaction rates at 87.3% and 83.2%, respectively. These high satisfaction results may reflect patient involvement in studies where their treating physicians are more thorough in their explanations than usual (Hawthorne effect) (French 1950; Levitt 2011). Results for satisfaction may not be as high in routine general practice.
Overall completeness and applicability of evidence
Studies comparing delayed and immediate antibiotics have been performed for two different motives. The studies of Pichichero 1987, Gerber 1990 and El‐Daher 1991 were concerned that immediate antibiotics for streptococcal pharyngitis might impair the body's immune response and predispose the patient to a relapse of pharyngitis. These studies are useful for determining the effect of delayed versus immediate antibiotics on the clinical course of suspected streptococcal pharyngitis. Six of the remaining studies were conducted to determine if the strategy of delayed antibiotics reduces the number of prescriptions filled for upper ARTIs (Arroll 2002a; Dowell 2001; Little 1997; Little 2001) while maintaining patient safety and satisfaction. The most recent study may indicate evolution in prescribing habits as it was the first to drop the immediate antibiotic arm (Chao 2008).
Useful data were collected for many symptom outcomes in all studies but were not always reported in a way that could be analysed. This problem was partially overcome by obtaining raw data from some trial authors. The seven studies conducted after 1992 all reported useful data on antibiotic use and six on patient satisfaction.
There are only three trials comparing delayed antibiotics with no antibiotics.
Quality of the evidence
All but one trial (El‐Daher 1991) were adequately randomised and accounted for incomplete data. El‐Daher 1991 did find large differences for clinical outcomes for sore throat in favour of immediate antibiotics compared to delayed antibiotics.
This intervention does not lend itself to blinding. However, three trials attempted to blind patients and doctors (Arroll 2002a; El‐Daher 1991; Pichichero 1987). For four studies (Chao 2008; Dowell 2001; Little 2005a; Spiro 2006), the outcomes assessor was blinded but not the patient nor the care giver.
Otherwise, studies were well reported and appeared to be high quality.
Potential biases in the review process
Heterogeneity of randomised controlled trials (RCTs) is one limitation of this review. Heterogeneity may have resulted from variable clinical presentations, differences in delay method, differences in antibiotic use and quality of included studies. Potential for type I error is another limitation of this review given the large number of reported outcome results. For example, multiple outcome measures are reported for the clinical outcomes comparing delayed and immediate antibiotic groups.
Agreements and disagreements with other studies or reviews
Findings for certain clinical outcomes in our review might have been anticipated. Systematic reviews on antibiotics for sore throat and AOM found that their time of greatest benefit for symptoms is apparent at days three or four after treatment has started (Spinks 2011; Venekamp 2013). Thus delaying antibiotics by 48 hours or more would overshoot this zenith. Nor is it surprising that we found more adverse reactions to antibiotics from immediate antibiotics in line with known adverse events from comparison RCTs with no antibiotics.
The greatest difference in clinical outcomes was found in the only trial of delayed antibiotics conducted in a low socio‐economic environment, favouring immediate antibiotics over delay (El‐Daher 1991). This trial was also the least methodologically sound but it highlighted that concerns expressed about delayed antibiotics for children, the elderly (Datta 2008) and those with language or cultural difficulties (Johnson 2007) may also need to be extended to low socio‐economic populations.
A parallel RCT of patients with acute infective conjunctivitis similarly reported shortest symptom duration with immediate, followed by delayed and then no antibiotics (the last resulting in least antibiotic use). There was no difference between the groups for patient satisfaction (Everitt 2006).
A recent randomised controlled trial published in 2010 (Worrall 2010) comparing delayed prescriptions dated either the day of the office visit or two days later, but not comparing with either immediate or no antibiotics, demonstrated no significant difference between the two groups in terms of antibiotic use.
