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Comparison of the effectiveness of levofloxacin and amoxicillin-clavulanate for the treatment of acute sinusitis in adults
Comparison of the effectiveness of levofloxacin and amoxicillin-clavulanate for the treatment of acute sinusitis in adults JEFFREY ADELGLASS, MD, C. ANDREW DEABATE, MD, PHILLIP MCELVAINE, MD, CYNTHIA L. FOWLER, MD, JOHN LOCOCCO, and THERESA CAMPBELL, MS, Dallas and El Paso, Texas, New Orleans, Louisiana, and Raritan, New Jersey
In this comparative trial, outpatients with acute sinusitis were randomly assigned to receive levofloxacin (500 mg orally once daily) or amoxicillinclavulanate (500/125 mg orally 3 times daily) for 10 to 14 days. The success rates (cured and improved) 2 to 5 days after the end of treatment were 88.4% for the 267 clinically evaluable patients who received levofloxacin and 87.3% for the 268 clinically evaluable patients who received amoxicillin-clavulanate. Drug-related adverse events occurred in a smaller percentage of patients in the levofloxacin treatment group (7.4%) than in the amoxicillinclavulanate treatment group (21.2%). The most common of these were nausea, diarrhea, vaginitis, and abdominal pain for levofloxacin-treated patients and diarrhea, vaginitis, nausea, genital moniliasis, abdominal pain, vomiting, and flatulence for amoxicillin-clavulanate–treated patients. The results of this study show that once-daily administration of levofloxacin is as effective and better tolerated than amoxicillin-clavulanate administered 3 times daily for treating acute sinusitis in adult outpatients. (Otolaryngol Head Neck Surg 1999;120:320-7.)
Acute sinusitis is a common clinical disorder among adult patients seen in general medical practice and usually occurs as a result of sinus ostia obstruction associated with an upper respiratory viral infection or allergies.1,2 Presenting signs and symptoms of acute sinusiFrom Research Across America, Dallas, (Dr Adelglass); Medical Research Center, New Orleans (Dr DeAbate); and The R.W. Johnson Pharmaceutical Research Institute, Raritan (Dr Fowler, Mr LoCocco, and Ms Campbell). Dr McElvaine is in private practice in El Paso, TX. This study was supported by The R.W. Johnson Pharmaceutical Research Institute. Presented at the Annual Meeting of the Infectious Diseases Society of America, New Orleans, LA, September 1996. Reprint requests: Jeffrey Adelglass, MD, RHD Professional Plaza, 9 Medical Parkway, Plaza 4, Suite 202, Dallas, TX 75234. Copyright © 1999 by the American Academy of Otolaryngology– Head and Neck Surgery Foundation, Inc. 0194-5998/99/$8.00 + 0 23/1/91406 320
tis can include facial pain, maxillary toothache, purulent nasal discharge, nasal obstruction, fever, cough, headache, halitosis, and sinus tenderness. The pathogens isolated most frequently from adults with acute sinusitis are Streptococcus pneumoniae and Haemophilus influenzae.1,3,4 Other pathogens cultured from patients with sinusitis include Moraxella catarrhalis and Staphylococcus aureus.4 Antibiotic therapy is the mainstay of treatment for acute sinusitis; adjunctive therapy can include decongestants and saline or steroid nasal sprays.3 Because identification of the pathogen associated with an episode of acute sinusitis requires antral puncture or nasal endoscopy to obtain an uncontaminated specimen for culture, the diagnosis is often presumptive without microbiologic confirmation and the treatment empiric. Complicating this empiric approach to the treatment of acute sinusitis is the increasing prevalence of penicillinase- and β-lactamase–producing strains of H influenzae and M catarrhalis and penicillin-resistant strains of S pneumoniae. The narrowing spectrum of activity of older antimicrobials for empiric therapy has propelled the search for more effective antibiotics with broadspectrum activity against respiratory pathogens. Any antibiotic chosen for the treatment of acute sinusitis should have known activity against resistant strains of the common pathogens. Levofloxacin, a new fluoroquinolone antimicrobial, is the l-isomer of the racemic compound ofloxacin, and accounts for most of the microbiologic activity of ofloxacin.5,6 Levofloxacin shows excellent in vitro activity against most aerobic gram-positive and gramnegative organisms, including the common upper respiratory pathogens S pneumoniae, H influenzae, M catarrhalis, and S aureus.5,6 Furthermore, levofloxacin demonstrates excellent in vitro activity against penicillin-sensitive, penicillin-intermediate, and penicillinresistant pneumococci.7-9 Levofloxacin demonstrates almost 100% bioavailability after oral administration and is widely distributed throughout the body.10 Mean concentrations in most tissues are higher than mean plasma concentrations after oral administration.5 Levofloxacin is excreted renally, and the elimination half-life is approximately 7 hours. These pharmacoki-
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netic characteristics, coupled with good in vitro activity, support the administration of levofloxacin as a single once-daily oral dose. The purpose of this study was to compare the efficacy and safety of levofloxacin 500 mg administered orally once daily for 10 to 14 days with those of amoxicillinclavulanate 500/125 mg administered orally 3 times daily for 10 to 14 days in treating acute sinusitis in adult outpatients. Amoxicillin-clavulanate is a first-line choice in treating acute sinusitis because of its broad spectrum of activity and its efficacy against β-lactamase–producing bacteria.3,4 The design of this study follows recommendations of the Infectious Diseases Society of America and the US Food and Drug Administration.11 METHODS AND PATIENTS Patient Selection The study design called for enrollment of approximately 490 male and female outpatients aged 18 years or older with acute sinusitis. A diagnosis of acute sinusitis was based on the presence of at least 2 of 5 typical clinical signs and symptoms (ie, fever, headache, purulent nasal discharge, facial pain, or malar tenderness) and radiographic evidence. Radiographic evidence included air-fluid level, opacification, or ≥4 mm mucosal thickening of at least 1 sinus on sinus x ray, CT, or sinus scope, with the vast majority of patients having x ray. Patients with a history of allergic or serious adverse reaction to levofloxacin or to any quinolone or β-lactam antimicrobial agent were excluded from the study. Also excluded were patients with known HIV infection or chronic sinusitis. Chronic sinusitis was defined as duration of current symptoms for more than 4 weeks or more than 2 other episodes of acute sinusitis within the previous 12 months. Patients who required a nonstudy systemic antimicrobial agent or who had received any investigational agent within 30 days were also ineligible for the study. The other exclusion criteria were as follows: presence of any disorder or disease that might interfere with evaluation of the study drug; receipt of previous treatment under this protocol; pregnancy (or inability to rule out pregnancy) or breast feeding; and presence of a seizure disorder or other condition necessitating the administration of major tranquilizers. Potential patients with calculated creatinine clearances of 20 mL/minute or less at the screening visit were excluded from the study; however, patients found on screening tests to have calculated creatinine clearances between 20 and 50 mL/minute could receive the study drug at an adjusted dosage. Patients who had received previous antibiotic therapy could be enrolled if therapy had lasted less than 24 hours and if the patient had not responded clinically, or if the responsible pathogen was known to be resistant to the previous therapy. All patients signed an informed consent document on
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study enrollment, and the study protocol was approved by the institutional review board of each participating center. Study Design This was a multicenter, randomized, open-label comparative study that included 28 centers throughout the United States. Patients were enrolled by both office-based primary care physicians and otolaryngologists. At the screening visit, patients who met study entry criteria provided a detailed medical history and underwent a physical examination, vital sign measurements, sign and symptom evaluation, and clinical laboratory testing (hematology, serum biochemical analysis, urinalysis, and for women of childbearing potential, a pregnancy test). Patients were then randomly assigned to receive either levofloxacin or amoxicillin-clavulanate for 10 to 14 days, as clinically indicated. Patients assigned to the levofloxacin treatment group with normal renal function received one 500 mg tablet once daily. Patients with creatinine clearances of 50 mL/minute received an initial loading dose of 500 mg levofloxacin followed by 500 mg every 48 hours. Patients assigned to the amoxicillin-clavulanate treatment group received one 500/125 mg tablet every 8 hours; the dosage was adjusted in accordance with package insert instructions for patients with renal impairment. The duration of therapy could be extended beyond 14 days if medically justified; the decision to extend therapy was made between days 10 and 14 of therapy. Levofloxacin was supplied by The R.W. Johnson Pharmaceutical Research Institute (Raritan, NJ) as 500 mg tablets and as 125 mg tablets, the latter for renally impaired patients. Amoxicillin-clavulanate was supplied as tablets containing 500 mg of amoxicillin as the trihydrate and 125 mg of clavulanic acid as the potassium salt (Augmentin; SmithKline Beecham Pharmaceuticals, Philadelphia, PA). The use of antihistamines and decongestants to facilitate sinus drainage during the study was encouraged. However, the use of other medications during the study was to be minimized, particularly aluminum- or magnesium-based antacids, mineral supplements, and vitamins with iron or minerals because of their potential to decrease bioavailability of levofloxacin. If administration of an antacid was necessary, it was to be administered at least 2 hours before or after study drug administration. The use of nonstudy systemic antimicrobials during the study was prohibited. All patients were contacted by telephone during therapy (study days 3 to 6). Patients showing clinical improvement continued therapy. Patients not showing clinical improvement were reexamined, removed from the study drug, and treated with alternative therapy as medically indicated; a sinus aspirate for Gram’s stain and culture was obtained at the discretion of the investigator. The treatment was deemed to have failed clinically in these patients. Patients with symptoms persisting at day 10 were seen
