|The impact of dosing frequency on the efficacy of 10-day penicillin or amoxicillin therapy for streptococcal tonsillopharyngitis: a meta-analysis
|Lan A J, Colford J M
To compare cure rates between once- or twice-daily (s.i.d. and b.i.d., respectively) and more frequent dosing schedules in the treatment of streptococcal tonsillopharyngitis.
MEDLINE and Dissertation Abstracts were searched to August 1998. For MEDLINE, the keywords were 'tonsillopharyngitis', 'pharyngitis', 'penicillin', 'amoxicillin' and 'clinical trials. For Dissertation Abstracts, combinations of the following words were used: 'streptococcus' or 'streptococcal' and 'penicillin' or 'amoxicillin'. Unpublished papers were located by scanning abstracts of the annual Interscience Conference on Antimicrobial Agents and Chemotherapy from 1983 to 1997, using the keywords 'pharyngitis' and 'tonsillopharyngitis'. The bibliographies of all retrieved studies, review articles and meta-analyses, were examined. Where multiple publications of the same study were found, the most recent version was selected.
Study designs of evaluations included in the review
Randomised controlled trials (RCTs) were eligible for inclusion.
Specific interventions included in the review
Comparisons of different dosing frequencies of 10-day oral penicillin or amoxicillin, which were initiated on diagnosis, were considered. Actual comparisons were of 3- or 4-times-daily dosing with either b.i.d. or s.i.d. dosing. The majority of the studies examined penicillin; only 1 study examined amoxicillin. One to 4 doses of antibiotics were administered per day, supplying a total daily dose of penicillin ranging from 500 to 1000 mg, or from 30 to 60 mg/kg for children. The total daily dose of amoxicillin was 50 mg/kg for children and 750 mg/kg for adults. Studies varied in their management of positive cultures during treatment: in some studies, culture positive patients were switched to the more frequent dosing regime; in one study, this group were excluded; and in another study, these patients were classified as failures.
Participants included in the review
Patients with acute group A beta-haemolytic streptococcus (GABHS) tonsillopharyngitis were eligible if the diagnosis was made on both symptoms and a positive throat culture or antigen detection test. Where stated, the participants ranged in age from 1 to 56 years.
Outcomes assessed in the review
The inclusion criteria were not defined in terms of outcomes. The difference in the proportion cured between the intervention groups was assessed. In the primary studies, cure was uniformly defined as a negative culture at every follow-up culture. The number of follow-up cultures varied from 1 to 3. The initial follow-up cultures were conducted from 1 to 28 days after initiation of antibiotic therapy, and the final cultures between 15 and 34 days.
How were decisions on the relevance of primary studies made?
The authors do not state how the papers were selected for the review, or how many of the reviewers performed the selection.
Assessment of study quality
Validity was assessed and scored on a number of criteria, which were assigned a maximum of 1 or 2 points.
One point was awarded for the fulfilment of the following criteria: study performed between December and May; patients under 3 years of age excluded; investigator responsible for follow-up assessment blinded to the treatment; compliance with antibiotic regime assessed; patient withdrawals and reasons for withdrawals discussed; and adequacy of randomisation evaluated for patient demographic variables.
Two points were awarded for fulfilling the criteria of: diagnosis based on signs and symptoms consistent with streptococcal tonsillopharyngitis, and signs and symptoms consistent with viral pharyngitis not included; data available on follow-up cultures, which were performed less than 14 days after completing treatment; and comparison of pre- and post-treatment GABHS serotypes for patients with positive follow-up cultures.
The validity criteria were assessed and scored in an unblinded manner using a standardised data abstraction form.
The data were extracted in an unblinded manner using a standardised data abstraction form. The following information was presented in tabular format: author and year of publication; age of patients; antibiotic; number of doses per day; total daily dose; number of participants per treatment arm; number cured; cure rate; and timing of follow-up cultures.
To avoid double counting in the meta-analysis, only culture data on day 2 were used, and to maintain consistency, all positive cultures were treated as failures. The difference in the proportion cured between treatments was calculated for each study, along with the 95% confidence intervals. In studies with more than 2 treatment arms, comparisons were made between treatment arms with a comparable total daily dose.
