A retrospective comparison of acute rhinosinusitis outcomes in patients prescribed antibiotics, mometasone furoate nasal spray, or both

Carl de Moor, Ph.D.,1 Gregory Reardon, R.Ph., Ph.D.,2,3 John McLaughlin, Ph.D.,2,4 Eric M. Maiese, Ph.D.,5 and Prakash Navaratnam, R.Ph., Ph.D.1,3
ABSTRACT

Background: Antibiotics are frequently used to treat acute rhinosinusitis (ARS; acute sinusitis), although many episodes are viral. Because of community resistance concerns, current evidence provides limited support for the use of antibiotics in ARS. We conducted a retrospective comparative effectiveness outcomes assessment of the nasal steroid mometasone furoate nasal spray (MFNS) versus antibiotics among ARS patients in clinical practice. Methods: Using the General Practice Research Database (United Kingdom), the earliest ARS event between January 1, 2005 and December 31, 2008 (index event) for patients aged 1275 years and an antibiotic or MFNS prescription 2 days was identified. Treatment cohorts were MFNS monotherapy (MM), MFNS antibiotic (MAT), and antibiotic monotherapy (AM). Logistic regression adjusted for potential confounders and compared odds of rhinosinusitisrelated medical encounters and related prescriptions in the 3- to 30-day postindex period. Results: There were 12,679 eligible patients (651 MM; 2285 MAT; 9743 AM). Compared with the reference cohort AM, during the 3- to 30-day postindex period, lower adjusted odds (p 0.001) of having one or more rhinosinusitis-related medical encounters was observed for MM (odds ratio [OR] 0.39; 95% CI, 0.26 0.58) and MAT (OR 0.51; 95% CI, 0.42 0.62); having one or more rhinosinusitis-related prescriptions for MM (OR 0.51; 95% CI, 0.42 0.63) and MAT (OR 0.58; 95% CI, 0.52 0.65); having one or more antibiotic, nasal steroid, or oral steroid prescriptions for MM (OR 0.36; 95% CI, 0.28 0.46) and MAT (OR 0.51; 95% CI, 0.46 0.58); and having one or more antibiotic prescriptions for MM (OR 0.43; 95% CI, 0.33 0.58) and MAT (OR 0.63; 95% CI, (0.55 0.72). Conclusion: Compared with AM, using MFNS for initial ARS treatment, alone or with an antibiotic, is associated with a decreased likelihood of both subsequent rhinosinusitis-related medical encounters and use of related prescriptions. (Am J Rhinol Allergy 26, 308 314, 2012; doi: 10.2500/ajra.2012.26.3781) hinosinusitis, one of the most common conditions encountered by general practitioners,1 is typically defined as inflammation of one or more of the paranasal sinuses and can manifest as an acute or chronic condition. Because inflammation of the nasal mucosa nearly always accompanies sinusitis, rhinosinusitis is currently the preferred term. Major symptoms include nasal congestion, purulent rhinorrhea, facial dental pain, postnasal drainage, headache, and cough. Although rhinosinusitis might appear benign, the impact on quality of life due to symptoms leads many patients to seek medical care.2 Antibiotics are commonly prescribed to treat rhinosinusitis. In the United Kingdom, rhinosinusitis is the eighth most common condition for which an antibiotic is prescribed.3 In the United States, more than one in five antibiotics prescribed in adults is for rhinosinusitis, making it the fifth most common condition for which antibiotics are prescribed.4,5 Despite frequent treatment with antibiotics, acute rhinosinusitis (ARS) episodes, defined as having symptoms lasting for 12 weeks,6 are typically viral, with only 0.52.0% of viral ARS cases complicated by bacterial infection.7 Current evidence provides limited support for the use of antibiotics in ARS.6 For determining whether to prescribe antibiotics, differentiating viral from acute bacterial rhinosinusitis (ABRS) is crucial.8 Indications for use of antibiotics for the treatment of ARS include
From the 1DataMed Solutions, LLC, Hilliard, Ohio, 2Informagenics, Worthington, Ohio, 3The Ohio State University College of Pharmacy, Columbus, Ohio, 4The Ohio State University College of Public Health, Division of Epidemiology, Columbus, Ohio, and 5Merck & Co., Inc., West Point, Pennsylvania Presented at the annual meeting of the American Academy of Allergy, Asthma and Immunology, San Francisco, California, March 18 22, 2011 Funded by Schering Plough Corporation and Merck & Co., Inc. E. Maiese was an employee and shareholder of Merck. C.de Moor, G. Reardon, J. McLaughlin, and P. Navaratnam were consultants for Schering Plough and Merck Address correspondence and reprint requests to Gregory Reardon, R.Ph., Ph.D., 450 West Wilson Bridge Road, Suite 340, Worthington, OH 43085 E-mail address greardon@informagenics.com Copyright 2012, OceanSide Publications, Inc., U.S.A.

