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Effect of Amoxicillin-Clavulanate
in Clinically Diagnosed Acute Rhinosinusitis
A Placebo-Controlled, Double-blind, Randomized Trial in General Practice
Heiner C. Bucher, MD, MPH; Peter Tschudi, MD; James Young, PhD; Pierre Pe´riat, MD;Antje Welge-Lu¨ssen, MD; Hansjo¨rg Zu¨st, MD; Christian Schindler, PhD;for the BASINUS (Basel Sinusitis Study) Investigators Background: Acute rhinosinusitis is one of the most
Results: The adjusted hazard ratio for the effect of amoxi-
common reasons for prescribing antibiotics in primary cillin-clavulanate was 0.99 (95% confidence interval [CI], care. However, it is not clear whether antibiotics im- 0.68-1.45) on time to cure and 1.28 (95% CI, 0.80-2.05) prove the outcome for patients with clinically diag- in the prespecified subgroup of patients with a positive rhi- nosed acute rhinosinusitis. We evaluated the effect of a noscopy result. At 7 days the mean difference between combination product of amoxicillin–potassium clavula- amoxicillin-clavulanate and placebo was −0.29 (95% CI, nate on adults with acute rhinosinusitis that was clini- −0.93 to 0.34) in the number of days with restrictions due cally diagnosed in a general practice setting.
to rhinosinusitis and −0.60 (95% CI, −1.41 to 0.21) in pa-tients with a positive rhinoscopy result. At 7 days pa- Methods: We conducted a randomized, placebo-
tients who took amoxicillin-clavulanate were more likely controlled, double-blind trial with 252 adults recruited at to have diarrhea (odds ratio, 3.89; 95% CI, 2.09-7.25).
24 general practices and 2 outpatient clinics. Each patienthad a history of purulent nasal discharge and maxillary or Conclusions: Adult patients in general practice with
frontal pain for at least 48 hours. Patients were given amoxi- clinically diagnosed acute rhinosinusitis experience no cillin, 875 mg, and clavulanic acid, 125 mg, or placebo twice advantage with antibiotic treatment with amoxicillin- daily for 6 days. Main outcome measures were time to cure clavulanate and are more likely to experience adverse (primary outcome), number of days during which rhino- sinusitis restricted activities at home or work, and fre-quency of adverse effects (secondary outcomes).
Arch Intern Med. 2003;163:1793-1798 From the Basel Institute forClinical Epidemiology(Drs Bucher and Young),MedizinischeUniversita¨ts-Poliklinik ACUTERHINOSINUSITISisone eralpractice,andaddadditionalcoststo
mon condition. Thus, misclassification of acute viral rhinosinusitis is an important reason for overuse of antibiotics in gen- tice.1,2 Although most cases of acute rhi- eral practice. This overuse contributes to nosinusitis in primary care are caused by an uncomplicated viral infection, antibi- otics are frequently prescribed.3 One rea- son for this overuse of antibiotics is the lack biotic treatment for acute rhinosinusitis in of a simple diagnostic test in primary care primary care is limited. A meta-analysis of that allows physicians to accurately dif- randomized, placebo-controlled trials for the fu¨r interdisziplina¨reHausarztmedizin (Drs Tschudi ferentiate between acute viral and bacte- treatment of acute rhinosinusitis found a rial rhinosinusitis. Acute bacterial rhino- higher likelihood of cure in patients treated with antibiotics.6 However, this analysis in- (Dr Schindler), Universita¨t Basel, cruited using diagnostic criteria that are not tional diagnostic tests, such as sonography, cebo-controlled, double-blind trial of an- presentationsand financial support for tests have intermediate specificities for the product of amoxicillin–potassium clavu- lanate in adults with suspected acute bac- itis, are not immediately available in gen- (REPRINTED) ARCH INTERN MED/ VOL 163, AUG 11/25, 2003 2003 American Medical Association. All rights reserved.
