Treatment of Acute Sinusitis With High-Dose vs. Standard-Dose Amoxicillin/Clavulanate

Double-blind comparative-effectiveness study of the treatment of acute bacterial sinusitis with standard dose of amoxicillin/clavulanate 875mg/125mg bid for 7 days, as recommended by the Infectious Disease Society of America, with or without the addition of immediate-release amoxicillin 875 mg bid x 7 days. The study aims are 1) to confirm, or not, our recent findings of more rapid improvement in overall symptoms with the additional amoxicillin, but also of more frequent diarrhea and vaginal yeast infections and 2) to assess, from the participants' point of view, the balance between improvement and adverse effects.

• Amoxicillin 875 mg (Drug), also known as Amoxil: Doubling the dose of amoxicillin by adding amoxicillin 875 to each dose of the standard treatment of amoxicillin/clavulanate 875/125
• Placebo (lactase) (Dietary supplement): Placebo (in place of additional amoxicillin in experimental arm)

Primary outcomes

• Number of Participants With a Global Rating of Improvement of 5 & 6 at the End of 3 Days of Treatment [At end of 3 days of treatment]: Rating on a scale of 1=a lot worse, 2=a little worse, 3=the same, 4=a little better, 5=a lot better, 6=no symptoms, with a higher score indicating greater improvement.

Secondary outcomes

• Number of Participants With a Global Rating of Improvement of 5 or 6 at End of 10 Days Since Enrollment [At end of 10 days since enrollment]: Rating of 5 (a lot better) or 6 (no symptoms) on Global Rating of Improvement scale, with range of 1 (a lot worse) to 6 (no symptoms), with a higher score indicating greater improvement
• Change From Baseline in the Total Score on the Sinonasal Outcome Test-16 (SNOT-16) at the End of 3 Days of Treatment [At end of 3 days of treatment]: The change between enrollment and the end of 3 days of treatment in the total score on the Sinonasal Outcome Test-16 (SNOT-16). The total SNOT-16 is the sum of the participant's ratings of 16 symptoms of illness on the scale of 0 (no problem) to 3 (severe problem), with a possible range of 0 to 48, with a higher sum indicating more troubling symptoms. A decrease in total score would indicate an improvement in symptoms.
• Change From Baseline in the Total Score on the Sinonasal Outcome Test-16 (SNOT-16) at the End of 10 Days Since Enrollment [At end of 10 days since enrollment]: The change between enrollment and the end of 10 days since enrollment in the total score on the Sinonasal Outcome Test-16 (SNOT-16). The total SNOT-16 is the sum of the participant's ratings of 16 symptoms of illness on the scale of 0 (no problem) to 3 (severe problem), with a possible range of 0 to 48, with a higher sum indicating more troubling symptoms. A decrease in total score would indicate an improvement in symptoms.
• Balance of Benefits and Detriments [At end of 10 days since enrollment]: Assessment of balance between good effects and bad effects of antibiotic on scale of -3=bad effects much greater than good effects to +3=good effects much greater than bad effects
• Number of Participants Answering "Yes" to Willingness to Take the Antibiotic Again in the Future [At end of 10 days since enrollment]: Response of "yes" at the end of 10 days since enrollment to the question whether the participant would take this antibiotic again, with possible answers of yes, no, or uncertain.

