Key words: Acute bacterial sinusitis – Amoxicillin/clavulanate – Anti-inflammatory – Clarithromycin
ABSTRACT
Objective: To compare the efficacy and tolerability of clarithromycin extended-release (ER) to amoxicillin/ clavulanate in patients diagnosed with acute bacterial sinusitis.
Research design and methods: In a controlled, multicenter, investigator-blinded study, 437 ambulatory patients at least 12 years old with signs/symptoms and radiographic findings of acute sinusitis were randomized to receive clarithromycin ER 1000mg once daily or amoxicillin/ clavulanate 875 mg/125 mg twice daily for 14 days.
Main outcome measures: Clinical and bacteriological response rates were determined at a test-of-cure visit, which was conducted up to 10 days following the completion of treatment. Radiological response was assessed at a follow-up visit.
Results: The clinical cure rate in clinically valuable patients was 98% (184/188) in the clarithromycin ER group and 97% (179/185) in the amoxicillin/clavulanate group (95% Cl for the difference in rates [-2.4%, 4.7%]). Clinical cure was sustained at the follow-up visit (96% for each treatment group). The pathogen eradication rates were 94% (61/65) in the clarithromycin ER group and 98% (61/62) in the amoxicillin/clavulanate group (95% Cl for difference in rates [- 12.0%, 2.9%]). The radiological success rate was 94% (172/183) in both the clarithromycin ER and amoxicillin/clavulanate groups (95% Cl for difference in rates [-4.9%, 4.9%]). Symptomatic improvement or relief was observed as early as 2days-5days after the initiation of study drug, with a statistically significantly higher resolution rate of sinus pressure (p = 0.027) and improvement/resolution rate of nasal congestion (p = 0.035) during treatment with clarithromycin ER. The resolution/improvement rate at the test-of-cure visit for each treatment group was ≥ 94% for the primary acute sinusitis signs/symptoms, with a statistically significantly higher resolution/ improvement rate of purulent nasal discharge with clarithromycin ER (p= 0.010). Both study drugs had a positive and rapid impact on quality of life. Patients reported a high level of satisfaction and probability of using either study antibiotic again, and health care resource use was low, with slightly fewer sinusitis-related physician and outpatient visits required by patients in the clarithromycin ER group (p = 0.055). The treatment groups were comparable with respect to incidence of drug-related adverse events.
Conclusion: In this multinational population of patients with acute bacterial sinusitis, clarithromycin ER was comparable, and for selected measures superior, to amoxicillin/clavulanate based on clinical, bacteriological, and radiological responses as well as quality of life measures, satisfaction with antibiotic therapy, and health care resource utilization.
Introduction
Acute bacterial sinusitis is a common infection with significant economic impact. Between 1% and 5% of adults are diagnosed with acute sinusitis each year in Europe1. In the United States, there are approximately 20 million cases of sinusitis annually2. Also, based on estimates from a prevalence-based cost-of-illness study, over $3.5 billion is spent annually for medical and surgical treatment of sinusitis3, including $400$600 million for antibiotics4- 5. Sinusitis diminishes quality of life6: between 1990 and 1992, sinusitisassociated symptoms resulted in over 70 million days of restricted activity7. Left untreated, sinusitis may lead to intracranial complications such as meningitis, brain abscess, cavernous-sinus and cortical-vein thrombosis, as well as orbital and respiratory complications.
An infection of one or more of the paranasal sinuses, bacterial sinusitis is generally preceded by an upper respiratory infection. In most cases, the antecedent infection is of viral etiology such as human rhinovirus, which causes approximately half of common colds. Subsequent impairment of the mucociliary transport system and sinus ventilation disrupts the local epithelial defense mechanisms and predisposes the individual with a viral upper respiratory tract infection to the development of sinusitis. The conditions responsible for secondary bacterial infection of the sinuses are unknown, but activities such as nose blowing and coughing may introduce bacteria into the paranasal sinuses during a viral upper respiratory tract infection. Inflammation of the sinus mucosa and mucus production are also important factors in the evolution of sinusitis8. The most common pathogens responsible for acute bacterial sinusitis are Streptococcus pneumoniae and Haemophilus influenzae, which combined, account for greater than 50% of cases8. Other microorganisms such as Moraxella catarrhalis, Staphylococcus aureus, Streptococcus pyogenes, and anaerobic bacteria may also be isolated from patients with acute bacterial sinusitis8.
