RESEARCH ARTICLE

High-dose versus standard-dose amoxicillin/

clavulanate for clinically-diagnosed acute
bacterial sinusitis: A randomized clinical trial
Andrea Matho1☯, Mary Mulqueen1☯, Miyuki Tanino1☯, Aaron Quidort1☯, Jesse Cheung2‡,
Jennifer Pollard2‡, Julieta Rodriguez2‡, Supraja Swamy2‡, Brittany Tayler2‡,
Gina Garrison3‡, Ashar Ata4‡, Paul Sorum5☯*
1 Albany Medical Center Hospital, Albany, NY, United States of America, 2 Albany Medical College, Albany,
NY, United States of America, 3 Albany College of Pharmacy and Health Sciences, Albany, NY, United
States of America, 4 Department of Surgery, Albany Medical College, Albany, NY, United States of America,
a1111111111 5 Departments of Medicine and Pediatrics, Albany Medical College, Albany, NY, United States of America
a1111111111
☯ These authors contributed equally to this work.
a1111111111
‡ These authors also contributed equally to this work.
a1111111111 * sorump@mail.amc.edu
a1111111111

Abstract
OPEN ACCESS
Background
Citation: Matho A, Mulqueen M, Tanino M, Quidort
A, Cheung J, Pollard J, et al. (2018) High-dose The recommended treatment for acute bacterial sinusitis in adults, amoxicillin with clavula-
versus standard-dose amoxicillin/clavulanate for nate, provides only modest benefit.
clinically-diagnosed acute bacterial sinusitis: A
randomized clinical trial. PLoS ONE 13(5):
e0196734. https://doi.org/10.1371/journal.
Objective
pone.0196734 To see if a higher dose of amoxicillin will lead to more rapid improvement.
Editor: Zheng Liu, Tongji Hospital of Tongji Medical
College of Huazhong University of Science and Design, setting, and participants
Technology, CHINA
Double-blind randomized trial in which, from November 2014 through February 2017, we
Received: December 12, 2017 enrolled 315 adult outpatients diagnosed with acute sinusitis in accordance with Infectious
Accepted: April 17, 2018 Disease Society of America guidelines.
Published: May 8, 2018
Interventions
Copyright: © 2018 Matho et al. This is an open
access article distributed under the terms of the Standard-dose (SD) immediate-release (IR) amoxicillin/clavulanate 875 /125 mg (n = 159)
Creative Commons Attribution License, which vs. high-dose (HD) (n = 156). The original HD formulation, 2000 mg of extended-release
permits unrestricted use, distribution, and (ER) amoxicillin with 125 mg of IR clavulanate twice a day, became unavailable half way
reproduction in any medium, provided the original
author and source are credited.
through the study. The IRB then approved a revised protocol after patient 180 to provide
1750 mg of IR amoxicillin twice a day in the HD formulation and to compare Time Period 1
Data Availability Statement: All relevant data are
within the paper and its Supporting Information
(ER) with Time Period 2 (IR).
files.
Main measure
Funding: The study was funded by contributions
from the corresponding author. The primary outcome was the percentage in each group reporting a major improvement—
Competing interests: The authors have declared defined as a global assessment of sinusitis symptoms as “a lot better” or “no symptoms”—
that no competing interests exist. after 3 days of treatment.

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 Treatment of acute sinusitis

Key results
Major improvement after 3 days was reported during Period 1 by 38.8% of ER HD versus
37.9% of SD patients (P = 0.91) and during Period 2 by 52.4% of IR HD versus 34.4% of SD
patients, an effect size of 18% (95% CI 0.75 to 35%, P = 0.04). No significant differences in
efficacy were seen at Day 10. The major side effect, severe diarrhea at Day 3, was reported
during Period 1 by 7.4% of HD and 5.7% of SD patients (P = 0.66) and during Period 2 by
15.8% of HD and 4.8% of SD patients (P = 0.048).

Conclusions
Adults with clinically diagnosed acute bacterial sinusitis were more likely to improve rapidly
when treated with IR HD than with SD but not when treated with ER HD. They were also
more likely to suffer severe diarrhea. Further study is needed to confirm these findings.

Trial registration
ClinicalTrials.gov Identifier: NCT02340000.

