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This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library
2014, Issue 2
http://www.thecochranelibrary.com
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
SUMMARY OF FINDINGS FOR THE MAIN COMPARISON . . . . . . . . . . . . . . . . . . . 3
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
ADDITIONAL SUMMARY OF FINDINGS . . . . . . . . . . . . . . . . . . . . . . . . . . 20
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145
Analysis 1.1. Comparison 1 Antibiotics versus placebo, Outcome 1 Clinical failure defined as a lack of full recovery or
improvement at 7 to 15 days of follow-up. . . . . . . . . . . . . . . . . . . . . . . . . 147
Analysis 1.2. Comparison 1 Antibiotics versus placebo, Outcome 2 Clinical failure defined as a lack of full recovery or
improvement at 16 to 60 days of follow-up. . . . . . . . . . . . . . . . . . . . . . . . 147
Analysis 1.3. Comparison 1 Antibiotics versus placebo, Outcome 3 Clinical failure defined as a lack of full recovery at 7 to
15 days of follow-up. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148
Analysis 1.4. Comparison 1 Antibiotics versus placebo, Outcome 4 Clinical failure defined as a lack of full recovery at 16 to
60 days of follow-up. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149
Analysis 1.5. Comparison 1 Antibiotics versus placebo, Outcome 5 Relapse rates after 60 days. . . . . . . . . 149
Analysis 1.6. Comparison 1 Antibiotics versus placebo, Outcome 6 Drop-outs due to adverse effects. . . . . . . 150
Analysis 2.1. Comparison 2 Cephalosporin/macrolide versus amoxicillin-clavulanate, Outcome 1 Ceph versus amox-clav;
clinical failure defined as a lack of full recovery or improvement at 7 to 15 days of follow-up. . . . . . . 151
Analysis 2.2. Comparison 2 Cephalosporin/macrolide versus amoxicillin-clavulanate, Outcome 2 Ceph versus amox-clav;
clinical failure defined as lack of full recovery or improvement at 16 to 60 days of follow-up. . . . . . . . 152
Analysis 2.3. Comparison 2 Cephalosporin/macrolide versus amoxicillin-clavulanate, Outcome 3 Drop-outs due to adverse
effects (cephalosporins). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153
Analysis 2.4. Comparison 2 Cephalosporin/macrolide versus amoxicillin-clavulanate, Outcome 4 Macrolides versus amox-
clav; clinical failure defined as a lack of full recovery or improvement at 7 to 15 days of follow-up. . . . . . 154
Analysis 2.5. Comparison 2 Cephalosporin/macrolide versus amoxicillin-clavulanate, Outcome 5 Macrolides versus amox-
clav; clinical failure defined as a lack of full recovery or improvement at 16 to 60 days of follow-up. . . . . 155
Analysis 2.6. Comparison 2 Cephalosporin/macrolide versus amoxicillin-clavulanate, Outcome 6 Drop-outs due to adverse
effects (macrolides). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156
Analysis 3.1. Comparison 3 Non-penicillin antibiotics versus beta-lactamase sensitive penicillins, Outcome 1 Clinical
failure defined as a lack of full recovery or improvement at 7 to 15 days of follow-up. . . . . . . . . . 157
Analysis 3.2. Comparison 3 Non-penicillin antibiotics versus beta-lactamase sensitive penicillins, Outcome 2 Clinical
failure defined as a lack of full recovery or improvement at 16 to 60 days of follow-up. . . . . . . . . . 158
Analysis 3.3. Comparison 3 Non-penicillin antibiotics versus beta-lactamase sensitive penicillins, Outcome 3 Drop-outs
due to adverse effects. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159
Analysis 4.1. Comparison 4 Tetracyclines versus mixed classes of antibiotics, Outcome 1 Clinical failure defined as a lack of
full recovery or improvement at 7 to 15 days of follow-up. . . . . . . . . . . . . . . . . . . 160
Analysis 4.2. Comparison 4 Tetracyclines versus mixed classes of antibiotics, Outcome 2 Drop-outs due to adverse
effects. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161
ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161
APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165
Antibiotics for acute maxillary sinusitis in adults (Review) i
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
FEEDBACK . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169
WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175
HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 176
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 176
SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 177
NOTES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 177
INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 177
Anneli Ahovuo-Saloranta1 , Ulla-Maija Rautakorpi1 , Oleg V Borisenko2 , Helena Liira3 , John W Williams Jr4 , Marjukka Mäkelä5
1 FinnishOffice for Health Technology Assessment (FinOHTA), National Institute for Health and Welfare (THL), Tampere office,
Tampere, Finland. 2 Synergus AB, Danderyd, Sweden. 3 Department of General Practice, University of Helsinki, Kirkkonummi, Finland.
4 Departments of Medicine and Psychiatry, Durham VAMC and Duke University Medical Center, Durham, NC, USA. 5 Finnish Office
for Health Technology Assessment (FinOHTA), National Institute for Health and Welfare (THL), Helsinki, Finland
Contact address: Anneli Ahovuo-Saloranta, Finnish Office for Health Technology Assessment (FinOHTA), National Institute for
Health and Welfare (THL), Tampere office, Finn-Medi 3, Biokatu 10, Tampere, FI-33520, Finland. anneli.ahovuo-saloranta@thl.fi.
Citation: Ahovuo-Saloranta A, Rautakorpi UM, Borisenko OV, Liira H, Williams Jr JW, Mäkelä M. Antibiotics for
acute maxillary sinusitis in adults. Cochrane Database of Systematic Reviews 2014, Issue 2. Art. No.: CD000243. DOI:
10.1002/14651858.CD000243.pub3.
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
ABSTRACT
Background
Sinusitis is one of the most common diagnoses among adults in ambulatory care, accounting for 15% to 21% of all adult outpatient
antibiotic prescriptions. However, the role of antibiotics for sinusitis is controversial.
Objectives
To assess the effects of antibiotics in adults with acute maxillary sinusitis by comparing antibiotics with placebo, antibiotics from
different classes and the side effects of different treatments.
Search methods
We searched CENTRAL 2013, Issue 2, MEDLINE (1946 to March week 3, 2013), EMBASE (1974 to March 2013), SIGLE
(OpenSIGLE, later OpenGrey (accessed 15 January 2013)), reference lists of the identified trials and systematic reviews of placebo-
controlled studies. We also searched for ongoing trials via ClinicalTrials.gov and the WHO International Clinical Trials Registry
Platform (ICTRP). We imposed no language or publication restrictions.
Selection criteria
Randomised controlled trials (RCTs) comparing antibiotics with placebo or antibiotics from different classes for acute maxillary sinusitis
in adults. We included trials with clinically diagnosed acute sinusitis, confirmed or not by imaging or bacterial culture.
Two review authors independently screened search results, extracted data and assessed trial quality. We calculated risk ratios (RRs)
for differences between intervention and control groups in whether the treatment failed or not. All measures are presented with 95%
confidence intervals (CIs). We conducted the meta-analyses using either the fixed-effect or random-effects model. In meta-analyses of
the placebo-controlled studies, we combined data across antibiotic classes. Primary outcomes were clinical failure rates at 7 to 15 days
and 16 to 60 days follow-up. We used GRADEpro to assess the quality of the evidence.
Antibiotics for acute maxillary sinusitis in adults (Review) 1
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Main results
We included 63 studies in this updated review; nine placebo-controlled studies involving 1915 participants (seven of the studies clearly
conducted in primary care settings) and 54 studies comparing different classes of antibiotics (10 different comparisons). Five studies
at low risk of bias comparing penicillin or amoxicillin to placebo provided information on the main outcome: clinical failure rate at 7
to 15 days follow-up, defined as a lack of full recovery or improvement, for participants with symptoms lasting at least seven days. In
these studies antibiotics decreased the risk of clinical failure (pooled RR of 0.66, 95% CI 0.47 to 0.94, 1084 participants randomised,
1058 evaluated, moderate quality evidence). However, the clinical benefit was small. Cure or improvement rates were high in both the
placebo group (86%) and the antibiotic group (91%) in these five studies. When clinical failure was defined as a lack of full recovery
(n = five studies), results were similar: antibiotics decreased the risk of failure (pooled RR of 0.73, 95% CI 0.63 to 0.85, high quality
evidence) at 7 to 15 days follow-up.
Adverse effects in seven of the nine placebo-controlled studies (comparing penicillin, amoxicillin, azithromycin or moxicillin to placebo)
were more common in antibiotic than in placebo groups (median of difference between groups 10.5%, range 2% to 23%). However,
drop-outs due to adverse effects were rare in both groups: 1.5% in antibiotic groups and 1% in control groups.
In the 10 head-to-head comparisons, none of the antibiotic preparations were superior to another. However, amoxicillin-clavulanate
had significantly more drop-outs due to adverse effects than cephalosporins and macrolides.
Authors’ conclusions
There is moderate evidence that antibiotics provide a small benefit for clinical outcomes in immunocompetent primary care patients
with uncomplicated acute sinusitis. However, about 80% of participants treated without antibiotics improved within two weeks.
Clinicians need to weigh the small benefits of antibiotic treatment against the potential for adverse effects at both the individual and
general population levels.
Sinusitis is one of the most common reasons for visiting a doctor and an estimated 20 million cases of acute sinusitis occur every year
in the USA alone. There are four pairs of sinuses linked to the bony structures around the nose: maxillary, frontal, ethmoidal and
sphenoidal sinuses. In sinusitis, these membrane-lined air spaces become infected, which causes pain and discharge from the nose.
Treatment options include decongestants, steroid drops or sprays, mucus-clearing drugs (mucolytics), antihistamines and antibiotics
and sometimes sinus puncture and irrigation for removal of purulent secretions.
In most cases sinusitis occurs during viral infections where antibiotics are ineffective, but the few cases that also have a bacterial infection
(one or two out of every 100 patients with sinus symptoms) could benefit. Unfortunately it is difficult to distinguish between those
who have a bacterial infection and those who do not. It is important to avoid unnecessary use of antibiotics and limit the potential for
antibiotic resistance.
This updated review compiled data from 63 separate studies that used a variety of antibiotics for simple maxillary sinus infection, i.e.
non-complicated acute sinusitis in a person with a healthy immune system. Nine of the studies compared antibiotics to placebo (1915
participants; seven of the studies conducted in primary care), and 54 studies compared different classes of antibiotics. Five of the nine
placebo-controlled studies involving 1058 participants found that most participants got better within two weeks, regardless of whether
they received the antibiotic or not (roughly 9 out of 10 participants in antibiotic groups and 8 out of 10 in placebo groups). Although all
the five studies in this main outcome were assessed as having low risk of bias, the overall evidence was assessed only as being of moderate
quality (it is possible that a new large study can change the estimate). In the remaining 54 studies comparing different antibiotics (10
different comparisons), no antibiotic was found to be superior to another. The evidence is current to March 2013.
The small benefit gained by antibiotics may be overridden by the negative effects of the drugs. In addition to patient-related adverse
effects (like skin rash and gastrointestinal problems such as diarrhea, abdominal pain and vomiting), side effects include the risk of
increased resistance to antibiotics amongst community-acquired pathogens (bacteria).
This review found that antibiotics will help some people a bit, but do not make a major difference to most people with acute maxillary
sinusitis being treated in primary care.
Antibiotics for acute maxillary sinusitis in adults (Review) 2
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Antibiotics for acute maxillary sinusitis in adults (Review) S U M M A R Y O F F I N D I N G S F O R T H E M A I N C O M P A R I S O N [Explanation]
Outcomes Illustrative comparative risks* (95% CI) Relative effect No of participants Quality of the evidence Comments
(95% CI) (studies) (GRADE)
Placebo Antibiotics
Clinical failure rate Failure defined as a lack Failure defined as a lack RR 0.66 1084 ⊕⊕⊕
Adverse effects8 :
Follow-up: of full recovery or im- of full recovery or im- (0.47 to 0.94) patients randomised and moderate2 antibiotics 8% to 59%;
7 to 15 days provement provement 1058 evaluated placebo 6% to 38%
(5 studies1 )
136 per 1000 90 per 1000
(64 to 128)
Failure defined as a lack Failure defined as a lack RR 0.73 716 patients randomised ⊕⊕⊕⊕
of full recovery of full recovery (0.63 to 0.85) and 680 evaluated high4
(5 studies3 )
614 per 1000 448 per 1000
(387 to 522)
Clinical failure rate Failure defined as a lack Failure defined as a lack RR 0.85 169 patients randomised ⊕⊕
Follow-up: 16 to 60 days of full recovery or im- of full recovery or im- (0.36 to 1.98) and 169 evaluated low5,6
provement provement (1 study)
Failure defined as a lack Failure defined as a lack RR 0.63 169 patients randomised ⊕⊕
of full recovery of full recovery (0.38 to 1.05) and 169 evaluated low5
(1 study)
329 per 1000 207 per 1000
(125 to 346)
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the
assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; RR: risk ratio
antibiotic and placebo either (RR value of 0.62, 95% CI 0.37 to 1.03). These two studies represent almost the utmost ends of the clinical
variation; Haye 1998 excluded participants with radiographic findings more than mild and Hadley 2010 included only participants with
bacteriologically confirmed sinusitis.
4
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Antibiotics for acute maxillary sinusitis in adults (Review)
7 Two studies at ’unclear’ risk of bias, published in 2010 and 2012 in the USA.
8 Variation of reported adverse effects in eight studies.
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5
BACKGROUND alone. Acute bacterial sinusitis is more likely if the symptoms have
lasted for more than one week (Gwaltney 2005).
Types of interventions
Types of studies
Types of outcome measures
Randomised controlled trials (RCTs) evaluating and comparing
antibiotics to a placebo, or different classes of antibiotics for acute
sinusitis, and reported in full-text. Primary outcomes
We included trials having a sample size of at least 30 participants 1. Clinical failure rate at 7 to 15 days after the start of
with acute maxillary sinusitis. This is to guarantee that data in treatment. Failure is defined as lack of full recovery or
individual studies are as unbiased as possible. Also in very small improvement of participants with acute maxillary sinusitis at
samples many estimators are known to be sensitive to variation. follow-up.
We excluded studies reported only as abstracts because there is 2. Clinical failure rate at 16 to 60 days after the start of
evidence that there are discrepancies between data reported in the treatment. Failure is defined as lack of full recovery or
abstract and the final published full report and that information improvement of participants with acute maxillary sinusitis at
on trial quality indicators is often lacking (Chokkalingam 1998; follow-up.
Hopewell 2006). Thus we required full-text reports to ensure re- As spontaneous cure rate or cure plus improvement rate in maxil-
liable data extraction and assessment of risk of bias. To diminish lary sinusitis is expected to also be fairly high in the placebo group,
the risk of publication bias, we attempted to contact authors of we decided after careful consideration to select the negative out-
potential abstracts to obtain information as to whether a full-text come ’failure’ instead of ’success’. This will enable clinicians to
report of the study (unpublished or published) was available. consider the risks of not prescribing antibiotics as opposed to the
benefits of prescribing them, compared to possible adverse effects
Types of participants of antibiotics.
Figure 1. ’Risk of bias’ graph: review authors’ judgements about each risk of bias item presented as
percentages across all included studies.
tervals (CI), using RevMan 2012. In calculating drop-out rates mates that is due to heterogeneity rather than sampling error. A
due to adverse effects, we used the Peto odds ratio (OR) as the value greater than 50% may be considered to represent substantial
outcome measure. In placebo-controlled studies with multiple an- heterogeneity (Higgins 2003).
tibiotic arms, the data from the antibiotic arms were combined
and compared to placebo or control group as recommended in the
Assessment of reporting biases
Cochrane Handbook for Systematic Reviews of Interventions (Higgins
2011b). If there had been sufficient numbers of trials (more than 10) in any
meta-analysis, publication bias would have been assessed according
to the recommendations on testing for funnel plot asymmetry
Unit of analysis issues as described in the Cochrane Handbook for Systematic Reviews of
The unit of analysis was an individual because all RCTs included in Interventions (Sterne 2011). If asymmetry was identified we would
this review were simple parallel-group trials in which participants have examined possible causes.
We assessed eight placebo-controlled studies to have ’low’ risk of All nine placebo-controlled studies reported all prespecified out-
bias in this domain (Axelsson 1970; Hadley 2010; Haye 1998; comes adequately and were graded as ’low’ risk of bias in this do-
Lindbaek 1996; Lindbaek 1998; Meltzer 2005; Merenstein 2005; main (Axelsson 1970; Garbutt 2012; Hadley 2010; Haye 1998;
van Buchem 1997). The reported total missing data rates were Lindbaek 1996; Lindbaek 1998; Meltzer 2005; Merenstein 2005;
between 0.6% and 14% at 7 to 15 days follow-up. All of those eight van Buchem 1997).
studies except one (Lindbaek 1998) adequately reported missing
data rates by study group. In the study by Lindbaek 1998 the Antibiotics versus antibiotics
total missing data rate was 5/68 (7.4%). However, we obtained
Prespecified outcomes were adequately reported in 47 out of 54
additional information from the trial author that there were drop-
studies (87%) comparing different classes of antibiotics. In two
outs in each of the three groups. Thus we assessed the study of
studies the reporting was deficient and they were graded as having
Lindbaek 1998 as having a ’low’ risk of bias in this domain.
’high’ risk of bias. In five studies the description was too vague to
The ninth placebo-controlled study by Garbutt 2012 was graded
make an assessment and the judgement was ’unclear’ risk of bias.
as ’unclear’ risk of bias at day 10. The study reported different
drop-out rates: in the amoxicillin group 4/85 (4.7%) and in the
placebo group 10/81 (12.3%) on day 10. Although there prob- Other potential sources of bias
ably was not any systematic difference in reasons for drop-outs
between the groups (the authors gave additional information that
participants simply missed the interviews), the difference in pro- Antibiotics versus placebo
portions of missing outcomes (7.6%) compared to the difference
in anticipated failure risks (10% to 20%) may be big enough to
cause bias. Baseline comparability
Two studies reported results at 16 to 60 days follow-up and had Demographic characteristics and disease severity ratings were de-
total missing data rates of 0% (Haye 1998) and 6% (Hadley 2010), scribed and assessed to be balanced across the groups in eight
indicating ’low’ risk of bias. placebo-controlled studies. In the study of Hadley 2010 this do-
main was graded as ’unclear’ risk of bias because in the placebo
group there were 9% more bilateral sinus infections than in the
Antibiotics versus antibiotics
moxifloxacin group (38% versus 29%) and no by-group descrip-
In this domain we assessed 31 out of 54 studies (57%) comparing tion was provided on allowed concomitant medications (especially
antibiotics with antibiotics to have ’low’ risk of bias, 12 studies stable-use nasal corticosteroids).
(22%) to have ’high’ risk of bias, and in 11 studies (20%) the
judgement was ’unclear’ risk of bias. The way of reporting the
results made it difficult to assess this domain in many of the stud- Co-interventions
ies. Several of the 12 studies graded as having ’high’ risk of bias Seven of the nine placebo-controlled studies reported co-interven-
reported responses only for per-protocol populations and the pro- tions during the trial (Axelsson 1970; Garbutt 2012; Hadley 2010;
portion of missing data was high. Even when studies reported clin- Lindbaek 1996; Lindbaek 1998; Merenstein 2005; van Buchem
ical responses for both intention-to-treat (ITT) and per-protocol 1997). In these studies co-interventions were mainly symptom-
populations, often only the clinical cure rates were reported while relieving over-the-counter medications which we judged not to
failure rates were not. The indeterminate/missing data were then cause bias. The study of Meltzer 2005 prohibited all concomitant
usually categorised as failures in ITT analyses and it remained un- medications, and the study of Haye 1998 did not provide any
clear how many of the responses were true failures in each group. information on co-interventions.
Three studies had to be downgraded from ’unclear’ to ’high’ risk We graded seven out of the nine studies as having a ’low’ risk of bias
of bias because of this particular problem. In the 11 studies with in this domain (Axelsson 1970; Garbutt 2012; Lindbaek 1996;
the judgement ’unclear’ risk, the description was not clear enough Lindbaek 1998; Meltzer 2005; Merenstein 2005; van Buchem
to assess this domain (especially regarding reasons for missing data 1997. The study of Hadley 2010 did not give a detailed descrip-
across groups). tion of the use of allowed co-interventions (especially nasal corti-
We excluded three studies from the meta-analyses because the costeroids which also may have a curative effect) and was judged
proportion of missing data was too high (38% in Marple 2010, as having ’unclear’ risk of bias, as well as Haye 1998 which had no
44% in Luterman 2003 and 52% in Steurer 2000). information on co-interventions.
Drop-outs due to adverse effects were rare in both groups: 15 In comparisons of antibiotic versus antibiotic, we only analyzed
out of 1013 (1.5%) in antibiotic groups and 8 out of 805 (1%) data for the primary outcomes measures: clinical failure rate at
in control groups (Analysis 1.6). Three out of the nine placebo- seven to 15 days follow-up and at 16 to 60 days follow-up (clinical
controlled studies reported no drop-outs due to side effects in the failure defined as a lack of full recovery or improvement) and for
antibiotic or control groups. two secondary outcome measures: relapse rates and drop-outs due
to adverse effects.
Clinical failure rate (fail- No difference in failure 54 studies representing ⊕⊕⊕
Adverse effects3
ure defined as a lack of rates 10 different comparisons moderate2
full recovery or improve- 1
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk
(and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and
its 95% CI).
CI: confidence interval; RR: risk ratio
DISCUSSION In this review, the risk of treatment failure (defined as lack of full
recovery or improvement) was statistically slightly smaller in an-
tibiotic groups than in placebo groups, at 7 to 15 days in partic-
Summary of main results ipants with acute sinusitis diagnosed either clinically or by radio-
graphy (main analysis, five studies; Summary of findings for the
main comparison). However, the clinical benefit was small. The
Antibiotics versus placebo difference between groups in the full recovery or improvement
Antibiotics for acute maxillary sinusitis in adults (Review) 21
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
rates was 10% at most in all of the eight studies available for this in favour of the antibiotic group. The significance of the results
comparison. The average cure or improvement rate in the antibi- remains unclear because baseline scores (in the scale 0 to 20) were
otic groups was 87% (range 78% to 98%) and in the placebo not reported, and even the five items of the questionnaire were
groups 81% (range 67% to 89%) (Table 1). not specified.
On the other hand, stronger statistical significance favouring an- In both studies it remained unclear whether data for participants
tibiotics in terms of clinical failure rates, defined as lack of full who received rescue therapy were included in these results.
recovery (at 7 to 15 days; five studies; Summary of findings for the In this review the primary outcome was failure at 7 to 15 days after
main comparison), might indicate a faster cure rate with antibi- the start of the treatment because recovery from acute maxillary
otics than without. The average full recovery rate in the antibiotic sinusitis takes generally more than one week (Gwaltney 2005).
groups was about 50% (range 30% to 65%) and in the control However, from the patient’s perspective, fast symptom relief is im-
groups 35% (range 11% to 52%) (all six available studies for this portant and data are also needed on short-term improvement. Six
comparison, Table 1). studies (Axelsson 1970; Garbutt 2012; Hadley 2010; Haye 1998;
At day 16 to 60 follow-up there was no significant difference be- Lindbaek 1996; Merenstein 2005) also reported cure or improve-
tween the antibiotic and placebo groups in relieving signs and ment rates prior to one-week follow-up. Three of the six stud-
symptoms regardless of the definition of failure (full recovery or ies reported higher improvement rates for antibiotic than placebo
improvement (Hadley 2010; Haye 1998); full recovery (Haye (Hadley 2010: improvement rate 85% versus 73% at day three;
1998)) (Summary of findings for the main comparison). Although Lindbaek 1996: improvement rate 60% versus 36% at day three;
not statistically significant, Haye 1998 reported higher full recov- Merenstein 2005: the average number of days to entire improve-
ery rates in the antibiotic group (69 out of 87 patients (79%)) ment was consistently two to two and a half days shorter in the
than in the placebo group (55 out of 82 of patients (67%)). antibiotic group among those participants who had entirely im-
None of the nine placebo-controlled studies reported severe com- proved by day 14). Two of these studies represented patients with
plications. a more severe form of disease (Hadley 2010; Lindbaek 1996). The
Even longer follow-up times would be needed to assess the efficacy other three studies reported only minor differences between the
of antibiotic treatment in the longer term and to assess potential groups at day three to five (Axelsson 1970: full recovery or im-
adverse effects. There is some evidence from other respiratory tract provement rate was 69% in the antibiotic group versus 65% in
infections that the use of antibiotics increases relapse rates and may the placebo group; Garbutt 2012: 37% versus 34%; Haye 1998:
end up increasing antibiotic consumption (Arason 2005; Joki- 80% versus 79%, respectively). The data do not make it possible
Erkkilä 2000). Therefore, in optimal circumstances, the sinusitis to draw strong conclusions on the short-term improvement of pa-
trials should monitor signs, infection rates and drug use over one tients’ symptoms.
year. Only one study in this review reported long-term relapse rates Although we found slight statistical significance and potentially
(van Buchem 1997) during a one-year follow-up. The relapse and faster resolution of symptoms favouring antibiotics, the clinical
recurrence rates were not significantly different between groups. significance of the result is questionable because of the consider-
able improvement rate in the placebo group. Also, the possible
benefit needs to be weighed against the potential for adverse ef-
Patient perspective on recovery fects at both the individual and population levels. The results were
based on studies of penicillin, amoxicillin, azithromycin and mox-
Quality of life and activity impairment were assessed in two studies
ifloxacin performed in middle and northern Europe in five stud-
(Garbutt 2012; Hadley 2010) (Summary of findings for the main
ies (Axelsson 1970; Haye 1998; Lindbaek 1996; Lindbaek 1998;
comparison). Both of these studies reported somewhat better qual-
van Buchem 1997), in the USA in three studies (Garbutt 2012;
ity of life in the antibiotic than in the placebo group at days six to
Hadley 2010; Merenstein 2005) and one study was multinational
eight. However, the Garbutt 2012 trial documented that quality
(Meltzer 2005).
of life was similar in the antibiotic and placebo groups at day three
Key information about placebo-controlled studies is collated in
and day 10 follow-ups. Garbutt 2012 also reported equal mean
Table 1.
periods missed from work in the antibiotic and placebo groups
(0.55 days) and a non-significant difference in the period where
participants were unable to do usual non-work activities (mean
1.15 days in amoxicillin and 1.67 days in the placebo group; P = Different classes of antibiotics
0.14). In the study designs comparing different classes of antibiotics,
Hadley 2010, on the other hand, reported that from day three the antibiotics had a similar efficacy to each other (Summary
to days six to eight, patients in the antibiotic group experienced of findings 2). However, at 7 to 15 days follow-up, the risk of
a greater improvement in activity impairment than patients in clinical failure was statistically significantly lower for amoxicillin-
the placebo group. The differences in change in mean activity clavulanate than for cephalosporins, but the significance of the
impairment scores were 1 at day three and 2.4 at days six to eight difference disappeared at longer follow-up.