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symptoms that last 10 days, symptoms or signs of ARS that worsen within 10 days after an initial improvement (double worsening), or severe symptoms of ARS infection including fever with purulent nasal discharge, facial pain or tenderness, and periorbital swelling.5 Studies have indicated, however, that many practitioners do not adhere to these guidelines,5,9 adding to the concern that overuse of antibiotics may lead to community antimicrobial resistance35,7,911 and underscoring the importance of understanding the clinical effectiveness of antibiotics and potential alternative treatments for ARS to inform treatment decisions. In a recent prospective cohort study, Blin et al.12 found that antibiotics compared with no antibiotics reduced by threefold the postindex prescribing of an (or another) antibiotic or sinus lavage within 10 days after the index ARS encounter. In a retrospective analysis, Pan et al.13 found that prescribing of an antibiotic (versus no antibiotic) for rhinosinusitis may reduce return visits to primary care physicians. Previous clinical trials,14,15 a Cochrane review,16 and three meta-analyses,1719 on the other hand, have shown that antibiotics may do little to nothing for treating ARS versus placebo, and that most cases of ARS resolve spontaneously. Differences reported on the effectiveness of antibiotics between studies may be caused by differences in ARS case definitions and inclusion criteria. However, studies also suggest consideration of alternatives to routine antibiotic use in ARS, including watchful waiting,19 more careful selection of candidates for antibiotic therapy,18 and use of other agents, including nasal steroids, for alleviation of sinonasal symptoms.18 Mometasone furoate nasal spray (MFNS) is an intranasal steroid that binds to the glucocorticoid receptors in the nasal passage, inhibiting the transcription of proinflammatory mediators. Several clinical trials have shown that MFNS reduces the symptoms of ARS. Two clinical trials20,21 found superiority in total symptom score and in some specific inflammatory symptoms (e.g., headache, congestion, and facial pain)20 when using adjunctive MFNS versus placebo spray in treating ARS patients who received prior amoxicillin therapy.

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Table 1 Study population flow Application of Inclusion/Exclusion Criteria to Patient Population All patients with ARS episode from January 1, 2005 through December 31, 2008 who had (1) age of 12 and 75 yr on the index event date and available gender information, (2) at least 2 yr of GPRD registration before the index event date, and (3) an antibiotic or MFNS prescribed (but no other nasal steroid spray) on or within 2 days after the index event Had more than one antibiotic (based on generic name) prescribed on or within 2 days on or after the index event Had a prescription for any nasal steroid or antibiotic within 30 days before the index event Had an acute or chronic rhinosinusitis event within 30 days before the index event Had any chronic rhinosinusitis event within 1 yr before or on the index event Had a lower or upper respiratory tract infection (nasopharyngitis, acute bronchitis/bronchiolitis, adenoid hypertrophy, influenza, otitis media, pneumonia, nasal polyposis, or tonsillitis) or bacteremia/septicemia within 30 days before or on the index event Had a chronic oral corticosteroid (four or more prescriptions in preindex year) or any oral or injectable corticosteroid within 2 days on or after the index event Had immunomodulator therapy within 1 yr before or on the index event Had a maxillaryfacial surgical procedure within 1 yr before or on the index event Eligible patients retained for analysis No. Excluded* No. Retained 16,481

167 2920 70 459 186

398 147 89

*Many patients met criteria for more than one of the exclusion rules shown. ARS acute rhinosinusitis; GPRD General Practice Research Database; MFNS mometasone furoate nasal spray.

