- Email: [email protected]
Short-term and Long-term Outcomes of Moxifloxacin Compared to Standard Antibiotic Treatment in Acute Exacerbations of Chronic Bronchitis
Short-term and Long-term Outcomes of Moxifloxacin Compared to Standard Antibiotic Treatment in Acute Exacerbations of Chronic Bronchitis* Robert Wilson, MD; Luigi Allegra, MD; Ge´rard Huchon, MD, FCCP; Jose-Luis Izquierdo, MD; Paul Jones, MD; Tom Schaberg, MD, FCCP; Pierre-Phillippe Sagnier, MD; and the MOSAIC Study Group†
Study objectives: To compare the effectiveness of oral moxifloxacin with standard antibiotic therapy in acute exacerbation of chronic bronchitis (AECB). Design: Multicenter, multinational, randomized, double-blind study of two parallel treatment arms. Patients: Outpatients > 45 years old with stable chronic bronchitis, smoking history of > 20 pack-years, two or more AECBs in the previous year, and FEV1 < 85% of predicted value. Patients were enrolled when in a stable condition, and patients with exacerbations within 12 months of enrollment were randomized. Interventions: Randomization (stratified on steroid use) between moxifloxacin (400 mg qd for 5 days) and standard therapy (amoxicillin [500 mg tid for 7 days], clarithromycin [500 mg bid for 7 days], or cefuroxime-axetil [250 mg bid for 7 days]). Measurements: Assessment at enrollment, randomization (Anthonisen type 1 exacerbation), 7 to 10 days after treatment, and monthly until next AECB or up to 9 months. The primary efficacy variable was clinical success (sufficient improvement, no alternative antimicrobial therapy required) 7 to 10 days after therapy. Secondary predefined end points were clinical cure (return to pre-exacerbation status), further antimicrobial use, time to next AECB, and bacteriologic success. Results: Three hundred fifty-four patients received moxifloxacin, and 376 patients received standard therapy. At 7 to 10 days after therapy, clinical success rates were similar in intentionto-treat (ITT) patients (95% confidence interval [CI], ⴚ 0.7 to 9.5) and per-protocol (PP) patients (95% CI, ⴚ 3.0 to 8.5). Moxifloxacin showed superior clinical cure rates over standard therapy in both ITT patients (95% CI, 1.4 to 14.9) and PP patients (95% CI, 0.3 to 15.6), and higher bacteriologic success in microbiologically valid patients (95% CI, 0.4 to 22.1). Fewer ITT patients required antimicrobials after treatment with moxifloxacin than standard therapy (p < 0.01). Time to next exacerbation was longer with moxifloxacin; median and mean times to new AECBs in ITT patients who did not require any further antibiotics were 131.0 days and 132.8 days in moxifloxacin, and 103.5 days and 118.0 days in standard therapy, respectively (p ⴝ 0.03). The occurrence of failure, new exacerbation, or any further antibiotic was less frequent in moxifloxacin-treated patients for up to 5 months of follow-up (p ⴝ 0.03). Conclusions: Moxifloxacin was equivalent to standard therapy for clinical success and showed superiority over standard therapy in clinical cure, bacteriologic eradication, and long-term outcomes. (CHEST 2004; 125:953–964) Key words: acute exacerbation of chronic bronchitis; antibiotic; moxifloxacin Abbreviations: AECB ⫽ acute exacerbation of chronic bronchitis; CB ⫽ chronic bronchitis; CI ⫽ confidence interval; ITT ⫽ intention to treat; MIC ⫽ minimun inhibitory concentration; MIC90 ⫽ minimum inhibitory concentration for 90% of isolates; PP ⫽ per protocol
exacerbations of chronic bronchitis (AECBs) A cute are both costly and detrimental to quality of life. 1–3
Bacterial infection is implicated in approximately 50 to 60% of AECBs based on microbiological testing.4 Recently, a correlation has been demonstrated between emergence of new strains among bacteria colowww.chestjournal.org
nizing the respiratory tract and AECB, providing support for the etiologic role of bacteria in AECB. Empirical antibiotic treatment of AECB in patients with a range of different conditions has become widely accepted as standard practice, especially in patients who present with increased dyspnea, sputum volume, CHEST / 125 / 3 / MARCH, 2004
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and purulent sputum5–13; the evidence that bacteria cause exacerbations, which contribute to loss of lung function, has emphasized the importance of appropriate antibiotic treatment of acute exacerbations.14 For editorial comment see page 811 Studies of antibiotic treatment of AECB have yielded comparable cure rates in the order of 75 to 87%.15,16 In light of the increasing resistance of common respiratory tract pathogens to recommended antibiotics, the use of newer broad-spectrum agents has increased,17,18 and there remains a need to determine whether these are more effective than current standard first-line treatments.19,20 To date, clinical studies of antimicrobial therapy for AECB have been limited by a number of factors. These include inadequate information on patient condition prior to AECB and lack of long-term follow-up, as well as a lack of prospective control for concomitant corticosteroid use, which can positively affect the outcome of AECB,21 or for prognostic factors such as cardiopulmonary disease that can have a negative impact.15,22–24 Especially when designed to satisfy regulatory requirements, randomized studies have used a single, carefully chosen antimicrobial comparator, and the study populations have sometimes included heterogeneous, nonrepresentative patients for this indication.6 Reviews19,23,25 have focused on stratification of patients into risk categories and better definitions of severity to rationalize antibiotic treatment. Current guidelines recommend the use of -lactams and macrolides for the treatment of AECB, but have not been updated to take into account the most recently developed antimicrobials, including the new respiratory quinolones.13,26,27 The fluoroquinolone moxifloxacin is highly active against common respiratory tract pathogens, includ*From the Royal Brompton Hospital (Dr. Wilson), London, UK; Clinica Delle Malattie Dell’Apparato Respiratorio (Dr. Allegra), Milan, Italy; Hotel Dieu (Dr. Huchon), Paris, France; Hospital General (Dr. Izquierdo), Guadalajara, Spain; St. George’s Hospital Medical School (Dr. Jones), London, UK; Diakoniekrankenhaus (Dr. Schaberg), Zentrum fu¨ r Pneumologie, Rotenburg, Germany; and Bayer Plc (Dr. Sagnier), Stoke Poges, UK. †A list of participants is given in the Appendix. This study was sponsored by Bayer AG. Dr. Wilson has received honoraria for presentation from the sponsor. Dr. Sagnier is a sponsor staff member. Manuscript received March 7, 2003; revision accepted September 23, 2003. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (e-mail: [email protected]). Correspondence to: Robert Wilson, MD, Consultant Physician, Royal Brompton Hospital, Sidney St, London SW3 6NP, United Kingdom; e-mail: [email protected] 954
ing penicillin-resistant pneumococci in communityacquired pneumonia.28 –30 Moxifloxacin shows rapid lung tissue penetration and bacterial eradication rates against common respiratory tract pathogens.31,32 Moxifloxacin has demonstrated effectiveness as short-course therapy for AECB in an extensive clinical program comprising comparative studies33,34 with various standard antimicrobials. We compared the effectiveness of oral moxifloxacin, 400 mg qd for 5 days, with standard oral 7-day antibiotic treatment regimens as first-line therapy for infectious AECB (Anthonisen type 1). The study was original in that it incorporated several design features that have been used in other studies, but never before together in an antibiotic trial of AECB: (1) the choice of the comparator was left to the clinician among three options, while the doubleblind design allowed to maintain a high degree of internal validity; (2) the pre-exacerbation health status was established to allow measuring the postexacerbation return to baseline; (3) the use of corticosteroids was taken into account by stratification; and (4) a long-term follow-up was performed up to 9 months, including administration of posttherapy antibiotics and time to next exacerbation. In this article, we report the overall design, cohort characteristics, and main clinical and bacteriologic results of our study, including long-term follow-up.
Materials and Methods This was a multicenter, multinational, randomized, doubleblind study of two parallel treatment arms of patients with AECB. Outpatients aged ⱖ 45 years with documented chronic bronchitis (CB) were eligible for enrollment during an AECB-free period if they had a history of cigarette smoking of at least 20 pack-years, two or more documented AECBs in the previous year, and FEV1 ⬍ 85% of predicted value at the enrollment visit. The main exclusion criteria were previous adverse reaction to study drugs, pregnancy or lactation, syndrome of QTc prolongation, severe renal or hepatic impairment, or lung disease other than CB that could affect the clinical evaluation of study medication. The study protocol was approved by ethics committees for all centers prior to implementation, and patients provided written informed consent. Four visits were scheduled: enrollment, randomization, 7 to 10 days after the end of treatment, and end of follow-up, which lasted either until the occurrence of a new exacerbation or 9 months after therapy at the latest (Fig 1). Enrolled patients were instructed to see their physicians as soon as clinical signs and symptoms of infectious AECB arose, and have with them a fresh sputum sample in a sterile container. They could be randomized within a maximum of 12 months from enrollment date if they presented with an Anthonisen type 1 AECB,6 defined as increased dyspnea and sputum volume, and sputum purulence that had to be confirmed macroscopically by the investigator. At this randomization visit, sputum was sent for microscopic examination and Gram staining.35 Valid samples (⬍ 10 squamous epithelial cells and ⬎ 25 polymorphonuclear leukocytes per low-powermagnification [⫻ 100] field) were cultured for pathogen identification, and isolates were subjected to susceptibility testing to Clinical Investigations
Figure 1. Study schedule. V1 ⫽ visit one; V2 ⫽ visit two; V3 ⫽ visit three; V4 ⫽ visit four.