cluded in the trial based on clinical diagnostic criteria exclusion criteria were approved by the ethics committee of the that are applicable in general practice. We designed a trial that reflects, to the greatest possible extent, a routine ap- A radiograph (occipitomental view) of the maxillary and proach to patients with uncomplicated acute rhinosi- frontal sinus was obtained for each patient. Radiographs were made either in the private practice or by referral to our hospi-tal. General practitioners and their technical staff were in-structed by a radiology technician from our hospital to stan- dardize radiographic technique. Two radiologists who weremasked to the groups independently assessed each radio- PATIENTS AND SETTING
graph. We used fluid levels or complete opacity as a positiveindicator for acute rhinosinusitis.9 Agreement between radi- Patients were recruited during the 4 winter seasons (Novem- ologists was only moderate for this criterion (␬=0.59). A blood ber 1 to April 30) of 1997 to 2001 from 24 general practices in specimen for white blood cell count (reference range, 3500- Basel, Switzerland, and surroundings and in the internal medi- 10000/µL) and CRP level (reference range, Ͻ10 mg/L) was ob- cine and otolaryngology outpatient clinics of the University Hos- tained. All specimens were analyzed at the laboratory of the Uni- pital Basel. Outpatient clinics were only allowed to treat walk-in patients or patients who had not been referred. The inclusioncriteria were a history of repeated purulent nasal discharge and RANDOMIZATION AND
maxillary or frontal unilateral or bilateral pain for at least 48 INTERVENTION
hours but less than 1 month and presence of pus under rhi-noscopy. Exclusion criteria were younger than 18 years, an up- We used stratified randomization, with the general practice or per respiratory tract infection or use of antibiotics for any rea- outpatient clinic as the stratification unit and patients random- son within the previous 4 weeks, an upper respiratory tract ized in blocks of 6. A computer random-number generator was infection or intermittent fever that persisted for more than 4 used, and the allocation sequence was performed by a statisti- weeks, pathologic features or malformation of nasal cavities or cian who was not involved in the final analysis. The random- the pharynx, immunosuppressive treatment, human immuno- ization code was kept at the 24-hour emergency call center in deficiency virus infection, allergy to amoxicillin-clavulanate, Basel. Operators had to immediately advise the principal in- pregnancy or breastfeeding, or no fluency in one of the na- vestigator of every case for which the code was broken. Pa- tients were consecutively enrolled, and we required study phy- After the first winter season, only 43 of 106 patients who sicians to record the reason why eligible patients were not fulfilled the first 2 inclusion criteria and consented to partici- pate in the trial had a positive rhinoscopy result. We therefore Patients were randomly assigned to receive either amoxi- decided to recruit patients without pus under rhinoscopy but cillin, 875 mg, and clavulanic acid, 125 mg, twice daily for 6 to continue rhinoscopy with all those recruited. In 2000 a pa- days, or placebo. Tablets of equal size, color, and taste were tient in the placebo group experienced a brain abscess. After provided in identical, numbered containers by GlaxoSmith- this, all patients with a C-reactive protein (CRP) level greater Kline (Mu¨nchenbuchsee, Switzerland). All patients received de- than 100 mg/L were excluded from the trial (none), and pa- congestant therapy with a xylometazolin hydrochloride spray tients with a CRP level between 50 and 99 mg/L were reas- (Otrivin; Novartis, Berne, Switzerland) and acetaminophen tab- sessed at day 3 (3 patients) and excluded if clinical worsening lets of 500 mg (Panadol; GlaxoSmithKline Switzerland), with was noted or the CRP level had increased to higher than 100 a maximal dose of 3 g/d. Concomitant therapy with steam in- CLINICAL EVALUATION
END POINTS AND
AT BASELINE
STATISTICAL ANALYSIS
For each patient, physicians recorded a focused medical his- The primary outcome was time to cure. We used 0 days (since tory for rhinosinusitis-related symptoms, the number of days the previous visit or interview) during which rhinosinusitis re- during which rhinosinusitis restricted activities at home or work, stricted activities at home or work as our definition of cure. To and previous upper respiratory tract infections. They col- confirm the primary outcome, we repeated our analysis using a lected clinical data on the presence of pus in the pharynx and second definition of cure: a rating of 1 on a 10-point, equal- in the medial meatus during rhinoscopy, pain on pressure and distance scale for the severity of restricted activity at home or work.