Definition of cure
Antibiotics versus antibiotics The definitions of full recovery, improvement and failure in in-
We assessed the quality of the body of evidence for comparing one dividual studies can influence the data extraction and the results,
class of antibiotic against another as being of moderate quality ac- both at study and meta-analysis level, especially in cases where only
cording to the GRADE assessment criteria (Summary of findings a few studies are available for analysis. In studies with a dichoto-
2). Although the number of the studies was large (54 studies) most mous classification of the outcomes, the criteria can vary between
of them were non-inferiority studies and often supported by phar- studies, as well as compared to studies with multi-level classifica-
maceutical companies. Because most patients with sinusitis will tions. In this review, four of the nine placebo-controlled studies
improve without antibiotics and the margin of getting added clin- reported success dichotomously. The highest number of categories
ical benefit from antibiotics on the whole, compared to placebo, was used in the studies by Lindbaek 1996 and Lindbaek 1998.
is small (about 10%), it is easy to show non-inferiority between The outcomes were classified into five categories: restored, much
antibiotics. better, somewhat better, unimproved and worse. Two other studies
There were 54 studies comparing an antibiotic to another an- reported outcomes in three categories and one in four categories.
tibiotic. In general, we assessed the methodological quality of the Dichotomising different outcome classifications for the analyses
studies to be modest, mostly due to incomplete blinding and/or causes uncertainty in the results.
incomplete reporting of other methodological issues, especially of
randomisation (Figure 1; Figure 2). We graded only four of the
54 studies as having ’low’ risk of bias based on the methodolog- Agreements and disagreements with other
ical criteria used in this review, and graded the other 50 as ’un- studies or reviews
clear’ or ’high’ risk of bias. In the only comparison in this review
Three other recent systematic reviews have considered comparison
where a slight statistical difference was found between antibiotics,
of antibiotics with placebo for acute maxillary sinusitis. These re-
we graded none of the studies as having ’low’ risk of bias and the
views have used more permissive eligibility criteria than our review
two studies having highest weight (70% altogether) in the meta-
and would therefore include a more heterogeneous sample of in-
analysis also had a ’high’ risk of bias. This comparison was for
dividuals with and without acute bacterial rhinosinusitis. Overall,
cephalosporins versus amoxicillin-clavulanate at seven to 15 days
these reviews found similar antibiotic treatment effects, despite
follow-up with clinical failure defined as a lack of full recovery or
differing eligibility criteria.
improvement (Analysis 2.1). Confidence in this finding is limited
The study by Rosenfeld 2007 found that antimicrobials, com-
by the low methodological quality and the disappearance of sig-
pared to placebo control, increased clinical improvement rates at
nificance at longer follow-up.
two weeks for 800 patients by an absolute difference of 7% (95%
CI 2 to 13%). Diarrhoea (1583 patients, risk difference (RD) of
0.05 (95% CI 0.01 to 0.09)) and any adverse events (1853 pa-
Potential biases in the review process tients, RD of 0.11 (95% CI 0.05 to 0.16)) were more common in
the group treated with antimicrobials. A patient-level meta-anal-
ysis (Young 2008) of 10 placebo-controlled trials involving 2640
Diagnosis patients specifically excluded trials that enrolled patients on the
We expected that the diagnostic method in an individual placebo- basis of laboratory, imaging or bacterial culture results. This study
controlled study (clinical diagnosis alone versus radiological/bac- found a small increase in clinical cures with antibiotics within two
teriological confirmation) might have had an influence on the re- weeks (OR of 1.35, 95% CI 1.15 to 1.59) and a number needed to
sults. In the meta-analyses, however, no statistically significant het- treat to benefit (NNTB) of 15 (95% CI 7 to infinity). The authors
erogeneity between individual study results was observed. Clinical conclude that “common clinical signs and symptoms cannot iden-
diversity was plausible in the studies of Lindbaek 1996 and Hadley tify patients with rhinosinusitis for whom antibiotic treatment is
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of Otorhinolaryngology 1993;250(Suppl 1):S23–5. (6):521–5.
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Adelglass 1998a
Participants The study setting was not described. Participants were 40 years old on average (range 18
to 83) and included 122 men and 69 women. ENT co-morbidity was assessed; about
50% of patients had hay fever. Country - USA
Outcomes Clinical outcomes were assessed in 190 out of 216 randomised patients (in 101 out of
108 patients in levofloxacin group and in 89 out of 108 patients in clarithromycin group)
. Outcomes were assessed on day 16 to 19. Second follow-up on 42 to 46 days
Risk of bias
Random sequence generation (selection Low risk Quote: “The subject randomization list was
bias) computer-generated and stratified by site.
Equal numbers of subjects were assigned to
each treatment group”
Allocation concealment (selection bias) Low risk Quote: “To reduce potential bias during
data collection and evaluation of clinical
end points, a qualified third party assumed
responsibility for all procedures related to
the study drugs including dispensing”
Selective reporting (reporting bias) Unclear risk Outcomes reported: clinical response, ad-
verse effects and quality of life
Comment: in the methods section it is
stated that repeat sinus X-rays were taken
at 16 to 19 days giving the impression that
Incomplete outcome data addressed? High risk Missing data: 7/108 (6%) in levofloxacin
(Clinical efficacy outcomes) group and 19/108 (18%) in clarithromycin
group on day 16 to 19
Comment: imbalance in numbers of miss-
ing data across groups
Free of other bias? Baseline comparability Low risk Comment: detailed description of demo-
graphic characteristics and sinusitis severity
rating with which to assess the comparabil-
ity of the groups at baseline
Free of other bias? Funding High risk Study supported by a pharmaceutical com-
pany. 5 of the authors were affiliated to a
pharmaceutical company
Adelglass 1998b
Methods Randomised, unblinded trial. Diagnosis by clinical signs and symptoms (mean duration
of symptoms prior to enrolment 9 days) and radiograph showing at least 4 mm mucosal
thickening. Cure defined as absence of symptoms or a score of 1 or less on a 10-point
symptom scale. At least 80% of assigned doses were taken by 94% of participants.
Proportion of the participants without known or reported clinical outcome 21% on day
11 to 15
Participants The study setting was not described. Mean age approximately 37; 128 men and 150
women. About 40% of patients had ENT or eye diseases. Country - USA
Outcomes Clinical outcomes assessed at day 11 to 15 in 219 out of 278 randomised patients (in
108 out of 140 patients in cefprozil group and in 111 out of 138 patients in amoxicillin-
clavulanate group). Second follow-up 2 weeks post-treatment. Radiographic and bacte-
riological outcomes not reported
Risk of bias
Selective reporting (reporting bias) Low risk Outcomes reported: clinical response, and
adverse effects
Comment: prespecified outcomes (in
methods) were reported in prespecified way
Incomplete outcome data addressed? High risk Missing data: 32/140 (22.9%) in cefprozil
(Clinical efficacy outcomes) group and 27/138 (19.6%) in amoxicillin-
clavulanate group on day 11 to 15. Total
missing data rate 21% on day 11 to 15 and
28% on day 24
Comment: total missing data rate over 20%
Free of other bias? Baseline comparability Low risk Comment: detailed description of demo-
graphic characteristics and sinusitis severity
rating with which to assess the comparabil-
ity of the groups at baseline
Free of other bias? Funding High risk Study was supported by a grant from a
pharmaceutical company
Methods Randomised, unblinded trial. Diagnosis by clinical symptoms and radiograph showing
at least 4 mm mucosal thickening, opacification or air-fluid level. Cure defined as dis-
appearance of symptoms and signs, and stabilisation or improvement of radiographic
findings. Treatment compliance not reported. Proportion of the participants included
in the clinically evaluable population was 87% on day 12 to 19
Participants Participants were recruited from community-based primary care and otolaryngology
clinics. Mean age 39 (range 18 to 85); 225 men and 390 women. Country - USA
Outcomes Study reported clinical responses for clinically evaluable patients only. Clinical outcomes
for clinically evaluable population were assessed on day 12 to 19 in 535 out of 615
randomised patients (in 267 out of 307 patients in levofloxacin group and in 268 out of
308 patients in amoxicillin-clavulanate group). (To be clinically evaluable, the patient
had to be evaluable for safety, have a confirmed clinical diagnosis of acute sinusitis, have
received at least 7 days of therapy, have followed the protocol, and have a clinical evalu-
ation within 2 to 10 days after ending therapy.) Radiographic outcomes not separately
reported. Long-term follow-up at 28 to 32 days after completion of therapy to assess
relapse
Risk of bias
Selective reporting (reporting bias) Unclear risk Outcomes reported: overall clinical re-
sponse (clinical response + radiographic re-
sponse) and adverse effects
Comment: prespecified outcomes (in
methods) were unclearly reported (3 anal-
yses groups for treatment comparison de-
fined in methods section but the role of
mITT and ITT populations in results re-
mains unclear)
Incomplete outcome data addressed? Low risk Missing data: 40/307 (13%) in levofloxacin
(Clinical efficacy outcomes) group and 40/308 (13%) in amoxicillin-
clavulanate group on day 12 to 19
Comment: the groups were balanced in
numbers and reasons for missing data
Free of other bias? Baseline comparability Unclear risk Comment: information on comparabil-
ity at baseline was insufficient to assess
whether the groups were comparable at
baseline or not (no information on severity
rating)
Free of other bias? Co-interventions Low risk Quote: “The use of antihistamines and de-
congestants was encouraged”
Comment: no co-interventions included in
the protocol. In both groups the same con-
comitant medication was allowed and was
of such quality that it did not have an effect
on recovery (thus did not cause bias)
Free of other bias? Funding High risk Study was supported by a pharmaceutical
company
Arndt 1994
Participants Participants were recruited from academic, outpatient otolaryngology clinics. Partici-
pants were 33 years old on average (range 18 to 65) and included 25 men and 31 women.
Country - Germany
Outcomes Clinical and radiographic outcomes were assessed in 56 out of 70 randomised patients.
Outcomes were assessed on day 8 to 12 after randomisation. Bacteriological outcomes
were reported in 50 patients
Risk of bias
Selective reporting (reporting bias) Low risk Outcomes reported: clinical, radiological
and bacteriological responses; and adverse
effects
Comment: prespecified outcomes (in
methods) were reported in prespecified way
Incomplete outcome data addressed? Unclear risk Quote: “In total 14 of 70 randomized par-
(Clinical efficacy outcomes) ticipants had to be excluded shortly after
the trial began due to negative culture at
baseline or because some of them did not
come back after the first visit”
Comment: the missing data rates not re-
ported by study group. It remains unclear
how many participants were excluded be-
cause of negative culture in each group
Free of other bias? Baseline comparability Low risk Comment: detailed description of demo-
graphic characteristics and sinusitis severity
rating with which to assess the comparabil-
ity of the groups at baseline
Free of other bias? Funding Unclear risk 1 of the authors was affiliated to a pharma-
ceutical company
Methods Randomised, unblinded design. Diagnosis by clinical signs and symptoms lasting 7 to
28 days, confirmed by computed tomography or X-ray (criteria not specified). Culture
by sinus puncture or endoscopy of middle meatus, or both (51% of participants had at
least 1 causative organism identified before study entry). Clinical resolution was defined
as total resolution of signs and symptoms related to acute sinusitis and, at least, improve-
ment in the radiographic or computer tomographic scan appearance of the sinuses to the
extent that no additional or alternative antimicrobial therapy was necessary. Treatment
compliance unclearly reported. Proportion of the participants included in the per-pro-
tocol population was 80% on day 17 to 24 (there was no description of missing data)
Participants Multicentre (31 centres), multinational trial (Argentina, Brazil, Chile and Mexico). De-
mographic data reported for per-protocol population at baseline: 459 outpatients, 172
men and 287 women; mean age was 37 years. ENT co-morbidity was not assessed
Outcomes Study reported clinical resolution rates for intention-to-treat and per-protocol popula-
tions. However, only per-protocol population could be used as basis for clinical outcome
calculating in this review because failure rates were not reported and there was no de-
scription of the reasons and amounts of missing data. Clinical outcomes for per-protocol
population (patients who completed the course of treatment) were assessed on day 17
to 24 in 459 out of 575 randomised participants (in 226 out of 289 participants in
moxifloxacin group and in 233 out of 286 participants in amoxicillin/clavulanate group)
. Bacteriological outcomes for per-protocol population were assessed in 234 participants
Notes Study supported by a pharmaceutical company but the authors stated that although
they received a grant from the company to conduct the study, results were in no way
modified in favour of the sponsor’s product. 4 of the authors were affiliated to the same
pharmaceutical company
Risk of bias
Selective reporting (reporting bias) Low risk Outcomes reported: clinical response (in-
cluding radiological findings), bacteriolog-
ical response in 234 participants and ad-
verse effects
Comment: prespecified outcomes (in
methods) were reported in prespecified way
Incomplete outcome data addressed? Unclear risk Missing data: 63/289 (22%) in moxi-
(Clinical efficacy outcomes) floxacin group and 53/286 (19%) in amox-
icillin/clavulanate group on day 17 to 24
Comment: no description of reasons for
missing data
Free of other bias? Baseline comparability Low risk Comment: very detailed description of
demographic characteristics and sinusitis
severity rating with which to assess the
comparability of the groups at baseline
Free of other bias? Funding Unclear risk Study supported by a pharmaceutical com-
pany but the authors stated that although
they received a grant from the company to
conduct the study, results were in no way
modified in favour of the sponsor’s prod-
uct. 4 of the authors were affiliated to the
same pharmaceutical company
Axelsson 1970
Methods Randomised trial. Blinding was not reported. Patients with clinically suspected sinusitis
were radiologically examined; only patients with secretion were included. Secretion was
confirmed by a single diagnostic irrigation for those with completely opaque maxillary
sinuses. Clinical outcomes assessed by an investigator but “cure” and “improvement” were
not defined. Compliance with treatment was not reported. Proportion of the participants
without known or reported clinical outcome 7% on day 10
Participants The study setting was not described. It is unclear if participants were a convenience
sample or a consecutive series of eligible patients. Participants were 33 years old on
average (range 13 to 80) and included 62 men and 94 women. Patients with a history
of nasal allergy were excluded. Country - Sweden
Outcomes Clinical outcomes were assessed in 142 out of 156 randomised participants (in 35 out
of 38 patients in penicillin group and in 32 out of 34 patients in oxymetazoline group)
. Outcomes were assessed on day 10 after randomisation. Radiographic outcomes were
reported as mean number of severity points per sinus (not by patient)
Risk of bias
Selective reporting (reporting bias) Low risk Outcomes reported: clinical response, radi-
ological response and adverse effects
Comment: prespecified outcomes (in
methods) were reported in prespecified way
Incomplete outcome data addressed? Low risk Missing data: 8% (3/38) in penicillin group
(Clinical efficacy outcomes) and 6% (2/34) in oxymetazoline group
Comment: although the reasons for miss-
ing data were not stated, we decided to
judge this domain ’low’ risk of bias because
the missing data rates were equal and mar-
ginal in both groups
Free of other bias? Baseline comparability Low risk Comment: detailed description of radio-
logical sinusitis severity rating at baseline.
It appears that the groups were balanced
although the information on demographic
characteristics was scarce
Free of other bias? Co-interventions Low risk Comment: both groups received the same
co-intervention during the trial
Boezeman 1988
Methods Randomised, but unblinded trial. Diagnosis by clinical symptoms, confirmed by radio-
graph showing sinus opacity and positive culture taken near the ostium of, or by aspira-
tion from, maxillary sinus. Clinical outcomes assessed by an investigator but a definition
of clinical cure was not given. Treatment compliance was not reported. Proportion of
the participants without known or reported clinical outcome 18%
Participants The study setting was not described. Outpatients were 30 years old on average (range
13 to 76) and included 23 men and 10 women. Country - The Netherlands
Outcomes Clinical outcomes were assessed in 27 out of 33 randomised participants (in 15 out of
18 patients in doxycycline group and in 12 out of 15 patients in spiramycin group).
Outcomes were assessed on day 11 after randomisation. Radiographic and bacteriological
outcomes were reported for 27 out of 33 patients
Risk of bias
Selective reporting (reporting bias) Low risk Outcomes reported: clinical, radiological
and bacteriological outcomes, and adverse
effects
Comment: prespecified outcomes (in
methods) were reported in prespecified way
Incomplete outcome data addressed? Low risk Exclusions from analyses: absence of
(Clinical efficacy outcomes) pathogen in pretreatment cultures 3/15 in
spiramycin group and 3/18 in doxycycline
group; other missing data 0%
Comment: the absence of pathogen was
seen not to cause bias
Free of other bias? Baseline comparability High risk Comment: the severity rating at baseline
was different across the groups
Free of other bias? Funding Unclear risk There was no identified funding source
Methods Randomised, double-blind design. Diagnosis by clinical signs and symptoms lasting
at least 7 days, confirmed by radiograph showing at least 10 mm mucosal thickening,
opacification or air fluid level in a sinus radiograph or CT. Bacteriological specimens
were obtained by sinus puncture (in US sites) or endoscopy collection (non-US sites).
Clinical cure assessed by investigators and defined as dichotomous - either cure or failure.
Cure defined according to the following criteria: return to preinfection state, with no
ABMS-related signs and symptoms present, as determined on a scale of 0 to 3 points
in which 0 = absent, 1 = mild, and 3 = severe, supplemented by a sinus X-ray/CT scan
confirming no worsening of infection or the presence of only those residual symptoms
indicative of a normal course of clearance in the infection process, with no requirement
for additional antibiotic treatment. Compliance among available patients was in average
95% (assessed by unused capsule count). Proportion of the participants included in the
per-protocol clinically evaluable population was 72% on day 16 to 24
Participants Multicentre, multinational trial (USA, Argentina, France, South Africa). 148 men and
208 women, mean age about 40 years (range from 14 to 84)
ENT co-morbidity was not assessed
Outcomes Study reported clinical cure rates for modified intention-to-treat and per-protocol evalu-
able populations. However, only per-protocol evaluable population could be used as
basis for clinical failure rate calculating in this review because true failures were not re-
ported and indeterminate responses were included in failures in mITT analyses. Clinical
outcomes for per-protocol evaluable population assessed on day 16 to 24 in 278 out of
385 randomised patients (in 189 out of 260 participants in telithromycin group and
in 89 out of 125 participants in cefuroxime axetil group). Per-protocol clinically evalu-
able population defined as patients who met the diagnostic criteria, and had no major
protocol violation. Bacteriologic outcomes assessed on day 16 to 24 in 149 patients.
Radiologic outcomes were not reported
Notes Study supported by a grant from a pharmaceutical company. 1 of the authors was affiliated
to pharmaceutical company
Risk of bias
Selective reporting (reporting bias) Low risk Outcomes reported: clinical response (in-
cluding radiological findings) and bacteri-
ological response, and adverse effects
Blinding? (Participant and investigator) Low risk Quote: “Double-blind”. “To ensure blind-
ing matched placebo capsules were used in
telithromycin group”
Comment: although the description of the
blinding was incomplete, this domain was
graded ’low’ risk of bias because the study
was reported to be double-blind and blind-
ing method was partly described
Incomplete outcome data addressed? High risk Missing data: 71/260 (27%) in
(Clinical efficacy outcomes) telithromycin group and 36/125 (29%) in
cefuroxime axetil group on day 16 to 24
Comment: total missing data rate 28%
Free of other bias? Baseline comparability Unclear risk Comment: information on comparability
of intervention and control groups at base-
line reported only for modified intention-
to-treat population, not for per-protocol
evaluable population which was used in the
analyses
Free of other bias? Funding High risk Study supported by a grant from a phar-
maceutical company. 1 of the authors was
affiliated to pharmaceutical company
Burke 1999
Methods Randomised, double-blind trial. Diagnosis by symptoms lasting 1 to 4 weeks and ra-
diograph showing air-fluid level, opacity or at least 6 mm mucosal thickening. Clini-
cal resolution was defined resolution or improvement of clinical symptoms and radio-
graphic findings and no need for additional antimicrobial treatment. To be included in
the efficacy-valid population the compliance had to be at least 80%. Proportion of the
participants without known or reported clinical outcome 16%
Participants Mixed otolaryngology and primary care. Mean age 40; 178 men, 279 women. Country
- USA
Outcomes Study reported clinical cure rates for intention-to-treat and efficacy-valid populations but
clinical failure rates only for efficacy-valid population. Clinical outcomes were assessed
on day 17 to 24 in 457 out of 542 randomised patients (in 234 out of 275 participants
in cefuroxime axetil group and in 223 out of 267 participants in moxifloxacin group).
The efficacy-valid population defined as patients who met diagnostic criteria and were
without major protocol violations. Radiographic outcomes not reported. Long-term
follow-up on 37 to 41 days
Notes Study supported by a research grant from a pharmaceutical company. 3 of the authors
were affiliated to a pharmaceutical company
Risk of bias
Random sequence generation (selection Low risk Quote: “Block-design random code”
bias) Comment: although the description of the
sequence generation was incomplete, this
domain was graded ’low’ risk of bias be-
cause description gives an impression of
computer-based method
Selective reporting (reporting bias) Low risk Outcomes reported: clinical response (in-
cluding radiological findings) and adverse
effects
Comment: prespecified outcomes (in
methods) were reported in prespecified way
Blinding? (Participant and investigator) Low risk Quote: “Double-blind study”. “Medica-
tions were encapsulated in gelatin for mask-
ing purposes. Placebo capsules used in
moxifloxacin group”
Comment: although the description of the
blinding was incomplete (regarding blind-
ing of investigator), this domain was graded
’low’ risk of bias because the study was
reported to be double-blind and blinding
method was partly described
Incomplete outcome data addressed? Low risk Missing data: 41/275 (15%) in cefuroxime
(Clinical efficacy outcomes) axetil group and 44/267 (16%) in moxi-
floxacin group on day 17 to 24
Comment: the groups were balanced in
numbers and reasons for missing data
Free of other bias? Baseline comparability Low risk Comment: although the proportion of pa-
tients with severe sinusitis was 47/223
(21%) in moxifloxacin group and 36/234
(15%) in cefuroxime axetil group, this do-
main was graded ’low’ risk of bias
Free of other bias? Funding High risk Study supported by a research grant from a
pharmaceutical company. 3 of the authors
were affiliated to a pharmaceutical com-
pany
Calhoun 1993
Participants Consecutive patients were recruited from academic, primary care clinics. Mean age was
37 (range 14 to 77); 84 women and 58 men. ENT co-morbidity was not assessed.
Country - USA
Outcomes Clinical outcomes were assessed in 116 out of 142 randomised participants (in 55 out of
70 patients in clarithromycin group and in 61 out of 72 patients in amoxicillin group)
. Outcomes were assessed on day 7 to 16 after randomisation. Radiographic outcomes
were assessed in 116 out of 142 patients randomised. Bacteriological outcomes were not
reported
Risk of bias
Selective reporting (reporting bias) Low risk Outcomes reported: clinical and radiolog-
ical responses, and adverse effects
Comment: prespecified outcomes (in
methods) were reported in prespecified way
Blinding? (Participant and investigator) High risk Quote: “A third party dispensed the antibi-
otics and assessed compliance, ensuring the
single-blind (investigator-blind) nature of
the study. The single-blind design was nec-
essary because of the difficulty in packaging
the two drugs in identical capsules. Patients
were instructed not to discuss the dosing
schedule with their physicians”
Comment: no blinding of the participants
Incomplete outcome data addressed? Unclear risk Missing data: 15/70 (21.4%) in clar-
(Clinical efficacy outcomes) ithromycin group and 11/72 (15.3%) in
amoxicillin group
Comment: all reasons for missing data were
not reported by group
Free of other bias? Baseline comparability Low risk Comment: detailed description of demo-
graphic characteristics and sinusitis severity
rating with which to assess the comparabil-
ity of the groups at baseline
Free of other bias? Co-interventions Low risk Comment: both groups received the same
co-intervention during the trial
Free of other bias? Funding High risk Study was supported in part by a grant from
a pharmaceutical company
Methods Randomised, single-blind design (investigator). Clinical diagnosis of acute sinusitis and
an abnormal radiograph (mucosal thickening, opacity or air-fluid level). Sinus puncture
performed. Clinical outcomes assessed by an investigator; cure defined as “resolution
of clinical symptoms with radiographic evidence of sinus decongestion with no further
therapy required”. Improvement defined as “clinical symptoms substantially reduced but
radiographic evidence of residual sinus congestion”. Treatment compliance not reported.
