Issuu on Google+

MAJOR ARTICLE

Higher Dosages of Azithromycin Are More Effective in Treatment of Group A Streptococcal Tonsillopharyngitis Janet R. Casey1 and Michael E. Pichichero2 Departments of 1Pediatrics and 2Microbiology/Immunology, Elmwood Pediatric Group, University of Rochester Medical Center, New York

Streptococcus pyogenes (group A streptococcus [GAS]) is the most common bacterial cause of tonsillopharyngitis requiring treatment with antibiotics. Prevention of acute rheumatic fever is the principle goal of treatment, although antibiotic therapy may also relieve the signs and symptoms of infection, shorten the infective period, and prevent suppurative complications [1, 2]. Penicillin has been the recommended drug of choice

Received 19 November 2004; accepted 26 January 2005; electronically published 13 May 2005. Presented in part: 44th Annual Meeting of the Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington, D.C., October 2004. Reprints or correspondence: Dr. Janet R. Casey, Elmwood Pediatric Group, 125 Lattimore Rd., Rochester, NY 14620 (jrcasey@rochester.rr.com). Clinical Infectious Diseases 2005; 40:1748–55  2005 by the Infectious Diseases Society of America. All rights reserved. 1058-4838/2005/4012-0007$15.00

1748 • CID 2005:40 (15 June) • Casey and Pichichero

for the treatment of GAS tonsillopharyngitis since the early 1950s [3–7]. Guidelines published by the Infectious Diseases Society of America recommend erythromycin as treatment for patients who have allergic reactions to penicillin [8]. Unfortunately, an estimated one-third of patients do not complete therapy with erythromycin because of drug-induced adverse events. The need for multiple daily doses and 10-day treatment regimens also compromises the efficacy of erythromycin therapy. Gastrointestinal adverse effects are frequent with erythromycin, and they limit its usefulness [9–11]. Because of the significant compliance barriers associated with erythromycin, azithromycin—with its convenient once-daily dosing for 3 or 5 days and its lower risk of gastrointestinal adverse events—has become a frequent choice for the treatment of GAS tonsillopharyngitis [12]. In the United States, azithromycin

Downloaded from http://cid.oxfordjournals.org/ by guest on April 30, 2012

Background. Azithromycin has become a frequent choice for the treatment of group A streptococcal (GAS) tonsillopharyngitis. In this study, our objective was to determine the optimal dose of azithromycin for treatment of GAS tonsillopharyngitis in children and adults by analyzing trials that used different dose regimens. Methods. We performed a meta-analysis of randomized, controlled trials that involved bacteriological confirmation of GAS tonsillopharyngitis, random assignment to receive either azithromycin or a 10-day comparator antibiotic, and assessment of bacteriological eradication by throat culture after therapy. The primary outcomes of interest were bacteriological and clinical cure rates. Results. Nineteen trials involving 4626 patients were included in the analysis. One trial used 10-day course of 2 different comparator antibiotics, and 2 trials compared 2 dose regimens of azithromycin with a 10-day course of comparator antibiotic; all other trials compared 1 dose regimen of azithromycin with a single 10-day course of comparator antibiotic. In children, azithromycin administered at 60 mg/kg per course was superior to the 10day courses of comparators (P ! .00001 ), with bacterial failure occurring 5 times more often in patients receiving the 10-day courses of antibiotics. Azithromycin administered at 30 mg/kg per course was inferior to the 10-day courses of comparators (P p .02 ), with bacterial failure occurring 3 times more frequently in patients receiving azithromycin. Three-day regimens were inferior to 5-day regimens (P p .002 ). In adults, no studies compared dosages by weight. Three-day regimens of 500 mg/day showed a trend favoring azithromycin over the 10-day courses of comparators (P p .14); 5-day regimens were inferior to 3-day regimens (Pp.006). Clinical cure rates were significantly different for the different azithromycin regimens, with differences that resembled those for bacterial cure rate. Conclusion. This analysis suggests that azithromycin administered at a dosage of 60 mg/kg in children or administered for 3 days at a dosage of 500 mg/day in adults is more effective than other treatment regimens in producing eradication and clinical cure of GAS tonsillopharyngitis.


is approved for treatment of GAS tonsillopharyngitis in children at a regimen of 12 mg/kg per day for 5 days; outside the United States, the approved treatment regimen for children is 10–12 mg/kg per day for 3 days. In the United States, a 5-day regimen of azithromycin is approved for treatment of GAS tonsillopharyngitis in adults; outside the United States, a 3-day regimen is approved. This study uses meta-analytic techniques to evaluate published, randomized, controlled trials involving GAS tonsillopharyngitis to determine the optimal treatment regimen for azithromycin. The results strongly suggest that regulatory agencies in the United States and Europe have licensed azithromycin for treatment durations and/or dosages that are suboptimal, compared with standard therapy. METHODS