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before the end of therapy; those considered to be improving but in need of further therapy continued taking the study drug. A posttherapy visit was scheduled for all enrolled patients 2 to 5 days after therapy or on early withdrawal for patients discontinuing the study. A final poststudy contact was made, either by telephone or as an office visit, 28 to 32 days after completion of therapy to assess relapse. Evaluation of Efficacy Efficacy evaluations included assessment of clinical signs and symptoms, radiographic findings, and an overall clinical response rating. The primary efficacy variable was clinical response at the posttherapy visit 2 to 5 days after the completion of therapy. The clinical cure rate was defined as the percentage of clinically evaluable patients who were cured, and the clinical success rate was defined as the percentage of clinically evaluable patients who were cured or improved. Clinical signs and symptoms were assessed on admission to the study, at the posttherapy office visit 2 to 5 days after the end of therapy, and at the poststudy contact 28 to 32 days after the end of therapy. The presence or absence of clinical signs and symptoms of acute sinusitis (ie, facial pain, headache, fever, purulent nasal discharge, and malar tenderness) was recorded. In addition, these signs and symptoms were assessed (but not recorded) at the telephone contact on days 3 to 6 of therapy to determine whether they had improved sufficiently for the patient to continue in the study. Radiographic studies were done on admission, at the posttherapy office visit 2 to 5 days after the end of therapy, and in patients with suspected relapse, again 28 to 32 days after completion of therapy. Radiographic findings were assessed as resolved, improved, worsened, or unchanged. The patient’s clinical response was determined at the posttherapy and poststudy evaluations. The assessment at the posttherapy evaluation constituted the primary efficacy variable, and this was made in the following terms: cured (disappearance of signs and symptoms with radiographic evidence of stabilization or improvement and no further therapy required); improved (incomplete resolution of signs, symptoms, and radiographic signs but no further therapy required); failed (no clinical response to therapy); or unable to evaluate (patient did not return for follow-up evaluation). For patients who discontinued the study early for reasons other than treatment failure, an evaluation of improved was defined as resolution of sinusitis with the expectation that, had therapy continued, therapy would have been successful. Patients with a successful clinical responses at the posttherapy visit, namely, those assessed as cured or improved, had a second clinical response assessment at the final poststudy evaluation. The second clinical response was rated as follows: cured (complete resolution of signs and symptoms); improved (continued incomplete resolution of signs and symptoms with no deterioration or relapse during the follow-up period and no further antibiotic therapy
required); relapse (resolution or improvement of signs and symptoms at the posttherapy visit but reappearance or deterioration of signs and symptoms of the infection at the poststudy visit); or unevaluable (no poststudy evaluation). Evaluation of Safety Safety evaluations were performed between the first dose of study drug through the initial posttherapy visit and included the recording of treatment-emergent adverse events, laboratory tests, and physical examination findings. Adverse events were graded as mild, moderate, or marked and as having no relation or a remote, possible, probable, or definite relation to study drug administration. Adverse events that were considered to be definitely or probably related to the study drug were termed drug related. Adverse events were recorded for up to 30 days after cessation of therapy. Laboratory tests, physical examinations, and vital sign measurements were performed on admission to the study and at the posttherapy visit 2 to 5 days after the end of therapy. The laboratory tests included a complete blood count, platelet count, serum biochemistry analysis, and urinalysis with microscopic examination of sediment. Vital sign measurements included oral temperature, respiration and pulse rates, and blood pressure. Methods of Analysis Treatment comparisons were based on 3 analysis groups: the intent-to-treat patients (all enrolled patients), the modified intent-to-treat patients (all enrolled patients according to drug actually received), and clinically evaluable patients. To be clinically evaluable, a patient had to be evaluable for safety, have a confirmed clinical diagnosis of acute sinusitis, have received at least 7 days of therapy, have followed the protocol, and have a posttherapy clinical evaluation within 2 to 10 days after ending study drug therapy. Demographic characteristics were tabulated by treatment for each analysis group. A 2-sided Student’s t test for 2 independent samples was used to compare mean ages of men, women, and both sexes combined. A 2-sided Fisher’s exact test was used to compare the proportions of men and of white patients. Clinical response to treatment of the clinically evaluable patients was the primary efficacy variable. A dichotomous analysis was performed by combining the clinical response categories of cured and improved into 1 category of clinical success. A 2-sided 95% confidence interval around the difference in clinical success rates (amoxicillin-clavulanate minus levofloxacin) between the 2 treatment groups was the basis for assessing therapeutic equivalence. Finally, summaries were made of poststudy clinical response rates for patients who were cured or improved after therapy. Changes in signs and symptoms of acute sinusitis from admission to posttherapy were recorded for clinically evaluable and modified intent-to-treat patients; from these, the per-
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Table 1. Demographic and baseline characteristics of modified intent-to-treat patients
Table 2. Patient disposition Treatment group
Treatment group
Sex Male Female Race White Black Asian Hispanic Other Age (y) Mean ± SD Range Weight (kg) Mean ± SD Range Height (cm) Mean ± SD Range
Levofloxacin (N = 306)
Amoxicillinclavulanate (N = 309)
Total patients (N = 615)
115 (38%) 191 (62%)
110 (36%) 199 (64%)
225 (37%) 390 (63%)
220 (72%) 44 (14%) 3 (1%) 37 (12%) 2 (0.7%)
229 (74%) 44 (14%) 1 (0.3%) 34 (11%) 1 (0.3%)
449 (73%) 88 (14%) 4 (0.7%) 71 (12%) 3 (0.5%)
39.2 ± 13.9 18–85 (n = 302) 78.9 ± 19.7 44.5–158.8 (n = 301) 169 ± 10 142–193
38.6 ± 12.8 18–84 (n = 304) 75.7 ± 18.4 43.5–158.6 (n = 307) 169 ± 10 135–198
38.9 ± 13.4 18–85 (n = 606) 77.3 ± 19.1 43.5–158.8 (n = 608) 169 ± 10 135–198
centages of patients with resolution of clinical signs and symptoms were calculated for clinically evaluable patients. Treatment-emergent adverse events were summarized by body system, primary term, and severity. Summary statistics for clinical laboratory test results were calculated for the values of the analyses at admission and after therapy and for the mean changes from admission to posttherapy. The KolmogorovSmirnov test was performed on percentage changes in laboratory test results from admission to posttherapy. Mean changes in vital signs from admission to posttherapy were calculated for each treatment group and tabulated. RESULTS Patients
In total 615 patients, 307 of whom were randomly assigned to receive levofloxacin and 308 who received amoxicillin-clavulanate, were enrolled at 28 centers. One patient assigned to the levofloxacin treatment group received amoxicillin-clavulanate instead; therefore 306 and 309 patients were in the modified intentto-treat groups for levofloxacin and amoxicillin-clavulanate, respectively. In total 267 (87.3% of enrolled) and 268 (86.7% of enrolled) patients, respectively, were considered clinically evaluable; 297 (97.1%) and 302 (97.7%) patients, respectively, were considered evaluable for safety. The demographic characteristics of the 2 treatment groups were statistically comparable for all analysis groups; these are summarized in Table 1 for the
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Reason for discontinuation
Levofloxacin (N = 306)
Amoxicillinclavulanate (N = 309)
Adverse event Clinical failure Personal reason Other Total patients discontinued Total with known disposition information Total lost to follow-up
11 (3.8%) 6 (2%) 2 (0.7%) 2 (0.7%) 21 (7.2%) 293 (100%)
16 (5.3%) 6 (2%) 1 (0.3%) 4 (1.3%) 27 (9%) 301 (100%)
13
8
Percentages are of patients with known disposition information.
