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Different antibiotic treatments for group A streptococcal pharyngitis

  1. Mieke L van Driel1,2,3,*,
  2. An IM De Sutter3,4,
  3. Natalija Keber5,
  4. Hilde Habraken6,
  5. Thierry Christiaens7

Editorial Group: Cochrane Acute Respiratory Infections Group

Published Online: 30 APR 2013

Assessed as up-to-date: 19 OCT 2012

DOI: 10.1002/14651858.CD004406.pub3


How to Cite

van Driel ML, De Sutter AIM, Keber N, Habraken H, Christiaens T. Different antibiotic treatments for group A streptococcal pharyngitis. Cochrane Database of Systematic Reviews 2013, Issue 4. Art. No.: CD004406. DOI: 10.1002/14651858.CD004406.pub3.

Author Information

  1. 1

    The University of Queensland, Discipline of General Practice, School of Medicine, Brisbane, Queensland, Australia

  2. 2

    Bond University, Centre for Research in Evidence-Based Practice, Gold Coast, QLD, Australia

  3. 3

    Ghent University, Department of General Practice and Primary Health Care, Ghent, Belgium

  4. 4

    Ghent University, Heymans Institute of Pharmacology, Ghent, Belgium

  5. 5

    University of Ljubljana, Medical Faculty, Ljubljana, Slovenia

  6. 6

    Farmaka, Ghent, Belgium

  7. 7

    Heymans Institute of Pharmacology, Ghent University, Department of General Practice and Primary Health Care and, Ghent, Belgium

*Mieke L van Driel, m.vandriel@uq.edu.au. mieke.vandriel@ugent.be.

Publication History

  1. Publication Status: New search for studies and content updated (no change to conclusions)
  2. Published Online: 30 APR 2013

SEARCH

 
Characteristics of included studies [ordered by study ID]
Bachand 1991

Methods- RCT, randomised 1:1
- Double-blinded
- Double-dummy


Participants- Number of randomised participants: 128 (108 S. pyogenes positive)
- Number of participants evaluated: 90
- Number of dropouts: 38 (29.7%)
- Setting: 17 clinical centres USA
- Age: 12 to 62 years
- Diagnosis: rapid immunoassay test, throat culture
- Inclusion criteria: confirmed GABHS pharyngitis
- Exclusion criteria: risk for pregnancy or lactation, weight < 34 kg, no sore throat with at least one sign of streptococcal pharyngitis, negative rapid immunoassay test, overall poor health, hypersensitivity to erythromycin or penicillin, renal impairment or hepatic disease, history of rheumatic fever or cardiac valvular disease, rash suggestive of scarlet fever, active eye inflammation, treated with systemic antibiotic within 2 weeks/an investigational drug within four weeks/ long-acting injectable penicillin within six weeks prior to trial, concurrent antimicrobial agents


Interventions- Groups: clarithromycin, 250 mg (2 x 125 mg) caps 12-hourly (n = 65); penicillin VK 250 mg (2 x 125 mg) caps 6-hourly (n = 63)
- Duration of therapy: 80% > 10 days
- Duration of follow-up: 15 to 56 days


Outcomes- Clinical outcomes at 2 to 10 days post-treatment: cure (pre-treatment signs and symptoms resolved and pathogen eradicated); improvement (pre-treatment signs and symptoms improved but not resolved); failure (pre-treatment signs and symptoms not improved or worsened and pathogen persisted); indeterminate (response could not be assigned); relapse/recurrence (pre-treatment signs and symptoms resolved but reappeared and pathogen recurred)
- Relapse at 15 to 56 days post-treatment
- Adverse effects
- Bacteriological outcomes
- Serology


Notes- Funding: not reported, but author is employee of Abbott International Ltd.
- Ethics approval: "the protocol was approved by local ethics committees"
- No ITT for efficacy reported
- No ITT reported


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskReported as "randomised (1:1)". Not described how sequence was generated

Allocation concealment (selection bias)Unclear riskNot described

Blinding (performance bias and detection bias)
All outcomes
Low risk"To maintain the double-blind nature of the study, placebos were administered and all drugs were placed in identical grey opaque capsules."

Incomplete outcome data (attrition bias)
All outcomes
Unclear risk26 participants prematurely discontinued and 38 were excluded from efficacy analysis (reasons reported)
No ITT analysis (128 randomised and 90 included in efficacy analysis)

Selective reporting (reporting bias)Unclear risk"There was no evidence of investigator bias in any of the analyses."

Carbon 1995

Methods- RCT
- Double-blinded
- Double-dummy


Participants- Number of participants enrolled: 250
- Number of participants randomised: 240
- Number of participants evaluated: 236
- Number of dropouts: 4 (2%)
- Setting: 60 French GP clinics
- Age: > 15 yrs
- Diagnosis: rapid antigen test, throat culture
- Inclusion criteria: fever =/> 38 °C, odynophagia, erythema or purulent exudate of pharynx, at least one tender submaxillary lymph node, rapid antigen test positive for GABHS, followed by positive throat culture
- Exclusion criteria: allergy to beta-lactams, pregnancy, lactation, chronic tonsillitis, antibiotics in 5 days preceding randomisation, no written consent


Interventions- Groups: cefotiam hexetil (CTM), 200 mg BID for 5 days and a penicillin V (PEV)-like placebo TID for 10 days (n = 119); penicillin V (PEV) megaunit (600 mg) TID for 10 days and CTM-like placebo BID for 5 days (n = 125)
- Duration of treatment: 15 days
- Duration of follow-up: 90 days


Outcomes- Clinical outcomes: success = cure (complete resolution of fever and symptoms) on days 10 and 30 or improvement on day 10 and cure on day 30 without further antibiotics)
- Failure = no response to therapy on day 10, or improvement on day 10 but required further AB or relapsed (recurrence of fever and/or symptoms), or cured on day 10 but subsequent relapse
- Relapse assessed on day 90
- Adverse effects
- Bacteriological outcomes


Notes- Funding: not reported
- Ethics approval: not mentioned
- Described as ITT analysis for efficacy, but post-randomisation exclusions not included in analyses


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskReported as "randomised", but no description of randomisation sequence

Allocation concealment (selection bias)Unclear riskNot described

Blinding (performance bias and detection bias)
All outcomes
Unclear riskReported as "double blind, double dummy", but no description of how blinding of different administration frequency and duration was maintained.