moxifloxacin and comparators, performed by E-test (AB Biodisk; Solna, Sweden) in accordance with current National Committee for Clinical Laboratory Standards guidelines.36 Prior to randomization, patients were stratified according to steroid use for the current episode of AECB in four groups defined as follows: (1) none: no steroid use at randomization or no increase in long-term steroid dosage; (2) long-term inhaled: administered for ⬎ 2 months prior to randomization; (3) systemic: started at randomization or increased dosage at randomization if previously administered; and (4) systemic and long-term: combination of last two definitions. Patients received in a double-blind fashion either moxifloxacin (one 400-mg tablet qd for 5 days) or the comparator drug, which the physician preselected from the three possible antibiotic options: amoxicillin (one 500-mg capsule tid for 7 days), clarithromycin (two 250-mg tablets bid for 7 days), or cefuroxime-axetil (one 250-mg tablet bid for 7 days). This choice was based on therapeutic habits, knowledge of local pathogens epidemiology, in vitro susceptibilities, and clinical presentation of the patient. The randomization list used a block size such that an equal number of patients were allocated to each treatment arm in each block, and patients were assigned sequential ascending random numbers within each center and stratum. The randomization list was not accessible to any individuals involved in study conduct, and patient codes could be broken only in case of emergency. In order to ensure blinding, all active drugs were encapsulated for identical appearance and placebo capsules were included in the blister packs as appropriate, including placebo capsules on treatment day 6 and day 7 in the moxifloxacin treatment arm. Patients were contacted by telephone toward the end of study treatment (days 5 to 7 after randomization), and were then examined 7 to 10 days after completing treatment, and sputum, if present, was sent for examination. Long-term www.chestjournal.org
follow-up was made by monthly telephone contacts up to a maximum of 9 months after study treatment. The last visit occurred either at the time of the next AECB or at 9 months, whichever came first, and comprised a clinical assessment and sputum sample. The primary outcome measure was clinical success assessed 7 to 10 days after the end of treatment, defined as the proportion of patients with clinical cure or improvement according to the following definition: clinical cure (return to pre-exacerbation status, no additional antimicrobial therapy required); clinical improvement (not complete return to pre-exacerbation status, but sufficient improvement in clinical signs and symptoms that no alternative antimicrobial therapy was required); clinical failure (no change, worsening, insufficient improvement or reappearance of signs and symptoms of infection such that alternative antimicrobial therapy is required); and indeterminate (clinical assessment not possible). Secondary clinical efficacy measures included the frequency of additional antimicrobial therapy, time to the next AECB, and bacteriologic success. Bacteriologic success was defined as eradication or presumed eradication 7 to 10 days after treatment according to the following definition: eradication (original causative organisms absent on sputum culture); presumed eradication (absence of appropriate culture material for evaluation because the patient improved clinically and was unable to produce sputum); persistence (original organisms still present on sputum culture); presumed persistence (absence of appropriate culture material for evaluation and patient assessed as clinical failure); superinfection (isolation of new pathogens/causative organisms judged to be causing an infectious process in the respiratory tract associated with clinical signs); and indeterminate (bacteriologic response of the study drug not evaluable for any reason). CHEST / 125 / 3 / MARCH, 2004
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Statistical Analysis
Results
The intent-to-treat (ITT) population included all randomized patients receiving at least one dose of study drug, and the per-protocol (PP) population included patients with confirmed infectious Anthonisen type 1 AECB, who received no systemic antimicrobial agents other than study drug for at least 3 days in the case of clinical failure or ⱖ 80% of study medication in case of cure, with adequate documentation of compliance and absence of major protocol violations. The microbiologically valid population included PP patients with at least one pretherapy causative organism and an appropriate posttherapy bacteriologic evaluation. The study was powered as a noninferiority study, and the sample size was calculated in order to demonstrate that moxifloxacin was not ⬎ 10% less effective than the comparator regimen. Sample size was based on a predicted failure rate of 15% in the comparator arm with a 10% equivalence ⌬ between study arms, ␣ ⫽ 2.5% (one sided) and  ⫽ 10%. On that basis, 318 patients were needed per treatment arm, including a 15% addition for multicenter design.37 With an assumed validity rate of approximately 95% for the primary efficacy parameter, 670 patients needed to be randomized. Baseline treatment arm comparability was tested using a one-way analysis of variance or Student t test for normally distributed variables, or Fisher exact test for categorical variables. For analyses of equivalence, a two-sided 95% confidence interval (CI) was calculated using Mantel-Haenszel weighting. If the lower limit of the 95% CI for the true difference of clinical success rates was within – 10%, moxifloxacin was proven to be no less effective than comparator. If the lower limit was ⬎ 0, superiority of treatment with moxifloxacin was proven. Exploratory life-table (Kaplan-Meier) analyses were performed for the time to first occurrence of a composite event, defined as failure of study treatment, or occurrence of a new AECB, or administration of any antibiotic treatment for AECB.
A total of 1,935 patients were enrolled in 103 centers, 733 of whom were randomized. The randomized and nonrandomized populations were comparable in age, sex, and FEV1, but mean duration of CB and number of AECB episodes in the previous year were significantly greater in the randomized population (Table 1). The trial population profile is shown in Figure 2. In the comparator arm, treatment selection was country dependent, with cefuroxime-axetil being administered from 0 to 65% of comparator recipients (174 patients overall), clarithromycin from 0 to 32% (114 patients), and amoxicillin from 0 to 58% (88 patients). The most frequent reasons given for comparator choice were clinical presentation of the patient and local susceptibility pattern of suspected pathogens. Treatment arms were comparable for all variables at both enrollment and randomization visits (Table 2). In 232 patients (31.8%), a total of 254 organisms were isolated at the randomization visit. As shown in Table 3, the most common organisms were Haemophilus influenzae, present in 41.8% of all isolates, and Streptococcus pneumoniae, detected in 20.3% of all isolates. H influenzae (45.6% compared to 38.8%), Enterobacteriaceae (15.5% compared to 10.1%), and Pseudomonas spp (7.8% compared to 3.9%) were more frequently isolated in patients with the greatest degree of airflow obstruction (FEV1
Table 1—Patient Characteristics by Randomization Status* Characteristics Male gender Age, yr ⱖ 65 ⬍ 65 Years since CB diagnosis‡ AECBs in previous year, No.§ ⬍4 ⱖ4 FEV1 % predicted㛳 ⬍ 50 ⱖ 50
Enrolled (n ⫽ 1,935)
Randomized (n ⫽ 733)
Nonrandomized (n ⫽ 1,202)
1,320 (68.2) 63.4 ⫾ 9.7 918 (47.4) 1,017 (52.6) 11.7 ⫾ 9.6 2.9 ⫾ 1.3 1,505 (77.8) 426 (22.0)
498 (67.9) 63.2 ⫾ 9.8 347 (47.3) 386 (52.7) 12.5 ⫾ 9.8 3.1 ⫾ 1.4 530 (72.3) 203 (27.7)
822 (68.4) 63.6 ⫾ 9.7 571 (47.5) 631 (52.5) 11.1 ⫾ 9.5 2.8 ⫾ 1.3 975 (81.1) 223 (18.6)
861 (44.5) 1,067 (55.1)
310 (42.3) 423 (57.7)
511 (42.5) 644 (53.6)
p Value† 0.84¶ 0.49# 0.94** 0.04# ⬍ 0.01# ⬍ 0.01††
0.41‡‡
*Data are presented as mean ⫾ SD or No. (%). †Nonrandomized vs randomized. ‡Not reported in six nonrandomized patients. §Not reported in four nonrandomized patients. 㛳Not reported in seven nonrandomized patients. ¶2 test. #t test. **2 test, ⱖ 65 years vs ⬍ 65 years. ††2 test, ⬍ 4 exacerbations vs ⱖ 4 exacerbations. ‡‡2 test, ⬍ 50% predicted vs ⱖ 50% predicted. 956
Clinical Investigations
Figure 2. Patient disposition.
⬍ 50%). Across organisms, pretreatment minimum inhibitory concentration for 90% of isolates (MIC90) ranged from 0.11 to 8 mg/L for moxifloxacin and 0.25 to 256.00 mg/L for comparator. With regard to www.chestjournal.org
treatment compliance, 342 patients (96.6%) and 370 patients (98.4%) received the full treatment course in the moxifloxacin and comparator arms, respectively. CHEST / 125 / 3 / MARCH, 2004
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Table 2—Patient Characteristics by Treatment Arm (ITT Population)* Characteristics Enrollment visit Male gender Age, yr Years since CB diagnosis FEV1 % predicted ⬍ 50 ⱖ 50 AECBs in previous year ⬍4 ⱖ4 Smoking history in years Previous smokers Current smokers Cardiopulmonary disease Not present Present Randomization visit Days between onset of AECB symptoms and randomization† ⬍4 4–7 ⬎7 Temperature, °C ⬎ 38.5°C Respiration rate, breaths/min Steroid use None‡ Long-term inhaled§ Systemic and long-term inhaled Systemic㛳
Moxifloxacin (n ⫽ 354)
Comparator (n ⫽ 376)
243 (68.6) 63.8 ⫾ 9.7 12.2 ⫾ 9.7
253 (67.3) 62.6 ⫾ 9.9 12.8 ⫾ 9.9
149 (42.1) 205 (57.9)
159 (42.3) 217 (57.7)
257 (72.6) 97 (27.4) 37.5 ⫾ 11.1 208 (58.8) 146 (41.2)
270 (71.8) 106 (28.2) 37.7 ⫾ 11.2 203 (54.0) 173 (46.0)
301 (85.0) 53 (15.0)
324 (86.2) 52 (13.8)
p Value 0.74¶ 0.08# 0.45# 0.81¶
0.79¶
0.80#
0.59¶
0.54¶ 249 (70.3) 63 (17.8) 41 (11.6) 37.6 ⫾ 0.8 52 (14.7) 21.5 ⫾ 5.2
275 (73.1) 67 (17.8) 34 (9.0) 37.6 ⫾ 0.8 58 (15.4) 21.9 ⫾ 5.8
151 (42.7) 97 (27.4) 55 (15.5) 51 (14.4)
160 (42.6) 119 (31.6) 57 (15.2) 40 (10.6)
0.31# 0.35# 0.36¶
*Data are presented as No. (%) or mean ⫾ SD. †Not reported for one patient in the moxifloxacin arm. ‡Or no increase in steroid dosage. §Administered for ⬎ 2 mo prior to randomization. 㛳Started at randomization or increased dosage at randomization if previously administered. ¶2 test. #t test.