RCTs comparing delayed with no antibiotics (concluding that they were both equally acceptable alternatives to immediate antibiotics as a means of reducing antibiotic prescriptions) (Little 2001; Little 2005a) led to recommending delayed instead of no antibiotics to address concerns about risks of complications (Little 2005b). Doctors worried about the risk of serious infective complications consequent to adopting a no antibiotic rather than delayed strategy might take comfort from a UK observational study showing that reduced prescribing resulted in no increase in admissions to hospital for peri‐tonsillar abscess or rheumatic fever (Sharland 2005), although mastoiditis might be a risk at the rate of 2500 children needing to be treated with antibiotics to prevent one case (Van Zuijlen 2001). Thirty‐five per cent of parents in the AOM trials (Chao 2008; Little 2001; Spiro 2006) used their delayed script suggesting that the number of delayed scripts required to prevent one case of mastoiditis would be significantly higher than 2500. Doctors often find it difficult to identify patients at risk of serious complications from respiratory infections (Kumar 2003). Patients probably perform even less well, despite their self confidence in making this decision if given a delayed antibiotic prescription. This concern is supported by empirical data: respiratory disease severity does not correlate with patients' immediate preference for an antibiotic prescription (Macfarlane 1997). This review did not find any significant difference for complication rates between prescribing strategies.
There is little controversy within published guidelines that immediate antibiotics are recommended for patients who appear to be seriously unwell, fit multiple criteria indicating bacterial tonsillitis, are under six months of age with AOM, have bilateral AOM or have AOM with otorrhoea (Tan 2008). American guidelines also recommend immediate antibiotics for children under two with definite AOM (OMTG 2004). It seems then that for the majority of respiratory infections that do not meet these criteria, clinicians have the option of delayed or no antibiotics. It seems clear that no antibiotics will result in least antibiotic use and therefore less antibiotic resistance. Concerns about patient and doctor satisfaction with no antibiotics appear to be driving the use of a delayed strategy. Some doctors use the delay strategy to reduce antibiotic use, empower patients and save the patient time and money without jeopardising the doctor‐patient relationship (Arroll 2002b). A qualitative study conducted in 2002 (Arroll 2002b) found that while some patients appreciated the option of controlling the decision as to whether and when to take antibiotics, others expected "the physician to decide". Concern was expressed by one physician that patients might view delayed prescribing as physician incompetence, substantiated by comments from some patients. Shared decision‐making (Butler 2001; Legare 2007) and education campaigns for doctors (Sung 2006) have been proposed as ways of helping doctors and patients avoid unnecessary antibiotic use. One suggestion is that delayed antibiotics may in time become redundant as doctors and their patients gain more reassurance in the safety of not using antibiotics (Arroll 2003b).
Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies.
Methodological quality summary: review authors' judgements about each methodological quality item for each included study.
Comparison 1 Sore throat ‐ pain; delayed versus immediate antibiotics, Outcome 1 Pain on day 3.
Comparison 1 Sore throat ‐ pain; delayed versus immediate antibiotics, Outcome 2 Pain severity on day 3.
Comparison 2 Sore throat ‐ malaise; delayed versus immediate antibiotics, Outcome 1 Malaise on day 3.
Comparison 2 Sore throat ‐ malaise; delayed versus immediate antibiotics, Outcome 2 Malaise severity.
Comparison 3 Sore throat ‐ fever; delayed versus immediate antibiotics, Outcome 1 Fever severity on day 3.
Comparison 3 Sore throat ‐ fever; delayed versus immediate antibiotics, Outcome 2 Fever severity on day 1.
Comparison 4 AOM ‐ pain; delayed versus immediate antibiotics, Outcome 1 Pain on day 3.
Comparison 4 AOM ‐ pain; delayed versus immediate antibiotics, Outcome 2 Pain on days 4 to 6.
Comparison 4 AOM ‐ pain; delayed versus immediate antibiotics, Outcome 3 Pain on day 7.
Comparison 4 AOM ‐ pain; delayed versus immediate antibiotics, Outcome 4 Pain severity on day 3.
Comparison 4 AOM ‐ pain; delayed versus immediate antibiotics, Outcome 5 Pain severity on day 7.
Comparison 5 AOM ‐ malaise; delayed versus immediate antibiotics, Outcome 1 Malaise on day 3.