Introduction
Acute sinusitis is typically treated with antibiotics even though most studies have shown little
benefit [1]. These studies are, however, hard to interpret because they used different inclusion
criteria, antibiotic regimens, and outcome measures. To maximize the benefit of treatment,
the Infectious Disease Society of America (IDSA) recommends in its 2012 guidelines [2] that
clinicians use strict criteria to diagnose acute bacterial sinusitis and prescribe amoxicillin/cla-
vulanate at the standard dose (SD) of 875 /125 mg bid for 7 days as first-line treatment (unless
the patient is allergic to penicillin). It recommends using the high dose (HD) of 2000 /125 mg
bid if the rate of penicillin-resistant Streptococcus pneumoniae in the community is greater
than 10%. The available HD is a pharmacokinetically-enhanced extended-release (ER) tablet
of amoxicillin/clavulanate that aims to achieve a longer duration of therapeutic amoxicillin
concentrations by providing ER amoxicillin along with immediate-release (IR) clavulanate [3].
Few clinicians will, however, know the level of penicillin resistance in their communities.
Furthermore, higher concentrations of amoxicillin in the sinuses may help in treating penicil-
lin-sensitive, as well as penicillin-resistant, pneumococci and other bacteria. First, in purulent
secretions, the low pO2 and high pCO2 may impair antibiotic effectiveness [4]. Moreover, the
diffusion of amoxicillin into closed spaces is difficult and may become increasingly difficult as
membranes thicken during the illness [5]. For middle ear infections in children, this line of
reasoning was confirmed by aspirates of middle ear fluid and by clinical experience [6–8] and
led to the adoption in 2004 of HD amoxicillin as the standard of care [9,10]. Its applicability to
acute sinusitis is suggested by the finding that, in patients with acute sinusitis, nasopharyngeal
cultures showed eradication of 4 of 5 penicillin-sensitive S. pneumoniae with HD amoxicillin/
clavulanate but only 2 of 6 with SD [11]. Studies of amoxicillin and clavulanate concentrations
in sinus tissue itself have, however, involved only patients with chronic sinus problems [12–
15].
Second, studies in children and adults of standard doses of amoxicillin [16,17] and even of
amoxicillin/clavulanate [18,19] have demonstrated little or no clinically significant benefit. In
contrast, among children aged 1–10 years (41% > 6), 50% of those receiving HD amoxicillin/

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 Treatment of acute sinusitis

clavulanate were cured at 14 days versus only 14% receiving placebo [20]. Adults with acute
sinusitis would not be expected to differ fundamentally from school-age children in their
response to antibiotics. Accordingly, even though HD amoxicillin/clavunate is not superior to
SD in adults with community-acquired pneumonia [3,21] or bronchitis [22] (or only slightly
so [23], it may provide added benefit in adults with acute sinusitis.
A further issue of importance is what outcome to measure. The first question is what mea-
sure to use. Most studies of acute sinusitis have measured changes over time in patients’ cur-
rent assessment of a set of symptoms [16,17,20], not their global assessment of improvement
[24]. Some health researchers argue, however, that the latter is more valid [25]. Indeed, overall
ratings are common in clinical medicine and simple for patients, and improvement is what
patients and clinicians want. The second question is when to make the primary measurement.
Most studies of acute sinusitis have focused on improvement at 7–15 days [1,16,19,26], not at
3–4 days [17]. Studies of common infectious diseases have shown, however, that, while most
people eventually get better, treatment—for example, antimicrobials for Streptococcal pharyn-
gitis [27], influenza [28], or acute otitis media [10]—can decrease the severity and duration of
illness, even if only by a day or two. These short-term outcomes can be important to patients.
The purpose of this study was to determine if, in an outpatient setting with a suspected low
prevalence of penicillin-resistant pneumococci, the early as well as late clinical benefits of HD
amoxicillin/clavulanate, as assessed primarily by a global rating of improvement, are greater
than its detriments when compared to SD.

Methods
We conducted this randomized, double-blinded, comparative-effectiveness, pragmatic [29]
trial from November 18, 2014, through March 29, February 2017 in the academic primary care
Internal Medicine/Pediatrics practice of Albany Medical College in Latham, New York (see S1
Table: Consort Checklist). The study protocol was approved by the Institutional Review Board
(IRB) at Albany Medical Center on October 16, 2014 (see S1 Text: Original Protocol). We
started the process of registration at ClinicalTrials.gov at the same time as we started recruiting
participants, with provisional registration on November 22, 2014; final registration, however,
was not completed until January 16, 2015. We confirm that our new trial of the same interven-
tion was registered at ClinicalTrials.gov prior to enrolling any participants. When, midway
through the trial, the ER HD formulation became unavailable from the manufacturer, the IRB
approved on February 9, 2016, a revised protocol to study the difference in efficacy and tolera-
bility, compared with SD, of 2 different HD formulations (see S2 Text: Revised Protocol). The
study was funded by contributions from the corresponding author. Written informed consent
was obtained from each participant.