Moxifloxacin and the comparator regimens were equivalent in terms of clinical success (cure plus improvement) rates at 7 to 10 days after therapy. This was confirmed in the subgroups of patients with bacteriologically documented AECB. Moxifloxacin showed superiority over comparator on clinical cure at 7 to 10 days after therapy in both the ITT and PP populations, with a consistent 7 to 8% difference between treatment arms (Table 4). When clinical failure was analyzed in patients who required additional antibiotic therapy when treatment failed, failure rates were significantly lower in the moxifloxacin group (27 of 354 patients, 7.6%) than in the comparator group (53 of 376 patients, 14.1%) in the ITT population (95% CI, 2.3 to 11.6), and in the PP population (24 of 274 patients [8.8%] vs 44 of 298 patients [14.8%]; 95% CI, 0.6 to 11.1). In the microbiologically valid population, the bac958
teriologic success rate with moxifloxacin was significantly higher than with the comparator (Table 5). There were 3 persisting organisms in the moxifloxacin regimen (Klebsiella pneumoniae [baseline minimum inhibitory concentration (MIC), 0.064 mg/L], Haemophilus parainfluenzae [MIC 0.125 mg/L], and S pneumoniae [MIC 0.125 mg/L]) and 11 persisting organisms in the comparator regimen (Moraxella catarrhalis [baseline MIC of cefuroxime, 1.0 mg/L], Pseudomonas aeruginosa [all three under cefuroxime, MIC 4.0 mg/L and 256 mg/L], H influenzae [amoxicillin, two strains: MIC 0.38 mg/L and 0.5 mg/L; clarithromycin, two strains: MIC 1.5 mg/L and 16 mg/L; cefuroxime, two strains: MIC 1.0 mg/L and 0.38 mg/L], H parainfluenzae [amoxicillin, MIC 128 mg/L]). A superinfection was observed in three patients and two patients in the moxifloxacin and comparator groups, respectively. In the moxifloxacin Clinical Investigations
10.5 10.0 48.2 0.0 68.5 12.00 (94) 1.50 (30) 256.00 (26) 20.00 (20) 256.00 (19) 19 (45.2) 7 (16.7) 4 (9.5) 1 (2.4) 2 (4.8) 14.8 20.0 53.9 5.0 77.8
31 (73.8)
36.00 (95) 25.00 (30) 256.00 (26) 1.50 (20) 256.00 (18) 18 (58.1) 2 (6.5) 1 (3.2) 5 (16.1) 1 (3.2) 45 (40.2) 13 (11.6) 16 (14.3) 11 (9.8) 11 (9.8)
0.0 0.0 0.0 0.0 30.0
27 (87.1) 90 (80.4)
0.19 (95) 0.11 (30) 1.50 (28) 0.25 (20) 8.00 (20)
*Percentages refer to patients with at least one organism; patients could have more than one organism isolated. †Data in parenthesis are numbers of strains with E-test MIC determination. ‡In vitro resistance is defined as MIC ⬎ 2 mg/L (moxifloxacin), ⬎ 16 mg/L (amoxicillin), ⬎ 4 mg/L (clarithromycin), and ⬎ 4 mg/L (cefuroxime-axetil).
54.2 3.3 100.0 85.0 94.7
42 (89.4)
15 (31.9) 9 (19.1) 8 (17.0) 4 (8.5) 8 (17.0)
16.00 (95) 14.50 (30) 256.00 (27) 2.00 (20) 256.00 (19)
21.8 0.0 8.00 (46) 1.50 (7) 7 (14.9) 6 (12.8) 1 (2.1) 28.3 0.0 14.00 (46) 0.25 (7) 12 (28.6) 10 (23.8) 2 (4.8) 0.0 14.3 0.38 (46) 24.00 (7) 6 (19.4) 5 (16.1) 1 (3.2) 2.2 0.0 0.19 (46) 0.13 (7) 29 (25.9) 26 (23.2) 3 (2.7)
Gram positive Any Gram-positive organism S pneumoniae Staphylococcus aureus Gram negative Any Gram-negative organism H influenzae Moraxella catarrhalis Enterobacteriaceae Haemophilus parainfluenzae Other Gram negative
% Resistance‡ MIC90, mg/L† No. (%)* % Resistance‡ Variables
No. (%)*
MIC90, mg/L†
% Resistance‡
No. (%)*
MIC90, mg/L†
% Resistance‡
No. (%)*
MIC90, mg/L†
Cefuroxime-Axetil (n ⫽ 47) Clarithromycin (n ⫽ 42) Amoxicillin (n ⫽ 31) Moxifloxacin (n ⫽ 112)
Table 3—Distribution and MIC90 of Test Antibiotics Against Pathogens Isolated From Pretreatment Samples
www.chestjournal.org
group, superinfecting organisms were S pneumoniae (MIC 0.064 mg/L), M catarrhalis (MIC 0.047 mg/L) and P aeruginosa (MIC 1.5 mg/L). In the comparator group, superinfecting organisms were S pneumoniae (MIC 4.0 mg/L) and K pneumoniae (MIC 2.0 mg/L), with both organisms affecting patients receiving cefuroxime. In the moxifloxacin study arm, there was a significantly lower frequency of additional antibiotic therapy than comparator regimen in the PP population (26 of 274 patients [9.5%] vs 45 of 298 patients [15.1%], p ⫽ 0.045), which was confirmed in the ITT population (p ⫽ 0.006). Clinical cure (p ⫽ 0.03) was achieved in a significantly higher proportion of patients with moxifloxacin than comparator among patients receiving no concomitant steroid treatment or with no change in systemic steroid treatment in the ITT population (Table 6). Both the clinical success and cure rates were lower in both treatment groups in patients with the greatest degree of airway obstruction; for the ITT population, moxifloxacin had a significantly (p ⬍ 0.03) higher clinical cure rate in patients with a FEV1ⱖ 50% (Table 7). During the follow-up period, and after exclusion of ITT patients who received a further antibiotic to the study treatment course for the presenting AECB, a new AECB was documented in 179 of 324 patients in the moxifloxacin arm and in 176 of 319 patients in the comparator arm. In that population, median times to the next AECB were 131.0 days (range, 18 to 289 days) and 103.5 days (range, 14 to 280 days) for moxifloxacin and comparator, respectively. Mean times to the next AECB were 132.8 days (SD 67.5) and 118.0 days (SD 67.9) for moxifloxacin and comparator, respectively; the difference was statistically significant (p ⫽ 0.03). In a life-table analysis of time to the first composite event (treatment failure, and/or new exacerbation and/or any further antibiotic treatment), the log-rank test showed a significant difference in favor of moxifloxacin for up to 5 months of follow-up (p ⫽ 0.03), a difference that was no longer statistically significant over the entire study follow-up (p ⫽ 0.11). When the same analysis was stratified according to the date of the last exacerbation, moxifloxacin was superior to comparator in the subgroup of patients who had an exacerbation ⬍ 6 months prior to randomization (Fig 3). Adverse events considered as possibly or probably related to study drug were reported in a similar number of patients in both groups (Table 8). These events were usually mild to moderate in intensity. Study medication was prematurely discontinued because of adverse events in four patients of each group (1.1%). Of 43 serious adverse events, 19 events were reported in the moxifloxacin treatment arm and 24 events in the comparator arm. Two CHEST / 125 / 3 / MARCH, 2004
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Table 4 —Summary of Clinical Efficacy Results at 7 to 10 Days of Therapy ITT Population Variables Clinical success*† Clinical cure Clinical success in patients with bacteriologically confirmed AECB*
PP Population
Moxifloxacin, No./Total (%)
Comparator, No./Total (%)
95% CI
Moxifloxacin, No./Total (%)
Comparator, No./Total (%)
95% CI
310/354 (87.6) 251/354 (70.9) 98/112 (87.5)
312/376 (83.0) 236/376 (62.8) 94/120 (78.3)
⫺ 0.7–9.5 1.4–14.9 ⫺ 1.4–17.9
239/274 (87.2) 191/274 (69.7) 62/71 (87.3)
251/298 (84.2) 185/298 (62.1) 66/79 (83.5)
⫺ 3.0–8.5 0.3–15.6 ⫺ 7.2–15.4
*Clinical cure and improvement combined. †Clinical success rates in amoxicillin, clarithromycin, and cefuroxime-axetil groups were 83.0%, 84.2%, and 82.2% in the ITT population, respectively; corresponding data were 81.5%, 87.4%, and 83.8% in the PP population.
serious events (sepsis and dyspnea) were considered possibly related to study medication in the comparator arm, both of which resolved. There were nine deaths during the study, three in the moxifloxacin treatment arm and six in the comparator arm. Two patients in the comparator arm died from respiratory failure. No deaths were associated with study treatment. Discussion In terms of clinical success 7 to 10 days after the end of treatment, 5 days of moxifloxacin was at least as effective as 7 days of conventional antibiotic therapy in all prospectively defined study populations. This result is consistent with previous stud-
ies33,34 comparing moxifloxacin to different antibiotic regimens. However, this study bears a greater significance for clinical practice, as the design more closely mimicked the real-life practice while maintaining a high degree of internal validity.38,39 In our study, equivalence was achieved under a demanding scheme: the comparator therapy was chosen for each patient among three well-established first-line treatments comprising two different drug classes (lactam and macrolides). Selection of comparators was based on current guidelines,13,26,27 and also reflected medical practice in participating countries. In making this probabilistic first-line choice, the physician could therefore take into account the individual patient clinical presentation, the regional or national guidelines, and the local epidemiology of
Table 5—Bacteriologic Response 7 to 10 days After Therapy ITT Population
Microbiologically Valid Population
Variables
Moxifloxacin, No. (%)
Comparator, No. (%)
Moxifloxacin, No. (%)
Comparator, No. (%)
Total Bacteriologic success Eradication Presumed eradication Bacteriologic failure Eradication with superinfection Persistence* S pneumoniae H influenzae H parainfluenzae K pneumoniae M catarrhalis P aeruginosa Serratia marcescens Presumed persistence Indeterminate/missing 95% CI§
112 (100.0) 86 (76.8) 42 (37.5) 44 (39.3) 26 (23.2) 3 (2.7) 7 (6.3) 1 (0.9) 1 (0.9) 1 (0.9) 1 (0.9) 0 2 (1.8) 1 (0.9) 1 (0.9)† 15 (13.4)
120 (100.0) 81 (67.5) 39 (32.5) 42 (35.0) 39 (32.5) 4 (3.3) 15 (12.5) 0 9 (7.5) 1 (0.8) 0 2 (1.7) 3 (2.5) 0 1 (0.8)‡ 19 (15.8)
71 (100.0) 65 (91.5) 36 (50.7) 29 (40.8) 6 (8.4) 3 (4.2) 3 (4.2) 1 (1.4) 0 1 (1.4) 1 (1.4) 0 0 0 0 0
79 (100.0) 64 (81.0) 35 (44.3) 29 (36.7) 15 (19.0) 4 (5.1) 11 (13.9) 0 6 (7.6) 1 (1.3) 0 1 (1.3) 3 (3.8) 0 0 0
⫺ 1.8–20.4
0.4–22.1
*Includes persistence with superinfection. †Enterobacter cloacae. ‡H influenzae. §CI calculated for the difference in bacteriologic success rate. 960
Clinical Investigations
Table 6 —Clinical Results by Steroid Use 7 to 10 Days After Therapy* ITT Population Variables Clinical success None† Systemic‡ Inhaled§ Systemic and inhaled Clinical cure None† Systemic‡ Inhaled§ Systemic and inhaled
PP Population
Moxifloxacin
Comparator
p Value
Moxifloxacin
Comparator
p Value
138/151 (91.4) 43/51 (84.3) 83/97 (85.6) 46/55 (83.6)
136/160 (85.0) 36/40 (90.0) 94/119 (79.0) 46/57 (80.7)
0.07 0.43 0.21 0.69
96/104 (92.3) 33/40 (82.5) 74/86 (86.0) 36/44 (81.8)
109/126 (86.5) 28/31 (90.3) 73/92 (79.3) 41/49 (83.7)
0.16 0.35 0.24 0.81
117/151 (77.5) 35/51 (68.6) 63/97 (64.9) 36/55 (65.5)
106/160 (66.3) 30/40 (75.0) 68/119 (57.1) 32/57 (56.1)
0.03 0.50 0.24 0.31
77/104 (74.0) 27/40 (67.5) 59/86 (68.6) 28/44 (63.6)
83/126 (65.9) 22/31 (71.0) 52/92 (56.5) 28/49 (57.1)
0.18 0.75 0.10 0.52
*Data are presented as No./Total (%). †Or no change in dosage of steroids at randomization; patients stratified in the “no steroids” stratum while on previous steroids: ITT, 24 (moxifloxacin) and 33 (comparator); PP, 18 (moxifloxacin), and 29 (comparator). ‡Started at randomization or increased dosage at randomization if previously administered. Mean dose of prednisone equivalent: 30.1 mg (SD 19.4) vs 29.8 mg (20.9) in moxifloxacin and comparator, respectively. §Administered for ⬎ 2 months prior to randomization.