In another clinical trial,22 MFNS monotherapy (MM) produced significant improvements in major symptom score when compared with amoxicillin monotherapy and to placebo. However, MFNS was equivalent to amoxicillin (although both were superior to placebo) in morning/evening major symptom score and in total symptom score. A fourth trial of ARS patients found a significant improvement in health-related quality of life score (20-item Sino-Nasal Outcome Test) after MM versus placebo but no significant difference after amoxicillin monotherapy versus placebo.23 Current EP3OS Guidelines (European Position Paper on the Primary Care Diagnosis and Management of Rhinosinusitis and Nasal Polyps 2007) state that overall, the evidence (grade I) supports the use of nasal corticosteroids both as monotherapy and as adjunctive therapy for ARS.6 However, no published studies have compared the effectiveness of MFNS with antibiotics among ARS patients in clinical practice. The primary goal of the current study was to examine the impact of MM, and MFNS as adjunctive therapy with an antibiotic (MAT), compared with antibiotic monotherapy (AM) for ARS in actual patient treatment settings. Specifically, the study explored the likelihood of the following postindex outcomes: subsequent rhinosinusitis-related clinical encounters; prescriptions for any rhinosinusitis-related medications; and rhinosinusitis-related prescriptions specifically for either an antibiotic, nasal steroid, or oral steroid.

METHODS

The General Practice Research Database (GPRD, now Clinical Practice Research Datalink),24 a repository of electronic medical and therapy records of a large subset of primary care physicians in the United Kingdom, was the data source for this analysis. The GPRD is the largest general practice research database in the world, representing 5.5% of the United Kingdom population. In this anonymized database, medical diagnoses, clinical procedures, and resource use data can be identified via the READ Clinical Terms. Each prescription product can be identified with a GPRD product code (Multilex) and cross-linked to the British National Formulary. For this study, READ codes used to identify ARS events within the GPRD clinical file were adapted and updated from an earlier study by Ashworth et al.25 This full set of codes is available on request from the corresponding author. This study applied a nonrandomized retrospective cohort analysis to the GPRD database. As required for use of the GPRD database, the

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current study protocol (no. 10-162) was approved by the Independent Scientific Advisory Committee for Medicines and Healthcare products Regulatory Agency in the United Kingdom. Over an intake period from January 1, 2005 through December 31, 2008, the earliest ARS-coded event (index event) for each patient in the GPRD database was identified. The date of this index event was assigned as the starting date of the ARS episode. Eligible patients with an index ARS episode had (1) age of 12 and 75 years on the index event date and available gender, (2) at least 2 years of GPRD registration before the index event, and (3) an antibiotic or MFNS (but no other nasal steroid spray) prescribed on or within 2 days after the index event. Patients with any of the following pharmacotherapies and conditions that might have impacted treatment decisions and response and classification of patient cohorts were excluded: (1) more than one antibiotic (based on generic name) prescribed on or within 2 days after the index event, (2) a prescription for any nasal steroid or antibiotic within 30 days before the index event, (3) an ARS event within 30 days before the index event, (4) a chronic rhinosinusitis event within 1 year before the index event, and (5) a lower or upper respiratory tract infection (nasopharyngitis, acute bronchitis, bronchiolitis, adenoid hypertrophy, influenza, otitis media, pneumonia, nasal polyposis, or tonsillitis) or bacteremia/septicemia on or within 30 days before the index event. Patients were also excluded if they had evidence of prior use of immunosuppressant therapies or recent sinus reconstruction that could complicate the response to ARS treatment including (1) chronic oral corticosteroid use (defined as 4 or more prescriptions within 1 year before the index event) or any oral or injectable corticosteroid on or within 2 days after the index event, (2) immunomodulator therapy on or within 1 year before the index event, or (3) a maxillaryfacial surgical procedure on or within 1 year before the index event. Eligible patients in the final sample were defined to be in only one of three cohorts based on the specific agents dispensed on or within 2 days after the index event: (1) AM, (2) MM, and (3) MAT. Four outcomes were assessed: (1) rhinosinusitis-coded clinical encounters including acute or chronic rhinosinusitis events that occurred within 330 days after the index event; (2) any rhinosinusitis-related prescription (antibiotic, nasal steroid, oral steroid, analgesic, antihistamine, decongestant, decongestant and antihistamine combination, nasal antihistamine, nasal antibiotic, nasal combination, nasal decongestant, nasal mast cell stabilizer, other nasal-administered agent, or