Participants
Patients age 18 and older who presented to the office with sinus symptoms were eligible for
inclusion if not previously enrolled and if, in the judgment of the treating clinician, they fit
into one of the three diagnostic categories for acute bacterial sinusitis, as defined by the 2012
IDSA clinical guidelines [2]: 1) persistent symptoms and not improving (lasting for  10
days); 2) severe symptoms or signs of fever  102 degrees F and nasal discharge or facial pain
(lasting for  3–4 days); or 3) worsening symptoms or signs characterized by new onset of
fever, headache, or increase in nasal discharge following a typical viral URI that lasted 5–6
days and was initially improving (double sickening).
Patients were excluded if they were allergic or intolerant to amoxicillin or amoxicillin/cla-
vulanate; were breastfeeding; were cognitively unable to give informed consent and/or to

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 Treatment of acute sinusitis

assess their symptoms; were taking allopurinol; had chronic or recurrent “sinus” problems,
defined as persistent “sinus” congestion, not attributed to nasal allergies, for 8 weeks or more
[30] or 2 or more episodes of antibiotic-treated “sinusitis” in the past 3 months; were judged
by clinicians to need HD amoxicillin/clavulanate, doxycycline, or levofloxacin because of
severe infection, treatment with amoxicillin or penicillin within the past month, or immune
compromise; needed hospitalization; were suspected to harbor methicillin-resistant Staphylo-
coccus aureus; or had a contraindication to amoxicillin/clavulanate because of chronic kidney
disease stage 4, hepatic impairment, current mononucleosis, or a history of antibiotic-associ-
ated colitis.

Interventions
Our pharmacist (GG) randomized participants in a 1:1 ratio by preparing and labeling pre-
scription bottles in medication bags with consecutive study numbers containing either SD or
HD amoxicillin/clavulanate. The enrolling clinicians, the patients, and the residents and medi-
cal students performing follow-up telephone calls were blinded to the dosage (although an
unknown number of patients found pictures of their pills on-line).
The participants received 2 bottles of tablets with instructions to take 1 tablet from each bot-
tle twice a day with food for 7 days. The SD participants had 1 bottle with amoxicillin/clavula-
nate 875/125 mg and the other with placebo tablets (of over-the-counter lactase); the total
daily dose of amoxicillin was 1750 mg. The HD participants had tablets of amoxicillin/clavula-
nate 1000/62.5 mg ER in each bottle until, with patient #180, we had to switch the HD formu-
lation to 1 bottle with amoxicillin/clavulanate 875/125 mg IR and the other with amoxicillin
875 mg IR. The total daily dose of amoxicillin in the HD group thus decreased from 4000 mg
to 3500 mg (from 2.3 to 2.0 times that of the SD group) with no change in the dose of
clavulanate.
All participants filled out the Sinonasal Outcome Test-16 (SNOT-16), the questionnaire val-
idated by Garbutt and colleagues [17,31,32], on which they rated the severity of 16 symptoms
on a scale of 0 = no problem to 4 = severe problem (Table 1).
The clinicians performed anterior nasal cultures to look for colonization with penicillin-
resistant pneumococci and other pathogens (stopped after participant #231 because of lack of
funds), gave participants written suggestions for symptomatic treatment with acetaminophen
and nasal saline (as described in S3 Text: Suggestions for Treating Symptoms), and gave them
a list of the questions they would be asked at the end of Day 3.

Outcomes
Participants were called at the end of 3 and 10 days of treatment, using a standardized script,
to ask about improvement and adverse effects. Improvement was assessed in 2 ways: by a
global rating of sinus symptom improvement on a 6-point scale of 1 = a lot worse, 2 = a little
worse, 3 = the same, 4 = a little better, 5 = a lot better, and 6 = no symptoms; and by the
responses again to the SNOT-16 questions. This global rating scale had been used by Garbutt
and colleagues to validate the SNOT-16 [31] and was a secondary outcome of their clinical
trial [17]. Tolerability was assessed by asking participants to rate on a scale of 0 = none to
3 = severe the degree of diarrhea, abdominal pain, vaginal discharge and itching (for women),
rash, and other. At Day 10, they were also asked how many doses they did not take and if they
would take this antibiotic again.
The primary efficacy outcome was the percent of patients in each group who gave a global
rating of 5 or 6 after 3 days of treatment. Day 3 was chosen because the study’s focus was on
rapid improvement (as discussed in the Introduction) and because Day 3 was Garbutt and

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 Treatment of acute sinusitis

Table 1. SNOT-16 questionnaire[17,28]. Rate how much you have been bothered, in terms of severity and frequency, by the following symptoms.
Symptoms No problem Mild or slight problem Moderate problem Severe problem
1. Need to blow nose 0 1 2 3
2. Sneezing 0 1 2 3
3. Runny nose 0 1 2 3
4. Cough 0 1 2 3
5. Postnasal discharge 0 1 2 3
6. Thick nasal discharge 0 1 2 3
7. Ear fullness 0 1 2 3
8. Headache 0 1 2 3
9. Facial pain or pressure 0 1 2 3
10. Wake up at night 0 1 2 3
11. Lack of a good night’s sleep 0 1 2 3
12. Wake up tired 0 1 2 3
13. Fatigue 0 1 2 3
14. Reduced productivity 0 1 2 3
15. Reduced concentration 0 1 2 3
16. Frustrated, restless, or irritable 0 1 2 3
Total score (maximum 48)
https://doi.org/10.1371/journal.pone.0196734.t001

colleagues’ first assessment point [17]. The secondary efficacy outcomes were the percent that
gave a global rating of 5 or 6 at Day 10 and the average changes in the ratings on the SNOT-16
questions at Day 3 and Day 10 compared to baseline ratings (with a minimally important dif-
ference of 0.5 units [31]).