on percussion of the frontal and maxillary sinuses, and body Secondary end points were the number of days during temperature. Patients completed a questionnaire with ques- which rhinosinusitis restricted activities at home or work, the tions on rhinosinusitis-related symptoms and adverse effects frequency of adverse effects, and the recurrence rate of rhino- from antibiotics (eg, purulent rhinorrhea and sputum, frontal sinusitis at 28 days. Patients were said to have recurrent rhi- or maxillary unilateral or bilateral pain, pain on bending, hy- nosinusitis if they were never cured and felt at least as re- posmia or anosmia, fatigue, sleep and mood disorders, abdomi- stricted at day 28 as at baseline. At day 7 physicians performed nal cramps and diarrhea, and vaginal pruritus or discharge).
a second clinical examination, and patients completed a sec- Patients rated the severity of symptoms on a 10-point, equal- ond questionnaire. Physicians also noted the number of tab- distance scale. The study physicians and the study nurse at- lets taken. At days 14 and 28, the study nurse interviewed pa- tended a 3-hour seminar to standardize data collection and the tients by telephone. Patients were always asked the same clinical examination of patients. All study physicians were trained questions on rhinosinusitis-related symptoms and adverse ef- in rhinoscopy by an otolaryngologist (A.W.-L.) and were shown fects, plus additional questions on use of other drugs or other how to use a rhinoscope with an integrated light source (the visits to physicians. All study physicians and the study nurse Heine rhinoscope; Heine Optotechnik, Herrsching, Germany).
were blinded to the treatment given to each patient. Data were One refresher seminar was held during the study. Patients were informed about the study goals and had to sign an informed To calculate the sample size, we assumed that 50% of the consent form. The study protocol and changes to inclusion and recruited patients had acute bacterial rhinosinusitis,10 and the (REPRINTED) ARCH INTERN MED/ VOL 163, AUG 11/25, 2003 2003 American Medical Association. All rights reserved.
spontaneous cure rate for acute bacterial rhinosinusitis at 7 dayswas 80%.7 We assumed a 50% increase in the cure rate at 7 days for patients with acute bacterial rhinosinusitis treated withamoxicillin-clavulanate (Laurant Kaiser, MD, personal writ- ten communication, September 15, 1997)11 and a spontane- ous cure rate of 60% at 7 days for patients without acute bac- terial rhinosinusitis.12 With a type I error of .05 (2-sided), a power of 90%, and an estimated 10% dropout rate, the required sample Our statistical analysis was of the intent-to-treat popula- tion and 2 subgroups: those with a positive rhinoscopy resultand those who felt restricted at baseline. The first subgroup was prespecified when the inclusion criteria were changed. The sec- ond subgroup was not anticipated but became of interest when10% of those recruited said before treatment that rhinosinus- itis did not restrict their activities at home or work. Three re-gression methods were used: Cox proportional hazards regres- sion for time to cure, linear regression for the number of days with restrictions due to rhinosinusitis, and logistic regressionfor the proportion of patients with anticipated adverse effects.
With all methods, models were fit without stepwise proce- 1 Had Serious Adverse Events1 Was Lost to Follow-up dures and with a small number of prespecified covariates. Eachmodel included covariates for the severity of the response at baseline, recruitment before or after the change in inclusioncriteria, open treatment, and use of concomitant medication.