Proportion of the participants without known or reported clinical outcome 25% on day
11 to 38
Participants Patients were recruited from academic and community settings; probably otolaryngology
practices. Mean age = 35 (range 18 to 79); 171 men and 146 women. ENT co-morbidity
was not assessed. Countries - Brazil, Chile, Columbia, USA
Outcomes Clinical outcomes were assessed on day 11 to 38 in 239 out of 317 randomised par-
ticipants (in 115 out of 157 participants in cefuroxime axetil group and in 124 out
of 160 participants in amoxicillin-clavulanate group). Radiographic outcomes were not
reported. Bacteriological outcomes were assessed in 76 participants
Risk of bias
Selective reporting (reporting bias) Low risk Outcomes reported: clinical response, bac-
teriological response for a proportion of
participants, adverse effects
Comment: prespecified outcomes (in
methods) were reported in prespecified way
Incomplete outcome data addressed? High risk Missing data: 42/157 (27%) in cefuroxime
(Clinical efficacy outcomes) axetil group and 36/160 (23%) in amoxi-
cillin-clavulanate group on day 11 to 38
Comment: total missing data over 20%
Free of other bias? Baseline comparability Unclear risk Comment: information on comparabil-
ity was insufficient to assess whether the
groups were comparable at baseline or not
Free of other bias? Funding High risk Study was supported in part by a pharma-
ceutical company
Chatzimanolis 1998
Participants Study setting not described. Mean age 38; 34 men and 26 women. ENT co-morbidity
not assessed. Country - Greece
Risk of bias
Selective reporting (reporting bias) Low risk Outcomes reported: clinical response and
adverse effects
Comment: prespecified outcomes (in
methods) were reported in prespecified way
Incomplete outcome data addressed? Low risk Missing data: 2/31 (6.5%) in rox-
(Clinical efficacy outcomes) ithromycin group and 2/29 (7%) in amox-
icillin-clavulanate group
Comment: the groups were balanced in
numbers and reasons for missing data
Free of other bias? Baseline comparability Low risk Comment: detailed description of demo-
graphic characteristics and sinusitis severity
rating with which to assess the comparabil-
ity of the groups at baseline
Free of other bias? Funding High risk Study funded by a pharmaceutical com-
pany
Clement 1998
Methods Randomised, unblinded design. Clinical diagnosis of ethmoid or maxillary sinusitis con-
firmed by fibre-optic examination (purulent discharge from ostium of affected sinus) and
computed tomography (criteria not specified). Pus samples were collected endoscopically
for bacteriological culture. Clinical outcomes assessed by an investigator but were not
defined. Compliance with treatment was not reported. Proportion of the participants
without known or reported clinical outcome 8% on day 10 to 14
Participants Participants were recruited from otolaryngology clinics. Mean age 41; 103 men, 151
women. ENT co-morbidity not assessed. Country - Belgium
Outcomes Clinical outcomes were assessed on day 10 to 14 in 233 of 254 participants (in 151 out of
165 participants in azithromycin group and in 82 out of 89 participants in amoxicillin-
clavulanate group) and on day 21 to 28 in 210 of 254 participants. Bacteriological
outcomes were assessed in 100 participants
Risk of bias
Selective reporting (reporting bias) Low risk Outcomes reported: clinical response, bac-
teriological response for a proportion of
participants and adverse effects
Comment: prespecified outcomes (in
methods) were reported in prespecified way
Incomplete outcome data addressed? Low risk Missing data: 14/165 (8.5%) in azithromy-
(Clinical efficacy outcomes) cin group and 7/89 (7.9%) in amoxicillin-
clavulanate group on day 10 to 14. Total
missing data 8% on day 10 to 14 and 17%
on day 21 to 28
Comment: the groups appeared to be bal-
anced in numbers and reasons for missing
data. Available case data given for both fol-
low-ups
Free of other bias? Baseline comparability Low risk Comment: detailed description of demo-
graphic characteristics and sinusitis severity
rating with which to assess the comparabil-
ity of the groups at baseline
Free of other bias? Funding High risk Study funding provided by a pharmaceuti-
cal company
Clifford 1999
Methods Randomised, double-blind trial. Participants with acute sinusitis and acute exacerbation
of chronic sinusitis included. Proportion of the participants with acute sinusitis 75% and
their results reported separately. Clinical diagnosis, confirmed by radiograph showing air-
fluid level, opacification or at least 6 mm mucosal thickening. Cure defined as symptom
resolution and radiographic improvement. Proportion of the participants without known
or reported clinical outcome 18% for the whole study population including participants
with acute sinusitis and participants with acute exacerbation of chronic sinusitis
Participants Study setting not described. Mean age approximately 41 (range 18 to 76); 187 men and
270 women. 25% of participants with acute exacerbation of chronic sinusitis in efficacy-
valid population. About 26% of participants had allergic rhinitis. Country - USA
Outcomes Clinical outcomes for participants with acute maxillary sinusitis were separately reported
only for efficacy-valid population (342 participants at day 14). Efficacy-valid population
was defined as participants who completed the course of treatment and did not use other
antimicrobial agents concomitantly with the study drug. Radiographic outcomes not
reported
Risk of bias
Random sequence generation (selection Low risk Quote: “The patients were randomly as-
bias) signed to 1 of 2 treatment groups by means
of a block design random code computer-
generated”
Allocation concealment (selection bias) Low risk Comment: central allocation (randomisa-
tion made at a pharmaceutical company)
Selective reporting (reporting bias) Low risk Outcomes reported: clinical response (in-
cluding radiographic findings) and adverse
effects
Comment: prespecified outcomes (in
methods) were reported in prespecified way
Blinding? (Participant and investigator) Low risk Quote: “Double-blind”. “The study drugs
were encapsulated in gelatin capsules for
blinding purposes. Matched placebos used”
Comment: although the description of
the blinding was incomplete (in respect
of investigator-blinding), this domain was
graded ’low’ risk of bias because the study
was reported to be double-blind and blind-
ing method was partly described
Incomplete outcome data addressed? Unclear risk Comment: missing data not described sep-
(Clinical efficacy outcomes) arately for the participants with acute si-
nusitis and participants with acute exacer-
bation of chronic sinusitis
Free of other bias? Baseline comparability Low risk Comment: detailed description of demo-
graphic characteristics and sinusitis severity
rating with which to assess the comparabil-
ity of the groups at baseline
Free of other bias? Funding High risk Study supported by a research grant from
a pharmaceutical company
Desrosiers 2008
Methods Randomised, unblinded trial. Diagnosis by clinical signs and symptoms lasting for 7 to
28 days (purulent nasal discharge; 1 additional major sign and symptom (facial pain/
pressure/tightness over the maxillary sinuses; nasal congestion/obstruction, hyposmia/
anosmia; fever) or 2 minor signs and symptoms (headache, halitosis, dental pain, ear
pressure/fullness, cough, fatigue)), confirmed by abnormal maxillary sinus X-rays or
limited sinus computed tomography scans or sinus ultrasound (at least 1 of the following:
air/fluid level, total opacification, mucosal thickening at least 10 mm). Samples for
microbiological analysis were taken by using rhinoscopic aspiration or micro-swabbing of
the maxillary sinus (middle meatus). Clinical outcome was defined as “success”, “failure”
or “indeterminate” (success was defined as cured or improved). Clinical failure was
recorded if at least on the following criteria was met: all signs/symptoms remained
unchanged or had worsened, at least 1 additional antibiotic had to be prescribed and/
or added to the study treatment for sinusitis, sinusitis-related complications occurred,
sinus puncture or drainage had been performed. Treatment compliance at least 80%
for those patients who were included in the per-protocol population. Proportion of the
participants included in the per-protocol population was 83% on day 17 to 21
Participants Multicentre (41 centres), multinational trial (Canada, Germany, Greece, Portugal and
Turkey). Demographic data reported for modified intention-to-treat population at base-
line: participants’ mean age was 39 years; 109 men and 181 women. ENT co-morbidity
was assessed; 1 participant had allergic rhinitis, 2 participants had chronic sinusitis and
5 participants had nasal septal deviation
Outcomes Study reported clinical cure rates for modified intention-to-treat and per-protocol pop-
ulations. However, only per-protocol population could be used as basis for clinical fail-
ure rate calculating in this review because true failures were not reported and it seemed
that indeterminate and missing responses were included in failures in mITT analyses.
Clinical outcomes for per-protocol population were assessed in 248 of 298 randomised
participants on day 17 to 21 and on day 41 to 49. Per-protocol population was defined
as all randomised participants with clinically and radiographically confirmed sinusitis,
and were without major protocol violations. Bacteriological outcomes reported for 103
participants on day 17 to 21. Health-related quality of life measured by SF-36 question-
naire completed by 278 participants at baseline, and on day 41 to 49
Risk of bias
Random sequence generation (selection Low risk Quote: “Centrally generated randomiza-
bias) tion list”
Allocation concealment (selection bias) Low risk Quote: “Centrally generated randomiza-
tion list”
Selective reporting (reporting bias) Low risk Outcomes reported: clinical response, bac-
teriological response for a proportion of
participants, quality of life and adverse ef-
fects
Comment: prespecified outcomes (in
methods) were reported in prespecified way
Incomplete outcome data addressed? Low risk 8 out of 298 randomised participants were
(Clinical efficacy outcomes) excluded at the beginning of the study
because of the unconfirmed sinusitis. No
information provided how these partici-
pants were divided across the 2 groups.
Calculating missing data by group was
therefore based on the modified intention-
to-treat (mITT) population (290 partici-
pants) which was defined as all randomised
participants with clinically and radiograph-
ically confirmed sinusitis, and who received
at least 1 dose of study medication
Missing data: 21/144 (14.6%) in
telithromycin group and 21/146 (14.4%)
in amoxicillin-clavulanate group on day 17
to 21
Comment: groups appeared to be balanced
in numbers and reasons for missing data
Free of other bias? Baseline comparability Low risk Comment: detailed description of demo-
graphic characteristics and sinusitis severity
rating with which to assess the comparabil-
ity of the groups at baseline
Free of other bias? Co-interventions Unclear risk Concomitant therapies were not clearly re-
ported
Free of other bias? Funding High risk Study funding provided by a pharmaceuti-
cal company
Dubois 1993
Participants Participants were recruited from outpatient ENT and primary care settings. It is unclear
if the study sample represents a consecutive series of participants or a convenience sample.
Country - Canada
Outcomes Clinical, radiographic and bacteriological outcomes were assessed in 260 out of 497
randomise participants (in 132 out of 246 participants in clarithromycin group and in
128 out of 251 participants in amoxicillin-clavulanate group). Outcomes were assessed
on about day 15 after randomisation
Risk of bias
Selective reporting (reporting bias) Low risk Outcomes reported: clinical, radiological
and bacteriological responses, and adverse
effects
Comment: prespecified outcomes (in
methods) were reported in prespecified way
Blinding? (Participant and investigator) High risk Quote: “Investigators were blind to the
drug being administered”
Comment: no description of blinding of
the participants
Incomplete outcome data addressed? Low risk Exclusions from analyses: absence of
(Clinical efficacy outcomes) pathogen in pretreatment cultures 103/246
in clarithromycin group and 117/251 in
amoxicillin-clavulanate group; other exclu-
sions 10 (4.1%) and 7 (2.8%) of partici-
pants in clarithromycin group and amoxi-
cillin-clavulanate group, respectively
Comment: the absence of pathogen was
seen not to cause bias. Other missing data
marginal
Free of other bias? Baseline comparability Low risk Comment: very detailed description of
demographic characteristics and sinusitis
severity rating with which to assess the
comparability of the groups at baseline
Free of other bias? Co-interventions Low risk Comment: both groups received the same
co-intervention during the first 3 days
Free of other bias? Funding High risk Study was supported in part by a grant from
a pharmaceutical company
Ferguson 2004
Methods Randomised, double-blind study. Diagnosis by clinical signs and symptoms, confirmed
by radiograph showing at least 10 mm mucosal thickening, total sinus opacity or air-
fluid level in a sinus radiograph. Pretreatment cultures of rhinoscopic aspirations or deep
nasal Calgiswab samples were compared with cultures taken at 17 to 24 days of follow-
up. Clinical success was defined: the patient was either cured or showed improvement
relative to baseline (including no worsening of radiological findings) without addition
of a new antibiotic. Treatment compliance reported as over 90% assessed by capsule
counts. Proportion of the participants included in the per-protocol population was 78%
on day 17 to 24
Participants Multicentre study, 41 sites in USA. Median age approximately 45 (range 18 to 85); 123
men and 199 women. ENT co-morbidity not described
Outcomes Study reported clinical success rates for modified intention-to-treat and per-protocol
populations. However, only per-protocol population could be used as basis for clinical
response calculating in this review because true failures were not reported and all in-
stances of not completing the study were included in failures in mITT analyses. Clinical
outcomes for per-protocol population were assessed at days 17 to 24 in 272 of 349 ran-
domised participants (in 135 out of 173 participants in telithromycin group and in 137
out of 176 participants in moxifloxacin group). The per-protocol population was defined
as all randomised participants who received at least 1 dose of study medication and had
signs and symptoms of acute maxillary sinusitis and radiologic findings supporting the
diagnosis and were without major protocol violations. Long-term follow-up at 31 to 36
days. Bacteriological outcomes were assessed in 67 participants
Notes Study supported by a grant from a pharmaceutical company. 4 of the authors had received
research support/grants from and/or acted as consultants for the same pharmaceutical
company
Risk of bias
Selective reporting (reporting bias) Low risk Outcomes reported: clinical response (in-
cluding radiologic findings), bacteriologi-
cal response in 67 participants and adverse
effects
Comment: prespecified outcomes (in
methods) were reported in prespecified way
Blinding? (Participant and investigator) Low risk Quote: “Double-blind study”. “Placebo-
capsules used”
Comment: although the description of the
blinding was incomplete, this domain was
graded ’low’ risk of bias because the study
was reported to be double-blind and blind-
ing method was partly described
Incomplete outcome data addressed? High risk Missing data: 38/173 (22%) in
(Clinical efficacy outcomes) telithromycin group and 39/176 (22%) in
moxifloxacin group on day 17 to 24
Comment: missing data over 20%, insuffi-
Free of other bias? Baseline comparability Unclear risk Comment: information on comparabil-
ity was insufficient to assess whether the
groups were comparable at baseline or not
(information given for mITT population,
not for per-protocol population)
Free of other bias? Funding High risk Study supported by a grant from a phar-
maceutical company. 4 of the authors had
received research support/grants from and/
or acted as consultants for the same phar-
maceutical company
Methods Randomised, placebo-controlled trial. Clinical diagnosis of acute sinusitis was based
on clinical findings, with history of maxillary pain or tenderness in the face or teeth,
purulent nasal secretions, and rhinosinusitis symptoms for 7 days or more and 28 days
or less that were not improving or worsening, or rhinosinusitis symptoms lasting for less
than 7 days that had significantly worsened after initial improvement. The symptoms
had to be moderate, severe or very severe. Mean duration of symptoms was 11 days in
both groups (median 10.0, interquartile range (25th to 75th percentile) 7.0 to 14.0).
Because the proportion of the participants with symptoms less than 7 days was small
(14%), and because the reason to include those patients was that patients’ symptoms
had significantly worsened, this study was included in this review
Clinical outcomes were assessed by telephone interview using a structured questionnaire.
Participants used a 6-point scale (a lot or a little worse or better, the same or no symp-
toms) to retrospectively assess symptom change since enrolment. Those reporting their
symptoms as a lot better or absent were categorised as significantly improved. In total, 23
participants (14%) (11 in the amoxicillin group and 12 in placebo group) did not com-
plete the 10-day course of treatment. Sixteen were treated with another antimicrobial (5
in the amoxicillin group and 11 in the placebo group). Proportion of the participants
without known or reported clinical outcome 7% on day 7; and 8% on day 10; and 4%
on day 28.
Follow-up time chosen for analyses of this review was 10 days. The 7-day follow-up
was not used because the treatments lasted for 10 days. The 28 day follow-up was not
considered because the outcome measure at this time point was recurrence or relapse and
did not include all failures, and thus the outcome is not in accordance with the outcome
definition of this review.
The study was not considered in the primary analysis of this review because it remained
unclear whether the patients who received rescue therapy were classified as non-improved
or not
The results, as reported in the original article, are presented in the Results section
Participants Participants recruited from 10 offices of primary care physicians. 60 men and 106 women;
mean age 32 (range 18 to 69) years. Allergic rhinitis in 32%, asthma in 11% and history
of sinus disease in 74% of participants in each group. Smokers 13% in amoxicillin and
26% in placebo group. Country - USA
Concomitant therapies
All patients received a 5 to 7-day supply of the following symptomatic treatments to
be used as needed: acetaminophen for pain or fever at a dose of 500 mg every 6 hours,
guaifenesin to thin secretions at a dose of 600 mg every 12 hours, 10 mg/5ml of dex-
tromethorphan hydrobromide and 100 mg/5 ml of guaifenesin for cough at a dose of 10
ml every 4 to 6 hours, pseudoephedrine-sustained action for nasal congestion at a dose
of 120 mg every 12 hours, and 0.65% saline spray using 2 puffs per nostril as needed
Concurrent use of symptomatic treatments was 92% and did not vary by study group.
No new nasal steroid use was reported
Outcomes Clinical outcomes were assessed on day 7 in 155 of 166 randomised participants (in 80
out of 85 participants in amoxicillin group and in 75 out of 81 participants in placebo
group), on day 10 in 152 of 166 randomised participants (in 81 out of 85 participants
in amoxicillin group and in 71 out of 81 participants in placebo group), and on day 28
in 159 of 166 randomised participants (in 82 out of 85 participants in amoxicillin group
and in 77 out of 81 participants in placebo group)
Outcomes were assessed by telephone interview using a structured questionnaire. Par-
ticipants used a 6-point scale (a lot or a little worse or better, the same or no symptoms)
to retrospectively assess symptom change since enrolment
Analyses were based on the intention-to-treat principle (all of the eligible participants as
randomised)
Notes Study supported by a grant from the National Institute of Allergy and Infectious Diseases,
which did not have a role in the design and conduct of the study, management and
analysis of data, or in the preparation, review or approval of the manuscript
Risk of bias
Random sequence generation (selection Low risk Quote: “Using a blocked randomiza-
bias) tion scheme, computer-generated random
numbers were used to determine how the 2
study drugs were allocated to the consecu-
tively numbered study treatment packages”
Allocation concealment (selection bias) Low risk Quote: “Randomisation was performed in
advance by the investigational pharmacist
who did not participate in patient enrol-
ment or outcome assessment. Randomisa-
tion occurred when the research assistant
assigned the treatment package”
Selective reporting (reporting bias) Low risk Outcomes reported: clinical responses,
quality of life and adverse effects
Comment: prespecified outcomes (in
methods) were reported in prespecified way
Blinding? (Participant and investigator) Low risk Quote: “Placebo was similar in appearance
and taste and dispensed in the same fashion
than the antibiotic. Telephone interviews
were conducted by trained research assis-
tants blinded to group assignment”
Incomplete outcome data addressed? Unclear risk Missing data: in amoxicillin group 5/85 (5.
(Clinical efficacy outcomes) 9%) and in placebo group 6/81 (7.4%) on
day 7; 4/85 (4.7%) and 10/81(12.3%) on
day 10; and 3/85 (3.5%) and 4/81 (4.9%)
Free of other bias? Baseline comparability Low risk Comment: very detailed description of
demographic characteristics and sinusitis
severity rating with which to assess the
comparability of the groups at baseline
Gehanno 1996a
Methods Randomised, unblinded study. Diagnosis established by clinical symptoms and radio-
graph showing sinus opacity or air-fluid level. Culture based on the sample from the
middle meatus; 79% of participants had positive cultures. Clinical outcomes assessed
by investigator; cure defined as resolution of facial pain, purulent discharge, air-fluid
level by radiograph and no recurrence of symptoms. Treatment compliance not reported.
Proportion of the participants without known or reported clinical outcome 7%
Participants Multicentre study, 284 outpatients; 136 men and 148 women. Mean age was 40. Fewer
than 25% of participants had concurrent allergic disease. Country - France
Outcomes Clinical outcomes were assessed on about day 10 in 263 out of 284 randomised partici-
pants (in 134 out of 145 participants in clarithromycin group and in 129 out of 139 par-
ticipants in amoxicillin-clavulanate group). Radiographic and bacteriological outcomes
were not reported
Risk of bias
Selective reporting (reporting bias) Low risk Outcomes reported: clinical response and
adverse effects
Comment: prespecified outcomes (in
methods) were reported in prespecified way
Incomplete outcome data addressed? Low risk Missing data: 11/145 (7.6%) in clar-
(Clinical efficacy outcomes) ithromycin group and 10/139 (7.2%) in
amoxicillin-clavulanate group on day 10
Comment: the groups appeared to be bal-
anced
Free of other bias? Baseline comparability Low risk Comment: very detailed description of
demographic characteristics and sinusitis
severity rating with which to assess the
comparability of the groups at baseline
Free of other bias? Funding Unclear risk 2 of the authors were affiliated to a phar-
maceutical company
Methods Randomised, double-blind study. Diagnosis by clinical signs and symptoms, confirmed
by radiograph (criteria not reported) and/or bacteriological culture of the middle meatus
aspirate (76% of participants had a positive culture). Clinical success defined as resolution
of all signs and symptoms. Treatment compliance was not reported. Total proportion
of the participants without known or reported clinical outcome 21%. Patients were
excluded mostly due to normal sinus X-ray and a negative bacteriological culture at
inclusion; exclusions because of other reasons 6%
Participants Multicentre study. 376 outpatients; 160 men and 216 women, mean age about 41 years.
ENT co-morbidity was not assessed. Country - France
Outcomes Clinical outcomes were assessed on days 10 to 12 in 302 of 382 randomised participants
(in 153 out of 193 participants in the sparfloxacin group and in 149 out of 189 partici-
pants in the cefuroxime axetil group)
Notes There was no identified funding source. However, 2 pharmaceutical companies were
mentioned in the methods section
Risk of bias
Selective reporting (reporting bias) Low risk Outcomes reported: clinical response, over-
all response (included clinical, radiological
and bacteriological efficacy) and adverse ef-
fects
Comment: prespecified outcomes (in
methods) were reported in prespecified way
Blinding? (Participant and investigator) Low risk Quote: “Double-blind study”. “Blinding
was prepared by a pharmaceutical com-
pany and maintained throughout the study.
Placebo-tablets used”
Comment: although the description of the
blinding was incomplete, this domain was
graded ’low’ risk of bias because the study
was reported to be double-blind and blind-
ing method was partly described
Incomplete outcome data addressed? Low risk Exclusions from analyses on day 10 to 12:
(Clinical efficacy outcomes) normal sinus X-ray and a negative bacteri-
ological culture at inclusion 28/193 in the
sparfloxacin group and 29/189 in the ce-
furoxime axetil group; other exclusions 12
(6%) and 11 (6%) of participants in the
sparfloxacin and cefuroxime axetil group,
respectively
Comment: exclusions because of lack of
inclusion criteria were seen not to cause
bias. The groups appeared to be balanced
in numbers and reasons for missing data
Free of other bias? Baseline comparability Unclear risk Comment: detailed description of demo-
graphic characteristics and sinusitis sever-
ity rating at baseline to assess the compara-
bility of the groups for whole randomised
population, not separately for the efficacy
evaluable population
Free of other bias? Funding Unclear risk There was no identified funding source.
However, 2 pharmaceutical companies
were mentioned in the methods section
Gehanno 1998
Methods Randomised, unblinded trial. Diagnosis by symptoms and radiograph showing > 5 mm
mucosal thickening, sinus opacity or air-fluid level. A causative pathogen was isolated
in the pus sample at study entry, in 51% of the 241 participants enrolled. Treatment
compliance not reported. Proportion of the participants without known or reported
clinical outcome 2% on day 10 to 12
Participants Participants recruited from community-based otolaryngology clinics. Mean age 42; 105
men and 136 women. Country - France
Outcomes Clinical outcomes assessed on days 10 to 12 in 236 out of 241 randomised participants
(in 121 out of 123 participants in cefatrizine group and in 115 out of 118 participants
in amoxicillin-clavulanate group). Second follow-up on day 30. Radiographic outcomes
assessed in 214. Bacteriologic outcomes not reported
Risk of bias
Random sequence generation (selection Low risk Quote: “Central random allocation” (com-
bias) puter-generated?)
Allocation concealment (selection bias) Low risk Quote: “Central random allocation”
Selective reporting (reporting bias) Low risk Outcomes reported: clinical and radio-
graphic responses, and adverse effects
Comment: prespecified outcomes (in
methods) were reported in prespecified way
Incomplete outcome data addressed? Low risk Missing data: 2/123 (1.6%) in cefatrizine
(Clinical efficacy outcomes) group and 3/118 (2.5%) in amoxicillin-
clavulanate group on days 10 to 12. Total
missing data rate 2% on day 10 to 12 and
4.5% at day 30
Comment: marginal missing data rate
Free of other bias? Baseline comparability Low risk Comment: very detailed description of
demographic characteristics and sinusitis
severity rating with which to assess the
comparability of the groups at baseline
Free of other bias? Funding Unclear risk 1 of the authors was affiliated to a pharma-
ceutical company
Gehanno 2004
Methods Randomised, double-blind design. Diagnosis by clinical signs and symptoms, confirmed
by radiograph showing at least 5 mm mucosal thickening, opacity or air-fluid level.
A rhinoscopic bacteriologic sampling was made on the middle nasal meatus (cultures
were positive in 46% of participants). Clinical cure based on resolution of symptoms.
Treatment compliance for per-protocol population 98%. Proportion of the participants
without known or reported clinical outcome 11%
Participants Participants were recruited by otorhinolaryngologists. The mean age of the participants
was 43 years; women 60% and men 40%. Multinational trial (France, Tunisia, Poland,
Argentina)
Outcomes Study reported clinical cure rates for modified intention-to-treat and per-protocol popu-
lations. However, only per-protocol population could be used as basis for clinical failure
rate calculating in this review because true failures were not reported in mITT popula-
tion. Clinical outcomes were assessed on day 12 to 19 in 434 out of 485 randomised
participants (in 220 out of 250 participants in pristinamycin group and in 214 out of
participants 235 in cefuroxime axetil group). The per-protocol population was defined
as participants who met the diagnostic criteria (radiologically confirmed) and had no
major protocol violation. Bacteriological outcomes reported in 199
Notes Study was supported by a pharmaceutical company. 3 of the authors were affiliated with
the same pharmaceutical company
Risk of bias
Random sequence generation (selection Low risk Comment: although the description of the
bias) sequence generation was incomplete, this
domain was graded ’low’ risk of bias be-
cause description gives an impression of
computer-based method
Allocation concealment (selection bias) Low risk Quote: “Central allocation in blocks of 4”
Selective reporting (reporting bias) Low risk Outcomes reported: clinical responses, bac-
teriological response in 199 and adverse ef-
fects
Comment: prespecified outcomes (in
methods) were reported in prespecified way
Blinding? (Participant and investigator) Low risk Quote: “Double-blind study”. “Placebo-
tablets used”
Comment: although the description of the
blinding was incomplete, this domain was
graded ’low’ risk of bias because the study
was reported to be double-blind and blind-
ing method was partly described
Incomplete outcome data addressed? Low risk Missing data: 30/250 (12%) in pristi-
(Clinical efficacy outcomes) namycin group and 21/235 (9%) in ce-
furoxime axetil group on day 12 to 19
Comment: the groups appeared to be bal-
anced in numbers and reasons for missing
data
Free of other bias? Baseline comparability Low risk Comment: detailed description of demo-
graphic characteristics and sinusitis severity
rating with which to assess the comparabil-
ity of the groups at baseline
Free of other bias? Funding High risk Study was supported by a pharmaceutical
company. 3 of the authors were affiliated
with the same pharmaceutical company
Gwaltney 1997
Participants Study setting not described. Median age 35; 789 men and 1009 women. ENT co-
morbidity not described. Countries - USA and Europe
Outcomes Clinical outcomes reported at day 7 to 14 in 1446 out of 1798 people randomised (in
474 out of 585 participants in cefdinir 600 mg once daily group and in 491 out of
603 participants in amoxicillin-clavulanate group). Long-term follow-up at 3 to 5 weeks
for participants cured or improved at the first follow-up. Radiographic outcomes not
reported. Bacteriological outcomes not reported by group
Risk of bias
Allocation concealment (selection bias) Low risk Quote: “Medications were dispensed by a
third party, and all records regarding study
medication were kept at a separate site”
Selective reporting (reporting bias) Low risk Outcomes reported: clinical and bacterio-
logical responses, and adverse effects
Comment: prespecified outcomes (in
methods) were reported in prespecified way
Blinding? (Participant and investigator) High risk Quote: “Investigator-blind study”. “Pa-
tients were instructed to with-hold details
of study medication appearance and dosing
schedule”
Incomplete outcome data addressed? Low risk Missing data: 111/585 (19%) in cefdinir
(Clinical efficacy outcomes) 600 mg once daily group and 112/603
(19%) in amoxicillin-clavulanate group on
day 7 to 14
Quote: “The 3 groups were comparable in
the reasons for their non-evaluability”
Comment: the groups appeared to be bal-
anced in numbers and reasons for missing
data on day 7 to 14
Additional missing data at 3 to 5 weeks
compared to the first follow-up about 12%.
