Intervention Review

You have free access to this content

Once or twice daily versus three times daily amoxicillin with or without clavulanate for the treatment of acute otitis media

  1. Sanguansak Thanaviratananich1,*,
  2. Malinee Laopaiboon2,
  3. Patravoot Vatanasapt1

Editorial Group: Cochrane Acute Respiratory Infections Group

Published Online: 13 DEC 2013

Assessed as up-to-date: 15 MAR 2013

DOI: 10.1002/14651858.CD004975.pub3


How to Cite

Thanaviratananich S, Laopaiboon M, Vatanasapt P. Once or twice daily versus three times daily amoxicillin with or without clavulanate for the treatment of acute otitis media. Cochrane Database of Systematic Reviews 2013, Issue 12. Art. No.: CD004975. DOI: 10.1002/14651858.CD004975.pub3.

Author Information

  1. 1

    Faculty of Medicine, Khon Kaen University, Department of Otorhinolaryngology, Khon Kaen, Thailand

  2. 2

    Khon Kaen University, Department of Biostatistics and Demography, Faculty of Public Health, Khon Kaen, Thailand

*Sanguansak Thanaviratananich, Department of Otorhinolaryngology, Faculty of Medicine, Khon Kaen University, 123 Friendship Road, Khon Kaen, 40002, Thailand. sthanaviratananich@gmail.com. sanguansak2011@gmail.com.

Publication History

  1. Publication Status: Edited (no change to conclusions), comment added to review
  2. Published Online: 13 DEC 2013

SEARCH

 
Characteristics of included studies [ordered by year of study]
Principi 1986

MethodsRandomised controlled study conducted in the outpatient ward of the Pediatric Department IV of the University of Milan between October 1984 and 1985

AOM was defined on clinical data (fever or otalgia or both), otoscopic finding of ear drum, and presence of ear effusion shown by tympanograms. Children with spontaneously perforated ear drums were also included only if the ear had been draining for no longer than 12 hours


Participants55 AOM children in each treatment group (total 110), aged 6 months to 12 years


Interventions10 days of amoxicillin 60 mg/kg/day 2 or 3 times daily


OutcomesPrimary outcome
1. Clinical cure rate at the end of therapy

- Clinical cure (normalisation of clinical or relief of acute signs and symptoms of AOM) assessed at day 15

Secondary outcome

1. Clinical cure rate during therapy (days 2 to 3), in terms of resolution of otalgia and resolution of fever: not reported
2. Clinical cure rate at post-treatment (1 to 3 months)
- Clinical cure at days 30, 60 and 90

3. AOM complications after completion of therapy: recurrent AOM

- Recurrent at days 30, 60 and 90

4. Adverse reactions to medication

- Diarrhoea which necessitated discontinuation of treatment

- Generalised rash

- Urticaria

5.Other outcomes

- Compliance: mentioned to be assessed but not reported


NotesSupported in part by a Farmitalia-Carlo Erba SpA Milano grant

Intention-to-treat principle analysis was not mentioned


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "randomly assigned"

Comment: method of randomisation was not described

Allocation concealment (selection bias)Unclear riskComment: allocation concealment methods were not mentioned

Blinding (performance bias and detection bias)
All outcomes
Unclear riskComment: no information

Incomplete outcome data (attrition bias)
All outcomes
Low riskComment: low rate of loss to follow-up

Selective reporting (reporting bias)Low riskComment: all important outcomes were reported

Other biasUnclear riskComment: no report of compliance rate

Murph 1993

MethodsDouble-blind, placebo-controlled study. A table of random numbers was used to generate a randomised sequence

AOM was defined as evidence on otoscopic assessment of an inflamed tympanic membrane and presence of middle ear effusion


Participants77 AOM children, aged 7 months to 12 years old, recruited from the Pediatric Child Health Clinic of the University of Iowa Hospitals and Clinics

10/77 (7.7%) children could not be evaluated because of failure to return for follow-up or because they withdrew from the study; 33 and 34 children in the once and 3 times daily groups, respectively, were left for the analysis