RESULTS The MEDLINE and Embase searches yielded 56 citations, 38 of which were randomized, clinical trials that compared a shortcourse treatment (i.e., !10 days) with a 10-day treatment course for GAS tonsillopharyngitis. Six trials were identified from reference listings. Forty-four citations were further assessed according to the inclusion criteria. Twenty-five of these trials were excluded from the meta-analysis for the following reasons: the short-course treatment did not use azithromycin; the data presented were a re-publication of previous data already present in trials included in the meta-analysis; or the publication could not be obtained for review. This left 19 publications [18–36]; of these, 1 publication used 10-day courses of 2 different comparator antibiotics [24], 2 publications used 2 different dose regimens for azithromycin, [22, 27], and 3 publications were abstracts presented at national conferences [29–31]. Fourteen of the 19 trials were pediatric studies, and 5 were adult trials (table 1). Six different antibiotics were used as comparator drugs, with penicillin being used most frequently (in 10 of the trials). The total dose of azithromycin was either 30 mg/kg (given as 10 mg/kg per day for 3 days or 10 mg/kg per day on day 1 and 5 mg/kg per day for days 2–5) or 60 mg/kg (given as 20 mg/kg for 3 days or 12 mg/kg /day for 5 days) in the pediatric trials. In the adult trials, the azithromycin dosage was either 500 mg on day 1 and 250 mg on days 2–5 (for 5day regimens) or 500 mg on days 1–3 (for 3-day regimens). For the 19 trials of azithromycin, the duration of treatment was 3 days in 15 trials and 5 days in 4 trials. Table 1 also details the methodological aspects of the inAzithromycin in GAS Tonsillopharyngitis • CID 2005:40 (15 June) • 1749

Downloaded from http://cid.oxfordjournals.org/ by guest on April 30, 2012

Randomized, controlled trials of azithromycin and a 10-day course of comparator antibiotic for the treatment of GAS tonsillopharyngitis in children and adults were identified from searches of the MEDLINE database (which contains citations from 1966 through 2004) and the Embase database (which contains citations from 1970 through 2004). The searches had no language restriction; the search terms used were “streptococcal pharyngitis,” “streptococcal tonsillitis,” “azithromycin,” “macrolide,” “cephalosporin,” and “penicillin.” Reference lists of included trials and relevant review articles were reviewed to identify additional trials. Abstracts from meetings of the Interscience Conference on Antimicrobial Agents and Chemotherapy, the Infectious Diseases Society of America, and the Society for Pediatric Research were searched to identify relevant trials that had not been published. Trials comparing azithromycin therapy and a 10-day course of treatment with a comparator antibiotic for GAS tonsillopharyngitis infections were reviewed independently by the authors for inclusion according to the following criteria: bacterial confirmation of GAS tonsillopharyngitis at study enrollment; random assignment to azithromycin treatment or a 10-day course of treatment with a comparator antibiotic; and assessment of bacteriological outcome using a throat culture after therapy. The quality of the included trials was assessed using the Jadad scale. The scale assigns scores from 0 (lowest-quality trial) to 5 (highest-quality trial) on the basis of the following criteria: random allocation of treatment and specification of the appropriate method, such as a random-number table, in the text of the trial (2 points); double-blind trial design (2 points); and a complete accounting and description of study withdrawals (1 point) [13] The primary outcome of interest was bacteriological cure, defined as the failure to isolate GAS from cultures of throat swab samples obtained after completion of the antibiotic course. Most trials had an “early” and “late” follow-up evaluation; when possible, the “early” follow-up result was used in

this analysis. The secondary outcome of interest was clinical cure, defined as the absence of GAS on throat culture and the resolution of or improvement in the presenting signs and symptoms of GAS infection on completion of the antibiotic course and throughout follow-up. This meta-analysis was conducted using Revman, version 4.2 (Cochrane). Differences in bacteriological cure rates after azithromycin treatment, compared with after 10-day courses of antibiotic treatment, were calculated and expressed as ORs with 95% CIs. An OR of 11 indicated a higher bacteriological cure rate for the azithromycin treatment than for the 10-day courses of antibiotic treatment. ORs were calculated for individual trial outcomes, and a summary OR was determined for trials grouped into pediatric and adult trials and further grouped by dose (30 mg/kg total treatment dose vs. 60 mg/kg total treatment dose) and by duration of azithromycin treatment (3 days vs. 5 days). Two methods were used to calculate ORs: the Peto fixed-effects model [14], which assumes trial homogeneity, and the DerSimonian and Laird random-effects model [15], which assumes trial heterogeneity. Statistical heterogeneity among the trials was assessed by x2 analysis [16, 17].