AECB-related pathogens and their in vitro susceptibilities, so that the study results can be interpreted in terms of global clinical effectiveness rather than efficacy only. The present study was designed to compare moxifloxacin to a basket of comparators in a two-arm manner; consequently, it was not powered for ad hoc comparisons of moxifloxacin with separate agents of the comparator group. Moreover, such comparisons would likely be biased since the selection of the comparator in the standard care arm was not randomized but resulted from the clinician’s choice. Therefore, inferential conclusions can only be drawn from the comparison of moxifloxacin to the standard care group, which was itself adjusted to individual patient needs. A significantly greater proportion of patients receiving moxifloxacin for 5 days showed clinical cure 7 to 10 days after the end of treatment than with a 7-day course of conventional antibiotic therapy. It can be argued that clinical cure, which required a complete return to pre-exacerbation status, is important with respect to patient satisfaction. Patients
treated with moxifloxacin for an acute bacterial exacerbation have been shown to have faster symptom relief and return to normal activities more rapidly than those treated with macrolides.40 Clinical cure could also influence long-term outcomes, in that patients who had only improved might be more susceptible to relapse. The significantly greater proportion of patients with bacteriologic success in the moxifloxacin arm is consistent with results reported previously in a study33 comparing moxifloxacin and clarithromycin in AECB. Whereas there were hardly any drugresistant S pneumoniae, comparator treatment showed markedly less eradication of H influenzae than moxifloxacin after treatment. This was likely a contributory factor for the significantly lower proportion of patients requiring further antimicrobials after moxifloxacin than comparator treatment. The proportion of patients with isolated pathogens (31.8%) was lower than expected, especially given Anthonisen type 1 criteria and macroscopic sputum purulence,41 but it is within the range reported in previous studies of AECB.42– 46 This might be ex-
Table 7—Clinical Results by Degree of Airway Obstruction 7 to 10 Days After Therapy* ITT Population Variables Clinical success FEV1 ⬍ 50% FEV1 ⱖ 50% Clinical cure FEV1 ⬍ 50% FEV1 ⱖ 50%
PP Population
Moxifloxacin
Comparator
p Value
Moxifloxacin
Comparator
p Value
124/149 (83.2) 186/205 (90.7)
126/159 (79.3) 186/217 (85.7)
0.37 0.11
98/119 (82.4) 141/155 (91.0)
105/130 (80.8) 146/168 (86.9)
0.75 0.25
89/149 (59.7) 162/205 (79.0)
85/159 (53.5) 151/217 (69.6)
0.27 0.03
70/119 (58.8) 121/155 (78.1)
69/130 (53.1) 116/168 (69.1)
0.36 0.07
*Data are presented as No./Total (%). www.chestjournal.org
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Figure 3. Life-table analysis of time to the first composite event (treatment failure, and/or new exacerbation and/or any further antibiotic treatment) stratified according to the time of the last exacerbation prior to randomization.
plained by the stringency of sputum assessment and an additional 30.3% proportion of patients who had respiratory pathogens without any stringent criteria. The a priori stratification according to steroid use was meant to avoid imbalance in steroid allocation to study treatment groups, therefore ensuring that the comparison between moxifloxacin and the comparator was not biased by the concomitant use of steroids. However, no inference on the clinical efficacy of steroids treatments can be drawn from this study since the allocation of steroids was not randomized. In that light, caution is needed in interpreting the
Table 8 —Incidence of More Frequent Drug-Related Adverse Events* Variables
Moxifloxacin (n ⫽ 354)
Comparator (n ⫽ 376)
Any adverse event Abdominal pain Headache Diarrhea Gastritis Nausea Dizziness Nervousness Taste perversion
25 (7.1) 3 (0.8) 4 (1.1) 9 (2.5) 2 (0.6) 3 (0.8) 3 (0.8) 2 (0.6) —
18 (4.8) 2 (0.5) 3 (0.8) 3 (0.8) — 2 (0.5) — — 3 (0.8)
*At least two patients reporting a possible or probable drug-related adverse event. Data are presented as No. of patients (%). 962
data for clinical success with moxifloxacin vs comparator in patients who did not concomitantly receive steroids for the presenting AECB or had no change in their long-term corticosteroids treatment. Further research will be needed, possibly using factorial study designs analyzing the correlations among several variables, to document whether there is a potential for treatment interaction between antibiotic and corticosteroid use. Corticosteroids might have an effect per se. Alternatively, their use may simply signal a more severe subgroup of the CB population with a different clinical prognosis. These considerations are also relevant to the lack of a difference between the two treatment groups in those patients with the most severe airflow obstruction, who would be more likely to receive corticosteroids, and the superiority of moxifloxacin over comparator in those patients with less severe airflow obstruction (clinical cure in ITT population), who would not. When factorial designs are not applicable, consideration should be given to excluding corticosteroid use in clinical trials seeking to investigate differences between antibiotics. One recent study47 included a long-term observational period after treatment follow-up to determine whether fluoroquinolone treatment prolongs the time to next AECB compared to a standard therapy. In that study,47 a significantly greater proportion of Clinical Investigations
patients receiving a 5-day course of gemifloxacin remained free of AECB over a 26-week period than those receiving a 7-day course of clarithromycin. In our study, the time to next exacerbation was significantly longer in the moxifloxacin arm, with an approximately 13% and 27% benefit for mean and median times, respectively. The superiority of moxifloxacin over standard antibiotic treatment in terms of the percentage of patients who had not failed during the first exacerbation or had a further exacerbation requiring antibiotic treatment was seen up to 5 months after randomization. Moxifloxacin was also superior over comparator therapy when considering those patients whose previous exacerbation had occurred within six months of randomization. These patients are likely to have more frequent exacerbations. Adverse events were usually mild to moderate in intensity and reported at comparable rates in both treatment arms. In line with the known safety profile of moxifloxacin, most of these events in the moxifloxacin arm were related to the digestive or nervous system.48 Taken together, this study demonstrated that moxifloxacin was equivalent to the comparator regimen for the primary outcome measure, ie, clinical success at 7 to 10 days after therapy. Superiority with moxifloxacin was shown for both short-term and long-term efficacy variables including cure rate, need for additional antimicrobial treatment of AECB, rate of bacteriologic eradication, and time to next exacerbation. All study treatments were safe and well tolerated. In conclusion, these consistent data support the use of moxifloxacin for the treatment of AECB. The methods of this study should be taken into consideration in the design of future clinical studies of AECB, and the results of this study should be considered for possible re-evaluation of current AECB treatment guidelines. Appendix MOSAIC Study Group members Argentina: Horacio Ariza, Luis Horacio Marquez, Lucia Cristina Marzoratti; Australia: David Mackenzie, Charles Mitchell, Matthew Peters, Martin Phillips, Anne-Marie Southcott; Austria: Norbert Vetter; Belgium: Guido Creytens, Jean-Benoit Martinot; Brazil: Alberto Cukier, Luiz Carlos Correˆ a Da Silva; Finland: Tuomo Kava, Esko Kurttila, Pekka Saarelainen, Anja Suontausta, Martti Torkko, Kari Venho; France: Nathan Abenhaim, Jacques Allix, Robert Arnou, Martial Boucheret, Nicolas Breton, Pierre Causse, Salam Farhat, Robert Francon, Jean-Paul Grazzini, Eric Mascherpa, Miche`le Pithon, Alain Simmons, Gilles Sorbe, JeanYves Vogel; Germany: Klaus Bo¨ ge, Manfred Bo¨ hm, Eduard Chesin, Klaus Colberg, Rolf Dichmann, Thomas Ginko, Klaus Harzbecker, Reinhard Hu¨ ting, Ina Itzigehl, Josef Junggeburth, Helmut Leiner, Karin Liebscher, Anneliese Linnhoff, Mechthild Otto, Beate Rosenblum, Johannes Rumpf, So¨ ren Schmidtmann, www.chestjournal.org
Renita Schnorr, Thomas Schultz, Peter Stutz, Harald Sudhoff, Ilona Szasz, Lutz Volgmann, Walter Vorderstrasse, Heinrich Weber; Greece: Harry Bassaris, Paul Nikolaidis, Emmanouel Papadakis; Hungary: Eleonora Babinszky, Eva Bauknecht, Agnes Forrai, Zoltan Kuberka, Katalin Major, Miklos Namenyi, Maria Poncsak, Katalin Rajkay, Amalia Weltner; Israel: Abraham Eliraz, Joel Greif, Robert Shiner, Daniel Weiler; Mexico: Raul Bates Flores, Ricardo Bujanos, Rodolfo Posadas Valay, Gerardo Rico Mendez, Raul Sansores; Norway: Kjell Langaker, Jetmund Ringstad; Poland: Małgorzata Czajkowska-Malinowska, Małgorzata Jeˆdrzejczak, Iwona Grzelewska-Rzymowska, Władysław Pierzchała, Tadeusz Płusa, Paweł Sliwin˜ski, Hanna Szelerska-Twardosz, Teresa Wilewska-Kłubo; Portugal: Cecı´lia Ba´rbara Louro Robalo Nunes Sousa, Joa˜o Manuel De Sousa Almeida; Slovenia: Ema Musˇic, Renato Er en; Spain: Cristian Domingo, Jose Maria Ignacio, Jose Morera, Santiago Romero, Candelaria Santana, Rafael Zalacain; Switzerland: Ju¨rg Baradun, Urs Honegger; United Kingdom: Gary Barlow, Neil Barnes, Barry Glekin, Charles Langan, R. Macleod, Gerry Mackaig, Robert Wilson.