Comparison 5 AOM ‐ malaise; delayed versus immediate antibiotics, Outcome 2 Malaise severity on day 3.
Comparison 5 AOM ‐ malaise; delayed versus immediate antibiotics, Outcome 3 Malaise severity on day 7.
Comparison 6 Supplementary medicine consumption; delayed versus immediate antibiotics, Outcome 1 Spoons of paracetamol/day.
Comparison 6 Supplementary medicine consumption; delayed versus immediate antibiotics, Outcome 2 Use of paracetamol and ibuprofen.
Comparison 7 AOM ‐ fever; delayed versus immediate antibiotics, Outcome 1 Fever Days 4 to 6.
Comparison 8 AOM ‐ pain; delayed versus no antibiotics, Outcome 1 Otitis media pain on Day 3 delayed versus none.
Comparison 9 AOM ‐ fever; delayed versus no antibiotics, Outcome 1 Otitis media number of patients with fever on day 3 delayed versus none.
Comparison 10 Common cold ‐ pain; delayed versus immediate antibiotics, Outcome 1 Pain on day 3.
Comparison 10 Common cold ‐ pain; delayed versus immediate antibiotics, Outcome 2 Pain on day 7.
Comparison 11 Common cold ‐ fever; delayed versus immediate antibiotics, Outcome 1 Fever on day 3.
Comparison 11 Common cold ‐ fever; delayed versus immediate antibiotics, Outcome 2 Fever on day 7.
Comparison 11 Common cold ‐ fever; delayed versus immediate antibiotics, Outcome 3 Fever severity on day 1.
Comparison 11 Common cold ‐ fever; delayed versus immediate antibiotics, Outcome 4 Fever severity on day 3.
Comparison 11 Common cold ‐ fever; delayed versus immediate antibiotics, Outcome 5 Fever severity on day 7.
Comparison 12 Common cold ‐ cough; delayed versus immediate antibiotics, Outcome 1 Cough on day 3.
Comparison 12 Common cold ‐ cough; delayed versus immediate antibiotics, Outcome 2 Cough on day 7.
Comparison 13 Antibiotic use: delayed versus immediate antibiotics, Outcome 1 Antibiotic use: delayed versus immediate antibiotics.
Comparison 14 Antibiotic use: delayed versus no antibiotics, Outcome 1 Antibiotic use: delayed versus no antibiotics.
Comparison 15 Patient satisfaction: delayed versus immediate antibiotics, Outcome 1 Patient satisfaction: delayed versus immediate antibiotics.
Comparison 16 Patient satisfaction: delayed versus no antibiotics, Outcome 1 Patient satisfaction: delayed versus no antibiotics.
Comparison 17 Adverse events: delayed versus immediate antibiotics, Outcome 1 Vomiting.
Comparison 17 Adverse events: delayed versus immediate antibiotics, Outcome 2 Diarrhoea.
Comparison 17 Adverse events: delayed versus immediate antibiotics, Outcome 3 Rash.
Comparison 17 Adverse events: delayed versus immediate antibiotics, Outcome 4 Stomach ache.
Comparison 18 Adverse events: delayed versus no antibiotics, Outcome 1 Vomiting.
Comparison 18 Adverse events: delayed versus no antibiotics, Outcome 2 Diarrhoea.
Comparison 18 Adverse events: delayed versus no antibiotics, Outcome 3 Rash.
Comparison 18 Adverse events: delayed versus no antibiotics, Outcome 4 Stomach ache.
Comparison 19 Re‐consultation rate; delayed versus immediate antibiotics, Outcome 1 Re‐consultation rate.
