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ORIGINAL RESEARCH
A Comparison of Moxifloxacin and Azithromycin
in the Treatment of Acute Exacerbations of
Chronic Bronchitis
Siegfried R. Kreis, MD, MSEd, Nilo Herrera, MD, Nasim Golzar, MD, H.D. Fuller, MD, Allen Heyd, PhD, and the
Therapeutic Circles Bronchitis Study Group
• Objective: To compare the efficacy, safety, and patient- reported effectiveness of short-course moxifloxacin ver- Acute exacerbation of chronic bronchitis (AECB) is a common respiratory condition associated with sub- sus azithromycin for the management of acute exacer- stantial patient morbidity. Approximately 50% of bation of chronic bronchitis (AECB) in a primary care patients who experience acute exacerbations report at least 2 episodes per year [1,2]. More than 12 million outpatient • Design: Prospective, multicenter, nonblinded, phase IIIb physician visits are related to AECB. Twenty percent of patients with AECB will require hospitalization due to the • Participants: 401 adult patients with signs and symptoms development of pneumonia and/or respiratory insufficien- • Intervention: Patients randomly received a 5-day oral Most patients experiencing an exacerbation consult a pri- regimen of either moxifloxacin (400 mg once-daily) mary care physician and are prescribed antibiotic therapy.
or azithromycin (500 mg on day 1, and 250 mg once Bacterial cultures generally are not performed due to the time, expense, and difficulty of obtaining uncontaminated • Outcome measures: Rate of clinical success at follow- bronchial sputum samples in the primary care setting. Al- up 14 to 21 days after completion of therapy. Patient- though bacteriologic eradication is an important marker of reported responses to therapy (time to symptom relief overall antimicrobial efficacy, a quick return to work or other and resumption of normal activities) were assessed by activities as reported by patients is also a clinically important questionnaire. Drug-related adverse events were also The Moxifloxacin Therapeutic Circles program was initi- • Results: Clinical resolution at 14 to 21 days was 85% ated to provide a clinically relevant practice perspective on for moxifloxacin- and 81% for azithromycin-treated pa- the treatment of AECB. This trial, which was conducted tients (95% confidence interval, –6.0% to 14.0%). Drug- exclusively in the primary care setting, compared moxi- related adverse events reported in the moxifloxacin and floxacin and azithromycin for the treatment of AECB.
azithromycin groups were 12% and 9%. Patients in the Although clinical efficacy was the primary outcome of inter- moxifloxacin group reported feeling better significant- est in this study, patient-reported outcomes were also ly faster than did patients in the azithromycin group assessed. The trial attempted to simulate actual clinical prac- (P = 0.0236). More moxifloxacin-treated patients (40%; tice conditions; accordingly, bacteriologic assessments and 71 of 176) reported symptomatic relief by day 3 than follow-up cultures were not conducted, reflecting an empir- did azithromycin-treated patients (27%; 45 of 165) (P = 0.012). More moxifloxacin-treated patients (36%;58 of 163) reported a return to normal activities within3 days of therapy than did azithromycin-treated patients Siegfried R. Kreis, MD, MSEd, Clinical Assistant Professor, Department of (26%; 41 of 159). No significant differences were ob- Family and Community Medicine, University of Texas Southwestern Medical Center, Dallas, TX, Staff Physician, Providence Clinic, Waco, TX; Nilo • Conclusions: Short-course moxifloxacin was as effective Herrera, MD, Southeast Medical Associates, Brewster, NY; Nasim Golzar, and safe as azithromycin in the treatment of AECB.
MD, Clinical Assistant Professor, Harbor–UCLA Medical Center, Torrance,CA, Staff Physician, Torrance Memorial Hospital; H.D. Fuller, MD, Fuller Patients treated with moxifloxacin reported faster symp- Family Practice, Barnhart, MO; and Allen Heyd, PhD, Pharmaceutical tom relief and returned to normal activities more rapidly.