Antibiotic therapy for acute bacterial sinusitis is recommended to shorten the duration of infection9 and related symptoms, decrease the risks of mucosal damage and progression to chronic disease, and prevent sequelae. According to 2004 treatment guidelines8 endorsed by the American Academy of Otolaryngology-Head and Neck Surgery, 10days-14days of therapy with amoxicillin or amoxicillin/ clavulanate at 1.5 g-4 g of amoxicillin daily, a cephalosporin (e.g., cefpodoxime, cefuroxime, cefdinir), or alternatively a macrolide/azalide in penicillin-allergic patients, is recommended for first-line treatment of acute bacterial sinusitis in patients with mild disease who have not recently used antimicrobials within the past 4weeks-6weeks. These treatment guidelines are based on considerations of the frequency and distribution of bacterial pathogens and their antimicrobial susceptibility, symptom severity, and the relationship between pharmacokinetic/ pharmacodynamic principles and efficacy of antimicrobial agents.
Clarithromycin possesses activity against the major respiratory tract pathogens10 and concentrates in respiratory tissues (tissue to serum concentration gradient of up to 10:1), making it well suited for the treatment of acute bacterial sinusitis”. The efficacy of clarithromycin in the treatment of acute sinusitis has been demonstrated previously in comparative clinical trials versus beta- lactams and fluoroquinolones12″ 20. Dubois et al. demonstrated that the pathogen eradication rate with clarithromycin was similar to that with amoxicillin/ clavulanate, in patients with acute sinusitis of confirmed bacterial etiology14. Murray et al. demonstrated, in a recent sinusitis study with clinical endpoints, that the extended- release (ER) formulation of clarithromycin was comparable to the immediaterelease (IR) tablet formulation of clarithromycin21. Based on its in vitro microbiological activity, once-daily dosing, and established safety profile10, clarithromycin ER should be included among first-line agents for treating acute bacterial sinusitis.
The objective of this study was to compare the clinical, bacteriological, and radiological efficacy and tolerability of clarithromycin ER with that of amoxicillin/clavulanate in patients with acute bacterial sinusitis.
Methods
Study design
This was a multi-center, multi-country, investigatorblinded, randomized trial. The study protocol was approved by an institutional review board or independent ethics committee for each study site. Before undergoing any study-related procedures, each patient reviewed and voluntarily signed an informed consent statement.
Patient selection
Patients enrolled in the study were ambulatory patients at least 12 years old with a diagnosis of acute, uncomplicated bacterial sinusitis. The diagnosis was based on the presence of: (1) opacification or an air/fluid level in a sinus radiograph (Water’s view) or computerized tomography (CT) scan of maxillary sinus (es), (2) purulent nasal discharge, and (3) at least two relevant signs and symptoms (facial pain or facial pressure over one or both maxillary sinus areas, nasal congestion, and fever) lasting longer than 7 days but no longer than 28 days prior to the screening visit.
Patients with chronic sinusitis or an anatomic abnormality involving the maxillary sinuses were excluded from the study, as were those with an uncontrolled, clinically significant co-morbid disease, including significant hepatic disease or renal insufficiency. Pregnant or lactating females and immunocompromised individuals were also considered ineligible for enrollment in this study.
The use of systemic antibiotics within 14 days before initiation of study drug (30 days for a long-acting, injectable antibiotic like benzathine penicillin) or concurrently with study drug was prohibited. Eligible patients were also prohibited from taking any immunosuppressant drug, including topical or inhaled corticosteroids. The use of decongestants, antihistamines, and other medications for sinusitis symptom relief was not restricted.
Study drug
Patients were randomized in a 1:1 ratio at each investigative site to receive 14 days of treatment with either clarithromycin ER 1000mg (Biaxin XL, Abbott Laboratories), administered once daily, or amoxicillin/ clavulanate 875mg/125mg (Augmentin, GlaxoSmithKline), a\dministered twice daily. Both study drugs were to be taken with food at about the same time each day. To maintain the study blind, patients were instructed not to discuss the appearance of study drug or any aspect of dosing with the investigator.