Data not used in the long-term follow-up
meta-analysis
Free of other bias? Baseline comparability Unclear risk Comment: information on comparabil-
ity was insufficient to assess whether the
groups were comparable at baseline or not
Free of other bias? Funding Unclear risk 3 of the authors were affiliated with a phar-
maceutical company
Methods Randomised (2:1), double-blind, multicentre, phase III trial. Diagnosis by clinical signs
and symptoms present for at least 7 days (but less than 28 days) as defined by radiographic
and clinical criteria. Radiographic criteria included the presence of air-fluid levels and/or
opacification on a radiographic paranasal sinus film. Eligible patients had to be at least
18 years of age and had to have 2 major symptoms (purulent anterior or posterior nasal
discharge and unilateral facial pain or malar tenderness) or at least 1 major and 1 minor
symptom (frontal headache or fever). A sinus puncture for bacterial culture of the sinuses
was performed; only culture positive patients with target pathogen (S. pneumoniae, H.
influenzae, M. catarrhalis, Streptococcus pyogenes or Staphylococcus aureus) were included
in the analyses.
Clinical cure was defined as resolution or improvement in the signs and symptoms such
that no further therapy (antimicrobial, corticosteroid or irrigation) was required. Patients
who received rescue therapy were deemed clinical failures. Compliance not reported for
modified intention-to-treat population (which was used in the primary analyses) but
in the per-protocol population 80% compliance was required. Total proportion of the
participants without known clinical outcome 68%. Patients were excluded mostly due
to negative culture or non-target pathogen in it; exclusions because of other reasons 6%
on day 6 to 8
The study was not considered in the primary analysis because the way of reporting left
the exact numbers of failures somewhat unclear. Further, the data were not seen to be
comparable with the data from the other trials (the clinical response was measured already
at days 6 to 8 after start of therapy while other studies included in the meta-analyses did
it at days 10 to 14; unlike the other placebo-controlled trials, in this study isolation of
pathogenic bacteria from the sinus secretion was a prerequisite for inclusion)
The results at day 6 to 8, as reported in the original article, are presented in the Results
section
The study was, however, included in the analysis of “clinical failure defined as a lack of
full recovery or improvement at 16 to 60 days follow-up” (but not pooled)
Participants Participants recruited from 37 centres (ear, nose and throat practices, family practitioners
and general medical clinics). Mean age 39 years; 45 men and 73 women (in modified
intention-to-treat population; 118 out of 374 randomised). ENT co-morbidity was not
assessed. Country - USA
Outcomes The modified intention-to-treat population was the main analysis population and con-
sisted of all patients who received at least 1 dose of study drug and whose initial quan-
titative culture was positive. Clinical outcomes were assessed on day 6 to 8 and on day
20 to 26 in 118 of 374 randomised participants (in 73 out of 251 participants in moxi-
floxacin group and in 45 out of 123 participants in placebo group). No radiological or
bacteriological outcomes
Risk of bias
Selective reporting (reporting bias) Low risk Outcomes reported: clinical response dur-
ing therapy and at follow-up, patient-re-
ported symptom improvement, question-
naire scores, assessment of activity impair-
ment via questionnaire and safety
Comment: prespecified outcomes (in
methods) were reported in prespecified way
Blinding? (Participant and investigator) Unclear risk Quote: “Double-blinded trial, matching
placebos”
Incomplete outcome data addressed? Low risk Exclusions from analyses: negative culture
(Clinical efficacy outcomes) or non-target pathogen 161/251 (64%) in
moxifloxacin group and 72/123 (58.5%)
in placebo group; other exclusions 17 (6.
8%) and 6 (4.9%) of participants in mox-
ifloxacin group and placebo group, respec-
tively, on day 6 to 8 and on day 20 to 26
Comment: non-target pathogen or absence
of pathogen was seen not to cause bias.
Other missing data were balanced in num-
bers and reasons across the groups
Free of other bias? Baseline comparability Unclear risk Comment: in the placebo group there were
9% more bilateral sinus infections than in
the moxifloxacin group (38% versus 29%)
and no by-group description was provided
on allowed concomitant medications (es-
Free of other bias? Co-interventions Unclear risk Comment: no detailed description of the
use of co-interventions (especially nasal
corticosteroids which may have also cura-
tive effect)
Free of other bias? Funding High risk Study supported by a pharmaceutical com-
pany. 3 of the 6 authors were employees of
the same pharmaceutical company
Haye 1996
Methods Randomised, double-blind design. Diagnosis established clinically (symptoms lasting for
10 to 30 days) and radiograph showing at least 6 mm mucosal thickening. Culture was
not done. Clinical outcomes assessed by investigator; cure defined as “disappearance of
all pretreatment symptoms relevant to infection.” Treatment compliance not reported.
Proportion of the participants without known or reported clinical outcome 0.9% on day
10 to 12
Participants Patients recruited from general practices in Norway; 150 men and 288 women. Mean
age 40 (range 19 to 71). ENT co-morbidity was not assessed. Country - Norway
Outcomes Clinical outcomes were assessed on day 10 to 12 in 434 out of 438 randomised partic-
ipants and on day 23 to 27 in 436 out of 438 participants. Radiographic and bacterio-
logical outcomes were not reported
Risk of bias
Random sequence generation (selection Low risk Quote: “Patients were computer-ran-
bias) domised in blocks of six to one of two treat-
ment groups”
Allocation concealment (selection bias) Low risk Comment: although there is no exact in-
formation on how the randomisation re-
sult was concealed, the method of sequence
generation and information that placebo
tablets were used give the impression that
the concealment was real
Selective reporting (reporting bias) Low risk Outcomes reported: clinical responses and
adverse effects
Comment: prespecified outcomes (in
methods) were reported in prespecified way
Incomplete outcome data addressed? Low risk Missing data: 4/438 on day 10 to 12 and
(Clinical efficacy outcomes) 2/438 participants on day 23 to 27
Comment: marginal missing data rates
Free of other bias? Baseline comparability Low risk Comment: detailed description of demo-
graphic characteristics and sinusitis severity
rating with which to assess the comparabil-
ity of the groups at baseline
Free of other bias? Co-interventions Low risk Quote: “In addition to the clinical assess-
ment, the amount of analgesics taken, com-
pliance, concomitant medication, and ad-
verse events were recorded”
Comment: although there was no informa-
tion on use of analgesics or concomitant
medication, this domain was graded ’low’
risk of bias, because the way of reporting
gives an impression that use of analgesics
and concomitant medication was allowed
for both groups but of such quality that
they would not cause bias
Free of other bias? Funding Unclear risk 1 of the authors had affiliation to a phar-
maceutical company
Participants Patients recruited from Norwegian General Practices. 44 men and 125 women; mean
age 40 (range 21 to 70) years in the azithromycin group and 43 (range 18 to 68) years
in placebo group. ENT co-morbidity was not assessed. Country - Norway
Outcomes Clinical outcomes were assessed on day 10 to 12 in 168 out of 169 participants ran-
domised (in 86 out of 87 patients in antibiotic group and in 82 out of 82 participants
in placebo group) and on day 23 to 27 in 169 participants
Risk of bias
Random sequence generation (selection Low risk Quote: “Patients were computer-ran-
bias) domised in blocks of six to either of the two
treatment groups”
Allocation concealment (selection bias) Low risk Comment: although there is no exact in-
formation on how the randomisation re-
sult was concealed, the method of sequence
generation and information that the tablets
were indistinguishable from each other give
the impression that the concealment was
real
Selective reporting (reporting bias) Low risk Outcomes reported: clinical response and
adverse effects
Comment: prespecified outcomes (in
methods) were reported in prespecified way
Incomplete outcome data addressed? Low risk Missing data: 0.6% at 10 to 12 days, and
(Clinical efficacy outcomes) 0% at 23 to 27 days
Comment: minimal missing data rates
Free of other bias? Baseline comparability Low risk Comment: detailed description of demo-
graphic characteristics and sinusitis severity
rating with which to assess the comparabil-
ity of the groups at baseline
Free of other bias? Co-interventions Low risk Quote: “In addition to the clinical assess-
ment, the amount of analgesics taken, com-
pliance, concomitant medication, and ad-
verse events were recorded”
Comment: although there was no informa-
tion on use of analgesics or concomitant
medication, this domain was graded ’low’
risk of bias, because the way of reporting
gives an impression that use of analgesics
and concomitant medication was allowed
for both groups but of such quality that
they would not cause bias
Free of other bias? Funding Unclear risk 1 of the authors had affiliation to a phar-
maceutical company
Methods Randomised, double-blind study. Diagnosis by clinical signs and symptoms (presence
of either purulent nasal discharge or facial pain and/or pressure and/or tightness for 7
to 28 days), confirmed radiologically by presence of opacity or air-fluid level or mucosal
thickening of more than 6 mm. Mean duration of symptoms prior to enrolment about
13 days. Clinical response was assessed by investigator; cure was defined as resolution of
signs and symptoms to the level that existed prior to the occurrence of the acute illness;
improvement defined as partial but incomplete resolution of the signs and symptoms.
Compliance was measured by investigators reporting exact doses taken, reasons for missed
doses and the amounts of study medication returned by participants at the end of therapy
visit. Compliance was reported as 99% in the 3-day azithromycin group and 82% in
the amoxicillin-clavulanate group. Proportion of the participants included in the per-
protocol population was 85% on day 8 to 15
Participants Multicentre study. 936 outpatients, 381 men and 555 women; mean age was 41 years
(range 18 to 84). Allergic rhinitis was reported in 39% of participants. Country - USA
Outcomes Study reported clinical cure rates for intention-to-treat and per-protocol populations.
However, only per-protocol population could be used as basis for clinical failure rate
calculating in this review because true failures were not reported and there was unclear
description of missing data in the ITT population. Clinical outcomes for per-protocol
population were assessed at days 8 to 15 in 799 out of 941 randomised participants
(in 269 out of 316 patient in azithromycin for 3 days - group and in 259 out of 314
participants in co-amoxiclav group). Second follow-up at days 22 to 36. Radiographic
outcomes were not reported
Risk of bias
Selective reporting (reporting bias) Low risk Outcomes reported: clinical response and
adverse effects
Comment: prespecified outcomes (in
methods) were reported in prespecified way
Incomplete outcome data addressed? Unclear risk Comment: there was not a clear statement
(Clinical efficacy outcomes) about missing data
Free of other bias? Baseline comparability Low risk Comment: very detailed description of
demographic characteristics and sinusitis
severity rating with which to assess the
comparability of the groups at baseline
Free of other bias? Funding High risk Study was supported by a grant from a
pharmaceutical company
Henry 2004
Participants Multicentre, multinational study (USA, Poland). 271 ambulatory participants, 146
women and 95 men, mean age was about 41 years. ENT co-morbidity was not assessed
Outcomes Clinical outcomes were reported for clinically evaluable population only and assessed in
241 out of 271 randomised participants on 19 to 24 days (in 123 out of 138 patients
in cefdinir group and in 118 out of 133 participants in levofloxacin group). Clinically
evaluable population defined as participants who met the study selection criteria, received
at least 80% of the intended amount of study drug, underwent an assessment at 19 to
24 days, and did not receive any other antibiotic before the assessment. Radiographic
outcomes were assessed in 239 participants at 19 to 24 days
Risk of bias
Selective reporting (reporting bias) Low risk Outcomes reported: clinical and radiolog-
ical responses, and adverse effects
Comment: prespecified outcomes (in
methods) were reported in prespecified way
Blinding? (Participant and investigator) Low risk Quote: “Double-blind study”. “Drugs were
over-encapsulated to achieve an identical
appearance. The drugs were prepackaged
and dispensed in blister cards in such a way
that each patient received the appropriate
quantity of active drug for 10 days of ther-
apy”
Comment: although the description of
the blinding was incomplete (in respect
of investigator blinding), this domain was
graded ’low’ risk of bias because the study
was reported to be double-blind and blind-
ing method was partly described
Incomplete outcome data addressed? Low risk Missing data: 15/138 (11%) in cefdinir
(Clinical efficacy outcomes) group and 15/133 (11%) in levofloxacin
group on 19 to 24 days
Comment: the groups were balanced in
numbers and reasons for missing data
Free of other bias? Baseline comparability Low risk Comment: detailed description of demo-
graphic characteristics and sinusitis severity
rating with which to assess the comparabil-
ity of the groups at baseline
Free of other bias? Funding Unclear risk 3 of the authors had affiliation to a phar-
maceutical company
Huck 1993
Participants Patients were recruited from community-based otolaryngology clinics. Participants were
38.4 years old on average (range 16 to 73) and included 50 men and 58 women. ENT co-
morbidity was assessed: fewer than 25% of participants had chronic sinusitis. Country
- USA
Outcomes Clinical outcomes were assessed in 96 out of 108 randomised participants overall. 56
participants with acute sinusitis and 25 participants with recurrent acute sinusitis with
more than 1 episode per year with clinical improvement between episodes were consid-
ered in this review (15 participants with chronic sinusitis were not included). Outcomes
were assessed on day 10 to 12 after randomisation. Radiographic and bacteriological
outcomes were not measured
Risk of bias
Selective reporting (reporting bias) Low risk Outcomes reported: clinical responses and
adverse effects
Comment: prespecified outcomes (in
methods) were reported in prespecified way
Blinding? (Participant and investigator) Low risk Quote: “Double-blind”. “To maintain
blinding, drugs and placebo were placed in
identical capsules and given to participants
in identical bottles”
Comment: although the description of the
blinding was incomplete, this domain was
graded ’low’ risk of bias because the study
was reported to be double-blind and blind-
ing method was partly described
Incomplete outcome data addressed? Unclear risk Total amount of missing data 11%
(Clinical efficacy outcomes) Comment: no description of missing data
across intervention groups (when chronic
participants are excluded)
Free of other bias? Baseline comparability Unclear risk Comment: information on comparabil-
ity at baseline was insufficient to assess
whether the groups were comparable at
baseline or not (no information on severity
rating)
Free of other bias? Funding High risk Study funding provided by a pharmaceuti-
cal company
Jareoncharsri 2004
Methods Randomised, unblinded design. 80% of participants had acute maxillary sinusitis and
20% had acute exacerbation of chronic sinusitis. Diagnosis by clinical symptoms and
signs confirmed by the finding of mucopurulent discharge in the middle meatus or
maxillary ostium as seen by nasal endoscopy and abnormal radiograph (criteria not
specified); about 88% of patients had air-fluid level or opacity on X-ray. Bacteriological
specimens were collected by sinus aspiration. Clinical cure was assessed by investigators
using a 4-point scale; cure was defined as complete resolution of signs and symptoms
with no radiological evidence of remaining disease; improvement defined as incomplete
resolution of signs and symptoms and improvement of radiological findings. Treatment
compliance was not reported. Proportion of participants without known or reported
clinical outcome 2%
Participants Participants (n = 60) were recruited from 2 otolaryngologic centres. Mean age 36 (range
17 to 68); 23 men and 37 women. 20% of participants had acute exacerbation of chronic
sinusitis (n = 12). About 28% of participants had allergic rhinitis. Country - Thailand
Outcomes Clinical outcomes were assessed in 47 out of 48 randomised participants with acute
maxillary sinusitis. Outcomes were assessed on day 21 after the start of treatment. Bac-
teriological outcomes were assessed in 37 participants with acute maxillary sinusitis on
day 14. Radiological findings were not reported separately for participants with acute
maxillary sinusitis
Risk of bias
Selective reporting (reporting bias) Low risk Outcomes reported for participants with
acute maxillary sinusitis: clinical response
(including radiological findings), bacterio-
logical response and adverse effects
Comment: prespecified outcomes (in
methods) were reported in prespecified way
Free of other bias? Baseline comparability Low risk Comment: detailed description of demo-
graphic characteristics and sinusitis severity
rating with which to assess the comparabil-
ity of the groups at baseline
Concomitant allergy was more frequent in
levofloxacin group than in co-amoxiclav
group, but this was seen not to cause bias
Free of other bias? Funding High risk Study was financially supported by a phar-
maceutical company
Participants Participants were recruited from academic, outpatient otolaryngology clinics. Mean age
was approximately 30 (range 17 to 69); 89 men and 11 women. Country - Finland and
Sweden
Outcomes Clinical outcomes were assessed in 67 out of 100 randomised participants (in 32 out of
50 participants in clarithromycin group and in 35 out of 50 participants in amoxicillin
group) on day 11 to 13. Radiographic and bacteriological outcomes were assessed in 68
participants
Risk of bias
Selective reporting (reporting bias) Low risk Outcomes reported: clinical, radiological
and bacteriological responses, and adverse
effects
Comment: prespecified outcomes (in
methods) were reported in prespecified way
Incomplete outcome data addressed? Low risk Exclusions from analyses: absence of appro-
(Clinical efficacy outcomes) priate pathogens in pretreatment cultures
16/50 in clarithromycin group and 14/50
in amoxicillin group; other exclusions 2
(4%) and 1 (2%) of participants in clar-
Free of other bias? Baseline comparability Low risk Comment: detailed description of demo-
graphic characteristics and sinusitis severity
rating with which to assess the comparabil-
ity of the groups at baseline
Free of other bias? Co-interventions Low risk Comment: both groups received the same
co-intervention during the trial
Free of other bias? Funding Unclear risk There was no identified funding source
Klapan 1999
Methods Randomised, unblinded design. Diagnosis based on symptoms (lasting on average 7 days)
and radiograph showing at least 4 mm mucosal thickening, opacity or air-fluid level. Sinus
puncture performed in a subset of participants. Cure defined as complete disappearance
of signs and symptoms; improvement as partial disappearance of symptoms without need
for further antibiotics. Treatment compliance not reported. Proportion of the participants
without known or reported clinical outcome 6% on day 10 to 12
Participants The study setting not described. Mean age approximately 33 years old (range 15 to 50)
; 77 men and 23 women. Coexisting allergic rhinitis in 30%. Country - Croatia
Risk of bias
Selective reporting (reporting bias) Low risk Outcomes reported: clinical and bacterio-
logical responses, and adverse effects
Comment: prespecified outcomes (in
methods) were reported in prespecified way
Incomplete outcome data addressed? Low risk Missing data: 3/50 (6%) in azithromycin
(Clinical efficacy outcomes) group and 3/50 (6%) in amoxicillin-clavu-
lanate group on day 10 to 12. Missing data
6% on day 10 to 12 and 11% at 4 weeks
Comment: the groups were balanced in
numbers and reasons for missing data.
Available case data given for both follow-
ups
Free of other bias? Baseline comparability Low risk Comment: detailed description of demo-
graphic characteristics and sinusitis severity
rating with which to assess the comparabil-
ity of the groups at baseline
Free of other bias? Funding High risk 1 of the authors had affiliation to a phar-
maceutical company. Copyright by phar-
maceutical company
Methods Randomised, single-blinded design. Outpatients, both genders, 18 years or older. Diag-
nosis of acute sinusitis was based on clinical symptoms of postnasal discharge and facial
pain and tenderness in maxillary sinus area for at least 7 and at last 28 days. Cure defined
as complete disappearance of signs and symptoms to the level that existed prior to the
occurrence of the acute illness and without requirement for other antibiotics; improve-
ment (applicable only at the end of the treatment) as partial disappearance of symptoms
without need for further antibiotics. Treatment compliance not reported. Proportion of
the participants without known clinical outcome not reported (results give, however, an
impression that at least at 10 days there are drop-outs)
Data not used in the meta-analysis in this review because exact data and participant
numbers remain unclear at follow-ups (results given only as percentages)
Participants Setting not described. In total 76 patients; detailed demographic characteristics not given.
Patients with chronic sinusitis were excluded (chronic sinusitis was defined as sinusitis 3
or more times during the past 6 months). Country - Iran
Outcomes Clinical outcomes assessed on day 10 and 30 but the numbers of participants are missing
and the results are given only as percentages
Notes There was no identified funding source. 2 authors were employees of a pharmaceutical
company
Risk of bias
Random sequence generation (selection Unclear risk Quote: “This was a single blind random-
bias) ized clinical trial”
No further information provided
Selective reporting (reporting bias) High risk Outcomes reported: clinical responses
Comment: in conclusions it was stated that
“results revealed that azithromycin has less
side effects, and patients were able to tol-
erate the medications better with a higher
compliance and less economic cost than co-
amoxiclav regimen”.
However, any results for adverse effects
were not reported
Blinding? (Participant and investigator) High risk Quote: “This was a single blind random-
ized clinical trial”
Comment: single-blinded trial
Incomplete outcome data addressed? Unclear risk Comment: the numbers of participants at
(Clinical efficacy outcomes) follow-ups are missing and the results give
an impression that at least at 10 days there
are drop-outs
Free of other bias? Baseline comparability Unclear risk Quote: “Signs and symptoms of patients
in both groups were more or less similar.
Symptoms and signs prevalence and du-
ration of symptoms before treatment were
similar in both therapy groups. Participants
also had similar age distribution”
Comment: no detailed information on the
severity of symptoms and demographic
characteristics
Free of other bias? Funding Unclear risk There was no identified funding source. 2
of the authors had affiliation to a pharma-
ceutical company
Lasko 1998
Methods Randomised, double-blind design. Clinical diagnosis confirmed by radiograph showing >
5 mm mucosal thickening, opacity or air-fluid level. Cure defined by symptom resolution.