Division, Bayer Corporation, West Haven, CT. JCOM December 2000 33
MOXIFLOXACIN AND AZITHROMYCIN
toms of chest pain or discomfort; change in cough frequency Patients
and severity; sputum characteristics (thickness and volume); Between September 1999 and May 2000, 401 patients were and dyspnea. Clinical response was graded as clinical resolu- enrolled in this open-label study conducted in 74 primary tion (disappearance of acute signs and symptoms related to care practice sites throughout the United States. Male or non- the infection or sufficient improvement such that additional pregnant female outpatients at least 18 years old with clini- or alternative antimicrobial therapy was not required), clini- cally documented AECB of suspected bacterial origin and cal failure (insufficient lessening of the signs and symptoms without a recent chest x-ray suggestive of a new pneumonia of infection such that additional or alternative antimicrobial or lobar consolidation were eligible. Underlying chronic therapy was required), or indeterminate (clinical assessment bronchitis was defined as the daily production of sputum on was not possible for any reason). Safety was assessed on the most days for at least 3 consecutive months and for more basis of investigator-determined drug-related adverse events than 2 consecutive years. Patients were included in the study if they had symptoms of increased sputum purulence and at Patient-reported outcomes were assessed during the test- least 1 of the following: increased sputum volume, increased of-cure visit using a series of 5 questions: cough, or increased dyspnea or fever (> 38°C orally). Pa- • When did the patient begin to feel better (ie, tients were excluded from enrollment if they had a severe symptom relief) after start of treatment? respiratory exacerbation; were allergic to carboxyquinolonederivatives or azalide/macrolide derivatives; had previous • When did the patient begin to return to normal history of fluoroquinolone-related tendonopathy; were un- able to take oral medication; were pregnant or lactating; had • Was the dosing schedule easy to understand? a recent diagnosis (< 5 years) of unresolved lung or chestcavity malignancy, active tuberculosis, cystic fibrosis, or sig- nificant bronchiectasis; had a neutrophil count < 1000/mm3, • How many hours of work (from the start of treat- CD4 cell count < 200/mm3, or other evidence of significant ment) did the patient miss due to illness? immunosuppression; had evidence of significant liverimpairment (aspartate aminotransferase, alanine amino-transferase, or total bilirubin > 3 times upper limit of nor- Statistical Analysis
mal); had renal insufficiency requiring dialysis; history of The attained sample size of 355 responses (excluding inde- inherited or sporadic syndromes of QTc prolongation; need- terminate responses) was sufficient to provide greater than ed a concomitant antibacterial agent with a spectrum of 85% power for testing the null hypothesis of inferiority of activity similar to the study drugs; received drugs known to moxifloxacin to azithromycin at the 0.05 level with a lower affect QT interval (eg, amiodarone, sotalol, terfenadine); or limit of noninferiority of 10% and predicted success rates of received previous therapy with a systemic antibiotic for more than 24 hours prior to enrollment, unless a treatment For each evaluation of clinical response, a 2-sided 95% failure. Patients were randomized by computer code in a confidence interval (CI) for the weighted difference between 1:1 ratio to receive a 5-day oral regimen of either moxi- treatment groups was constructed using Mantel-Haenszel floxacin (400 mg once daily) or azithromycin (500 mg on the weights (weighting by center). Equivalence was defined as first day of therapy and then 250 mg once daily for 4 days). the lower limit of the 2-sided 95% CI for the difference The trial protocol was reviewed and approved by each between groups being greater than –10%. Patient-reported investigator’s independent ethics committee, and informed outcomes data were evaluated using the Wilcoxon test and consent was obtained from each patient prior to enrollment the Fisher’s exact test (both 2-sided). Significance was de- Outcome Measures
All patients receiving at least 1 dose of study drug (the intent- Clinical Outcomes
to-treat population) were evaluated for clinical response at A total of 203 patients were randomized to the moxifloxacin the test-of-cure visit (14 to 21 days after completion of thera- regimen and 198 to the azithromycin regimen. Of these, py). Clinical response was based on patient examination 201 patients received at least 1 dose of moxifloxacin and using the following parameters: objective signs of auscultato- 198 received at least 1 dose of azithromycin. The 2 treatment ry findings (rales, rhonchi, wheezing, breath sounds); prolon- groups were well matched with respect to demographic gation of expiratory phase; presence of fever > 38°C; white variables, although a higher proportion of moxifloxacin- blood cell (WBC) count > 12,000 cells/mm3; subjective symp- treated patients had a history of smoking (Table 1).