Incomplete outcome data (attrition bias)
All outcomes
Low riskDropouts: 4 lost to follow-up (all in penicillin group)

Selective reporting (reporting bias)Unclear riskOnly clinical success reported, no specific symptoms; no ITT analysis (although reported in table that ITT, the numbers to not correspond to ITT)
Adverse events reported, but no ITT analysis. 3 participants in each group discontinued because of adverse events

Disney 1992a

Methods- RCT
- Double-blinded


Participants- Number of participants eligible: 654
- Number of participants randomised: 525
- Number of participants evaluated: 525
- Number of dropouts: not specified
- Setting: 7 paediatric practices in USA
- Age: 4 to 17 yrs
- Diagnosis: clinical tonsillitis or pharyngitis, throat cultures
- Inclusion criteria: clinical tonsillopharyngitis and throat cultures strongly positive for GABHS
- Exclusion criteria: concurrent enrolment of siblings, 2 or more sore throats in previous 6 months, treated with AB in previous 2 weeks, throat culture negative for GABHS


Interventions- Groups: cephalexin 27 mg/kg 4 times per day (n = 263); penicillin 27 mg/kg 4 times per day (n = 262)
- Duration of treatment: 10 days
- Duration of follow-up: 32 to 35 days


Outcomes- Clinical outcomes: clinical failure (not defined) at 32 to 35 days
- Clinical relapse (new infection with different serotype)
- Bacteriological outcomes
- Antistreptolysin-O titers
- Anti-DNase B titers


Notes- Funding: not reported
- Ethics approval: not mentioned
- ITT analysis on 525 participants completing the protocol, no information on dropouts


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskReported as "randomised", but no description of randomisation sequence

Allocation concealment (selection bias)Unclear risk"The participants were assigned...on a random schedule supplied by Eli Lilly and Co.,..."

Blinding (performance bias and detection bias)
All outcomes
Low risk"...the physician and parents were not appraised as to who was in which group."

Incomplete outcome data (attrition bias)
All outcomes
High riskNo description of dropouts
ITT analysis for clinical outcome

Selective reporting (reporting bias)High riskOnly clinical (and bacteriological) failure reported, no symptoms specified
No reporting of adverse events

Disney 1992b

Methods- RCT, randomised 1:1
- Double-blinded
- Double-dummy


Participants- Number of participants enrolled: 233 (19 negative culture)
- Number of evaluated participants: 192
- Number of dropouts: 31 (13%)
- Setting: 11 paediatric offices in USA
- Age: 6 months to 12 years
- Diagnosis: rapid antigen test, throat culture
- Inclusion criteria: clinical diagnosis of acute streptococcal pharyngitis/tonsillitis, inflammation and swelling, with or without fever =/> 38°C or exudate, rapid antigen test or throat culture positive for GABHS, history of compliance
- Exclusion criteria: history of renal impairment (serum creatinine =/>177 µmol/l, 2.0 mg/dl), any condition that could preclude evaluation of response, requirement for systemic AB, any AB therapy within 3 days of start, hypersensitivity to penicillins and/or cephalosporins


Interventions- Groups: loracarbef oral suspension, 15 mg/kg/day 2 divided doses, or 200 mg caps 2 per day (patient > 25 kg) (n = 120); penicillin VK oral suspension 20 mg/kg/day 4 doses, daily max. 500 mg or 250 mg caps 4 per day (patient > 25 kg) (n = 113)
- Duration of treatment: 10 days
- Duration of follow-up: 4 to 5 weeks


Outcomes- Clinical outcomes at 3 to 5 days post-treatment: cure (absence of presenting signs/symptoms); significant improvement (persistence of signs/symptoms); failure (insignificant change in signs/symptoms); relapse (recurrence of one or more signs/symptoms)
- Relapse at 5 to 6 weeks post-treatment
- Adverse effects
- Bacteriological outcomes


Notes- Funding: Eli Lilly Company
- Ethics approval: not mentioned
- No ITT reported for efficacy, but ITT for adverse events


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskReported as "randomised (1:1), but no reporting of randomisation sequence

Allocation concealment (selection bias)Unclear riskNot described

Blinding (performance bias and detection bias)
All outcomes
Low risk"Placebo was administered twice daily to the loracarbef group to maintain double blind conditions."

Incomplete outcome data (attrition bias)
All outcomes
Low risk"unevaluable": 16 in loracarbef group and 25 in penicillin group (negative pre-therapy culture, insufficient therapy, incomplete data, lost to follow-up, late for visit, concomitant use of other antibiotic)
No ITT for clinical outcome

Selective reporting (reporting bias)High riskITT for adverse events

Henness 1982a

Methods- RCT
- Double-blinded


Participants- Number of participants randomised: 214 (47 no S. pyogenes)
- Number of evaluated participants: 162
- Number of dropouts: 3 lost to follow-up from evaluable participants
- Setting: private paediatric practices in USA
- Age: 1 to 16 yrs
- Diagnosis: throat culture
- Inclusion criteria: acute untreated tonsillopharyngitis
- Exclusion criteria: not reported


Interventions- Groups: penicillin V suspension 8 mg/kg every 6 hours (n = 114); cefadroxil suspension 15 mg/kg twice daily (n = 100)
- Duration of treatment: 10 days
- Duration of follow-up: 27 to 43 days


Outcomes- Clinical outcomes: cure (clinical improvement within first 24 hours of therapy and all follow-up cultures no S. pyogenes); failure (illness consistent with streptococcal infection and positive throat culture at 4 days post-therapy); carrier (asymptomatic with same type S. pyogenes in throat culture obtained between 5 to 33 days post-therapy)
- Bacteriological outcomes
- Complete blood counts
- Urinalysis
- Streptozyme titers
- Susceptibility studies


Notes- Funding: not mentioned, author employee of Mead Johnson Pharmaceutical Division, Evansville, USA
- Ethics approval: not mentioned
- First study in the publication
- No ITT reported


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskReported as "randomised", but no description of randomisation sequence

Allocation concealment (selection bias)Unclear risk"...participants were assigned randomly..."