Interventions10 days of amoxicillin 40 mg/kg/day 1 versus 3 times daily


OutcomesPrimary outcome

1. Clinical cure rate at the end of therapy (days 7 to 14)

- Resolved AOM with or without MEE at days 10 to 14

Secondary outcome

1. Clinical cure rate during therapy (days 2 to 3), in terms of resolution of otalgia and resolution of fever

2. Clinical cure rate at post-treatment (1 to 3 months)

- not reported

3. AOM complications after completion of therapy: Recurrent AOM

- not reported

4. Adverse reactions to medication

- There were no differences in the 2 groups for the total number of complaints of diarrhoea (P = 0.30), vomiting (P = 0.66) or stomach pain (P = 0.23). No details were described

Other outcome
1. Compliance rate


NotesNo pharmaceutical industry support

Intention-to-treat principle analysis was not mentioned


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "A table of random numbers was used to assign children to one of two treatment groups"

Comment: probably done

Allocation concealment (selection bias)Unclear riskThe authors did not mention allocation concealment

Blinding (performance bias and detection bias)
All outcomes
Low riskQuote: "double-blind, placebo-controlled study"

Comment: probably done

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskQuote: "10 children (14.9%) could not be evaluated (failed to return for follow-up or withdrew from the study)"

Comment: no information on whether those lost to follow-up or who withdrew were in the once or thrice daily dose group

Selective reporting (reporting bias)High riskComments: clinical cure rate at follow-up (1 to 3 months) and AOM complications were not reported

Other biasLow risk

Hoberman 1997

MethodsMulticentre, randomised, non-placebo-controlled trial conducted at 4 university-affiliated hospitals and 20 private practices in the US and Canada between January and July 1994

AOM was defined as either presence of purulent otorrhoea for less than 24 hours or evidence of middle ear effusion in addition to at least 1 indicator of acute middle ear inflammation

Investigators were blinded to treatment assignments and participants, parents and guardians were asked not to discuss medications or duration of treatment with investigators


Participants575 children aged 2 months to 12 years were included (287 and 288 in the 2 and 3 times daily groups, respectively)


Interventions10 days of amoxicillin/clavulanate 40/10 mg/kg/day 2 times daily versus 45/6.4 mg/kg/day 3 times daily


OutcomesPrimary outcome

1. Clinical cure rate at the end of therapy (days 7 to 15)

- Clinical cure (completely/improved symptoms and signs of AOM at days 12 to 14

Secondary outcomes  

1. Clinical cure rate during therapy (days 2 to 3), in terms of resolution of otalgia and resolution of fever: not accounted

2. Clinical cure rate at post-treatment (1 to 3 months): clinical cure at days 31 to 38

3. AOM complications after completion of therapy: recurrent AOM

4. Adverse reactions to medication
- Adverse events: diaper rash: vomiting, diarrhoea

Other outcome

- Compliance rate


NotesSupported by SmithKline Beecham Pharmaceuticals


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "assigned randomly"

Comment: method of randomisation was not mentioned

Allocation concealment (selection bias)Unclear riskQuote: "Investigators were blinded to treatment assignments"

Comment: no information on the allocation concealment

Blinding (performance bias and detection bias)
All outcomes
Low riskQuote: "..parents and guardians were asked not to discuss medications or duration of treatment with investigators"

Comment: probably done

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo loss to follow-up

Selective reporting (reporting bias)Low riskAll important outcomes were accounted for

Other biasLow riskQuote: "Comparable demographic data and compliance rate"

Behre 1997

MethodsMulticentre, randomised, single-blinded (observer-blinded) controlled trial conducted in 26 centres in Germany, Belgium, Switzerland, the UK and Eire

AOM was defined by the visual appearance of the ear drum or presence of middle ear effusion on otoscopy, and the presence of 2 of the following symptoms: ear pain, ear discharge, hearing loss, fever, lethargy, irritability, anorexia, vomiting or diarrhoea

Analysis was performed based on the intention-to-treat and per-protocol principle, however only the intention-to-treat analysis was shown


Participants463 AOM children aged 2 to 12 years (231 and 232 children in the 2 and 3 times daily groups, respectively)


Interventions10 days with amoxicillin/clavulanate (70/10 mg/kg/day and 60/15 mg/kg/day for the 2 and 3 times daily groups, respectively)