Study procedures
Patients were assessed five times during the study: once at baseline (≤ 48 h prior to the initiation of study drug) during an office/clinic visit, twice by telephone during treatment (day 3- day 5 and day 7-day 9), and twice following the completion of treatment during an office/clinic visit on day 16-day 18 (test-of- cure) and day 24-day 31 (follow-up).
Clinical signs and symptoms of acute bacterial sinusitis were assessed at each study visit. Sinus fluid samples were obtained at baseline and, if clinically indicated, also at the test-of-cure visit and sent for culture and antibiotic susceptibility testing22. The samples were collected by either needle aspiration or swab of middle meatus exudates guided by fiberoptic endoscopy from all patients at selected sites. Sinus radiograph or CT scan was performed at baseline and the follow-up visit. The amount of nasal mucus produced was estimated by counting the number of tissues used between day 2 and day 3, day 6 and day 7, and day 13 and day 14.
Throughout the study, patients completed several questionnaires; the symptom assessment and the SinoNasal Outcome Test (SNOT-16)23 measured the impact of the study drug on quality of life, while two additional surveys obtained the patients’ opinions about their experience with the study drug and their use of health care resources during the study period. The symptom assessment questionnaire consisted of a general question about how the patient felt based on current sinusitis symptoms (rated as 1 = excellent to 5 = poor), and a second question about change in sinusitis symptoms since the start of study drug (rated as 1 = much better to 5 = much worse). Patients completed the symptom assessment questionnaire at each study visit. The SNOT16 is a shortened version of the 31-item Rhinosinusitis Outcome Measure and was chosen because it is a reliable, valid, and responsive instrument for measuring rhinosinusitis-specific health-related quality of life24. At all except the second visit, patients rated 16 sinusitis-related items (e.g., need to blow nose, facial pain-pressure, lack of a good night’s sleep) using a 4-point scale (0 = no problem to 3 = severe problem). At the test-of-cure visit, patients completed an additional questionnaire about their experience with the antibiotic prescribed for them. Patients used a 7-point scale to rate their general satisfaction with the study drug (O = very dissatisfied to 6 = very satisfied) as well as the likelihood that the patient would use the medication again (O = definitely no to 6 = definitely yes). In addition, after the initial screening visit patients were asked at each study visit about their use of health care resources (e.g., physician office visit, outpatient visit, emergency room visit, hospitalization, procedures, laboratory tests) since the previous visit.
Adverse events were assessed throughout the study and blood specimens were collected at baseline and the test-of-cure visit for hematology and serum chemistry analyses. Third-party designees of the investigators assessed compliance with the study drug by counting unused study medication in returned containers at the test- of-cure visit.
Efficacy endpoints
Clinical response was the primary efficacy endpoint. At test-of- cure visit, patients were classified as either clinical cure or clinical failure, and at the follow-up visit, the clinical cure patients were further classified as sustained cure or recurrence. Clinical cure was defined as resolution or improvement in purulent nasal discharge and at least one additional sinusitis sign or symptom observed at baseline, with no worsening in the remaining signs and symptoms and no additional requirement for antimicrobial therapy. The definition of clinical failure was the worsening of at least one of fhe sinusitis signs or symptoms observed at baseline or appearance of new signs or symptoms at the test-of-cure visit and the necessity of additional antimicrobial therapy. Sustained clinical cure was defined as continued improvement or no worsening of sinusitis signs and symptoms and no worsening in the radiographie appearance of the sinus. Clinical recurrence was defined as signs and symptoms recurring any time prior to the follow-up visit and additional antimicrobial therapy was warranted. Clinical response was classified as indeterminate when a clinical response evaluation was not possible.
A comparison of the culture results from the baseline and test- of-cure visits was performed for specific target pathogens and was used to determine if eradication or persistence resulted following antibacterial treatment. The target pathogens were S. pneumoniae, S. aureus, H. influenzae, M. catarrhalis, and H. parainfluenzae. Eradication was defined as the absence of the original infecting pathogen(s) in a repeat sinus aspirate or endoscopie culture. If the original pathogen(s) was isolated in a repeat aspirate or endoscopie culture, the bacteriological response was persistence. In the absence of repeat culture results, the initial pathogen (s) was presumed eradicated if the patient was classified as a clinical cure and presumed persistent if the patient was classified as a clinical failure. New infection was defined as isolation of a new pathogen at post-treatment from a repeat sinus aspirate or endoscopie culture. Bacteriological response was classified as indeterminate when an evaluation was impossible.