Treatment compliance not reported. Proportion of the participants without known or
reported clinical outcome 19%
Participants Setting not described. Mean age 40; 102 men and 134 women. Country - Canada
Outcomes Clinical outcomes reported at day 12 to 19 in 191 out of 236 participants randomised
(in 98 out of 119 participants in levofloxacin group and in 93 out of 117 participants
in clarithromycin group). Radiographic and bacteriological outcomes not reported
Notes Study funding provided by a pharmaceutical company. 2 of the authors affiliated to the
same pharmaceutical company
Risk of bias
Random sequence generation (selection Low risk Quote: “Patients were assigned either to
bias) levofloxacin 500 mg once daily or to clar-
ithromycin 500 mg twice daily, based on a
computer-generated randomization sched-
ule”
Selective reporting (reporting bias) Unclear risk Outcomes reported: clinical response and
adverse effects
Comment: in the methods section it is
stated that repeat sinus X-rays were taken
at 42 to 46 days giving the impression that
this was an outcome. However, the results
were not reported
Blinding? (Participant and investigator) Low risk Quote: “Double-blinding was accom-
plished by encapsulation of tablets. The size
of the capsule necessitated the use of the
250 mg tablet and each dose was therefore 2
capsules morning and evening”. “Identical
morning and evening bottles”. “Placebo-
tablets used”
Comment: although the description of the
blinding was incomplete (in respect of in-
vestigator), this domain was graded ’low’
risk of bias because the study was reported
to be double-blind and blinding method
was partly described
Incomplete outcome data addressed? Low risk Missing data: 21/119 (18%) in levofloxacin
(Clinical efficacy outcomes) group and in 24/117 (21%) in clar-
ithromycin group
Comment: the groups were balanced in
numbers and reasons for missing data
Free of other bias? Baseline comparability Low risk Comment: detailed description of demo-
graphic characteristics and sinusitis severity
rating with which to assess the comparabil-
ity of the groups at baseline
Free of other bias? Funding High risk Study funding provided by a pharmaceuti-
cal company. 2 of the authors affiliated to
the same pharmaceutical company
Methods Randomised, double-blind design. Clinical diagnosis of acute sinusitis (> 7 and < 30
days), confirmed by computed tomography (the criteria for confirming the diagnosis
were presence of fluid level or total opacification in any sinus). Bacteriological specimens
were obtained from the nasopharynx of 125 participants (42% had “normal nasal flora”)
. Participants assessed response as “restored”, “much better”, “somewhat better”, “unim-
proved” or “worse”
Treatment compliance was not reported. In total, 12 participants (9%) (5 in the amoxi-
cillin group and 7 in placebo group) did not complete the 10-day course of treatment. 9
were treated with another antimicrobial (2 in the amoxicillin group and 7 in the placebo
group)
Proportion of the participants without known or reported clinical outcome 2% on day
10
Participants Participants recruited from Norwegian General Practices. 45 men and 85 women; mean
age 39 (range 16 to 74) years. ENT co-morbidity was not assessed. Country - Norway
Outcomes Clinical and radiographic outcomes were assessed on day 10 in 127 out of 130 partici-
pants randomised (in 83 out of 86 participants in antibiotic groups and in 44 out of 44
participants in placebo group)
Risk of bias
Random sequence generation (selection Low risk Quote: “The randomization was per-
bias) formed in blocks of three within each of
the six subgroups (3 subgroups by CT and
2 subgroups by a severity scale) by using a
dice to generate the random allocations”
Comment: randomisation was done by a
statistician (information obtained from the
author)
Allocation concealment (selection bias) Low risk The statistician sent the randomisation list
to the company who produced the med-
ication boxes with numbers according to
the list. The author received the numbered
boxes for each of the subgroups from the
company. The randomisation codes were
Selective reporting (reporting bias) Low risk Outcomes reported: clinical and radiolog-
ical responses, and adverse effects
Comment: prespecified outcomes (in
methods) were reported in prespecified way
Blinding? (Participant and investigator) Low risk Quote: “The trial was double blind; neither
the patients, the general practitioner, nor
the radiologists were aware of the allocation
of treatment”
Comment: the randomisation codes were
broken after the whole study was finished
(information obtained from the author)
Free of other bias? Baseline comparability Low risk Comment: detailed description of demo-
graphic characteristics and sinusitis severity
rating at baseline but actual numbers are
not given
Free of other bias? Co-interventions Low risk Quote: “Nasal decongestants and mild
analgesics allowed in both groups”
Comment: no co-interventions included in
the protocol. In both groups the same con-
comitant medication was allowed and was
of such quality that it did not have an effect
on recovery (thus did not cause bias)
Free of other bias? Funding Low risk Study was funded by governmental sources
Lindbaek 1998
Participants Patients recruited from Norwegian General Practices. 27 men and 43 women; mean age
40 (range 16 to 83) years. ENT co-morbidity was not assessed. Country - Norway
Outcomes Clinical outcomes (based on patient diary) were assessed on day 10 in 63 out of 68
participants randomised (no information for drop-outs per group)
Risk of bias
Allocation concealment (selection bias) Low risk The statistician sent the randomisation re-
sults to the company who produced the
medication boxes. The author received the
numbered boxes from the company. The
randomisation codes were broken after the
whole study was finished
Comment: information obtained from the
author
Selective reporting (reporting bias) Low risk Outcomes reported: clinical responses and
adverse effects
Comment: prespecified outcomes (in
methods) were reported in prespecified way
Blinding? (Participant and investigator) Low risk Quote: “The trial was double-blind: Nei-
ther the patients, the general practitioner,
nor the radiologists were aware of the treat-
ment allocation”
Comment: the randomisation codes were
broken after the whole study was finished
(information obtained from the author)
Incomplete outcome data addressed? Low risk Total drop-out rate 5/68 (7.4%)
(Clinical efficacy outcomes) Comment: although there were no exact
numbers on the drop-out rates across the 3
groups, this domain was graded ’low’ risk
of bias. The total drop-out rate was seen
Free of other bias? Baseline comparability Low risk Comment: detailed description of demo-
graphic characteristics and sinusitis severity
rating with which to assess the comparabil-
ity of the groups at baseline
Free of other bias? Co-interventions Low risk Quote: “Nasal decongestants and mild
analgesics allowed in both groups”
Comment: no co-interventions included in
the protocol. In both groups the same con-
comitant medication was allowed and was
of such quality that it did not have an effect
on recovery (thus did not cause bias)
Free of other bias? Funding Low risk Study was funded by governmental sources
Luterman 2003
Participants Multicentre, multinational trial (USA, Canada, South Africa, Argentina and Chile). De-
mographic data reported for modified intention-to-treat population at baseline: partic-
ipants’ mean age was 39 years (range 16 to 84); 248 men and 359 women. ENT co-
morbidity was not assessed
Outcomes Results reported for per-protocol population only. Clinical outcomes were assessed on
day 17 to 24 in 423 out of 754 randomised participants; and on day 31 to 45 in
399 participants. The per-protocol population was defined as participants who met the
diagnostic criteria and had no major protocol violation. Bacteriological outcomes were
assessed in 24 participants
Risk of bias
Selective reporting (reporting bias) Low risk Outcomes reported: clinical response (in-
cluding radiological findings) and bacteri-
ological response for a small proportion of
the participants, adverse effects
Comment: prespecified outcomes (in
methods) were reported in prespecified way
Blinding? (Participant and investigator) Low risk Quote: “Double-blind study”. “The iden-
tity of all drugs was concealed by placing
them in identical opaque capsules. Placebo-
capsules were also used”
Comment: although the description of the
blinding was incomplete, this domain was
graded ’low’ risk of bias because the study
was reported to be double-blind and blind-
ing method was partly described
Incomplete outcome data addressed? High risk Total missing data 44% on day 17 to 24
(Clinical efficacy outcomes)
Free of other bias? Baseline comparability Unclear risk Comment: the demographic and severity
rating reported only on modified inten-
tion-to-treat population, not on the per-
protocol population used in analysis of the
study
Free of other bias? Funding Unclear risk Study funded by an unrestricted grant from
a pharmaceutical company
Methods Randomised, open-label study. Clinical diagnosis of acute sinusitis was based on signs
and symptoms lasting for between 7 and 30 days (pain, pressure and/or tightness as-
sociated with 1 or both maxillary sinuses that worsened with movement or percussion,
and discoloured (yellow-green) nasal discharge or discoloured drainage in the posterior
pharynx or from the maxillary sinus orifice, together with 2 or more of fever, frequent
coughing, nasal congestion or postnasal drainage). Treatment success by day 28 (the
only time point eligible in this review) was defined as resolution of symptoms within the
study period, no unscheduled sinusitis visits and no additional antibiotics prescribed for
sinusitis. Treatment compliance not reported. Proportion of the participants included
in the per-protocol population was 62% on day 28; data not used in the meta-analyses
of this review
Participants Multicentre study, participants were recruited in primary care settings by 70 study inves-
tigators. Demographic data for per-protocol population at baseline: participants’ mean
age was 46 years; 151 men and 323 women. ENT co-morbidity was assessed; about 37%
of participants had history of allergic rhinitis. Country - USA
Outcomes Clinical responses on day 28 were reported for per-protocol population only. Clinical
responses (based on follow-up telephone interviews) were assessed on day 28 in 462 out
of 751 participants randomised (in 231 out of 380 participants in azithromycin group
and in 231 out of 371 participants in amoxicillin-clavulanate group). The per-protocol
population was defined as all eligible randomised participants who completed the diary
and first telephone interview (at day 5) and reported taking at least 1 dose of the study
medication
Notes The study was sponsored by a pharmaceutical company. 3 of the authors had affiliation
to, and other 3 of the authors were paid consultants of, the same pharmaceutical company
Risk of bias
Selective reporting (reporting bias) Low risk Outcomes reported: clinical responses,
quality of life, satisfaction with treatment
and adverse effects
Comment: prespecified outcomes (in
methods) were reported in prespecified way
Incomplete outcome data addressed? High risk Missing data: 149/380 (39%) in azithro-
(Clinical efficacy outcomes) mycin group and 140/371 (38%) in amox-
icillin-clavulanate group on day 28
Comment: total missing data over 20%
Free of other bias? Baseline comparability Low risk Comment: detailed description of demo-
graphic characteristics and sinusitis severity
rating for per-protocol population to assess
the comparability of the groups at baseline
Free of other bias? Funding High risk The study was sponsored by a pharmaceu-
tical company. 3 of the authors had affili-
ation to, and other 3 of the authors were
paid consultants of, the same pharmaceu-
tical company
Matthews 1997
Methods Randomised, unblinded design. Diagnosis by clinical symptoms and signs, confirmed by
radiograph showing opacity, clouding or air-fluid level. Bacteriological specimens were
obtained by antral puncture. Acute and chronic sinusitis included (acute reported sepa-
rately). Success defined as cure or improvement. Proportion of the participants without
known or reported clinical outcome 24% among participants with acute sinusitis. Data
not used in the meta-analyses of this review because time points for outcome measure
were not clearly reported
Participants Participants recruited from otolaryngology clinics. Mean age of 42 (range 18 to 78). 93
of 182 participants had acute sinusitis. Country - USA
Outcomes Clinical outcomes reported in 71 out of 93 randomised participants with acute sinusitis
(in 37 out of 49 participants in cefixime group and in 34 out of 44 participants in amox-
icillin group). Bacteriological outcomes assessed in 32 participants with acute sinusitis.
Drop-outs due to adverse events reported for acute and chronic sinusitis combined
Risk of bias
Random sequence generation (selection Low risk Quote: “Patients were randomized by a
bias) computer-generated schedule to receive
oral doses of either 400 mg of cefixime
once daily or 500 mg of amoxicillin every
8 hours”
Selective reporting (reporting bias) Low risk Outcomes reported: clinical and bacterio-
logic responses, and adverse effects
Comment: prespecified outcomes (in
methods) were reported in prespecified way
Blinding? (Participant and investigator) High risk Quote: “Open label study”
Incomplete outcome data addressed? High risk Missing data: 12/49 (24%) in cefixime
(Clinical efficacy outcomes) group and 10/44 (23%) in amoxicillin
group
Comment: missing data over 20%
Free of other bias? Baseline comparability Unclear risk Comment: information on comparability
was insufficient to assess whether the in-
tervention groups with acute sinusitis were
comparable at baseline or not
Free of other bias? Funding Unclear risk Study funding not stated
Mattucci 1986
Methods Randomised trial; unblinded. Diagnosis was established by a clinical diagnosis of acute
sinusitis plus a radiograph showing “clouding” of the nasal sinus and a positive culture
from or near the sinus ostium. Clinical outcomes were assessed by an investigator; clinical
cure was not defined. Compliance with treatment was not reported. Proportion of the
participants without known or reported clinical outcome 19%
Participants Patients were recruited from outpatient otolaryngology clinics. Participants were 40 years
old on average (range 12 to 76) and included 23 men and 35 women. ENT co-morbidity
was not assessed. Country - USA
Both groups were allowed to take decongestants or analgesics but these were not pre-
scribed by the investigators (all of the participants took decongestants during the trial)
Outcomes Clinical outcomes were assessed in 47 out of 58 randomised participants (in 25 out of 29
participants in minocycline group and in 22 out of 29 participants in amoxicillin group)
. Outcomes were assessed on day 10 to 20 after randomisation. Radiographic outcomes
were assessed in 42 participants and bacteriological in 46
Risk of bias
Selective reporting (reporting bias) Low risk Outcomes reported: clinical response, radi-
ological response for 42 participants, bacte-
riological response for 46 participants and
adverse effects
Comment: prespecified outcomes (in
methods) were reported in prespecified way
Incomplete outcome data addressed? Unclear risk Exclusions from analyses: absence of
(Clinical efficacy outcomes) pathogen in pretreatment cultures 3/29 in
minocycline group and 3/29 in amoxicillin
group; other exclusions 1 (3.4%) and 4 (13.
8%) of participants in minocycline group
and amoxicillin group, respectively
Comment: the absence of pathogen was
seen not to cause bias. Other missing
data in numbers not balanced between the
groups
Free of other bias? Baseline comparability High risk Quote: “The proportion of participants
with severe sinusitis 68% in minocycline
group and 43% in amoxicillin group”
Free of other bias? Funding Unclear risk There was no identified funding source
Meltzer 2005
Participants Participants recruited from 71 medical centres in 14 countries. Study population con-
sisted of a total of 981 randomised patients in 4 groups: 243 in mometasone furoate nasal
spray (MFNS) 200 µg once daily, 235 in MFNS 200 µg twice daily, 251 in amoxicillin
and 252 in placebo. 338 men and 643 women; mean age 35 years (4% of participants
were 12 to 17 years of age in amoxicillin group and 6% in placebo group). ENT co-
morbidity: 42% of participants had either seasonal or perennial allergic rhinitis in amox-
icillin and placebo groups
Outcomes The original article reported the total failure rates during the 15-day treatment phase per
group but exact numbers of the assessed participants were not given (only numbers and
reasons for discontinued participants per group). It remains unclear whether all other
discontinued participants than those lost to follow-up were assessed or not. The original
article used intention-to-treat principle in the analyses. We decided to exclude in our
analyses those randomised participants who were reported to be lost to follow-up (1 in
antibiotic group and 4 in placebo group) and those 4 participants in placebo group who
did not meet the protocol criteria for entry. Thus clinical failures were assessed during
the 15-day treatment phase in 494 out of 503 randomised participants (in 250 out of
251 participants in amoxicillin group and in 244 out of 252 participants in placebo
group). Figures for failures at the follow-up phase (days 16 to 29) not given
Notes Study supported by a grant from a pharmaceutical company. 1 of the authors was affiliated
to a pharmaceutical company
Risk of bias
Random sequence generation (selection Low risk Quote: “Randomisation was performed ac-
bias) cording to a computer-generated code,
stratified on the basis of duration of rhi-
nosinusitis symptoms before baseline (7-14
days and 15-28 days)”
Allocation concealment (selection bias) Low risk Comment: although there is no exact in-
formation on how the randomisation re-
sult was concealed, the method of sequence
generation of this multicentre study (71
centres in 14 countries) and information
that placebo nasal sprays and placebo cap-
sules were used, give the impression that
the concealment was real
Selective reporting (reporting bias) Low risk Outcomes reported: clinical responses and
adverse effects
Comment: prespecified outcomes (in
methods) were reported in prespecified way
Incomplete outcome data addressed? Low risk Missing data: 1/251 (0.4%) in amoxicillin
(Clinical efficacy outcomes) group and in 8/252 (3.2%) in placebo
group
Comment: marginal missing data rate
Free of other bias? Baseline comparability Low risk Comment: detailed description of demo-
graphic characteristics and sinusitis severity
rating with which to assess the comparabil-
ity of the groups at baseline
Free of other bias? Co-interventions Low risk Quote: “Concomitant medications that
would interfere with study evaluations were
not permitted”
Comment: medications that might cause
bias were prohibited
Free of other bias? Funding High risk Study supported by a grant from a phar-
maceutical company. 1 of the authors was
affiliated to a pharmaceutical company
Merenstein 2005
Methods Randomised, double-blind design. Clinical diagnosis of acute sinusitis was based on
clinical findings, which had to include at least 1 of the following: purulent nasal discharge
predominating on 1 side, facial pain on 1 side, purulent nasal discharge on both sides,
pus in the nasal cavity, lasting for at least 7 days. About 50% of participants had at least
2 of these signs at baseline (the study did not report any subjective symptoms); mean
duration of symptoms prior to enrolment 11 days. Clinical cure defined as dichotomous
- either “completely improved” or “not improved”. Treatment compliance not reported.
Proportion of the participants without known or reported clinical outcome 14% on day
14
Participants Participants recruited from a suburban primary care office. 42 men and 93 women; mean
age 34 years. ENT co-morbidity was not assessed. Country - USA
Outcomes Clinical outcomes (based on follow-up telephone interviews of participants) were assessed
on day 14 in 116 out of 135 participants randomised (in 56 out of 67 participants in
antibiotic group and in 60 out of 68 participants in placebo group)
Random sequence generation (selection Low risk Quote: “Permuted block randomization
bias) stratified for the 3 participating clinicians
was used to determine treatment assign-
ment”
Comment: computer-generated by a statis-
tician who gave the authors a list to follow
(information obtained from the authors)
Allocation concealment (selection bias) Low risk Comment: a statistician made the ran-
domisation and gave the authors a list that
they followed (information obtained from
the authors)
Selective reporting (reporting bias) Low risk Outcomes reported: several clinical re-
sponses and adverse effects
Comment: prespecified outcomes (in
methods) were reported in prespecified way
Blinding? (Participant and investigator) Low risk Quote: “Patients were given an enve-
lope containing either a placebo medicine
taken twice daily for 10 days or antibiotic
medicine taken twice daily for 10 days. The
envelopes were opaque, and each had 40
identical-appearing pills”
Comment: the authors followed the ran-
domisation list without knowing which
medicine was given to each patient (infor-
mation obtained from the authors)
Incomplete outcome data addressed? Low risk Missing data: 16.4% (11/67) in antibiotic
(Clinical efficacy outcomes) group and 11.8% (8/68) in placebo group
at 14 days
Comment: the groups appeared to be bal-
anced in numbers and reasons for missing
data
Free of other bias? Baseline comparability Low risk Comment: very detailed description of
demographic characteristics and sinusitis
severity rating with which to assess the
comparability of the groups at baseline.
The groups appeared to be balanced at
baseline
Free of other bias? Funding Low risk Funded mostly by academic sources
Murray 2005
Methods Randomised, double-blind trial. Clinical diagnosis of acute sinusitis (> 6 and < 29 days)
, confirmed by radiograph (the criteria for confirming the diagnosis were presence of air-
fluid level or total or partial opacification). Sinus puncture for all participants. Clinical
outcomes were assessed by an investigator. Clinical failure was defined as the persistence
or worsening of signs and symptoms requiring additional antibiotics or development
of new signs and symptoms requiring antibiotics. Treatment compliance reported over
96%. Proportion of the participants without known or reported clinical outcome 6%
Participants Multicentre study; 81 outpatient centres in the United States, India, Europe and Latin
America. 225 men and 313 women; mean age 38 (range 18 to 88) years. ENT co-
morbidity was assessed; about one-third of participants suffered from allergic rhinitis
Outcomes Clinical outcomes were assessed at days 17 to 24 in 507 out of 541 participants ran-
domised. Bacteriologic outcomes assessed in 213 participants
Notes Study funded by a pharmaceutical company. 2 of the authors were affiliated to a phar-
maceutical company
Risk of bias
Selective reporting (reporting bias) Low risk Outcomes reported: clinical and bacterio-
logic responses, clinical response by base-
line pathogen and adverse effects
Comment: prespecified outcomes (in
methods) were reported in prespecified way
Incomplete outcome data addressed? Low risk Missing data: 14/270 (5%) in azithromy-
(Clinical efficacy outcomes) cin group and 17/268 (6%) in levofloxacin
group
The information on number of randomised
participants across groups was insuffi-
ciently reported. In calculating the missing
data, the population who received at least
1 dose of study medication was used as the
baseline population (missing only 3 partic-
ipants from the total randomised popula-
tion)
Comment: although reasons for missing
data across groups were not reported, this
domain was graded ’low’ risk of bias be-
cause missing data were marginal and bal-
anced in numbers
Free of other bias? Baseline comparability Low risk Comment: detailed description of demo-
graphic characteristics and sinusitis severity
rating with which to assess the comparabil-
ity of the groups at baseline
Although the information was provided
only for the whole treated population (not
for clinically evaluable population which
was the primary efficacy endpoint) this do-
main was graded ’low’ risk of bias because
the missing data rate was small
Free of other bias? Funding High risk Study funded by a pharmaceutical com-
pany. 2 of the authors were affiliated to a
pharmaceutical company
Methods Randomised, unblinded study. Diagnosis was established by a clinical diagnosis of acute
sinusitis, confirmed by a radiograph (criteria were not specified), transillumination and
a positive bacterial culture obtained from samples of discharge from the sinuses. Clinical
outcomes were assessed by an investigator. Clinical cure was defined as complete disap-
pearance of clinical symptoms at completion of treatment; improvement was defined as
a clear regression of the clinical symptomatology. Compliance with treatment was not
reported. Proportion of the participants without known or reported clinical outcome
0%
Participants Participants were recruited from an outpatient otolaryngology clinic. Participants repre-
sented a convenience sample, not a consecutive series. Participants were 37.8 years old
on average (range 18 to 75) and included 30 men and 50 women. ENT co-morbidity
was not assessed. Country - Switzerland
Outcomes Clinical outcomes were assessed in 80 out of 80 randomised participants. Outcomes were
assessed on day 7 to 10 after randomisation. Radiographic outcomes were not reported.
Bacteriological outcomes were reported for 40 participants
Risk of bias
Selective reporting (reporting bias) Unclear risk Outcomes reported: clinical response, bac-
teriological response for 40 patients and ad-
verse effects
Comment: it remains unclear why only a
proportion of the population was included
in the bacteriological response and how
were they selected
Free of other bias? Baseline comparability Unclear risk Comment: detailed description of demo-
graphic characteristics. However, no infor-
mation on the severity rating across the
groups
Free of other bias? Funding Unclear risk 2 of the authors were affiliated to pharma-
ceutical company
O’Doherty 1996
Participants Recruitment settings were not described. Mean age was 35 for all diagnoses. ENT co-
morbidity was not assessed. Countries - UK, Ireland
Outcomes Clinical outcomes were assessed on day 11 to 15 and reported separately for 78 out of
91 randomised participants with sinusitis (in 41 out of 48 participants in azithromycin
group and in 37 out of 43 participants in cefaclor group). Radiographic outcomes were
not reported. Bacteriological outcomes were assessed in 18 participants
Risk of bias
Selective reporting (reporting bias) Low risk Outcomes reported: clinical response, bac-
teriological response for 18 participants
and adverse effects
Comment: prespecified outcomes (in
methods) were reported in prespecified way
Incomplete outcome data addressed? Unclear risk Missing data: 7/48 (15%) in azithromycin
(Clinical efficacy outcomes) group and 6/43 (14%) in cefaclor group on
day 11 to 15
Comment: no information on reasons for
missing data separately for sinusitis partic-
ipants across groups
Free of other bias? Baseline comparability Unclear risk Comment: information on comparabil-
ity was insufficient to assess whether the
groups were comparable at baseline or not
(information not stated separately for par-
ticipants with sinusitis)
Free of other bias? Funding Unclear risk There was no identified funding source
Olmo 1994
Methods Randomised, obviously unblinded design. Diagnosis was established by clinical symp-
toms and a radiograph showing sinus opacity or air-fluid level. 66% of participants had
positive culture. Clinical outcomes were assessed by an investigator; clinical cure was
“remission of symptoms within the treatment time”. Compliance with treatment was
not reported. Proportion of the participants without known or reported clinical outcome
0% on day 24 to 26
Participants Participants were recruited from emergency rooms. Mean age was not reported (>= 20
for inclusion); 28 men and 19 women. ENT co-morbidity was not assessed. Country -
Spain
Outcomes Overall clinical outcomes (including also radiological response and bacteriological re-
sponse for those participants with positive culture at baseline) were assessed in 48 out of
48 randomised participants on day 24 to 26. Bacteriological outcomes were also reported
separately for the 31 participants with positive culture at baseline
Risk of bias
Random sequence generation (selection Low risk Quote: “Random numbers table”
bias)
Selective reporting (reporting bias) Low risk Outcomes reported: clinical response, bac-
teriological response and adverse effects
Comment: prespecified outcomes (in
methods) were reported in prespecified way
Free of other bias? Baseline comparability Unclear risk Comment: information on comparabil-
ity was insufficient to assess whether the
groups were comparable at baseline or not
Free of other bias? Funding Unclear risk There was no identified funding source
Otte 1983
Methods Randomised, double-blind design. Diagnosis based on symptoms and abnormal radio-
graph (criteria not given). Bacteriological culture was performed. Clinical cure based on
resolution of symptoms and normal radiograph. Treatment compliance was not reported.
Proportion of the participants without known or reported clinical outcome 0% on day
10
Participants Patients recruited from outpatient otolaryngology clinics. Mean age was 32 (range 17 to
56); 12 men and 19 women. ENT co-morbidity was not assessed. Country - Chile
Outcomes Clinical outcomes were assessed on day 10 in all 31 participants randomised. Radiolog-
ical outcomes reported on day 20 in 31 participants, bacteriological outcomes for 27
participants
Risk of bias
Selective reporting (reporting bias) Low risk Outcomes reported: clinical and radiolog-
ical responses for all participants, bacterio-
logical response for a proportion of the par-
ticipants and adverse effects
Comment: prespecified outcomes (in
methods) were reported in prespecified way
Blinding? (Participant and investigator) Low risk Quote: “Double-blind study”. “Placebo-
tables were used; antibiotics and placebo
tablets were identical. Tablets were deliv-
ered in numbered envelopes”
Free of other bias? Baseline comparability Unclear risk Comment: information on comparabil-
ity was insufficient to assess whether the
groups were comparable at baseline or not
Free of other bias? Funding Unclear risk There was no identified funding source
Methods Randomised, open design. Diagnosis established clinically and by a radiograph showing
at least 5 mm mucosal thickening, sinus opacity or fluid-level. Clinical outcomes were
assessed by an investigator and clinical cure was defined as resolution of clinical symptoms
and radiographic cure or improvement. Compliance with treatment was not reported.
Proportion of the participants without known or reported clinical outcome 4% on day
10 to 15
Participants Participants were recruited from community, otolaryngology clinics. Mean age = 43; 99
men and 143 women. Country - France
Outcomes Clinical outcomes were assessed on day 10 to 15 in 242 out of 253 randomised partic-
ipants (in 85 out of 87 participants in cefixime for 10 days group and in 77 out of 82
participants in amoxicillin clavulanic acid group). Second follow-up on day 33. Radio-
graphic outcome was not reported separately
Risk of bias
Selective reporting (reporting bias) Low risk Outcomes reported: overall response in-
cluding clinical and radiological responses,
and adverse effects
Comment: prespecified outcomes (in
methods) were reported in prespecified way
Blinding? (Participant and investigator) High risk Quote: “Open study” (when comparing
group 2 to group 3)
Incomplete outcome data addressed? Low risk Missing data: 2/87 (2.3%) in cefixime
(Clinical efficacy outcomes) group and 5/82 (6.1%) in amoxicillin
clavulanic acid group on day 10 to 15. To-
tal missing data 4% on day 10 to 15 and
9% on day 33
Comment: missing data rate marginal on
day 10 to 15. The judgement on day 33 was
Free of other bias? Baseline comparability Low risk Comment: very detailed description of
demographic characteristics and sinusitis
severity rating with which to assess the
comparability of the groups at baseline
Free of other bias? Co-interventions Low risk Comment: groups received the same co-
interventions during the trial
Free of other bias? Funding Unclear risk 2 of the authors were affiliated to a phar-
maceutical company(?)
Pessey 2001
Methods Randomised, double-blind design. Diagnosis based on clinical signs and symptoms con-
firmed by radiograph (total opacity of sinus or air-fluid level). Culture based on an as-
pirate from the middle meatus; 52% of participants had positive cultures. Clinical cure
based on resolution of symptoms. Treatment compliance over 90%. Proportion of the
participants without known or reported clinical outcome 0.6% on day 10 to 12
Outcomes Clinical outcomes were assessed on day 10 to 12 in 308 out of 310 randomised partic-
ipants (in 160 out of 161 participants in pristinamycin group and in 148 out of 149
participants in cefuroxime axetil group). Follow-up (29 to 36 days) for those participants
who were cured at the end of treatment. Participant-related radiographic and bacterio-
logical outcomes were not reported
Risk of bias
Random sequence generation (selection Low risk Quote: “Treatment was allocated by means
bias) of a randomization code. The randomiza-
tion was balanced in each center by blocks
of 4 participants”
Comment: although the description of the
sequence generation was incomplete, this
Allocation concealment (selection bias) Low risk Quote: “Sealed individual envelopes con-
taining the identification of the treatment
to be administered to each patient were
handed to each investigator”
Comment: although the description of the
allocation concealment was incomplete,
this domain was graded ’low’ risk of bias
because the way of reporting the blinding
also gives an impression of adequate alloca-
tion concealment
Selective reporting (reporting bias) Low risk Outcomes reported: clinical response and
adverse effects
Comment: prespecified outcomes (in
methods) were reported in prespecified way
Incomplete outcome data addressed? Low risk Missing data: 1/161 (0.6%) in pristi-
(Clinical efficacy outcomes) namycin group and 1/149 (0.7%) in ce-
furoxime axetil group on day 10 to 12
Comment: marginal missing data rate
Free of other bias? Baseline comparability Low risk Comment: detailed description of demo-
graphic characteristics and sinusitis severity
rating with which to assess the comparabil-
ity of the groups at baseline
Free of other bias? Co-interventions Low risk Comment: in both groups the same con-
comitant medication was prescribed
Free of other bias? Funding Unclear risk There was no identified funding source
Methods Randomised, unblinded design. Diagnosis of acute sinusitis was based on clinical findings
(purulent nasal discharge, nasal congestion, postnasal drainage, frequent coughing or
throat clearing, frontal headache, malar tenderness/pain); lasting for at least 7 days.