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Table 2 Characteristics of the study population by medication cohort Cohort AM (n 9743) MM (n 651) MFNS Adjunctive Therapy (n 2285) n 136 206 176 133 229 422 445 153 42 11 636 11 4 % 16.8 32.9 30.2 20.1 37.2 62.8 67.6 24.9 5.0 2.5 96.3 2.6 1.1 n 383 752 691 459 850 1435 1545 569 114 57 2201 60 24 % 14.5 32.1 32.9 20.5 31.4 68.6 61.7 29.3 5.9 3.1 93.6 4.4 2.0 n 1837 4071 4177 2594 3980 8699 Total (n 12,679)

Age (yr) 1229 13.5 1318 20.9 3044 32.0 3113 31.6 4559 34.0 3310 27.0 6075 20.5 2002 20.4 Gender Male 29.8 2901 35.2 Female 70.2 6842 64.8 Charlson comorbidity index score 0 59.8 5831 68.4 1 30.8 2997 23.5 2 6.1 590 6.5 3 3.3 325 1.7 No. of ARS events in preindex year 0 92.7 9031 97.7 1 5.0 486 1.7 2 2.3 226 0.6 ARS index year 2005 36.6 3567 23.7 2006 25.9 2520 21.7 2007 22.3 2176 25.0 2008 15.2 1480 29.6 Any (1) rhinosinusitis-related agent (exc. oral corticosteroid, antibiotics, Yes 13.7 1333 18.0 Any antibiotic in preindex year Yes 54.3 5290 42.4 Any nasal steroid in preindex year Yes 29.9 2915 16.7 Any oral corticosteroid in preindex year Yes 5.3 519 3.8 Any other sinus prescriptions in preindex year* Yes 52.9 5155 41.8

*Includes analgesics, antihistamines, decongestants, decongestant and antihistamine combinations, nasal antihistamines, nasal antibiotics, nasal combinations, nasal decongestants, nasal mast cell stabilizers, other nasal-administered agents, and nasal saline. AM antibiotic monotherapy; MM MFNS monotherapy; MFNS mometasone furoate nasal spray; ARS acute rhinosinusitis.

nasal saline) within 330 days after the index event; (3) any antibiotic, nasal steroid, or oral steroid rhinosinusitis-related prescription within 330 days after the index event; and (4) any antibiotic prescription within 330 days after the index event. Separate multivariate logistic regression models were developed for each of the outcomes mentioned previously. In each multivariate model, the AM cohort was set as the reference cohort for comparison with the MM and MAT groups separately. To adjust for confounding, the following covariates were included in each model: age on the date of the index event (1229, 3044, 4559, and 6075 years); gender; Charlson comorbidity index score26 (0, 1, 2, or 3; adapted using Deyo et al.27 and Quan et al.28 updates); number of ARS-coded events during the 12 months before the index event date (0, 1, 2); year of the ARS index event; use of any concurrent rhinosinusitis-related pharmacotherapy agents (excluding antibiotics, nasal steroids, or oral steroids) on or within 2 days after the index event; and use of any antibiotic, any nasal steroid, any oral corticosteroid or any other ARS-related prescription in the preindex year. All analyses were performed in Stata 10.0 (StataCorp, College Station, TX).

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276 109 25 272

154 22.9 523 33.5 141 23.6 539 25.2 163 25.2 575 23.0 193 28.4 648 18.3 or nasal steroids) on or within 2 days after the index date 117 14.9 340 14.1 47.3 25.0 4.6 43.9 1080 571 105 1002 52.4 28.4 5.1 50.7

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7,821 3719 746 393 11,868 557 254 4244 3200 2914 2321 1790 6646 3595 649 6429

RESULTS
A total of 12,679 eligible patients with an ARS index event were identified (Table 1). Of these, 9743 were in the AM cohort, 651 were in the MM cohort, and 2285 were in the MAT cohort. Study population characteristics are described in Table 2. Patients in the MM and MAT cohorts were younger, more likely to be male patients, and more likely to have a lower Charlson comorbidity index score compared with patients in the AM cohort. Compared with the AM cohort, patients in the MM and MAT cohorts were slightly less likely to have had one or more ARS events in the 12 months before the index event, had greater proportions of index ARS events in later study years (e.g., 2008 versus 2005), and were slightly more likely to be prescribed a concurrent rhinosinusitis-related pharmacotherapy agent (other than antibiotic, nasal steroid, or oral steroid) during the index event. Patients in the MM cohort had lower use of antibiotics, nasal steroids, and oral steroids in the preindex year compared with the AM and MAT cohorts. Patients in the AM cohort had higher rates of other rhinosinusitis-related prescriptions (i.e., analgesics, antihistamines, decongestants, decongestant and antihistamine combinations, nasal