Table 3. Incidence of drug-related adverse events reported by 1% or more of patients in 1 or both treatment groups Treatment group
Levofloxacin (N = 297)
Nausea Diarrhea Abdominal pain Vaginitis* Genital moniliasis* Flatulence Vomiting
5 (1.7%) 4 (1.3%) 3 (1.0%) 2 (1.1%) 2 (0.7%) 1 (0.3%) 0
Amoxicillinclavulanate (N = 302)
12 (4.0%) 35 (11.6%) 5 (1.7%) 8 (4.1%) 10 (3.3%) 4 (1.3%) 5 (1.7%)
*Percentages calculated from the total number of women in each treatment group.
modified intent-to-treat patients. The mean age of all patients was 39 years (range 18 to 85 years); 63% were women, and 73% were white. All those considered clinically evaluable underwent 1 of the following radiographic procedures: sinus x ray, CT, or sinus scope. The vast majority—98.1% (262 of 267) in the levofloxacin arm and 97.8% (262 of 268) in the amoxicillin-clavulanate arm—had sinus x rays. Five patients in the levofloxacin treatment group and 5 patients in the amoxicillin-clavulanate group had CT; sinus scope was the radiographic procedure for 1 patient from the amoxicillin-clavulanate group. In the levofloxacin treatment group, 272 of 306 (88.9%) enrolled patients completed therapy, 21 (6.9%) patients discontinued therapy prematurely, and 13 (4.2%) patients were lost to follow-up. In the amoxicillin-clavulanate treatment group, 274 of 309 (88.7%) enrolled patients completed therapy, 27 (8.7%) patients discontinued therapy prematurely, and 8 (2.6%) patients
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Fig 1. Clinical response to therapy for clinically evaluable patients.
were lost to follow-up. The most common reason for premature discontinuation in both treatment groups was an adverse event. Patient disposition is summarized in Table 2. The mean duration of therapy was 13 days (range 1 to 22 days) for levofloxacin-treated patients and 12 days (range 1 to 23 days) for amoxicillin-clavulanate–treated patients; the median durations were 14 and 12 days, respectively. Efficacy Clinical efficacy. The clinical response to therapy was similar for the 2 treatment groups at the posttherapy evaluation 2 to 5 days after the end of treatment. Among clinically evaluable patients in the levofloxacin treatment group, 156 of 267 (58.4%) were cured and 80 of 267 (30%) improved, compared with 157 of 268 (58.6%) and 77 of 268 (28.7%) in the amoxicillinclavulanate treatment group. Treatment failed in 31 patients (11.6%) in the levofloxacin treatment group and 34 patients (12.7%) in the amoxicillin-clavulanate treatment group (Fig 1). Among clinically evaluable patients, levofloxacin treatment resulted in 88.4% clinical success (cured plus improved), and amoxicillin-clavulanate treatment resulted in 87.3% clinical success, with a 95% confidence interval of [–6.8, 4.6] around the difference (amoxicillin-clavulanate minus levofloxacin) in success rates. Results were consistent across study centers, analysis groups, and various sex, age, and race subgroups. Of the 233 levofloxacin-treated patients who were cured or improved at the posttherapy evaluation and who had a poststudy evaluation approximately 4 weeks later, only 5 (2.1%) had relapsed by the poststudy evaluation, including 2 of the 154 (1.3%) who had been cured and 3 of the 79 (3.8%) who had improved. Among 231 amoxicillin-clavulanate–treated patients
who were cured or improved at the posttherapy evaluation, 9 (3.9%) had relapsed, including 3 of 155 (1.9%) who had been cured and 6 of the 76 (7.9%) who had been improved at the posttherapy evaluation. At the initial posttherapy evaluation, each of the 5 clinical signs and symptoms of sinusitis was resolved in 80% to 100% of patients in both treatment groups in which it was reported on admission (Fig 2). Of 262 clinically evaluable levofloxacin-treated patients with abnormal admission radiographic findings who underwent posttherapy radiographic examination at the 2- to 5-day posttherapy visit, 215 (82.1%) showed either resolution (35.9%) or improvement (46.2%). Similarly, of 262 clinically evaluable amoxicillin-clavulanate–treated patients, 215 (82.1%) showed either resolution (35.5%) or improvement (46.6%). Microbiology. Sinus cultures were obtained from 4 of 65 patients in whom therapy failed. No pathogen was grown on 3 cultures; Haemophilus aphrophilus, Eikenella corrodens, and Streptococcus milleri, all susceptible to both study drugs, grew in the fourth, which was from an amoxicillin-clavulanate–treated patient. Safety
Drug-related adverse events were reported by a smaller percentage of patients in the levofloxacin treatment group (7.4%) than in the amoxicillin-clavulanate treatment group (21.2%). Drug-related adverse events reported by 1% or more of levofloxacin-treated patients were nausea (1.7%), diarrhea (1.3%), vaginitis (1.1%), and abdominal pain (1%). Drug-related adverse events reported by 1% or more of amoxicillin-clavulanate– treated patients were diarrhea (11.6%), vaginitis (4.1%), nausea (4%), genital moniliasis (3.3%), abdominal pain (1.7%), vomiting (1.7%), and flatulence (1.3%) (Table 3). Adverse events, regardless of relationship to study drug, were reported by 114 levofloxacin-treated patients (38.4%) and 146 amoxicillin-clavulanate–treated patients (48.3%) (P < 0.05). Most adverse events were assessed as mild or moderate in severity. Of 22 patients with adverse events considered to be marked in severity, 7 were in the levofloxacin treatment group and 15 were in the amoxicillin-clavulanate treatment group. Of 9 patients with marked drug-related adverse events, 3 were in the levofloxacin treatment group and experienced abdominal pain and diarrhea, constipation, and urticaria, while 6 were in the amoxicillin-clavulanate treatment group, all of whom experienced gastrointestinal (GI) tract–related symptoms (eg, abdominal pain, nausea, or diarrhea). Twenty-seven patients discontinued the study because of adverse events, 11 patients (3.7%) in the levofloxacin treatment group and 16 patients (5.3%) in the amoxi-
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Fig 2. Percentages of clinically evaluable patients with resolution at the posttherapy evaluation of clinical signs or symptoms that were present on admission to the study.
