pharyngitis OR tonsillitis OR amygdalitis OR pharyngoamygdalitis) AND (antimicrobials OR antibiotic OR treatment OR drug therapy) AND (short OR long O

Transcription

1 ORIGINAL ARTICLE DURATION OF TREATMENT OF GAS TONSILLOPHARYNGITIS Effectiveness and Safety of Short-Course vs Long-Course Antibiotic Therapy for Group A β-hemolytic Streptococcal Tonsillopharyngitis: A Meta-analysis of Randomized Trials MATTHEW E. FALAGAS, MD, DSC; EVRIDIKI K. VOULOUMANOU, MD; DIMITRIOS K. MATTHAIOU, MD; ANASTASIOS M. KAPASKELIS, MD; AND DROSOS E. KARAGEORGOPOULOS, MD OBJECTIVE: To evaluate the effectiveness and safety of shortcourse antibiotic treatment of group A β-hemolytic streptococcal (GAS) tonsillopharyngitis. METHODS: We performed a meta-analysis of randomized controlled trials (RCTs) retrieved from PubMed and the Cochrane Central Register of Controlled Trials using a structured search strategy. The last date either database was accessed was November 14, We included RCTs that involved patients of any age with GAS tonsillopharyngitis, comparing short-course ( 7 days) vs long-course (at least 2 days longer than short-course) treatment with the same antibiotics. The primary analysis compared 5 to 7 days with 10 days of treatment, using a random effects model. RESULTS: Eleven RCTs comparing short-course vs long-course treatment (5 with penicillin V, 4 with oral cephalosporins, 1 with intramuscular ceftriaxone, and 1 with clindamycin; 6 of the 11 were open label) were included. In the primary analysis, microbiological eradication rates of GAS were inferior for short-course vs long-course treatment (8 RCTs, 1607 patients; odds ratio [OR], 0.49; 95% confidence interval [CI], ). This association was noted with penicillin V treatment (3 RCTs, 500 patients; OR, 0.36; 95% CI, ) but was nonsignificant with cephalosporin treatment (4 RCTs, 1018 patients; OR, 0.62; 95% CI, ). Microbiological eradication was less likely with shortcourse treatment in trials involving primarily children and adolescents (aged <18 years) (6 RCTs, 1258 patients; OR, 0.63; 95% CI, ). Clinical success was inferior in patients who received short-course treatment (5 RCTs, 1217 patients; OR, 0.49; 95% CI, ). Adverse events did not differ between compared groups. The above associations were consistent in the analyses involving all included RCTs. CONCLUSION: Short-course treatment for GAS tonsillopharyngitis, particularly with penicillin V, is associated with inferior bacteriological eradication rates. Mayo Clin Proc. 2008;83(8): CI = confidence interval; GAS = group A β-hemolytic streptococcus; OR = odds ratio; RCT = randomized controlled trial Tonsillopharyngitis caused by group A β-hemolytic streptococcus (GAS) is one of the most common bacterial infections in the community, particularly among children aged 5 to 15 years. 1,2 Although the traditionally recommended antibiotic treatment is a 10-day course of penicillin V, administered 2 or 3 times daily, 3 patient adherence to the full course of treatment is suboptimal. This poor adherence can be attributed in part to the rapid resolution of symptoms typically observed after institution of treatment. 4-7 Moreover, the rationale for eradicating streptococcal pharyngeal infection may not be as strong as it was in the past, because the incidence of acute rheumatic fever and the prevalence of rheumatic heart disease have substantially declined, at least in developed countries. 8 In this context, several agents have been evaluated for the treatment of GAS tonsillopharyngitis in dosage regimens of shorter duration than standard-course penicillin therapy However, it has not been well established whether these shorter courses of antibacterial agents are as effective as longer courses of the same agents. A prior meta-analysis of randomized controlled trials (RCTs) found a difference in microbiological cure rates of GAS tonsillopharyngitis between short-course and standardcourse penicillin regimens, but no such difference between shorter-course (<10 days) and longer-course (10 days) cephalosporin treatment. 15 However, the number of trials included in the above comparisons was rather limited, and findings regarding cephalosporin treatment lacked sufficient statistical power, as the authors themselves concluded. In this regard, we aimed to evaluate the safety and effectiveness of shorter courses of antibacterial therapy compared with longer courses of therapy with the same regimens for the treatment of GAS tonsillopharyngitis by performing a comprehensive meta-analysis of relevant RCTs. METHODS DATA SOURCES The clinical trials included in this meta-analysis were retrieved from PubMed and the Cochrane Central Register of Controlled Trials, both of which we last accessed on November 14, A lower time limit for the literature search was not applied. Bibliographies of relevant articles were also carefully reviewed. The PubMed search strategy used was (pharyngitis OR pharyngotonsillitis OR tonsillo- From the Alfa Institute of Biomedical Sciences, Athens, Greece (M.E.F., E.K.V., D.K.M., A.M.K., D.E.K.); Department of Medicine, Henry Dunant Hospital, Athens, Greece (M.E.F., A.M.K.); and Department of Medicine, Tufts University School of Medicine, Boston, MA (M.E.F.). Individual reprints of this article are not available. Address correspondence to Matthew E. Falagas, MD, DSc, Alfa Institute of Biomedical Sciences, 9 Neapoleos St, Marousi, Athens, Greece (m.falagas@aibs.gr) Mayo Foundation for Medical Education and Research 880 Mayo Clin Proc. August 2008;83(8):

