ORIGINAL STUDIES

Metaanalysis of Short Course Antibiotic Treatment for Group A Streptococcal Tonsillopharyngitis

Janet R. Casey, MD,* and Michael E. Pichichero, MD
Objective: To compare bacterial and clinical cure rates in patients with group A streptococcal (GAS) tonsillopharyngitis treated with oral -lactam or macrolide antibiotics for 4 5 days versus 10-day comparators. Methods: Medline, Embase, reference lists and abstract searches were used to identify available publications. Trials were included if there was bacteriologic conrmation of GAS tonsillopharyngitis, random assignment to antibiotic therapy for a -lactam or macrolide antibiotic of a shortened course versus a 10-day comparator and assessment of bacteriologic outcome using a throat culture. Results: Twenty-two trials involving 7470 patients were included in 4 separate analyses. Trials were grouped by a short course of cephalosporins (n 14), macrolides (other than azithromycin) (n 6) and penicillin (n 2). Cephalosporin trials were further grouped by the comparator, penicillin or the same cephalosporin. Short course cephalosporin treatment was superior for bacterial cure rate compared with 10 days of penicillin odds ratio (OR), 1.47; 95% condence interval (CI), 1.06 2.03. For trials with short course macrolide therapy, OR 0.79 (95% CI 0.59 1.06) neither the macrolides nor the 10-day comparators. Short course penicillin therapy was inferior in achieving bacterial cure versus 10 days of penicillin, OR 0.29 (95% CI 0.13 0.63). Clinical cure rates mirrored bacteriologic cure rates. Conclusion: Superior cure rates can be achieved with shortened courses of cephalosporin therapy, but 5 days is inferior to 10 days of penicillin treatment. Key Words: group A streptococci, tonsillopharyngitis, cephalosporins, penicillin, macrolides, metaanalysis (Pediatr Infect Dis J 2005;24: 909 917)

trapolated from comparative studies of depot penicillin and orally administered penicillin in adults.4,5 However, 10day treatment courses are associated with poor patient compliance.6 12 If shorter duration therapy for GAS tonsillopharyngitis is as effective as 10-day treatment, reducing the duration of treatment could have an important impact on improved compliance, fewer antibiotic adverse events, a reduction in the development of bacterial resistance and a positive impact on the pharmacoeconomics of treatment. Shorter antibiotic treatment courses for GAS tonsillopharyngitis have been evaluated during the past 10 years as an alternative to traditional 10-day courses of therapy. The objective of this study was to use metaanalysis to compare the relative efcacy of short course antibiotic treatment with standard 10-day treatment courses for GAS tonsillopharyngitis. Additionally compliance and adverse event rates of short course antibiotic treatment and 10-day treatment were compared.

METHODS
Trial Identication. Randomized, controlled trials comparing antibiotic treatment for 4 5 days with 10 days for GAS tonsillopharyngitis in children and adults were identied from Medline (1966 2003) and Embase (1974 2003) searches. The searches had no language restriction; the search terms used were streptococcal pharyngitis/tonsillitis, cephalosporin, macrolide, amoxicillin and penicillin. Reference lists of relevant publications were reviewed to identify additional trials. Trial Selection and Quality. Trials comparing 4- to 5-day versus 10-day antibiotic treatment of GAS tonsillopharyngitis infections were independently reviewed for inclusion by the authors according to the following criteria: (1) bacteriologic conrmation of GAS tonsillopharyngitis; (2) random assignment to antibiotic therapy for a -lactam or macrolide (other than azithromycin) antibiotic of a 4- to 5-day course versus a 10-day comparator; and (3) assessment of bacteriologic outcome with the use of a throat culture after therapy. The Jadad scale was used to assess the quality of the included trials. The scale assigned scores from 0 to 5 (best quality trial) based on the following criteria: (1) study participants were allocated randomly to treatment using an appropriate method such as a random numbers table; (2) the intervention was double blinded; and (3) accounting and description of study withdrawals were done.13 Data Abstraction and Denition of Terms. The primary outcomes of interest were: (1) bacteriologic cure dened as failure to isolate GAS by throat culture after completion of the antibiotic course; and (2) clinical cure, dened as

roup A streptococcal (GAS) tonsillopharyngitis is one of the most common diagnoses in children and adults for which an antibiotic is prescribed.1 The 10-day duration of antibiotic therapy for GAS tonsillopharyngitis is based on well-conducted studies with depot penicillin.2,3 Duration of therapy with oral penicillin preparations was ex-

Accepted for publication May 6, 2005. From the Departments of *Pediatrics and Microbiology/Immunology, Elmwood Pediatric Group, University of Rochester Medical Center, Rochester, NY Presented at the 44th Annual Meeting of the Interscience Conference on Antimicrobial Agents and Chemotherapy, October 2004, Washington, DC.51 E-mail jrcasey@rochester.rr.com. Reprint not available. Copyright 2005 by Lippincott Williams & Wilkins ISSN: 0891-3668/05/2410-0909 DOI: 10.1097/01.inf.0000180573.21718.36