Figure 1. Trial profile. Reasons for nonparticipation included the following:
Statistical analysis was performed using SAS statistical soft- not meeting inclusion criteria for 439 eligible patients (antibiotic treatment in ware version 8.02 (SAS Institute Inc, Cary, NC). All signifi- the previous 4 weeks, 105; chronic sinusitis, 58; recurrent infection in the cant levels and confidence intervals (CIs) given are 2-sided.
previous 4 weeks, 51; immunosuppression such as humanimmunodeficiency virus, 26; pathologic findings of sinus or cavum nasi, 12;allergic to amoxicillin–potassium clavulanate combination product, 66; age younger than 18 years, 32; pregnancy or breastfeeding, 23; and no fluency innational languages, 66); refused consent for 441 (wanted antibiotics, 220;did not want antibiotics, 74; and refused consent for other reasons, 147); or PATIENT ENROLLMENT
other reasons for 433 (comorbidity, organizational reasons, expected AND CHARACTERISTICS
In total, 1565 patients were eligible (Figure 1). The main
rhinosinusitis-related symptoms was 5 days in the amoxi- reason for not participating in the trial was refused con- cillin-clavulanate group and 4 days in the placebo group.
sent (441 patients: 220 definitely wanted antibiotics, 74 In the 2 groups, 65.3% and 66.9% of patients had pus at definitely did not want antibiotics, and 147 refused con- sent for other reasons). We enrolled 252 patients, and249 (98.8%) completed the trial. One patient was ran- PRIMARY OUTCOME
domized but never took any medication, 1 medical rec-ord was lost, and 1 patient in the placebo group had a We found no difference in the time to cure between the severe complication. Eleven patients (8.8%) in the amoxi- amoxicillin-clavulanate and placebo groups (Figure 2).
cillin-clavulanate group and 19 patients in the placebo At 1 week, 29.8% and 30.7% in the amoxicillin-clavulanate group (14.9%) received open antibiotic therapy. Of these and placebo groups were cured and at 2 weeks, the cor- patients, 5 received open amoxicillin-clavulanate (2 pa- responding figures were 76.6% and 74.0%, respectively.
tients in the intervention and 3 patients in the placebo In the Cox proportional analysis, with adjustment for se- group); the remaining patients received antibiotics cho- verity of restrictions at baseline, modification of the in- sen by their treating physician. Thirty-nine (15.5%) of clusion criteria, open treatment, and concomitant medi- 251 patients took fewer tablets than instructed, and of cation with steam inhalation, the hazard ratio for the effect these patients 24 (61.5%) were receiving antibiotics. Com- of antibiotic treatment on time to cure was 0.99 (95% pliance with the interview schedule was good: at day 7, CI, 0.68-1.45) (Table 2). In patients with a positive rhi-
93.6% of all visits were within ±1 day of the scheduled noscopy result, the hazard ratio for time to cure was 1.28 date, and at days 14 and 28, 89.2% and 94.8%, respec- (95% CI, 0.80-2.05), and in patients who reported re- tively, of the interviews were within ±1 day of the sched- strictions at baseline, the hazard ratio was 1.23 (95% CI, 0.81-1.87). We used 0 days (since the previous inter- The 2 groups were similar in terms of sex, age, num- view) with restrictions due to rhinosinusitis as a defini- ber of days with rhinosinusitis-related symptoms, and tion of cure. With cure alternatively defined as a rating clinical findings for pus under rhinoscopy and in the epi- of 1 on a 10-point, equal-distance scale for degree of re- pharynx, occipitomental x-ray films with fluid levels or striction at home or work, hazards ratios for the effect complete opacity, laboratory variables (CRP, leuko- of antibiotic treatment on time to cure were 1.03 (95% cytes, and neutrophils), and the additional use of con- CI, 0.71-1.50) for all patients, 1.40 (95% CI, 0.88-2.25) comitant medication (Table 1). More than 50% of par-
for those with a positive rhinoscopy result, and 1.22 (95% ticipants were women. The median number of days with CI, 0.81-1.85) for those restricted at baseline. For both (REPRINTED) ARCH INTERN MED/ VOL 163, AUG 11/25, 2003 2003 American Medical Association. All rights reserved.