Figure 1. Study populations
Radiological response was determined by the investigators at the follow-up visit and classified as resolution, improvement, unchanged, or worsening. Resolution was defined as complete clearing of sinus radiograph or CT scan evidence of acute bacterial sinusitis. The definition of improvement was reduction in the radiographic or CT scan evidence of acute bacterial sinusitis as compared to baseline findings. Unchanged or worsening radiological response was determined by comparing radiographie sinus findings with baseline radiographie or CT scan findings.
Data analysis
Assuming the clinical cure rate for each treatment group was approximately 87% and the clinical evaluability rate was 85%; then approximately 400 patients were to be enrolled. This sample size provides at least 80% power to assure that the two-tailed 95% confidence interval (CI) around the difference in response between treatments will remain within the lower bound of -0.10 or less in order to establish non-inferiority between the treatments. Statistical analyses were conducted using SAS version 8.2.
Clinical and radiological responses were determined in clinically evaluable and clinical intent-to-treat patient populations (Figure 1). Patient bacteriologic cure rate and pathogen eradication rate were determined in clinically and bacteriologically evaluable and bacteriological intent-to-treat populations. All patients who received at least one dose of the study drug and met the clinical and radiological criteria for acute sinusitis were included in the clinical intent-to-treat population; those meeting these criteria and who had a target pathogen isolated pre-treatment were included in the bacteriological intent-to-treat population. In addition, patients must have received at least 80% of the intended amount of study drug (or at least 3 days of study drug for patients classified as a clinical failure) and not received any other antibiotic prior to the test-of-cure visit (unless the patient was classified as a clinical failure) in order to be considered clinically evaluable. The clinically and bacteriologically evaluable population included patients who met the criteria for clinical evaluability and from whom a pre-treatment target pathogen was isolated.
The comparability of the treatment groups at baseline was analyzed using Fisher’s exact test (gender, race, tobacco use, alcohol use, and prior medical evaluation and treatment for the current acute sinusitis episode) and one-way analysis of variance (ANOVA) (age and number of sinusitis episodes in previous year). Baseline clinical signs and symptoms results were summarized by treatment group and compared between treatment groups using the Cochran-Mantel-Haenszel method. Fisher’s exact test was used to compare the treatment groups based on clinical cure rate, patient bacteriological cure rate, and eradication rate for target pathogens at the test-of-cure visit and clinical cure rate and radiological resolution/ improvement rate at the follow-up visit. A 95% CI with a continuity correction around the difference in the clinical cure, patient bacteriological cure, and radiological resolution/ improvement rates, was computed. The treatment groups were further compared using the Cochran-Mantel-Haenszel test with stratification by centers within and outside of the US, country, investigator, gender, race, age, weight, treatment duration, study drug compliance, tobacco and alcohol use, prior medical evaluation and treatment for the current acute sinusitis episode, presence of sinus radiographie evidence of acute bacterial sinusitis, presence of purulent nasal discharge, and presence of at least two supportive signs and symptoms of acute sinusitis. Fisher’s exact test was also used to determine differences between treatment groups, based on the rate of resolution/improvement in clinical signs and symptoms. Treatment group differences based on patient symptom assessment, SNOT-16 evaluation, and treatment satisfaction were evaluated using a between-groups f-test. Usage of sinusitis-related health care resource utilization and incidence of treatment-related adverse events (those classified as probably- or possibly-related) were compared using Fisher’s exact test.