The Pediatric Infectious Disease Journal Volume 24, Number 10, October 2005

909

Casey and Pichichero

The Pediatric Infectious Disease Journal Volume 24, Number 10, October 2005

failure to isolate GAS by throat culture and resolution of, or improvement in, the presenting signs and symptoms of GAS infection after completion of antibiotic treatment and continuing throughout follow-up. To test the robustness of the analysis, sensitivity analyses were performed to assess the impact of detailed clinical illness descriptions, compliance monitoring, GAS serotyping or genotyping and timing of the test-of-cure culture. Secondary outcomes of interest were compliance rates and antibiotic adverse event rates of the treatment courses. We independently abstracted primary and secondary outcomes, and sensitivity analysis data from each trial using a data extraction form. Differences were settled by discussion, and consensus was reached. Data Analysis. Metaanalyses were performed on the trials grouped by shortened course antibiotic. Shortened course cephalosporin trials were further grouped by the 10-day comparator, penicillin or the same cephalosporin. The metaanalyses were performed with the Cochrane Collaborations Revman 4.2 program (Cochrane Collaboration, Oxford, U.K.). The bacterial and clinical cure rates after 4 5 days of treatment compared with a 10-day comparator were calculated and expressed as an odds ratio (OR) with 95% condence intervals (CIs). An OR 1 indicated a higher bacteriologic and clinical cure rate for the 4- to 5-day treatment, as compared with the 10-day comparator. ORs were calculated for individual trial outcomes with the Peto xed effects model, when there was trial homogeneity,14 and the DerSimonian and Laird random effects model, when there was trial heterogeneity.15 A summary OR was determined for trials grouped by short course antibiotic. Statistical heterogeneity among trials was assessed by 2 analysis.16,17 Sensitivity analyses were conducted to assess the robustness of the overall metaanalysis of the cephalosporin short course versus penicillin 10-day trials and to investigate potential clinical heterogeneity among the trials by comparing summary ORs among groups redened by (1) excluding trials that were not investigator or double blinded, (2) excluding trials of a lower methodologic quality (Jadad score 2), (3) excluding trials that did not give specic details of the clinical status of the patients, (4) excluding trials that did not monitor compliance, (5) excluding trials that did not perform serotyping or genotyping of the GAS organism isolated on the initial and follow-up throat culture and (6) excluding trials that did not perform the test-of-cure follow-up culture 314 days after completion of the antibiotic treatment. Additional analyses included (1) studies grouped by site (ie, U.S. and European), (2) studies grouped by cephalosporin generation and (3) studies of individual cephalosporins grouped and analyzed separately. A funnel graph of the standard effect versus the OR was plotted to determine whether publication bias existed. Compliance rates and antibiotic adverse event rates were secondary outcomes analyzed by the same metaanalytic methods. ORs were calculated for individual trial compliance, and adverse events rates and summary ORs were determined for trials that reported the data.

RESULTS
Literature Search and Trial Inclusion. The Medline and Embase searches yielded 144 citations; 39 were randomized clinical trials comparing a shortened course (4 5 days) of treatment with another treatment course for GAS tonsillopharyngitis. Two trials not identied by Medline or Embase were retrieved from reference listings. The 41 citations were assessed further according to the inclusion criteria. Fifteen of these trials were excluded from the metaanalysis for the following reasons: (1) the trial did not evaluate a -lactam antibiotic or a macrolide other than azithromycin (n 12); (2) the data presented were a republication of previous data already included in the metaanalysis (n 1); or (3) the treatment lengths were the same (n 2). Twenty-two trials remained.18 41 Two trials had 3 treatment arms: cefpodoxime 5 days versus penicillin 10 days or cefpodoxime 10 days22; and clarithromycin 15 and 30 mg/kg versus penicillin 10 days.37 The treatment arms were analyzed separately in this metaanalysis. Two trials comparing 6 days of treatment of amoxicillin versus penicillin for 10 days40,41 were analyzed separately and not included in the main metaanalysis. Methodologic Quality. The mean quality score for the trials was 2.5 (SD 1.53.5), of a maximum score of 5; 39% of the trials were of higher quality (Jadad score, 2) (Table 1). Four trials were double blind,25,35,36,39 and the investigators were blinded to treatment allocation in 4 additional trials.22,27,29,30 Eighteen trials adequately described the reasons for patient dropouts, with nearly all patients dropped from analysis because GAS was not isolated on the initial throat culture. Description of Trials. Twenty-two trials involving 7470 patients were analyzed (Table 1). Trials were grouped by short courses of cephalosporins (n 14), macrolides (other than azithromycin) (n 6), penicillin (n 2) and amoxicillin (n 2). Cephalosporin trials were further grouped by the comparator, penicillin (n 12) or the same cephalosporin (n 3). Five trials were conducted in the United States22,27,29,38,43; the remainder were conducted in Europe. Nineteen of the 22 trials were conducted in an outpatient private practice setting; 3 trials did not specify the setting.20,21,26 All trials required isolation of GAS on throat culture and all but 2 trials20, 38 performed a rapid antigen test at enrollment, but patients were dropped from analysis if GAS was not isolated from the throat culture. Twelve trials gave detailed descriptions of patient signs and symptoms at enrollment.21,22,24,30,3338,40,41 Seven trials did not perform serotyping or genotyping of the infecting GAS organism.19,21,26,30,32,34,36 When serotyping or genotyping was performed, true bacterial failures could be distinguished from reinfection with another serotype of GAS. When available, true bacterial failure rates were used in the metaanalysis calculations. One trial specically discussed identication and elimination of carriers from analysis.38 The timing of the test-of-cure follow-up culture varied among the trials. Most trials had an early and late follow-up culture and reported bacterial and clinical cure rates for each evaluation time point. Two trials had 2 follow-up visits but
2005 Lippincott Williams & Wilkins

910

The Pediatric Infectious Disease Journal Volume 24, Number 10, October 2005

GAS Tonsillopharyngitis

TABLE 1. Methodologic Details of Included Trials

Quality Score Cephalosporin trials: penicillin as 10-d comparator Portier et al18 Gehanno and Chiche19 Milatovic20 Portier et al21 Pichichero et al22 Peyramond et al23 Aujard et al24 Carbon et al25 Adam et al26 Tack et al27 Adam et al28 Tack et al29 Concealment of Treatment Allocation No. of ITT/ Evaluable No. in Arm Antibiotic Clinical Status at Diagnosis* Compliance Monitoring Serotyping Performed Test of Cure