2 pharyngitis OR tonsillitis OR amygdalitis OR pharyngoamygdalitis) AND (antimicrobials OR antibiotic OR treatment OR drug therapy) AND (short OR long OR course OR duration OR days OR day) AND clinical trial NOT case reports[pt] NOT review[pt]. The search term applied to the Cochrane Central Register of Controlled Trials was (tonsillitis OR pharyngitis OR pharyngotonsillitis OR tonsillopharyngitis) AND (short OR long OR course OR duration OR days OR day). Two reviewers (E.K.V. and D.K.M.) independently performed the literature search, evaluated eligibility of retrieved studies for inclusion in the meta-analysis, and extracted the data from included articles. STUDY SELECTION CRITERIA Randomized controlled trials were considered eligible for inclusion in this meta-analysis if they enrolled at least 25 patients in each relevant treatment arm; involved patients of any age who had been diagnosed as having GAS tonsillopharyngitis; compared antibiotic treatment with the same agents, administered at the same daily dosage, but for different durations (a short-course [ 7 days] and a long-course [at least 2 days longer than the short-course] treatment arm); and reported specific data on the effectiveness or safety of treatment. Abstracts presented at scientific conferences and studies published in languages other than English, Spanish, French, German, Italian, or Greek were excluded. DATA EXTRACTION From each of the included RCTs, we extracted information regarding the type of study design, the characteristics of the included population, the diagnostic inclusion criteria, the types of regimens compared, any concomitantly administered therapy, and the size of the intention-to-treat population, as well as specific data regarding the effectiveness and safety outcomes of this meta-analysis and the timing of the evaluation of these outcomes. DEFINITIONS AND OUTCOMES We used the presence of characteristic symptoms and signs, such as sore throat, fever, tender and enlarged anterior cervical lymph nodes, tonsillar exudates, tonsillopharyngeal erythema, palatal petechiae, and scarlatiniform rash. The evaluable population included patients who satisfied the criteria of eligibility for evaluation for each specific outcome examined. The primary outcome of this meta-analysis was microbiological eradication of GAS from the throat at end-oftherapy evaluation. The secondary outcomes of the metaanalysis included clinical success, defined as complete or substantial resolution of symptoms and signs of the disease at end-of-therapy evaluation; bacteriological relapse, defined as the growth in throat culture of the same type of GAS as the initial isolate after prior microbiological eradication at the end of therapy; bacteriological recurrence, defined as the growth in throat culture of a different type of GAS than the initial isolate after prior microbiological eradication at the end of therapy; total adverse events reported in the population of the included RCTs; study withdrawals due to adverse events; as well as immunologic complications of tonsillopharyngitis. All outcomes of the meta-analysis referred to the respective evaluable populations. The primary analysis was limited to patients receiving short-course (5-7 days) or long-course (10 days) therapy. The secondary analysis included patients treated with shorter-course regimens compared with those treated with longer-course regimens of any duration that were consistent with inclusion criteria. Subset analyses involved specific age groups or patients treated with specific classes of antibiotics. A sensitivity analysis that evaluated microbiological eradication included only RCTs with a single- or double-blind design. QUALITY ASSESSMENT Jadad criteria were used to assess the methodological quality of the included RCTs. According to these criteria, randomization, blinding, and data regarding study withdrawals are valued at 1 point each. One point is awarded or subtracted depending on the appropriateness of the randomization and blinding procedures. The highest that a trial can score is 5 points. A score higher than 2 points was used to denote a trial of adequate methodological quality. 