Table 1. Characteristics of Randomized Patients
Amoxicillin-
Potassium
Characteristic
Clavulanate
Figure 2. Time to cure for patients treated with amoxicillin–potassium
clavulanate combination product or placebo, with cure defined as 0 days
(since the previous interview) during which rhinosinusitis restricted activities seemed more likely in the amoxicillin-clavulanate group, but these odds ratios were not statistically significant.
There were 4 adverse events of moderate or severe in- tensity that were thought to be drug related: 2 in the amoxicillin-clavulanate group (diarrhea) and 2 in the pla- cebo group (diarrhea and vomiting). In the placebo group, there was 1 serious disease-related adverse event. After 2 weeks of symptomatic treatment, the patient was then treated for 1 week with amoxicillin-clavulanate (1 g twice daily) but experienced a brain abscess caused by an amoxi- cillin-clavulanate–sensitive strain of Streptococcus mil- leri. The patient was operated on and recovered but has a frontal syndrome. There were 2 additional serious ad- verse events in the placebo group, 1 myocardial infarc- tion and 1 severe depressive episode; both were thoughtto be neither disease nor drug related.
*Independent agreement by 2 radiologists.
definitions of cure, there was no evidence of correlationbetween time and the Schoenfeld residuals for treat- In this randomized controlled trial in general practice, ment, which suggests that a proportional hazards as- we were unable to show that antibiotic treatment with amoxicillin-clavulanate improves time to cure in adultswith clinically diagnosed acute rhinosinusitis. We also SECONDARY OUTCOMES
found no difference in the number of days during whichrhinosinusitis restricted activities at home or work. Pa- At 7 and 14 days, there was no statistically significant dif- tients treated with antibiotics tended to report more ad- ference between amoxicillin-clavulanate and placebo in verse effects, particularly diarrhea, during the first week.
the mean days of restrictions due to rhinosinusitis in nei- Our study has several limitations. First, time to cure ther the intent-to-treat population nor our subgroups. At could be insensitive to any treatment difference, be- 7 days patients with a positive rhinoscopy result had a cause there were only 2 measurements during the pe- mean difference of −0.60 days of restrictions due to rhi- riod when cure typically takes place (within 14 days).
nosinusitis (95% CI, −1.41 to 0.21), and patients re- We decided not to use patient diaries, because we be- stricted at baseline had a mean difference of −0.60 days lieved that patients might not complete these at the pre- (95% CI, −1.25 to 0.06). Two patients (1.6%) in the specified time points. In practice, this limitation is un- amoxicillin-clavulanate group and 5 patients (4.0%) in likely to affect the findings of our study. Any appreciable the placebo group had recurrent rhinosinusitis at 28 days.
difference in the rate of cure between amoxicillin- At 7 and 14 days, diarrhea was significantly more clavulanate and placebo should have been seen at either likely in the amoxicillin-clavulanate group than in the 7 or 14 days but was not. Second, the prevalence of acute placebo group, with odds ratios of 3.89 (95% CI, 2.09- bacterial rhinosinusitis is likely to have been lower in our 7.25) and 1.71 (95% CI, 0.91-3.23) at 7 and 14 days, re- trial than anticipated. The inclusion criteria of our trial spectively (Table 3). Other prespecified adverse ef-
had to be modified, because we could not recruit enough fects (abdominal pain and vaginal discharge or pruritus) patients with a positive rhinoscopy result. The study phy- (REPRINTED) ARCH INTERN MED/ VOL 163, AUG 11/25, 2003 2003 American Medical Association. All rights reserved.
Table 2. The Effect of Amoxicillin–Potassium Clavulanate Relative to Placebo on Time to Cure and Mean Difference
at 7 and 14 Days in the Number of Days Where Rhinosinusitis Restricted Activities at Home or Work
No. of Patients
Days Restricted, Mean Difference (95% CI)†
Time to Cure,
Amoxicillin-Clavulanate
HR (95% CI)*
Abbreviations: CI, confidence interval; HR, hazards ratio.