OutcomesPrimary outcome
1. Clinical cure at the end of therapy (days 10 to 17)

- defined as complete or partial resolution

Secondary outcomes
1. Clinical cure rate during therapy (days 2 to 3), in terms of resolution of otalgia and resolution of fever, was not described

2. Clinical cure rate at post-treatment:

- Clinical cure at day 28
3. AOM complications after completion of therapy: recurrent AOM

- not described

4. Adverse reactions to medication: other outcome
- Compliance rate (at least 80%)


Notes- Supported by SmithKline Beecham Pharmaceuticals

- 34 and 44 children were noted to withdraw from the study, the total number of children at the end of therapy and follow-up visit was the same as at the entry

- For clinical cure rate post-treatment, indeterminate (10 versus 11) and 'lost' patients (11 versus 19) were counted as failures in both groups


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "The patients were randomised to treatment"

Comment: the authors did not describe the method of randomisation

Allocation concealment (selection bias)Unclear riskComment: the authors did not mention anything about allocation concealment

Blinding (performance bias and detection bias)
All outcomes
Low riskQuote: "The study was observer-blind"

Comment: probably done to prevent detection bias

Incomplete outcome data (attrition bias)
All outcomes
High riskQuote: "This fall in the success rate is partly accounted for by increased numbers of patients lost to follow-up and those with an indeterminate outcome at follow-up who were categorised as failures"

Comment: for robustness, 'loss to follow-up' and 'indeterminate outcome' should be counted as failure in the 2 times daily and success in the 3 times daily groups. If it was recalculated, success rate should be 185/231(80.1%) and 210/232 (90.5%) for the 2 times daily and 3 times daily groups, respectively

Selective reporting (reporting bias)Low riskComment: important outcomes were accounted for

Other biasLow risk

Damrikarnlert 2000

MethodsMulticentre, randomised, single-blinded (observer-blinded) trial conducted at 18 centres in Argentina, Brazil, Costa Rica, India, Kenya, Mexico, Morocco, Nigeria, Thailand and Turkey between August 1996 and March 1998

Block of 6 randomisation was performed using SAS software. Although analyses using the intention-to-treat and per-protocol principle were planned, only the intention-to-treat principle analysis was shown


Participants415 AOM children aged 2 months to 12 years (209 and 206 children in the 2 and 3 times daily groups, respectively). However, 199 and 187 participants were analysed for primary outcome


Interventions7 to 10 days (depending on national prescribing practice) with amoxicillin/clavulanate 45/6.4 mg/kg/day and 40/10 mg/kg/day (2 versus 3 times daily groups, respectively)


OutcomesPrimary outcome
1. Clinical cure rate at the end of therapy

- Clinical success at days 7 to 12

Secondary outcome
1. Clinical cure rate during therapy

2. Clinical cure rate post-treatment (1 to 3 months):

- Successful clinical response at days 38 to 42

3. AOM complications after completion of therapy: recurrent AOM

4. Adverse events: other outcomes

- Bacteriological response rate at the end of therapy

- Compliance rate (at least 80%)


NotesSupported by Smithkline Beecham Pharmaceuticals


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "Randomization was performed in a 1:1 ratio for the two treatments in blocks of 6 using a randomisation schedule generated by the sponsor using SAS software"

Comment: probably done

Allocation concealment (selection bias)Unclear riskComment: did not mention the method of allocation concealment

Blinding (performance bias and detection bias)
All outcomes
Low riskQuote: "This was a single-blind, randomised, comparative, parallel-group study". "These data were recorded in a dispensing register rather than the case report form to maintain observer blinding"

Comment: probably done

Incomplete outcome data (attrition bias)
All outcomes
High riskQuote: "The primary efficacy variable was the clinical response (success or failure) at the end of therapy (Day 7-12). Secondary efficacy variables were clinical response at follow-up (Day 38-42) and bacteriological response (success or failure) at the end of therapy. A tertiary efficacy variable was the clinical response at the on-therapy visit (Day 3-5)"

Selective reporting (reporting bias)Low risk

Other biasLow risk

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Jacobsson 19931. Included only recurrence or cases that were not responsive to amoxicillin/penicillin or cefaclor, which was different from other studies
2. The total daily dosage for amoxicillin was quite low (20 to 33.2 mg/kg/day)