Blinding (performance bias and detection bias)
All outcomes
Unclear riskReported as "double blind", but no description of blinding

Incomplete outcome data (attrition bias)
All outcomes
Unclear risk52 participants discontinued (cefadroxil 35 and penicillin 17); reasons: negative culture (total 47; cefadroxil 31 and penicillin 16), lost to follow-up (total 3; cefadroxil 2 and penicillin 1), other (total 2; cefadroxil 2 and penicillin 0)
No ITT analysis for clinical outcomes

Selective reporting (reporting bias)Unclear riskOnly clinical (and bacteriological) cure reported, no specific symptoms; no ITT
Adverse events not reported

Henness 1982b

Methods- RCT, randomised
- Double-blinded


Participants- Number of participants randomised: 198
- Number of evaluated participants: 198
- Number of dropouts: 0?
- Setting: private paediatric practices in USA
- Age: 1 to 16 years
- Diagnosis: throat culture
- Inclusion criteria: acute untreated tonsillopharyngitis
- Exclusion criteria: not reported


Interventions- Groups: penicillin V suspension 10 mg/kg every 8 hours (n = 50); cefadroxil suspension 15 mg/kg twice daily (n = 50); erythromycin 15 mg/kg orally twice daily (n = 49); benzathine penicillin G (900,000 U) and procaine penicillin (300,000 U) once intramuscular
- Duration of treatment: 10 days for all oral treatments
- Duration of follow-up: 27 to 43 days


Outcomes- Clinical outcomes: not reported
- Bacteriological outcomes
- Streptozyme titers
- Susceptibility


Notes- Funding: not mentioned, author employee of Mead Johnson Pharmaceutical Division, Evansville, USA
- Ethics approval: not mentioned
- Second study in the publication
- No ITT reported


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskReported as "randomised", but no description of randomisation sequence

Allocation concealment (selection bias)Unclear riskNot described

Blinding (performance bias and detection bias)
All outcomes
Unclear riskReported as "double blind", but no description of blinding

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNo dropouts described; according to reported numbers no participants dropped out

Selective reporting (reporting bias)Unclear riskNo clinical outcomes reported

Jackson 1973

Methods- RCT
- Double-blinded


Participants- Number of participants randomised: 314 (95 negative culture excluded from analysis)
- Number of participants evaluated: 207
- Number of dropouts: 12 reported
- Setting: not described
- Age: not described
- Diagnosis: throat culture
- Inclusion criteria: child in weight range 11.4 to 45.4 kg, pharyngitis, positive culture or white blood count > 10,000
- Exclusion criteria: allergy to penicillin or lincomycin, received any antibiotics within previous 6 weeks


Interventions- Groups: clindamycin daily dose 150 to 450 mg (n = 156); ampicillin daily dose 750 to 2000 mg (n = 158)
- Duration of treatment: 10 days
- Duration of follow-up: 26 to 28 days post-therapy


Outcomes- Adverse effects
- Bacteriological outcomes


Notes- Funding: Upjohn Company
- Ethics approval: not mentioned
- ITT for adverse events


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskReported as "randomised", but no description of randomisation sequence

Allocation concealment (selection bias)Low risk"Labels for each group were randomised, sealed in sequentially numbered envelopes,....."

Blinding (performance bias and detection bias)
All outcomes
Low riskSee above

Incomplete outcome data (attrition bias)
All outcomes
Unclear risk95 negative cultures excluded after randomisation; 12 positive cultures excluded due to failure to return first follow-up culture (C7 and A5)

Selective reporting (reporting bias)High riskOnly clinical outcome for poststreptococcal sequelae
ITT for adverse events

Levenstein 1991

Methods- RCT
- Double-blinded
- Double-dummy


Participants- Number of participants enrolled: 243 (82 S. pyogenes negative)
- Number of participants evaluated in clinical outcome analysis: 125
- Number of dropouts: 28 (12%)
- Setting: multicenter (Australia, New Zealand, Chile, South Africa) outpatient clinics
- Age: 13 to 59 years
- Diagnosis: rapid antigen test, throat culture
- Inclusion criteria: body weight =/> 50 kg, ability to swallow capsules, sore throat with at least one other sign of streptococcal pharyngitis (pharyngeal erythema/exudate, cervical lymph node tenderness, fever), positive rapid immunoassay for GABHS antigen
- Exclusion criteria: hypersensitivity to erythromycin or penicillin, previous course clarithromycin or penicillin VK in this trial, renal impairment or history of glomerulonephritis, history of hepatic disease or liver enzyme elevation, history of cardiac valvular disease, rash symptomatic of scarlet fever, history of allergies and/or asthma


Interventions- Groups: clarithromycin, 250 mg capsules every 12 hours (n = 128); penicillin VK, 250 mg caps every 6 hours (n = 115)
- Duration of treatment: clarithromycin 8 to 10 days; penicillin VK 10 to 14 days
- Duration of follow-up: 15 to 56 days


Outcomes- Clinical outcomes at 2 to 10 days post-treatment: cure (pre-treatment signs and symptoms resolved); improvement (symptoms improved but not totally resolved); failure (symptoms not improved or worsened); indeterminate (clinical response could not be assigned because of non-compliance or other reasons)
- Relapse 15 to 56 days post-treatment
- Adverse effects
- Bacteriological outcomes
- Blood haematology and chemistry
- Urinalysis


Notes- Funding: not reported
- Informed consent obtained
- Ethics approval: "the study was approved by local ethics committees"
- No ITT for efficacy, but ITT for adverse effects


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskReported as "randomised" but no description of randomisation sequence

Allocation concealment (selection bias)Unclear riskNot described

Blinding (performance bias and detection bias)
All outcomes
Low riskDescription of medication and placebo to ensure blinding

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskDropouts accounted for the bacteriological outcome analysis, but not for the clinical outcome analysis (only 125 of 243 randomised participants included in clinical outcome analysis)
No ITT for clinical outcomes

Selective reporting (reporting bias)High riskSafety analysis on all 243 randomised participants; clinical and bacteriological outcome on only 125 participants

McCarty 1992a

Methods- RCT
- Double-blinded
- Double-dummy


Participants- Number of enrolled participants: 218
- Number of participants randomised: 218 (31 negative culture)
- Number of participants evaluated: 171
- Number of dropouts: 47 (22%)
- Setting: 12 study centres in North America
- Age: > 12 years
- Diagnosis: rapid antigen test, throat culture
- Inclusion criteria: clinical diagnosis of streptococcal pharyngitis or tonsillitis - inflammation of pharynx and tonsils with pain in the throat, with or without fever or exudate, rapid antigen test or throat culture positive for GABHS
- Exclusion criteria: pregnancy, lactation, history of renal impairment (serum creatinine levels =/> 177 µmol/L, 2.0 mg/dL), physical or mental condition that might preclude evaluation of response, possible future need for other systemic AB during study, use of AB therapy within 3 days of pre therapy evaluation, use of other investigational agents within previous 28 days, hypersensitivity to beta-lactam AB


Interventions- Groups: loracarbef oral suspension 15 mg/kg/day 2 doses, daily max. 375 mg, or 200 mg caps 2 per day (n = 107); penicillin VK oral suspension 20 mg/kg/day 4 doses daily max. 500 mg, or 250 mg caps 4 per day (n = 111)
- Duration of treatment: 10 days
- Duration of follow-up: 28 to 35 days


Outcomes- Clinical outcomes at 3 to 5 days post-treatment: cure (total alleviation of difficulty in swallowing, pharyngeal pain); improvement (substantial improvement in signs and symptoms); failure (signs and symptoms not substantially alleviated); relapse (initial improvement or alleviation of symptoms, but subsequent worsening or recurrence); unable to evaluate
- Relapse at 28 to 35 days post-treatment
- Adverse effects
- Bacteriological outcomes


Notes- Funding: Eli Lilly and Company
- Informed consent obtained
- Ethics approval: not mentioned
- No ITT reported for efficacy, but ITT reported for adverse events


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskReported as "randomised"; no description of randomisation sequence

Allocation concealment (selection bias)Unclear riskNot described

Blinding (performance bias and detection bias)
All outcomes
Low risk"In order to maintain blinding, placebo was administered twice daily to participants in the loracarbef group so that all participants received 4 doses daily."