Other outcomes

• Number of Participants Reporting Any Diarrhea at Day 3 Among Those Self-identified as Prone or Not Prone to Diarrhea [At the end of 3 days]: Among those who indicated at enrollment whether prone to diarrhea or not, the number giving ratings of 1, 2, or 3 on diarrhea scale ranging from 0 (none) to 3 (severe)
• Number of Participants Reporting Severe Diarrhea at Day 3 Among Those Self-identified as Prone or Not Prone to Diarrhea [At end of day 3]: Among those reporting proneness to diarrhea or not at enrollment, the number rating 3 on diarrhea scale ranging from 0 (none) to 3 (severe)
• Number of Participants Reporting Any Diarrhea at Day 10 Among Those Self-identified as Prone or Not Prone to Diarrhea [At 10 days since enrollment]: Among those indicating at enrollment a proneness or not to diarrhea, the number giving ratings of 1, 2, or 3 on the diarrhea scale ranging from 0 (none) to 3 (severe)
• Number of Participants Reporting Severe Diarrhea at Day 10 Among Those Self-identified as Prone or Not Prone to Diarrhea [At 10 days since enrollment]: Among those indicating proneness to diarrhea or not at enrollment, the number who gave a rating of 3 on the diarrhea scale ranging from 0 (none) to 3 (severe)
• Number of Female Participants Reporting Any Vaginal Symptoms at Day 3 Among Those Self-identified as Prone or Not Prone to Vaginal Itching or Discharge [After 3 days of treatment]: Female participants contacted after 3 days of treatment were divided into two groups: those who had or had not reported at baseline a proneness to vaginal symptoms. The measure was the number in each group who gave ratings of 1, 2, or 3 on the vaginal symptoms scale, ranging from 0 (none) to 3 (severe), with a higher score indicating more severe symptoms.
• Number of Female Participants Reporting Severe Vaginal Symptoms at Day 3 Among Those Self-identified as Prone or Not Prone to Vaginal Itching or Discharge [At the end of 3 days of treatment]: Among female participants indicating a proneness or not to vaginal itching or discharge, the number of ratings of 3 on the vaginal symptom scale ranging from 0 (none) to 3 (severe)Female participants contacted after 3 days of treatment were divided into two groups: those who had or had not reported at baseline a proneness to vaginal symptoms. The measure was the number in each group who gave a rating of 1, 3 on the vaginal symptoms scale, ranging from 0 (none) to 3 (severe), with a higher score indicating more severe symptoms.
• Number of Female Participants Reporting Any Vaginal Symptoms at Day 10 Among Those Self-identified as Prone or Not Prone to Vaginal Itching or Discharge [At 10 days since enrollment]: Female participants contacted after 10 days since enrollment were divided into two groups: those who had or had not reported at baseline a proneness to vaginal symptoms. The measure was the number in each group who gave ratings of 1, 2, or 3 on the vaginal symptoms scale, ranging from 0 (none) to 3 (severe), with a higher score indicating more severe symptoms.
• Number of Female Participants Reporting Severe Vaginal Symptoms at Day 10 Among Those Self-identified as Prone or Not Prone to Vaginal Itching or Discharge [At 10 days since enrollment]: Female participants contacted at 10 days since enrollment were divided into two groups: those who had or had not reported at baseline a proneness to vaginal symptoms. The measure was the number in each group who gave rating of 3 on the vaginal symptoms scale, ranging from 0 (none) to 3 (severe), with a higher score indicating more severe symptoms.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

1. Adults 18 and older who are patients at the Albany Medical Center Internal Medicine and Pediatrics practice (study site).
2. Clinical diagnosis of acute bacterial sinusitis in accordance with the guidelines of the Infectious Disease Society of America (fitting into one of 3 categories: persistent sinus symptoms for 10 days or more; severe sinus symptoms for 3 days or more; or worsening sinus symptoms after initial improvement (double sickening).

Exclusion Criteria:

1. Previous enrollment in the current study
2. Allergy or intolerance to any penicillin or to amoxicillin/clavulanate
3. Serious hypersensitivity reaction to any beta lactam
4. Elevated risk of amoxicillin-resistant bacteria: a. amoxicillin, penicillin, or other beta-lactam within the past month; b. known to have had methicillin-resistant Staph aureus
5. Chronic or recurrent "sinus" problems (defined as a) persistent symptoms of "sinus" congestion, not attributed to nasal allergies, for 8 weeks or more or b) 2 or more episodes of antibiotic-treated "sinusitis" in past 3 months
6. Need to use high-dose amoxicillin/clavulanate or levofloxacin or to send to emergency department or to hospitalize because of a) signs of severe infection or b) immunocompromise
7. Cognitive impairment, so unable to give reliable symptom ratings (even if a health proxy can give consent)
8. Pregnant women and nursing mothers
9. Drug warnings: a) taking allopurinol; b) current mononucleosis; c) chronic kidney disease stage 4 (estimated glomerular filtration rate <30); d) hepatic impairment (not including isolated transaminase elevated < 2 times upper limit of normal); e) history of antibiotic-associated colitis (C. difficile)