2 2 1 2 3 1 3 3 2 2 2 3

Unblinded Unblinded Unblinded Unblinded Investigatorblinded Unblinded Unblinded Double blinded Unblinded Investigatorblinded Unblinded Investigatorblinded

162/125 (23) 324/256 (9) 209/209 (0) 220/150 (32) 324/256 (21) 177/119 (33) 308/200 (35) 236/190 (19) 160/138 (14) 558/432 (23) 2364/1975 (16) 482/440 (9)

65 60 81 73 105 104 82 68 126 130 67 52 97 103 97 93 69 68 218 214 490 1422 224 242

Cefpodoxime, 5 d Penicillin, 10 d Cefuroxime, 4 d Penicillin, 10 d Cefadroxil, 5 d Penicillin, 10 d Cefpodoxime, 5 d Penicillin, 10 d Cefpodoxime, 5 d Penicillin, 10 d Cefixime, 4 d Penicillin, 10 d Cefuroxime, 5 d Penicillin, 10 d Cefotiam, 5 d Penicillin, 10 d Cefixime, 5 d Penicillin, 10 d Cefdinir, 5 d Penicillin, 10 d Cefuroxime, 5 d Penicillin, 10 d Cefdinir, 5 d Penicillin, 10 d

No details No details No details Detailed Detailed No details Detailed No details No details No details No details No details

TC, PQ ND ND TC

Yes No Yes No

57 d 3d 15 d 23 d 48 d 12 d 2 4 d 120 d 15 d 510 d 2 4 d 510 d

TC, RC, UT Yes (DNA) ND TC TC, RC ND TC, RC ND RC, PQ Yes Yes Yes (DNA) No Yes Yes Yes

Cephalosporin trials: cephalosporins as 10-d comparator Pichichero et al22 Esposito et al30 Mehra et al31 Macrolide trials Portier et al32 Adam et al
33

3 3 2

Investigatorblinded Investigatorblinded Unblinded

310/247 (22) 420/120 (71) 520/406 (22)

126 121 61 55 201 205 98 101 102 99 126 113 115 119 117 154 135 132 135 73 99 70 70 125 109 141 136

Cefpodoxime, 5 d Cefpodoxime, 10 d Cefaclor, 5 d Cefaclor, 10 d Cefuroxime, 5 d Cefuroxime, 10 d Josamycin, 5 d Penicillin, 10 d Erythromycin, 5 d Penicillin, 10 d Clarithromycin, 5 d Penicillin, 10 d Telithromycin, 5 d Penicillin, 10 d Clarithromycin, 5 d Penicillin, 10 d Clarithromycin, 5 d Clarithromycin, 5 d Penicillin, 10 d Penicillin, Penicillin, Penicillin, Penicillin, 5d 10 d 5d 10 d

Detailed Detailed No details

TC, RC, UT Yes (DNA) TC, PQ TC, PQ No Yes

48 d 23 d 4 7 d

2 3 2 3 5 3

Unblinded Unblinded Unblinded Double blinded Double blinded Unblinded

265/199 (25) 227/201 (11) 349/239 (32) 395/234 (41) 360/331 (19) 626/537 (14)

No details Detailed Detailed Detailed Detailed Detailed

ND RC TC, RD TC TC TC

No Yes No Yes No Yes (DNA)

12 d 13 d 3d 10 d 310 d 48 d

Portier et al

34

Norrby et al

35

Takker et al

36

Syrogiannopoulos et al37 Penicillin trials Gerber et al38 Stromberg et al

39

2 5

Unblinded Double blinded

210/171 (18) 216/209 (3)

Detailed No details

UT TC, RC

Yes Yes

4 21 d 7d

Amoxicillin trials Peyramond et al40 Cohen et al41

3 3

Unblinded Unblinded

342/243 (32) 321/277 (14)

Amoxicillin, 6 d Penicillin, 10 d Amoxicillin, 6 d Penicillin, 10 d

Detailed Detailed

TC TC, RC

Yes Yes (DNA)

9 13 d 4d

*Detailed signs and symptoms given at diagnosis. Test of cure is reported as number of days after completion of antibiotic therapy. Numbers in parentheses, percent dropouts. ITT indicates intention to treat; TC, tablet count; RC, record cards; UT, urine testing; PQ, parent questionnaire; ND, no data.

2005 Lippincott Williams & Wilkins

911

Casey and Pichichero

The Pediatric Infectious Disease Journal Volume 24, Number 10, October 2005

FIGURE 1. Short course cephalosporin therapy versus 10 days penicillin therapy for GAS tonsillopharyngitis. Bacterial cure rate.

reported only 1 overall bacterial and clinical cure rate.25,38 Thirteen trials obtained test-of-cure cultures between 3 and 14 days after antibiotic completion.18,19,22,27,29,31,34 37,39 41 This timing is optimal because it occurs late enough to avoid antibiotic interference with culture results and early enough to avoid data contamination with reacquisitions or new infections. When available, the early follow-up test-of-cure data were used in the metaanalysis whenever possible. Eighteen trials gave detailed compliance monitoring methods that included parent/patient questionnaires, tablet counts, record cards and urine testing.18,21,22,24,25,27,29 31,33 41 Six studies evaluated compliance as a study outcome and gave additional statistical data.18,21,23,25,33,41 Antibiotic-induced adverse events during therapy were assessed in 15 trials.2327,29 31,3337,40,41 Outcome of Bacterial and Clinical Cure Rates. The primary outcome analyzed was the bacterial cure rate, comparing a 4to 5-day treatment course with a 10-day treatment course. The summary OR for bacterial cure for the individual short course treatments gave differing results. Treatment with a cephalosporin for 4 or 5 days was superior for bacterial cure rate when compared with 10 days of penicillin treatment (12 trials, 4301 patients), OR 1.47 (95% CI 1.06 2.03) (P 0.002) (Fig. 1).