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskDropouts: 18 in loracarbef group and 29 in penicillin group. Reasons for dropout: negative culture (L12 and P19) insufficient therapy, incomplete data, use of other antibiotic, noncompliance, lack of post-therapy culture)
No ITT for clinical outcome

Selective reporting (reporting bias)High riskITT for adverse events analysis

Muller 1992

Methods- RCT
- Double-blind


Participants- Number of enrolled participants: 344
- Number of participants randomised: 344
- Number of participants evaluated: 239
- Number of dropouts: 105 (31%)
- Setting: study centres in Europe and Israel
- Age: 3 to 80 yrs (mean 28.2) 10.8% < 12 yrs, 2.0% > 65 yrs
- Diagnosis: rapid antigen test and confirmed by throat culture
- Inclusion criteria: clinical diagnosis of streptococcal pharyngitis or tonsillitis and a positive rapid streptococcal antigen test. Selections were made on the basis of a demonstrated history of therapeutic compliance on the part of the patient and/or the patient's parent/guardian
- Exclusion criteria: pregnant or nursing or history of renal impairment; any condition, including significant underlying disease or concomitant infection, which in the opinion of the investigator could have precluded evaluation of response; anticipated need for systemic antibiotics; use of AB < 3 days; or hypersensitivity to penicillins and/or cephalosporins


Interventions- Groups: 1) loracarbef (n = 169) suspension of 15 mg/kg/day in 2 divided doses up to a max daily dose 375 mg or as a 200 mg capsule twice daily, with placebo twice daily to maintain double-blind conditions. 2) penicillin V (n = 175 suspension of 20 mg/kg/day in 4 divided doses up to a max daily dose of 500 mg or as 250 mg capsules) 4 times daily
- Duration of treatment: 10 days
- Duration of follow-up: 38 to 45 days
- Concomitant medication for treatment of underlying diseases or conditions was allowed with the exception of systemic antibiotics. During therapy paracetamol was used by 5.5% of the patients


Outcomes- Clinical outcomes at days 4 to 6: the patients' symptomatic responses and adherence to the treatment regimen; at days 13 to 15): physical examination to determine symptomatic response to therapy; at days 38 to 45: physical examination to evaluate possible recurrence of pharyngitis or tonsillitis. Throat cultures were required at every observation period
- Global symptomatic response based on symptom score (difficulty in swallowing, pharyngeal pain, pharyngeal redness, tonsillar inflammation, tonsillar swelling and temperature): cure, improvement (substantial), failure, relapse, or unable to evaluate
- Relapse: no definition given
- A patient was discontinued from the study if the pathogen isolated from initial culture was resistant to study antibiotic; if there was obvious symptomatic failure of the study antibiotic at any time during treatment; if there was a significant adverse event or a clinically significant alteration in a laboratory parameter; if a patient or parent/guardian wished to withdraw from the study; if the blinding was broken for safety reasons; or if the patient had an elevated pre-therapy serum creatinine
- Adverse events: at least one adverse event was reported by loracarbef = 22 (13.0%) and penicillin V = 19 (10.9%) patients. Headache and nausea/vomiting were the only 2 events reported during therapy by more than 2% of the total population. Headache was reported by loracarbef = 5/169 (3.0%) and by penicillin V = 4/175 (2.3%) (P = 0.696). Nausea or vomiting was reported by loracarbef = 2/169 (1.2%) and by penicillin V = 5/175 (2.9%) (P = 0.272). Few patients (approximately 5% of the total population) reported adverse events during the 28 to 35 day post-therapy follow-up period


Notes- Funding: grants from Lilly Research Centre Ltd.
- Informed consent obtained
- Ethics: "conducted according to ethical committee guidelines, including the Declaration of Helsinki (1983 Venice Amendment)."
- No ITT analysis


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot described

Allocation concealment (selection bias)Unclear riskNot described

Blinding (performance bias and detection bias)
All outcomes
Low risk"with placebo twice daily to maintain double-blind conditions"

Incomplete outcome data (attrition bias)
All outcomes
Low risk54 of the 169 (31.9%) loracarbef-treated and 51/115 (29.1%) penicillin-treated patients did not qualify for efficacy evaluation. The most common reasons for disqualification in each therapy group were bacteriological (loracarbef = 37, penicillin V = 3); 12 patients in each group received either insufficient therapy, had no follow-up data (lost to follow-up) or had incomplete data; loracarbef = 3 patients and penicillin V = 1 were disqualified from the efficacy analysis due to protocol violations; loracarbef = 1 patient was disqualified for efficacy evaluation because of the use of another antibiotic during the study period, and loracarbef = 1 patient was unevaluable because the post-therapy evaluation was performed 22 days after discontinuing therapy

Selective reporting (reporting bias)Low riskAll indicated outcomes are reported

Nemeth 1999

Methods- RCT, randomised 1:1:1
- Double-blinded
- Double-dummy


Participants- Number of participants enrolled: 919
- Number of positive throat cultures susceptible to study drugs: 725
- Number of participants evaluated: 644
- Number of dropouts: 275 (30%)
- Setting: 25 study centres in USA and Canada
- Age: =/> 13 years
- Diagnosis: rapid antigen test, throat culture
- Inclusion criteria: throat culture positive for GABHS, at least 1 clinical sign or symptom of pharyngitis
- Exclusion criteria: pregnancy, history of rheumatic fever or rheumatic heart disease, peritonsillar abscess or invasive disease, hypersensitivity to beta-lactam drugs, hepatic disease, hepatic enzyme levels or serum creatinine > 2 times upper limit of normal, another systemic AB within 3 days before first dose of study medication or for which < 5 half-lives had elapsed, enrolled in this study previously, received another investigational drug within 4 weeks before study admission


Interventions- Groups: cefdinir 600 mg QID (n = 305); cefdinir 300 mg BID (n = 304); penicillin V 250 mg QID (n = 310)
- Duration of treatment 10 days
- Duration of follow-up 17 to 24 days post-therapy


Outcomes- Clinical outcomes at day 4 to 9 after treatment: cure (all signs and symptoms absent or in satisfactory remission and no further AB therapy required); failure (absence of significant remission of signs and symptoms or need for further AB therapy); relapse (worsening of, or absence of significant remission of, signs and symptoms 17 to 24 days post-therapy or need for further AB therapy)
- Relapse at day 17 to 24 after treatment
- Adverse effects
- Bacteriological outcomes


Notes- Funding: Parke-Davis Pharmaceutical Research, Ann Arbor, Michigan (first author is employee)
- Informed consent obtained
- Ethics approval: institutional review board approval obtained at each site
- No ITT for efficacy reported, but ITT for adverse events


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskReported as "randomised", but no description of the randomisation sequence

Allocation concealment (selection bias)Unclear risk"Patients were randomly assigned in a 1:1:1 ratio.."