Comparison 20 Subsequent consultation rates in the 12 months following the index consultation (excluding first month following consultation); delayed versus immediate antibiotics, Outcome 1 Re‐consultation in the 12 months following the index consultation (excluding the first month following the index consultation).
| Study | Outcome | Favours | Result (with 95% CI) | Notes |
| Sore throat | ||||
| Outcomes in this table are the result of a comparison between delayed and immediate antibiotics unless otherwise specified | ||||
| Pichichero 1987 | Fever severity on day 3 | SMD 0.40 (0.05 to 0.75) | ||
| Malaise severity on day 3 | No difference | MD 0.20 (‐0.11 to 0.51) | ||
| Pain severity on day 3 | No difference | MD 0.30 (‐0.15 to 0.75) | ||
| Compliance | No difference | 100% in both groups | ||
| Gerber 1990 | Recurrence rate | No difference | ||
| Compliance | Delayed antibiotics | 88% in immediate group and 93% in the delayed group | ||
| El Daher 1991 | Vomiting | Immediate antibiotics | OR 25.00 (8.65 to 72.25) | |
| Pain on day 3 | Immediate antibiotics | OR 14.51 (7.14 to 29.50) | ||
| Malaise on day 3 | Immediate antibiotics | OR 16.49 (5.68 to 47.83) | ||
| Fever severity on day 3 | Immediate antibiotics | SMD 0.58 (0.31 to 0.84) | ||
| Compliance | ||||
| Little 1997 | Vomiting | No difference | OR 1.00 (0.49 to 2.05) | |
| Diarrhoea | No difference | OR 1.23 (0.67 to 2.28) | ||
| Rash | No difference | OR 0.93 (0.41 to 2.11) | ||
| Stomach ache | No difference | OR 0.82 (0.53 to 1.27) | ||
| Fever (> 37.0 ºC) | Immediate antibiotics | |||
| Sore throat | No difference | |||
| Cough | No difference | |||
| Malaise | No difference | |||
| Analgesic use | No difference | |||
| Time off work | No difference | |||
| AOM | ||||
| Little 2001 | Diarrhoea | Delayed antibiotics | OR 0.45 (0.22 to 0.91) | |
| Rash | No difference | OR 1.21 (0.41 to 2.58) | ||
| Patients with pain on day 3 | No difference | OR 1.93 (0.96 to 3.88) | ||
| Patients with pain on day 7 | No difference | OR 6.55 (0.33 to 128.35) | ||
| Patients with malaise on day 3 | Immediate antibiotics | OR 2.62 (1.44 to 4.76) | ||
| Malaise severity day 3 | Immediate antibiotics | MD 0.43 (0.11 to 0.75) | ||
| Malaise severity on day 7 | No difference | MD 0.01 (‐0.11 to 0.13) | ||
| Pain severity on day 3 | Immediate antibiotics | MD 0.75 (0.26 to 1.24) | ||
| Pain severity on day 7 | No difference | MD 0.12 (‐0.04 to 0.28) | ||
| Paracetamol consumption | Immediate antibiotics | MD 0.59 (0.25 to 0.93) | ||
| Last day of crying | Immediate antibiotics | MD 0.69 (0.31 to 1.07) | ||
| Little 2001 (published in Little 2006) | Episodes of earache in the 3 months since randomisation | No difference | OR 0.89 (0.48 to 1.65) | |
| Episodes of earache over 1 year | No difference | OR 1.03 (0.6 to 1.78) | ||
| Spiro 2006 | Fever day 4 to 6 | No difference | OR 0.88 (0.53 to 1.47) | |
| Vomiting | No difference | OR 1.01 (0.47 to 2.16) | ||
| Diarrhoea | Delayed antibiotics | OR 0.27 (0.13 to 0.58) | ||
| Chao 2008 | Fever day 3 | No difference | OR 1.45 (0.50 to 4.24) | |
| Pain day 3 | No difference | OR 0.64 (0.29 to 1.38) | ||
| Cough | ||||
| Dowell 2001 | Clinical outcomes | No difference | ||
| Little 2005a | All clinical outcomes | No difference | ||
| Common cold | ||||
| Arroll 2002 | Patients with fever on day 3 | No difference | OR 0.75 (0.22 to 2.6) | |
| Patients with fever on day 7 | No difference | OR 0.68 (0.15 to 3.17) | ||
| Patients with diarrhoea | No difference | OR 0.79 (0.53 to 1.19) | ||
| Patients with pain on day 3 | No difference | OR 1.47 (0.58 to 3.77) | ||
| Patients with pain on day 7 | No difference | OR 0.31 (0.03 to 3.03) | ||
| Patients with cough on day 3 | No difference | OR 0.90 (0.37 to 2.18) | ||
| Patients with cough on day 7 | No difference | OR 0.72 (0.32 to 1.58) | ||
| Fever severity day 3 | No difference | MD ‐0.24 (‐0.48 to 0.00) | ||
| Fever severity on day 7 | Delayed antibiotics | MD ‐0.32 (‐0.57 to ‐0.07) | Mean temperature for both < 37 ºC | |