Sensitivity analyses were conducted with the trials comparing cephalosporin short course treatment to 10 days of penicillin treatment to evaluate the robustness of the overall summary OR for the outcomes of bacterial and clinical cure rates. (Tables 2 and 3) Sensitivity analyses were not performed on the other groups of trials as there were too few trials. As a method to examine the validity of the overall analysis, we grouped the trials excluded from each of the sensitivity analyses and analyzed those for persistence of statistical signicance. For bacteriologic cure, the OR favored short course cephalosporins in all groups except the trials that did not perform GAS typing: for the 8 trials18 21,23,24,26,28 that were not investigator or double blind, the OR was 1.32 (95% CI 1.04 1.68), P 0.02; for the 8 trials18 21,23,26 28 with a low quality score (/ 2), the OR was 1.40 (95% CI 1.121.76), P 0.003; for the 9 trials18 20,23,2529 that did not dene the clinical signs and symptoms of the studied patients, the OR was 1.59 (95% CI 1.30 1.95), P 0.00001; for the 5 trials19,20,23,26,28 that did not monitor compliance, the OR was 1.34 (95% CI 1.04 1.73), P 0.03; for the 7 trials20,21,2326,28 with test-of-cure assessment outside of the 3- to 14-day period, the OR was 1.29 (95% CI 1.021.64), P 0.03. In the 3 trials19,21,26 that did not perform GAS

TABLE 2. Sensitivity Analysis of Cephalosporin Short Course Trials Versus Penicillin as a 10-Day Comparator Primary Outcome: Bacterial Cure Rate
Description All trials Investigator or double blinded trials Quality score 2 Clinical status well-defined Compliance monitoring detailed GAS serotyping or genotyping performed Test of cure 314 d after therapy completed
*Numbers in parentheses, 95% CI.

Reference 18 29 22, 25, 22, 24, 21, 22, 18, 21, 18, 20, 18, 19,

No. of Trials 12 4 4 3 7 9 5

No. of Participants 4301 1307 1075 604 717 3860 1393

OR 1.47 (1.06 2.03)* 2.20 (1.632.96) 2.17 (1.56 3.02) 1.74 (1.06 2.86) 1.74 (1.08 2.81) 1.68 (1.352.05) 2.32 (1.723.15)

P 0.02 0.00001 0.00001 0.03 0.02 0.00001 0.00001

27, 29 25, 29 24 22, 24, 25, 27, 29 2225, 2729 22, 27, 29

912

2005 Lippincott Williams & Wilkins

The Pediatric Infectious Disease Journal Volume 24, Number 10, October 2005

GAS Tonsillopharyngitis

TABLE 3. Sensitivity Analysis of Cephalosporin Short Course Trials Versus Penicillin as a 10-Day Comparator Primary Outcome: Clinical Cure Rate
Description All trials Investigator or double blinded trials Quality score 2 Clinical status well-defined Compliance monitoring detailed GAS serotyping or genotyping performed Test of cure 314 d after therapy completed
*Numbers in parentheses, 95% CI.

Reference 18, 22, 22, 21, 18, 18, 18, 19, 2129 25, 27, 29 24, 25, 29 22, 24 21, 22, 24, 25, 27, 29 2225, 2729 19, 22, 27, 29

No. of Trials 11 4 4 3 7 8 5

No. of Participants 4188 1279 1047 583 708 3701 1384

OR 1.35 (0.90 2.03)* 1.14 (0.811.61) 0.96 (0.64 1.44) 0.85 (0.471.52) 0.93 (0.521.65) 1.52 (1.171.97) 1.23 (0.86 1.76)

P 0.14 0.45 0.84 0.92 0.81 0.002 0.25

typing, the OR favored neither treatment arm: OR was 0.87 (95% CI 0.421.83), P 0.72. For clinical cure, the same analyses were performed. In all but 1 analysis, the OR favored short course cephalosporin: OR was 2.10 (95% CI 1.44 3.07), P 0.0001 for the 7 trials18,19,21,23,24,26,28 that were not investigator or double blind; OR was 1.98 (95% CI 1.432.73), P 0.00001 for the 7 trials18,19,21,23,26 28 with a low quality score (/ 2); OR was 1.71 (95% CI 1.29 2.26), P 0.0002 for the 8 trials18,19,23,2529 with poorly dened clinical signs and symptoms of the included patients; OR 2.34 (95% CI 1.553.54), P 0.0001 for the 4 trials19,23,26,28 that did not monitor compliance; OR was 1.83 (95% CI 1.272.61), P 0.001 for the 6 trials21,2326,28 with the test-of-cure assessment outside of the 3- to 14-day period. The OR favored neither treatment of the 3 trials19,21,26 that did not perform GAS typing; OR 1.24 (95% CI 0.44 3.46), P 0.68. Tests for statistical heterogeneity were performed for all of the analyses. There was statistical heterogeneity for the primary outcome of bacterial cure for 4- to 5-day cephalosporin treatment compared with 10-day penicillin treatment, P 0.03. However, we noted statistical heterogeneity was not present when the short course cephalosporin trials were grouped into U.S. and European trials (P 0.20 and P 0.41). The difference between the U.S. and European trials was caused by different bacterial cure rates from the 10-day penicillin therapy, 77% versus 86%, respectively; P 0.0001. The overall short course cephalosporin bacterial cure rate was not different between the U.S. and European trials, 89% versus 90%, P 0.579. We also noted that statistical heterogeneity for the 4- to 5-day cephalosporin result was not present when grouped by generation, P 0.50 and P 0.06 for second and third generation cephalosporins, respectively. Heterogeneity was not present when the same cephalosporin was compared as a 4- to 5-day and 10-day therapy; P 0.23.