Blinding (performance bias and detection bias)
All outcomes
Unclear risk"All participants took the same number of capsules daily. All regimens were administered for 10 days." No description of the appearance of the capsules

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskDropouts 275: no GABHS at admission culture (194); failure to return or noncompliance (not specified in which group)
No ITT analysis for clinical outcomes

Selective reporting (reporting bias)Unclear riskOnly clinical cure reported, no symptoms specified
Adverse events analysed by ITT: 21 participants discontinued due to adverse events (cefdinir = 17 and penicillin V = 4); difference between both groups not significant

Norrby 2002

Methods- RCT, randomised 1:1
- Double-blinded
- Double-dummy


Participants- Number of participants enrolled: 398
- Number of participants randomised: 396 (1 negative culture)
- Number of participants evaluated: 395
- Number of dropouts: 34 (9%)
- Setting: 62 centres in 10 countries (Europe, New Zealand, S. Africa)
- Age: 15 to 74 years
- Diagnosis: rapid antigen test, throat culture
- Inclusion criteria: clinical signs and symptoms of acute pharyngitis/tonsillitis, including sore throat and 1 or more others; presumed diagnosis of acute GABHS pharyngitis/tonsillitis, based on positive rapid antigen detection test or throat culture within 24 hours prior to starting study medication
- Exclusion criteria: infection of deep tissues of upper respiratory tract or subpharyngeal respiratory tract; head or neck cancer; history of rheumatic heart disease or valve disease, infectious mononucleosis, rash; immunocompromised, impaired renal or hepatic function, history heart rhythm diseases, severe hypokalaemia, any concomitant condition likely to preclude assessment of treatment response, non-streptococcal or viral pharyngitis/tonsillitis, chronic streptococcal carrier, environmental risk of reinfection, treatment with penicillin V, systemic or local AB within 7 days prior to study entry; pregnancy, lactation, hypersensitivity to study AB, infection with a pathogen known to be resistant to study drugs, concurrent treatment with other AB or probenecid, or any medication that may interact with study medication


Interventions- Groups: telithromycin 800 mg oral once daily (n = 198); penicillin V 500 mg oral 3 times daily (n = 197)
- Duration of treatment: telithromycin 5 days; penicillin V 10 days
- Duration of follow-up: 38 to 45 days


Outcomes- Clinical outcomes at day 16 to 20: cure (improvement, disappearance or return to preinfection state of all infection-related signs and symptoms, without additional AB); failure (infection-related signs and symptoms unchanged or worsened, or clinical improvement but required additional AB, developed new clinical findings consistent with active infection); indeterminate (missing post-treatment information, discontinued early for reasons unrelated to study drug)
- Relapse at day 38 to 45
- Adverse effects
- Bacteriological outcomes
- Blood haematology
- Urinalysis
- Mean symptom score reported in second publication; no SD reported


Notes- Funding: Aventis Pharma
- Informed consent obtained
- Ethics approval: "approved by and independent ethics committee in each country"
- Modified ITT (1 patient with negative GABHS excluded)
- 2 publications of same study with different outcomes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot described

Allocation concealment (selection bias)Unclear riskReported as "randomised (1:1)"; Randomisation not described

Blinding (performance bias and detection bias)
All outcomes
Low risk"Blinding was maintained by masking the tablets in capsules and matching placebo capsules where appropriate."

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskITT for clinical outcomes excluded one randomised patient with negative culture; 34 participants discontinued, mainly due to withdrawal of consent or adverse events; not clear how these reasons were distributed in the 2 groups

Selective reporting (reporting bias)Unclear riskCure was predefined clinical outcome; adverse events reported

O'Doherty 1996

Methods- RCT
- Double-blinded
- Double-dummy


Participants- Number of participants enrolled: 489 (92 negative culture) (Azithromycin 20 mg = 160; Azithromycin 10 mg = 166; Penicillin V = 163)
- Number of participants evaluated: 358
- Number of dropouts: 131 excluded (Azithromycin 20 mg = 57; Azithromycin 10 mg = 43; Penicillin V = 31) (27%)
- Setting: 19 outpatient clinical centres (Europe)
- Age: 2 to 13 years
- Diagnosis: clinical examination, rapid antigen test
- Inclusion criteria: clinical signs and symptoms suggestive of GABHS pharyngitis/tonsillitis, rapid antigen test positive for GABHS
- Exclusion criteria: within 72 hours prior to the study other AB which could interfere with evaluation of therapy, hypersensitivity to macrolide or beta-lactam antibiotic, terminal illness or other serious disease, any gastrointestinal condition that might affect drug absorption, other investigational drug in the previous month or long-acting penicillin injections within the previous 6 weeks


Interventions- Groups: azithromycin suspension single oral dose 10 mg/kg (n = 166); azithromycin suspension one single dose 20 mg/kg (n = 160); penicillin V solution 50 mg/ml orally 4 times daily (total daily dose 500 to 1000 mg) (n = 163)
- Duration of treatment: azithromycin 3 days; penicillin V 10 days
- Duration of follow-up: 28 to 30 days


Outcomes- Clinical outcomes at day 12 to 14: cure; improvement; failure; relapse
- Relapse at day 28 to 30
- Adverse effects
- Bacteriological outcomes
- Blood haematology and chemistry
- Urinalysis


Notes- Funding: not reported
- Informed consent obtained
- Ethics approval: institutional review board approval obtained
- Definition of outcomes not reported
- No ITT for efficacy, but ITT for adverse effects


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskReported as "randomised", but no description of randomisation sequence

Allocation concealment (selection bias)Unclear riskNot described

Blinding (performance bias and detection bias)
All outcomes
Low risk"Matched placebo suspensions or solutions were administered to maintain blinding of the study."