Table 1. Methodological details of trials comparing azithromycin therapy with 10-day comparator antibiotic therapy for treatment of group A streptococcal (GAS) tonsillopharyngitis.

Trial subjects, study Pediatric Hamill [18] Weippl [19]

Azithromycin course (no. of subjects)

Comparator antibiotic (no. of subjects)

QS

10 mg/kg per day for 3 days (41) 10 mg/kg per day for 3 days (44)

Penicillin V (44) Erythromycin estolate (46)

2 2

Open-label Open-label

No details Not reported No details Not reported

Yes No

9–11 days 10–11 days

Penicillin V (78) Penicillin V (160) Penicillin V (132)

3 3 4

Open-label Open-label Double-blind

Detailed TC, RC Detailed PQ No details TC

Yes Yes Yes

12–14 days 9–20 days 12–14 days

Clarithromycin (99) Amoxicillin-clavulanate (19); Cefaclor (12) Clarithromycin (63) Cefaclor (46) Penicillin V (146)

1 2

Open-label Open-label

No details Not reported Detailed Not reported

No No

3 days 14 days

2 2 3

Investigator blinded Detailed Not reported No 17–20 days Open-label No details Not reported Yes 7–25 days Azithromycin; arms, Detailed TC, RS Yes, DNA 4–11 days double-blind

Pacifico et al. [20] 10 mg/kg per day for 3 days (76) Schaad and Heynen [21] 10 mg/kg per day for 3 days (160) O’Doherty [22] 10 mg/kg per day for 3 days (123); 20 mg/kg per day for 3 days (103) Padilla-Raygoza [23] 10 mg/kg per day for 3 days (112) Garcia Callejo et al. [24] 10 mg/kg per day for 3 days (74) Venuta et al. [25] Cremer et al. [26] Cohen et al. [27]

Schaad et al. [28] Still [29] Still [30] Still [31] Adult Muller [32] Muller [33] O’Doherty [34] Hooten [35] Kaplan et al. [36]

NOTE.

500 mg per day for 3 days (71) 500 mg per day for 3 days (74) 500 mg per day for 3 days (117) 500 mg on day 1 and 250 mg on days 2–5 (152) 500 mg on day 1 and 250 mg on days 2–5 (198)

Clinical status

Compliance Serotyping Test-of-cure monitoring performed daya

Penicillin V (130) Penicillin V (87)

2 Open-label Abstract Open-label

No details Not reported No details Not reported

Yes No

4–9 days 11 days

Penicillin V (190) Penicillin V (127)

Abstract Double-blind Abstract Double-blind

No details Not reported No details Not reported

No No

14 days 14 days

No No No No

No No No No

10–14 days 11–15 days 11–15 days 11 days

Yes

13–19 days

Clarithromyicn (73) Roxithromycin (63) Cefaclor (119) Penicillin (90)

2 2 2 3

Open-label Open-label Open-label Open-label

Clarithromyicn (194)

3

Investigator blinded Detailed

PQ, patient/parent questioned; QS, Jadad quality score; RC, record card; TC, tablet count.

Test-of-cure day is recorded as day after start of medication.

Downloaded from http://cid.oxfordjournals.org/ by guest on April 30, 2012

a

10 mg/kg per day for 3 days (74) 10 mg/kg per day for 3 days (52) 10 mg/kg per day for 3 days (135); 20 mg/kg per day for 3 days (139) 10 mg/kg per day for 3 days (141) 10 mg/kg on 1 day and 5 mg/kg per day on days 2–5 days (81) 12 mg/kg per day for 5 days (176) 12 mg/kg per day for 5 days (147)

Concealment of treatment allocation

details details details details

Not Not Not Not TC

reported reported reported reported


romycin treatment (either 3 or 5 days) (figures 1–3). When the pediatric trials were analyzed according to the total treatment dose of azithromycin, there was a striking difference in outcome. The summary OR for bacterial cure rate favored the comparator regimen when the total azithromycin dose was 30 mg/kg (OR, 0.47; 95% CI, 0.24–0.91; P p .02). Conversely, when the total azithromycin dose was 60 mg/kg, the summary OR for bacterial cure rate significantly favored azithromycin (OR, 5.27; 95% CI, 3.34–8.32; P ! .00001) (figure 1). All 5 adult trials, involving a total of 1070 patients, evaluated only the 30mg/kg total dose of azithromycin. In these trials, the bacterial cure rate favored neither azithromycin nor the comparators (summary OR, 0.86; 95% CI, 0.37–1.99; P p .73) (figure 2). Results of the pediatric trials, analyzed according to the length of azithromycin treatment (3 or 5 days), are shown in figure 3. The bacterial cure rate favored neither the comparators nor azithromycin when the 3-day azithromycin trials were analyzed (summary OR, 0.62; 95% CI, 0.30–1.27; P p .19) but favored azithromycin when the 5-day trials were analyzed (summary OR, 4.37; 95% CI, 1.70–11.27; P p .002). In adults, the 3-day trials (all with 500 mg/day dosing) had bacterial cure rates favoring neither azithromycin nor the comparators (summary OR, 1.87; 95% CI, 0.81–4.27; P p .14). However, the 10day courses of comparators were statistically superior to the 5day course of azithromycin (known as the “Z Pak”) (OR, 0.41; 95% CI, 0.22–0.78; P p .006) (figure 2). All trials reported clinical cure rates. The studies were grouped into pediatric trials and adult trials and were further divided according to dose (either 30-mg/kg total dose or 60-