Clinical response was assessed by investigator and it was defined as disappearance of
acute signs and symptoms related to the infection or sufficient improvement such that
additional or alternative antimicrobial therapy was not required. Treatment compliance
not reported but to be included in the per-protocol population the patient had to have
received at least 80% of study medication. Proportion of the participants included in
the per-protocol population was 72% on day 24 to 31
Participants Multicentre study; primary care participants. 156 men and 315 women; mean age ap-
proximately 42 (range 18 to 87) years. ENT co-morbidity was not assessed. Country -
USA
Outcomes Available case data were basically possible to extract for per-protocol population only.
However, the way of reporting does not enable identification of clinical failure rates
because of inconsistent description of clinical response in results (it remains unclear in
which outcome group improvements are included). Clinical outcomes for per-protocol
population on day 24 to 31 were reported in 341 out of 475 randomised participants (in
170 out of 238 participants in moxifloxacin group and in 171 out of 237 participants in
amoxicillin clavulanate group). (The per-protocol population included all participants
with no major protocol violation who had received a study antibiotic for at least 72 hours
if a clinical failure, had completed the evaluation at 14 to 21 days post-treatment, and had
adequate compliance documented with at least 80% of study medication administered)
Notes Study supported by a research grant from a pharmaceutical company. 2 of the authors
were affiliated to the same pharmaceutical company
Risk of bias
Random sequence generation (selection Low risk Quote: “Block design random code”
bias) Comment: although the description of the
sequence generation was incomplete, this
domain was graded ’low’ risk of bias be-
cause description gives an impression of
computer-based method
Selective reporting (reporting bias) Low risk Outcomes reported: clinical responses and
adverse effects
Incomplete outcome data addressed? High risk Missing data: 68/238 (29%) in moxi-
(Clinical efficacy outcomes) floxacin group and 66/237 (28%) in amox-
icillin clavulanate group
Comment: missing data rate over 20%
Free of other bias? Baseline comparability Low risk Comment: very detailed description of
demographic characteristics and sinusitis
severity rating with which to assess the
comparability of the groups at baseline
Free of other bias? Funding High risk Study supported by a research grant from a
pharmaceutical company. 2 of the authors
were affiliated to the same pharmaceutical
company
Riffer 2005
Participants Multicentre, multi-country trial. Mean age was 37 (range 13 to 79); 194 men and 243
women. ENT co-morbidity was not assessed
Outcomes Study reported clinical cure rates for intention-to-treat and clinically evaluable popu-
lations. However, only clinically evaluable population could be used as basis for clin-
ical failure rate calculation in this review because true failures were not reported and
it seemed that indeterminate and missing responses were included in failures in ITT
analyses. Clinical outcomes were assessed on day 16 to 18 in 373 of 437 randomised
participants (in 188 out of 221 participants in clarithromycin group and in 185 out of
216 participants in amoxicillin-clavulanate group) and on day 24 to 31 in 361 partic-
ipants. The clinically evaluable population was defined as all randomised participants
with clinically and radiographically confirmed sinusitis, and were without major protocol
violations. Bacteriological outcomes assessed on day 16 to 18 in 109 of 218 participants.
Radiographic outcomes assessed on day 24 to 31 in 366 of 423 participants. Quality of
life measured by symptom assessment and the SNOT-16 test
Risk of bias
Selective reporting (reporting bias) Low risk Outcomes reported: clinical, radiological
and bacteriological responses, adverse ef-
fects and quality of life
Comment: prespecified outcomes (in
methods) were reported in prespecified way
Incomplete outcome data addressed? Low risk Missing data: 33/188 (17.5%) in clar-
(Clinical efficacy outcomes) ithromycin group and 31/216 (14.4%) in
amoxicillin-clavulanate group on day 16 to
18. Total missing data 16% on day 16 to
18 and 17% day 24 to 31
Comment: the groups appeared to be bal-
anced in numbers and reasons for missing
data
Free of other bias? Baseline comparability Low risk Comment: very detailed description of
demographic characteristics and sinusitis
severity rating with which to assess the
comparability of the groups at baseline
Free of other bias? Funding High risk The study was supported by a grant from a
pharmaceutical company
Russell 1997
Methods Randomised trial. Blinding not stated. Diagnosis by clinical signs and symptoms, con-
firmed by X-ray or CT (opacification, air/fluid level or mucosal thickening). Clinical
outcomes were assessed by an investigator; clinical cure defined as all clinical signs and
symptoms were resolved and no new clinical signs and symptoms were present and/or the
follow-up radiograph showed resolution/improvement. Approximately 80% of partici-
pants received the prescribed antibiotic course. Proportion of the participants without
known or reported clinical outcome 12% on day 20 to 35
Participants Study setting not described. Mean age was approximately 38 (range 13 to 79); 172
men and 256 women. 84% of participants had a history of ENT or eye-related medical
conditions. Country - USA
Outcomes Clinical outcomes were assessed on day 20 to 35 in 428 out of 479 participants (in 146
out of 158 participants in cefprozil 250 mg group, in 147 out of 160 participants in
cefprozil 500 mg group and in 135 out of 161 participants in amoxicillin-clavulanate
group). Radiographic and bacteriological outcomes not reported
Notes Study was supported by a pharmaceutical company. 3 of the authors were affiliated to
pharmaceutical company
Risk of bias
Selective reporting (reporting bias) Low risk Outcomes reported: clinical response and
adverse effects
Comment: prespecified outcomes (in
methods) were reported in prespecified way
Incomplete outcome data addressed? High risk Missing data: 12/158 (8%) in cefprozil 250
(Clinical efficacy outcomes) mg group and 26/161 (16%) in amoxi-
cillin-clavulanate group on day 20 to 35
Comment: the groups were imbalanced in
numbers of missing data
Free of other bias? Baseline comparability Low risk Comment: detailed description of demo-
graphic characteristics and sinusitis severity
rating with which to assess the comparabil-
ity of the groups at baseline
Free of other bias? Funding High risk Study was supported by a pharmaceutical
company. 3 of the authors were affiliated to
pharmaceutical company
Sher 2002
Methods Randomised, investigator-blinded design. Diagnosis by clinical signs and symptoms last-
ing at least 7 days, confirmed by radiograph showing at least 5 mm mucosal thickening,
opacification or air fluid level in a sinus radiograph. Clinical outcomes were assessed by
an investigator and clinical cure was defined as improvement in or resolution of all acute
signs and symptoms of the original infection, with no need for further antimicrobial
therapy. Treatment compliance for clinically evaluable population over 80% by counting
unused study medication. Proportion of the participants without known or reported
clinical outcome 9%
Participants Multicentre study; 30 centres. Participants were 42 years old on average (range 18 to
89); 159 men and 286 women. ENT co-morbidity was assessed; for example, 60% of
participants had a history of allergic rhinitis. Country - USA
Outcomes Study reported results for clinically evaluable participants only. Clinical outcomes were
assessed on day 10 to 13 and on day 17 to 24 in 405 out of 445 randomised participants
(in 137 out of 149 participants in 5-day gatifloxacin group, in 127 out of 141 participants
in 10-day gatifloxacin group and in 141 out of 155 participants in amoxicillin-clavulanate
group). Clinically evaluable participants were those who met the inclusion criteria and
had received at least 80% of the intended amount of study drug, had undergone the test-
of-cure assessment (7 to 14 days after the completion of treatment), and had not received
any other antibiotic during the study or before the test-of-cure visit for an infection other
than sinusitis. Long-term follow-up on day 31 to 38 by telephone
Radiographic and bacteriological outcomes not reported
Risk of bias
Random sequence generation (selection Low risk Quote: “Patients were randomized to treat-
bias) ment by means of a centralized telephone
system. A permuted block design was used
to minimize imbalance in treatment arms
at each site and in the study overall”
Allocation concealment (selection bias) Low risk Quote: “Patients were randomized to treat-
ment by means of a centralized telephone
system. A permuted block design was used
to minimize imbalance in treatment arms
at each site and in the study overall”
Selective reporting (reporting bias) Low risk Outcomes reported: clinical response and
adverse effects
Comment: prespecified outcomes (in
methods) were reported in prespecified way
Incomplete outcome data addressed? Low risk Missing data: 12/149 (8%) in 5-day gat-
(Clinical efficacy outcomes) ifloxacin group, 14/141 (10%) in 10-day
gatifloxacin group and 14/155 (9%) in
amoxicillin/clavulanate group
Quote: “The 40 unevaluable participants
Free of other bias? Baseline comparability Unclear risk Comment: detailed description of demo-
graphic characteristics and sinusitis severity
rating at baseline to assess the comparability
of the groups for whole randomised pop-
ulation, not separately for clinically evalu-
able population
Free of other bias? Funding Unclear risk 2 of the authors were affiliated with a phar-
maceutical company
Siegert 2000
Methods Randomised, double-blind trial. Diagnosis by clinical signs and symptoms, confirmed
by radiograph (mucosal thickening, opacification or air-fluid level) or bacteriologically
(either by a swab collected under endoscopic view, cannulation of the middle meatus
or a sinus puncture; positive cultures were obtained in 52% of participants). Clinical
cure was not defined. Treatment compliance not reported. Proportion of the participants
without known or reported clinical outcome 5%
Participants Multicentre (60 centres), multinational trial (Finland, France, Germany, Greece, Israel,
Spain, Sweden). Mean age 40; 220 men, 273 women. ENT co-morbidity not reported
Outcomes Clinical outcomes assessed on day 14 in 468 out of 493 randomised (in 241 out of 251
participants in cefuroxime axetil group and in 227 out of 242 participants in moxifloxacin
group). Bacteriological outcomes in 224; radiographic outcomes not assessed
Risk of bias
Selective reporting (reporting bias) Low risk Outcomes reported: clinical response, bac-
teriological response for 224 participants
and adverse effects
Comment: prespecified outcomes (in
methods) were reported in prespecified way
Blinding? (Participant and investigator) Low risk Quote: “Double-blind study”. “Placebo-
capsules used”
Comment: although the description of the
blinding was incomplete, this domain was
graded ’low’ risk of bias because the study
was reported to be double-blind and blind-
ing method was partly described
Incomplete outcome data addressed? Low risk Missing data: 10/251 (4%) in cefuroxime
(Clinical efficacy outcomes) axetil group and 15/242 (6%) in moxi-
floxacin group on day 14
Comment: marginal missing data rate
Free of other bias? Baseline comparability Unclear risk Comment: it appears that the groups were
imbalanced in respect of severity of the si-
nusitis (more participants with severe dis-
ease in moxifloxacin group)
Free of other bias? Funding Unclear risk 2 of the authors were affiliated to a phar-
maceutical company
Methods Randomised, double-blind trial. Diagnosis by clinical symptoms and radiograph show-
ing at least 6 mm mucosal thickening, opacification or air-fluid level. Sinus material
for bacteriological culture by puncture or by middle meatus swab under endoscopic
guidance. Clinical cure defined as disappearance of signs and symptoms or significant
improvement and no further therapy required. Treatment compliance was not reported.
Proportion of the participants without known or reported clinical outcome 19% on day
14 to 23
Outcomes Study reported clinical responses for clinically evaluable patients only. Clinical outcomes
assessed on day 14 to 23 in 452 out of 558 randomised participants (in 228 out of
279 participants in faropenem daloxate group and in 224 out of 279 participants in
cefuroxime axetil group). Clinically evaluable population was defined as patients who
had clinically and radiologically confirmed diagnosis, did not receive any concomitant
antimicrobials and/or corticosteroids, and were assessed on day 14 to 23. Bacteriological
outcomes were assessed in 136 participants
Notes Study was supported by a grant from a pharmaceutical company. 2 of the authors were
affiliated to a pharmaceutical company
Risk of bias
Random sequence generation (selection Low risk Quote: “Patients were randomly assigned
bias) 1:1 to one of two treatment groups using a
block design computer-generated random
code”
Selective reporting (reporting bias) Low risk Outcomes reported: clinical and bacterio-
logical responses, and adverse effects
Comment: prespecified outcomes (in
methods) were reported in prespecified way
Blinding? (Participant and investigator) Low risk Quote: “Double-blind study”. “For blind-
ing purposes, matched placebos were used
in one group and encapsulated tablets in
Incomplete outcome data addressed? Unclear risk Missing data: 51/279 (18%) in faropenem
(Clinical efficacy outcomes) daloxate group and 55/279 (20%) in ce-
furoxime axetil group on day 14 to 23
Comment: reasons for missing data across
groups insufficiently described
Free of other bias? Baseline comparability Low risk Comment: very detailed description of
demographic characteristics and sinusitis
severity rating with which to assess the
comparability of the groups at baseline
Free of other bias? Funding High risk Study was supported by a grant from a
pharmaceutical company. 2 of the authors
were affiliated to a pharmaceutical com-
pany
SSG 1993
Participants Participants were recruited from outpatient otolaryngology clinics. Demographic data
reported only for evaluable participants (defined as participants with isolated bacterial
pathogen plus no protocol violations): mean age approximately 35 (range 16 to 73);
186 men and 152 women. ENT co-morbidity was not assessed. Countries - Sweden,
Finland, Iceland
Group 2: doxycycline 200 mg first dose followed by 100 mg daily for 10 days
Adjuvant therapies were not described
Outcomes Clinical outcomes were assessed in 648 out of 662 randomised participants (in 323 out
of 330 participants in doxycycline group and in 325 out of 332 participants in loracarbef
group). Outcomes were assessed on day 7 to 13 after randomisation. Radiographic
outcomes were not reported. Bacteriological outcomes were assessed in 324 participants
Risk of bias
Selective reporting (reporting bias) Low risk Outcomes reported: clinical response, bac-
teriological response for those participants
who had positive culture at baseline and ad-
verse effects
Comment: prespecified outcomes (in
methods) were reported in prespecified way
Incomplete outcome data addressed? Low risk Missing data: 7/332 (2%) in loracarbef
(Clinical efficacy outcomes) group and 7/330 (2%) in doxycycline
group
Comment: minimal missing data rate
Free of other bias? Baseline comparability Unclear risk Comment: information on comparability
of intervention and control groups at base-
line reported only from evaluable partici-
pants which was half of the enrolled popu-
lation
Free of other bias? Funding High risk Study was financially supported by a phar-
maceutical company
Stefansson 1998
Methods Randomised, double-blind trial. Diagnosis by symptoms and sinus opacity or air-fluid
level on radiograph. Cure defined as clinical signs and symptoms improved or resolved
at post-treatment (11 to 13 days) and radiographically confirmed absence at follow-up
(38 to 45 days). Treatment compliance was not reported. Proportion of the participants
without known or reported clinical outcome 4% on day 11 to 13
Participants Study setting not described. Mean age 37; 157 men and 213 women. ENT co-morbidity
was not assessed. Countries - 8 European, Middle Eastern and African
Outcomes Clinical outcomes were assessed on day 11 to 13 in 354 out of 370 randomised partici-
pants. Second follow-up on day 38 to 45 in 310 participants
Risk of bias
Selective reporting (reporting bias) Unclear risk Outcomes reported: clinical response (in-
cluding also radiological findings at second
follow-up) and adverse effects
Comment: the radiological responses are
reported also separately. It remains unclear
whether radiological response was an inde-
pendent outcome or not
Blinding? (Participant and investigator) Low risk Quote: “Double-blind study”. “Placebo-
tablets used”
Comment: although the description of the
blinding was incomplete, this domain was
Incomplete outcome data addressed? Low risk Missing data: 10/185 (5%) in cefurox-
(Clinical efficacy outcomes) ime axetil group and 6/185 (3%) in clar-
ithromycin group at 11 to 13 days (primary
outcome)
Comment: this assessment has been based
on the numbers given in a table. Although
the corresponding exact numbers given in
the text were slightly different, this domain
was graded ’low’ risk of bias because the
missing data rate is marginal
Free of other bias? Baseline comparability Low risk Comment: very detailed description of
demographic characteristics and sinusitis
severity rating with which to assess the
comparability of the groups at baseline
Free of other bias? Funding Unclear risk 2 of the authors was affiliated to a pharma-
ceutical company
Sterkers 1997
Methods Randomised, unblinded design. Diagnosis by symptoms (duration not described) and
fluid or opacity on radiograph. Clinical cure defined as disappearance of purulent nasal
discharge. Treatment compliance not reported. Proportion of the participants without
known or reported clinical outcome 13%
Participants Multicentre, but settings not described. Mean age approximately 41; 178 men and 280
women. Country - France
Interventions 3 treatment arms: (only group 1 - the standard dosing and group 3 used in the analysis)
Group 1: ceftibuten 400 mg once daily for 8 days
Group 2: ceftibuten 200 mg twice daily for 8 days
Group 3: amoxicillin-clavulanate (500 mg/125 mg) 3 times daily
Adjuvant treatments not described
Outcomes Overall, clinical and radiographic outcomes reported on day 10 in 400 out of 458
randomised participants (in 134 participants out of 152 in ceftibuten 400 mg once daily
group; 138 out of 157 in ceftibuten 200 mg twice daily group and 128 out of 149
Risk of bias
Selective reporting (reporting bias) Low risk Outcomes reported: clinical and radio-
graphic responses, and adverse affects
Comment: prespecified outcomes (in
methods) were reported in prespecified way
Incomplete outcome data addressed? Unclear risk Total missing data 13% on day 10 and 14%
(Clinical efficacy outcomes) on day 40
Comment: no description of reasons for
missing data across groups
Free of other bias? Baseline comparability Unclear risk Comment: information on comparabil-
ity was insufficient to assess whether the
groups were comparable at baseline or not
Free of other bias? Funding Unclear risk Funding source not identified
Methods Randomised, investigator-blinded trial. Diagnosis by clinical signs and symptoms, con-
firmed by a radiograph (criteria not specified). Sinus aspirate and culture (1 or more
pathogens were isolated from the maxillary sinus aspirates of 66% participants). Clinical
cure defined dichotomously - “cure” or “failure”. Compliance not reported. Proportion
of randomised participants without known clinical outcome was not reported. Study
reported only clinical cure rates for intention-to-treat population (all randomised partic-
ipants) and for “evaluable” population (participants all of whose clinical and microbial
data were available). The data from this study were not used in the meta-analyses of this
review because all non-cures in the ITT population (11%) were categorised as failures
in analyses (it remains unclear how many responses were true failures in each group and
how much was missing data); the missing data in the “evaluable” population was high
(52%)
Participants Participants recruited from 16 medical centres throughout Europe. Setting not described.
Mean age 31; 336 men, 233 women. ENT co-morbidity not reported
Outcomes Study did not report description of missing data. Study reported only clinical cure rates for
intention-to-treat population and all clinical responses were known only for “evaluable”
populations. Clinical outcomes for “evaluable population” were reported on day 17 to
25 and on day 31 to 35 in 295 out of 569 randomised participants (in 93 participants
out of 182 in cefdinir 600 mg once daily group, in 96 out of 198 in cefdinir 300 mg
twice daily group and in 106 out of 189 participants in amoxicillin-clavulanate group)
. Radiographic outcomes reported on day 17 to 25 for 295. Bacteriological outcomes
reported in 248
Risk of bias
Random sequence generation (selection Unclear risk Quote: “For each study centre an indepen-
bias) dent randomized schedule was prepared”
Allocation concealment (selection bias) Low risk Quote: “Study monitored by a pharmaceu-
tical company. Medication was dispensed
by a third person and all records concern-
ing medications were kept in a separate lo-
cation”
Selective reporting (reporting bias) Low risk Outcomes reported: clinical, radiological
and bacteriological responses, and adverse
effects
Comment: prespecified outcomes (in
methods) were reported in prespecified way
Blinding? (Participant and investigator) High risk Quote: “Participants were given consecu-
tive patient numbers after screening. As
this was investigator-blinded study, medi-
cation was dispensed by a third person and
all records concerning medications were
kept in a separate location. The participants
were instructed not to reveal the type of
medication to the investigator”
Comment: no blinding of the participants
Incomplete outcome data addressed? High risk Missing data: 89/182 (49%) in cefdinir
(Clinical efficacy outcomes) 600 mg once daily group, 102/198 (52%)
in cefdinir 300 mg twice daily group, and
83/189 (44%) in amoxicillin-clavulanate
group on day 17 to 25
Comment: missing data rate over 20%
Free of other bias? Baseline comparability Low risk Comment: detailed description of demo-
graphic characteristics and sinusitis severity
rating with which to assess the comparabil-
ity of the groups at baseline
Free of other bias? Funding High risk Study sponsored by a pharmaceutical com-
pany
Participants The study setting was not well described. Participants’ mean age was approximately 38
(range 18 to 78); 39 men and 74 women. Country - USA
Notes Study supported by grants from a pharmaceutical company. 1 of the authors was affiliated
to the same pharmaceutical company
Risk of bias
Selective reporting (reporting bias) Low risk Outcomes reported: clinical and bacterio-
logic responses, and adverse effects
Comment: prespecified outcomes (in
methods) were reported in prespecified way
Incomplete outcome data addressed? Low risk Exclusions from analyses: bacteriologic rea-
(Clinical efficacy outcomes) sons 36/59 in loracarbef group and 32/
54 in amoxicillin clavulanate group; other
exclusions 1 (2%) and 1 (2%) of par-
ticipants, respectively. (Bacteriologic rea-
sons included resistant causative organ-
Antibiotics for acute maxillary sinusitis in adults (Review) 132
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Sydnor 1992 (Continued)
Free of other bias? Baseline comparability Low risk Comment: detailed description of demo-
graphic characteristics and sinusitis severity
rating with which to assess the comparabil-
ity of the groups at baseline
Free of other bias? Funding High risk Study supported by grants from a pharma-
ceutical company. 1 of the authors was affil-
iated to the same pharmaceutical company
Upchurch 2006
Methods Randomised, double-blind design. Diagnosis by clinical signs and symptoms > 7 days
but < 28 days, confirmed by radiograph showing air fluid level, opacification and/or at
least 6 mm mucosal thickening. Clinical outcomes were assessed by an investigator and
clinical cure was defined as resolution or improvement of clinical symptoms and signs
such that no additional antimicrobial treatment was necessary. Treatment compliance
91%. Proportion of the participants included in the efficacy-valid population was 78%
on day 17 to 31
Participants Multicentre trial (57 centres) in USA and Canada. 1099 outpatients, 481 male and 618
women. Participants were 43 years old on average (range 15 to 90). 37% of participants
had a history of allergic rhinitis
Outcomes Study reported clinical cure rates for intention-to-treat and efficacy-valid populations.
However, only efficacy-valid population could be used as basis for clinical failure rate
calculating in this review because true failures were not reported and both indeterminate
and missing responses were included in failures in ITT analyses. Clinical outcomes for
efficacy-valid population were assessed on day 17 to 31 in 861 out of 1106 randomised
participants (in 295 out of 370 participants in faropenem medoxomil for 7 days group, in
280 out of 365 participants in faropenem medoxomil for 10 days group, and in 286 out
of 371 participants in cefuroxime axetil group). Efficacy-valid population was defined
as participants who met inclusion criteria, had radiologically confirmed sinusitis, study
drug given for a minimum of 72 hours for participants considered treatment failures
and a minimum of 5 days to be a treatment success, adequate adherence documented
with over 80% of medication, absence of any protocol violation influencing treatment
efficacy, and no essential data missing or indeterminate. Second follow-up 28 to 38 days
post-treatment. Radiographic outcomes not reported
Risk of bias
Random sequence generation (selection Low risk Quote: “Participants were randomly as-
bias) signed in a 1:1:1, double-blind fashion by
using a computer-generated random code
to one of three oral-treatment groups”
Selective reporting (reporting bias) Low risk Outcomes reported: clinical response and
adverse effects
Comment: prespecified outcomes (in
methods) were reported in prespecified way
Blinding? (Participant and investigator) Low risk Quote: “Double-blind study”. “Because
faropenem medoxomil could not be encap-
sulated, a double-dummy design was used
to maintain blinding”. “Matching placebo-
capsules used”
Comment: although the description of
blinding was incomplete (no description
of investigator blinding), this domain was
graded ’low’ risk of bias because the study
was reported to be double-blind and blind-
ing method was partly described
Incomplete outcome data addressed? High risk Missing data: 75/370 (20%) in faropenem
(Clinical efficacy outcomes) medoxomil for 7 days group, 85/365
(23%) in faropenem medoxomil for 10
days group and 85/371 (23%) in cefurox-
ime axetil group on day 17 to 31
Comment: missing data rate over 20%
Free of other bias? Baseline comparability Low risk Quote: “Demographic and baseline medi-
cal characteristics for the efficacy-valid pop-
ulation were generally consistent with those
of the intent-to-treat population”
Comment: although data on baseline com-
Free of other bias? Funding High risk Funding for trial provided by a pharmaceu-
tical company
Methods Randomised, double-blind design. Diagnosis made clinically (the mean duration of
the symptomatic period before treatment was 2.2 weeks), confirmed by radiograph
showing > 5 mm mucosal thickening, opacity or air-fluid level. Clinical cure was not
defined. Treatment compliance reported as 98% assessed by pills taking by participants.
Proportion of the participants without known or reported clinical outcome 4% on day
14
Participants Participants were recruited from community-based, general medical practices. Mean age
was 34; 79 men and 135 women. ENT co-morbidity was assessed; approximately 12%
had allergic disease. Country - The Netherlands
Outcomes Clinical and radiographic outcomes were assessed on day 14 for 206 out of 214 partici-
pants randomised (in 105 out of 108 participants in antibiotic group and in 101 out of
106 participants in placebo group). Long-term relapse rates during 1 year. Bacteriological
outcomes were not assessed
Risk of bias
Random sequence generation (selection Low risk Quote: “The randomization of allocation
bias) of the amoxycillin or placebo (distributed
Allocation concealment (selection bias) Low risk Quote: “Randomisation of patients was
carried out and capsules were provided by
the hospital pharmacy in the hospital were
patients were to see the ENT specialist. The
code of the allocation schedule was kept in
the office of the head of the hospital phar-
macy, and was broken prematurely only if
a severe clinical development or severe ad-
verse effects occurred”
Comment: central allocation
Selective reporting (reporting bias) Low risk Outcomes reported: clinical and radiolog-
ical responses, relapses, chronic evolution
and adverse effects
Comment: prespecified outcomes (in
methods) were reported in prespecified way
Blinding? (Participant and investigator) Low risk Quote: “Neither the pharmacist’s assistant
who distributed the bottles (identical bot-
tles for both groups), the patient, nor the
ENT specialist was aware of the nature of
the medication”
Incomplete outcome data addressed? Low risk Missing data: 2.7% (3/108) in antibiotic
(Clinical efficacy outcomes) group and 4.7% (5/106) in placebo group
at 14 days
Comment: marginal missing data rate
Free of other bias? Baseline comparability Low risk Comment: very detailed description of
demographic characteristics and sinusitis
severity rating with which to assess the
comparability of the groups at baseline
Free of other bias? Co-interventions Low risk Comment: both groups received the same
co-intervention during the trial
Methods Randomised, double-blind design. Diagnosis based on clinical symptoms and radiograph
showing air-fluid level or opacity (verified by sinus aspiration). Failure defined as clinical
signs and sinus X-ray points unchanged or worsened. Treatment compliance not reported.