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskDropout 131 participants: absence of pathogen (azithromycin 20 mg = 36; azithromycin 10 mg = 30; penicillin = 26), deviation from protocol (azithromycin 20 mg = 10; azithromycin 10 mg = 8; penicillin = 3), adverse event (azithromycin 20 mg = 11; azithromycin 10 mg = 5; penicillin = 2)
No ITT analysis

Selective reporting (reporting bias)Unclear riskOnly clinical (and bacteriological) cure reported, no specific symptoms in outcome analysis
Adverse events reported with ITT analysis

Randolph 1985

Methods- RCT
- Double-blinded


Participants- Number of eligible participants: 260
- Number of randomised participants: 194
- Number of participants evaluated: 194
- Number of dropouts: 0
- Setting: a private paediatric office
- Age: 2 to 20 years
- Diagnosis: throat culture
- Inclusion criteria: clinically suggestive GABHS pharyngitis
- Exclusion criteria: history of hypersensitivity to penicillin or cephalosporins, AB within previous 72 hours


Interventions- Groups: cefadroxil 250 mg in 3 doses over next 18 to 24 hours (n = 70); penicillin V 250 mg in 3 doses over next 18 to 24 hours (n = 68); placebo (n = 56)
- Duration of treatment: 10 days
- Duration of follow-up: 4 weeks (only results from examination 18 to 24 hours after initiation of treatment reported)


Outcomes- Clinical outcomes 24 hours after treatment start assessed by physician: improvement
- Sore throat (numbers only reported in graph)
- Fever (numbers only reported in graph)
- Bacteriological outcomes


Notes- Funding: Mead Johnson and Company
- Ethics approval: not mentioned
- ITT analysis reported


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"All participants were then assigned by a table of random numbers..."

Allocation concealment (selection bias)Low risk"Randomization of treatment regimens was performed by a study nurse so that the evaluating physician, parents and participants were unaware of which agent was dispensed."

Blinding (performance bias and detection bias)
All outcomes
Low riskSee above

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo dropouts (all randomised participants evaluated)

Selective reporting (reporting bias)Unclear riskSpecific signs and symptoms reported
No reporting of adverse events

Reed 1991

Methods- RCT
- Double-blinded


Participants- Number of participants enrolled and randomised: 116
- Number of evaluated participants: 93
- Number of dropouts: 23 (20%)
- Setting: 4 primary care offices in USA
- Age: > 1 month
- Diagnosis: rapid test, throat culture
- Inclusion criteria: sore throat or poor eating, rapid test positive for GABHS
- Exclusion criteria: allergy to penicillin or cephalosporins, pregnancy, history of renal or hepatic impairment, significant underlying disease or concomitant infection that could preclude evaluation of response to treatment, AB in the previous 3 days


Interventions- Groups: cefaclor 20 mg/kg/d in 3 doses (n = 60); penicillin VK 20 mg/kg/d in 3 doses (n = 56)
- Duration of treatment: 10 days
- Duration of follow-up: 28 to 30 days post-therapy


Outcomes- Clinical outcomes (not defined; according to clinician's impression at 2 days after treatment completion): cure, improvement, relapse, failure
- Relapse at day 28 to 30
- Adverse effects
- Bacteriological outcomes
- Beta-lactamase enzyme production


Notes- Funding: Eli Lily & Company, Indianapolis, Indiana USA
- Informed consent obtained
- Ethics approval not mentioned
- No ITT reported


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot described

Allocation concealment (selection bias)Low risk"The patient was given a prescription that used a code number to identify the medication to be used."

Blinding (performance bias and detection bias)
All outcomes
Low risk"The identity of the antibiotic was unknown to the physician and to the patient, and was randomised by a coding sheet that was available only to the pharmacists dispensing the study medication."

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskDropouts 23: no GABHS on culture (cefaclor 6 and penicillin 2), insufficient therapy (cefaclor 0 and penicillin 1), no follow-up culture (cefaclor 3 and penicillin 0), other antibiotic (cefaclor 1 and penicillin 2), unevaluable according to investigator (cefaclor 3 and penicillin 5)
No ITT analysis

Selective reporting (reporting bias)Unclear riskOnly clinical (and bacteriological) outcome reported, no specific symptom outcomes reported
Adverse events reported; no ITT analysis

Stein 1991

Methods- RCT
- Double-blinded
- Double-dummy


Participants- Number of participants enrolled and randomised: 128 (clarithromycin 65 and penicillin 63)
- Number of participants with S. pyogenes: 109
- Number of participants evaluated: 95 (clarithromycin 47 and penicillin 48)
- Number of dropouts: 33 (26%)
- Setting: multicentre (not specified)
- Age: 12 to 58 years
- Diagnosis: clinical examination, rapid immunoassay test
- Inclusion criteria: signs and symptoms of streptococcal throat infection, rapid immunoassay test positive for GABHS antigen
- Exclusion criteria: age < 12 years, pregnancy, lactation, hypersensitivity to erythromycin or penicillin, receiving antibiotics, impaired renal or liver function


Interventions- Groups: clarithromycin 250 mg capsule every 12 hours (n = 65); penicillin V 250 mg capsule every 6 hours (n = 63)
- Duration of treatment: 10 days
- Duration of follow-up: 29 to 35 days


Outcomes- Clinical outcomes at day 5 to 7 and at day 14 to 16: cure (complete resolution of signs and symptoms); improved (considerable resolution of presenting signs and symptoms); failure (no improvement)
- Relapse at day 29 to 35
- Adverse effects
- Bacteriological outcomes
- Blood haematology and chemistry
- Urinalysis
- Serology (antistreptolysin-O titers, anti-DNase B titres)


Notes- Funding: not reported
- Ethics approval: not mentioned
- No ITT for efficacy, but ITT for adverse effects


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear risk"random number code" was used, but unclear how it was generated

Allocation concealment (selection bias)Unclear riskNot described

Blinding (performance bias and detection bias)
All outcomes
Low risk"In order to maintain blinding of the study placebo capsules were alternated with clarithromycin capsules every six hours."