 
Comparison 1. One or two daily doses versus three daily doses

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Clinical cure rate at the end of therapy51601Risk Ratio (M-H, Fixed, 95% CI)1.03 [0.99, 1.07]

 2 Clinical cure rate during therapy2448Risk Ratio (M-H, Fixed, 95% CI)1.06 [0.85, 1.33]

 3 Clinical cure rate at post-treatment41476Risk Ratio (M-H, Random, 95% CI)1.02 [0.95, 1.09]

 4 AOM complications: Recurrent AOM after completion of therapy31029Risk Ratio (M-H, Random, 95% CI)1.21 [0.52, 2.81]

 5 Adverse reactions to medication (overall)2878Risk Ratio (M-H, Random, 95% CI)0.92 [0.52, 1.63]

 6 Specific adverse reactions to medication: Diarrhoea41563Risk Ratio (M-H, Fixed, 95% CI)0.70 [0.49, 1.00]

 7 Specific reactions to medication: Skin adverse events31100Risk Ratio (M-H, Fixed, 95% CI)0.74 [0.46, 1.18]

 8 Compliance rate41520Risk Ratio (M-H, Random, 95% CI)1.04 [0.98, 1.10]

 
Comparison 2. Analysis for amoxicillin treatment trials only

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Clinical cure rate at the end of therapy2177Risk Ratio (M-H, Random, 95% CI)1.05 [0.82, 1.34]

 2 Clinical cure rate during therapy163Risk Ratio (M-H, Fixed, 95% CI)1.17 [1.01, 1.37]

 3 Clinical cure rate at post-treatment195Risk Ratio (M-H, Fixed, 95% CI)0.93 [0.85, 1.03]

 4 AOM complications: Recurrent AOM after completion of therapy1100Risk Ratio (M-H, Random, 95% CI)4.16 [0.48, 35.95]

 5 Specific adverse reactions to medication: Diarrhoea1110Risk Ratio (M-H, Fixed, 95% CI)1.0 [0.06, 15.59]

 6 Specific adverse reactions to medication: Skin adverse events1110Risk Ratio (M-H, Fixed, 95% CI)1.0 [0.21, 4.74]

 7 Compliance rate167Risk Ratio (M-H, Random, 95% CI)1.0 [0.94, 1.06]

 
Comparison 3. Analysis for amoxicillin/clavulanate treatment trials only

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Clinical cure rate at the end of therapy31424Risk Ratio (M-H, Fixed, 95% CI)1.03 [0.99, 1.07]

 2 Clinical cure rate during therapy1385Risk Ratio (M-H, Fixed, 95% CI)1.00 [0.70, 1.42]

 3 Clinical cure rate at post-treatment31381Risk Ratio (M-H, Fixed, 95% CI)1.04 [0.98, 1.10]

 4 AOM complications: Recurrent AOM after completion of therapy2929Risk Ratio (M-H, Random, 95% CI)1.01 [0.39, 2.60]

 5 Adverse reactions to medication: Overall2878Risk Ratio (M-H, Random, 95% CI)0.92 [0.52, 1.63]

 6 Specific adverse reactions of medication: Diarrhoea31453Risk Ratio (M-H, Fixed, 95% CI)0.70 [0.48, 1.00]

 7 Specific adverse reactions to medication: Skin adverse events2990Risk Ratio (M-H, Fixed, 95% CI)0.72 [0.44, 1.17]

 8 Compliance rate31453Risk Ratio (M-H, Random, 95% CI)1.05 [0.98, 1.13]

 
Comparison 4. Analysis excluding the studies with many unclear risk of bias characteristics (Principi 1986)

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Clinical cure rate at the end of therapy41491Risk Ratio (M-H, Fixed, 95% CI)1.03 [0.99, 1.07]