cillin-clavulanate treatment group. In the levofloxacin group, those who discontinued because of adverse events included 4 patients with urticaria, rash, or pruritus; 4 patients with GI tract–related adverse events; 1 patient with both skin and GI tract–related adverse events; and 1 patient each with asthenia-dizziness and symptoms of influenza. In the amoxicillin-clavulanate treatment group, all adverse event discontinuations were because of GI tract–related symptoms, except for 1 instance of fatigue. No serious drug-related events or deaths occurred during the study. Clinically significant treatment-emergent changes in clinical laboratory tests occurred infrequently and were comparable across treatment groups. No clinically significant treatment-emergent changes in physical examination findings or vital signs were found in either treatment group. DISCUSSION
The findings of this multicenter study demonstrate that the once-daily administration of levofloxacin 500 mg was as effective as 3 times daily administration of amoxicillin-clavulanate 500/125 mg in treating acute sinusitis in adult outpatients. The clinical success rate (cured or improved) for the clinically evaluable patients at the posttherapy evaluation 2 to 5 days after the end of therapy was high for both drugs: 88.4% for levofloxacin and 87.3% for amoxicillin-clavulanate. Treatment failed in 31 patients (11.6%) in the levofloxacin treatment group and 34 patients (12.7%) in the amoxicillin-clavulanate treatment group. At a poststudy evaluation approximately 4 weeks later, 5 levofloxacin-treated
patients and 9 amoxicillin-clavulanate–treated patients had had a relapse in clinical signs and symptoms. Our results are among the first describing the clinical efficacy of levofloxacin in the treatment of acute sinusitis. Recently, the results of another multicenter trial of levofloxacin (500 mg once daily) given for 10 to 14 days12 demonstrated similar results to those observed in our study. Of 300 clinically evaluable patients, 175 (58%) were cured and 90 (30%) were improved at the posttherapy evaluation, resulting in a clinical success rate of 88%. The microbiologic eradication rate among 138 microbiologically evaluable patients was 92%. In a published study of Japanese patients with acute sinusitis, investigators reported bacteriologic eradication rates of 93% for gram-positive pathogens, 92% for gramnegative pathogens, and 100% for anaerobes. These excellent responses were observed despite the use of a short-term, low-dose course of therapy (300 mg total daily dose for 3 days).13 These results with levofloxacin in the treatment of acute sinusitis correlate with efficacy results from trials with other oral antibiotics for the treatment of this infection. Ferguson3 summarized selected studies of antibiotic therapy in acute sinusitis, and efficacy results ranged from 74% to 95%. Evaluation of new agents for the treatment of sinusitis is important because of the emerging problem of resistance of common respiratory pathogens (eg, S pneumoniae and H influenzae) to traditional antimicrobial agents. Resistance of antibiotics to β-lactamases and activity against penicillin-resistant S pneumoniae are now primary considerations in the choice of an
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agent for treating acute sinusitis. Levofloxacin has been shown to have good in vitro activity against common respiratory pathogens, including β-lactamase–producing strains of H influenzae and M catarrhalis, as well as penicillin-resistant strains of S pneumoniae.7-9 The MIC90 for levofloxacin is 1.0 µg/mL against S pneumoniae, 0.015 µg/mL against H influenzae, and 0.03 µg/mL against M catarrhalis.7,14 There are limited data on the use of other quinolones for the treatment of acute sinusitis. Two Japanese studies showed good results with ofloxacin; however, the numbers of patients treated were small (n = 13, n = 5).15 The limited data for the treatment of sinusitis with commercially available quinolones may in part be the result of poor activity of some quinolones against S pneumoniae. However, levofloxacin has been shown to have good in vitro activity against S pneumoniae, including penicillin-sensitive and penicillin-resistant strains. 7-9 More importantly, levofloxacin has been shown to be effective in treating patients with infections caused by S pneumoniae. In 2 multicenter trials evaluating the use of levofloxacin for the treatment of patients with community-acquired pneumonia, the clinical success rates (patients cured or improved) were 100% in both trials for patients with S pneumoniae infections.16,17 Similarly, in 2 multicenter trials evaluating the efficacy of levofloxacin for the treatment of patients with acute exacerbations of chronic bronchitis, the clinical success rates were 88% and 90% for patients with S pneumoniae infections.18,19 The combination of amoxicillin and clavulanic acid has a broad spectrum of activity that includes many upper respiratory tract pathogens; however, most penicillin-resistant S pneumoniae isolates are also resistant to amoxicillin in vitro.20 Amoxicillin-clavulanate has been shown to be effective for the treatment of acute sinusitis and thus is a common comparator in clinical trials of new antimicrobial agents for the treatment of acute sinusitis.21-23 Reported clinical success rates (cure or improvement) for acute sinusitis after treatment with amoxicillin-clavulanate were 93% in one study21 and 88% in a second study,22 similar to the results in the present study. Reported microbiologic eradication rates with amoxicillin-clavulanate were 90% in the first study21 and 92% in a third study.4 A drawback of treatment with amoxicillin-clavulanate is the high incidence of drug-related GI side effects, particularly diarrhea and nausea, which were reported by 11.6% and 4%, respectively, of patients in the amoxicillin-clavulanate treatment group in this study. By comparison, levofloxacin was better tolerated, with the most common drug-related adverse events occurring in only 1.7% (nausea) and 1.3% (diarrhea) of
levofloxacin-treated patients. However, since the completion of this study, a new formulation of amoxicillinclavulanate has become available that may be better tolerated than the original formulation and can be administered twice daily. The results of this study show that once-daily administration of levofloxacin is as effective and better tolerated than 3 times daily administration of amoxicillinclavulanate in treating acute sinusitis in adult outpatients. Additionally, levofloxacin is associated with the convenience of once-daily administration versus 3 times daily administration of amoxicillin-clavulanate. REFERENCES 1. Diaz I, Bamberger DM. Acute sinusitis. Semin Respir Infect 1995;10:14-20. 2. Williams JW Jr, Simel DL. Does this patient have sinusitis? Diagnosing acute sinusitis by history and physical examination. JAMA 1993;270:1242-6. 3. Ferguson BJ. Acute and chronic sinusitis. How to ease symptoms and locate the cause. Postgrad Med 1995;97:45-57. 4. Gwaltney JM Jr, Scheld WM, Sande MA, et al. The microbial etiology and antimicrobial therapy of adults with acute communityacquired sinusitis: a fifteen-year experience at the University of Virginia and review of other selected studies. J Allergy Clin Immunol 1992;90(Suppl):457-62. 5. Davis R, Bryson HM. Levofloxacin. A review of its antibacterial activity, pharmacokinetics and therapeutic efficacy. Drugs 1994; 47:677-700. 6. Fu KP, Lafredo SC, Foleno B, et al. In vitro and in vivo antibacterial activities of levofloxacin (l-ofloxacin), an optically active ofloxacin. Antimicrob Agents Chemother 1992;36:860-6. 7. Eliopoulos GM, Wennersten CB, Moellering RC Jr. Comparative in vitro activity of levofloxacin and ofloxacin against gram-positive bacteria. Diagn Microbiol Infect Dis 1996;25:35-41. 8. Plouffe JF. Levofloxacin in vitro activity against bacteremic isolates of Streptococcus pneumoniae. Diagn Microbiol Infect Dis 1996;25:43-5. 9. Biedenbach DJ, Jones RN. The comparative antimicrobial activity of levofloxacin tested against 350 clinical isolates of streptococci. Diagn Microbiol Infect Dis 1996;25:47-51. 10. Chien SC, Rogge MC, Gisclon LG, et al. Pharmacokinetic profile of levofloxacin following once daily 500 mg oral or intravenous doses. Antimicrob Agents Chemother 1997;41:225660. 11. Chow AW, Hall CB, Klein JO. General guidelines for the evaluation of new anti-infective drugs for the treatment of respiratory tract infections. Clin Infect Dis 1992;15(Suppl 1):S62-88. 12. Sydnor TA, Kopp EJ, Anthony K, et al. An open-label assessment of the activity of levofloxacin for the treatment of acute bacterial sinusitis in adults. Presented at the Annual Meeting of the American College of Allergy, Asthma and Immunology; 1996 Nov 8; Boston (MA). 13. Baba S, Miyamoto N, Unno T, et al. Clinical evaluation of the effect of levofloxacin on sinusitis. Chemotherapy 1992;4(Suppl 3):365-78. 14. Cormican MG, Erwin ME, Marshall SA, et al. Susceptibility testing interpretive criteria for levofloxacin when testing respiratory pathogens, Haemophilus influenzae and Moraxella catarrhalis. Diagn Microbiol Infect Dis 1996;24:155-60. 15. Barza M. Pharmacokinetics and efficacy of the new quinolones in infections of the eye, ear, nose, and throat. Rev Infect Dis 1988;10(Suppl 1):S241-7. 16. Fogarty C, Sullivan JG, Chattman MS, et al. Once a day levofloxacin in the treatment of severe and mild to moderate community-acquired pneumonia in adults. Presented at the Infectious
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Diseases Society of America Annual Meeting; 1996 Sep; New Orleans (LA). 17. File TM, Segreti J, Dunbar L, et al. A multicenter, randomized study comparing the efficacy and safety of IV/PO levofloxacin vs ceftriaxone/cefuroxime axetil in the treatment of adults with community-acquired pneumonia. Antimicrob Agents Chemother 1997;41:1965-72. 18. DeAbate CA, Russell M, McElvaine P, et al. Safety and efficacy of oral levofloxacin versus cefuroxime axetil in acute bacterial exacerbation of chronic bronchitis. Respir Care 1997;42: 206-13. 19. Habib MP, Gentry LO, Rodriguez-Gomez G, et al. A multicenter, randomized study comparing the efficacy and safety of oral levofloxacin vs cefaclor in the treatment of acute bacterial exacerbations of chronic bronchitis. Presented at the 36th Interscience
20. 21. 22.
23.
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Conference on Antimicrobial Agents and Chemotherapy; 1996 Sep; New Orleans (LA). Esposito AL. Role of oral antimicrobial drugs in the treatment of respiratory tract infections: overview and summary of newer agents. Infect Dis Clin Pract 1995;4(Suppl 4):S250-8. Dubois J, Saint-Pierre C, Tremblay C. Efficacy of clarithromycin vs. amoxicillin/clavulanate in the treatment of acute maxillary sinusitis. Ear Nose Throat J 1993;72:804-10. DeAbate CA, Perrotta RJ, Dennington ML, et al. The efficacy and safety of once-daily ceftibuten compared with co-amoxiclav in the treatment of acute bacterial sinusitis. J Chemother 1992; 4:358-63. Legent F, Bordure P, Beauvillain C, et al. A double-blind comparison of ciprofloxacin and amoxycillin/clavulanic acid in the treatment of chronic sinusitis. Chemotherapy 1994;40(Suppl 1):8-15.