16,17 STATISTICAL ANALYSES Pooled odds ratios (ORs) and 95% confidence intervals (CIs) regarding the analyzed outcomes were estimated using the DerSimonian-Laird random effects model. 18 The assessment of statistical heterogeneity between trials was performed using the χ 2 test; P<.10 denoted significant heterogeneity. 19 All statistical analyses were performed with the Review Manager (RevMan) software (Copenhagen, Denmark). 20 RESULTS SELECTED RCTS The searches performed in the PubMed database and the Cochrane Central Register of Controlled Trials generated 523 and 592 articles, respectively. Of these, 11 RCTs were eligible for inclusion Figure 1 depicts the process we used for selecting eligible trials in detail. The main characteristics of the 11 RCTs included in the meta-analysis (type of study, population group, inclusion diagnostic criteria, compared treatments, concomitant therapy, and timing of evaluation of outcomes) are presented in Mayo Clin Proc. August 2008;83(8):

3 523 Results retrieved from PubMed 592 Results retrieved from the Cochrane Central Register of Controlled Trials 162 Selected for further evaluation after screening title and abstract by general criteria 200 Selected for further evaluation after screening title and abstract by general criteria 152 Excluded after detailed screening 132 Comparison of different antibiotics 14 Comparison of different daily dosages of the same antibiotics 2 Review/meta-analysis 2 Noncomparative trial 1 Small sample size 1 Noneligible language and no abstract available 189 Excluded after detailed screening 163 Comparison of different antibiotics 18 Comparison of different daily dosages of the same antibiotics 3 Conference abstract 1 Duplicate publication 1 Review/meta-analysis 2 Small sample size 1 Noneligible language 10 Met inclusion criteria 11 Met inclusion criteria 11 Selected for inclusion in the meta-analysis FIGURE 1. Flow diagram of the process of selection of articles for inclusion in the meta-analysis. Table 1. Of the 11 overall included RCTs, 4 had a doubleblind design, 21,23,28,31 and one was investigator-blinded. 25 Three of the included RCTs were assigned a Jadad score of more than 2 21,22,28 ; all but one 27 of the rest were assigned a score of 2. Seven RCTs exclusively enrolled children or adolescents (one of which 29 enrolled patients aged 3 to 25 years, with a mean age of 9.8 years). 21,22,24,25,27,29,30 Two RCTs enrolled both children and adults, 26,28 one enrolled adolescents or adults, 23 and one did not specify age selection criteria. 31 With the exception of 2 RCTs, in which specific data for clinical criteria were not reported, 26,31 clinical diagnostic inclusion criteria involved various combinations of characteristic symptoms and signs. In 2 RCTs, the enrollment of patients was based on clinical criteria alone, and microbiological methods were used to categorize patients with regard to causative pathogens. 21,23 The 9 remaining RCTs 22,24-31 exclusively enrolled patients with GAS tonsillopharyngitis that had been verified by throat culture alone or throat culture in addition to rapid antigen detection tests (5 RCTs) or serology (antistreptolysin-o) (1 RCT). 26 Of the 11 included RCTs, 5 used oral penicillin V: 2 compared 5- vs 10-day treatment, 28,29 one compared 7- vs 10- day treatment, 30 and 2 compared 3- vs 7-day treatment. 21,23 Oral second- and third-generation cephalosporins, specifically cefaclor, cefuroxime, cefetamet, and cefpodoxime, were used in 4 other RCTs, comparing 5 days 22,24,25 or 7 days 26 to 10 days of treatment. One RCT 27 compared 1- vs 3- day intramuscular administration of ceftriaxone. In the remaining included RCT, 31 oral clindamycin was evaluated for 5 vs 10 days of treatment. OUTCOMES The specific data extracted from each of the included RCTs and entered into the meta-analysis of the respective outcomes are shown in Table 2 and summarized in the following section. 882 Mayo Clin Proc. August 2008;83(8):

4 TABLE 1. Characteristics of RCTs Comparing Short-Course vs Long-Course Antibiotic Treatment for GAS Tonsillopharyngitis a Timing of ITT evaluation population, (Clinical Population No. of patients Bacteriological (age group, type of infection, Regimen Concomitant (short course vs Relapse Jadad Reference Study design duration, diagnostic criteria) (type, dosage, duration) therapy long course) Recurrence) score Zwart et al, 21 Double-blind 4-15 y; sore throat; <7 d; clinical Penicillin V (oral); age Analgesics 100 NA b RCT ( 2 Centor criteria c ) 4-10 y, 250 mg 3 times (54 vs 46) 14 d PT daily; age >10 y, 500 mg NA 3 times daily; 3 d: short NA course; 7 d: long course Esposito Open-label 3-12 y; GAS tonsillopharyngitis; Cefaclor (oral); Analgesics d PT 3 et al, d RCT clinical (oropharyngeal erythema, 25 mg/kg twice daily; allowed (61 vs 59) 2-3 d PT temperature >38 o C, sore throat, 5 d: short course; NA tonsillar exudates, cervical lymph- 10 d: long course NA adenitis) plus microbiobiological (throat culture) Zwart et al, 23 Double-blind y; sore throat; 7 d; Penicillin V (oral); 250 mg Paracetamol 384 NR b RCT clinical ( 3 Centor criteria c ) 3 times daily; 3 d: short on demand (194 vs 190) NR course; 7 d: long course 6 mo PT 6 mo PT Mehra et al, 24 Multicenter 3-13 y; GAS tonsillopharyngitis; Cefuroxime (oral); Not d PT b open-label clinical (oropharyngeal erythema, 10 mg/kg; 5 d: short allowed (266 vs 254) 4-7 d PT RCT fever, sore throat, tonsillar course; 10 d: long course d PT exudates, cervical lymphadenitis) d PT plus microbiological (throat culture, RADT) Pichichero Multicenter 2-17 y; GAS tonsillopharyngitis; Cefpodoxime (oral); NR d PT 2 et al, b investigator- clinical (sore throat, fever 7 d; 10 mg/kg per day e (126 vs 121) 4-7 d PT blinded RCT tonsillopharyngeal redness, (maximum daily dose, Days swelling or exudates, cervical 200 mg); 5 d: short Days lymphadenitis, dysphagia, other course; 10 d: long course constitutional symptoms) plus microbiological (throat culture, RADT) Peixoto et al, 26 Multicenter 1-80 y; GAS tonsillopharyngitis; Cefetamet (oral); adults, None 361 (245 vs 116) NR b open-label <9 d; clinical plus microbiological 500 mg twice daily; received Adults: NR RCT (throat culture, RADT) or children, 10 mg/kg twice 175 (118 vs 57) NA serological (ASO) daily; 7 d: short course; Children: NA 10 d: long course 186 (127 vs 59) Pavesio et al, 27 Open-label 2-11 y; GAS tonsillopharyngitis Ceftriaxone (IM); 50 mg/kg NR 60 Day d RCT and scarlet fever; clinical once daily; 1 d: short (30 vs 30) Day 15 (Randolph criteria f ) plus micro- course; 3 d: long course NA biological (examination of pharyn- NA geal smear, throat culture, RADT) Stromberg Double-blind 7-70 y; GAS tonsillopharyngitis; Penicillin V (oral); NR d PT 5 et al, b RCT clinical (history of temperature 7-12 y, 400 mg twice (72 vs 72) 7 d PT 38.5 C, absence of rhinorrhea daily; y, 800 mg 2 mo PT and cough) plus microbiological twice daily; 5 d: short 2 mo PT (throat culture, RADT) course; 10 d: long course Gerber et al, 29 Open-label 3-25 y, GAS tonsillopharyngitis; Penicillin V (oral); NR 172 NA d RCT clinical (pharyngeal infection, 250 mg 3 times daily; (73 vs 99) 4-6 d PT fever, cervical lymphadenitis, sore 5 d: short course; NA throat, headache, abdominal pain) 10 d: long course NA plus microbiological (throat culture) Schwartz Open-label 1-18 y; GAS tonsillopharyngitis; Penicillin V (oral); NR 191 NA 2 et al, b RCT clinical (fever, sore throat, weight, 50 kg, 20 mg/kg (96 vs 95) 2-6 d PT tonsillopharyngeal erythema, 3 times daily; weight, NA exudates, palatal petechiae, >50 kg, 15 mg/kg daily; NA cervical lymphadenitis, scarlatini- 7 d: short course; form rash) plus microbiological 10 d: long course (throat culture) Sinanian Double-blind GAS tonsillopharyngitis; clinical Clindamycin (oral); <55 lbs, NR 90 NA 2 et al, b RCT plus microbiological (throat 75 mg once daily to 150 mg (23 vs 67) Day 7 culture) 3 times daily; lbs, Day mg, 3 to 4 times daily; NA >75 lbs, mg 4 times daily; 5 d: short course; 10 d: long course a ASO = antistreptolysin-o; GAS = group A β-hemolytic streptococcus; IM = intramuscular; ITT = intention-to-treat; NA = not applicable; NR = not reported; PT = posttreatment; RADT = rapid antigen detection test; RCT = randomized controlled trial. b Statistically significant improvement in microbiological eradication with long- vs short-course antibiotic treatment. c History of fever, absence of cough, swollen tender anterior cervical lymph nodes, and tonsillar exudates. d No significant difference in microbiological eradication in long- vs short-course antibiotic treatment. e Daily dose was divided into 2 doses (every 12 h) for short-course arm and given as a single dose in long-course arm. f Red throat, nasal speech without mucoid rhinorrhea, tender anterior cervical nodes, tonsillar exudates, petechiae of the palate, excoriated nares, scarlet fever rash. Mayo Clin Proc. August 2008;83(8):

5 TABLE 2. Outcomes for Short-Course vs Long-Course Antibiotic Treatment of GAS Tonsillopharyngitis Reported in RCTs a Clinical cure Microbiological eradication Relapse Adverse event Recurrence Short Long Short Long Short Long Short Long Short Long Reference course course course course course course course course course course Zwart et al, NR NR 9/26 (35) 19/28 (68) NR NR NR NR NR NR Esposito et al, /61 (100) 59/59 (100) 56/61 (92) 54/59 (92) NR NR 4/70 (6) 6/68 (9) NR NR Zwart et al, NR NR 36/87 (41) 57/79 (72) NR NR NR NR NR NR Mehra et al, /195 (96) 197/201 (98) 177/201 (88) 189/205 (92) 17/162 (10) 12/167 (7) 15/327 (5) b 17/324 (5) b 3/162 (2) 2/167 (1) Pichichero et al, /126 (75) 108/121 (89) 113/125 (90) 112/118 (95) 13/124 (10) 14/111 (13) NR