*Proportional hazards regression with strata (recruited before or after change in inclusion criteria) and covariates (severity of restriction at baseline, open treatment, concominant medication, eg, steam inhalation).
†Linear regression with covariates (recruited before or after change in inclusion criteria, severity of restriction at baseline, open treatment, concomitant Table 3. The Effect of Treatment With Amoxicillin–Potassium Clavulanate Relative to Placebo
on the Proportion of Patients With Adverse Effects at 7 and 14 Days
No. of Patients
OR (95% CI) for Adverse Effects*
Adverse Effect
Amoxicillin-Clavulanate
Abbreviations: CI, confidence interval; OR, odds ratio.
*Logistic regression with covariates (recruited before or after change in inclusion criteria, severity of adverse effect at baseline, open treatment, concomitant medication, eg, use of nonsteroidal anti-inflammatory drugs).
sicians were experienced, highly motivated general prac- cedures in general practice. We strictly limited the titioners trained for this trial. A lack of technical skill is inclusion criteria to clinical signs and symptoms known therefore unlikely to be the reason for this slow recruit- to generate the highest likelihood ratio for acute bacte- ment. In addition, US guidelines recommend treatment rial rhinosinusitis when compared with the gold stan- of acute rhinosinusitis with antibiotics only after 7 days dard of sinus puncture.10 We also collected additional in- of symptoms or in patients with severe facial pain irre- formation about laboratory and x-ray data. Only 1 in 4 spective of the duration.13 In our trial, only 32% of pa- patients showed fluid levels or complete opacity on tients had a history of 7 days or more of rhinosinusitis- x-ray films, radiologic signs that are most likely associ- related symptoms. Therefore, both the necessary ated with bacterial rhinosinusitis.4,9,15 This underlines how modification of the inclusion criteria and the short du- difficult it is to accurately diagnose acute rhinosinusitis ration of symptoms suggest a lower prevalence of bac- terial rhinosinusitis than planned, reducing the power Patients treated with amoxicillin-clavulanate were of this trial to detect differences between treatments.
more likely to experience adverse effects such as diar- We do not believe that bacterial infection with re- rhea and abdominal pain. Other randomized controlled sistant strains could be an explanation for the negative trials of antibiotic treatment for acute rhinosinusitis or findings of this study. Amoxicillin-clavulanate shows ex- for sinusitis-like symptoms report similar findings us- cellent activities against Streptococcus pneumoniae, Hae- ing different antibiotics.8,11 Three placebo-controlled, ran- mophilus influenzae, and Moraxella catarrhalis, the most domized trials (all somewhat smaller than the present common bacteria in upper respiratory tract infection and study) have evaluated different antibiotics in general prac- acute bacterial rhinosinusitis. In Switzerland, preva- tice for the treatment of acute rhinosinusitis. Two trials lence of penicillin resistance against S pneumoniae is ap- included patients based on clinical symptoms for acute proximately 5% and ␤-lactamase production in H influ- rhinosinusitis in conjunction with either radiologic signs enzae and M catarrhalis is lower compared with most other for maxillary sinusitis or raised values of CRP or eryth- rocyte sedimentation.7,16 The third trial included pa- The strengths of our trial are the double-blind de- tients solely on the basis of clinical signs and symp- sign with blinded outcome assessment, a high fol- toms.17 Although these studies used different diagnostic low-up rate of more than 98%, and high external valid- criteria to identify patients with suspected acute bacte- ity. We recruited all patients in a general practice setting.
rial rhinosinusitis, they all showed no difference in im- Most of those who refused consent did so because they provement of symptoms or cure rates under treatment had their own opinion about the benefit or otherwise of with antibiotics. The present study suggests that adults antibiotics and explicitly required or declined antibiot- with a positive rhinoscopy result who are undergoing an- ics. We used inclusion criteria that are applicable in gen- tibiotic treatment may have fewer days during which rhi- eral practice and correspond with generally accepted pro- nosinusitis restricts their activities at home or work. The (REPRINTED) ARCH INTERN MED/ VOL 163, AUG 11/25, 2003 2003 American Medical Association. All rights reserved.