| Antibiotic use | ||||
| Sore throat | ||||
| Little 1997 | Antibiotic use (none versus delayed) | No antibiotics (least antibiotic use) | OR 3.18 (1.85 to 5.46) | |
| Antibiotic use (delayed versus immediate) | Delayed antibiotics (less than immediate) | OR 0.00 (0.00 to 0.02) | ||
| AOM | ||||
| Little 2001 | Antibiotic use | Delayed antibiotics | OR 0.05 (0.02 to 0.08) | |
| Spiro 2006 | Antibiotic use | Delayed antibiotics | OR 0.09 (0.05 to 0.17) | |
| Chao 2008 | Antibiotic use | No antibiotics | OR 4.06 (2.01 to 8.19) | |
| Cough | ||||
| Dowell 2001 | Antibiotic use | Delayed antibiotics | OR 0.00 (0.00 to 0.07) | |
| Little 2005 | Antibiotic use (none versus delayed) | No difference | OR 1.30 (0.77 to 2.21) | |
| Little 2005 | Antibiotic use (delayed versus immediate) | Delayed antibiotics | OR 0.01 (0.00 to 0.02) | |
| Common cold | ||||
| Arroll 2002 | Antibiotic use | Delayed antibiotics | OR 0.20 (0.09 to 0.44) | |
| Patient satisfaction | ||||
| Sore throat | ||||
| Little 1997 | Patient satisfaction (none versus delayed) | No difference | OR 1.49 (0.70 to 3.19) | |
| Patient satisfaction (delayed versus immediate) | No difference | OR 0.61 (0.25 to 1.49) | ||
| AOM | ||||
| Little 2001 | Patient satisfaction (immediate versus delayed) | Immediate antibiotics | OR 0.32 (0.16 to 0.65) | |
| Chao 2008 | Patient satisfaction (delayed versus none) | No difference | OR 2.00 (0.65 to 6.18) | |
| Cough | ||||
| Dowell 2001 | Patient satisfaction | Immediate antibiotics | OR 0.19 (0.01 to 4.01) | |
| Little 2005 | Patient satisfaction (none versus delayed) | No difference | OR 1.34 (0.84 to 2.14) | |
| Little 2005 | Patient satisfaction (delayed versus immediate) | Immediate antibiotics | OR 0.58 (0.34 to 0.97) | |
| Common cold | ||||
| Arroll 2002 | Patient satisfaction | No difference | OR 1.47 (0.32 to 6.85) | |
| Secondary outcomes | ||||
| Sore throat | ||||
| Pichichero 1987 | Re‐consultation rate | No difference | OR 0.83 (0.30 to 2.29) | |
| AOM | ||||
| Spiro 2006 | Re‐consultation rate | No difference | OR 1.21 (0.52 to 2.81) | |
| LRTI | ||||
| Little 2005a (published in Moore 2009) | Re‐consultation in the year following the index consultation (excluding the first month after consultation) | No difference | IRR 0.81 (0.51 to 1.28) | |
| AOM: acute otitis media | ||||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Pain on day 3 Show forest plot | 1 | Odds Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 2 Pain severity on day 3 Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Malaise on day 3 Show forest plot | 1 | Odds Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 2 Malaise severity Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Fever severity on day 3 Show forest plot | 2 | 343 | Std. Mean Difference (IV, Fixed, 95% CI) | 0.53 [0.31, 0.74] |
| 2 Fever severity on day 1 Show forest plot | 2 | 343 | Std. Mean Difference (IV, Fixed, 95% CI) | ‐0.07 [‐0.29, 0.14] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Pain on day 3 Show forest plot | 1 | Odds Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 2 Pain on days 4 to 6 Show forest plot | 1 | Odds Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 3 Pain on day 7 Show forest plot | 1 | Odds Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 4 Pain severity on day 3 Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 5 Pain severity on day 7 Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Malaise on day 3 Show forest plot | 1 | Odds Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 2 Malaise severity on day 3 Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 3 Malaise severity on day 7 Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Spoons of paracetamol/day Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 2 Use of paracetamol and ibuprofen Show forest plot | 1 | Odds Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Fever Days 4 to 6 Show forest plot | 1 | Odds Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Otitis media pain on Day 