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Table 3 Antibiotics prescribed on or within 2 days after the index acute rhinosinusitis event Cohort AM (n 9743) % Amoxicillin Amoxicillin-clavulanate Cephalosporins Ciprofloxacin Clarithromycin Doxycycline Erythromycin Oxytetracycline Other 51.4 5.9 4.8 0.9 1.9 25.5 6.3 1.7 1.7 n 5005 571 470 87 183 2485 613 161 168 MFNS Adjunctive Therapy (n 2285) % 51.1 7.3 4.2 0.7 2.4 25.1 6.3 1.3 1.6 n 1167 166 97 17 55 573 143 30 37 % 51.3 6.1 4.7 0.9 2.0 25.4 6.3 1.6 1.7 n 6172 737 567 104 238 3058 756 191 205 Total (n 12,028)

*Difference in frequency distribution between AM and MFNS adjunctive therapy is not significant (2, p 0.151). AM antibiotic monotherapy; MFNS mometasone furoate nasal spray.

Table 4 Description of rhinosinusitis outcomes during 330 days postindex time period by medication cohort (univariate analysis) Outcome AM Cohort MM

% One or more rhinosinusitis-related medical encounters One or more rhinosinusitis-related prescriptions* One or more antibiotic, nasal steroid, or oral steroid prescriptions One or more antibiotic prescriptions 9.8 37.7 28.3

958

*Includes antibiotics, nasal steroids, oral steroids, analgesics, antihistamines, decongestants, decongestant and antihistamine combinations, nasal antihistamines, nasal antibiotics, nasal combinations, nasal decongestants, nasal mast cell stabilizers, other nasal-administered agents, and nasal saline. AM antibiotic monotherapy; MM MFNS monotherapy; MFNS mometasone furoate nasal spray.

antihistamines, nasal antibiotics, nasal combinations, nasal decongestants, nasal mast cell stabilizers, other nasal-administered agents, or nasal saline) in the preindex year compared with MM and MAT cohorts. Table 3 shows the most common antibiotic products prescribed on or within 2 days of the index ARS event, separately for the AM and MAT cohorts. Overall product usage patterns were similar between these two cohorts (p 0.151). Amoxicillin, doxycycline, and amoxicillin/clavulanate together accounted for more than four of every five antibiotic prescriptions in each cohort. Table 4 describes the rhinosinusitis-related outcomes during 330 days postindex time period for each cohort. In the total study population 8.7% of patients had one or more repeated rhinosinusitis-related medical encounters; 34.6% had one or more rhinosinusitis-related prescriptions; 25.4% had one or more antibiotic, nasal steroid, or oral steroid prescriptions; and 17.1% had one or more antibiotic prescriptions during postindex days 330. Among the 25.4% with an antibiotic, nasal steroid, or oral steroid prescribed during this postindex period, 57.0% were for antibiotics, 39.7% for nasal steroids, and 3.3% for oral steroids. Both the MM and the MAT cohorts had lower rates of having one or more rhinosinusitis-coded clinical encounters; one or more rhinosinusitis-related prescriptions; one or more antibiotic, nasal steroid, or oral steroid prescriptions; and one or more antibiotic prescriptions (p 0.001 for all chisquare) during postindex days 330 when compared with the AM cohort. Figure 1 shows results from the adjusted logistic regression models for the four outcomes. Compared with the AM cohort, patients in the

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MFNS Adjunctive Therapy n % n 26 5.2 119 143 77 56 24.9 16.7 12.2 569 381 279

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Total % 8.7 34.6 25.4 17.1 n 1103 4380 3214 2163