NR 7/124 (6) 2/111 (2) Peixoto et al, c 107/113 (95) 53/55 (96) 79/81 (98) 45/45 (100) NR NR NR NR NR NR 99/100 (99) 46/49 (94) 77/78 (99) 45/45 (100) Pavesio et al, /30 (100) 30/30 (100) 57/60 (95) d NR NR NR NR NR NR Stromberg et al, /67 (82) 66/70 (94) 47/67 (70) 64/70 (91) 18/67 (27) 4/70 (6) NR NR 6/66 (9) 1/68 (1) Gerber et al, NR NR 67/73 (92) 92/99 (93) NR NR NR NR NR NR Schwartz et al, NR NR 91/96 (95) 94/95 (99) 25/96 (26) 16/95 (17) NR NR NR NR Sinanian et al, NR NR 18/22 (82) 64/67 (96) 0/22 (0) 0/67 (0) 7/23 (30) 14/67 (21) NR NR a All values are expressed as number (percentage) of patients. GAS = group A β-hemolytic streptococcal; NR = not reported; RCT = randomized controlled trial. b Drug-related adverse event. c The upper row refers to children and the lower row refers to adults. d This study did not provide separate data for short- and long-course treatment arms. Primary Analysis: Comparison of Treatment for 5 to 7 Days vs 10 Days. Microbiological eradication of GAS was significantly less likely in patients with tonsillopharyngitis treated with short-course (5-7 days) regimens compared with long-course (10 days) regimens (8 RCTs, 1607 patients; OR, 0.49; 95% CI, ; χ 2 test for heterogeneity, P=.40). This analysis is presented graphically in Figure 2, divided in 2 separate sub-analyses of 5- and 7-day shortcourse treatments. Treatment for 5 to 7 days was associated with lower microbiological eradication rates in the subset analysis limited to patients who received penicillin V therapy (3 RCTs, 500 patients; OR, 0.36; 95% CI, ; χ 2 test for heterogeneity, P=.18), but relevant findings did not reach statistical significance in the subset of patients treated with cephalosporins (4 RCTs, 1018 patients; OR, 0.62; 95% CI, ; χ 2 test for heterogeneity, P=.77). In trials involving mainly children or adolescents (aged <18 years), microbiological eradication rates were significantly lower for short-course than for long-course treatment (6 RCTs, 1258 patients; OR, 0.63; 95% CI, ; χ 2 test for heterogeneity, P=.80; Figure 3). In the sensitivity analysis limited to blinded RCTs, microbiological eradication rates were lower in patients treated with short-course than with long-course regimens (3 RCTs, 469 patients; OR, 0.31; 95% CI, ; χ 2 test for heterogeneity, P=.46). Clinical success was significantly less likely in patients with GAS tonsillopharyngitis treated with short-course vs long-course antibacterial regimens (5 RCTs, 1217 patients; OR, 0.49; 95% CI, ; χ 2 test for heterogeneity, P=.18; Figure 4). Bacteriological relapse was not found to differ among patients treated with short-course vs longcourse regimens (5 RCTs, 981 patients; OR, 1.74; 95% CI, ; χ 2 test for heterogeneity, P=.47). Bacteriological recurrence was significantly more likely in patients with tonsillopharyngitis treated with short-course vs long-course antibacterial regimens (3 RCTs, 698 patients; OR, 3.02; 95% CI, ; χ 2 test for heterogeneity, P=.58). Adverse events were not found to differ between patients with tonsillopharyngitis treated with short-course vs long-course antibacterial regimens (3 RCTs, 879 patients; OR, 0.97; 95% CI, ; χ 2 test for heterogeneity, P=.47). Study withdrawals due to adverse events attributed to the allocated treatment were reported in one of the included RCTs. Specifically, one study withdrawal was recorded regarding a patient treated with short-course antibiotic therapy. 31 Secondary Analysis: Comparison of Shorter to Longer Courses of Treatment. Microbiological eradication of GAS was significantly less likely in patients with tonsillopharyngitis treated with short-course antibacterial regimens ( 7 days) compared with patients treated with long-course regimens (at least 2 days longer than the corre- 884 Mayo Clin Proc. August 2008;83(8):

6 Treatment duration and reference Events, No./Total No. Short course Long course Weight % 5 vs 10 d Sinanian et al, /22 64/ ( ) Gerber et al, /73 92/ ( ) Stromberg et al, /67 64/ ( ) Pichichero et al, / / ( ) Mehra et al, / / ( ) Esposito et al, /61 54/ ( ) Subtotal 478/ / ( ) Test for heterogeneity: χ 2 = 6.26; df=5 (P=.28), I 2 =20.1% Test for overall effect: z=2.82 (P=.005) 7 vs 10 d Schwartz et al, /96 94/ ( ) Peixoto et al, /159 90/ ( ) Subtotal 247/ / ( ) Test for heterogeneity: χ 2 = 0.02; df=1 (P=.90), I 2 =0% Test for overall effect: z=1.74 (P=.08) Total 725/ / ( ) Test for heterogeneity: χ 2 = 7.23, df=7 (P=.40), I 2 =3.2% Test for overall effect: z=3.44 (P<.001) Favors long course Favors short course FIGURE 2. Meta-analysis of microbiological eradication of group A β-hemolytic streptococci in patients with tonsillopharyngitis treated with short-course (5-7 days) vs long-course (10 days) therapy with the same antibiotic. The vertical line is the no difference line between compared treatments. Horizontal lines represent 