Figure 1. Bacterial cure rates in pediatric trials comparing azithromycin therapy with 10-day comparator antibiotic therapy (10-day comp) for treatment of group A streptococcal tonsillopharyngitis. Studies are grouped according to total treatment dose of azithromycin (30 mg/kg or 60 mg/kg). Azithromycin in GAS Tonsillopharyngitis • CID 2005:40 (15 June) • 1751

Downloaded from http://cid.oxfordjournals.org/ by guest on April 30, 2012

cluded trials. The mean Jadad quality score (SD) for the trials, excluding the abstracts, was 2.5 (.8), out of a maximum score of 5; 38% of the trials were of relatively high quality (Jadad score, 12). One trial [22] was double-blind, and another trial [27] had the azithromycin arms blinded. The investigators were blinded to treatment allocation in 2 other trials [25, 36]. Five of the trials [29–31, 35, 36] were conducted in multiple outpatient treatment sites in the United States. The remaining trials were conducted in 7 countries other than the United States. All trials required isolation of GAS from a throat culture for inclusion in the study. Most trials used rapid antigen testing at enrollment but excluded patients from the study if the throat culture did not grow GAS. Fifteen of the trials gave detailed descriptions of the clinical signs and symptoms of the study subjects at enrollment. Detailed compliance monitoring was performed in 7 of the trials; 2 trials [25, 27] reported a statistical difference in compliance favoring the azithromycin treatment. Serotyping or genotyping of GAS at enrollment and again if GAS was isolated at a follow-up visit was performed in 8 trials. True bacterial failure rates from these 8 trials were used in this meta-analysis. The timing of the test-of-cure follow-up culture varied among the trials; most trials had an early and a late follow-up visit and culture. When possible, bacteriological and clinical cure rates used in this meta-analysis were taken from the early follow-up test-of-cure visit. The primary outcome analyzed was bacterial cure rate. The studies were grouped into pediatric trials and adult trials and were further classified by azithromycin dose (either 30-mg/kg total dose or 60-mg/kg total dose) and by duration of azith-


mg/kg total dose) and duration of treatment (either 3 or 5 days). When the pediatric trials were divided according to the azithromycin total treatment dose, there was a difference in outcome. The summary OR for clinical cure rate favored neither the comparator regimen nor the 30-mg/kg total azithromycin dose (summary OR, 0.92; 95% CI, 0.46–1.83; P p .80), but the 60-mg/kg total azithromycin dose significantly favored

azithromycin (summary OR, 7.51; 95% CI, 3.66–15.39; P ! .00001). The clinical cure rate favored neither azithromycin treatment nor the 10-day courses of comparators in adults (summary OR, 0.86; 95% CI, 0.37–1.99; P p .73). The clinical cure rate favored neither azithromycin nor the comparators when the 3-day azithromycin pediatric trials were analyzed (summary OR, 1.04; 95% CI, 0.51–2.13; P p .91) and

Figure 3. Bacterial cure rates in pediatric trials comparing azithromycin therapy with 10-day comparator antibiotic therapy (10-day comp) for treatment of group A streptococcal tonsillopharyngitis. Studies are grouped according to whether a 3-day or 5-day course of azithromycin was used. 1752 • CID 2005:40 (15 June) • Casey and Pichichero

Downloaded from http://cid.oxfordjournals.org/ by guest on April 30, 2012

Figure 2. Bacterial cure rates in adult trials comparing azithromycin therapy with 10-day comparator antibiotic therapy (10-day comp) for treatment of group A streptococcal tonsillopharyngitis. All studies used a total treatment dose of azithromycin of 30 mg/kg. Comparisons are shown for all trials and for trials grouped according to whether a 3-day or 5-day course of azithromycin was used.