References 1 Doll H, Grey-Amante P, Duprat-Lomon I, et al. Quality of life in acute exacerbations of chronic bronchitis: results from a German population study. Respir Med 2002; 96:39 –51 2 Miravitlles M, Murio C, Guerrero T, et al, on behalf of the DAFNE study group. Pharmacoeconomic evaluation of acute exacerbations of chronic bronchitis and COPD. Chest 2002; 121:1449 –1455 3 Seemungal TAR, Donaldson GC, Paul EA, et al. Effect of exacerbation on quality of life in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1998; 157:1418 –1422 4 Sethi S. Infectious etiology of acute exacerbations of chronic bronchitis. Chest 2000; 117(Suppl):380 –385 5 Adams SG, Anzueto A. Antibiotic therapy in acute exacerbations of chronic bronchitis. Semin Respir Infect 2000; 15: 234 –247 6 Anthonisen NR, Manfreda J, Warren CP, et al. Antibiotic therapy in exacerbations of chronic obstructive pulmonary disease. Ann Intern Med 1987; 106:196 –204 7 Ball P, Make B. Acute exacerbations of chronic bronchitis: an international comparison. Chest 1998; 113:1995–2045 8 Destache CJ. Optimizing economic outcomes in acute exacerbations of chronic bronchitis. Pharmacotherapy 2002; 22(Suppl):12S–17S 9 Pauwels R. Global initiative for chronic obstructive lung diseases (GOLD): time to act. Eur Respir J 2001; 18:901–902 10 Reynolds HY. Chronic bronchitis and acute infectious exacerbations. In: Mandell GL, Bennett JE, Dolin R, eds. Principles and practice of infectious diseases. 5th ed. New York, NY: Churchill Livingstone, 2000:706 –710 11 Siafakas NM, Vermeire P, Pride NB, et al. Optimal assessment and management of chronic obstructive pulmonary disease (COPD): The European Respiratory Society Task Force. Eur Respir J 1995; 8:1398 –1420 12 Saint S, Bent S, Vittinghoff E, et al. Antibiotics in chronic obstructive pulmonary disease exacerbations: a meta-analysis. J Am Med Assoc 1995; 273:957–960 13 Snow V, Lascher S, Mottur-Pilson C. Evidence base for management of acute exacerbations of chronic obstructive pulmonary disease. Ann Intern Med 2001; 134:595–599 14 Sethi S. The role of antibiotics in acute exacerbations of chronic obstructive pulmonary disease. Curr Infect Dis Rep 2003; 5:9 –15 15 Dewan NA, Rafique S, Kanwar B, et al. Acute exacerbation of CHEST / 125 / 3 / MARCH, 2004
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COPD: factors associated with poor treatment outcome. Chest 2000; 117:662– 671 Grossman R. The value of antibiotics and the outcomes of antibiotic therapy in exacerbation of COPD. Chest 1998; 113(Suppl):249 –255 Hoban DJ, Doern GV, Fluit AC, et al. Worldwide prevalence of antimicrobial resistance in Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis in the SENTRY Antibiotic Surveillance Program, 1997–1999. Clin Infect Dis 2001; 32(Suppl):81–93 Lin˜ ares J, de la Campa AG, Pallares R. Fluoroquinolone resistance in Streptococcus pneumoniae. N Engl J Med 1999; 341:1546 –1548 Sethi S, Evans N, Grant BJB, et al. New strains of bacteria and exacerbations of chronic obstructive pulmonary disease. N Engl J Med 2002; 347:465– 471 Anthonisen NR. Bacteria and exacerbations of chronic obstructive pulmonary disease. N Engl J Med 2002; 347:526 – 527 Niewoehner DE, Erbland ML, Deupree RH, et al. Effect of systemic glucocorticoids on exacerbations of chronic obstructive pulmonary disease. N Engl J Med 1999; 340:1941–1953 Ball P, Harris JM, Lowson D, et al. Acute infective exacerbations of chronic bronchitis. QJM 1995; 88:61– 68 Grossman R, Mukherjee J, Vaughan D, et al. A 1-year community-based health economic study of ciprofloxacin vs usual antibiotic treatment in acute exacerbations of chronic bronchitis. Chest 1998; 113:131–141 Miravitlles M, Murio C, Guerrero T, on behalf of the DAFNE Study Group. Factors associated with relapse after ambulatory treatment of acute exacerbations of chronic bronchitis: a prospective multicenter study in the community. Eur Respir J: 2001; 17:928 –933 Wilson R, Tillotson G, Ball P. Clinical studies in chronic bronchitis: a need for better definition and classification of severity. J Antimicrob Chemother 1996; 37:205–208 Grossman RF. Guidelines for the treatment of acute exacerbations of chronic bronchitis. Chest 1997; 112(Suppl):310 – 313 European Study on Community-Acquired Pneumonia (ESOCAP) Committee. Guidelines for management of adult community-acquired lower respiratory infections. Eur Respir J 1998; 11:986 –991 Blondeau J, Zhao X, Hansen G, et al. Mutant prevention concentrations (MPC) for fluoroquinolones with clinical isolates of Streptococcus pneumoniae. Antimicrob Agents Chemother 2001; 45:433– 438 Jones ME, Karlowsky JA, Blosser-Middleton R, et al. Apparent plateau in -lactamase production among clinical isolates of Haemophilus influenzae and Moraxella catarrhalis in the United States: results from the LIBRA Surveillance initiative. Int J Antimicrob Agents 2002; 19:119 –123 Li X, Zhao X, Drlica K. Selection of Streptococcus pneumoniae having reduced susceptibility to levofloxacin and moxifloxacin. Antimicrob Agents Chemother 2002; 46:522– 524 Soman A, Honeybourne D, Andrews J, et al. Concentrations of moxifloxacin in serum and pulmonary compartments following a single 400 mg oral dose in patients undergoing fibre-optic bronchoscopy. J Antimicrob Chemother 1999; 44:835– 838 Lister PD, Sanders CC. Pharmacodynamics of moxifloxacin,
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levofloxacin and sparfloxacin against Streptococcus pneumoniae. J Antimicrob Chemother 2001; 47:811– 818 Wilson R, Kubin R, Ballin I, et al. Five day moxifloxacin therapy compared with 7 day clarithromycin therapy for the treatment of acute exacerbations of chronic bronchitis. J Antimicrob Chemother 1999; 44:501–513 Lode H, Garau J. Improving care for patients with respiratory tract infections. J Chemother 2002; 14(suppl 2):22–28 Reimer LG, Carroll KC. Role of the microbiology laboratory in the diagnosis of lower respiratory tract infections. Clin Infect Dis 1998; 26:742–748 Approved standard M100 –S8 performance standards for antimicrobial susceptibility testing: eighth informational supplement. Wayne, PA: National Committee for Clinical Laboratory Standards, 1998 Rodary C, Com-Nougue C, Tournade MF. How to establish equivalence between treatments: a one-sided clinical trial in paediatric oncology. Stat Med 1989; 8:593–598 Torres A, Muir J-F, Corris P, et al. Effectiveness of oral moxifloxacin in standard first-line therapy in communityacquired pneumonia. Eur Respir J 2003; 21:135–143 Lamping DL, Schroter S, Marquis P, et al. The communityacquired pneumonia symptom questionnaire: a new, patientbased outcome measure to evaluate symptoms in patients with community-acquired pneumonia. Chest 2002; 122:920 – 929 Kreis SR, and the Therapeutic Circles Bronchitis Study Group. A comparison of moxifloxacin and azithromycin in the treatment of acute exacerbations of chronic bronchitis. J Clin Outcomes Manage 2000; 7:33–37 Hill AT, Campbell EJ, Hill SL, et al. Association between airway bacterial load and markers of airway inflammation in patients with stable chronic bronchitis. Am J Med 2000; 109:288 –295 Chodosh S, Lakshminarayan S, Swarz H, et al. Efficacy and safety of a 10-day course of 400 or 600 milligrams of grepafloxacin once daily for treatment of acute bacterial exacerbations of chronic bronchitis: comparison with a 10-day course of 500 milligrams of ciprofloxacin twice daily. Antimicrob Agents Chemother 1998; 42:114 –120 Periti P, Novelli A, Schildwachter G, et al. Efficacy and tolerance of cefpodoxime proxetil compared with co-amoxiclav in the treatment of exacerbations of chronic bronchitis. J Antimicrob Chemother 1990; 26:63– 69 Rademaker CMA, Sips AP, Beumer HM, et al. A doubleblind comparison of low-dose ofloxacin and amoxycillinclavulanic acid in acute exacerbations of chronic bronchitis. J Antimicrob Chemother 1990; 26:75– 81 Ziering W, McElvaine P. Randomized comparison of oncedaily ceftibuten and twice-daily clarithromycin in the treatment of acute exacerbations of chronic bronchitis. Infection 1998; 26:68 –75 Sufarlan AW, Zainudin BMZ, Pit S, et al. Causative organisms in acute exacerbation of chronic airways disease and response to ofloxacin therapy. Drugs 1995; 49:442– 445 Wilson R, Schentag J, Ball P, et al. A comparison of gemifloxacin and clarythromycin in acute exacerbations of chronic bronchitis and long-term clinical outcomes. Clin Ther 2002; 24:639 – 652 Lode H, Kubin R, Reiter C. Safety update of oral moxifloxacin: a review of worldwide post-marketing surveillance [abstract]. Clin Microbiol Infect 2002; 8:323
Clinical Investigations
Study objectives: To compare the effectiveness of oral moxifloxacin with standard antibiotic therapy in acute exacerbation of chronic bronchitis (AECB). Design: Multicenter, multinational, randomized, double-blind study of two parallel treatment arms. Patients: Outpatients > 45 years old with stable chronic bronchitis, smoking history of > 20 pack-years, two or more AECBs in the previous year, and FEV1 < 85% of predicted value. Patients were enrolled when in a stable condition, and patients with exacerbations within 12 months of enrollment were randomized. Interventions: Randomization (stratified on steroid use) between moxifloxacin (400 mg qd for 5 days) and standard therapy (amoxicillin [500 mg tid for 7 days], clarithromycin [500 mg bid for 7 days], or cefuroxime-axetil [250 mg bid for 7 days]). Measurements: Assessment at enrollment, randomization (Anthonisen type 1 exacerbation), 7 to 10 days after treatment, and monthly until next AECB or up to 9 months. The primary efficacy variable was clinical success (sufficient improvement, no alternative antimicrobial therapy required) 7 to 10 days after therapy. Secondary predefined end points were clinical cure (return to pre-exacerbation status), further antimicrobial use, time to next AECB, and bacteriologic success. Results: Three hundred fifty-four patients received moxifloxacin, and 376 patients received standard therapy. At 7 to 10 days after therapy, clinical success rates were similar in intentionto-treat (ITT) patients (95% confidence interval [CI], ⴚ 0.7 to 9.5) and per-protocol (PP) patients (95% CI, ⴚ 3.0 to 8.5). Moxifloxacin showed superior clinical cure rates over standard therapy in both ITT patients (95% CI, 1.4 to 14.9) and PP patients (95% CI, 0.3 to 15.6), and higher bacteriologic success in microbiologically valid patients (95% CI, 0.4 to 22.1). Fewer ITT patients required antimicrobials after treatment with moxifloxacin than standard therapy (p < 0.01). Time to next exacerbation was longer with moxifloxacin; median and mean times to new AECBs in ITT patients who did not require any further antibiotics were 131.0 days and 132.8 days in moxifloxacin, and 103.5 days and 118.0 days in standard therapy, respectively (p ⴝ 0.03). The occurrence of failure, new exacerbation, or any further antibiotic was less frequent in moxifloxacin-treated patients for up to 5 months of follow-up (p ⴝ 0.03). Conclusions: Moxifloxacin was equivalent to standard therapy for clinical success and showed superiority over standard therapy in clinical cure, bacteriologic eradication, and long-term outcomes. (CHEST 2004; 125:953–964) Key words: acute exacerbation of chronic bronchitis; antibiotic; moxifloxacin Abbreviations: AECB ⫽ acute exacerbation of chronic bronchitis; CB ⫽ chronic bronchitis; CI ⫽ confidence interval; ITT ⫽ intention to treat; MIC ⫽ minimun inhibitory concentration; MIC90 ⫽ minimum inhibitory concentration for 90% of isolates; PP ⫽ per protocol
exacerbations of chronic bronchitis (AECBs) A cute are both costly and detrimental to quality of life. 1–3
Bacterial infection is implicated in approximately 50 to 60% of AECBs based on microbiological testing.4 Recently, a correlation has been demonstrated between emergence of new strains among bacteria colowww.chestjournal.org
nizing the respiratory tract and AECB, providing support for the etiologic role of bacteria in AECB. Empirical antibiotic treatment of AECB in patients with a range of different conditions has become widely accepted as standard practice, especially in patients who present with increased dyspnea, sputum volume, CHEST / 125 / 3 / MARCH, 2004