Cefadroxil,20 the only rst generation cephalosporin evaluated, had bacterial cure rates that favored neither cefadroxil nor the 10-day penicillin therapy; OR 0.72 (95% CI 0.331.58), P 0.41. There were 3 trials evaluating the second generation cephalosporin cefuroxime.19,24,28 Cefuroxime achieved superior bacterial cure rates; OR 1.52 (95% CI 1.16 2.00), P 0.003. There were 3 third generation cephalosporins evaluated in 7 trials; cefpodoxime,18,21,22 cexime23,26 and cefdinir.27,29 The third generation cephalosporins produced superior bacterial cure rates when compared with 10-day penicillin therapy; OR 1.77 (95% CI 1.08 2.90), P 0.02. Individual cephalosporins were analyzed separately. Cefadroxil,20 and cefotiam25 were evaluated in one trial. Cexime23,26 and cefdinir27,29 were evaluated by 2 trials, cefuroxime19,24,28 and cefpodoxime18,21,22 in 3 trials. Cefadroxil, cefotiam and cexime did not demonstrate inferiority or superiority to 10 days of penicillin treatment: OR 0.72 (95% CI 0.331.58); OR .95 (95% CI 0.372.44); and OR 0.62 (95% CI 0.271.45), respectively. Cefdinir, cefpodoxime and cefuroxime were superior to 10 days of penicillin treatment: OR 2.39 (95% CI 1.673.41). P 0.02; OR 2.21(95% CI 1.313.74), P 0.007; and OR 1.52 (95% CI 1.16 2.00), P 0.003, respectively. Three trials (773 patients) compared 4- or 5-day treatment to 10-day treatment with the same cephalosporin. There was a trend toward superior bacterial cure rates with 10-day treatment: OR 0.70 (95% CI 0.421.14), P 0.15 (Fig. 2). However, statistical power resulting from small sample size limited the strength of conclusion for this analysis. Heterogeneity was not signicant; P 0.98. Results from trials comparing macrolide therapy for 5 days (6 trials, 1673 patients) with 10 days of penicillin treatment favored neither therapy; OR 0.79 (95% CI 0.59 1.06), P 0.11 (Fig. 3). Statistical power resulting

FIGURE 2. Short course cephalosporin therapy versus 10 days of cephalosporin therapy for GAS tonsillopharyngitis. Bacterial cure rate. 2005 Lippincott Williams & Wilkins

913

Casey and Pichichero

The Pediatric Infectious Disease Journal Volume 24, Number 10, October 2005

FIGURE 3. Short course macrolide therapy versus 10 days of penicillin therapy for GAS tonsillopharyngitis. Bacterial cure rate.

from small sample size limited the strength of conclusion for this analysis. Heterogeneity was not signicant; P 0.14. Two trials involving 309 patients, comparing 5 days of penicillin therapy with 10 days, showed short course penicillin therapy to be inferior in achieving bacterial cure; OR 0.29 (95% CI 0.13 0.63); P 0.002 (Fig. 4). Heterogeneity was not signicant; P 0.93. Six day amoxicillin therapy compared with 10-day penicillin therapy was evaluated in 2 trials with 511 patients.40,41 Results from the combined analysis favored neither therapy; OR 0.89 (95% CI 0.521.53), P 0.7. Small sample size limited the statistical power and the strength of conclusion for this analysis. Two trials20,38 did not report data on clinical cure. Therefore the primary outcome of clinical cure rate comparing a 4- to 5-day treatment course with a 10-day treatment course was assessed in 20 trials. Again the trials were grouped by short course of cephalosporins (13 trials, 4961 patients), macrolides (other than azithromycin) (6 trials, 1673 patients) and penicillin (1 trial, 137 patients). The cephalosporin trials were further grouped by the differing 10-day comparator. The summary ORs for clinical cure rate mirrored the bacterial cure rate results: 4 or 5 days of cephalosporin therapy was superior to 10 days of penicillin therapy OR 1.50 (95% CI 1.16 1.93), P 0.002, and 5 days of penicillin was inferior to 10 days OR 0.28 (95% CI 0.08 0.91), P 0.03. Small sample size limited the conclusions and statistical power of the short course macrolide trials and the trials of 4 or 5 days of cephalosporin therapy compared with 10 days. There was no signicant statistical heterogeneity for any of the analyses of the clinical cure rates: cephalosporin trials versus 10 days of penicillin therapy P 0.10 and versus 10 days of cephalosporin therapy P 0.98;

macrolide trials P 0.86; and the sole penicillin trial had no determinable heterogeneity. Secondary Outcomes. Specic compliance monitoring methods were used by 16 trials (Table 1),18,21,22,24,25,27,29 31,3339 and 6 trials gave compliance rates for each of the treatment arms.21,22,25,28,33,39 The summary OR for compliance rate signicantly favored the short course treatment OR 3.10 (95% CI 2.22 4.32), P 0.00001 (Fig. 5). Adverse events associated with the antibiotic therapy were reported in 15 of 22 trials. The majority of events were gastrointestinal complaints. Eleven trials2527,29,31,3335,37,40,41 reported specic rates for both treatment arms. The rate of adverse events was equivalent between short course treatment and the 10-day treatment comparator OR 1.01 (95% CI 0.80 1.27), P 0.9. One trial25 found signicantly lower adverse events in the short course treatment group. Statistical heterogeneity was assessed for the secondary outcomes of compliance and adverse event rates, and this approached signicance at P 0.06 for both. Publication Bias. Funnel plot analysis revealed no asymmetry (data not shown). Therefore publication bias, or bias introduced by smaller studies, was not found.