22.0 11.8 8.6

MM cohort had 60% reduced odds (odds ratio [OR] 0.39; p 0.001; 95% CI, 0.26, 0.58) and those in the MAT group had 50% reduced odds (OR 0.51; p 0.001; 95% CI, 0.42, 0.62) of having one or more postindex (days 330) rhinosinusitis-coded clinical encounters. Patients in both the MM group (OR 0.51; p 0.001; 95% CI, 0.42, 0.63) and the MAT cohort (OR 0.58; p 0.001; 95% CI, 0.52, 0.65) had 50% reduced odds of having any postindex rhinosinusitisrelated prescription in postindex days 330 compared with the AM cohort. Patients in the MM cohort (OR 0.36; p 0.001; 95% CI, 0.28, 0.46) and those in the MAT group (OR 0.51; p 0.001; 95% CI, 0.46, 0.58) had 65 and 50% reduced odds, respectively, of being prescribed any postindex antibiotic, nasal steroid, or oral steroid prescription in postindex days 330 compared with patients in the AM group. Patients in both the MM group (OR 0.43; p 0.001; 95% CI, 0.33, 0.58) and the MAT cohort (OR 0.63; p 0.001; 95% CI, 0.55, 0.72) also had reduced odds of having any antibiotic prescription in postindex days 330 compared with the AM cohort.

DISCUSSION
In this retrospective analysis of the GPRD, after adjusting for patient characteristics, usage of concurrent sinus-related agents at the time of the index ARS event and preindex year health care resource use, we observed significantly lower odds of both rhinosinusitisrelated medical encounters and subsequent use of rhinosinusitisrelated prescriptions during postindex days 330 for both the MM and the MAT cohorts when compared with the AM cohort. Although

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Figure 1. Multivariate adjusted odds of acute rhinosinusitis outcomes during 330 days postindex time period compared with the antibiotic monotherapy (AM) cohort. *Adjusted for age; gender; Charlson comorbidity index; rhinosinusitis events in preindex period; ARS index year; any rhinosinusitis-related pharmacotherapy (excluding oral corticosteroid, antibiotics, or nasal steroids) on or within 2 days after the index date; and any antibiotic, nasal steroid, oral corticosteroid, or any other sinus-related prescription in the preindex year. **Includes antibiotics, nasal steroids, oral steroids, analgesics, antihistamines, decongestants, decongestant and antihistamine combinations, nasal antihistamines, nasal antibiotics, nasal combinations, nasal decongestants, nasal mast cell stabilizers, other nasal-administered agents, and nasal saline.

the retrospective design of this analysis cannot indicate causation, current study findings complement previously conducted clinical trials and suggest that MFNS (as adjunctive or monotherapy) may be a more effective treatment for ARS than AM commonly prescribed in clinical practice. A recent Cochrane review has concluded for ARS confirmed by radiology or nasal endoscopy that evidence is limited but supports the use of an inhaled corticosteroid as monotherapy or adjuvant therapy to antibiotics.29 A separate recent Cochrane review concluded that antibiotics have a small treatment effect in uncomplicated ARS and that clinicians need to weigh these small benefits against the potential for adverse effects at both the individual and community levels,16 such as emerging antibiotic resistance to some bacterial pathogens. Recent guidelines for managing adult rhinosinusitis5 strongly recommend that clinicians should distinguish presumed ABRS from ARS caused by viral upper respiratory infections and noninfectious conditions. Unlike rhinosinusitis of a viral origin, antibiotics are indicated for ABRS, but these guidelines offer physicians options to withhold use of antibiotics for even some cases of ABRS where the patient has mild illness with the assurance of follow-up,5 because the ability of oral antibiotic therapy to induce resistance by selective pressure on existing microflora is well documented.5,30,31

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Regardless of initial therapy (AM, MM, or MAT), we found that a subsequent prescription (especially an antibiotic, nasal steroid, or oral steroid) was a more common indicator of therapeutic failure in the month after the initial ARS event than was a subsequent rhinosinusitis-coded encounter with the physician. In the current study, 9% of patients had a postindex medical encounter for rhinosinusitis and 35% had received any postindex rhinosinusitis-related pharmacotherapy. Furthermore, of the patients who had received any postindex rhinosinusitis-related pharmacotherapy, 73% (25.4/34.6 from Table 4) were prescribed either an antibiotic, nasal steroid, or oral steroid. Of the 73% prescribed either an antibiotic, nasal steroid, or oral steroid, antibiotics and nasal steroids account for 97% of these postindex prescriptions. These findings suggest that in the United Kingdom, prescribing of additional medications after an initial encounter for ARS is anticipated, given that subsequent medical visits do not appear to be required for patients to receive these prescriptions. These findings may also suggest that many physicians might be considering use of these additional medications at the time of the initial ARS consultation, perhaps issuing these postindex prescriptions without expectation of need for a return visit. This could reflect pressure on health systems to quickly treat patients, a lack of physician time for