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and purulent sputum5–13; the evidence that bacteria cause exacerbations, which contribute to loss of lung function, has emphasized the importance of appropriate antibiotic treatment of acute exacerbations.14 For editorial comment see page 811 Studies of antibiotic treatment of AECB have yielded comparable cure rates in the order of 75 to 87%.15,16 In light of the increasing resistance of common respiratory tract pathogens to recommended antibiotics, the use of newer broad-spectrum agents has increased,17,18 and there remains a need to determine whether these are more effective than current standard first-line treatments.19,20 To date, clinical studies of antimicrobial therapy for AECB have been limited by a number of factors. These include inadequate information on patient condition prior to AECB and lack of long-term follow-up, as well as a lack of prospective control for concomitant corticosteroid use, which can positively affect the outcome of AECB,21 or for prognostic factors such as cardiopulmonary disease that can have a negative impact.15,22–24 Especially when designed to satisfy regulatory requirements, randomized studies have used a single, carefully chosen antimicrobial comparator, and the study populations have sometimes included heterogeneous, nonrepresentative patients for this indication.6 Reviews19,23,25 have focused on stratification of patients into risk categories and better definitions of severity to rationalize antibiotic treatment. Current guidelines recommend the use of -lactams and macrolides for the treatment of AECB, but have not been updated to take into account the most recently developed antimicrobials, including the new respiratory quinolones.13,26,27 The fluoroquinolone moxifloxacin is highly active against common respiratory tract pathogens, includ*From the Royal Brompton Hospital (Dr. Wilson), London, UK; Clinica Delle Malattie Dell’Apparato Respiratorio (Dr. Allegra), Milan, Italy; Hotel Dieu (Dr. Huchon), Paris, France; Hospital General (Dr. Izquierdo), Guadalajara, Spain; St. George’s Hospital Medical School (Dr. Jones), London, UK; Diakoniekrankenhaus (Dr. Schaberg), Zentrum fu¨ r Pneumologie, Rotenburg, Germany; and Bayer Plc (Dr. Sagnier), Stoke Poges, UK. †A list of participants is given in the Appendix. This study was sponsored by Bayer AG. Dr. Wilson has received honoraria for presentation from the sponsor. Dr. Sagnier is a sponsor staff member. Manuscript received March 7, 2003; revision accepted September 23, 2003. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (e-mail: [email protected]). Correspondence to: Robert Wilson, MD, Consultant Physician, Royal Brompton Hospital, Sidney St, London SW3 6NP, United Kingdom; e-mail: [email protected] 954
ing penicillin-resistant pneumococci in communityacquired pneumonia.28 –30 Moxifloxacin shows rapid lung tissue penetration and bacterial eradication rates against common respiratory tract pathogens.31,32 Moxifloxacin has demonstrated effectiveness as short-course therapy for AECB in an extensive clinical program comprising comparative studies33,34 with various standard antimicrobials. We compared the effectiveness of oral moxifloxacin, 400 mg qd for 5 days, with standard oral 7-day antibiotic treatment regimens as first-line therapy for infectious AECB (Anthonisen type 1). The study was original in that it incorporated several design features that have been used in other studies, but never before together in an antibiotic trial of AECB: (1) the choice of the comparator was left to the clinician among three options, while the doubleblind design allowed to maintain a high degree of internal validity; (2) the pre-exacerbation health status was established to allow measuring the postexacerbation return to baseline; (3) the use of corticosteroids was taken into account by stratification; and (4) a long-term follow-up was performed up to 9 months, including administration of posttherapy antibiotics and time to next exacerbation. In this article, we report the overall design, cohort characteristics, and main clinical and bacteriologic results of our study, including long-term follow-up.
Materials and Methods This was a multicenter, multinational, randomized, doubleblind study of two parallel treatment arms of patients with AECB. Outpatients aged ⱖ 45 years with documented chronic bronchitis (CB) were eligible for enrollment during an AECB-free period if they had a history of cigarette smoking of at least 20 pack-years, two or more documented AECBs in the previous year, and FEV1 ⬍ 85% of predicted value at the enrollment visit. The main exclusion criteria were previous adverse reaction to study drugs, pregnancy or lactation, syndrome of QTc prolongation, severe renal or hepatic impairment, or lung disease other than CB that could affect the clinical evaluation of study medication. The study protocol was approved by ethics committees for all centers prior to implementation, and patients provided written informed consent. Four visits were scheduled: enrollment, randomization, 7 to 10 days after the end of treatment, and end of follow-up, which lasted either until the occurrence of a new exacerbation or 9 months after therapy at the latest (Fig 1). Enrolled patients were instructed to see their physicians as soon as clinical signs and symptoms of infectious AECB arose, and have with them a fresh sputum sample in a sterile container. They could be randomized within a maximum of 12 months from enrollment date if they presented with an Anthonisen type 1 AECB,6 defined as increased dyspnea and sputum volume, and sputum purulence that had to be confirmed macroscopically by the investigator. At this randomization visit, sputum was sent for microscopic examination and Gram staining.35 Valid samples (⬍ 10 squamous epithelial cells and ⬎ 25 polymorphonuclear leukocytes per low-powermagnification [⫻ 100] field) were cultured for pathogen identification, and isolates were subjected to susceptibility testing to Clinical Investigations
Figure 1. Study schedule. V1 ⫽ visit one; V2 ⫽ visit two; V3 ⫽ visit three; V4 ⫽ visit four.
moxifloxacin and comparators, performed by E-test (AB Biodisk; Solna, Sweden) in accordance with current National Committee for Clinical Laboratory Standards guidelines.36 Prior to randomization, patients were stratified according to steroid use for the current episode of AECB in four groups defined as follows: (1) none: no steroid use at randomization or no increase in long-term steroid dosage; (2) long-term inhaled: administered for ⬎ 2 months prior to randomization; (3) systemic: started at randomization or increased dosage at randomization if previously administered; and (4) systemic and long-term: combination of last two definitions. Patients received in a double-blind fashion either moxifloxacin (one 400-mg tablet qd for 5 days) or the comparator drug, which the physician preselected from the three possible antibiotic options: amoxicillin (one 500-mg capsule tid for 7 days), clarithromycin (two 250-mg tablets bid for 7 days), or cefuroxime-axetil (one 250-mg tablet bid for 7 days). This choice was based on therapeutic habits, knowledge of local pathogens epidemiology, in vitro susceptibilities, and clinical presentation of the patient. The randomization list used a block size such that an equal number of patients were allocated to each treatment arm in each block, and patients were assigned sequential ascending random numbers within each center and stratum. The randomization list was not accessible to any individuals involved in study conduct, and patient codes could be broken only in case of emergency. In order to ensure blinding, all active drugs were encapsulated for identical appearance and placebo capsules were included in the blister packs as appropriate, including placebo capsules on treatment day 6 and day 7 in the moxifloxacin treatment arm. Patients were contacted by telephone toward the end of study treatment (days 5 to 7 after randomization), and were then examined 7 to 10 days after completing treatment, and sputum, if present, was sent for examination. Long-term www.chestjournal.org
follow-up was made by monthly telephone contacts up to a maximum of 9 months after study treatment. The last visit occurred either at the time of the next AECB or at 9 months, whichever came first, and comprised a clinical assessment and sputum sample. The primary outcome measure was clinical success assessed 7 to 10 days after the end of treatment, defined as the proportion of patients with clinical cure or improvement according to the following definition: clinical cure (return to pre-exacerbation status, no additional antimicrobial therapy required); clinical improvement (not complete return to pre-exacerbation status, but sufficient improvement in clinical signs and symptoms that no alternative antimicrobial therapy was required); clinical failure (no change, worsening, insufficient improvement or reappearance of signs and symptoms of infection such that alternative antimicrobial therapy is required); and indeterminate (clinical assessment not possible). Secondary clinical efficacy measures included the frequency of additional antimicrobial therapy, time to the next AECB, and bacteriologic success. Bacteriologic success was defined as eradication or presumed eradication 7 to 10 days after treatment according to the following definition: eradication (original causative organisms absent on sputum culture); presumed eradication (absence of appropriate culture material for evaluation because the patient improved clinically and was unable to produce sputum); persistence (original organisms still present on sputum culture); presumed persistence (absence of appropriate culture material for evaluation and patient assessed as clinical failure); superinfection (isolation of new pathogens/causative organisms judged to be causing an infectious process in the respiratory tract associated with clinical signs); and indeterminate (bacteriologic response of the study drug not evaluable for any reason). CHEST / 125 / 3 / MARCH, 2004
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Statistical Analysis
Results
The intent-to-treat (ITT) population included all randomized patients receiving at least one dose of study drug, and the per-protocol (PP) population included patients with confirmed infectious Anthonisen type 1 AECB, who received no systemic antimicrobial agents other than study drug for at least 3 days in the case of clinical failure or ⱖ 80% of study medication in case of cure, with adequate documentation of compliance and absence of major protocol violations. The microbiologically valid population included PP patients with at least one pretherapy causative organism and an appropriate posttherapy bacteriologic evaluation. The study was powered as a noninferiority study, and the sample size was calculated in order to demonstrate that moxifloxacin was not ⬎ 10% less effective than the comparator regimen. Sample size was based on a predicted failure rate of 15% in the comparator arm with a 10% equivalence ⌬ between study arms, ␣ ⫽ 2.5% (one sided) and  ⫽ 10%. On that basis, 318 patients were needed per treatment arm, including a 15% addition for multicenter design.37 With an assumed validity rate of approximately 95% for the primary efficacy parameter, 670 patients needed to be randomized. Baseline treatment arm comparability was tested using a one-way analysis of variance or Student t test for normally distributed variables, or Fisher exact test for categorical variables. For analyses of equivalence, a two-sided 95% confidence interval (CI) was calculated using Mantel-Haenszel weighting. If the lower limit of the 95% CI for the true difference of clinical success rates was within – 10%, moxifloxacin was proven to be no less effective than comparator. If the lower limit was ⬎ 0, superiority of treatment with moxifloxacin was proven. Exploratory life-table (Kaplan-Meier) analyses were performed for the time to first occurrence of a composite event, defined as failure of study treatment, or occurrence of a new AECB, or administration of any antibiotic treatment for AECB.