 2 Clinical cure rate during therapy31381Risk Ratio (M-H, Fixed, 95% CI)1.04 [0.98, 1.10]

 3 AOM complications: Recurrent AOM after completion of therapy2929Risk Ratio (M-H, Random, 95% CI)1.01 [0.39, 2.60]

 4 Adverse reactions to medication: Overall adverse events2878Risk Ratio (M-H, Random, 95% CI)0.92 [0.52, 1.63]

 5 Specific adverse reactions to medication: Diarrhoea31453Risk Ratio (M-H, Fixed, 95% CI)0.70 [0.48, 1.00]

 6 Specific adverse events to medication: Skin adverse events2990Risk Ratio (M-H, Fixed, 95% CI)0.72 [0.44, 1.17]

 
Table 1. Quality assessment for individual trials

TrialRandomisation processAllocation concealmentBlindingIncomplete outcome dataSelective reportingOther biasDrop-outs

Principi 1986Unclear riskUnclear riskUnclear riskLow riskLow riskUnclear risk0%

Murph 1993Low riskUnclear riskLow riskUnclear riskHigh riskLow risk7.7%

Behre 1997Unclear riskUnclear riskLow riskHigh riskLow riskLow risk4.8% to 8.2%

Hoberman 1997Unclear riskUnclear riskLow riskLow riskLow riskLow risk5.2% to 5.6%

Damrikarnlert 2000Low riskUnclear riskLow riskHigh riskLow riskLow risk10.7% to 11%

 
Table 2. Clinical cure rate at the end of therapy

StudyOne or two daily doses (n/N)Three daily doses (n/N)Risk ratio95% CI

Principi 198649/5551/550.960.85 to 1.08

Murph 199327/3323/341.210.91 to 1.60

Hoberman 1997241/287229/2881.060.98 to 1.14

Behre 1997212/231210/2321.010.96 to 1.07

Damrikarnlert 2000187/199175/1871.000.95 to 1.06

 CI: confidence interval
 
Table 3. Clinical cure rate during therapy

StudyOne or two daily doses (n/N)Three daily doses (n/N)Risk ratio95% CI

Behre 199730/3028/331.171.01 to 1.37

Damrikarnlert 200048/19945/18610.80 to 1.25

 CI: confidence interval
 
Table 4. Clinical cure rate at post-treatment (1 to 3 months)

StudyOne or two daily doses (n/N)Three daily doses (n/N)Risk ratio95% CI

Principi 198642/4648/490.930.85 to 1.03

Behre 1997185/220180/2321.250.96 to 1.66

Hoberman 1997172/287176/2880.980.83 to 1.15

Damrikarnlert 2000168/180153/1741.440.81 to 2.29

 CI: confidence interval
 
Table 5. AOM complications: Recurrent AOM after completion of therapy

StudyOne or two daily doses (n/N)Three daily doses (n/N)Risk ratio95% CI

Principi 19864/491/514.160.48 to 35.95

Hoberman 199751/28754/2880.970.78 to 1.2

Damrikarnlert 20007/8012/1741.190.64 to 2.2

 CI: confidence interval
 
Table 6. Overall adverse events

StudyOne or two daily doses (n/N)Three daily doses (n/N)Risk ratio95% CI

Behre 1997111/23194/2321.190.97 to 1.46

Damrikarnlert 200025/20937/2060.670.42 to 1.07

 CI: confidence interval
 
Table 7. Specific adverse events to medication

Adverse eventsStudyOne or two daily doses (n/N)Three daily doses (n/N)Risk ratio95% CI

DiarrhoeaPrincipi 19861/551/551.000.06 to 16.40

Hoberman 199716/28720/2880.800.42 to 1.52

Behre 199715/23124/2320.630.34 to 1.17

Damrikarnlert 200015/20922/2060.650.3 to 1.28

Skin adverse eventsPrincipi 19863/553/551.000.19 to 5.19

Hoberman 199723/28730/2880.770.46 to 1.29

Damrikarnlert 20002/2095/2060.390.07 to 2.02

 CI: confidence interval
 
Table 8. Compliance rate

StudyOne or two daily doses (n/N)Three daily doses (n/N)Risk ratio95% CI

Murph 199333/3334/3410.94 to 1.06

Hoberman 1997257/287246/2881.050.99 to 1.12

Behre 1997192/231169/2321.141.03 to 1.26

Damrikarnlert 2000173/209173/2060.990.90 to 1.07

 CI: confidence interval