3 delayed versus none Show forest plot | 1 | Odds Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Otitis media number of patients with fever on day 3 delayed versus none Show forest plot | 1 | Odds Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Pain on day 3 Show forest plot | 1 | Odds Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 2 Pain on day 7 Show forest plot | 1 | Odds Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Fever on day 3 Show forest plot | 1 | Odds Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 2 Fever on day 7 Show forest plot | 1 | Odds Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 3 Fever severity on day 1 Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 4 Fever severity on day 3 Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 5 Fever severity on day 7 Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Cough on day 3 Show forest plot | 1 | Odds Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 2 Cough on day 7 Show forest plot | 1 | Odds Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Antibiotic use: delayed versus immediate antibiotics Show forest plot | 6 | Odds Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 1.1 Antibiotic use: delayed (prescription at time of visit) versus immediate antibiotics | 2 | Odds Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 1.2 Antibiotic use: delayed (return for prescription) versus immediate antibiotics | 4 | Odds Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Antibiotic use: delayed versus no antibiotics Show forest plot | 3 | Odds Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 1.1 Antibiotic use: delayed (prescription at time of visit) versus no antibiotics | 1 | Odds Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 1.2 Antibiotic use: delayed (return for prescription) versus no antibiotics | 2 | Odds Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Patient satisfaction: delayed versus immediate antibiotics Show forest plot | 5 | 1334 | Odds Ratio (M‐H, Random, 95% CI) | 0.52 [0.35, 0.76] |
| 1.1 Patient satisfaction: delayed (prescription at time of consult) versus immediate antibiotics | 1 | 129 | Odds Ratio (M‐H, Random, 95% CI) | 1.47 [0.32, 6.85] |
| 1.2 Patient satisfaction: delayed (return for prescription) versus immediate antibiotics | 4 | 1205 | Odds Ratio (M‐H, Random, 95% CI) | 0.48 [0.33, 0.71] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Patient satisfaction: delayed versus no antibiotics Show forest plot | 3 | 938 | Odds Ratio (M‐H, Random, 95% CI) | 1.44 [0.99, 2.10] |
| 1.1 Patient satisfaction: delayed (prescription provided at visit) versus no antibiotics | 1 | 206 | Odds Ratio (M‐H, Random, 95% CI) | 2.00 [0.65, 6.18] |
| 1.2 Patient satisfaction: delayed (return for prescription) versus no antibiotics | 2 | 732 | Odds Ratio (M‐H, Random, 95% CI) | 1.38 [0.93, 2.06] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Vomiting Show forest plot | 3 | Odds Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 2 Diarrhoea Show forest plot | 4 | Odds Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 3 Rash Show forest plot | 2 | Odds Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 4 Stomach ache Show forest plot | 1 | Odds Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Vomiting Show forest plot | 1 | Odds Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 2 Diarrhoea Show forest plot | 2 | Odds Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 3 Rash Show forest plot | 1 | Odds Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 4 Stomach ache Show forest plot | 1 | Odds Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Re‐consultation rate Show forest plot | 2 | 379 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.04 [0.55, 1.98] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Re‐consultation in the 12 months following the index consultation (excluding the first month following the index consultation) Show forest plot | 1 | Rate Ratio (Fixed, 95% CI) | Totals not selected | |
