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

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Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

(1) To compare the effectiveness of amoxicillin with or without clavulanate between once or twice daily doses, with three or four times daily doses for the treatment of acute otitis media in children.
(2) To compare the complication rates between once or twice daily doses with three or four times daily doses.
(3) To compare the adverse reactions between the dosing intervals.

Background

Acute otitis media is one of the most common diseases in children. During the first six months of life about 48% of infants have an episode of acute otitis media (AOM) or otitis media with effusion (OME) and about 20% have two or more episodes (Daly 1999). The peak incidence of AOM occurs between six and 12 months of age. It had been found that by the first year of life 62.4% of infants have one or more episodes of AOM and 17.3% have three or more episodes (Teele 1989). The risk of developing another episode within one month after the onset of the primary infection is estimated at 35% (Carlin 1987).

The common microbiology of acute otitis media was found to be Streptococcal pneumoniae (S. pneumoniae), Haemophilus influenzae (H. influenzae) andMoraxella catarrhalis (M. catarrhalis) (Jacobs 1998). These three most common bacterial causes of AOM are becoming increasingly resistant to antibiotics (Barnett 1995; Faden 1994; Henderson 1988; Johnson 1996; Kaplan 1995). Systematic reviews demonstrated that in uncomplicated AOM, about 15 children must be treated with antibiotics to prevent one child having some pain after two days (Glasziou 2004) and about eight children must receive antibiotics to avoid one clinical failure (Rosenfeld 2001). However the emergence of multiple‐drug resistant strains, particularlyS. pneumoniae, complicates the management of AOM and increases the risk of treatment failure.

Antibiotics are frequently used for AOM in the United States of America (USA) (Froom 1997; Glasziou 2004). AOM was the most frequent disease that antibiotics were used to treat in outpatients in the USA (McCaig 1995). In contrast, the national Dutch guideline recommends that children be treated for symptoms but not receive antibiotics unless fever or pain persists (Froom 1997). Children in Britain also usually receive antibiotics (Appelman 1990). Due to growing bacterial resistance, the Centers for Disease Control and the American Academy of Pediatrics promote the judicious use of antibiotics in the treatment of AOM. Antibiotic therapy remains an appropriate treatment option for most children with AOM because spontaneous cure rates are lower in complicated AOM and AOM secondary to S. pneumoniae infection. When amoxicillin, the treatment of choice in AOM is not effective or not tolerated in children, an alternative antibiotic such as amoxicillin/clavulanate, second‐ and third‐generation cephalosporins which can cover beta‐lactamase producing bacteria should be considered (Pichichero 2003).

The effectiveness of antibiotics does not depend solely on its antimicrobial activity against the suspected pathogens, but also on characteristics such as dosage; appropriate dosing intervals; and tolerability and palatability that promote compliance and adherence. A convenient once‐ or twice‐daily dosing schedule increases the likelihood of compliance with the full course of therapy (Leibovitz 2003). The traditional dosing interval for prescribing amoxicillin with or without clavulanate is every six to eight hours. These dosing intervals may result in poor compliance especially for children at school or at a daycare centres which necessitates the involvement and co‐operation of a third person. The duration of time that serum levels of antibiotics are above the Minimal Inhibitory Concentration (MIC) or time above the MIC was demonstrated to be a major determinant in predicting successful clinical outcome for beta‐lactam antimicrobial agents (Cars 1997; Drusano 1997). This finding denotes that the dosing frequency of beta‐lactam antimicrobial agents could be reduced by increasing the amount of each dose with comparable total daily dose in order to maximize time above the MIC. By this practice it will enhance compliance over three‐times‐daily dosing (Grob 1992; Urquhart 1992). It is reasonable to assess the effectiveness of clinical trials comparing reduced dosing intervals with traditional dosing intervals.

Objectives

(1) To compare the effectiveness of amoxicillin with or without clavulanate between once or twice daily doses, with three or four times daily doses for the treatment of acute otitis media in children.
(2) To compare the complication rates between once or twice daily doses with three or four times daily doses.
(3) To compare the adverse reactions between the dosing intervals.

Methods

Criteria for considering studies for this review

Types of studies

Randomized controlled trials comparing two different dosing intervals of the same intervention, amoxicillin with or without clavulanate.

Types of participants

Patients aged 12 years or younger, with acute otitis media diagnosed by explicit criteria: acute ear pain (otalgia), inflamed ear drum (confirmed by positive tympanocentesis or tympanogram) of type B or C or not. (Tympanogram is the printout of an impedance bridge showing the stiffness or the compliance of the middle ear structures as it varies with changes in pressure within the external ear canal. Type B suggests fluid in the middle ear; type C suggests that the pressure within the middle ear is below atmospheric pressure.