Incomplete outcome data (attrition bias)
All outcomes
High riskDropouts 33; no description of reasons; no ITT for clinical outcomes

Selective reporting (reporting bias)Unclear riskClinical (and bacteriological) cure rate reported, no specific symptoms
Adverse events reported with ITT analysis

Trickett 1973

Methods- RCT
- Double-blinded
- Double-dummy


Participants- Number of enrolled participants: 96
- Number of participants evaluated: 87
- Number of dropouts: 9 (9%)
- Setting: 3 institutions (regular clinics + emergency rooms )
- Age: > 16 years
- Diagnosis: throat culture
- Inclusion criteria: acute sore throat suggestive of acute streptococcal pharyngitis and/or tonsillitis, throat culture positive for GABHS
- Exclusion criteria: pregnancy, breast-feeding, AB other than study drugs during the trial period, inadequate folate reserves, malabsorption syndrome, haemolytic anaemia, anti-convulsant therapy (dilantin, primidone), AB 1 week preceding acute streptococcal infection, renal insufficiency, abnormal liver function, low platelets, total white cells, neutrophils, haemoglobin, hematocrit; glucose-6-phosphate dehydrogenase deficiency, systemic lupus erythematosus, history of idiosyncratic or allergic reactions to any of the drugs


Interventions- Groups: sulphamethoxazole (SMZ) 400 mg and trimethoprim (TMP) 80 mg 2 tablets 4 times per day (n = 48); penicillin G 250 mg 1 tablet 4 times per day (n = 48)
- Duration of therapy: 10 days
- Duration of follow-up: 28 days


Outcomes- No clinical outcomes reported
- Adverse effects
- Bacteriological outcomes
- Urinalysis
- Creatinine
- Liver function: Serum Glutamic Oxaloacetic Transaminase (SGOT) or Aspartate transaminase (AST)


Notes- Funding: medication supplied by Hoffmann-LaRoche Inc.
- Ethics approval: not mentioned


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskReported as "randomised" but no description of randomisation sequence; "both groups were evenly matched as to age, sex, physical condition, and concurrent diagnoses."

Allocation concealment (selection bias)Unclear riskNot described

Blinding (performance bias and detection bias)
All outcomes
Low risk"all test medications were supplied in individually coded bottles of identical appearance and were administered according to the randomised double blind code."

Incomplete outcome data (attrition bias)
All outcomes
Unclear risk9 dropouts: lost to follow-up, failed to take medication or negative on strep A tests (not specified per group)
No ITT analysis

Selective reporting (reporting bias)Unclear riskCure rates reported, not individual symptoms
Adverse events mentioned, but not tested

Watkins 1997

Methods- RCT
- Double-blinded
- Double-dummy


Participants- Number of participants randomised: 345 (dirithromycin 170 and penicillin 175)
- Number of participants evaluated: 257 (dirithromycin 121 and penicillin 136)
- Number of dropouts: 66 in each group (38%)
- Setting: 15 clinical centres in North America
- Age: > 12 years
- Diagnosis: rapid antigen test, throat culture
- Inclusion criteria: weight > 81 lb, positive throat culture, informed consent, ability to return for follow-up, negative pregnancy test and use of a reliable method of contraception during therapy and for 30 days thereafter
- Exclusion criteria: any condition precluding evaluation of response to treatment, systemic AB other than the study AB; hypersensitivity to macrolides, penicillins, cephalosporins, pregnancy, breast-feeding, systemic AB in 7 days before study; participation in a previous dirithromycin study or any study involving and investigational drug in the 30 days prior to this study


Interventions- Groups: dirithromycin, 500 mg once daily (n = 170); penicillin VK 250 mg 4 times daily (n = 175)
- Duration of treatment: 10 days
- Duration of follow-up: 3 to 5 weeks post-treatment


Outcomes- Clinical outcomes 3 to 5 days post-treatment: cure (elimination of signs and symptoms); improvement (significant but incomplete resolution of signs and symptoms); relapse (worsening of signs and symptoms after initial improvement); failure (no improvement in signs and symptoms during treatment)
- Clinical relapse at 3 to 5 weeks post-treatment not reported
- Adverse effects
- Bacteriological outcomes


Notes- Funding: Eli Lilly and Company (2 authors are employees)
- Ethics approval: not mentioned
- No ITT for efficacy, but ITT for adverse effects


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskSequence generated by computer program

Allocation concealment (selection bias)Low risk"The randomisation list was not provided to the investigators until the study was complete.."

Blinding (performance bias and detection bias)
All outcomes
Low risk"Double dummy design" "This was accomplished by giving two bottles to each patient, one containing 20 tablets (dirithromycin or placebo) and one containing 40 capsules (penicillin or placebo)."

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskDescription of dropouts in each group: lack of efficacy (dirithromycin 20; penicillin 26), lost to follow-up (dirithromycin 4; penicillin 1), patient's decision (dirithromycin 3; penicillin 0), entry criteria exclusion (dirithromycin 25; penicillin 22), protocol violation (dirithromycin 8; penicillin 8), adverse event (dirithromycin 6; penicillin 9)
No ITT analysis

Selective reporting (reporting bias)Unclear riskOnly clinical cure reported, no specific symptoms
Adverse events reported with ITT

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Adam 1994Not double-blinded

Adam 1995Not double-blinded

Adam 1996Not double-blinded

Adam 2000aNot double-blinded

Adam 2000bNot double-blinded

Adam 2001Not double-blinded

Aujard 1995Not double-blinded

Bottaro 2012Open-label study

Breese 1974Did not compare 2 different classes of antibiotics

Cohen 2002Not double-blinded

Cruz 2011Meta-analysis

Davies 1995Not only acute GABHS tonsillopharyngitis

De Meyere 1992Not RCT

Del Mar 2008Commentary of RCT

Denny 1953Not double-blinded

Disney 1979Did not compare 2 different classes of antibiotics

Dykhuizen 1996Not double-blinded

Esposito 2002Not double-blinded

Feder 1999Not double-blinded

Gerber 1986Not double-blinded

Gerber 1999aDid not report any clinical outcomes

Gooch 1993Not double-blinded

Granizio 2008Pooled analysis; not original studies

Hamill 1993Not double-blinded

Haverkorn 1971Not RCT
Did not compare 2 different classes of antibiotics

Holm 1991Not double-blinded

Howe 1997Not double-blinded

Lennon 2008Not double-blinded (investigator blinded only)

Matsen 1974Did not compare 2 different classes of antibiotics

McCarty 1992bNot double-blinded

McCarty 1994Not double-blinded

McIsaac 2004Did not compare 2 different classes of antibiotics

Milatovic 1991Not double-blinded

Milatovic 1993Not double-blinded

Pacifico 1996Not double-blinded

Perkins 1969Not double-blinded

Pichichero 2000Not double-blinded

Pichichero 2008Not double-blinded (investigator blinded only)