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follow-up visits, or the expectation that first-line treatment of ARS is frequently not successful. In this study, MFNS was more frequently prescribed as adjunctive therapy with an antibiotic than as a monotherapy to treat ARS (Table 2). Reasons for this observation are not clear. One possible explanation is that physicians are more likely to use combined antibiotic and MFNS therapy for more severe ARS cases compared with those prescribed AM. Although physician perceptions of ARS severity for the sampled patients are not known, patient attributes and treatment history in this study (Table 2) do not support this hypothesis: patients receiving AM were more likely to have had an ARS event and to have received any antibiotic, nasal steroid, or other sinus prescription in the preindex year than those receiving an antibiotic with adjunctive MFNS. Perhaps this combined therapy is used more often in cases where the etiology (viral versus bacterial) is more equivocal. Perhaps patients with bacterial ARS are much more likely to seek medical attention and receive an antibiotic than patients with viral ARS, or possibly many primary care physicians remain reluctant to avoid prescribing an antibiotic for presumptive bacterial ARS and also prescribe MFNS to treat the inflammation associated with ARS. Published reports over the past 10 years have suggested that physicians continue to rely heavily on antibiotics to treat ARS. For instance, despite reductions in the antibiotic prescribing rate for many common respiratory conditions in Great Britain, antibiotics were still prescribed in the year 2000 for 90% of medical encounters for rhinosinusitis24 and between the years 1998 and 2001 at a rate of 85%.3 More recently, 69% of patients in a Medicare plan in the United States who had a medical visit for rhinosinusitis32 and 67% of patients with rhinosinusitis-like complaints in a Dutch general practice database were prescribed antibiotics for rhinosinusitis.33 In an earlier analysis of the GPRD for common respiratory conditions, Petersen et al.3 found, as we did for rhinosinusitis, a high usage in the United Kingdom of the recommended first-line, narrow-spectrum antibiotics relative to wide-spectrum second-line agents. However, these authors expressed concern for the continued widespread use of antibiotics for these respiratory conditions, including rhinosinusitis, by stating that it is clear that there remains scope for further reductions in antibacterial prescribing,3 Bjerrum et al.34 cite this issue primarily as a challenge for general practice physicians, who account for 90% of all antibiotics prescribed. Despite the exaggerated use of antibiotics and the growing development of bacterial resistance, few initiatives have been undertaken to reduce the inappropriate use of antibiotics.34

dispensed or consumed. Thus, actual use of medications could not be determined, and the use of over-the-counter medications available in the United Kingdom at the time of this study (including decongestants, antihistamines, and the nasal steroids beclomethasone and fluticasone) could not be considered in this analysis. Finally, the relationship of these treatments with patient quality of life and with costs of each therapy and associated medical costs were not considered in this analysis but would be worthwhile subjects for future research.

CONCLUSION

The current study provides evidence that MFNS, alone or in combination with an antibiotic, in the treatment of ARS is associated with reductions in rhinosinusitis-related medical encounters and rhinosinusitis-related prescription drug use when compared with antibiotics alone.

REFERENCES
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2. 3. 4.

Limitations

Although the naturalistic design of this study provides benefits for observing real-world use of therapies, this study has a number of limitations. First, there may have been coding issues within GPRD that may have led to the misclassification of ARS (e.g., patient may have had chronic rather than ARS). Second, although important confounding variables were adjusted in the models, ARS severity, length of time between onset of symptoms and presentation to the primary care physician, and other factors potentially associated with the prescribing of antibiotics or MFNS and ARS symptoms may not have been adequately controlled thus potentially leading to residual confounding. Differences in physician prescribing behavior between the study cohorts could not be addressed in this analysis. For example, it is not known if physicians were more likely to prescribe MM to patients whose ARS was easier to manage or who had concurrent allergic rhinitis. Furthermore, in the case of rhinosinusitis, it may be that not all consultations for minor infections are recorded in the data and that those that are more serious and result in a prescription are more likely to be recorded. Likewise, some general practice physicians may use delayed prescribing such that although they issue a prescription, they ask the patient not to redeem the prescription unless they fail to improve. This prescribing behavior has been reported to occur for antibiotics,35 and may have led to some antibiotics in the AM and MAT cohorts being shown as prescribed but not actually being

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6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17.

5.

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