favored azithromycin when the 5-day pediatric trials were analyzed (summary OR, 6.80; 95% CI, 3.30–14.01; P ! .00001). The 3-day (summary OR, 0.56; 95% CI, 0.22–1.46; P p .23) and 5-day (summary OR, 1.53; 95% CI, 0.69–3.38; P p .29) adult trial clinical cure rates favored neither azithromycin nor the comparators. There was significant heterogeneity among the pediatric trials. To evaluate this heterogeneity further, the 7 pediatric trials using penicillin as a comparator were grouped and analyzed; the bacterial cure rate favored neither azithromycin nor the 10day penicillin therapy (OR, 0.49; 95% CI, 0.20–1.17), and statistical heterogeneity persisted (P ! .00001 ). With a jackknife analysis (in which studies are eliminated from the analysis one at a time and then in groups), statistical heterogeneity persisted until 3 of the studies with the widest 95% CIs [22, 24, 31] were excluded.

This paper examined the results of azithromycin trials involving children and adults with GAS tonsillopharyngitis. We found that, in pediatric trials, a total dose of 60 mg/kg (administered either as 20 mg/kg for 3 days or 12 mg/kg for 5 days) was superior to the 10-day comparator antibiotic therapy (with penicillin, erythromycin estolate, amoxicillin-clavulanate, cefaclor, or clarithromycin) in bacteriological eradication. In contrast, an azithromycin total dose of 30 mg/kg (administered as either 10 mg/kg for 3 days or 10 mg/kg for 1 day followed by 5 mg/kg for 4 days) resulted in bacteriological eradication that was inferior to that acheived with the 10-day comparator antibiotic therapy. In adults, only the 30 mg/kg total azithromycin dose was compared with a 10-day antibiotic regimen, and we found bacteriological eradication rates favored neither azithromycin nor the comparators. However, results acheived with the US-approved 5-day azithromycin dose schedule (“Z Pak”) were significantly inferior to those acheived with the 10-day comparator therapy (P p .006). Paradoxically, the 3-day regimen approved outside the United States for azithromycin treatment (using the same total dose as the 5-day regimen) neared a significantly better outcome, compared with that for the 10-day comparator treatment. However, the width of the 95% CI makes it difficult to conclude superiority for either treatment regimen. The 3 trials involving 3-day treatment were conducted in Europe, and the 2 trials involving 5-day treatment were conducted in the United States. At the time the studies were conducted, macrolide-resistant GAS strains were not widely prevalent in Europe or the United States. Patients with GAS tonsillopharyngitis experience clinical improvement over time, with or without antibiotic therapy. Therefore, measurement of clinical response during treatment is largely meaningless in antibiotic trials. However, after comple-

Azithromycin in GAS Tonsillopharyngitis • CID 2005:40 (15 June) • 1753

Downloaded from http://cid.oxfordjournals.org/ by guest on April 30, 2012

DISCUSSION

tion of therapy, some patients experience relapse or recurrence with symptoms and signs of tonsillopharyngitis and with recovery of GAS on culture of a throat swab sample. Such patients are more likely to have bona fide renewed risks for suppurative and nonsuppurative sequelae and are less likely to be GAS carriers [37]. The 60-mg/kg total azithromycin dose demonstrated superior clinical cure rates in children, compared with 10-day comparator regimen. In all other comparisons, the width of the 95% CIs precludes any conclusion about the superiority of one treatment over another. The use of meta-analysis as a statistical tool involves certain shortcomings. Specifically, a meta-analysis can incorporate existing biases from the included trials and can introduce additional biases [38–41]. To minimize bias during trial selection, we used predetermined inclusion criteria. In addition, we included data from unpublished abstracts to avoid publication bias [42], and trials published outside the United States were included to avoid a possible “tower of babble” bias (wherein investigators from countries other than the United States only publish studies with positive results in US journals) [43]. In some of the analyses, the 95% CIs were broad, and although we interpreted the results as showing equivalence, superiority, or inferiority, the upper and lower limits of the 95% CIs suggest a need for caution because of the possibility of type II error. Clinical and statistical heterogeneity is a hazard associated with meta-analyses. Grouping the trials into pediatric trials and adult trials and further grouping the trials according to treatment dose and length of treatment was done to minimize clinical heterogeneity. In addition, stratified analyses with the same 10-day comparator regimen and jackknife analysis eliminating those trials with the widest 95% CIs were additional tools used to evaluate the effects of clinical heterogeneity. To be conservative, all statistical analyses were carried out using a randomeffects model, which accounts for trial heterogeneity. In GAS tonsillopharyngitis, as in other community-acquired upper respiratory infections (such as acute otitis media), one of the most common reasons for treatment failure is poor compliance with therapy [44–50]. Poor compliance appears to be more common with longer treatment courses, because patients sometimes stop their antibiotic treatment once symptoms have resolved [48]. In GAS tonsillopharyngitis, this typically occurs after 3–5 days. Given this reality of patient behavior, a short course of antibiotic treatment lasting 3–5 days would be optimal if it is equally as effective as the standard 10-day treatment course. The duration of azithromycin treatment is 3–5 days because of its unique pharmacokinetic profile, and in children, this analysis shows that a treatment dose of 60 mg/kg is more effective than a 10-day comparator antibiotic regimen. Azithromycin’s shortened course is a compliance-enhancing factor [51]. Adverse events are a common reason for poor patient com-


Acknowledgments Potential conflicts of interest. All authors: no conflicts.