DISCUSSION
This metaanalysis shows that superior bacteriologic cure rates can be achieved with 4 or 5 days of treatment with an oral cephalosporin as compared with penicillin treatment of 10 days. Analysis of trials to date do not favor either short course macrolide therapy compared with 10-day penicillin therapy or short course treatment of a cephalosporin compared with 10-day cephalosporin treatment. With metaanalysis, 5 days of penicillin is conrmed to be inferior to 10 days

FIGURE 4. Penicillin 10 days versus 10 days of penicillin therapy for GAS tonsillopharyngitis. Bacterial cure rate.

914

2005 Lippincott Williams & Wilkins

The Pediatric Infectious Disease Journal Volume 24, Number 10, October 2005

GAS Tonsillopharyngitis

FIGURE 5. Short course therapy versus 10-day comparator antibiotic therapy for GAS tonsillopharyngitis. Compliance rate.

of treatment. The 2 amoxicillin trials comparing 6 days of therapy were small, and there was insufcient power to conclude that there was a signicant difference with 10 days of penicillin treatment. There are important issues in interpreting the results of this metaanalysis. First, the trials were grouped according to the individual antibiotic (penicillin V) or the class of antibiotic (macrolides and cephalosporins). This grouping allowed trials evaluating the same antibiotic or antibiotics with similar pharmacokinetic/pharmacodynamic properties to be assessed together. Trials evaluating azithromycin were not included in this metaanalysis given that the action of azithromycin is not of short duration even though the antibiotic is administered for 5 days or fewer. We have analyzed and reported those results in another publication.42 There were 6 trials in the macrolide group, studying 4 different macrolides (erythromycin estolate, josamycin, clarithromycin and telithromycin), grouped together. The cephalosporin group included 7 different cephalosporins (1, rst generation; 2, second generation; and 4, third generation). The 22 trials included in this metaanalysis were randomized, prospective, trials; however, they were of varying quality according to the Jadad scale and used different methodologic designs. Sensitivity analysis was used to address this issue. The bacterial cure rates of short course cephalosporins as compared with 10-day penicillin therapy was remained superior in every analysis. When we performed a subset analysis on the 6 subsets of trials that were not in the sensitivity analysis of bacterial and clinical cure rate, 5 of 6 subsets maintained statistical signicance, and 1 subset analysis was not signicant. This approach enhances the statistical robustness of the overall analysis and strengthens the condence about the appropriateness of combining all of the studies into a single metaanalysis. In GAS tonsillopharyngitis, as in other communityacquired upper respiratory infections such as acute otitis media and sinusitis, one of the most common reasons for treatment failure is poor patient compliance.6 12 Therefore it is important that a compliance-enhancing antibiotic regimen be chosen. Poor compliance appears to be more common with longer treatment courses, because patients tend to stop their medication once symptoms have resolved.10 This typically occurs after 35 days in GAS tonsillopharyngitis. Given this reality of patient behavior, it is quite rational to prescribe short course therapy if it is as effective as the standard 10-day antibiotic treatment course. A metaanalysis comparing shortened course treatment to 10 days of treatment for acute otitis
2005 Lippincott Williams & Wilkins

media in children found that the short course treatments were as effective as the 10-day treatment.43 The results of this metaanalysis show that short course treatment of GAS tonsillopharyngitis, another common upper respiratory infection, is as effective as, or even more effective than, the standard 10-day penicillin treatment if a cephalosporin is used. Adverse events from antibiotic therapy are a common reason for poor patient compliance and can cause overall increased treatment costs due to additional physician visits, medications and monitoring. Shortened course treatment has been shown to reduce adverse events associated with antibiotic therapy.44,45 Although the overall the adverse event rates were equivalent in this metaanalysis between the short course treatment and the 10-day comparator, several of the trials included in this metaanalysis demonstrated fewer adverse events with the short course treatment arm. Another important advantage of shortened therapy is the reduced impact on development of antibiotic resistance and nasopharyngeal colonization with resistant bacteria. Guillemot et al46 showed that inappropriate low dosages of aminopenicillins or third generation cephalosporins in children (as may occur in the latter half of a 10-day treatment course when patient compliance falls) is associated with an increased risk of penicillin-resistant Streptococcus pneumoniae nasopharyngeal carriage. Additionally their ndings showed that longer duration of treatment was associated with increased risk of resistant S. pneumoniae carriage. Short course high dose therapy for GAS tonsillopharyngitis has the potential to have a positive impact on this important complication of antibiotic treatment. Metaanalysis as a statistical tool has shortcomings. Specically, a metaanalysis can incorporate existing biases from the included trials and introduce additional new biases.47 49 To minimize bias during trial selection, we used predetermined inclusion criteria. Publication bias was assessed,50 and no signicant bias was evident. Statistical and clinical heterogeneity is a potential hazard of metaanalyses. Even though the trials included in this metaanalysis evaluated different antibiotics in both children and adults, signicant heterogeneity was found only with the cephalosporin class and was eliminated when trials were grouped and analyzed by U.S. versus non-U.S. sites. Lastly statistical power was limited in several of the analyses because of small sample size; larger samples or additional studies would be of value in clarifying the comparator efcacy of short courses of macrolides and amoxicillin.