34 JCOM December 2000
ORIGINAL RESEARCH
Table 1. Demographic Variables
Table 2. Drug-Related Adverse Events (Intention-to-Treat
Population)
Moxifloxacin
Azithromycin
n (%)
Variable
(n = 201)
(n = 198)
Moxifloxacin Azithromycin
Adverse Event
(n = 201)
(n = 198)
Note: Events occurring in ≥ 1% of either group were recorded.
data. Regarding the intent-to-treat population, 40% (71 of 176) of patients who received moxifloxacin and 27% (45 of 165) of those receiving azithromycin subjectively reported an improvement in their bronchitis within 1 to 3 days of initia- tion of therapy (Figure). The mean time to patient-reported
symptom relief was 5.1 days for moxifloxacin versus 5.8 days for azithromycin. This difference was not statistically signifi- cant using the Student’s t-test but was significant at the 0.05 level (P = 0.0236) using the more appropriate 2-sided Ninety percent (64 of 71) of moxifloxacin- and 93% (42 of 45) of azithromycin-treated patients who reported symptom relief by day 3 of treatment went on to become clinical suc- cesses (resolution of symptoms). A higher percentage of moxifloxacin-treated patients (36%; 58 of 163) reported resuming normal activities within the first 3 days of therapythan did azithromycin-treated patients (26%; 41 of 159). In the per-protocol population, a higher percentage of At least 94% of patients completed the full course of thera- patients treated with moxifloxacin reported symptomatic py (193 moxifloxacin, 186 azithromycin); the rate of premature improvement (39%; 49/127) and return to normal activity discontinuation was similar between treatment groups (5% within 3 days of therapy initiation (35%; 41/118) than did moxifloxacin, 6% azithromycin) and was primarily due to inad- patients receiving azithromycin (31%; 39/127; 28%, 34/123).
equate therapeutic effect. In the intent-to-treat population, there These differences were not statistically significant. The per- were 22 indeterminate responses in each group. Excluding protocol population included all patients with no major pro- these responses, clinical resolution at the test-of-cure visit was tocol violation who had (1) received a study antibiotic for at 85% (152/179) for moxifloxacin and 81% (143/176) for least 72 hours if a clinical failure, (2) completed the test-of- azithromycin (95% CI, –6.0% to 14.0%). The incidence of drug- cure evaluation at post-therapy days 14 through 21, and related events was 12% in the moxifloxacin group and 9% in (3) had been at least 80% compliant (assessed by pill count) the azithromycin group (Table 2). Premature discontinuation
due to drug-related adverse events was ≤ 1% in both groups. An equal proportion of patients from each group (48%) indicated working for pay. The total amount of work time Patient-Reported Outcomes
lost is shown in Table 3. There were no statistically signifi-
The number of patient responses was less than the total cant differences in terms of the average amount of work intent-to-treat population due to missing or indeterminate time lost (12 hours for moxifloxacin group versus 11 hours JCOM December 2000 35
MOXIFLOXACIN AND AZITHROMYCIN
Figure. Patient-reported therapy outcomes at the test-of-cure visit (14 to 21 days after completion of therapy). Data are expressed
as the cumulative percentage of all patients’ responses for each time interval. *P = 0.012 using Fisher’s exact test (2-tailed); NS =
P = 0.07 (2-tailed).
Table 3. Hours Missed from Work
resolution of their infection. Specifically, by day 3 of therapy,significantly more moxifloxacin-treated patients (40%) n (%)
reported that their condition had improved than didazithromycin-treated patients (27%). This trend toward a Moxifloxacin
Azithromycin
faster rate of improvement with moxifloxacin is consistent Hours Missed
(n = 96)
(n = 93)
with a larger proportion moxifloxacin patients reportingreturn to normal activity within 3 days of therapy. Although the statistical significance of these data must be interpreted cautiously considering the retrospective deter- mination of analyzed time interval, the choice of a 3-day analysis is reasonable given the bacteriologic eradication data shown by DeAbate and colleagues [5]. In this study, Note: Reduction of n is due to missing responses (105 in each group).
eradication of the original causative organism was higher byday 3 in the moxifloxacin group (63%) than in the azithro-mycin group (48%). This earlier study, however, did not for azithromycin group). Both groups were similar when examine or report any meaningful differences in the time to comparing lost work time of > 1 to 2 days and > 3 days, but improvement of symptoms. In the current study, it is note- moxifloxacin-treated patients indicated missing 1 to 8 hours worthy that 90% of moxifloxacin-treated patients who half as often (8%) as those receiving azithromycin (17%). reported symptomatic relief by day 3 were categorized by At least 90% of patients from each treatment group their primary care physician at the test-of-cure visit as hav- reported understanding the dosing regimens. ing clinical resolution of infection. The corresponding ratefor the azithromycin group was 93%. These data further sug- Discussion
gest that the outcome measure of “time to symptomatic The moxifloxacin and azithromycin regimens used in this improvement on day 3” has validity.