1754 • CID 2005:40 (15 June) • Casey and Pichichero

References 1. Krober MS, Bass JW, Michels GN. Streptococcal pharyngitis: placebocontrolled double-blind evaluation of clinical response to penicillin therapy. JAMA 1985; 253:1271–4. 2. Nelson JD. The effect of penicillin therapy on the symptoms and signs of streptococcal pharyngitis. Pediatr Infect Dis 1984; 3:10–3. 3. Wannamaker LW, Rammelkamp CH Jr, Denny FW, et al. Prophylaxis of acute rheumatic fever by treatment of the preceeding streptococcal infection with various amounts of depot penicllin. Am J Med 1951; 10:673–95. 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; 249:1–7. 5. Denny FW, Wannamaker LW, Brink WR, Rammelkamp CH Jr, Custer EA. Prevention of rheumatic fever. JAMA 1950; 143:151–3. 6. Breese BB. Treatment of betahemolytic streptococcic infections in the home. JAMA 1953; 152:10–4. 7. Breese BB, Denny FW, Dillon HC, et al. Consensus: difficult management problems in children with streptococcal pharyngitis. Pediatr Infect Dis 1985; 4:10–3. 8. Bisno AL, Gerber MA, Gwaltney JM Jr, Kaplan EL, Schwartz RH. Practice guidelines for the diagnosis and management of group A streptococcal pharyngitis. Infectious Diseases Society of America. Clin Infect Dis 2002; 35:113–25. 9. Vukmir RB. Adult and pediatric pharyngitis: a review. J Emerg Med 1992; 10:607–16. 10. Jacoby GA. Prevalence and resistance mechanisms of common bacterial respiratory pathogens. Clin Infect Dis 1994; 18:951–7. 11. Pichichero ME. Controversies in the treatment of streptococcal pharyngitis. Am Fam Physician 1990; 42:1567–76. 12. Hopkins S. Clinical safety and tolerance of azithromycin in children. J Antimicrob Chemother 1993; 31(Suppl E):111–7. 13. Jadad AR, Moore RA, Carroll D, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Controlled Clin Trials 1996; 17:1–12. 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; 7:177–88. 16. Thompson SG. Why sources of heterogeneity in meta-analysis should be investigated. BMJ 1994; 309:1351–5. 17. Petitti DB. Approaches to heterogeneity in meta-analysis. Stat Med 2001; 20:3625–33. 18. Hamill J. Multicentre evaluation of azithromycin and penicillin V in the treatment of acute streptococcal pharyngitis and tonsillitis in children. J Antimicrob Chemother 1993; 31(Suppl E):89–94. 19. Weippl G. Multicentre comparison of azithromycin versus erythromycin in the treatment of paediatric pharyngitis or tonsillitis caused by group A streptococci. J Antimicrob Chemother 1993; 31(Suppl E): 95–101. 20. Pacifico L, Scopetti F, Ranucci A, et al. Comparative efficacy and safety of 3-day azithromycin and 10-day penicillin V treatment of group A b-hemolytic streptococcal pharyngitis in children. Antimicrob Agents Chemother 1996; 40:1005–8. 21. Schaad UB, Heynen G. Evaluation of the efficacy, safety and toleration of azithromycin vs. penicillin V in the treatment of acute streptococcal pharyngitis in children: results of a multicenter, open comparative study. The Swiss Tonsillopharyngitis Study Group. Pediatr Infect Dis J 1996; 15:791–5. 22. O’Doherty B. Azithromycin versus penicillin V in the treatment of paediatric patients with acute streptococcal pharyngitis/tonsillitis. Paediatric Azithromycin Study Group. Eur J Clin Microbiol Infect Dis 1996; 15:718–24. 23. Padilla-Raygoza N. Comparison of clarithromycin and azithromycin for treatment of streptococcal pharyngotonsillitis in children. Infect Med 1998; 15(Suppl. D):23–7.