Statistical analyses
To determine sample size, we assumed that 34% of the SD group would give a rating of 5 or 6
at the end of Day 3 (the improvement with placebo in Garbutt’s study [17]); decided that an
improvement to 50% in the HD group (an effect size of 16%) would be clinically significant;
and calculated a need for 292 patients to provide an 80% power to detect this amount of
improvement with an alpha of 0.05 [33].
Using SPSS version 24 (IBM SPSS), we performed chi-square analyses, using a two-tailed P
of <0.05 to determine significance, to compare baseline characteristics, global symptom rat-
ings, adverse effects after 3 and 10 days, and percent declaring at Day 10 that they would not
take the antibiotic again. We performed t-tests to compare changes in SNOT-16 scores. We
did these analyses first for the study as a whole and then for each time period. In the latter anal-
yses, we compared each of the two HD formulations only to the SD participants during the
same time period to reduce confounding by differences in other factors, such as circulating
viruses, pollen counts, or weather.

Results
For the full data, see S1 Dataset: Sinusitis Study.

Patient characteristics
Fig 1 shows the flow of potential and actual participants. Of 680 eligible patients during the
study period, we enrolled 315, the first 179 in Time Period 1 (November 18, 2014, through
February 5, 2016) and the next 136 in Time Period 2 (February 6, 2016, through February 27,

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 Treatment of acute sinusitis

Fig 1. CONSORT flowchart of study participants. Reasons for exclusion before randomization were mostly inferred from chart review. We had 30 dropouts during
the course of the study. Reason for dropping out included failure to improve or worsening illness (12), adverse reaction (10), allergic reaction (2), fear of side effects
(2), misplaced medication bottle (1), switched to different antibiotic for another infection (1), tablet size too large (1), self-discontinuation because of marked
symptom improvement (1), and unknown (1). Some participants had multiple reasons for exclusion or for dropping out.
https://doi.org/10.1371/journal.pone.0196734.g001

2017). The most common reason eligible patients were not enrolled was allergy or intolerance
to penicillin (155). We had dropouts during the study because of patient choice or inability to
contact patients for follow-up (as shown in Fig 1), but we were able to assess the primary effi-
cacy endpoint in 93% of participants. We stopped the trial because we had met our recruitment
goal and needed to analyze the data before the primary authors finished their residencies.
The baseline characteristics of patients randomized to SD or HD amoxicillin/clavulanate
over the entire study were not statistically different (Table 2) and did not differ between SD
and HD in each time period except for smoking in Time Period 2 (2.9% of SD participants vs
13.4% of HD, P = 0.02) (Table 3). No participant had been hospitalized in the preceding
month.

Efficacy
As shown in Table 4, the primary outcome of a major improvement in symptoms—either “a
lot better” or “no symptoms” at the end of Day 3—was reported overall by 36.4% of SD vs.
44.8% of HD participants (P = 0.15); during Time Period 1 by 37.9% of SD vs. 38.8% of ER
HD participants (P = 0.91); and during Time Period 2 by 34.4% of SD vs. 52.4% of IR HD par-
ticipants, an effect size of 18% (95% CI 0.75 to 35.26%, P = 0.04).

Table 2. Baseline characteristics of participants as a whole by dose.

Standard Dose High Dose P-value
Total (No. [%]) 159 (50.5%) 156 (49.5%) 0.94
Age in years (mean ± SD) 48.0 ± 15.9 45.9 ± 14.8 0.22
Gender 0.55
Male (No. [%]) 44 (27.7%) 48 (30.8%)
Female (No. [%]) 115 (70.8%) 108 (69.2%)
Active tobacco use (No. [%]) 19 (12.0%) 20 (12.85) 0.82
COPD/asthma (No. [%]) 29 (18.2%) 30 (19.2%) 0.82
Allergic rhinitis (No. [%]) 82 (51.6%) 80 (51.3%) 0.96
Nasal steroid use (No. [%]) 34 (21.4%) 31 (19.9%) 0.74
Antibiotic use in past month (No. [%]) 2 (1.3%) 4 (2.6%) 0.45
Diabetes (No. [%]) 16 (10.1%) 15 (9.6%) 0.89
Heart disease (No. [%]) 11 (6.9%) 8 (5.1%) 0.51
History of sinusitis (No. [%]) 63 (39.6%) 60 (38.5%) 0.83
Days of illness (mean ± SD) 14.8 ± 8.8 14.3 ± 8.1 0.55
Sinusitis category (No. [%]) 0.78
1) Duration  10 days 101 (63.5%) 103 (66.0%)
2) Severe symptoms 18 (11.3%) 19 (12.2%)
3) Double sickening 40 (25.2%) 34 (21.8%)

Mean Day 0 SNOT-16 item score (mean ± SD) 1.89 ± 0.56 1.99 ± 0.55 0.11

Ascertained by chart review.