A total of 1,935 patients were enrolled in 103 centers, 733 of whom were randomized. The randomized and nonrandomized populations were comparable in age, sex, and FEV1, but mean duration of CB and number of AECB episodes in the previous year were significantly greater in the randomized population (Table 1). The trial population profile is shown in Figure 2. In the comparator arm, treatment selection was country dependent, with cefuroxime-axetil being administered from 0 to 65% of comparator recipients (174 patients overall), clarithromycin from 0 to 32% (114 patients), and amoxicillin from 0 to 58% (88 patients). The most frequent reasons given for comparator choice were clinical presentation of the patient and local susceptibility pattern of suspected pathogens. Treatment arms were comparable for all variables at both enrollment and randomization visits (Table 2). In 232 patients (31.8%), a total of 254 organisms were isolated at the randomization visit. As shown in Table 3, the most common organisms were Haemophilus influenzae, present in 41.8% of all isolates, and Streptococcus pneumoniae, detected in 20.3% of all isolates. H influenzae (45.6% compared to 38.8%), Enterobacteriaceae (15.5% compared to 10.1%), and Pseudomonas spp (7.8% compared to 3.9%) were more frequently isolated in patients with the greatest degree of airflow obstruction (FEV1
Table 1—Patient Characteristics by Randomization Status* Characteristics Male gender Age, yr ⱖ 65 ⬍ 65 Years since CB diagnosis‡ AECBs in previous year, No.§ ⬍4 ⱖ4 FEV1 % predicted㛳 ⬍ 50 ⱖ 50
Enrolled (n ⫽ 1,935)
Randomized (n ⫽ 733)
Nonrandomized (n ⫽ 1,202)
1,320 (68.2) 63.4 ⫾ 9.7 918 (47.4) 1,017 (52.6) 11.7 ⫾ 9.6 2.9 ⫾ 1.3 1,505 (77.8) 426 (22.0)
498 (67.9) 63.2 ⫾ 9.8 347 (47.3) 386 (52.7) 12.5 ⫾ 9.8 3.1 ⫾ 1.4 530 (72.3) 203 (27.7)
822 (68.4) 63.6 ⫾ 9.7 571 (47.5) 631 (52.5) 11.1 ⫾ 9.5 2.8 ⫾ 1.3 975 (81.1) 223 (18.6)
861 (44.5) 1,067 (55.1)
310 (42.3) 423 (57.7)
511 (42.5) 644 (53.6)
p Value† 0.84¶ 0.49# 0.94** 0.04# ⬍ 0.01# ⬍ 0.01††
0.41‡‡
*Data are presented as mean ⫾ SD or No. (%). †Nonrandomized vs randomized. ‡Not reported in six nonrandomized patients. §Not reported in four nonrandomized patients. 㛳Not reported in seven nonrandomized patients. ¶2 test. #t test. **2 test, ⱖ 65 years vs ⬍ 65 years. ††2 test, ⬍ 4 exacerbations vs ⱖ 4 exacerbations. ‡‡2 test, ⬍ 50% predicted vs ⱖ 50% predicted. 956
Clinical Investigations
Figure 2. Patient disposition.
⬍ 50%). Across organisms, pretreatment minimum inhibitory concentration for 90% of isolates (MIC90) ranged from 0.11 to 8 mg/L for moxifloxacin and 0.25 to 256.00 mg/L for comparator. With regard to www.chestjournal.org
treatment compliance, 342 patients (96.6%) and 370 patients (98.4%) received the full treatment course in the moxifloxacin and comparator arms, respectively. CHEST / 125 / 3 / MARCH, 2004
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Table 2—Patient Characteristics by Treatment Arm (ITT Population)* Characteristics Enrollment visit Male gender Age, yr Years since CB diagnosis FEV1 % predicted ⬍ 50 ⱖ 50 AECBs in previous year ⬍4 ⱖ4 Smoking history in years Previous smokers Current smokers Cardiopulmonary disease Not present Present Randomization visit Days between onset of AECB symptoms and randomization† ⬍4 4–7 ⬎7 Temperature, °C ⬎ 38.5°C Respiration rate, breaths/min Steroid use None‡ Long-term inhaled§ Systemic and long-term inhaled Systemic㛳
Moxifloxacin (n ⫽ 354)
Comparator (n ⫽ 376)
243 (68.6) 63.8 ⫾ 9.7 12.2 ⫾ 9.7
253 (67.3) 62.6 ⫾ 9.9 12.8 ⫾ 9.9
149 (42.1) 205 (57.9)
159 (42.3) 217 (57.7)
257 (72.6) 97 (27.4) 37.5 ⫾ 11.1 208 (58.8) 146 (41.2)
270 (71.8) 106 (28.2) 37.7 ⫾ 11.2 203 (54.0) 173 (46.0)
301 (85.0) 53 (15.0)
324 (86.2) 52 (13.8)
p Value 0.74¶ 0.08# 0.45# 0.81¶
0.79¶
0.80#
0.59¶
0.54¶ 249 (70.3) 63 (17.8) 41 (11.6) 37.6 ⫾ 0.8 52 (14.7) 21.5 ⫾ 5.2
275 (73.1) 67 (17.8) 34 (9.0) 37.6 ⫾ 0.8 58 (15.4) 21.9 ⫾ 5.8
151 (42.7) 97 (27.4) 55 (15.5) 51 (14.4)
160 (42.6) 119 (31.6) 57 (15.2) 40 (10.6)
0.31# 0.35# 0.36¶
*Data are presented as No. (%) or mean ⫾ SD. †Not reported for one patient in the moxifloxacin arm. ‡Or no increase in steroid dosage. §Administered for ⬎ 2 mo prior to randomization. 㛳Started at randomization or increased dosage at randomization if previously administered. ¶2 test. #t test.
Moxifloxacin and the comparator regimens were equivalent in terms of clinical success (cure plus improvement) rates at 7 to 10 days after therapy. This was confirmed in the subgroups of patients with bacteriologically documented AECB. Moxifloxacin showed superiority over comparator on clinical cure at 7 to 10 days after therapy in both the ITT and PP populations, with a consistent 7 to 8% difference between treatment arms (Table 4). When clinical failure was analyzed in patients who required additional antibiotic therapy when treatment failed, failure rates were significantly lower in the moxifloxacin group (27 of 354 patients, 7.6%) than in the comparator group (53 of 376 patients, 14.1%) in the ITT population (95% CI, 2.3 to 11.6), and in the PP population (24 of 274 patients [8.8%] vs 44 of 298 patients [14.8%]; 95% CI, 0.6 to 11.1). In the microbiologically valid population, the bac958
teriologic success rate with moxifloxacin was significantly higher than with the comparator (Table 5). There were 3 persisting organisms in the moxifloxacin regimen (Klebsiella pneumoniae [baseline minimum inhibitory concentration (MIC), 0.064 mg/L], Haemophilus parainfluenzae [MIC 0.125 mg/L], and S pneumoniae [MIC 0.125 mg/L]) and 11 persisting organisms in the comparator regimen (Moraxella catarrhalis [baseline MIC of cefuroxime, 1.0 mg/L], Pseudomonas aeruginosa [all three under cefuroxime, MIC 4.0 mg/L and 256 mg/L], H influenzae [amoxicillin, two strains: MIC 0.38 mg/L and 0.5 mg/L; clarithromycin, two strains: MIC 1.5 mg/L and 16 mg/L; cefuroxime, two strains: MIC 1.0 mg/L and 0.38 mg/L], H parainfluenzae [amoxicillin, MIC 128 mg/L]). A superinfection was observed in three patients and two patients in the moxifloxacin and comparator groups, respectively. In the moxifloxacin Clinical Investigations
10.5 10.0 48.2 0.0 68.5 12.00 (94) 1.50 (30) 256.00 (26) 20.00 (20) 256.00 (19) 19 (45.2) 7 (16.7) 4 (9.5) 1 (2.4) 2 (4.8) 14.8 20.0 53.9 5.0 77.8
31 (73.8)
36.00 (95) 25.00 (30) 256.00 (26) 1.50 (20) 256.00 (18) 18 (58.1) 2 (6.5) 1 (3.2) 5 (16.1) 1 (3.2) 45 (40.2) 13 (11.6) 16 (14.3) 11 (9.8) 11 (9.8)
0.0 0.0 0.0 0.0 30.0
27 (87.1) 90 (80.4)
0.19 (95) 0.11 (30) 1.50 (28) 0.25 (20) 8.00 (20)
*Percentages refer to patients with at least one organism; patients could have more than one organism isolated. †Data in parenthesis are numbers of strains with E-test MIC determination. ‡In vitro resistance is defined as MIC ⬎ 2 mg/L (moxifloxacin), ⬎ 16 mg/L (amoxicillin), ⬎ 4 mg/L (clarithromycin), and ⬎ 4 mg/L (cefuroxime-axetil).