expected benefit from antibiotic therapy, however, might of Basel. The Basel Institute for Clinical Epidemiology is be at best moderate and comparable to the treatment with funded by sante´suisse (Solothurn) and the Gottfried and neuraminidase inhibitors in patients with early symp- Julia Bangerter-Rhyner-Stiftung (Berne). toms from influenza.18,19 Further studies are needed us- We thank the patients who participated in the trial ing better diagnostic tests for acute bacterial rhinosinus- and Peter Hersberger, PhD, and Wolf Langewitz, MD, for itis. These tests might include a refined symptom score helping us with the patient recruitment. that identifies those severely restricted by rhinosinusitis Corresponding author and reprints: Heiner C. Bucher, or with a prolonged upper respiratory tract infection.
MD, MPH, Basel Institute for Clinical Epidemiology, Most patients with acute rhinosinusitis are seen in Kantonsspital Basel, Universita¨tskliniken, CH-4031 Basel, general practice. Because of the low specificity of avail- Switzerland (e-mail: [email protected]). able imaging tests, the costs, and the need to refer pa-tients, most patients with acute rhinosinusitis in gen-eral practice do not receive a diagnostic workup that allows the physician to accurately differentiate between acuteviral and bacterial rhinosinusitis. The decision to treat 1. US Department of Health and Human Services. Ambulatory Care Visits to Phy- with antibiotics is therefore based on clinical diagnostic sicians’ Offices Hospital Outpatient Departments, and Emergency Departments: criteria or other reasons related to physicians’ or pa- United States, 1996. Hyattsville, Md: National Center for Health Statistics; 2001.
2. Willett LR, Carson JL, Williams JW Jr. Current diagnosis and management of sinusitis. J Gen Intern Med. 1994;9:38-45.
3. de Melker RA, Kuyvenhoven MM. Management of upper respiratory tract infec- tion in Dutch general practice. Br J Gen Pract. 1991;41:504-507.
4. Varonen H, Makela M, Savolainen S, Laara E, Hilden J. Comparison of ultra- Evidence from the present study suggests that antibiotic sound, radiography, and clinical examination in the diagnosis of acute maxillary treatment with amoxicillin-clavulanate offers no benefit sinusitis: a systematic review. J Clin Epidemiol. 2000;53:940-948.
5. Kunin CM. Resistance to antimicrobial drugs—a worldwide calamity. Ann In- for adults with acute rhinosinusitis clinically diagnosed in general practice. We conclude that antibiotics should 6. de Ferranti SD, Ioannidis JP, Lau J, Anninger WV, Barza M. Are amoxycillin and not be given at first to patients with acute rhinosinus- folate inhibitors as effective as other antibiotics for acute sinusitis? a meta-analysis. BMJ. 1998;317:632-637.
itis, and symptomatic treatment is justified. This policy 7. van Buchem FL, Knottnerus JA, Schrijnemaekers VJJ, Peeters MF. Primary-care- should help limit the emergence of antibiotic-resistant based randomised placebo controlled trial of antibiotic treatment in acute max- strains and reduce costs. Some individual patients profit illary sinusitis. Lancet. 1997;349:683-687.
8. Lindbaek M, Hjortdahl P, Johnsen UL-H. Randomised, double blind, placebo con- from antibiotic therapy. Whether such individuals can trolled trial of penicillin V and amoxycillin in treatment of acute sinus infections be identified by clinical tests such as rhinoscopy has yet in adults. BMJ. 1996;313:325-329.
9. Engels EA, Terrin N, Barza M, Lau J. Meta-analysis of diagnostic tests for acute sinusitis. J Clin Epidemiol. 2000;53:852-862.