Categories of sinusitis according to Infectious Diseases Society of American guidelines [2].

Mean rating for each group of all ratings, on a severity scale from 0 to 3, of the 16 items of the SNOT-16 questionnaire (shown in Table 1).

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 Treatment of acute sinusitis

Table 3. Baseline characteristics by Time Period and Dose.

Time Period 1 Time Period 2
Standard Dose High Dose P-value Standard Dose High Dose P-value
Total (No. [%]) 90 (50.3%) 89 (49.7%) 69 (50.7%) 67 (49.3%)
Age (years ± SD) 47.4 ± 15.3 46.8 ± 14.5 0.80 48.8 ± 16.6 44.6 ± 15.3 0.13
Gender: 0.91 0.28
Male (No. [%]) 29 (32.2%) 28 (31.5%) 15 (21.7%) 20 (29.9%)
Female (No. [%]) 61 (67.8%) 61 (68.5%) 54 (78.3%) 47 (70.2%)
Active tobacco use (No. [%]) 17 (18.9%) 11 (12.4%) 0.23 2 (2.9%) 9 (13.4%) 0.02
COPD/asthma (No. [%]) 19 (21.1%) 18 (20.2%) 0.88 10 (14.5%) 12 (17.9%) 0.59
Allergic rhinitis (No. [%]) 46 (51.1%) 45 (50.6%) 0.94 36 (52.2%) 35 (52.2%) 0.99
Nasal steroid use (No. [%]) 21 (23%) 16 (17.9%) 0.38 13 (18.8%) 15 (22.4%) 0.61
Antibiotic use in past month (No. [%]) 2 (2.7%) 1 (1.1%) 1 0 (0%) 3 (4.5%) 0.12
Diabetes (No. [%]) 10 (11.1%) 9 (10.1%) 0.83 6 (8.7%) 6 (9.0%) 0.96
Heart Disease (No. [%]d 9 (10.0%) 6 (6.7%) 0.43 2 (2.9%) 2 (3.0%) 0.98
History of sinusitis (No. [%]) 39 (43.3%) 39 (43.8%) 0.95 24 (34.8%) 21 (31.3%) 0.67
Days of illness (No. ± SD) 15.2 ± 9.4 15.3 ± 9.3 0.94 14.3 ± 8.1 12.9 ± 6.1 0.23
Sinusitis category (N [%]) 0.60 0.59
1) Duration  10 days 61 (67.8%) 66 (74.2%) 40 (58.0%) 1. 37 (55.2%)
2) Severe symptoms 9 (10.0%) 6 (6.7%) 9 (13.0%) 13 (19.4%)
3) Double sickening 20 (22.2%) 17 (19.1%) 20 (29.0%) 17 (25.4%)
Mean Day 0 SNOT-16 item score (mean ± SD) 1.89 ± 0.57 2.02 ± 0.54 0.12 1.89 ± .54 1.95 ± 0.55 0.521

Ascertained by chart review.

Categories of sinusitis according to Infectious Diseases Society of American guidelines [2].

+ Mean rating for each group of all ratings, on a severity scale from 0 to 3, of the 16 items of the SNOT-16 questionnaire (shown in Table 1).

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The secondary efficacy outcomes did not differ significantly. Most patients in both arms
reported major improvement at Day 10 regardless of time period. The mean SNOT-16 item
scores from Day 0 did not improve significantly at either Day 3 or Day 10.
The only potential confounder that differed between groups, smoking status in Time Period
2, had no impact on Day 3 outcomes: among smokers, 3 of 9 taking HD in Time Period 2 had
significant improvement vs. 1 of 2 taking SD (P = 0.66). Use of nasals steroids was associated
with a trend toward a better outcome among those taking both SD and HD, but was not a con-
founder (see S4 Text: Impact of Nasal Steroid Use).
Since there was no difference between outcomes at Day 10, the day 30 data were of little
value. We report them in S2 Table: Day 30 Results.

Adverse effects
As shown in Table 5, the most frequent adverse effects were diarrhea (with or without
abdominal pain) and, in women, vaginal discharge and itching. At Day 3, diarrhea was
common, more so in HD than SD groups; diarrhea reported as severe (3 on the scale of
0–3) was uncommon except in IR HD patients (15.8% vs. 4.8%, an increase of 11.0%, 95%
CI 0.1 to 21.8%, P = 0.05). Most diarrhea resolved by Day 10. Vaginal discharge and itch-
ing was also more common in HD than SD groups, especially in ER HD at Day 3 (19.6%
vs. 4.6%, an increase of 15.0%, P = 0.01), but severe vaginal symptoms were uncommon.
Abdominal pain without diarrhea was reported by only 23 participants (12 SD and 11 HD,
P = 0.94) and rash by only 6.