95% confidence intervals (CIs). The squares represent the point-estimates, and their size reflects the weight of the study in the meta-analysis. The diamond shape shows the pooled odds ratios (ORs) plus 95% CIs. sponding short-course regimens) (10 RCTs, 1827 patients; OR, 0.40; 95% CI, ; χ 2 test for heterogeneity, P=.33; Figure 5). This association was also observed in the subset analysis limited to patients treated with penicillin V (5 RCTs, 720 patients; OR, 0.30; 95% CI, ; χ 2 test for heterogeneity, P=.41; Figure 5). In the subset of patients treated with cephalosporins, relevant findings (Figure 5) were the same as in the primary analysis regarding this Reference Events, No./Total No. Short course Long course Weight % Schwartz et al, /96 94/ ( ) Gerber et al, /73 92/ ( ) Peixoto et al, /81 45/ ( ) Pichichero et al, / / ( ) Mehra et al, / / ( ) Esposito et al, /61 54/ ( ) Total 583/ / ( ) Test for heterogeneity: χ 2 = 2.31, df=5 (P=.80), I 2 =0% Test for overall effect: _ z=2.03 (P=.04) _ Favors long course Favors short course FIGURE 3. Meta-analysis of microbiological eradication of group A β-hemolytic streptococci in children and adolescents with tonsillopharyngitis treated with short-course (5-7 days) vs long-course (10 days) therapy with the same antibiotic. The vertical line is the no difference line between compared treatments. The squares represent the point-estimates, and their size reflects the weight of the study in the meta-analysis. Horizontal lines represent 95% confidence intervals (CIs). The diamond shape shows the pooled odds ratios (ORs) plus 95% CIs. Mayo Clin Proc. August 2008;83(8):

7 Reference Events, No./Total No. Short course Long course Weight % Stromberg et al, /67 66/ ( ) Peixoto et al, /213 99/ ( ) Pichichero et al, / / ( ) Mehra et al, / / ( ) 61/61 59/59 Not estimable Esposito et al, Total 604/ / ( ) Test for heterogeneity: χ 2 = 4.92, df=3 (P=.18), I 2 =39.0% Test for overall effect: z=2.09 (P=.04) Favors long course Favors short course FIGURE 4. Meta-analysis of clinical success in patients with group A β-hemolytic streptococcal tonsillopharyngitis treated with short-course (5-7 days) vs long-course (10 days) therapy with the same antibiotic. The vertical line is the no difference line between compared treatments. The squares represent the point-estimates, and their size reflects the weight of the study in the meta-analysis. Horizontal lines represent 95% confidence intervals (CIs). The diamond shape shows the pooled odds ratios (ORs) plus 95% CIs. Medication and reference Events, No./Total No. Short course Long course Weight % Penicillin V Schwartz et al, /96 94/ ( ) Gerber et al, /73 92/ ( ) Stromberg et al, /67 64/ ( ) Zwart et al, /87 57/ ( ) Zwart et al, /26 19/ ( ) Subtotal 250/ / ( ) Test for heterogeneity: χ 2 = 3.95, df=4 (P=.41), I 2 =0% Test for overall effect: z=5.33 (P<.001) Cephalosporins Peixoto et al, /159 90/ ( ) Pichichero et al, / / ( ) Mehra et al, / / ( ) Esposito et al, /61 54/ ( ) Subtotal 502/ / ( ) Test for heterogeneity: χ 2 = 1.14, df=3 (P=.77), I 2 =0% Test for overall effect: z=1.84 (P=.07) Clindamycin Sinanian et al, /22 64/ ( ) Subtotal 18/22 64/ ( ) Test for heterogeneity: not applicable Test for overall effect: z=1.92 (P=.05) Total 770/ / ( ) Test for heterogeneity: χ 2 = 10.25, df=9 (P=.33), I 2 =12.2% Test for overall effect: z=4.98 (P<.001) Favors long course Favors short course FIGURE 5. Meta-analysis of microbiological eradication of group A β-hemolytic streptococci in patients with tonsillopharyngitis treated with shorter courses of antibiotics vs longer courses of the same antibiotics. The vertical line is the no difference line between compared treatments. The squares represent the point-estimates, and their size reflects the weight of the study in the meta-analysis. Horizontal lines represent 95% confidence intervals (CIs). The diamond shape shows the pooled odds ratios (ORs) plus 95% CIs. 886 Mayo Clin Proc. August 2008;83(8):

8 specific subset of patients. In trials enrolling primarily children or adolescents, microbiological eradication rates were inferior in patients treated with short-course vs long-course regimens (7 RCTs, 1312 patients; OR, 0.55; 95% CI, ; χ 2 test for heterogeneity, P=.61). In the sensitivity analysis limited to blinded RCTs, microbiological eradication was significantly more likely in patients treated with long-course vs short-course regimens (5 RCTs, 689 patients; OR, 0.28; 95% CI, ; χ 2 test for heterogeneity, P=.79). IMMUNOLOGIC COMPLICATIONS Immunologic complications of tonsillopharyngitis were reported in 2 of the included RCTs. In one of these RCTs, the rate of immunologic complications, including arthritis, myocarditis, and exacerbation of psoriasis, was 2.8% in patients assigned to the short-course treatment arm and 6.9% in patients assigned to the long-course treatment arm. 28 In the other RCT, the rate of proteinuria was reported to be the same in both treatment arms at end-of-therapy and follow-up evaluations (4% and 0%, respectively). 