915

Casey and Pichichero

The Pediatric Infectious Disease Journal Volume 24, Number 10, October 2005

In conclusion, this metaanalysis shows that short course treatment of GAS tonsillopharyngitis can be more effective when prescribing 4 or 5 days of cefdinir, cefpodoxime or cefuroxime treatment than the standard 10-day treatment of penicillin. In the United States, 3 antibiotics have an indication for short course treatment of GAS tonsillopharyngitis, cefdinir, cefpodoxime and azithromycin, and meet the medicolegal standard of care. A 5-day treatment with cefuroxime was more effective than a 10-day penicillin treatment; however, it is not approved in the United States for a shortened course of treatment. The data to date are insufcient to recommend short course macrolide or amoxicillin treatment. Shortened course antibiotic therapy for GAS tonsillopharyngitis has the potential to improve the treatment efcacy by producing better compliance and fewer adverse events. REFERENCES
1. McCraig LF, Besser RE, Hughes JM. Trends in antimicrobial prescribing rates for children and adolescents. JAMA. 2002;287:3096 3102. 2. Denny FW, Wannamaker LW, Brink WR, Rammelkamp CH Jr, Custer EA. Prevention of rheumatic fever. JAMA. 1950;143:151153. 3. Wannamaker LW, Rammelkamp CH Jr, Denny FW, et al. Prophylaxis of acute rheumatic fever by treatment of the preceding streptococcal infection with various amounts of depot penicillin. Am J Med. 1951;10: 673395. 4. Wannamaker LW, Denny FW, Perry WD, et al. The effect of penicillin prophylaxis on streptococcal disease rates and the carrier state. N Engl J Med. 1953;249:17. 5. Breese BB. Treatment of -hemolytic streptococcic infections in the home. JAMA. 1953;152:10 14. 6. Mohler DN, Wallin DG, Dreyfus EG. Studies in the home treatment of streptococcal disease, I: failure of patients to take penicillin by mouth as prescribed. N Engl J Med. 1955;252:1116 1118. 7. Bergman AB, Werner RJ. Failure of children to receive penicillin by mouth. N Engl J Med. 1963;268:1334 1338. 8. Leistyna JA, Macaulay JC. Therapy of streptococcal infections: do pediatric patients receive prescribed oral medication? Am J Dis Child. 1966;111:2226. 9. Charney E, Bynum R, Eldredge D, et al. How well do patients take oral penicillin? A collaborative study in private practice. Pediatrics. 1967; 40:188 195. 10. Green JL, Ray SP, Charney E. Recurrence rate of streptococcal pharyngitis related to oral penicillin. J Pediatr. 1969;75:292294. 11. Schwartz RH, Rodriquez WJ, Grundfast KM. Pharmacologic compliance with antibiotic therapy for acute otitis media: inuence on subsequent middle ear effusion. Pediatrics. 1981;68:619 622. 12. Finney JW, Friman PC, Rapoff MA, Christophersen ER. Improving compliance with antibiotic regimens for otitis media. Am J Dis Child. 1985;139:89 95. 13. Jadad AR, Moore RA, Carroll D, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials. 1996;17:112. 14. Peto R, Collins R, Gray R. Large-scale randomized evidence: Large, simple trials and overviews of trials. J Clin Epidemiol. 1995;48:23 40. 15. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7:177188. 16. Thompson SG. Why sources of heterogeneity in meta-analysis should be investigated. BMJ. 1994;309:13511355. 17. Deeks JJ, Altman DG, Bradburn MJ. Fifteen statistical methods for examining heterogeneity and combining results from several studies in meta-analysis. In: Egger M, Smith G, Attman D, eds. Systematic Reviews in Health Care. 2nd ed. Oxford, United Kingdom: Blackwell BMJ Books; 2001:285312. 18. Portier H, Chavanet P, Gouyan JB, Guetar F. Five day treatment of pharyngotonsillitis with cefpodoxime proxetil. J Antimicrob Chemother. 1990;26(suppl E):79 85. 19. Gehanno P, Chiche E. Traitement des angines a streptocoque hemolytique du groupe A par le cefuroxime axetil pendant 4 jours: etude

20. 21.

22. 23. 24.

25.

26. 27. 28.

29. 30. 31. 32. 33.

34.

35.

36.

37.

38. 39.