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 Treatment of acute sinusitis

Table 4. Efficacy by Time Period and Dose.

Standard Dose High Dose Effect size P-Value
(95% CI)
Day 3 Overall 36.42% 44.76% 8.33% 0.15
Patients Reporting Major Improvement  (55/151) (64/143) (-2.94 to 19.60)
% (No.) Time Period 1 37.93% 38.75% 0.82% 0.91
(33/87) (31/80) (-14.14 to 15.78)
Time Period 2 34.38% 52.38% 18.01% 0.04
(22/64) (33/63) (0.75 to 35.26)
Day 10 Overall 76.56% (98/128) 78.57% (99/126) 2.01% 0.70
(-8.79 to 12.74)
Time Period 1 80.77% 79.73% (59/74) -1.04% 0.87
(63/78) (-12.44 to 14.63)
Time Period 2 70.00% 76.92% 6.92% 0.43
(35/50) (40/52) (-11.43 to 24.94)
Day 3 Overall 0.81 pt. 0.91 pt. 0.10 pt. 0.19
Decrease in the Average SNOT 16 Item Score (-0.05 to 0.25)
Points on scale of 0–3 Time Period 1 0.75 pt. 0.87 pt. 0.12 pt. 0.19
(-0.06 to 0.31)
Time Period 2 0.91 pt. 0.97 pt. 0.07 pt. 0.58
(-0.17 to 0.31)
Day 10 Overall 1.34 pt. 1.45 pt. 0.11 pt. 0.20
(-0.28 to 0.59)
Time Period 1 1.32 pt. 1.48 pt. 0.16 pt. 0.14
(-0.38 to 0.55)
Time Period 2 1.37 pt. 1.40 pt. 0.03 pt. 0.806
(-0.31 to 0.24)

Percentage in each group reporting symptoms as “a lot better” or “no symptoms”

The average decrease for each group in the mean item score on the SNOT-16 from baseline at Day 0 on a scale of 0–3. Minimally important difference = 0.5 [31].

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Additional analyses
At Day 10, 91.3% of SD and 90.5% of HD participants reported taking all 14 doses of antibiot-
ics (P = 0.83). The percent unwilling to take the antibiotic again did not differ significantly
after treatment with SD vs. HD (10.5% vs. 15.1%, P = 0.28) (Table 6).

Bacterial colonization
Among the 231 anterior nasal cultures (Table 7), only 11 grew S. pneumoniae, none resistant
to penicillin (although resistance may not have been tested in 3). Only 4 of the 38 cultures
growing Staphylococcus aureus were resistant to methicillin. Thus, at most 7 of the first 231
patients were colonized with pathogens resistant to amoxicillin/clavulanate.

Discussion
Primary care patients with clinically-diagnosed acute bacterial sinusitis had a markedly greater
improvement in symptoms after 3 days of treatment with an IR formulation of HD amoxicil-
lin/clavulanate than with SD—an increase from 34.4% to 52.4% in those reporting symptoms
“a lot better” or “no symptoms” (a number-needed-to-treat of 6). Patients taking the ER for-
mulation had an increase only from 37.9% to 38.8%.
This difference in efficacy was unexpected. One explanation might be a difference in patient
populations. Patients taking SD vs. HD in the two time periods were very similar except for a
larger percentage of smokers among those taking IR HD, but this had no impact on relative

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 Treatment of acute sinusitis

Table 5. Adverse effects by Time Period and Dose.