26 DISCUSSION The main finding of this meta-analysis is that short-course (5-7 days) treatment of GAS tonsillopharyngitis is associated with inferior microbiological eradication rates compared with the standard 10-day treatment. This finding was also noted in the subset of patients treated with penicillin V, although it did not reach statistical significance in the subset of patients treated with second- and third-generation cephalosporins. A 5- to 7-day course of antibiotic treatment was found to be associated with inferior bacteriological eradication rates in the subset analysis of children and adolescents. The association of shorter courses of antibiotic therapy with inferior eradication rates was also noted in a broader analysis comparing treatment with various shortcourse regimens ( 7 days) to long-course regimens that were at least 2 days longer than the corresponding shortcourse regimens. Several factors might explain why a longer duration of treatment is required for optimal bacteriological results in GAS tonsillopharyngitis relative to other common community-acquired respiratory tract infections. Most data refer to penicillin, which has been associated with a relatively high bacteriological failure rate, considering that resistance of Streptococcus pyogenes to this long-used agent has not yet been observed and that streptococcal infection tends to resolve over time even without treatment in a substantial proportion of cases. 6 Reported penicillin failures could be attributed primarily to the inclusion of many cases with chronic streptococcal carriage and concurrent viral infection in the clinical trials performed thus far; penicillin has limited ability to eradicate nonmultiplying streptococci. 32,35 Yet, the reduced activity of penicillin against dormant bacteria may also be of relevance in active streptococcal infection, because within large populations of infectious bacteria the growth rate of some bacteria may decrease. 37 Additional factors that could contribute to penicillin failures in GAS tonsillopharyngitis include the poor activity of penicillin against streptococci that invade epithelial cells 32,38,39 ; the development of tolerance (reflected in a high ratio of minimum bactericidal concentration to minimum inhibitory concentration) 40 ; the role of interfering bacterial pathogens, which may produce β-lactamases that inactivate penicillin 32,41 and may also enhance the virulent ability of streptococci by coaggregating to epithelial cells 34 ; and finally the disruption by antibiotics of the normal protective bacterial oropharyngeal flora. 32,36,42 Apart from the above biological factors, decreased patient adherence to the suggested regimen should be considered seriously in cases of treatment failure in GAS tonsillopharyngitis. 15,32,34 For the determination of the appropriate duration of treatment for GAS tonsillopharyngitis, the clinical relevance of inferior microbiological outcomes associated with short-course treatment in this meta-analysis should be considered. This meta-analysis showed that inferior microbiological efficacy of short-course treatment is related to inferior outcomes in end-of-therapy clinical success. However, in the RCTs included in the meta-analysis, the determination of clinical effectiveness may have been made earlier in the course of the disease in the short-course treatment arms, thus potentially confounding outcomes by not allowing adequate time for some of the symptoms to subside in comparison with the long-course treatment arms. Moreover, the rates of end-of-therapy clinical success in patients treated with short-course regimens were greater than 90% and differed little from those obtained with longcourse treatment. Given this small degree of difference and the mainly self-remitting natural history of the disease, 4,43,44 it can be assumed that clinical success rates in patients treated with short-course regimens would have reached those of patients treated with long-course regimens if assessed at an equally distant time point. Additionally, because the symptoms of GAS tonsillopharyngitis typically resolve quickly after institution of therapy, the time to the resolution of symptoms, an important clinical parameter that was not assessed in the included studies, would not be expected to differ to a clinically relevant degree between short-course and long-course treatment regimens. 4,43,44 Because the trials included in this meta-analysis focused primarily on bacteriological relapses, they did not adequately examine the association of inferior microbiological eradication with clinical relapses. No difference in bacteriological relapse rates was observed between the short-course Mayo Clin Proc. 