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In this comparative trial, outpatients with acute sinusitis were randomly assigned to receive levofloxacin (500 mg orally once daily) or amoxicillinclavulanate (500/125 mg orally 3 times daily) for 10 to 14 days. The success rates (cured and improved) 2 to 5 days after the end of treatment were 88.4% for the 267 clinically evaluable patients who received levofloxacin and 87.3% for the 268 clinically evaluable patients who received amoxicillin-clavulanate. Drug-related adverse events occurred in a smaller percentage of patients in the levofloxacin treatment group (7.4%) than in the amoxicillinclavulanate treatment group (21.2%). The most common of these were nausea, diarrhea, vaginitis, and abdominal pain for levofloxacin-treated patients and diarrhea, vaginitis, nausea, genital moniliasis, abdominal pain, vomiting, and flatulence for amoxicillin-clavulanate–treated patients. The results of this study show that once-daily administration of levofloxacin is as effective and better tolerated than amoxicillin-clavulanate administered 3 times daily for treating acute sinusitis in adult outpatients. (Otolaryngol Head Neck Surg 1999;120:320-7.)
Acute sinusitis is a common clinical disorder among adult patients seen in general medical practice and usually occurs as a result of sinus ostia obstruction associated with an upper respiratory viral infection or allergies.1,2 Presenting signs and symptoms of acute sinusiFrom Research Across America, Dallas, (Dr Adelglass); Medical Research Center, New Orleans (Dr DeAbate); and The R.W. Johnson Pharmaceutical Research Institute, Raritan (Dr Fowler, Mr LoCocco, and Ms Campbell). Dr McElvaine is in private practice in El Paso, TX. This study was supported by The R.W. Johnson Pharmaceutical Research Institute. Presented at the Annual Meeting of the Infectious Diseases Society of America, New Orleans, LA, September 1996. Reprint requests: Jeffrey Adelglass, MD, RHD Professional Plaza, 9 Medical Parkway, Plaza 4, Suite 202, Dallas, TX 75234. Copyright © 1999 by the American Academy of Otolaryngology– Head and Neck Surgery Foundation, Inc. 0194-5998/99/$8.00 + 0 23/1/91406 320
tis can include facial pain, maxillary toothache, purulent nasal discharge, nasal obstruction, fever, cough, headache, halitosis, and sinus tenderness. The pathogens isolated most frequently from adults with acute sinusitis are Streptococcus pneumoniae and Haemophilus influenzae.1,3,4 Other pathogens cultured from patients with sinusitis include Moraxella catarrhalis and Staphylococcus aureus.4 Antibiotic therapy is the mainstay of treatment for acute sinusitis; adjunctive therapy can include decongestants and saline or steroid nasal sprays.3 Because identification of the pathogen associated with an episode of acute sinusitis requires antral puncture or nasal endoscopy to obtain an uncontaminated specimen for culture, the diagnosis is often presumptive without microbiologic confirmation and the treatment empiric. Complicating this empiric approach to the treatment of acute sinusitis is the increasing prevalence of penicillinase- and β-lactamase–producing strains of H influenzae and M catarrhalis and penicillin-resistant strains of S pneumoniae. The narrowing spectrum of activity of older antimicrobials for empiric therapy has propelled the search for more effective antibiotics with broadspectrum activity against respiratory pathogens. Any antibiotic chosen for the treatment of acute sinusitis should have known activity against resistant strains of the common pathogens. Levofloxacin, a new fluoroquinolone antimicrobial, is the l-isomer of the racemic compound ofloxacin, and accounts for most of the microbiologic activity of ofloxacin.5,6 Levofloxacin shows excellent in vitro activity against most aerobic gram-positive and gramnegative organisms, including the common upper respiratory pathogens S pneumoniae, H influenzae, M catarrhalis, and S aureus.5,6 Furthermore, levofloxacin demonstrates excellent in vitro activity against penicillin-sensitive, penicillin-intermediate, and penicillinresistant pneumococci.7-9 Levofloxacin demonstrates almost 100% bioavailability after oral administration and is widely distributed throughout the body.10 Mean concentrations in most tissues are higher than mean plasma concentrations after oral administration.5 Levofloxacin is excreted renally, and the elimination half-life is approximately 7 hours. These pharmacoki-
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netic characteristics, coupled with good in vitro activity, support the administration of levofloxacin as a single once-daily oral dose. The purpose of this study was to compare the efficacy and safety of levofloxacin 500 mg administered orally once daily for 10 to 14 days with those of amoxicillinclavulanate 500/125 mg administered orally 3 times daily for 10 to 14 days in treating acute sinusitis in adult outpatients. Amoxicillin-clavulanate is a first-line choice in treating acute sinusitis because of its broad spectrum of activity and its efficacy against β-lactamase–producing bacteria.3,4 The design of this study follows recommendations of the Infectious Diseases Society of America and the US Food and Drug Administration.11 METHODS AND PATIENTS Patient Selection The study design called for enrollment of approximately 490 male and female outpatients aged 18 years or older with acute sinusitis. A diagnosis of acute sinusitis was based on the presence of at least 2 of 5 typical clinical signs and symptoms (ie, fever, headache, purulent nasal discharge, facial pain, or malar tenderness) and radiographic evidence. Radiographic evidence included air-fluid level, opacification, or ≥4 mm mucosal thickening of at least 1 sinus on sinus x ray, CT, or sinus scope, with the vast majority of patients having x ray. Patients with a history of allergic or serious adverse reaction to levofloxacin or to any quinolone or β-lactam antimicrobial agent were excluded from the study. Also excluded were patients with known HIV infection or chronic sinusitis. Chronic sinusitis was defined as duration of current symptoms for more than 4 weeks or more than 2 other episodes of acute sinusitis within the previous 12 months. Patients who required a nonstudy systemic antimicrobial agent or who had received any investigational agent within 30 days were also ineligible for the study. The other exclusion criteria were as follows: presence of any disorder or disease that might interfere with evaluation of the study drug; receipt of previous treatment under this protocol; pregnancy (or inability to rule out pregnancy) or breast feeding; and presence of a seizure disorder or other condition necessitating the administration of major tranquilizers. Potential patients with calculated creatinine clearances of 20 mL/minute or less at the screening visit were excluded from the study; however, patients found on screening tests to have calculated creatinine clearances between 20 and 50 mL/minute could receive the study drug at an adjusted dosage. Patients who had received previous antibiotic therapy could be enrolled if therapy had lasted less than 24 hours and if the patient had not responded clinically, or if the responsible pathogen was known to be resistant to the previous therapy. All patients signed an informed consent document on
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study enrollment, and the study protocol was approved by the institutional review board of each participating center. Study Design This was a multicenter, randomized, open-label comparative study that included 28 centers throughout the United States. Patients were enrolled by both office-based primary care physicians and otolaryngologists. At the screening visit, patients who met study entry criteria provided a detailed medical history and underwent a physical examination, vital sign measurements, sign and symptom evaluation, and clinical laboratory testing (hematology, serum biochemical analysis, urinalysis, and for women of childbearing potential, a pregnancy test). Patients were then randomly assigned to receive either levofloxacin or amoxicillin-clavulanate for 10 to 14 days, as clinically indicated. Patients assigned to the levofloxacin treatment group with normal renal function received one 500 mg tablet once daily. Patients with creatinine clearances of 50 mL/minute received an initial loading dose of 500 mg levofloxacin followed by 500 mg every 48 hours. Patients assigned to the amoxicillin-clavulanate treatment group received one 500/125 mg tablet every 8 hours; the dosage was adjusted in accordance with package insert instructions for patients with renal impairment. The duration of therapy could be extended beyond 14 days if medically justified; the decision to extend therapy was made between days 10 and 14 of therapy. Levofloxacin was supplied by The R.W. Johnson Pharmaceutical Research Institute (Raritan, NJ) as 500 mg tablets and as 125 mg tablets, the latter for renally impaired patients. Amoxicillin-clavulanate was supplied as tablets containing 500 mg of amoxicillin as the trihydrate and 125 mg of clavulanic acid as the potassium salt (Augmentin; SmithKline Beecham Pharmaceuticals, Philadelphia, PA). The use of antihistamines and decongestants to facilitate sinus drainage during the study was encouraged. However, the use of other medications during the study was to be minimized, particularly aluminum- or magnesium-based antacids, mineral supplements, and vitamins with iron or minerals because of their potential to decrease bioavailability of levofloxacin. If administration of an antacid was necessary, it was to be administered at least 2 hours before or after study drug administration. The use of nonstudy systemic antimicrobials during the study was prohibited. All patients were contacted by telephone during therapy (study days 3 to 6). Patients showing clinical improvement continued therapy. Patients not showing clinical improvement were reexamined, removed from the study drug, and treated with alternative therapy as medically indicated; a sinus aspirate for Gram’s stain and culture was obtained at the discretion of the investigator. The treatment was deemed to have failed clinically in these patients. Patients with symptoms persisting at day 10 were seen