Participant flow

Outcome results

• Number of Participants With a Global Rating of Improvement of 5 & 6 at the End of 3 Days of Treatment (Primary), Count of participants, Participants: High Dose 24; Standard Dose 31
• Number of Participants With a Global Rating of Improvement of 5 or 6 at End of 10 Days Since Enrollment (Secondary), Count of participants, Participants: High Dose 35; Standard Dose 47
• Change From Baseline in the Total Score on the Sinonasal Outcome Test-16 (SNOT-16) at the End of 3 Days of Treatment (Secondary), Mean, score on a scale: High Dose 13.3 +/- 8.8; Standard Dose 12.3 +/- 11.5
• Change From Baseline in the Total Score on the Sinonasal Outcome Test-16 (SNOT-16) at the End of 10 Days Since Enrollment (Secondary), Mean, score on a scale: High Dose 18.4 +/- 11.4; Standard Dose 21.4 +/- 10.2
• Balance of Benefits and Detriments (Secondary), Mean, score on a scale: High Dose 1.8 +/- 1.8; Standard Dose 2.2 +/- 1.5
• Number of Participants Answering "Yes" to Willingness to Take the Antibiotic Again in the Future (Secondary), Count of participants, Participants: High Dose 34; Standard Dose 47
• Number of Participants Reporting Any Diarrhea at Day 3 Among Those Self-identified as Prone or Not Prone to Diarrhea (Other pre specified), Count of participants, Participants: Prone to Diarrhea 16; Not Prone to Diarrhea 41
• Number of Participants Reporting Severe Diarrhea at Day 3 Among Those Self-identified as Prone or Not Prone to Diarrhea (Other pre specified), Count of participants, Participants: Prone to Diarrhea 4; Not Prone to Diarrhea 6
• Number of Participants Reporting Any Diarrhea at Day 10 Among Those Self-identified as Prone or Not Prone to Diarrhea (Other pre specified), Count of participants, Participants: Prone to Diarrhea 6; Not Prone to Diarrhea 21
• Number of Participants Reporting Severe Diarrhea at Day 10 Among Those Self-identified as Prone or Not Prone to Diarrhea (Other pre specified), Count of participants, Participants: Prone to Diarrhea 1; Not Prone to Diarrhea 4
• Number of Female Participants Reporting Any Vaginal Symptoms at Day 3 Among Those Self-identified as Prone or Not Prone to Vaginal Itching or Discharge (Other pre specified), Count of participants, Participants: Prone to Vaginal Itching or Discharge 6; Not Prone to Vaginal Itching or Discharge 11
• Number of Female Participants Reporting Severe Vaginal Symptoms at Day 3 Among Those Self-identified as Prone or Not Prone to Vaginal Itching or Discharge (Other pre specified), Count of participants, Participants: Prone to Vaginal Itching or Discharge 0; Not Prone to Vaginal Itching or Discharge 2
• Number of Female Participants Reporting Any Vaginal Symptoms at Day 10 Among Those Self-identified as Prone or Not Prone to Vaginal Itching or Discharge (Other pre specified), Count of participants, Participants: Prone to Vaginal Itching or Discharge 10; Not Prone to Vaginal Itching or Discharge 9
• Number of Female Participants Reporting Severe Vaginal Symptoms at Day 10 Among Those Self-identified as Prone or Not Prone to Vaginal Itching or Discharge (Other pre specified), Count of participants, Participants: Prone to Vaginal Itching or Discharge 0; Not Prone to Vaginal Itching or Discharge 1

Adverse events

Time frame: 10 days since enrollment

Other adverse events by term

Limitations and caveats: 1. Early termination midway in the study after a preliminary analysis demonstrated futility 2. Underestimation of non-serious adverse effects because of dropouts and difficulty contacting participants

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• Results publication: Gregory J, Huynh B, Tayler B, Korgaonkar-Cherala C, Garrison G, Ata A, Sorum P. High-Dose vs Standard-Dose Amoxicillin Plus Clavulanate for Adults With Acute Sinusitis: A Randomized Clinical Trial. JAMA Netw Open. 2021 Mar 1;4(3):e212713. doi: 10.1001/jamanetworkopen.2021.2713. PMID 33755168

• Study Protocol and Statistical Analysis Plan (PDF, 2018-02-11)

• Paul C Sorum, MD, PhD, Principal investigator, Albany Medical College