Methods of synthesis
How were the studies combined?
The summary measure of effect for each comparison was calculated using the general variance-based method (see Other Publications of Related Interest).
How were differences between studies investigated?
Statistical heterogeneity was assessed using the general variance-based method, where the level of significance was set at a p-value of less than 0.10 (see Other Publications of Related Interest). Forest plots, with ordering by study quality, provided a graphical illustration of heterogeneity. Where significant heterogeneity was found, an investigation was conducted to determine the likely source. A sensitivity analysis was conducted by restricting analysis to those studies enrolling predominantly children. A separate analysis was conducted for studies using higher and lower daily doses.
Results of the review
Six RCTs (1,206 participants) were included.
The study quality was variable with scores ranging from 1 to 12. The mean score was 5 and the median score was 4.
Dosing frequency of 3 or 4 times daily versus b.i.d. (4 RCTs; quality scores of 1, 4, 4 and 7): no difference was found in the cure rates between the dosing regimes. No differences in cure rates were found when restricting the analysis to children (those less than 21 years), and no differences in efficacy were found when grouping the studies by total dose size (higher or lower total doses).
Dosing frequency of 3 or 4 times daily versus s.i.d. (3 RCTs): significant heterogeneity was found (p=0.014). One RCT (quality score 4) examining amoxicillin reported no difference in efficacy, whereas 2 RCTs (quality scores 9 and 4) showed significantly greater efficacy with more frequent dosing. The analysis was repeated after excluding the one study that examined amoxicillin; significantly greater efficacy of the more frequent dosing regime was demonstrated. The authors reported the limitations of the review were the shortage of high-quality studies, and the variation in the number of follow-up cultures.
This review supported recommendations for b.i.d. dosing of penicillin in treating streptococcal tonsillopharyngitis. Penicillin, s.i.d., was associated with decreased efficacy and should not be used. Simplified regimes of amoxicillin of shorter duration or less frequent dosing should be further investigated.
The aims were stated and the inclusion criteria were defined in terms of study design, participants and intervention. Several relevant sources were searched, keywords were listed and an attempt was made to locate unpublished material. However, it was not reported whether any language restrictions were applied, and the methods used to select studies were not described. The excluded studies were listed and reasons for their exclusion were presented. Validity was assessed and scored using defined criteria, and the methods used to assess validity and extract data were described. Statistical heterogeneity was assessed and illustrated graphically and, when appropriate, a meta-analysis was conducted. Sensitivity analyses were conducted to examine the influence of total daily dose and target population (children only) on the results.
As the authors acknowledged, results from the meta-analysis should be interpreted with caution in view of the low quality of the included trials.
Implications of the review for practice and research
Practice: The authors state that the review supported recommendations for b.i.d. dosing of penicillin in treating streptococcal tonsillopharyngitis, and that s.i.d. penicillin should not be used since it is associated with decreased efficacy.
Research: The authors state that existing study designs should be improved and incorporated into future clinical trials. In addition, simplified regimes of amoxicillin of shorter duration or less frequent dosing require further investigation.
Lan A J, Colford J M. The impact of dosing frequency on the efficacy of 10-day penicillin or amoxicillin therapy for streptococcal tonsillopharyngitis: a meta-analysis. Pediatrics 2000; 105(2): E19
Other publications of related interest
Petitti DB. Meta-analysis, decision-analysis, and cost-effectiveness analysis: methods for quantitative synthesis in medicine. New York (NY): Oxford University Press; 1994.
This additional published commentary may also be of interest. Bradley C. Review: twice daily dosing of penicillin V is as effective as more frequent dosing for streptococcal tonsillopharyngitis. Therapeutics 2000;5:168.
Subject indexing assigned by NLM
Administration, Oral; Amoxicillin /administration & Drug Administration Schedule; Humans; Penicillins /administration & Pharyngitis /drug therapy /microbiology; Streptococcal Infections /drug therapy /microbiology; Streptococcus pyogenes; Tonsillitis /drug therapy /microbiology; Treatment Outcome; dosage; dosage
Date bibliographic record published
Date abstract record published
This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.