Standard Dose High Dose Effect Size (95% CI) P-Value
Diarrhea, Any Day 3 Time Period 1 34.48% (30/87) 46.25% (37/80) 11.77% 0.12
% (No.) (-3.92 to 26.93)
Time Period 2 30.65% (19/62) 47.37% (27/57) 16.72% 0.06
(-1.94 to 34.32)
Day 10 Time Period 1 16.67% (13/78) 28.38% (21/74) 11.71% 0.08
(-2.45 to 25.58)
Time Period 2 12.00% (6/50) 17.31% (9/52) 5.31% 0.45
(-9.98 to 20.32)
Diarrhea, Severe Day 3 Time Period 1 5.75% (5/87) 7.50% (6/80) 1.75% 0.65
% (No.) (-5.87 to 9.38)
Time Period 2 4.84% (3/62) 15.79% (9/57 10.95% (0.10 to 21.80) 0.05
Day 10 Time Period 1 1.25% (1/80) 5.33% (4/75) 4.08% 0.15
(-2.65 to 11.94)
Time Period 2 0.00% (0/51) 3.85% (2/52) 3.85% 0.16
(-3.90 to 13.22)
Vaginal Itching or Discharge, Any Day 3 Time Period 1 4.62% (3/65) 19.64% (11/56) 15.02% (2.48 to 28.32) 0.01
% (No.) Time Period 2 7.84% (4/51) 15.91% (7/44) 8.07% 0.22
(-6.34 to 23.32)
Day 10 Time Period 1 15.79% (9/57) 23.08% (12/52) 7.29% 0.34
(-8.74 to 23.37)
Time Period 2 17.50% (7/40) 23.68% (9/38) 6.18% 0.50
(-13.40 to 25.61)
Vaginal Itching or Discharge. Severe Day 3 Time Period 1 0% (0/65) 0% (0/56) 0 1.00
% (No.) Time Period 2 1.96% (1/51) 2.27% (1/44) 0.31% 0.92
(-8.46 to 10.25)
Day 10 Time Period 1 5.26% (3/57) 3.85% (2/52) 1.41% 0.73
(-8.84 to 11.36)
Time Period 2 2.56% (1/39) 0.00% (0/37) 2.56% 0.33
(-7.25 to 13.47)

Diarrhea with or without abdominal pain.

https://doi.org/10.1371/journal.pone.0196734.t005

outcomes. It would seem hard for other, unmeasured differences to explain the large difference
in efficacy. The more likely explanation is the pharmacokinetic and pharmacodynamic differ-
ences in the two formulations. Since the absorption of clavulanate in combined formulations
is independent of the absorption of amoxicillin [34–35], the key is likely the difference between
the HD amoxicillin formulations. Even though amoxicillin absorption is non-linear, ER pro-
vides elevated serum levels for longer periods of time, while IR reaches higher peak levels [36].

Table 6. Reasons for not taking antibiotic again .

Time Period 1 Time Period 2
Standard dose High dose P-value Standard dose High dose P-value
N = 75 N = 74 N = 49 N = 52
Number who would not take (% of total) 8 (10.7) 11 (14.9) 0.44 5 (10.2) 8 (15.4) 0.44
Severe diarrhea 1 (12.5) 2 (18.2) 0 (0) 4 (50.0)
Any side effect 4 (50.0) 7 (63.6) 2 (40) 8 (100)
Lack of improvement 3 (37.5) 3 (27.3) 1 (20) 1 (12.5)
Unclear 1 (12.5) 1 (9.1) 2 (40) 0 (0)

Reasons inferred from chart review.

https://doi.org/10.1371/journal.pone.0196734.t006

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 Treatment of acute sinusitis

Table 7. Bacterial colonization .

Culture Report Number (Percent)
No growth or normal flora 139 (60)
Methicillin-sensitive Staphylococcus aureus 32 (14)
Haemophilus influenzae 25 (11)
Streptococcus pneumoniae 9 (4)
Moxarella catarrhalis 9 (4)
Staphylococcus epidermidis 7 (3)
Methicillin-resistant Staphylococcus aureus 5 (2)
Other 5 (2)

Cultures of the anterior nares of the first 231 patients

https://doi.org/10.1371/journal.pone.0196734.t007

It is possible that, for acute sinusitis, high peak serum levels are needed to achieve adequate
amoxicillin concentrations in the inflamed, fluid-filled sinus cavities. This would fit with the
data on acute otitis media in children [6–8].
This implication about treatment should, however, be qualified. First, the improvements in
the SNOT-16 scores were neither clinically nor statistically significant. In designing the study,
we considered the overall judgment of improvement by the patient a clinically more important
—and possibly more valid [25]—endpoint than the change in a composite score of multiple
different symptoms. The data collectors found that participants gave improvement ratings
quickly and confidently. In measuring health-related quality of life, however, researchers con-
tinue to debate the relative validities of an overall judgment vs. a sum of separate judgments
and of assessing improvement directly vs. inferring it from changes in assessments of current
states [25,37–43]. Second, the IR HD caused a considerable increase by Day 3 in diarrhea per-
ceived as severe—15.8% vs. 4.8% (a number-needed-to-harm of 9). Studies of ER HD have,
overall, found slightly higher rates of diarrhea with ER HD than with lower doses—11.5% vs.
11.9% [3], 12.4% vs. 8.6% [21], 16.7% vs. 14,4% [22], and 16.5% vs. 13% [23]—but with very
few cases reported as severe. No data exists on IR HD, but the intestinal flora or other aspects
of the gastrointestinal tract may be sensitive to the IR’s higher peaks. By Day 10, however,
most severe diarrhea (and other adverse effects) had resolved. Third, as we expected, by Day
10, most patients felt very much improved or without symptoms, with no significant differ-
ences among patients treated with HD vs. SD in either time period. Fourth, the percent of
patients at Day 10 who, after experiencing adverse effects, said they would not take the antibi-
otic again was higher for both HD formulations (although not significantly so) and even
included a few patients who had major improvement at Day 3. Patients may place less weight
on achieving the improvement they expect from any antibiotic than on suffering adverse
effects they attribute to this particular antibiotic. Fifth, our findings may not be applicable to
areas with a high prevalence of resistant bacteria since the prevalence in our patients was very
low. The findings would, however, be applicable to most outpatient practices.
The study has multiple limitations. First, owing to the need to change the HD formulation
midway through the trial when the study medication became unavailable, the power of each
time period was diminished. The important impact of the IR formulation of HD should not be
disregarded [44], but needs to be confirmed. Second, the original effort to collect information
on patients treated for sinusitis outside of the study had to be abandoned as an unnecessary
burden in a busy primary care practice. We had to perform a retrospective chart review of
those diagnosed with acute sinusitis to ascertain the reasons for non-participation. Third, the
clinicians no doubt enrolled some patients who did not have true bacterial sinusitis and, by