R\esults
A total of 437 patients were enrolled at 49 study centers (4 in Canada, 4 in Greece, 8 in Hungary, 3 in Italy, 4 in Lithuania, 8 in Poland, 4 in Romania, 5 in Spain, 9 in the United States) between May 30, 2003 and February 16, 2004. Of the enrolled patients, 221 were randomized to treatment with clarithromycin ER and 216 to treatment with amoxicillin/clavulanate. Fourteen patients, seven in each treatment group, were excluded from the clinical intent-to- treat population because they did not meet the inclusion criteria for acute sinusitis (Figure 1). Of the randomized patients, 373 (85%) were classified as clinically valuable. In general, the 64 clinically unevaluable patients were distributed evenly by treatment group and reason for non-evaluability, the most common reasons being the patient did not satisfy the entry selection criteria (21 patients) or no post-treatment evaluation was conducted (15 patients). Lack of a target pathogen or lack of a sinus aspiration/ endoscopy were the most common reasons for 328 patients being excluded from the clinically and bacteriologically evaluable population.
There were no statistically significant differences between the treatment groups at baseline based on demographic data, medical history, presenting signs and symptoms, radiographie findings, and sinusitis history (Table 1). The most common presenting signs and symptoms among treated patients were purulent nasal discharge (100%), nasal congestion (99%), sinus pressure (97%), and sinus pain (95%), with most (> 72% in each treatment group) being classified as moderate or severe. Overall, patients had experienced a mean (SD) of 1.3 (0.7) episodes of acute bacterial sinusitis in the year prior to enrollment in the study.
Regarding the current infection, 98% of treated patients had radiological confirmation of their infection at baseline: 57% of patients had involvement of one maxillary sinus and 43% of patients had bilateral infection. Opacification was observed in 77% of patients in each treatment group. Air fluid levels were observed in 43% and 42% of patients in the clarithromycin ER and amoxicillin/ clavulanate groups, respectively.
Sinus secretions were obtained endoscopically in 269 patients and by needle aspiration in 73. The methods had similar overall rates of positive culture (33% and 44%, respectively). A comparison of the target pathogens isolated by the two culture methods is shown in Table 2. The majority of cultures had a single pathogen isolated (80% and 63% of endoscopie and aspiration cultures, respectively). The eradication rate of each target pathogen (44% of all pathogens isolated) is shown in Table 3. For pathogens isolated from samples collected at baseline, the MIC90 values for clarithromycin and amoxicillin/ clavulanate were 8 g/mL and 2 g/mL for H. influenzae, 2g/mL and 0.25g/mL for S. pneumoniae (9%, 4/47 resistant to penicillin), 0.12 g/mL and 0.25 g/mL for M. catarrhalis, and > 32g/ mL and 1 g/mL for S. aureus, respectively. There were seven (15%) S, pneumoniae that were resistant to clarithromycin at baseline, five isolates with high-level ErmB (ribosomal methylase)-mediated resistance and two isolates with intermediate level, MefA (macrolide efflux)-mediated resistance.
Table 1. Demographic and pre-treatment patient characteristics of treated patients
Among the clinically evaluable patients, mean (SD) duration of treatment was 14.0 (0.8 9) day s and 14.2 ( 0.86) days for the clarithromycin ER and amoxicillin/ clavulanate groups, respectively. Oral sympathomimetic agents (e.g., psuedoephedrine, phenylephrine), nasal decongestants, and antihistamines were used by 23.8%, 8.9%, and 6.9% of patients, respectively, during their participation in the study.
Clinical, bacteriological, and radiological responses
Clarithromycin ER was comparable to amoxicillin/ clavulanate based on clinical cure rate in clinically evaluable patients at the test-of-cure visit (98% [184/188] and 97% [179/185] for the respective treatment groups; 95% CI for the difference in cure rates [-2.4%, 4.7%]) (Table 4). The comparison of cure rates between treatment groups was not affected by prognostic risk factor (e.g., age, prior medical evaluation/ treatment for the current infection, unilateral/bilateral sinusitis, etc.). Similar findings were observed in the clinical intent-to-treat population (Table 4). Clinical cure was sustained in 96% of patients in each treatment group at the follow-up visit.