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9 and long-course treatment arms. Nevertheless, bacteriological recurrence with a different type of GAS than the one isolated before treatment was shown to be more likely in patients who received short-course therapy in 3 trials comparing short-course vs long-course treatment with penicillin V. 24,25,28 Penicillin V is known to suppress the normal protective pharyngeal flora long after the end of therapy, thereby increasing the susceptibility to recurrences. 42 The complications related to asymptomatic persistence of GAS after treatment of tonsillopharyngitis are difficult to assess. After full courses of treatment, persistence of GAS has been attributed more to a transition into a carrier state than to perpetuation of an active infectious process. Few of these patients show an immunologic response to streptococcal antigens. 35 Accordingly, the rates of immunologic complications would not be expected to be affected substantially. In fact, no case of rheumatic fever was reported in the trials included in this meta-analysis. Other immunologic complications were rarely reported and were not described as severe. Likewise, in a large study evaluating the sequelae of GAS tonsillopharyngitis treated with either standard-course penicillin V or 5-day courses of other oral antibiotics, the rate of various disease complications observed was approximately 0.1%. 33 Thus, it has not been well established whether the suboptimal microbiological outcomes associated with short-course treatment of GAS tonsillopharyngitis in this meta-analysis portend an increased risk of complications. These considerations call into question the clinical relevance of microbiological eradication in the treatment of GAS tonsillopharyngitis. The main rationale for clearing GAS from the throat is to diminish the likelihood that complications will develop. Some have expressed concern about the 10-day treatment for GAS tonsillopharyngitis because poor adherence to the regimen could lead to inappropriately low antibiotic concentrations and promote the development of antimicrobial drug resistance in potentially pathogenic colonizing bacteria. 5,34,45 However, it should be remembered that the global burden of complications of GAS tonsillopharyngitis is high. 46 Acute rheumatic fever continues to cause substantial morbidity and mortality in developing countries, and resurgences of the disease may occur occasionally in developed countries Because the value of antibiotic treatment of GAS tonsillopharyngitis for the prevention of disease complications has long been established, 43,54,55 a conservative approach regarding the duration of such treatment may be the safest one, until otherwise shown. Several limitations should be taken into consideration in the interpretation and extrapolation of the findings of this meta-analysis. First, the included trials did not assess certain types of antibiotics, including amoxicillin, which has been proposed as a reasonable alternative for penicillin, 56 and macrolides, which are valuable in cases of penicillin allergy, 56 although they are associated with varying degrees of resistance in different countries. 38,57,58 Moreover, the trials included in this meta-analysis focused primarily on children or adolescents. The methodological quality of most of the included RCTs was not good, according to the criteria used, largely because 6 of the 11 included trials had an openlabel design. However, the findings of this meta-analysis regarding the outcome of microbiological eradication remained statistically significant when only the 5 blinded trials were analyzed. Additionally, in most included RCTs, well-defined clinical criteria for the diagnosis of GAS tonsillopharyngitis were used in conjunction with microbiological ones. Thus, long-term streptococcal carriers with concurrent viral upper respiratory tract infections should not have constituted a substantial percentage of the included population. CONCLUSION In this meta-analysis of 11 relevant RCTs, performed for the most part in children and adolescents, shorter courses of treatment with the same antibiotic for GAS tonsillopharyngitis (particularly of 5-7 days duration) were associated with inferior eradication rates at the end-of-therapy assessment. This association was more pronounced in trials using penicillin V than in those using cephalosporins. In the latter case, findings did not reach statistical significance. Although the clinical relevance of these findings may not be clear-cut, they support the long-standing but currently rather neglected concept that penicillin V should be administered for the full 10-day treatment course of GAS tonsillopharyngitis. REFERENCES 1. Kaplan EL. 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