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 MedicalCenter, 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
clinical improvement suggested by this study has socioeco-
1. Standards for the diagnosis and care of patients with chronic
nomic implications and warrants further investigation.
obstructive pulmonary disease. American Thoracic Society. Am J Respir Crit Care Med 1995;152 (5 Pt 2): S77–121. The authors thank David M. Weinstein, PhD, for editorial contribu-
2. Ball P, Harris JM, Lowson D, et al. Acute infective exacerba-
tions and acknowledge the participants in the Therapeutic Circles
tions of chronic bronchitis. Q J Med 1995;88:61–8.
3. Chodosh S. Bronchitis and asthma. In: Gorbach SL, Bartlett
JG, Blacklow NR, editors. Infectious diseases. 1st ed. Phila-
Therapeutic Circles Bronchitis Study Group
delphia: WB Saunders; 1992:476–85. M. Attanasio, Philadelphia, PA; J. Badolato, Philadelphia, PA; S.
4. COSTART: coding symbols for thesaurus of adverse reaction
Bander, Sachse, TX; A. Bates, Central Point, OR; J. Bautista, Fresno,
terms. 5th ed. Rockville (MD): U.S. Department of Health
CA; W. Beliveau, Johnston, RI; B. Bethancourt, Phoenix, AZ; J. Budi,Oconto Falls, WI; G. Burgess, Downingtown, PA; R. Castaldo, Buffalo,
5. DeAbate CA, Mathew CP, Warner JH, et al. The safety and
NY; A. Castiel, Orange Park, FL; C. Chappel, Kissimmee, FL; F. Cole,
efficacy of short course (5-day) moxifloxacin versus azith-
Fayetteville, GA; C. D’Angelo, West Irondequoit, NY; R. DeAmicis,
romycin in the treatment of patients with acute exacerbation
Chelmsford, MA; T. Dimovski, Shelby Township, MI; F. Dumont,
of chronic bronchitis. Respir Med 2000;94:1029–37.
Copyright 2000 by Turner White Communications Inc., Wayne, PA. All rights reserved. JCOM December 2000 37
A Selective HIV-Protease Assay Based on a Chromogenic Amino Acidby Fabrizio Badalassia)b), Hong Khan Nguyenc), Paolo Crottib), and Jean-Louis Reymond*a)a) Departement für Chemie und Biochemie, Universität Bern, Freiestrasse 3, CH-3012 Bern (fax:41316318057; e-mail: jean-louis.reymond@ioc.unibe.ch)b) Dipartimento di Chimica Bioorganica e Biofarmacia, UniversitaÁ di Pisa, I-56126 Pisac) Pr
Datum: 06-08-2009 Onderwerp: Informatie over de Nieuwe Influenza A (h1n1) voor scholen Ons kenmerk : Geachte Directie, In Nederland krijgen steeds meer mensen de Nieuwe Influenza A (H1N1), ook wel ‘Mexicaanse griep’ en ‘nieuwe griep‘ genoemd. Kinderen kunnen door hun intensieve onderlinge contact makkelijk griep onder elkaar verspreiden. Met deze brief willen wij u, aan het beg