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before the end of therapy; those considered to be improving but in need of further therapy continued taking the study drug. A posttherapy visit was scheduled for all enrolled patients 2 to 5 days after therapy or on early withdrawal for patients discontinuing the study. A final poststudy contact was made, either by telephone or as an office visit, 28 to 32 days after completion of therapy to assess relapse. Evaluation of Efficacy Efficacy evaluations included assessment of clinical signs and symptoms, radiographic findings, and an overall clinical response rating. The primary efficacy variable was clinical response at the posttherapy visit 2 to 5 days after the completion of therapy. The clinical cure rate was defined as the percentage of clinically evaluable patients who were cured, and the clinical success rate was defined as the percentage of clinically evaluable patients who were cured or improved. Clinical signs and symptoms were assessed on admission to the study, at the posttherapy office visit 2 to 5 days after the end of therapy, and at the poststudy contact 28 to 32 days after the end of therapy. The presence or absence of clinical signs and symptoms of acute sinusitis (ie, facial pain, headache, fever, purulent nasal discharge, and malar tenderness) was recorded. In addition, these signs and symptoms were assessed (but not recorded) at the telephone contact on days 3 to 6 of therapy to determine whether they had improved sufficiently for the patient to continue in the study. Radiographic studies were done on admission, at the posttherapy office visit 2 to 5 days after the end of therapy, and in patients with suspected relapse, again 28 to 32 days after completion of therapy. Radiographic findings were assessed as resolved, improved, worsened, or unchanged. The patient’s clinical response was determined at the posttherapy and poststudy evaluations. The assessment at the posttherapy evaluation constituted the primary efficacy variable, and this was made in the following terms: cured (disappearance of signs and symptoms with radiographic evidence of stabilization or improvement and no further therapy required); improved (incomplete resolution of signs, symptoms, and radiographic signs but no further therapy required); failed (no clinical response to therapy); or unable to evaluate (patient did not return for follow-up evaluation). For patients who discontinued the study early for reasons other than treatment failure, an evaluation of improved was defined as resolution of sinusitis with the expectation that, had therapy continued, therapy would have been successful. Patients with a successful clinical responses at the posttherapy visit, namely, those assessed as cured or improved, had a second clinical response assessment at the final poststudy evaluation. The second clinical response was rated as follows: cured (complete resolution of signs and symptoms); improved (continued incomplete resolution of signs and symptoms with no deterioration or relapse during the follow-up period and no further antibiotic therapy
required); relapse (resolution or improvement of signs and symptoms at the posttherapy visit but reappearance or deterioration of signs and symptoms of the infection at the poststudy visit); or unevaluable (no poststudy evaluation). Evaluation of Safety Safety evaluations were performed between the first dose of study drug through the initial posttherapy visit and included the recording of treatment-emergent adverse events, laboratory tests, and physical examination findings. Adverse events were graded as mild, moderate, or marked and as having no relation or a remote, possible, probable, or definite relation to study drug administration. Adverse events that were considered to be definitely or probably related to the study drug were termed drug related. Adverse events were recorded for up to 30 days after cessation of therapy. Laboratory tests, physical examinations, and vital sign measurements were performed on admission to the study and at the posttherapy visit 2 to 5 days after the end of therapy. The laboratory tests included a complete blood count, platelet count, serum biochemistry analysis, and urinalysis with microscopic examination of sediment. Vital sign measurements included oral temperature, respiration and pulse rates, and blood pressure. Methods of Analysis Treatment comparisons were based on 3 analysis groups: the intent-to-treat patients (all enrolled patients), the modified intent-to-treat patients (all enrolled patients according to drug actually received), and clinically evaluable patients. To be clinically evaluable, a patient had to be evaluable for safety, have a confirmed clinical diagnosis of acute sinusitis, have received at least 7 days of therapy, have followed the protocol, and have a posttherapy clinical evaluation within 2 to 10 days after ending study drug therapy. Demographic characteristics were tabulated by treatment for each analysis group. A 2-sided Student’s t test for 2 independent samples was used to compare mean ages of men, women, and both sexes combined. A 2-sided Fisher’s exact test was used to compare the proportions of men and of white patients. Clinical response to treatment of the clinically evaluable patients was the primary efficacy variable. A dichotomous analysis was performed by combining the clinical response categories of cured and improved into 1 category of clinical success. A 2-sided 95% confidence interval around the difference in clinical success rates (amoxicillin-clavulanate minus levofloxacin) between the 2 treatment groups was the basis for assessing therapeutic equivalence. Finally, summaries were made of poststudy clinical response rates for patients who were cured or improved after therapy. Changes in signs and symptoms of acute sinusitis from admission to posttherapy were recorded for clinically evaluable and modified intent-to-treat patients; from these, the per-
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Table 1. Demographic and baseline characteristics of modified intent-to-treat patients
Table 2. Patient disposition Treatment group
Treatment group
Sex Male Female Race White Black Asian Hispanic Other Age (y) Mean ± SD Range Weight (kg) Mean ± SD Range Height (cm) Mean ± SD Range
Levofloxacin (N = 306)
Amoxicillinclavulanate (N = 309)
Total patients (N = 615)
115 (38%) 191 (62%)
110 (36%) 199 (64%)
225 (37%) 390 (63%)
220 (72%) 44 (14%) 3 (1%) 37 (12%) 2 (0.7%)
229 (74%) 44 (14%) 1 (0.3%) 34 (11%) 1 (0.3%)
449 (73%) 88 (14%) 4 (0.7%) 71 (12%) 3 (0.5%)
39.2 ± 13.9 18–85 (n = 302) 78.9 ± 19.7 44.5–158.8 (n = 301) 169 ± 10 142–193
38.6 ± 12.8 18–84 (n = 304) 75.7 ± 18.4 43.5–158.6 (n = 307) 169 ± 10 135–198
38.9 ± 13.4 18–85 (n = 606) 77.3 ± 19.1 43.5–158.8 (n = 608) 169 ± 10 135–198
centages of patients with resolution of clinical signs and symptoms were calculated for clinically evaluable patients. Treatment-emergent adverse events were summarized by body system, primary term, and severity. Summary statistics for clinical laboratory test results were calculated for the values of the analyses at admission and after therapy and for the mean changes from admission to posttherapy. The KolmogorovSmirnov test was performed on percentage changes in laboratory test results from admission to posttherapy. Mean changes in vital signs from admission to posttherapy were calculated for each treatment group and tabulated. RESULTS Patients
In total 615 patients, 307 of whom were randomly assigned to receive levofloxacin and 308 who received amoxicillin-clavulanate, were enrolled at 28 centers. One patient assigned to the levofloxacin treatment group received amoxicillin-clavulanate instead; therefore 306 and 309 patients were in the modified intentto-treat groups for levofloxacin and amoxicillin-clavulanate, respectively. In total 267 (87.3% of enrolled) and 268 (86.7% of enrolled) patients, respectively, were considered clinically evaluable; 297 (97.1%) and 302 (97.7%) patients, respectively, were considered evaluable for safety. The demographic characteristics of the 2 treatment groups were statistically comparable for all analysis groups; these are summarized in Table 1 for the
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Reason for discontinuation
Levofloxacin (N = 306)
Amoxicillinclavulanate (N = 309)
Adverse event Clinical failure Personal reason Other Total patients discontinued Total with known disposition information Total lost to follow-up
11 (3.8%) 6 (2%) 2 (0.7%) 2 (0.7%) 21 (7.2%) 293 (100%)
16 (5.3%) 6 (2%) 1 (0.3%) 4 (1.3%) 27 (9%) 301 (100%)
13
8
Percentages are of patients with known disposition information.