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 Treatment of acute sinusitis

decreasing the number who might respond quickly to antibiotics, reduced the differences
between the SD and HD groups. Fourth, all follow-up calls were made by the 4 residents and 5
medical students who were busy with clinical rotations and occasionally had trouble contact-
ing participants. Fifth, we did not advise participants to start taking nasal steroids although
their use has been shown to improve symptoms [45] and is recommend by the IDSA [2]. We
did not ask participants about current nasal steroid use at enrollment and, therefore, had to
infer its use from a subsequent review of the electronic record of the enrollment office visit.
We determined that use was not a confounder, but cannot be certain that all patients were
actually taking the steroids listed in their health record. Sixth, we did not ask participants at
days 3 and 10 if they had irrigated with nasal saline (as suggested in our handout to enrollees).
Whether nasal saline irrigation actually improves symptoms significantly is, however, still
uncertain [46].
Our findings need, of course, to be replicated. In particular, both the impact on patients of
IR HD amoxicillin/clavulanate and the use of the global rating of sinus symptom improvement
as a primary outcome need further investigation (as we are now doing). In the meantime, how-
ever, we make the following recommendations. First, clinicians should consider offering IR
HD amoxicillin/clavulanate—amoxicillin/clavulanate 875/125 plus amoxicillin 875 mg twice a
day for 7 days—to adults with sinusitis defined in accordance with IDSA criteria. They can
consider this, contrary to IDSA guidelines [2], even if they know or suspect that the prevalence
of penicillin-resistant pneumococci is low (as in our study population). Second, they should
highlight the increased likelihoods of both more rapid improvement (and, therefore, the ability
to resume normal activities) and severe diarrhea, so that patients can choose which is of greater
importance. Patients with a pressing need to return to work or school might opt for IR HD;
those who prefer a lower risk of diarrhea might choose either SD or another antibiotic. Third,
clinicians should stress that benefits and detriments are largely short-term, with most patients
getting better by Day 10 regardless of treatment.

Supporting information
S1 Dataset. Sinusitis study.
(XLSX)
S1 Table. Consort checklist for acute sinusitis study.
(DOC)
S2 Table. Day 30 results.
(DOCX)
S1 Text. Original protocol for acute sinusitis study.
(DOC)
S2 Text. Revised protocol for acute sinusitis study.
(DOC)
S3 Text. Suggestions for treating sinusitis symptoms.
(DOCX)
S4 Text. Effect of nasal steroid use.
(DOCX)

Author Contributions
Conceptualization: Gina Garrison, Paul Sorum.

PLOS ONE | https://doi.org/10.1371/journal.pone.0196734 May 8, 2018 12 / 15

 Treatment of acute sinusitis

Data curation: Andrea Matho, Mary Mulqueen, Miyuki Tanino, Aaron Quidort.
Formal analysis: Ashar Ata.
Funding acquisition: Paul Sorum.
Investigation: Andrea Matho, Mary Mulqueen, Miyuki Tanino, Aaron Quidort, Jesse Cheung,
Jennifer Pollard, Julieta Rodriguez, Supraja Swamy, Brittany Tayler.
Methodology: Gina Garrison, Paul Sorum.
Project administration: Paul Sorum.
Resources: Gina Garrison.
Software: Ashar Ata.
Supervision: Paul Sorum.
Writing – original draft: Andrea Matho, Mary Mulqueen, Miyuki Tanino, Aaron Quidort,
Brittany Tayler, Gina Garrison, Paul Sorum.
Writing – review & editing: Andrea Matho, Mary Mulqueen, Miyuki Tanino, Aaron Quidort,
Jesse Cheung, Jennifer Pollard, Julieta Rodriguez, Supraja Swamy, Brittany Tayler, Gina
Garrison, Ashar Ata, Paul Sorum.

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