Proportion of the participants without known or reported clinical outcome 10%
Participants Participants recruited from academic affiliated, otolaryngology practices. Mean age 33
(range 18 to 78); 149 men and 137 women. ENT co-morbidity was not assessed. Coun-
tries - Sweden, Finland, Norway
Outcomes Clinical outcomes were assessed on day 11 to 20 in 258 out of 286 participants ran-
domised (in 130 out of 143 participants in cefpodoxime proxetil group and in 128 out
of 143 participants in amoxicillin group). Bacteriological outcomes reported in 150 par-
ticipants
Notes Study was financially supported by a pharmaceutical company. 1 of the authors had
affiliation to pharmaceutical company
Risk of bias
Selective reporting (reporting bias) High risk Outcomes reported: clinical response (in-
cluding radiological findings), bacteriolog-
ical response for 150 participants and ad-
verse effects
Comment: in the protocol it is stated that
the second follow-up would be at days 28 to
35. Those results are, however, not reported
Incomplete outcome data addressed? Low risk Missing data: 13/143 (9.1%) in cefpo-
(Clinical efficacy outcomes) doxime proxetil group and 15/143 (10.5%)
in amoxicillin group
Comment: although description of the rea-
sons for the missing data by group was un-
Free of other bias? Baseline comparability Low risk Comment: very detailed description of
demographic characteristics and sinusitis
severity rating with which to assess the
comparability of the groups at baseline
Free of other bias? Co-interventions Low risk Comment: both groups received the same
co-intervention during the trial
Free of other bias? Funding High risk Study was financially supported by a phar-
maceutical company. 1 of the authors had
affiliation to a pharmaceutical company
Agbim 1974 Antibiotic versus antibiotic - study design. Diagnostic criteria for acute sinusitis did not fulfil the inclusion
criteria for this review (diagnosis by clinical signs and symptoms but the minimum duration of those before
study entry not reported). Results not reported separately for participants with acute sinusitis
Alvart 1992 Antibiotic versus antibiotic - study design. Sample size for acute sinusitis < 30
Axelsson 1971 Antibiotic versus antibiotic - study design. Not randomised study. No clinical outcomes
Axelsson 1973 Antibiotic versus antibiotic - study design. Not randomised study
Axelsson 1975 Antibiotic versus antibiotic - study design. Not randomised study. No clinical outcomes, only radiological
outcomes
Axelsson 1981 Antibiotic versus antibiotic - study design. Not randomised study
Bandak 1999 Antibiotic versus antibiotic - study design. Diagnostic criteria for acute sinusitis did not fulfil the inclusion
criteria for this review (diagnosis by clinical signs and symptoms but the minimum duration of those before
study entry not reported)
Beatson 1985 Antibiotic versus antibiotic - study design. Inclusion criteria for this review not fulfilled (no definition
reported for acute sinusitis)
Bockmeyer 1994 Antibiotic versus antibiotic - study design. Diagnostic criteria for acute sinusitis did not fulfil the inclusion
criteria for this review (diagnosis by clinical signs and symptoms but the minimum duration of those before
study entry not reported; bacteriological specimens taken from nasal discharge)
Brodie 1989 Antibiotic versus antibiotic - study design. Diagnostic criteria for acute sinusitis did not fulfil the inclusion
criteria for this review (diagnosis mainly by clinical signs and symptoms but the minimum duration of those
before study entry not reported)
Brook 2006 Antibiotic versus antibiotic - study design. Not randomised study. No clinical outcomes
Bucher 2003 Antibiotic versus placebo - study design. Diagnostic criteria for acute sinusitis did not fulfil the inclusion
criteria for this review (diagnosis based on clinical findings; only 32% of participants had symptoms for 7
days or longer before study entry)
Carenfelt 1975 Antibiotic versus antibiotic - study design. Random allocation not stated
Casiano 1991 Antibiotic versus antibiotic - study design. Insufficient information on diagnostic criteria for acute sinusitis
Correa 1986 Antibiotic versus antibiotic - study design. Clinical outcomes measured are clinical plus bacteriological; they
are not separated individually
De Abate 1992 Antibiotic versus antibiotic - study design. Inclusion criteria for this review not fulfilled (no definition
reported for acute sinusitis)
De Sutter 2002 Antibiotic versus placebo - study design. Diagnostic criteria for acute sinusitis did not fulfil the inclusion
criteria for this review (diagnosis based on clinical findings; about 50% of participants with symptoms less
than 7 days at study entry). The information obtained from the authors
Edelstein 1993 Antibiotic versus antibiotic - study design. Approximately 50% of participants with acute exacerbation of
chronic sinusitis. Results not reported separately for acute maxillary sinusitis
Elies 2001 Antibiotic versus antibiotic - study design. Inclusion criteria for this review not fulfilled; proportion of
included complicated cases (frontal sinusitis or pansinusitis) was not reported
Falser 1988 Antibiotic versus antibiotic - study design including participants with otitis and sinusitis. Results not reported
separately for participants with sinusitis
Federspil 1983 Antibiotic versus antibiotic - study design. Mixed ENT infections. Sample size for acute sinusitis < 30
Felstead 1991 Antibiotic versus antibiotic - study design. The criteria for diagnosis of acute maxillary sinusitis not clearly
stated
Fiscella 1991 Antibiotic versus antibiotic - study design. Sample size for acute maxillary sinusitis < 30 (the total number
of the participants was > 30, but about 50% of participants had acute exacerbation of chronic sinusitis)
Freche 1988 Antibiotic versus antibiotic - study design. The definition of acute maxillary sinusitis unclear
Gananca 1973 Antibiotic versus placebo - study design. Diagnostic criteria for acute sinusitis did not fulfil the inclusion
criteria for this review (definition of sinusitis by clinical signs and symptoms or by X-ray not reported;
bacteriological specimens taken from purulent nasal discharge, site not specified)
Gananca 1977 Antibiotic versus placebo - study design. Diagnostic criteria for acute sinusitis did not fulfil the inclusion
criteria for this review (diagnosis based on clinical findings without detailed description of signs and symp-
toms and duration)
Garcia 1998 Antibiotic versus antibiotic - study design. Sample size for acute sinusitis < 30
Gladkov 1979 Antibiotic versus dexamethazone and formaldehyde - study design. Randomisation not stated. Sample size
for acute sinusitis < 30
Gurdogan 2001 Antibiotic versus antibiotic - study design. Sample size for acute sinusitis < 30
Gwaltney 1981 Antibiotic versus antibiotic - study design. Randomised trial for some of the participants. Out of 113 partic-
ipants randomised only 32 had outcomes reported. Uncertain if outcomes relate only to those randomised
Hansen 2000 Antibiotic versus placebo - study design. Diagnostic criteria for acute sinusitis did not fulfil the inclusion
criteria for this review (diagnosis based on clinical findings; at least 50% of participants had symptoms
lasting for 6 days or less at study entry)
Hebblethwaite 1987 Antibiotic versus antibiotic - study design. Diagnostic criteria for acute maxillary sinusitis insufficiently
stated
Henry 1999a Antibiotic versus antibiotic - study design. Diagnostic criteria for acute sinusitis did not fulfil the inclusion
criteria for this review (the duration of symptoms before study entry not reported; the diagnosis in 30% of
participants not confirmed by X-ray)
Henry 1999b Antibiotic versus antibiotic - study design. Unclear data, contradictory results in table and text
Husfeldt 1993 Antibiotic versus antibiotic - study design. Random allocation not stated
Jeppesen 1970 Antibiotic versus placebo - study design. Quasi-randomised design. Puncture and irrigation (every second
day) used as co-intervention. Sample size for acute maxillary sinusitis < 30
Johnson 1999 Antibiotic versus antibiotic - study design. Approximately 30% of participants had acute exacerbation of
chronic sinusitis. Results not reported separately for acute maxillary sinusitis
Klein 1998 Antibiotic versus antibiotic - study design. Approximately 60% of participants had acute exacerbation of
chronic sinusitis. Results not reported separately for acute maxillary sinusitis
Lacroix 2002 Study mainly designed to identify signs to predict the presence of bacteria in acute rhinosinusitis (including
common cold and acute sinusitis). Inclusion criteria for the study did not fulfil the inclusion criteria for this
review (69% of patients had other URTIs than sinusitis confirmed by X-ray; median duration of clinical
symptoms 4 days for all randomised patients; data not reported separately for patients with acute sinusitis)
Li 2000 Antibiotic versus antibiotic - study design. Approximately 67% of participants had chronic sinusitis. Ran-
domisation unclear
Luchikhin 2005 Antibiotic versus antibiotic - study design. Sample size for acute maxillary sinusitis < 30
Mannhardt 1980 Antibiotic versus antibiotic - study design. Mixed sample of acute (n = 30) and chronic (n = 22) sinusitis.
Only combined results are reported
Manzini 1993 Antibiotic versus antibiotic - study design. Insufficient information on diagnostic criteria for acute maxillary
sinusitis
Marchi 1990 Antibiotic versus antibiotic - study design. Random allocation not stated
Marcolino 1999 Antibiotic versus antibiotic - study design. Diagnostic criteria for acute sinusitis did not fulfil the inclusion
criteria for this review (clinical symptoms lasting at least 4 weeks)
Mesure 1973 Antibiotic versus antibiotic - study design. Diagnostic criteria for acute sinusitis did not fulfil the inclusion
criteria for this review (no definition of acute maxillary sinusitis). Sample size for acute sinusitis < 30
Mira 2001 Antibiotic versus antibiotic - study design. Sample size for acute sinusitis < 30. Insufficient information on
diagnostic criteria for acute maxillary sinusitis
Miyamoto 2005 Antibiotic versus antibiotic - study design. Diagnostic criteria for acute sinusitis did not fulfil the inclusion
criteria for this review (diagnosis on clinical basis; the duration of symptoms before study entry not stated)
Moorhouse 1985 Antibiotic versus antibiotic - study design. Diagnostic criteria for acute sinusitis did not fulfil the inclusion
criteria for this review (diagnosis on clinical basis; the duration of symptoms before study entry not stated)
Norrelund 1978 Antibiotic versus placebo - study design. Diagnostic criteria for acute sinusitis did not fulfil the inclusion
criteria for this review (diagnosis on clinical basis; the duration of symptoms before study entry not stated)
Olsson 1976 Antibiotic versus antibiotic - study design. Questionable random allocation. Sample size for acute sinusitis
< 30
Osman 1983 Antibiotic versus antibiotic - study design. Diagnostic criteria for acute maxillary sinusitis not stated
Pallestrini 1995 Antibiotic versus antibiotic - study design. Approximately 27% of participants had acute exacerbation of
chronic sinusitis. Results not reported separately for acute maxillary sinusitis
Panosetti 1992 Antibiotic versus antibiotic - study design. Hospitalised participants, ENT ward
Peyramond 1991 Antibiotic versus antibiotic - study design. Diagnostic criteria for acute sinusitis did not fulfil the inclusion
criteria for this review (diagnosis on clinical basis; duration of symptoms before study entry not stated)
Piragine 1988 Antibiotic versus antibiotic - study design. Sample size for acute sinusitis < 30 (7 participants)
Podvinec 1982 Antibiotic versus antibiotic - study design. Mixed sample of acute (< 80%) and chronic sinusitis. Results
not reported separately
Polonovski 2006 Antibiotic versus antibiotic - study design. Diagnostic criteria for acute sinusitis did not fulfil the inclusion
criteria for this review (diagnosis on clinical basis, median duration of symptoms 4 days before study entry)
Quick 1973 Antibiotic versus antibiotic - study design. Random allocation not stated. Sample size for acute sinusitis <
30
Quick 1975 Antibiotic versus antibiotic - study design. Random allocation not stated. Sample size for acute sinusitis <
30
Rantanen 1973 Antibiotic versus no antibiotic - study design. Study design not suitable for this review because weekly
irrigation was used as co-intervention. Random allocation not stated
Rechtweg 2004 Antibiotic versus antibiotic - study design. Sample size for acute sinusitis < 30
Riedel 1987 Study design comparing antibiotic + serrapeptase versus serrapeptase. Not a randomised study
Rimmer 1997 Antibiotic versus antibiotic - study design. Insufficient information on diagnostic criteria for sinusitis
Roenning 1987 Antibiotic versus antibiotic - study design. Diagnostic criteria for acute sinusitis did not fulfil the inclusion
criteria for this review
Overall clinical outcomes not reported
Sabater 1995 Antibiotic versus antibiotic - study design. Assessment of the study was based on the abstract. Additional
information was requested from the authors to assess the adequacy of the study for this review but the
authors were not able to deliver the necessary information
Salmi 1986 Antibiotic versus antibiotic - study design. Sample size for acute sinusitis < 30
Salmi 1993 Antibiotic versus antibiotic - study design. Mixed respiratory tract infections. Sample size for acute sinusitis
< 30. Insufficient information on diagnostic criteria for acute maxillary sinusitis
Schering-Plough 2003 Unpublished study (assessment of the study based on the study synopsis which was obtained from the
pharmaceutical company). The study was a randomised clinical trial comparing intranasal corticosteroid
with antibiotic and placebo. In the synopsis, definition of outcome and data were not in a usable form for
this review
Antibiotics for acute maxillary sinusitis in adults (Review) 142
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
(Continued)
Serra 2007 Antibiotic versus antibiotic - study design. Diagnostic criteria for acute sinusitis did not fulfil the inclusion
criteria for this review (sinusitis not defined by clinical signs and symptoms; microbiological evaluation
reported to be based on specimens taken by swab without specification of where they were taken from)
Spindler 1985 Antibiotic versus antibiotic - study design. Inclusion criteria for this review not fulfilled (criteria for acute
sinusitis not reported)
Stahl 1989 Antibiotic versus antibiotic - study design. Included also other URTI than sinusitis. Inclusion criteria for
this review not fulfilled: criteria for acute sinusitis not reported, the proportion of participants with chronic
sinusitis > 20% and clinical outcomes for acute sinusitis not reported separately
Stalman 1997a Antibiotic versus placebo - study design. Diagnostic criteria for acute sinusitis did not fulfil the inclusion
criteria for this review (diagnosis based on clinical findings; duration of symptoms reported to have lasted at
least 5 days). Additional information was requested from the authors about the proportion of the participants
with symptoms for less than 7 days but the authors were not able to deliver the information
Strachunskii 1993 Antibiotic versus antibiotic - study design. Not randomised study
Söderström 1991 Antibiotic versus antibiotic - study design. Clinical outcomes not measured for sinusitis (included also other
URTI)
Varonen 2003a Antibiotics versus placebo - study design. Diagnostic criteria for acute sinusitis did not fulfil the inclusion
criteria for this review (about 27% of participants with symptoms for less than 6 days at study entry.
Ultrasound positive about 50% of participants)
von Sydow 1984 Antibiotic versus antibiotic - study design. Insufficient information (for example, the follow-up time and
duration of the therapy were not stated)
Wallace 1985 Antibiotic versus antibiotic - study design. Mixed respiratory tract infections. Insufficient information on
diagnostic criteria for acute maxillary sinusitis
Weis 1998 Antibiotic versus antibiotic - study design. Diagnostic criteria for acute sinusitis did not fulfil the inclusion
criteria for this review (diagnosis by clinical signs and symptoms but the minimum duration of those before
study entry not reported)
Westerman 1975 Antibiotic versus antibiotic - study design. Insufficient information on diagnostic criteria for acute maxillary
sinusitis
Williamson 2007 Antibiotic versus placebo - study design. Diagnostic criteria for acute sinusitis did not fulfil the inclusion
criteria for this review (diagnosis based on clinical findings; only 57% of participants had symptoms for 7
days or longer at study entry). The information was obtained from the authors
Young 2003 The study design mainly intended to examine the diagnostic indicators for acute bacterial rhinosinusitis
than comparing antibiotic versus placebo. Diagnostic criteria for acute sinusitis did not fulfil the inclusion
criteria for this review (diagnosis by clinical signs and symptoms; median duration of symptoms 4 days)
Zbären 1983 Antibiotic versus antibiotic - study design. Sample size for acute maxillary sinusitis < 30
No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size
1 Clinical failure defined as a lack 5 1058 Risk Ratio (M-H, Random, 95% CI) 0.66 [0.47, 0.94]
of full recovery or improvement
at 7 to 15 days of follow-up
2 Clinical failure defined as a lack 2 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected
of full recovery or improvement
at 16 to 60 days of follow-up
3 Clinical failure defined as a lack 5 680 Risk Ratio (M-H, Random, 95% CI) 0.73 [0.63, 0.85]
of full recovery at 7 to 15 days
of follow-up
4 Clinical failure defined as a lack 1 169 Risk Ratio (M-H, Fixed, 95% CI) 0.63 [0.38, 1.05]
of full recovery at 16 to 60 days
of follow-up
5 Relapse rates after 60 days 1 214 Risk Ratio (M-H, Fixed, 95% CI) 1.25 [0.72, 2.19]
6 Drop-outs due to adverse effects 9 1818 Peto Odds Ratio (Peto, Fixed, 95% CI) 1.40 [0.60, 3.25]
No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size
1 Ceph versus amox-clav; clinical 6 1887 Risk Ratio (M-H, Random, 95% CI) 1.37 [1.04, 1.80]
failure defined as a lack of full
recovery or improvement at 7
to 15 days of follow-up
2 Ceph versus amox-clav; clinical 7 1415 Risk Ratio (M-H, Random, 95% CI) 1.08 [0.85, 1.37]
failure defined as lack of full
recovery or improvement at 16
to 60 days of follow-up
3 Drop-outs due to adverse effects 9 2973 Peto Odds Ratio (Peto, Fixed, 95% CI) 0.32 [0.21, 0.49]
(cephalosporins)
4 Macrolides versus amox-clav; 7 1807 Risk Ratio (M-H, Random, 95% CI) 0.83 [0.62, 1.13]
clinical failure defined as a lack
of full recovery or improvement
at 7 to 15 days of follow-up
5 Macrolides versus amox-clav; 4 908 Risk Ratio (M-H, Random, 95% CI) 0.85 [0.57, 1.27]
clinical failure defined as a lack
of full recovery or improvement
at 16 to 60 days of follow-up
6 Drop-outs due to adverse effects 8 2550 Peto Odds Ratio (Peto, Fixed, 95% CI) 0.47 [0.30, 0.72]
(macrolides)
No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size
1 Clinical failure defined as a lack 7 1083 Risk Ratio (M-H, Random, 95% CI) 0.70 [0.47, 1.06]
of full recovery or improvement
at 7 to 15 days of follow-up
2 Clinical failure defined as a lack 1 436 Risk Ratio (M-H, Fixed, 95% CI) 0.67 [0.37, 1.20]
of full recovery or improvement
at 16 to 60 days of follow-up
3 Drop-outs due to adverse effects 7 1208 Peto Odds Ratio (Peto, Fixed, 95% CI) 0.58 [0.25, 1.35]
No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size
1 Clinical failure defined as a lack 5 807 Risk Ratio (M-H, Random, 95% CI) 1.09 [0.70, 1.71]
of full recovery or improvement
at 7 to 15 days of follow-up
2 Drop-outs due to adverse effects 5 854 Peto Odds Ratio (Peto, Fixed, 95% CI) 0.73 [0.33, 1.60]
Outcome: 1 Clinical failure defined as a lack of full recovery or improvement at 7 to 15 days of follow-up
Analysis 1.2. Comparison 1 Antibiotics versus placebo, Outcome 2 Clinical failure defined as a lack of full
recovery or improvement at 16 to 60 days of follow-up.
Outcome: 2 Clinical failure defined as a lack of full recovery or improvement at 16 to 60 days of follow-up
Analysis 1.5. Comparison 1 Antibiotics versus placebo, Outcome 5 Relapse rates after 60 days.
Peto Peto
Study or subgroup Antibiotics Placebo Odds Ratio Odds Ratio
n/N n/N Peto,Fixed,95% CI Peto,Fixed,95% CI
Axelsson 1970 0/35 0/32 0.0 [ 0.0, 0.0 ]
Outcome: 1 Ceph versus amox-clav; clinical failure defined as a lack of full recovery or improvement at 7 to 15 days of follow-up
Outcome: 2 Ceph versus amox-clav; clinical failure defined as lack of full recovery or improvement at 16 to 60 days of follow-up
Peto Peto
Study or subgroup Cephalosporins Amox-clav Odds Ratio Odds Ratio
n/N n/N Peto,Fixed,95% CI Peto,Fixed,95% CI
Outcome: 4 Macrolides versus amox-clav; clinical failure defined as a lack of full recovery or improvement at 7 to 15 days of follow-up
Outcome: 5 Macrolides versus amox-clav; clinical failure defined as a lack of full recovery or improvement at 16 to 60 days of follow-up
Peto Peto
Study or subgroup Macrolides Amox-clav Odds Ratio Odds Ratio
n/N n/N Peto,Fixed,95% CI Peto,Fixed,95% CI
Outcome: 1 Clinical failure defined as a lack of full recovery or improvement at 7 to 15 days of follow-up
Study or subgroup Non-penicillin Penicillin class Risk Ratio Weight Risk Ratio
M- M-
H,Random,95% H,Random,95%
n/N n/N CI CI
Calhoun 1993 5/55 7/61 14.0 % 0.79 [ 0.27, 2.35 ]
Outcome: 2 Clinical failure defined as a lack of full recovery or improvement at 16 to 60 days of follow-up
Study or subgroup Non-penicillin Penicillin class Risk Ratio Weight Risk Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
Haye 1996 17/220 25/216 100.0 % 0.67 [ 0.37, 1.20 ]
Peto Peto
Study or subgroup Non-penicillin Penicillin class Odds Ratio Odds Ratio
n/N n/N Peto,Fixed,95% CI Peto,Fixed,95% CI
Outcome: 1 Clinical failure defined as a lack of full recovery or improvement at 7 to 15 days of follow-up
Study or subgroup Tetracyclines Mixed group Risk Ratio Weight Risk Ratio
M- M-
H,Random,95% H,Random,95%
n/N n/N CI CI
Arndt 1994 1/26 1/28 2.7 % 1.08 [ 0.07, 16.35 ]
Peto Peto
Study or subgroup Tetracycline Mixed group Odds Ratio Odds Ratio
n/N n/N Peto,Fixed,95% CI Peto,Fixed,95% CI
ADDITIONAL TABLES
Table 1. Collected information from placebo-controlled studies
Study Compari- Diagnos- Day Missing FR1 con- FR1 an- FR + I2 FR + I2 Side
son tic assessed data trol tibiotics control antibi- effects
method otics
included
Garbutt Amox- Clin- 10; 8%; Infor- Infor- 80%; 78%; Amoxi-
2012 icillin (500 ical symp- 28 4% mation not mation not 92% 85% cillin: 16%
(USA) mg 3 times toms > 7 available available Placebo:
daily for 10 days, puru- 14%
days) ver- lent nasal
sus placebo discharge,
Ac- facial pain
etaminophen,
guaifen-
esin, dex-
tromethor-
phan
hydro-
bromide
and pseu-
doephedrine
prescribed
to be used
as needed
Haye 1998 Azithro- Clinical 10 to 12; 0.6%; 33%; 58%; 89%; 93%; Azithro-
(Norway) mycin symptoms 23 to 27 0% 67% 79% 88% 90% mycin:
(500 mg lasting 11 28%
once daily to 29 days Placebo:
for 3 days) (symp-
Meltzer Amox- Clinical During the 1.8% Infor- Infor- 89% 93% Treat-
2005 icillin (500 signs 15-day mation not mation not ment-
(14 coun- mg 3 times and symp- treatment available available emergent
tries, not daily for 10 toms last- phase adverse ef-
specified) days) ver- ing at least fects
sus placebo 7 but less Amoxi-
Concomi- than 29 cillin: 34%
tant medi- days Placebo:
cations not (rhinor- 38%
allowed rhoea,
postnasal
drip, nasal
conges-
tion/stuffi-
ness, sinus
headache,
and facial
pain/
pressure/
tender-
ness on
palpation
over the
paranasal
sinuses)
FEEDBACK
Summary
There are 4 primary questions to be answered by this systematic review:
1) Is antibiotic therapy effective for acute sinusitis?
2) Which antibiotic is most effective?
3) What is the best duration for antibiotic therapy?
4) Is there a change in the efficacy of antibiotics over time?
Question 1
Firstly, all 4 questions are clinically important. But it is paramount to recognize the interrelationships of all 4 questions, such that, if
the answer to the first question is negative, the value of the other answers is significantly diminished. It is therefore essential to include
all the evidence unless the exclusion is completely justified.
On the efficacy of antibiotics for acute sinusitis, there are only 6 published randomised clinical trials with control groups: Axelsson
1970, Gananca 1973, Wald 1986, Lindbaek 1996, van Buchen 1997, and Stalman 1997.
I agree that the Wald study involving children and the Gananca study from Brazil should be excluded. Gananca trial had only 50
subjects, with 50% more patients in the antibiotic group after randomisation. It also had extreme differences in cure rates between
antibiotic and placebo groups (15/30 versus 0/20).
The last 3 trials on this list, according to the recent meta-analysis by de Ferranti et al (BMJ 1998;317:632-7), received a quality score
of 5 by the Jadad scale (a maximum score indicating highest quality). The Axelsson study had a score of 1. The Williams et al answered
this first question, “Is antibiotic therapy effective?”, by excluding Stalman 1997 (with quality score of 5) and by doubling the control
group populations in Axelsson 1970 (n=34) and in Lindbaek 1996 (n=44). This artificially created population of 156 controls from 78
real controls would inflate the contributions of those 2 trials on the outcome. The exclusion of those true placebo-controls in Stalman
1997 (n=94), while adding 78 phantom controls, is not a reasonable approach to answer the antibiotic efficacy question for sinusitis.
The Stalman study was excluded, according to the author’s, because it did not use radiographic images for diagnosis. The same is
true however for the included Axelsson study. Though Axelsson et al took several different radiographic views of sinuses, they did not
describe a radiographic criteria for diagnosis.
Moreover, the relationship between radiograms, even the more advanced images of paranasal sinuses obtained by computed tomography
(CT scan), and the clinical description of sinusitis is extremely poor. The 1997 study of Bhattaharyya et al involving 586 patients (the
largest published data set) failed to find any correlation between CT scan results and patient described symptoms of sinusitis (See Arch.