Table 3. Incidence of drug-related adverse events reported by 1% or more of patients in 1 or both treatment groups Treatment group
Levofloxacin (N = 297)
Nausea Diarrhea Abdominal pain Vaginitis* Genital moniliasis* Flatulence Vomiting
5 (1.7%) 4 (1.3%) 3 (1.0%) 2 (1.1%) 2 (0.7%) 1 (0.3%) 0
Amoxicillinclavulanate (N = 302)
12 (4.0%) 35 (11.6%) 5 (1.7%) 8 (4.1%) 10 (3.3%) 4 (1.3%) 5 (1.7%)
*Percentages calculated from the total number of women in each treatment group.
modified intent-to-treat patients. The mean age of all patients was 39 years (range 18 to 85 years); 63% were women, and 73% were white. All those considered clinically evaluable underwent 1 of the following radiographic procedures: sinus x ray, CT, or sinus scope. The vast majority—98.1% (262 of 267) in the levofloxacin arm and 97.8% (262 of 268) in the amoxicillin-clavulanate arm—had sinus x rays. Five patients in the levofloxacin treatment group and 5 patients in the amoxicillin-clavulanate group had CT; sinus scope was the radiographic procedure for 1 patient from the amoxicillin-clavulanate group. In the levofloxacin treatment group, 272 of 306 (88.9%) enrolled patients completed therapy, 21 (6.9%) patients discontinued therapy prematurely, and 13 (4.2%) patients were lost to follow-up. In the amoxicillin-clavulanate treatment group, 274 of 309 (88.7%) enrolled patients completed therapy, 27 (8.7%) patients discontinued therapy prematurely, and 8 (2.6%) patients
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Fig 1. Clinical response to therapy for clinically evaluable patients.
were lost to follow-up. The most common reason for premature discontinuation in both treatment groups was an adverse event. Patient disposition is summarized in Table 2. The mean duration of therapy was 13 days (range 1 to 22 days) for levofloxacin-treated patients and 12 days (range 1 to 23 days) for amoxicillin-clavulanate–treated patients; the median durations were 14 and 12 days, respectively. Efficacy Clinical efficacy. The clinical response to therapy was similar for the 2 treatment groups at the posttherapy evaluation 2 to 5 days after the end of treatment. Among clinically evaluable patients in the levofloxacin treatment group, 156 of 267 (58.4%) were cured and 80 of 267 (30%) improved, compared with 157 of 268 (58.6%) and 77 of 268 (28.7%) in the amoxicillinclavulanate treatment group. Treatment failed in 31 patients (11.6%) in the levofloxacin treatment group and 34 patients (12.7%) in the amoxicillin-clavulanate treatment group (Fig 1). Among clinically evaluable patients, levofloxacin treatment resulted in 88.4% clinical success (cured plus improved), and amoxicillin-clavulanate treatment resulted in 87.3% clinical success, with a 95% confidence interval of [–6.8, 4.6] around the difference (amoxicillin-clavulanate minus levofloxacin) in success rates. Results were consistent across study centers, analysis groups, and various sex, age, and race subgroups. Of the 233 levofloxacin-treated patients who were cured or improved at the posttherapy evaluation and who had a poststudy evaluation approximately 4 weeks later, only 5 (2.1%) had relapsed by the poststudy evaluation, including 2 of the 154 (1.3%) who had been cured and 3 of the 79 (3.8%) who had improved. Among 231 amoxicillin-clavulanate–treated patients
who were cured or improved at the posttherapy evaluation, 9 (3.9%) had relapsed, including 3 of 155 (1.9%) who had been cured and 6 of the 76 (7.9%) who had been improved at the posttherapy evaluation. At the initial posttherapy evaluation, each of the 5 clinical signs and symptoms of sinusitis was resolved in 80% to 100% of patients in both treatment groups in which it was reported on admission (Fig 2). Of 262 clinically evaluable levofloxacin-treated patients with abnormal admission radiographic findings who underwent posttherapy radiographic examination at the 2- to 5-day posttherapy visit, 215 (82.1%) showed either resolution (35.9%) or improvement (46.2%). Similarly, of 262 clinically evaluable amoxicillin-clavulanate–treated patients, 215 (82.1%) showed either resolution (35.5%) or improvement (46.6%). Microbiology. Sinus cultures were obtained from 4 of 65 patients in whom therapy failed. No pathogen was grown on 3 cultures; Haemophilus aphrophilus, Eikenella corrodens, and Streptococcus milleri, all susceptible to both study drugs, grew in the fourth, which was from an amoxicillin-clavulanate–treated patient. Safety
Drug-related adverse events were reported by a smaller percentage of patients in the levofloxacin treatment group (7.4%) than in the amoxicillin-clavulanate treatment group (21.2%). Drug-related adverse events reported by 1% or more of levofloxacin-treated patients were nausea (1.7%), diarrhea (1.3%), vaginitis (1.1%), and abdominal pain (1%). Drug-related adverse events reported by 1% or more of amoxicillin-clavulanate– treated patients were diarrhea (11.6%), vaginitis (4.1%), nausea (4%), genital moniliasis (3.3%), abdominal pain (1.7%), vomiting (1.7%), and flatulence (1.3%) (Table 3). Adverse events, regardless of relationship to study drug, were reported by 114 levofloxacin-treated patients (38.4%) and 146 amoxicillin-clavulanate–treated patients (48.3%) (P < 0.05). Most adverse events were assessed as mild or moderate in severity. Of 22 patients with adverse events considered to be marked in severity, 7 were in the levofloxacin treatment group and 15 were in the amoxicillin-clavulanate treatment group. Of 9 patients with marked drug-related adverse events, 3 were in the levofloxacin treatment group and experienced abdominal pain and diarrhea, constipation, and urticaria, while 6 were in the amoxicillin-clavulanate treatment group, all of whom experienced gastrointestinal (GI) tract–related symptoms (eg, abdominal pain, nausea, or diarrhea). Twenty-seven patients discontinued the study because of adverse events, 11 patients (3.7%) in the levofloxacin treatment group and 16 patients (5.3%) in the amoxi-
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Fig 2. Percentages of clinically evaluable patients with resolution at the posttherapy evaluation of clinical signs or symptoms that were present on admission to the study.