Types of interventions

Amoxicillin with or without clavulanate comparing between once or twice daily with three or four times daily

Types of outcome measures

(1) Clinical cure rate will be assessed during therapy (days two to three), at the end of antibiotics therapy (days seven to 14) and post‐treatment (one to three months):
1.1 resolution of otalgia (ear pain)
1.2 resolution of fever
1.3 resolution of middle ear effusion as determined by tympanometry, assessed only in those who do not have recurrences of AOM after completion of therapy
1.4 Bacteriological cure rate if the data is provided
(2) AOM complications: recurrent AOM (after completion of therapy), acute mastoiditis
(3) Medication adverse reactions.

Search methods for identification of studies

Multiple strategies will be used to identify as many trials as possible that meet the inclusion criteria, regardless of language or publication status. Electronic searches of the following databases will be conducted:
(1) The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, latest issue)
(2) MEDLINE (January 1966 to present)
(3) EMBASE (January 1990 to present)
(4) Science Citation Index (SCI)
(5) NLM Gateway which searches Health Services Research Meetings and HSRProj
(6) Health Services/Technology Assessment Texts (HSTAT)

The following search terms will be used, with appropriate modifications where necessary, on all databases listed above:
exp Otitis Media/ OR otitis media
AND
exp Amoxicillin/ OR exp Amoxicillin‐Potassium Clavulanate Combination/ OR amoxycillin OR amoxicillin OR amoxicillin clavulanate

These search terms will be used in combination with parts I and II of the highly sensitive search strategy designed by the Cochrane Collaboration (the Cochrane Handbook version 4.2, Appendix 5b) (Dickersin 1994). This filter will be adapted for searching the other databases listed.

We will check the reference lists of identified clinical trials and any relevant reviews or meta‐analyses. We will contact the major pharmaceutical companies that manufacture antibiotics and the relevant experts in the field for additional trial information. We intend to contact the first author of relevant trials if any questions arise. We will also undertake handsearching with the help of the Cochrane Collaboration.

Data collection and analysis

Data extraction
After retrieval of titles and abstracts from the literature search, two physician reviewers (ST & PW) will review the abstracts against the inclusion/exclusion criteria to determine eligibility for inclusion in the evidence synthesis. we will record reviews on a pre‐designed screening form. The screening results for each title/abstract will be matched between the two reviewers by the third reviewer (ML). Disagreements on inclusion or exclusion will be solved in the meeting among the three reviewers. The articles which pass the screening criteria and those that fail will be summarized with the reasons for exclusion. The titles/abstracts identified as requiring further review will be requested from the librarian for full article retrieval with the help of Cochrane Acute Respiratory Infections Group. Two physician reviewers will then independently review each article and fill out the data extraction forms. We will resolve disagreements between reviewers on inclusion/exclusion through group discussion.

Quality assessment
The criteria for the assessment of study quality will include (1) random allocation concealment; (2) blinding; and (3) follow‐up. Risk of bias will be graded as A (low risk: plausible bias unlikely to seriously alter the result); B (moderate risk: plausible bias that raises some doubt about the result); and C (high risk: plausible bias that seriously weakens confidence in the result).

Statistical analyses
Where appropriate we will perform meta‐analyses to pool trial data using the Review Manager (RevMan 4.2.7) software. The method of meta‐analysis will be dependent upon the nature of the outcomes. For categorical data (for example, proportion of participants with cure), we will relate the numbers reporting an outcome to the numbers at risk in each group to derive a relative risk (RR) and 95% confidence interval. We will show continuous differences between groups in the meta‐analysis (for example, pain relief on a visual analogue scale) as a weighted mean difference (WMD) and 95% confidence interval. As a general rule, a fixed effect model will be used for calculations of summary estimates and their 95% confidence intervals.

When important heterogeneity is suspected from the chi squared test for heterogeneity (at 10%) or from visual inspection of the results, this will be investigated by looking for differences of clinical and methodological factors between the trials that may be the explanation. When concern about heterogeneity persists, consideration will be given to using a random effects model. The I2 statistics will also be calculated to estimate degree of the heterogeneity. We will examine for publication bias using funnel plots (Light 1984). When asymmetry is observed, the Trim and Fill method will be used to assess the effect of this asymmetry on the conclusions. The sensitivity analysis will also be done for assessing the effect of quality of trials on the conclusions. When meta‐analysis is inappropriate, conclusions will be drawn by the trials' descriptive elements, methodological quality, number of trials with consistent findings, plausibility of the results, the strength of the associations in the primary trials as well as consensus among reviewers.

Subgroup analysis will be performed according to the total dosages of antibiotics: equal and unequal.