study for the treatment of AECB were shown to be equiva- The significance of the lost work time data is unclear. It lent in terms of clinical response at the test-of-cure visit and was interesting that among patients who were actively work- incidence of drug-related adverse events. Overall patient- ing for pay, nearly twice as many azithromycin-treated reported outcomes were similar in the treatment groups; patients compared to moxifloxacin-treated patients reported however, patients receiving moxifloxacin had more rapid missing 1 to 8 hours of work, presumably as a result of their 36 JCOM December 2000
ORIGINAL RESEARCH
illness. Considering that other captured time intervals (ie, Cincinnati, OH; S. Dyke, Grand Rapids, MI; J. Eck, Boise, ID; S. 9 to 16, and 17 to 24 hours) were nearly equivalent between Flores, San Antonio, TX; A. Fulambarker, North Chicago, IL; H. Fuller, treatment groups, the disparity between treatments shown Barnhart, MO; N. Golzar, Palos Verdes, CA; I. Golzari, South Venice,FL; G. Greenwald, Rancho Mirage, CA; E. Haffizulla, Lauderhill, FL; for the 1 to 8 hour interval may suggest up to a 1-day differ- C. Hanna, Austin, TX; K. Hendrick, Flushing, MI; N. Herrera, ence in patient response for a percentage of patients. This Brewster, NY; T. Hyzer, Madison, WI; D. Hitz, King of Prussia, PA; T. concept is not unrealistic considering the aforementioned Howard, Huntsville, AL; G. Johnson, Simpsonville, SC; S. Kreis, Waco, outcome results for symptom relief and time to return to nor- TX; Y. Kurtzer, Scranton, PA; R. Landefeld, Marion, OH; M. Lucas, Florissant, MO; T. Mandat, Independence, OH; F. Mayorquin, The interpretation of this study may be limited by the Nashville, TN; E. McDavid, Sandersville, GA; D. McLaughlin, Idaho open-label design and lack of confirmative bacteriologic Falls, ID; D. McMahon, Annandale, VA; S. Meade, Eden Prairie, MN, analyses. Furthermore, the subjective nature of the patient R. Moraleda, Devil’s Lake, ND; R. Morman, North Cincinnati, OH; L. responses could be influenced by interpretation bias. How- Morrisey, Burlington, NC; J. Morrow, Longwood, FL; S. Myers, ever, the intention of this trial was not only to compare clin- FeSolana Beach, CA; J. O’Connor; Marathon, FL; M. Perlman, La Jolla, ical efficacy and safety of moxifloxacin and azithromycin in CA; F. Petruzziello, Hamden, CT; A. Pacia, Trenton, NJ; G. Phillips,Fort Worth, TX; T. Poling, Wichita, KS; G. Rada, Phoenix, AZ; M. the treatment of AECB, but also to reflect a true primary care Raikhel, Torrance, CA; S. Rakkar, Plano, TX; P. Reeb, San Diego, CA; approach to community-based patients with AECB in a less L. Reznick, Glendale, NY; M. Riederman, Lake Bluff, IL; S Rieux, protocol-driven manner. The determination of a chosen Beverly Hills, CA; A. Rizzo, Amherst, NY; K. Roberts, Mechanicsville, treatment option’s success or failure is most often based on VA; N. Sabio, Huntsville, AL; R. Saini, Fulton, NY; S. Shaffer, clinical judgment in the office and on whether the patient Overland Park, KS; T. Shetter, Butler, PA; A. Skladman, Arlington communicates to his or her physician whether the pre- Heights, IL; M. Soiferman, Philadelphia, PA; D. Sova, Holland, MI; R. scribed drug worked. This analysis provides some insight Tafel, Euless, TX; B. Towe, Thomson, GA; S. Thumasathit, Mesquite, into potential differences between treatment drugs not only TX; J. Vitali, Howell, NJ; C. Vorenkamp, Owosso, MI; P. Bailey- in terms of clinical response rates but also in terms of patient- Walton, Beverly Hills, CA; and G. Yuil, Lawrence, MA. reported outcomes. The ability of an antibiotic to morerapidly improve a patient’s symptoms, thereby permitting Author addresses: Dr. Kreis: 405 Londonderry St. 110, Waco, TX the patient to return to work or resume normal activities 76712. Dr. Golzar: 26516 Crenshaw Blvd., Palos Verdes, CA 90274. faster, should be considered in the selection of empiric ther- Dr. Heyd: 400 Morgan Lane, West Haven, CT 06516, Allen.Heyd.b@ apy. Moreover, more rapid patient improvement is impor- tant in reducing morbidity and mortality in patients pre-senting with comorbid disease. The potential for faster References
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JCOM December 2000 37

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