Downloaded from http://cid.oxfordjournals.org/ by guest on April 30, 2012

pliance and for increases in overall treatment costs associated with additional physician visits, medications, and monitoring. Shortened-course treatment has been shown to reduce the number of adverse events associated with antibiotic therapy [52, 53]. Overall, the trials included in this analysis did not show a difference in the number of adverse events associated with the different treatment courses, and the 2 trials that compared 2 different dosages of azithromycin [22, 27] showed no association between an increase in adverse events and a higher dosage. Although macrolide-resistant GAS was not prevalent when the azithromycin trials were conducted, it is a growing problem worldwide and in the United States [54–58]. An additional important advantage of shortened-course antibiotic treatment is the reduced impact on the development of antibiotic resistance and nasopharyngeal colonization with resistant bacteria. Guillemot et al. [59] showed that inappropriately low dosages of aminopenicillins or third-generation cephalosporins administered to children (such as might occur in the later half of a 10-day treatment course, when patient compliance decreases) is associated with an increased risk of penicillin-resistant Streptococcus pneumoniae nasopharyngeal carriage. In addition, their findings showed that a longer duration of treatment was associated with an increased risk of drug-resistant S. pneumoniae carriage. Cohen et al. [27] showed a lower rate of macrolide resistance among GAS isolates after administration of a 60-mg/ kg total treatment dose than after a 30-mg/kg total treatment dose. Higher azithromycin doses for shorter treatment courses may result in higher concentrations of the drug in tonsillar tissue and could positively impact the development of macrolide resistance. In conclusion, this analysis of—to the best of our knowledge—all published, randomized trials of azithromycin treatment for GAS tonsillopharyngitis shows that a total treatment dose of 60 mg/kg is needed to adequately eradicate GAS tonsillopharyngitis in children. Adults trials show that a 3-day, 500-mg/day regimen of azithromycin is superior to other regimens in eradicating GAS tonsillopharyngitis. Azithromycin therapy for GAS tonsillopharyngitis has the potential to result in better compliance, and because macrolides concentrate in nasopharyngeal tissues, including tonsillar tissues, higher dosages should result in higher bacterial eradication rates; this may have a positive impact on the emergence of macrolide resistance. The issue of macrolide resistance in GAS isolates may be the limiting factor in determining azithromycin’s usefulness for treating GAS tonsillopharyngitis in the future.


42.

43. 44.

45. 46.

47.

48. 49.

50.

51.

52.

53.

54.

55.

56.

57.

58.

59.

bias: dimensions of methodological quality associated with estimates of treatment effects in controlled trials. JAMA 1995; 273:408–12. Klassen TP, Wiebe N, Russell KL, et al. Abstracts of randomized controlled trials presented at the society for pediatric research meeting. Arch Pediatr Adolesc Med 2002; 156:474–9. Shulman ST, Gerber MA. So what’s wrong with penicillin for strep throat? Pediatrics 2004; 113:1816–9. 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; 252:1116–8. Bergman AB, Werner RJ. Failure of children to receive penicillin by mouth. N Engl J Med 1963; 268:1334–8. Leistyna JA, Macaulay JC. Therapy of streptococcal infections: do pediatric patients receive prescribed oral medication? Amer J Dis Child 1966; 111:22–6. Charney E, Bynum R, Eldredge D, et al. How well do patients take oral penicillin? A collaborative study in private practice. Pediatrics 1967; 40:188–95. Green JL, Ray SP, Charney E. Recurrence rate of streptococcal pharyngitis related to oral penicillin. J Pediatr 1969; 75:292–4. Schwartz RH, Rodriquez WJ, Grundfast KM. Pharmacologic compliance with antibiotic therapy for acute otitis media: influence on subsequent middle ear effusion. Pediatrics 1981; 68:619–22. Finney JW, Friman PC, Rapoff MA, Christophersen ER. Improving compliance with antibiotic regimens for otitis media. Am J Dis Child 1985; 139:89–95. Cohen R. Defining the optimum treatment regimen for azithromycin in acute tonsillopharyngitis. Pediatr Infect Dis J 2004; 23(2 Suppl): S129–34. Gooch WM, Blair E, Puopolo A, et al. Effectiveness of five days of therapy with cefuroxime axetil suspension for treatment of acute otitis media. Pediatric Infect Dis J 1996; 15:157–64. Gehanno P, Taillebe M, Denis P, et al. Short course cefotaxime compared with 5-day co-amoxyclav in acute otitis media in children. J Antimicrob Chemother 1990; 26(Suppl A):29–36. Syrogiannopoulos GA, Grivea IN, Fitoussi F, et al. High prevalence of erythromycin resistance of Streptococcus pyogenes in Greek children. Pediatr Infect Dis J 2001; 20:863–8. Martin JM, Green M, Barbadora KA, Wald ER. Erythromycin-resistant group A streptococci in schoolchildren in Pittsburgh. N Engl J Med 2002; 346:1200–6. Dicuonzo G, Fiscarelli E, Gherardi G, et al. Erythromycin-resistant pharyngeal isolates of Streptococcus pyogenes recovered in Italy. Antimicrob Agents Chemother 2002; 46:3987–90. Reinert RR, Lutticken R, Bryskier A, Al-Lahham A. Macrolide-resistant Streptococcus pneumoniae and Streptococcus pyogenes in the pediatric population in Germany during 2000–2001. Antimicrob Agents Chemother 2003; 47:489–93. Bergman M, Huikko S, Pihlajamaki M, et al. Effect of macrolide consumption on erythromycin resistance in Streptococcus pyogenes in Finland in 1997–2001. Clin Infect Dis 2004; 38:1251–6. Guillemot D, Carbon C, Balkau B, et al. Low dosage and long treatment duration of b-lactam: risk factors for carriage of penicillin resistant Streptococcus pneumoniae. JAMA 1998; 279:365–70.