cillin-clavulanate treatment group. In the levofloxacin group, those who discontinued because of adverse events included 4 patients with urticaria, rash, or pruritus; 4 patients with GI tract–related adverse events; 1 patient with both skin and GI tract–related adverse events; and 1 patient each with asthenia-dizziness and symptoms of influenza. In the amoxicillin-clavulanate treatment group, all adverse event discontinuations were because of GI tract–related symptoms, except for 1 instance of fatigue. No serious drug-related events or deaths occurred during the study. Clinically significant treatment-emergent changes in clinical laboratory tests occurred infrequently and were comparable across treatment groups. No clinically significant treatment-emergent changes in physical examination findings or vital signs were found in either treatment group. DISCUSSION
The findings of this multicenter study demonstrate that the once-daily administration of levofloxacin 500 mg was as effective as 3 times daily administration of amoxicillin-clavulanate 500/125 mg in treating acute sinusitis in adult outpatients. The clinical success rate (cured or improved) for the clinically evaluable patients at the posttherapy evaluation 2 to 5 days after the end of therapy was high for both drugs: 88.4% for levofloxacin and 87.3% for amoxicillin-clavulanate. Treatment failed in 31 patients (11.6%) in the levofloxacin treatment group and 34 patients (12.7%) in the amoxicillin-clavulanate treatment group. At a poststudy evaluation approximately 4 weeks later, 5 levofloxacin-treated
patients and 9 amoxicillin-clavulanate–treated patients had had a relapse in clinical signs and symptoms. Our results are among the first describing the clinical efficacy of levofloxacin in the treatment of acute sinusitis. Recently, the results of another multicenter trial of levofloxacin (500 mg once daily) given for 10 to 14 days12 demonstrated similar results to those observed in our study. Of 300 clinically evaluable patients, 175 (58%) were cured and 90 (30%) were improved at the posttherapy evaluation, resulting in a clinical success rate of 88%. The microbiologic eradication rate among 138 microbiologically evaluable patients was 92%. In a published study of Japanese patients with acute sinusitis, investigators reported bacteriologic eradication rates of 93% for gram-positive pathogens, 92% for gramnegative pathogens, and 100% for anaerobes. These excellent responses were observed despite the use of a short-term, low-dose course of therapy (300 mg total daily dose for 3 days).13 These results with levofloxacin in the treatment of acute sinusitis correlate with efficacy results from trials with other oral antibiotics for the treatment of this infection. Ferguson3 summarized selected studies of antibiotic therapy in acute sinusitis, and efficacy results ranged from 74% to 95%. Evaluation of new agents for the treatment of sinusitis is important because of the emerging problem of resistance of common respiratory pathogens (eg, S pneumoniae and H influenzae) to traditional antimicrobial agents. Resistance of antibiotics to β-lactamases and activity against penicillin-resistant S pneumoniae are now primary considerations in the choice of an
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agent for treating acute sinusitis. Levofloxacin has been shown to have good in vitro activity against common respiratory pathogens, including β-lactamase–producing strains of H influenzae and M catarrhalis, as well as penicillin-resistant strains of S pneumoniae.7-9 The MIC90 for levofloxacin is 1.0 µg/mL against S pneumoniae, 0.015 µg/mL against H influenzae, and 0.03 µg/mL against M catarrhalis.7,14 There are limited data on the use of other quinolones for the treatment of acute sinusitis. Two Japanese studies showed good results with ofloxacin; however, the numbers of patients treated were small (n = 13, n = 5).15 The limited data for the treatment of sinusitis with commercially available quinolones may in part be the result of poor activity of some quinolones against S pneumoniae. However, levofloxacin has been shown to have good in vitro activity against S pneumoniae, including penicillin-sensitive and penicillin-resistant strains. 7-9 More importantly, levofloxacin has been shown to be effective in treating patients with infections caused by S pneumoniae. In 2 multicenter trials evaluating the use of levofloxacin for the treatment of patients with community-acquired pneumonia, the clinical success rates (patients cured or improved) were 100% in both trials for patients with S pneumoniae infections.16,17 Similarly, in 2 multicenter trials evaluating the efficacy of levofloxacin for the treatment of patients with acute exacerbations of chronic bronchitis, the clinical success rates were 88% and 90% for patients with S pneumoniae infections.18,19 The combination of amoxicillin and clavulanic acid has a broad spectrum of activity that includes many upper respiratory tract pathogens; however, most penicillin-resistant S pneumoniae isolates are also resistant to amoxicillin in vitro.20 Amoxicillin-clavulanate has been shown to be effective for the treatment of acute sinusitis and thus is a common comparator in clinical trials of new antimicrobial agents for the treatment of acute sinusitis.21-23 Reported clinical success rates (cure or improvement) for acute sinusitis after treatment with amoxicillin-clavulanate were 93% in one study21 and 88% in a second study,22 similar to the results in the present study. Reported microbiologic eradication rates with amoxicillin-clavulanate were 90% in the first study21 and 92% in a third study.4 A drawback of treatment with amoxicillin-clavulanate is the high incidence of drug-related GI side effects, particularly diarrhea and nausea, which were reported by 11.6% and 4%, respectively, of patients in the amoxicillin-clavulanate treatment group in this study. By comparison, levofloxacin was better tolerated, with the most common drug-related adverse events occurring in only 1.7% (nausea) and 1.3% (diarrhea) of
levofloxacin-treated patients. However, since the completion of this study, a new formulation of amoxicillinclavulanate has become available that may be better tolerated than the original formulation and can be administered twice daily. The results of this study show that once-daily administration of levofloxacin is as effective and better tolerated than 3 times daily administration of amoxicillinclavulanate in treating acute sinusitis in adult outpatients. Additionally, levofloxacin is associated with the convenience of once-daily administration versus 3 times daily administration of amoxicillin-clavulanate. REFERENCES 1. Diaz I, Bamberger DM. Acute sinusitis. Semin Respir Infect 1995;10:14-20. 2. Williams JW Jr, Simel DL. Does this patient have sinusitis? Diagnosing acute sinusitis by history and physical examination. JAMA 1993;270:1242-6. 3. Ferguson BJ. Acute and chronic sinusitis. How to ease symptoms and locate the cause. Postgrad Med 1995;97:45-57. 4. Gwaltney JM Jr, Scheld WM, Sande MA, et al. The microbial etiology and antimicrobial therapy of adults with acute communityacquired sinusitis: a fifteen-year experience at the University of Virginia and review of other selected studies. J Allergy Clin Immunol 1992;90(Suppl):457-62. 5. Davis R, Bryson HM. Levofloxacin. A review of its antibacterial activity, pharmacokinetics and therapeutic efficacy. Drugs 1994; 47:677-700. 6. Fu KP, Lafredo SC, Foleno B, et al. In vitro and in vivo antibacterial activities of levofloxacin (l-ofloxacin), an optically active ofloxacin. Antimicrob Agents Chemother 1992;36:860-6. 7. Eliopoulos GM, Wennersten CB, Moellering RC Jr. Comparative in vitro activity of levofloxacin and ofloxacin against gram-positive bacteria. Diagn Microbiol Infect Dis 1996;25:35-41. 8. Plouffe JF. Levofloxacin in vitro activity against bacteremic isolates of Streptococcus pneumoniae. Diagn Microbiol Infect Dis 1996;25:43-5. 9. Biedenbach DJ, Jones RN. The comparative antimicrobial activity of levofloxacin tested against 350 clinical isolates of streptococci. Diagn Microbiol Infect Dis 1996;25:47-51. 10. Chien SC, Rogge MC, Gisclon LG, et al. Pharmacokinetic profile of levofloxacin following once daily 500 mg oral or intravenous doses. Antimicrob Agents Chemother 1997;41:225660. 11. Chow AW, Hall CB, Klein JO. General guidelines for the evaluation of new anti-infective drugs for the treatment of respiratory tract infections. Clin Infect Dis 1992;15(Suppl 1):S62-88. 12. Sydnor TA, Kopp EJ, Anthony K, et al. An open-label assessment of the activity of levofloxacin for the treatment of acute bacterial sinusitis in adults. Presented at the Annual Meeting of the American College of Allergy, Asthma and Immunology; 1996 Nov 8; Boston (MA). 13. Baba S, Miyamoto N, Unno T, et al. Clinical evaluation of the effect of levofloxacin on sinusitis. Chemotherapy 1992;4(Suppl 3):365-78. 14. Cormican MG, Erwin ME, Marshall SA, et al. Susceptibility testing interpretive criteria for levofloxacin when testing respiratory pathogens, Haemophilus influenzae and Moraxella catarrhalis. Diagn Microbiol Infect Dis 1996;24:155-60. 15. Barza M. Pharmacokinetics and efficacy of the new quinolones in infections of the eye, ear, nose, and throat. Rev Infect Dis 1988;10(Suppl 1):S241-7. 16. Fogarty C, Sullivan JG, Chattman MS, et al. Once a day levofloxacin in the treatment of severe and mild to moderate community-acquired pneumonia in adults. Presented at the Infectious
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Diseases Society of America Annual Meeting; 1996 Sep; New Orleans (LA). 17. File TM, Segreti J, Dunbar L, et al. A multicenter, randomized study comparing the efficacy and safety of IV/PO levofloxacin vs ceftriaxone/cefuroxime axetil in the treatment of adults with community-acquired pneumonia. Antimicrob Agents Chemother 1997;41:1965-72. 18. DeAbate CA, Russell M, McElvaine P, et al. Safety and efficacy of oral levofloxacin versus cefuroxime axetil in acute bacterial exacerbation of chronic bronchitis. Respir Care 1997;42: 206-13. 19. Habib MP, Gentry LO, Rodriguez-Gomez G, et al. A multicenter, randomized study comparing the efficacy and safety of oral levofloxacin vs cefaclor in the treatment of acute bacterial exacerbations of chronic bronchitis. Presented at the 36th Interscience
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Conference on Antimicrobial Agents and Chemotherapy; 1996 Sep; New Orleans (LA). Esposito AL. Role of oral antimicrobial drugs in the treatment of respiratory tract infections: overview and summary of newer agents. Infect Dis Clin Pract 1995;4(Suppl 4):S250-8. Dubois J, Saint-Pierre C, Tremblay C. Efficacy of clarithromycin vs. amoxicillin/clavulanate in the treatment of acute maxillary sinusitis. Ear Nose Throat J 1993;72:804-10. DeAbate CA, Perrotta RJ, Dennington ML, et al. The efficacy and safety of once-daily ceftibuten compared with co-amoxiclav in the treatment of acute bacterial sinusitis. J Chemother 1992; 4:358-63. Legent F, Bordure P, Beauvillain C, et al. A double-blind comparison of ciprofloxacin and amoxycillin/clavulanic acid in the treatment of chronic sinusitis. Chemotherapy 1994;40(Suppl 1):8-15.
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