Otolaryngol. 1997;123:1189-92). Also note that Williams et al argue that the cure rate differences between Lindbaek and van Buchem
were probably related to the diagnostic criteria. That is, a diagnosis confirmed by CT scan is more likely associated with bacterial
sinusitis than a diagnosis by radiography. This new theory of differential diagnosis of bacterial sinusitis however is not supported by
any published data.
Antibiotics for acute maxillary sinusitis in adults (Review) 169
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
To be consistent, either both Axelsson and Stalman should be included, or both should be excluded. If they are both excluded, then the
meta-analysis of Williams et al on the efficacy of antibiotics for sinusitis would depend on only 2 placebo controlled trials - Lindbaek
1996 and van Buchem 1997 - with opposite conclusions.
The Lindbaek study was terminated early with 130 patients instead of the original sample size of 180 subjects. This was done without
correction and without predefined stopping rules. Also, the randomisation was in a most unusual fashion for a modern clinical trial
using dice. Lindbeak et al do not provide a table, as customary, showing the baseline patient characteristics at entry indicating their
randomisation was effective. In contrast to those deficits, van Buchem reports this baseline information about randomisation and an
analysis of prognostic factors on the outcome. It shows that initial severity of sinusitis does not change the results. The van Buchem study
has a much higher quality and reliability than the Lindbaek trial. If the entire evidence has to be based on combining or contrasting
only those 2 trials, then conclusion has to follow the van Buchem results.
Most important, the Stalman trial which was published 9 months later completely supports the van Buchem results. Among the 3
trials with Jadad score of 5, reasonable people can easily conclude that van Buchem and Stalman clearly show that antibiotics for acute
sinusitis are not effective; and, Lindbaek et al is an outlier. Lindbaek’s efficacy claim based on one endpoint (cure) is not sustained by
his second endpoint (improvement). This inconsistent outcome and those basic problems associated with early termination and poor
randomisation perhaps is why Lindbaek results are not replicated by the last 2 trials (van Buchem and Stalman).
I suggest however that we include all 4 clinical trials to combine results and estimate a pooled efficacy. As such, even this would yield
still a meager sample size, a total of 648 subjects with only 278 controls. Consequently, this is the entire dataset we have to establish the
scientific evidence-base in justifying 15 million antibiotic prescriptions in the U.S. for sinusitis. Instead of finding excuses to exclude
the few controls in this limited database, we should savor them.
The answer to the first question, then, is a simple pooling of the results from those 4 clinical trials: Axelsson 1970 (n=112), Lindbaek
1996 (n=130), van Buchem 1997 (n=214), and Stalman 1997(n=192).
In all sinusitis trials the primary outcome measures of at 10-14 days are subjective. Outcomes are not based on some “Gold Standard”
but study-variant definitions of cure and success (cure/improvement) by each investigator. Those primary data unfortunately are not
based on objective endpoints. A well defined diagnostic criteria, such as combining radiographs with symptoms, validated against a
standard is lacking.
I argue that if the entry includes radiograms to make the diagnosis of sinusitis, then to be consistent for at least in defining cure,
the primary endpoint should also include both measures (e.g.. combination of normal radiograph with symptom free status). If both
measures are not negative, then improvement (or scaled improvement) is the only logical alternative. Without a normal radiogram,
cured diagnosis would be in contradiction with the entry criteria.
Regardless of these problems associated with an objective and study invariant outcome, the combined results from 4 trials are as follows:
Cure
Controls: 10/34 + 5/44 + 53/106 + 56/94 = 124/278 or 44.6%
Antibiotics: 27/78 + 32/86 + 68/108 + 59/98 = 186/370 or 50.3%
Success
Controls: 23/34 + 39/44 + 78/106 + 80/94 = 220/278 or 79.1%
Antibiotics: 51/78 + 81/86 + 87/108 + 83/98 = 302/370 or 81.6%
Antibiotic-placebo rate difference in cure is 5.7% (OR=1.26) and the rate difference in success is 2.5% (OR=1.17). These marginal
differences, neither statistically nor clinically significant, indicate the lack of efficacy of antibiotic therapy for the treatment of acute
paranasal sinusitis.
The methods used by Williams et al in their meta-analysis therefore must be re-examined. Relying on magical statistical packages, with
interesting inclusions and exclusions, can sometimes lead to positively misleading results. As in this case, claiming antibiotic efficacy
for sinusitis is not a reasonable conclusion but perhaps an artifact of meta-analysis.
The answer to this first question, “Are antibiotics for acute sinusitis effective?”, therefore is negative.
Question 2
Now the second question, which antibiotic is most effective, is a less important scientific issue. Notwithstanding, in real life clinical
practice, this question continues to be a primary issue because of the ongoing campaign of promoting newer, wider spectrum antibiotics
for sinusitis with higher costs.
Though there is no clinical trial which exclusively has focused on bacterial sinusitis caused by resistant bacteria, and which has shown the
benefit of such drugs, the emergence of multi-drug resistant bacteria is always cited to advocate those wide spectrum drugs. Therefore,
the second part of the Williams meta-analysis is clinically most significant.
Using a large sample size, Williams et al (n=7330 patients in 32 trials) show that there is no superior antibiotic. This result supports
the earlier findings of de Bock 1997 (n=3358 patients in 16 trials) and de Ferranti 1998 (n=2717 patients in 27 trials) meta-analyses.
The ineffectiveness of wide spectrum drugs are based on a wide collection of clinical trials. In fact, among those 3 meta-analyses,
Antibiotics for acute maxillary sinusitis in adults (Review) 170
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
the inclusion of the same trials are not common. The number of trials commonly inclusive between meta-analyses are: Williams -
de Ferranti (13/47), Williams - de Bock (3/45), and de Ferranti - de Bock (5/39). This diversity in inclusion/exclusion indicates the
arbitrary nature of selection of trials included in meta-analyses while supporting the robustness of conclusions.
Note also that this result, ineffectiveness of wide spectrum antibiotics for sinusitis, is consistent with the meta-analysis findings in acute
otitis media. It is a logical result since acute otitis media in general has the same pathogenic bacterial spectrum as acute sinusitis.
There is however an interesting point to consider. If the antibiotics are not better than placebo, then it is logical not to find a superior
antibiotic for sinusitis. Unless each new antibiotic is concurrently matched with a placebo control in the primary clinical trial, it would
be impossible to show the usefulness of new, wide spectrum antibiotics. Without such data, I think it is irresponsible to advocate wide
spectrum antibiotics for sinusitis.
I hope that Williams et al would reduce the complexity of their presentation to make this point by decreasing the number of figures and
by selecting a single primary endpoint to display. I suggest success (cure/improvement) as the measure of choice as I discussed above.
The remaining measures can be simply stated as not being different with some odds ratios or rate differences. Also, those redundant
figures with confidence intervals all over the place, are they necessary? It only illustrates that poor evidence is being included in the
meta-analysis.
I suggest that their Summary figure should also include sample sizes, exclude tetracycline’s, include duration of therapy analysis (short
versus long), and finally include some cumulative meta-analysis to indicate change in efficacy over time.
Question 3
Authors conclude in recommending 10-days of amoxicillin therapy for acute sinusitis but do not provide evidence-based arguments for
selecting this particular duration of therapy. This is not scientific and somewhat odd, because a few years ago, Dr.Williams published
arguably the best study showing that 3-days of antibiotic therapy is as good as the standard 10-days of therapy (See JAMA 1995;273:
1015-21).
A recent review by Pichichero and Cohen (Pediatr Infect Dis J 1997;16:680-95) indicates that there are at least 5 published studies
involving adult patients which show that short duration therapy is as effective as long duration therapy. I suggest Williams et al provide
a meta-analysis to answer this question or explain why such combination of data is not possible. This part on duration of therapy I
think is extremely important.
Question 4
The recent increase in the prevalence of multi-drug resistant bacteria is clearly shown to be changing rapidly and is caused by the misuse
or overuse of antibiotics. However, the research about the change of efficacy of antibiotics in vivo for common respiratory diseases is
lacking. This is an important question. I am not sure how it can be answered. The approach taken by Williams et al seems a reasonable
one, but I doubt that it can really answer the question of changing antibiotic efficacy for sinusitis.
The change in efficacy over time perhaps can be best approached by using a cumulative meta-analysis (See N Eng J Med 1992;327:248-
54, JAMA 1992;268:240-8). Williams et al state that they have performed such a cumulative meta-analysis as well as a meta-regression.
However, they do not show those results. I think the cumulative meta-analysis involving 32 trials in some chronological order (by the
date of the trial, and not the publication date) would be an excellent figure to make the point.
We must also keep in mind another possibility. The lack of change in efficacy over time, suggesting that the emergence of drug resistant
bacteria had no effect, could be simply untrue but related to the ineffectiveness of antibiotics for sinusitis in general.
With $2 billion over the counter medications, 15 million antibiotic prescriptions, 17 million office visits, 300,000 endoscopic sinus
surgeries, and 37 million Americans suffering from chronic sinus disease, this is not a trivial healthcare issue. If the Cochrane is going
to enter a systematic review in it’s library, it should be based on the best evidence and analysis. William et al require many changes and
much improvement before it is suitable for the Cochrane database.
I certify that I have no affiliations with or involvement in any organisation or entity with a direct financial interest in the subject matter
of my criticisms.
Reply
Dr. Cantekin identifies the question - “are antibiotics more effective than placebo for acute sinusitis” as critically important but disagrees
with a number of our methods for answering this question. We will address each point.
First, it is stated that the control populations are double counted. This is an important and difficult methodological issue that occurs
when trials have more than two treatment arms. It was only problematic for the Lindbaek trial, which had amoxicillin, penicillin and
placebo arms. To avoid “double counting,” we analysed the amoxicillin and penicillin trials separately, thereby including the control
populations only once in each of these separate analyses.
Second, it is argued that the Stalman trial should be included in the analysis. We agree that the Stalman study is high quality, but it was
excluded because it lacked a diagnostic radiographic or sinus puncture. Our review was restricted to studies enrolling adult subjects with
Antibiotics for acute maxillary sinusitis in adults (Review) 171
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
sinusitis as determined by clinical symptoms and either an abnormal radiographic or sinus aspiration (the Stalman study used neither).
Because clinical symptoms alone lead to relatively high rates of misclassification, we thought the requirement for an objective measure
(x-ray or aspiration) was important. Studies with high rates of misclassification may include large proportions of subjects without
bacterial sinusitis, leading to a negative result because antibiotics are unlikely to help allergic or viral rhinosinusitis. These criteria were
applied to all studies considered for inclusion. Although we excluded studies without a diagnostic criterion standard, authors of other
literature syntheses on this topic have used more liberal inclusion criteria by dropping the requirement for an objective measure of
sinusitis. Their results were consistent with our findings (risk ratio to prevent clinical failure 0.54, 95% CI 0.37 to 0.79)1 .
Third, simple pooling is suggested as an appropriate method for combining trial results. We disagree. Simple pooling (as opposed to
meta-analytic techniques), can lead to biased results for a variety of reasons. These include bias if there is imbalance in the number of
subjects in treatment arms, underestimation of the variance, and inappropriate weighting of small and large trials. Further, it is not
possible to evaluate heterogeneity through simple pooling.
Next, the reviewer reaches the conclusion that antibiotics are no more effective than placebo. Although the trials are few, and the results
limited to patients with maxillary sinusitis confirmed radiographically or by aspiration, we interpret the current evidence as showing
that penicillin is more effective than placebo and that there are similar, but more heterogeneous findings for amoxicillin.
The reviewer asks for a single endpoint to simplify the presentation. We agree that it increases the complexity of the presentation to
consider both clinical cure and clinical cure or improvement. However, we think that these two clinical outcomes give information that
is worth the additional complexity. As clinicians, we think it is useful to be able to tell patients that on average 50% will be well and
75% will feel substantially better within the next 10 days.
The issue of cumulative meta-analysis is important. We report the findings of these results without showing the forest plots because
of limitations of the software. For newer non-penicillins versus penicillins, there was no effect over time for clinical cure (P = 0.17) or
for clinical cure or improvement (P = 0.60). It is difficult to draw robust conclusions from this analysis because clinically important
changes (other than bacterial resistance) may affect the results.
The reviewer asks for an analysis addressing the duration of treatment. We agree that treatment duration is a clinically important issue.
In fact we completed a study showing therapeutic equivalency for three versus 10 days of TMP/SMX2 . This study was excluded from
the current literature synthesis because it was a within-class antibiotic comparison (not eligible). Four other studies compared two
antibiotics with differing duration of treatment. Three of these compared two different antibiotics for differing duration making it
difficult to isolate treatment duration as the key variable. Only one study compared two durations for the same antibiotic (cefixime
four versus 10 days) and found similar efficacy. Because of differing pharmacokinetics and tissue penetration, we do not think it is
wise to generalise results about TMP/SMX and cefixime to antibiotics in general. Readers should incorporate these findings cautiously.
Because study duration was not one of our study questions, we have not done a systematic search to identify relevant literature. We
will consider adding this question to future reviews.
We strongly endorse the reviewer’s call for more clinical trials in this area, particularly with placebo control and look forward to other
readers’ comments.
Reference list
1 de Ferranti SD, Ioannidis JPA, Lau j, Anninger WV, Barza M. Are amoxycillin and folate inhibitors as effective as other antibiotics
for acute sinusitis? A meta-analysis. BMJ 1998;317:632-637
2 Williams JW, Jr., Holleman DR, Jr., Samsa GP, Simel DL. Randomized controlled trial of 3 vs 10 days of trimethoprim/sulfamethoxazole
Contributors
Erdem Cantekin
This response was originally added to the Cochrane Review in 2000.
Summary
The heterogeneity in this outcome may be explained by the choice of cure as your outcome measure. You are pooling relative benefit
instead of relative risk. If the outcome is entered as failure to cure the heterogeneity disappears and the pooled RR is significant even
with a random model. RR = 0.68 (95% CI 0.55 to 0.83).
In my view it is therefore wrong to conclude that Amoxicillin does not have significant benefit in maxillary sinusitis.
I certify that I have no affiliations with or involvement in any organisation or entity with a direct financial interest in the subject matter
of my criticisms.
Reply
The current author group has analysed the data differently to the earlier authors group. Unlike the previous version, in the meta-
analyses the data of all placebo-controlled studies were combined across antibiotic classes. In the new analyses pooled risk ratios using
the clinical failure rate as an outcome measure were calculated.
The new meta-analyses results do not have any statistically significant heterogeneity between the individual study results.
The data of all placebo-controlled studies were combined despite which antibiotic was used because it was anticipated that there would
be only a few placebo-controlled studies available in the analyses. Further, it was presumed that researchers in different countries had
had local reasons for selecting particular antibiotics for their trials, taking into account for example, local resistance rates to antibiotics
among community-acquired pathogens.
This reply was added 9 October 2007.
Contributors
Christopher Cates
This feedback comment was posted 1999.
Summary
Dear Authors,
The Cochrane Report on “acute maxillary rhinosinusitis” is not very helpful for GPs because it is misleading in some points:
A) Most of the relevant studies are ruled out by not fulfilling the inclusion criterion “Duration of symptoms > 1 week”. But “Acute
maxillary sinusitis as defined by: a history of URTI lasting 7 to 30 days...”. But there are important issues besides diagnostic via duration
of sickness and CT findings.
B) For 5 of the remaining 6 placebo-controlled RCTs used for the meta-analyses, the external validity is weak. For practical applicability
it is not so important to know if there might be any subgroups in acute rhinosinusitis that profit from antibiotics. Rather, we need
results from trials with completely realistic practice conditions. Mixed inclusion criteria for meta-analyses are therefore questionable.
* X-ray or CT is not routinely accessible in general practice nor indicated for diagnosis of acute rhinosinusitis. As stated in the report
“In the referral guidelines for imaging of the European Commission, radiograph is not indicated as a routine diagnostic method (ECRP
2007)”. The results of the following studies are therefore not applicable: Axelsson 1970, Lindbaek 1996a+b, Lindbaek 1998a+b, van
Buchem 1997.
* The Haye-trial used x-ray to exclude those with positive findings. As there has been yet no general-practice-based-trial to prove that
these findings would be a good reason for antibiotics anyway, this filter criterion seems not only artificial but also deletes the practical
use.
C) Most of the Cochrane-report is concerned with the comparative trials. But very few of these studies applied any of the successful
diagnostic criteria (see below) - so unequivocal results were likely to result.
In fact, my main point is that for us GPs it is very important to keep in mind the special prevalences, supplies and priorities of
primary care.Thus we focused our german DEGAM (German Society of General Practitioners) guideline “akute rhinosinusitis” (http:/
Antibiotics for acute maxillary sinusitis in adults (Review) 173
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
/www.degam-leitlinien.de/) on primary care. We grouped the evidence from diagnostic and therapeutic clinical trials in the categories
“predominantly primary care/secondary care/unknown setting”. (The guideline included literature on sinusitis until April 2007 - the
trials of Haye and Merenstein were not included).
Evaluating literature on acute rhinosinusitis in adults, this focus leads to interesting discoveries:
1. In primary care, antibiotics proved only helpful when a technical diagnostic test was added to clinical evaluation: CT (Lindbaek
1996) / nasal swabs + culture (Kaiser 2001) / CRP (Hansen 2000); trials with clinical evaluation only (Stalman 1997, Bucher 2003,
Merenstein 2005) or added plain-x-ray (van Buchem 1997, Rantanen 1973, Norrelund 1978, Kristo 2005) or added ultrasound (Laine
1998, Varonen 2000, Varonen 2003) were negative.
2. Strikingly, in secondary care (ENT) studies with CE plus plain x-ray were significantly positive (Axelsson 1970, Wald 1976)
3. Comparative studies showed no significant difference between various types of antibiotics (Stalman 1997, de Ferranti 1998, de Bock
1997, Williams 2000, Piccirillo 2001)
4. Nearly all trials with positive effect of corticoid nasal spray for acute rhinosinusitis were done by allergologists (Sinusitis Study Group)
- thus making confounding by allergies likely.
The above findings might be explained by combining the following observations:
1. In cases of acute maxillary sinusitis the prevalence of pathogenic bacteria in sinus puncture differs by setting: 34% in primary care
(Hansen 1995, van Buchem 1995) / ENT 45% (Axelsson 1973) / soldiers 72-78% (Savolainen 1997, Penttil? 1997) - the latter probably
due to endemic spreads of hemophilus influenzae.
2. Diagnostic tests can moderately “raise” the prevalence of bacterial vs viral infections. Positive Likelihood-ratios for diagnostic test
are approximately 4 for CT (Hansen 1995) / plain X-ray 3,4 (Vaaronen 2000) / ultrasound 2,8 (Vaaronen 2000) / clinical test 1-2
(Hansen 1995) and 2.1-3.3 for CRP (Lindbaek 1996)
3. Calculating post-test prevalence by applying LR to pre-test prevalence suggests that antibiotic trials were only significantly positive
when post-test bacterial prevalence was > 60% (probably due to relatively small trials)
Comment: In a health system with immediate direct accessibility to specialists (like in Germany), the study results suggest that primary
care guidelines should be applied for example by ENT-specialists when involved directly. Referred patients would probably merit from
secondary care guideline.
Because of interpretation of mixed data, we discarded the use of the results of the preceding Cochrane-report of Williams “Antibiotics
for acute maxillary sinusitis”.
Conclusion: after reading your interesting report, I would summarize the primary-care-related evidence on antibiotics for acute rhinos-
inusitis as follows
* Antibiotics + referral if complications are suspected
* Antibiotics with small proven effect if symptoms >7days (Merenstein 2005, ?Haye?)
* Antibiotics with small proven effect if symptoms <7days + severe pain + CRP and/or ESR is markedly raised (Hansen 2000)
I would like to suggest that future Cochrane reports reflect the difference of primary and secondary (+maybe tertiary) care.
With best greetings from Germany and thanks for your work.
Uwe Popert
Submitter agrees with default conflict of interest statement: I certify that I have no affiliations with or involvement in any organization
or entity with a financial interest in the subject matter of my feedback.
Reply
Thank you for these comments. We understand the need to have guidance in primary care; however, the review only can use the
available studies. Cochrane Reviews typically do not provide a strong recommendation on how to apply the results in clinical practice
but leave these conclusions to be done locally, as practice also depends on many other factors than evidence of effectiveness.
The purpose of this review was to quantify the effectiveness of antibiotic therapy for adult patients diagnosed with acute sinusitis and
treated in ambulatory settings (primary or secondary care). In this review only randomised controlled studies with adults were included
and thus studies with children, e.g. Kristo 2005 and Wald 1976, were excluded.
We aimed to find trials which focused on patients who most probably had bacterial sinusitis. In primary care, diagnosis of adult acute
sinusitis is often symptom-based alone, without e.g. any imaging (e.g. Meltzer 2004; Fokkens 2007). Many clinical guidelines in US
and Europe state that patients with URTI and sinus symptoms should not be treated with antibiotics during the first seven to 10 days
in case the signs and symptoms are not severe. Bacterial sinusitis is more probable if the signs and symptoms have lasted at least seven
days (Meltzer 2004). Therefore we defined that if study inclusion criteria were clinical only, symptoms had to have lasted at least seven
days. Although CT or endoscopy or culture are not investigations of primary care, studies which used these diagnostic methods were
Antibiotics for acute maxillary sinusitis in adults (Review) 174
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
not excluded, however, from the analyses of studies conducted with primary care patients, although it may be that the proportion of
the patients with bacterial infection is higher.
Five of the six placebo-controlled studies (which fulfilled our definition of acute maxillary sinusitis) enrolled study participants from
unselected primary care patients, even though the study procedures were conducted in secondary care. The study by Axelsson 1970 did
not define the setting where the patients were enrolled. None of the included studies reported patients to be enrolled from secondary
care.
Results and conclusions
The main outcome in this review was clinical failure defined as a lack of cure or improvement at seven to 15 days of follow-up. On
average 80% of participants in placebo group were found to be cured or improved at seven to 15 days after the start of treatment,
in antibiotic group the figure was 90% (difference of 10% in the number of failures). One study (Lindbaek 1996+Lindbaek 1996b)
accepted solely participants with opacity or fluid-level by using CT scan. In this study pathogenic bacteria connected with acute sinusitis
were documented in 58% of participants. It is obvious that the participants selected for this study represented patients with a more
severe form of disease. Another study (Haye 1998) included patients with clinical symptoms and signs of acute maxillary sinusitis
but excluded those with radiological evidence of empyema thereby selecting probably the mildest end of the diseased. Even in these
two studies representing extreme ends of the severity spectrum of the disease, the differences between antibiotic and placebo groups
regarding the numbers of failures were similar (10% and 4%, respectively).
The patients in the placebo-controlled studies were enrolled from unselected primary care populations (except perhaps Axelsson 1970).
The individual studies represented clinical conditions ranging from mild to more severe, depending on the inclusion criteria, like in
real GP practice setting. All these studies favoured antibiotics to some extent or were inconclusive. After pooling the results of the
individual studies we have made several sensitivity analyses for the main outcome and have discussed the uncertainty issues related to
the results.
In conclusion, we see that the overall result of the meta-analysis of this outcome corresponds to the mixture of patients in GP practice.
However, compared to the situation where no imaging is used, the benefit of antibiotics may be somewhat overestimated. Even when
special effort is put to select those patients from primary care who most probable have bacterial sinusitis, the benefit of antibiotics seems
to be modest. It is obvious that there are patients who benefit from antibiotics but we do not have proper means to identify them so far.
This reply was added 20 December 2010.
Contributors
Uwe Popert
WHAT’S NEW
Last assessed as up-to-date: 20 March 2013.
20 March 2013 New citation required but conclusions have not changed We amended the secondary outcome ’Ability to work’
to include activity impairment in general.
Our conclusions remain unchanged.
20 March 2013 New search has been performed Searches conducted. We included three new studies com-
paring antibiotic against placebo (Garbutt 2012; Hadley
2010; Meltzer 2005) and one new study comparing an-
tibiotic against antibiotic (Lari 2010) in this updated re-
view. We excluded one new study comparing antibiotic
against placebo (Gananca 1977).
19 March 2010 New search has been performed Searches conducted. We included two new studies
comparing antibiotic against antibiotic (Desrosiers
2008; Marple 2010) in this updated review. We ex-
cluded six new studies (Miyamoto 2005; Sabater
1995; Schering-Plough 2003; Serra 2007; Stalman
1997a; Williamson 2007). The conclusions remain
unchanged.
5 October 2007 New citation required and conclusions have changed Substantive amendment.
6 October 1998 New search has been performed Searches conducted. Review first published Issue 3,
1999.
CONTRIBUTIONS OF AUTHORS
Anneli Ahovuo-Saloranta (AAS) was responsible for study selection, data extraction, analysis and writing the review.
Ulla-Maija Rautakorpi (UMR) was responsible for study selection, data extraction and writing the review.
Oleg Borisenko (OB) was responsible for writing the review (and study selection and data extraction in the previous version).
Marjukka Mäkelä (MM), Helena Liira (HL) and John Williams (JW) were responsible for writing the review.
SOURCES OF SUPPORT
Internal sources
• Finnish Office for Health Technology Assessment/FinOHTA, National Institute for Health and Welfare/THL, Finland.
External sources
• No sources of support supplied
NOTES
The 2008 update contained substantial changes to the previous version published in 2003 (Williams 2003). There was a near total
change in the authors from the previous version. Only two of the previous authors (John W. Williams, Jr. and Marjukka Mäkelä)
participated in the 2008 revision.
1. We updated the objectives and added two new objectives:
a) to compare the effect of short versus long courses of antibiotics for acute maxillary sinusitis; and
b) to compare the side effects of different treatments.
We discarded the previous objective of studying the effects of microbial resistance on the efficacy of antibiotics, as it was not feasible
to find reliable resistance data on population levels.
2. Several changes were made to the inclusion criteria. This version now also includes participants with a clinical diagnosis of acute
maxillary sinusitis without imaging or culture. This is because many of these patients are seen in primary care settings where imaging
is not always available and the culture does not provide help to the clinician at the point of decision on whether to prescribe antibiotics
or not. Studies with adolescents (at least 12 years old) were also included provided that less than 20% of participants were under 18
years of age. Trials including patients with acute exacerbations of chronic sinusitis were included only if they reported separately the
data on the subgroup with acute sinusitis or if at least 80% of participants had acute sinusitis (the acute exacerbation was considered as
part of the chronic form of the disease, which is a separate and more complicated entity often related to background factors that have
an effect on recovery).
3. The search strategy was amended.
4. Unlike the previous version, in meta-analyses the data from all placebo-controlled studies were combined across antibiotic classes.
In the new analyses the clinical failure rate was used as an outcome measure.
5. Risk of bias was assessed for each included study as an additional quality assessment tool.
Compared to the 2003 version of the review the overall clinical conclusions were unchanged.