Azithromycin in GAS Tonsillopharyngitis • CID 2005:40 (15 June) • 1755

Downloaded from http://cid.oxfordjournals.org/ by guest on April 30, 2012

24. Garcia Callejo FJ, Velert Vila MM, Orts Alborch MH, Pardo Mateu L, Esparcia Navarro M. Comparison of azithromycin, amoxicillin/clavulanic acid and cefaclor in the treatment of acute ENT infections [in Spanish]. Acta Otorrinolaringol Esp 1998; 49:306–12. 25. Venuta A, Laudizi L, Beverelli A, et al. Azithromycin compared with clarithromycin for the treatment of streptococcal pharyngitis in children. J Int Med Res 1998; 26:152–8. 26. Cremer J, Wallrauch C, Milatovic D, Braveny I. Azithromycin versus cefaclor in the treatment of pediatric patients with acute group A bhemolytic streptococcal tonsillopharyngitis. Eur J Clin Microbiol Infect Dis 1998; 17:235–9. 27. Cohen R, Reinert P, De La Rocque F, et al. Comparison of two dosages of azithromycin for three days versus penicillin V for ten days in acute group A streptococcal tonsillopharyngitis. Pediatr Infect Dis J 2002; 21:297–303. 28. Schaad UB, Kellerhals P, Altwegg M. Azithromycin versus penicillin V for treatment of acute group A streptococcal pharyngitis. Pediatr Infect Dis J 2002; 21:304–8. 29. Still JG. Azithromycin suspension vs. penicillin suspension in treatment of children with streptococcal pharyngitis [abstract PII-101]. Clin Pharm Ther 1993; 53:195. 30. Still JG. Management of pediatric patients with group A beta-hemolytic streptococcus pharyngitis: treatment options. Pediatr Infect Dis 1995; 14:S57–61. 31. Still JG. Treatment of streptococci pharyngitis in children with five days of azithromycin suspension [abstract M67]. In: Proceedings and abstracts of the 34th Annual Meeting of the Interscience Conference on Antimicrobial Agents and Chemotherapy (Orlando, Florida). 1994. 32. Muller O. Comparison of azithromycin versus clarithromycin in the treatment of patients with upper respiratory tract infections. J Antimicrob Chemother 1993; 31(Suppl E):137–46. 33. Muller O. An open comparative study of azithromycin and roxithromycin in the treatment of acute upper respiratory tract infections. J Antimicrob Chemother 1996; 37(Suppl C):83–92. 34. O’Doherty B. An open comparative study of azithromycin versus cefaclor in the treatment of patients with upper respiratory tract infections. J Antimicrob Chemother 1996; 37(Suppl C):71–81. 35. Hooton TM. A comparison of azithromycin and penicillin V for the treatment of streptococcal pharyngitis. Am J Med 1991; 91:23S–6S. 36. Kaplan EL, Gooch Iii Wm, Notario GF, Craft JC. Macrolide therapy of group A streptococcal pharyngitis: 10 days of macrolide therapy (clarithromycin) is more effective in streptococcal eradication than 5 days (azithromycin). Clin Infect Dis 2001; 32:1798–802. 37. Lee LH, Ayoub E, Pichichero ME. Fewer symptoms occur in sameserotype recurrent streptococcal tonsillopharyngitis. Arch Otolaryngol Head Neck Surg 2000; 126:1359–62. 38. 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; 354:1896–900. 39. Moher D, Pham B, Jones A, et al. Does quality of reports of randomized trials affect estimates of intervention efficacy reported in meta-analyses? Lancet 1998; 352:609–13. 40. Egger M, Smith GD, Schneider M, Minder C. Bias in meta-analysis detected by simple, graphical test. BMJ 1997; 315:629–34. 41. Schultz KF, Chalmers I, Hayes RJ, Altman DG. Empirical evidence of


Higher Dosages of Azithromycin Are More Effectivein Treatment of Group A Streptococcal