The treatment groups were also comparable based on target pathogen eradication (includes both eradicated and presumed eradicated) (Table 3). The overall pathogen eradication rate in clinically and bacteriologically evaluable patients was 94% (61/65) for the clarithromycin ER group and 98% (61/62) for the amoxicillin/ clavulanate group (95% CI for the difference in eradication rates [- 12.0%, 2.9%]). This rate was 90% among the bacteriological intent- to-treat patients for both treatment groups. The eradication rates were similar for pathogens from patients with single or multiple pathogens isolated. Eradication of S. pneumoniae was 95% for clarithromycin ER and 100% for amoxicillin/clavulanate. Of the 22 S. pneumoniae isolates from the clinically and bacteriologically evaluable patients in the clarithromycin ER group, five were resistant to clarithromycin (four had ErmB with high-level resistance and one had MefA efflux with intermediate-level resistance). All five pneumococcal isolates classified as resistant to clarithromycin by in vitro susceptibility testing were eradicated; and patients were clinical cures when treated with clarithromycin ER. One additional ErmB-containing S. pneumoniae was included in the intent-to-treat population of the clarithromycin ER group; this isolate was also eradicated and the patient was a clinical cure. The eradication of H. influenzae was 100% for clarithromycin ER and 95% for amoxicillin/ clavulanate.
Table 2. Target pathogen isolation rates compared by culture method (intent-to-treat population)
Table 3. Target pathogen eradication rate at the test-of-cure visit in clinically and bacteriologically evaluable patients
Table 4. Clinical, bacteriological, and radiological responses
Efficacy was also evaluated at the follow-up visit based on change from baseline radiographie findings. Resolution or improvement in these findings was observed in 94% (172/183) of patients in both the clarithromycin ER and amoxicillin/ clavulanategroups (95% CI forthe difference in success rates [- 4.9%, 4.9%]). The radiological success rates were also unaffected by prognostic risk factor.
Symptomatic improvement or relief was observed as early as 2 days- 5 days after the initiation of the study drug. At the first assessment, the majority of clinically evaluable patients had experienced resolution or improvement in the primary presenting signs/symptoms of acute sinusitis, with selected statistically significant differences favoring clarithromycin ER: A significantly higher proportion of clarithromycin-ER treated patients reported improvement/resolution of nasal congestion (p = 0.035) and resolution of sinus pressure (p = 0.027). At the test-of-cure visit, the resolution/improvement rate for each treatment group was > 94% for the primary acute sinusitis signs/symptoms in clinically evaluable patients, with a statistically significantly higher rate of resolution/ improvement for purulent nasal discharge with clarithromycin ER (p = 0.010) (Table 5).
A decrease in nasal secretions over the course of the study, as estimated by tissue use, was observed with both treatment groups. Compared to the first collection period (day 2 and day 3), there was a 40% and 69% decrease in the use of tissues in both treatment groups during the second (day 6 and day 7) and third (day 13 and day 14) collection periods, respectively.
Quality of life, patient satisfaction, and health care resource utilization
According to the patients’ self-assessment of their symptoms, 92% of the clinical intent-to-treat patients stated they felt either ‘fair’ or ‘poor’ due to their sinusitis symptoms at baseline. At subsequent visits, increasing proportions of patients in both treatment groups indicated improvement, with 53% and 27% stating they felt ‘excellent’ and ‘very good’, respectively, at the follow- up visit. Rating their change from baseline at follow-up, 85% of patients reported being ‘much better’. Mean score for the S NOT-16 decreased from 1.6 in the clarithromycin ER group and 1.7 in the amoxicillin/clavulanate group at baseline to 0.2 in both groups at the follow-up visit.
Table 5. Rate of resolution or improvement in pretreatment signs and symptoms of acute sinusitis in clinically evaluable patients
Across the treatment groups at the follow-up visit, 80% of the clinical intent-to-treat patients were satisfied with the medication they received in the study, rating their satisfaction 5 or 6, with 78% satisfied enough to use the medication again. Patients’ use of health care resources related to sinusitis was very low during their participation in the study, with fewer physician and outpatient visits in the clarithromycin ER group (four patients in the clarithromycin ER group made six visits vs. 10 patients in the amoxicillin/clavulanate group who made 12 visits, p = 0.055).