10. Berg O, Carenfelt C. Analysis of symptoms and clinical signs in the maxillary si- Accepted for publication October 21, 2002. nus empyema. Acta Otolaryngol. 1988;105:343-349.
11. Kaiser L, Morabia A, Stalder H, et al. Role of nasopharyngeal culture in antibiotic BASINUS Investigators: study nurse and manager: prescription for patients with common cold or acute sinusitis. Eur J Clin Micro- Christa Hugenschmidt; study physicians in general prac- biol Infect Dis. 2001;20:445-451.
tice: Fritz Ammann, MD, Ruedi Bachmann, MD, Anselm Benz, 12. Mossad SB, Mackin ML, Medendorp V, Mason P. Zinc gluconate lozenges for treating the common cold: a randomized, double-blind, placebo-controlled study.
MD, Ruedi Burger, MD, Jadi Fabbri, MD, Remigius Faesch, Ann Intern Med. 1996;125:81-88.
MD, Peter Flubacher, MD, Josef Forrer, MD, Daniel Gelzer, 13. Hickner JM, Bartlett JG, Besser RE, Gonzales R, Hoffman JR, Sande MA. Prin- ciples of appropriate antibiotic use for acute rhinosinusitis in adults: back- MD, Michael Gonon, MD, Alexander Haegeli, MD, Fried- ground 1. Ann Intern Med. 2001;134:498-505.
rich Hugenschmidt, MD, Ruedi Isler, MD, Hanspeter Lien- 14. Schito GC, Debbia EA, Marchese A. The evolving threat of antibiotic resistance hardt, MD, Louis Litschgi, MD, Michael Nu¨scheler, MD, Chris- in Europe: new data from the Alexander Project. J Antimicrob Chemother. 2000;46(suppl T1):3-9.
tian Ott, MD, Pierre Pe´riat, MD, Alexander Ruckstuhl, MD, 15. Lindbaek M, Hjortdahl P, Johnsen UL. Use of symptoms, signs, and blood tests Florian Suter, MD, Claude Scheidegger, MD, Alex Schwank, to diagnose acute sinus infections in primary care: comparison with computed MD, Andreas Schlumpf, MD, Andreas Stoll, MD, Peter Tschu- tomography. Fam Med. 1996;28:183-188.
16. Hansen JG, Schmidt H, Grinsted P. Randomised, double blind, placebo con- di, MD, Christoph Waldmann, MD, Ju¨rg Weber, MD, Rolf trolled trial of penicillin V in the treatment of acute maxillary sinusitis in adults in Wenger, MD; study physicians at the medical and otolar- general practice. Scand J Prim Health Care. 2000;18:44-47.
17. Stalman W, van Essen GA, van Der GY, de Melker RA. The end of antibiotic treat- yngology outpatient clinics: Pia Schneider, MD, Tatiana Spi- ment in adults with acute sinusitis-like complaints in general practice? a placebo- cher, MD, Andreas Zeller, MD; radiologists: Monika Meier, controlled double-blind randomized doxycycline trial. Br J Gen Pract. 1997;47: MD, Thomas Lacina, MD, Ulrike Otto, MD. 18. Monto AS, Webster A, Keene O. Randomized, placebo-controlled studies of in- This study was supported by grants from GlaxoSmith- haled zanamivir in the treatment of influenza A and B: pooled efficacy analysis.
Kline Switzerland, Swiss Academy of the Medical Sciences J Antimicrob Chemother. 1999;44(suppl B):23-29.
(Basel), Astra Klinik Fonds University Hospital Basel, and 19. Nicholson KG, Aoki FY, Osterhaus AD, et al, Neuraminidase Inhibitor Flu Treat- ment Investigator Group. Efficacy and safety of oseltamivir in treatment of acute Forum fu¨r interdisziplina¨re Hausarztmedizin, University influenza: a randomised controlled trial. Lancet. 2000;355:1845-1850.
(REPRINTED) ARCH INTERN MED/ VOL 163, AUG 11/25, 2003 2003 American Medical Association. All rights reserved.

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