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Penicillin V four times daily for five days versus three times daily for 10 days in patients with pharyngotonsillitis caused by group A streptococci: randomised controlled, open label, non-inferiority study

BMJ 2019; 367 doi: (Published 04 October 2019) Cite this as: BMJ 2019;367:l5337
  1. Gunilla Skoog Ståhlgren, clinical research coordinator1,
  2. Mia Tyrstrup, general practitioner2 3,
  3. Charlotta Edlund, professor of microbiology1,
  4. Christian G Giske, professor of clinical microbiology45,
  5. Sigvard Mölstad, professor emeritus of general practice3,
  6. Christer Norman, general practitioner6,
  7. Karin Rystedt, resident in general practice7 8,
  8. Pär-Daniel Sundvall, general practitioner8 9,
  9. Katarina Hedin, associate professor of general practice3 10
  1. 1Unit for Antibiotics and Infection Control, The Public Health Agency of Sweden, SE 171 82 Solna, Sweden
  2. 2Lundbergsgatan Primary Health Care Centre, Malmö, Sweden
  3. 3Department of Clinical Sciences in Malmö, Family Medicine, Lund University, Malmö, Sweden
  4. 4Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
  5. 5Department of Clinical Microbiology, Karolinska University Hospital, Stockholm, Sweden
  6. 6Salem Primary Health Care Centre, Rönninge, Sweden
  7. 7Närhälsan Södra Ryd Primary Health Care Center, Skövde, Sweden
  8. 8Department of Public Health and Community Medicine/Primary Health Care, Institute of Medicine, Sahlgrenska Academy at the University of Gothenburg, Göteborg, Sweden
  9. 9Research and Development Primary Health Care, Region Västra Götaland, R & D Center Södra Älvsborg, Borås, Sweden
  10. 10Futurum, Region Jönköping County and Department of Medical and Health Sciences, Linköping University, Linköping, Sweden
  1. Correspondence to: G Skoog Ståhlgren gunilla.skoog.stahlgren{at}
  • Accepted 8 August 2019


Objective To determine whether total exposure to penicillin V can be reduced while maintaining adequate clinical efficacy when treating pharyngotonsillitis caused by group A streptococci.

Design Open label, randomised controlled non-inferiority study.

Setting 17 primary healthcare centres in Sweden between September 2015 and February 2018.

Participants Patients aged 6 years and over with pharyngotonsillitis caused by group A streptococci and three or four Centor criteria (fever ≥38.5°C, tender lymph nodes, coatings of the tonsils, and absence of cough).

Interventions Penicillin V 800 mg four times daily for five days (total 16 g) compared with the current recommended dose of 1000 mg three times daily for 10 days (total 30 g).

Main outcome measures Primary outcome was clinical cure five to seven days after the end of antibiotic treatment. The non-inferiority margin was prespecified to 10 percentage points. Secondary outcomes were bacteriological eradication, time to relief of symptoms, frequency of relapses, complications and new tonsillitis, and patterns of adverse events.

Results Patients (n=433) were randomly allocated to the five day (n=215) or 10 day (n=218) regimen. Clinical cure in the per protocol population was 89.6% (n=181/202) in the five day group and 93.3% (n=182/195) in the 10 day group (95% confidence interval −9.7 to 2.2). Bacteriological eradication was 80.4% (n=156/194) in the five day group and 90.7% (n=165/182) in the 10 day group. Eight and seven patients had relapses, no patients and four patients had complications, and six and 13 patients had new tonsillitis in the five day and 10 day groups, respectively. Time to relief of symptoms was shorter in the five day group. Adverse events were mainly diarrhoea, nausea, and vulvovaginal disorders; the 10 day group had higher incidence and longer duration of adverse events.

Conclusions Penicillin V four times daily for five days was non-inferior in clinical outcome to penicillin V three times daily for 10 days in patients with pharyngotonsillitis caused by group A streptococci. The number of relapses and complications did not differ between the two intervention groups. Five day treatment with penicillin V four times daily might be an alternative to the currently recommended 10 day regimen.

Trial registration EudraCT 2015-001752-30; NCT02712307.


  • Contributors: CE, SM, KH, PDS, GSS, CN, and CGG contributed to study conception and design. KH, SM, MT, KR, and PDS acted as investigators or regional investigators and contributed to the acquisition of data. Analysis and interpretation of data was performed by the Public Health Agency of Sweden by CE and GSS in cooperation with KH, MT, PDS, and CN. GSS and MT drafted and contributed equally to the manuscript. All authors were involved in revising the work critically for important intellectual content and approval of the final manuscript. KH is the guarantor of the paper. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted.

  • Funding: The study was funded by the Public Health Agency of Sweden. The Healthcare Committee, Region Västra Götaland, funded the salaries for the regional investigator and a doctoral student.

  • Competing interests: All authors have completed the ICMJE uniform disclosure form at and declare: support from the Public Health Agency of Sweden and the Healthcare Committee, Region Västra Götaland for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.

  • Ethical approval: This study was approved by the Regional Ethical Review board in Lund, 25 June 2015 (reference number 2015/396).

  • Data sharing: The full trial protocol can be obtained from the authors on request.

  • The lead author (KH) affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned have been explained.

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