Tolerability
The overall frequency of drug-related adverse events was 22% (48/ 221) and 20% (43/216) in the clarithromycin ER and amoxicillin/ clavulanate groups, respectively, with the majority of affected patients reporting events of either mild or moderate intensity. The most commonly reported drug-related adverse events were diarrhea (4% with clarithromycin ER and 6% with amoxicillin/ clavulanate), abnormal taste (11% and 1%, respectively, p
Less than 2% of patients in the clarithromycin ER group and 3% of patients in the amoxicillin\/clavulanate group discontinued therapy prematurely as a result of a drug-related adverse event (s): four patients in the clarithromycin ER group (one each with abnormal taste, nausea/vomiting, allergic reaction, and urticaria) and six patients in the amoxicillin/clavulanate group (one each with diarrhea, bloody diarrhea, dyspnea, abdominal pain/diarrhea, gastroenteritis, and headache/ hypertension). There were no clinically significant changes from baseline in hematology indices. A clinically significant increase, defined as three times the upper limit of normal, from baseline in transaminase level was observed at the post-treatment evaluation in two patients (one patient’s SGPT and one patient’s SGOT) in the amoxicillin/ clavulanate group (from within the reference range of 141IU/L and 172IU/L).
Discussion
The results of this multi-center, multi-country, randomized, investigator-blinded study demonstrate that clarithromycin ER administered once daily for 14 days is comparable to amoxicillin/ clavulanate administered twice daily for 14 days in patients with acute bacterial sinusitis. There was no difference between treatment groups in clinical response, with clinical cure rates of at least 97% in both groups. Likewise, clarithromycin ER and amoxicillin/ clavulanate were comparable (rates ≥ 94%) based on overall target pathogen eradication and radiological response. All five pneumococcal isolates classified as resistant to clarithromycin by in vitro susceptibility testing were eradicated and patients were clinical cures when treated with clarithromycin ER. The ability of clarithromycin to successfully eradicate organisms that are considered resistant by in vitro testing is likely associated with concentrations of clarithromycin that are higher in tissue and in white blood cells as compared to blood25 as well as the complexity of the relationship between the host’s immune response and the virulence of the pathogen.
In this study, the use of endoscopy, a less invasive culture method, yielded similar culture results as compared to the standard sinus puncture method. This is consistent with the findings of others: In a review by Benninger et al., there was 60%-85% concordance between results derived from endoscopically-guided middle meatal cultures and those from maxillary sinus (puncture) cultures26. Thus, the use of endoscopy may allow more frequent culture and identification of causative pathogens, leading to improved diagnosis and treatment of acute bacterial sinusitis. Clarithromycin ER was superior to amoxicillin/clavulanate based on differences in symptomatic response observed as early as 2days- 5days after the initiation of the study drug (improvement/ resolution of nasal congestion and resolution of sinus pressure) and at the test-of-cure visit (resolution/improvement of purulent nasal discharge).
Results across the patient-reported outcomes supported the effectiveness of both treatments. Based on patients’ responses to symptom assessment and SNOT-16, clarithromycin ER and amoxicillin/ clavulanate had a positive and rapid impact on quality of life. Using other tests of quality of life (i.e., Allergy Outcomes Survey, Rhinoconjunctivitis QOL Questionnaire, the Short Form 36 survey, instantaneous six-item Symptom Severity Survey, and a Visual Analogue Scale), Rechtweg et al. found clarithromycin-treated patients felt better more quickly, but were comparable to those treated with amoxicillin/clavulanate based on long-term (28 days) improvement in sinusitis symptoms”. Our patients reported a high level of satisfaction with and probability of using either study antibiotic again. This suggests that the patients felt that the reduction in symptoms greatly ameliorated the problems created by sinusitis. The efficacy of both study drugs was also demonstrated in very low health care resource utilization rates, with slightly fewer visits required by patients in the clarithromycin ER group.