Portier 1990Not double-blinded

Portier 1994Not double-blinded

Rimoin 2011Did not compare 2 different classes of antibiotics

Roos 1997Recurrent sore throat

Sakata 2008Not double-blinded

Sanofi Aventis 2010Not double-blinded

Shapera 1973Not double-blinded

Shvartzman 1993Not double-blinded

Siegel 1961Did not compare 2 different classes of antibiotics

Standaert 1997Not only acute GABHS tonsillopharyngitis

Stillerman 1986Not double-blinded

Tack 1997Not double-blinded

Tack 1998Not double-blinded

Uysal 2000Not double-blinded

Zwart 2000Did not compare 2 different classes of antibiotics

 
Characteristics of studies awaiting assessment [ordered by study ID]
Pfizer 2011

MethodsRCT

ParticipantsChildren 2 to 12 years

InterventionsAmoxicillin and azithromycin SR

OutcomesBacteriological cure and clinical success

NotesContact Pfizer clinical trials

 
Comparison 1. Cephalosporin versus penicillin

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Resolution of symptoms post-treatment (ITT analysis)52018Odds Ratio (M-H, Random, 95% CI)0.79 [0.55, 1.12]

    1.1 Adults
21163Odds Ratio (M-H, Random, 95% CI)0.78 [0.60, 1.01]

    1.2 Children
3855Odds Ratio (M-H, Random, 95% CI)0.83 [0.40, 1.73]

 2 Resolution of symptoms post-treatment (evaluable participants)51660Odds Ratio (M-H, Random, 95% CI)0.51 [0.27, 0.97]

    2.1 Adults
2880Odds Ratio (M-H, Random, 95% CI)0.56 [0.24, 1.32]

    2.2 Children
3780Odds Ratio (M-H, Random, 95% CI)0.46 [0.14, 1.52]

 3 Resolution of symptoms within 24 hours of treatment (ITT analysis)1138Odds Ratio (M-H, Fixed, 95% CI)0.97 [0.34, 2.74]

    3.1 Children
1138Odds Ratio (M-H, Fixed, 95% CI)0.97 [0.34, 2.74]

 4 Sore throat (ITT analysis)1138Odds Ratio (M-H, Fixed, 95% CI)0.97 [0.23, 4.04]

 5 Fever (ITT analysis)1138Odds Ratio (M-H, Fixed, 95% CI)0.97 [0.19, 4.98]

 6 Incidence of relapse (evaluable participants)41386Odds Ratio (M-H, Fixed, 95% CI)0.55 [0.31, 0.99]

    6.1 Adults
2770Odds Ratio (M-H, Fixed, 95% CI)0.42 [0.20, 0.88]

    6.2 Children
2616Odds Ratio (M-H, Fixed, 95% CI)0.89 [0.33, 2.43]

 7 Complications (ITT analysis)1244Odds Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 8 Adverse events (ITT analysis)31279Odds Ratio (M-H, Random, 95% CI)0.99 [0.31, 3.16]

 9 Resolution of symptoms ITT (subgroup sponsored versus no sponsor reported)52018Odds Ratio (M-H, Random, 95% CI)0.79 [0.55, 1.12]

    9.1 Sponsor not reported
2769Odds Ratio (M-H, Random, 95% CI)0.47 [0.27, 0.81]

    9.2 Sponsored studies
31249Odds Ratio (M-H, Random, 95% CI)0.90 [0.70, 1.16]

 
Comparison 2. Macrolide versus penicillin

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Resolution of symptoms post-treatment (ITT analysis)61728Odds Ratio (M-H, Fixed, 95% CI)1.11 [0.92, 1.35]

    1.1 Adults
51239Odds Ratio (M-H, Fixed, 95% CI)1.07 [0.86, 1.34]

    1.2 Children
1489Odds Ratio (M-H, Fixed, 95% CI)1.25 [0.85, 1.84]

 2 Resolution of symptoms post-treatment (evaluable participants only)61159Odds Ratio (M-H, Fixed, 95% CI)0.79 [0.57, 1.09]

    2.1 Adults
5801Odds Ratio (M-H, Fixed, 95% CI)0.88 [0.59, 1.31]

    2.2 Children
1358Odds Ratio (M-H, Fixed, 95% CI)0.64 [0.36, 1.11]

 3 Sore throat post-treatment (ITT analysis)2371Odds Ratio (M-H, Fixed, 95% CI)0.97 [0.64, 1.46]

 4 Fever post-treatment (ITT analysis)2371Odds Ratio (M-H, Fixed, 95% CI)1.05 [0.69, 1.59]

 5 Incidence of relapse (evaluable participants)6802Odds Ratio (M-H, Random, 95% CI)1.21 [0.48, 3.03]

    5.1 Adults
5495Odds Ratio (M-H, Random, 95% CI)0.90 [0.34, 2.39]

    5.2 Children
1307Odds Ratio (M-H, Random, 95% CI)3.10 [0.67, 14.25]

 6 Adverse events (ITT analysis)61727Odds Ratio (M-H, Random, 95% CI)1.19 [0.82, 1.73]

    6.1 Adults
51238Odds Ratio (M-H, Random, 95% CI)1.06 [0.75, 1.50]

    6.2 Children
1489Odds Ratio (M-H, Random, 95% CI)2.33 [1.06, 5.15]

 7 Resolution of symptoms ITT (subgroup sponsored versus no sponsor reported)61728Odds Ratio (M-H, Fixed, 95% CI)1.11 [0.92, 1.35]

    7.1 Sponsor not reported
3860Odds Ratio (M-H, Fixed, 95% CI)1.11 [0.84, 1.48]

    7.2 Sponsored studies
3868Odds Ratio (M-H, Fixed, 95% CI)1.12 [0.85, 1.46]

 
Comparison 3. Carbacephem versus penicillin

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Resolution of symptoms post-treatment (ITT analysis)3795Odds Ratio (M-H, Random, 95% CI)0.70 [0.49, 0.99]

    1.1 Adults
2562Odds Ratio (M-H, Random, 95% CI)0.75 [0.46, 1.22]

    1.2 Children
1233Odds Ratio (M-H, Random, 95% CI)0.57 [0.33, 0.99]

 2 Resolution of symptoms post-treatment (evaluable participants)3602Odds Ratio (M-H, Fixed, 95% CI)0.62 [0.38, 1.01]

    2.1 Adults
2410Odds Ratio (M-H, Fixed, 95% CI)0.59 [0.31, 1.13]

    2.2 Children
1192Odds Ratio (M-H, Fixed, 95% CI)0.66 [0.32, 1.38]

 3 Incidence of relapse (evaluable participants)3523Odds Ratio (M-H, Fixed, 95% CI)1.27 [0.64, 2.50]

 4 Adverse events (ITT analysis)3795Odds Ratio (M-H, Random, 95% CI)1.08 [0.75, 1.55]

 
Comparison 4. Clindamycin versus ampicillin

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Adverse events (ITT analysis)1314Odds Ratio (Peto, Fixed, 95% CI)0.41 [0.15, 1.10]

 
Comparison 5. Sulfonamide versus penicillin

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Adverse events (ITT analysis)187Odds Ratio (M-H, Fixed, 95% CI)1.37 [0.43, 4.34]