comparative a la penicilline V pendant 10 jours. Med Mal Infect. 1991;21:66 70. Milatovic D. Evaluation of cefadroxil, penicillin, and erythromycin in the treatment of streptococcal tonsillopharyngitis. Pediatr Infect Dis J. 1991;10:S61S63. Portier H, Chavanet P, Waldner-Combernoux A, et al. Five versus ten days treatment of streptococcal pharyngotonsillitis: a randomized controlled trial comparing cefpodoxime proxetil and phenoxymethyl penicillin. Scand J Infect Dis. 1994;26:59 66. Pichichero ME, Gooch WM, Rodriguez M, et al. Effective short-course treatment of acute group A -hemolytic streptococcal tonsillopharyngitis. Arch Pediatr Adolesc Med. 1994;148:10531060. Peyramond D, Tigaud S, Bremard-Oury C, Scheimberg A. Multicenter comparative trial of cexime and phenoxymethylpenicillin for group A -hemolytic streptococcal tonsillitis. Curr Ther Res. 1994;55(A):14 21. Aujard Y, Boucot I, Brahimi N, Chiche D, Bingen E. Comparative efcacy and safety of four-day cefuroxime axetil and ten-day penicillin treatment of group A -hemolytic streptococcal pharyngitis in children. Pediatr Infect Dis J. 1995;14:295300. Carbon C, Chatelin A, Bingen E, et al. A double-blind randomized trial comparing the efcacy and safety of a 5-day course of cefotiam hexetil with that of a 10-day course of penicillin V in adult patients with pharyngitis caused by group A -haemolytic streptococci. J Antimicrob Chemother. 1995;35:843 854. Adam D, Group Cexime Study, Hostalk U, Troster K. Five-day cexime therapy for bacterial pharyngitis and/or tonsillitis: comparison with 10-day penicillin V therapy. Infection. 1995;23(suppl 2):S83S86. Tack KJ, Henry DC, Gooch WM, et al. Five-day cefdinir treatment of streptococcal pharyngitis. Antimicrob Agents Chemother. 1998;42:1073 1075. Adam D, Scholz H, Helmerking M. Comparison of short-course (5 day) cefuroxime axetil with a standard 10 day oral penicillin V regimen in the treatment of tonsillopharyngitis. J Antimicrob Chemother. 2000;45: 2330. Tack KJ, Hedrick JA, Rothstein E, et al. A study of 5-day cefdinir treatment for streptococcal pharyngitis in children. Arch Pediatr Adolesc Med. 1997;151:45 49. Esposito S, Noviello S, Iannielo F, DErrico G. Short-course therapy with cefaclor for treatment of streptococcal pharyngotonsillitis. Int J Antimicrob Agents. 2001;18:341345. Mehra S, VanMoerkerke M, Melck J, et al. Short course therapy with cefuroxime axetil for group A streptococcal tonsillopharyngitis in children. Pediatr Infect Dis J. 1998;17:452 457. Portier H, Lucht F, Lescale O, et al. Josamycine 5 jours versus penicilline V 10 jours dans le traitement des angines aigues a streptocoque -hemolytique du groupe A. Med Mal Infect. 1995;25:10051010. Adam D, Scholz H, Pharyngitis Study Group. Five days of erythromycin estolate versus ten days of penicillin V in the treatment of group A streptococcal tonsillopharyngitis in children. Eur J Clin Microbiol Infect Dis. 1996;15:712717. Portier H, Filipecki J, Weber F, et al. Five day clarithromycin modied release versus 10 day penicillin V for group A streptococcal pharyngitis: a multi-centre, open-label, randomized study. J Antimicrob Chemother. 2002;49:337344. Norrby SR, Rabie WJ, Bacart P, et al. Efcacy of short-course therapy with the ketolide telithromycin compared with 10 days of penicillin V for the treatment of pharyngitis/tonsillitis. Scand J Infect Dis. 2002;33: 883 890. Takker U, Dzyublyk O, Busman T, Notario G. Comparison of 5 days of extended-release clarithromycin versus 10 days of penicillin V for the treatment of streptococcal pharyngitis/tonsillitis: results of a multicenter, double-blind, randomized study in adolescent and adult patients. Curr Med Res Opin. 2003;19:421 429. Syrogiannopoulos GA, Bozdogan B, Grivea IN, et al. Two dosages of clarithromycin for ve days, amoxicillin/clavulanate for ve days or penicillin V for ten days in acute group A streptococcal tonsillopharyngitis. Pediatr Infect Dis J. 2004;23:857 865. Gerber MA, Randolph MF, Chanatry J, et al. Five vs. ten days of penicillin V therapy for streptococcal pharyngitis. Am J Dis Child. 1987;141:224 227. Stromberg A, Schwan A, Cars O. Five versus ten days treatment of group A streptococcal pharyngotonsillitis: a randomized controlled clin-

916

2005 Lippincott Williams & Wilkins

The Pediatric Infectious Disease Journal Volume 24, Number 10, October 2005

GAS Tonsillopharyngitis

40.

41. 42. 43. 44. 45.

ical trial with phenoxymethyl-penicillin and cefadroxil. Scand J Infect Dis. 1988;20:37 46. Clamorange French Study Group.Peyramond D, Portier H, Geslina P, Cohen R, Six-day amoxicillin versus 10-day penicillin V for group A -haemolytic streptococcal acute tonsillitis in adults: a French multicentre, open-label, randomized study. Scand J Infect Dis. 1996;28:497501. Cohen R, Levy C, Doit C, et al. Six-day amoxicillin vs. ten-day penicillin V therapy for group A streptococcal tonsillopharyngitis. Pediatr Infect Dis J. 1996;15:678 682. Casey JR, Pichichero ME. Higher dosages of azithromycin are more effective in group A streptococcal tonsillopharyngitis treatment. Clin Infect Dis. 2005;40:1748 1755. Kozyrskyj AL, Hildes-Ripstein E, Longstaffe SEA, et al. Treatment of acute otitis media with a shortened course of antibiotics: a meta-analysis. JAMA. 1998;279:1736 1742. Gooch WM, Blair E, Puopolo A, et al. Effectiveness of ve days of therapy with cefuroxime axetil suspension for treatment of acute otitis media. Pediatr Infect Dis J. 1996;15:157164. Gehanno P, Taillebe M, Denis P, al et. Short course cefotaxime compared with 5-day co-amoxyclav in acute otitis media in children. J Antimicrob Chemother. 1990;26(suppl A):29 36.

46. Guillemot D, Carbon C, Balkau B, Geslin P, Lecoeur H, et al. Low dosage and long treatment duration of -lactam: risk factors for carriage of penicillin resistant Streptococcus pneumoniae. JAMA. 1998;279:365 370. 47. Moher D, Cook DJ, Eastwood S, et al. Improving the quality of reports from meta-analyses of randomized controlled trials: the QUOROM statement. Lancet. 1999;354:1896 1900. 48. Moher D, Pham B, Jones A, et al. Does quality of reports of randomized trials affect estimates of intervention efcacy reported in meta-analyses? Lancet. 1998;352:609 613. 49. Egger M, Smith GD, Schneider M, Minder C. Bias in meta-analysis detected by simple, graphical test. BMJ. 1997;315:629 634. 50. Schultz KF, Chalmers I, Hayes RJ, Altman DG. Empirical evidence of bias: dimensions of methodological quality associated with estimates of treatment effects in controlled trials. JAMA. 1995;273:408 412. 51. Casey JR, Pichichero ME. In: Interscience Conference on Antimicrobial Agents and Chemotherapy, October 30 November 2, 2004, Washington, DC. Washington, DC: American Society for Microbiology; 2004.

2005 Lippincott Williams & Wilkins

917