Our clinical results are consistent with those from six recently conducted, randomized, double- or investigatorblinded studies of acute bacterial sinusitis, in which similar clinical results were observed when clarithromycin IR was compared to other agents (levofloxacin, gatifloxacin, ciprofloxacin, sparfloxacin, and cefuroxime axetil)12 ,i3,is,i7,)9,2o_ Bacteriological response was not assessed in any of these studies. There has been only one previous comparison of clarithromycin and amoxicillin/ clavulanate in patients with sinusitis. In a multi-center, randomized, single- blind study of almost 500 patients with acute maxillary sinusitis, Dubois et al. documented pathogen eradication rates of 87% and 90% and clinical success rates of 97% and 93% with clarithromycin and amoxicillin/clavulanate, respectively14. The pathogen eradication rate with clarithromycin ER in our study, conducted over a decade after the study of Dubois et al., shows no change over time in bacteriological efficacy. More recently, Murray et al. established comparability between the ER and IR formulations of clarithromycin based on only clinical endpoints in adults with acute maxillary sinusitis21. Across the studies, including our own, the most common adverse events involved the gastrointestinal tract12-15,17,19-21.
Conclusions
In this multinational population of patients with acute bacterial sinusitis, clarithromycin ER was comparable, and for selected measures superior, to amoxicillin/clavulanate, an agent recommended for first-line therapy, based on clinical, bacteriological, and radiological responses as well as quality of life measures, satisfaction with antibiotic therapy, and health care resource utilization.
Acknowledgments
This study was supported by a grant from Abbott Laboratories, Abbott Park, IL,USA.
We wish to acknowledge the following investigators who enrolled patients in this study:
Canada: I. Dan Dattani, Saskatoon, Saskatchewan; Benjamin Lasko, Toronto, Ontario; Donald Rhodes, Kitchener, Ontario; Claude St- Pierre, Sherbrooke, Quebec.
Greece: Harry Bassaris, Patra; Dimitrios Ganetsos, Athens; Efstratios Moschovakis, Piraeus; Paul Nikolaidis, Thessaloniki.
Hungary: Istvan Gati, Veszprem; Peter Halmos, Salgtotarjan; Livia Hende, Szombathely; Janos Huszka, Budapest; Mihaly Kisely, Szombathely; Laszlo Paput, Budapest; Peter RasonyiKovacs, Budapest; Hajnalka Szabadka, Budapest.
Italy: Eugenio Mira, Pavia; Eugenio Pallestrini, Geneva; Agostino Serra, Catania.
Lithuania: Romas Kasinkas, Vilnius; Jonas Laimutis Martinkenas, Vilnius; Kestutis Povilaitis, Kaunas; Virgilijus S akalinskas, Vilnius.
Poland: Stanislaw Betlejewski, Bydgoszcz; Stanislaw Chodynicki, Bialystok; Wieslaw Golabek, Lublin; Jacek Iwko, Gilwice; Pawel Kubik, Jelenia Gora; Wojciech Mikulewicz, Wroclaw; Krzysztof Prs, Wroclaw; Zbigniew Swierczynski, Bielsko-Biala.
Romania: Florian Bucovici, Bucharest; Romeo Calarasu, Bucharest; Constantin Mocanu, Bucharest; Dorin Sarafoleanu, Bucharest.
Spain: Manuel Bernai, Barcelona; Ignacio Cobeta, Madrid; Miguel Angel Diez, Vallodolid; Emilio Salguero, Badajoz; Manuel Tomas, Palma de Mallorca.
USA: Patricia Buchanan, Eugene, OR; Wayne Gilbert, Johnson City, TN; Trevor Goldberg, Charlotte, NC; C. Scott Horn, San Antonio, TX; Frank Mazzone, San Luis Obispo, CA; Donald L. McNeil, Jr., Columbus, OH; Paul M. Obert, Birmingham, AL; Kevin Wingert, Clovis, CA.
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CrossRef links are available in the online published version of this paper: http://www.cmrojournal.com
Paper CMRO-2837_4, Accepted for publication: 24 November 2004
Published Online: 21 December 2004
doi: 10.1185/030079904X18009
Ernie Riffer(a), Joy Spiller(b), Robert Palmer(b), Virginia Shortridge(b), Todd A. Busman(b) and Joaquin Valdes(b)
a Central Phoenix Medical Clinic, Phoenix, AZ, USA
b Abbott Laboratories, North Chicago, IL, USA
Address for correspondence: Dr Ernie Riffer, Central Phoenix Medical Clinic, 4747 N. 7th Street, Suite 100, Phoenix, AZ 85014, USA. Tel.: +1 602 200 3814; Fax: +1 602 200 3839; email: [email protected]
Copyright Librapharm Jan 2005
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