54.2 3.3 100.0 85.0 94.7
42 (89.4)
15 (31.9) 9 (19.1) 8 (17.0) 4 (8.5) 8 (17.0)
16.00 (95) 14.50 (30) 256.00 (27) 2.00 (20) 256.00 (19)
21.8 0.0 8.00 (46) 1.50 (7) 7 (14.9) 6 (12.8) 1 (2.1) 28.3 0.0 14.00 (46) 0.25 (7) 12 (28.6) 10 (23.8) 2 (4.8) 0.0 14.3 0.38 (46) 24.00 (7) 6 (19.4) 5 (16.1) 1 (3.2) 2.2 0.0 0.19 (46) 0.13 (7) 29 (25.9) 26 (23.2) 3 (2.7)
Gram positive Any Gram-positive organism S pneumoniae Staphylococcus aureus Gram negative Any Gram-negative organism H influenzae Moraxella catarrhalis Enterobacteriaceae Haemophilus parainfluenzae Other Gram negative
% Resistance‡ MIC90, mg/L† No. (%)* % Resistance‡ Variables
No. (%)*
MIC90, mg/L†
% Resistance‡
No. (%)*
MIC90, mg/L†
% Resistance‡
No. (%)*
MIC90, mg/L†
Cefuroxime-Axetil (n ⫽ 47) Clarithromycin (n ⫽ 42) Amoxicillin (n ⫽ 31) Moxifloxacin (n ⫽ 112)
Table 3—Distribution and MIC90 of Test Antibiotics Against Pathogens Isolated From Pretreatment Samples
www.chestjournal.org
group, superinfecting organisms were S pneumoniae (MIC 0.064 mg/L), M catarrhalis (MIC 0.047 mg/L) and P aeruginosa (MIC 1.5 mg/L). In the comparator group, superinfecting organisms were S pneumoniae (MIC 4.0 mg/L) and K pneumoniae (MIC 2.0 mg/L), with both organisms affecting patients receiving cefuroxime. In the moxifloxacin study arm, there was a significantly lower frequency of additional antibiotic therapy than comparator regimen in the PP population (26 of 274 patients [9.5%] vs 45 of 298 patients [15.1%], p ⫽ 0.045), which was confirmed in the ITT population (p ⫽ 0.006). Clinical cure (p ⫽ 0.03) was achieved in a significantly higher proportion of patients with moxifloxacin than comparator among patients receiving no concomitant steroid treatment or with no change in systemic steroid treatment in the ITT population (Table 6). Both the clinical success and cure rates were lower in both treatment groups in patients with the greatest degree of airway obstruction; for the ITT population, moxifloxacin had a significantly (p ⬍ 0.03) higher clinical cure rate in patients with a FEV1ⱖ 50% (Table 7). During the follow-up period, and after exclusion of ITT patients who received a further antibiotic to the study treatment course for the presenting AECB, a new AECB was documented in 179 of 324 patients in the moxifloxacin arm and in 176 of 319 patients in the comparator arm. In that population, median times to the next AECB were 131.0 days (range, 18 to 289 days) and 103.5 days (range, 14 to 280 days) for moxifloxacin and comparator, respectively. Mean times to the next AECB were 132.8 days (SD 67.5) and 118.0 days (SD 67.9) for moxifloxacin and comparator, respectively; the difference was statistically significant (p ⫽ 0.03). In a life-table analysis of time to the first composite event (treatment failure, and/or new exacerbation and/or any further antibiotic treatment), the log-rank test showed a significant difference in favor of moxifloxacin for up to 5 months of follow-up (p ⫽ 0.03), a difference that was no longer statistically significant over the entire study follow-up (p ⫽ 0.11). When the same analysis was stratified according to the date of the last exacerbation, moxifloxacin was superior to comparator in the subgroup of patients who had an exacerbation ⬍ 6 months prior to randomization (Fig 3). Adverse events considered as possibly or probably related to study drug were reported in a similar number of patients in both groups (Table 8). These events were usually mild to moderate in intensity. Study medication was prematurely discontinued because of adverse events in four patients of each group (1.1%). Of 43 serious adverse events, 19 events were reported in the moxifloxacin treatment arm and 24 events in the comparator arm. Two CHEST / 125 / 3 / MARCH, 2004
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Table 4 —Summary of Clinical Efficacy Results at 7 to 10 Days of Therapy ITT Population Variables Clinical success*† Clinical cure Clinical success in patients with bacteriologically confirmed AECB*
PP Population
Moxifloxacin, No./Total (%)
Comparator, No./Total (%)
95% CI
Moxifloxacin, No./Total (%)
Comparator, No./Total (%)
95% CI
310/354 (87.6) 251/354 (70.9) 98/112 (87.5)
312/376 (83.0) 236/376 (62.8) 94/120 (78.3)
⫺ 0.7–9.5 1.4–14.9 ⫺ 1.4–17.9
239/274 (87.2) 191/274 (69.7) 62/71 (87.3)
251/298 (84.2) 185/298 (62.1) 66/79 (83.5)
⫺ 3.0–8.5 0.3–15.6 ⫺ 7.2–15.4
*Clinical cure and improvement combined. †Clinical success rates in amoxicillin, clarithromycin, and cefuroxime-axetil groups were 83.0%, 84.2%, and 82.2% in the ITT population, respectively; corresponding data were 81.5%, 87.4%, and 83.8% in the PP population.
serious events (sepsis and dyspnea) were considered possibly related to study medication in the comparator arm, both of which resolved. There were nine deaths during the study, three in the moxifloxacin treatment arm and six in the comparator arm. Two patients in the comparator arm died from respiratory failure. No deaths were associated with study treatment. Discussion In terms of clinical success 7 to 10 days after the end of treatment, 5 days of moxifloxacin was at least as effective as 7 days of conventional antibiotic therapy in all prospectively defined study populations. This result is consistent with previous stud-
ies33,34 comparing moxifloxacin to different antibiotic regimens. However, this study bears a greater significance for clinical practice, as the design more closely mimicked the real-life practice while maintaining a high degree of internal validity.38,39 In our study, equivalence was achieved under a demanding scheme: the comparator therapy was chosen for each patient among three well-established first-line treatments comprising two different drug classes (lactam and macrolides). Selection of comparators was based on current guidelines,13,26,27 and also reflected medical practice in participating countries. In making this probabilistic first-line choice, the physician could therefore take into account the individual patient clinical presentation, the regional or national guidelines, and the local epidemiology of
Table 5—Bacteriologic Response 7 to 10 days After Therapy ITT Population
Microbiologically Valid Population
Variables
Moxifloxacin, No. (%)
Comparator, No. (%)
Moxifloxacin, No. (%)
Comparator, No. (%)
Total Bacteriologic success Eradication Presumed eradication Bacteriologic failure Eradication with superinfection Persistence* S pneumoniae H influenzae H parainfluenzae K pneumoniae M catarrhalis P aeruginosa Serratia marcescens Presumed persistence Indeterminate/missing 95% CI§
112 (100.0) 86 (76.8) 42 (37.5) 44 (39.3) 26 (23.2) 3 (2.7) 7 (6.3) 1 (0.9) 1 (0.9) 1 (0.9) 1 (0.9) 0 2 (1.8) 1 (0.9) 1 (0.9)† 15 (13.4)
120 (100.0) 81 (67.5) 39 (32.5) 42 (35.0) 39 (32.5) 4 (3.3) 15 (12.5) 0 9 (7.5) 1 (0.8) 0 2 (1.7) 3 (2.5) 0 1 (0.8)‡ 19 (15.8)
71 (100.0) 65 (91.5) 36 (50.7) 29 (40.8) 6 (8.4) 3 (4.2) 3 (4.2) 1 (1.4) 0 1 (1.4) 1 (1.4) 0 0 0 0 0
79 (100.0) 64 (81.0) 35 (44.3) 29 (36.7) 15 (19.0) 4 (5.1) 11 (13.9) 0 6 (7.6) 1 (1.3) 0 1 (1.3) 3 (3.8) 0 0 0
⫺ 1.8–20.4
0.4–22.1
*Includes persistence with superinfection. †Enterobacter cloacae. ‡H influenzae. §CI calculated for the difference in bacteriologic success rate. 960
Clinical Investigations
Table 6 —Clinical Results by Steroid Use 7 to 10 Days After Therapy* ITT Population Variables Clinical success None† Systemic‡ Inhaled§ Systemic and inhaled Clinical cure None† Systemic‡ Inhaled§ Systemic and inhaled
PP Population
Moxifloxacin
Comparator
p Value
Moxifloxacin
Comparator
p Value
138/151 (91.4) 43/51 (84.3) 83/97 (85.6) 46/55 (83.6)
136/160 (85.0) 36/40 (90.0) 94/119 (79.0) 46/57 (80.7)
0.07 0.43 0.21 0.69
96/104 (92.3) 33/40 (82.5) 74/86 (86.0) 36/44 (81.8)
109/126 (86.5) 28/31 (90.3) 73/92 (79.3) 41/49 (83.7)
0.16 0.35 0.24 0.81
117/151 (77.5) 35/51 (68.6) 63/97 (64.9) 36/55 (65.5)
106/160 (66.3) 30/40 (75.0) 68/119 (57.1) 32/57 (56.1)
0.03 0.50 0.24 0.31
77/104 (74.0) 27/40 (67.5) 59/86 (68.6) 28/44 (63.6)
83/126 (65.9) 22/31 (71.0) 52/92 (56.5) 28/49 (57.1)
0.18 0.75 0.10 0.52
*Data are presented as No./Total (%). †Or no change in dosage of steroids at randomization; patients stratified in the “no steroids” stratum while on previous steroids: ITT, 24 (moxifloxacin) and 33 (comparator); PP, 18 (moxifloxacin), and 29 (comparator). ‡Started at randomization or increased dosage at randomization if previously administered. Mean dose of prednisone equivalent: 30.1 mg (SD 19.4) vs 29.8 mg (20.9) in moxifloxacin and comparator, respectively. §Administered for ⬎ 2 months prior to randomization.
AECB-related pathogens and their in vitro susceptibilities, so that the study results can be interpreted in terms of global clinical effectiveness rather than efficacy only. The present study was designed to compare moxifloxacin to a basket of comparators in a two-arm manner; consequently, it was not powered for ad hoc comparisons of moxifloxacin with separate agents of the comparator group. Moreover, such comparisons would likely be biased since the selection of the comparator in the standard care arm was not randomized but resulted from the clinician’s choice. Therefore, inferential conclusions can only be drawn from the comparison of moxifloxacin to the standard care group, which was itself adjusted to individual patient needs. A significantly greater proportion of patients receiving moxifloxacin for 5 days showed clinical cure 7 to 10 days after the end of treatment than with a 7-day course of conventional antibiotic therapy. It can be argued that clinical cure, which required a complete return to pre-exacerbation status, is important with respect to patient satisfaction. Patients
treated with moxifloxacin for an acute bacterial exacerbation have been shown to have faster symptom relief and return to normal activities more rapidly than those treated with macrolides.40 Clinical cure could also influence long-term outcomes, in that patients who had only improved might be more susceptible to relapse. The significantly greater proportion of patients with bacteriologic success in the moxifloxacin arm is consistent with results reported previously in a study33 comparing moxifloxacin and clarithromycin in AECB. Whereas there were hardly any drugresistant S pneumoniae, comparator treatment showed markedly less eradication of H influenzae than moxifloxacin after treatment. This was likely a contributory factor for the significantly lower proportion of patients requiring further antimicrobials after moxifloxacin than comparator treatment. The proportion of patients with isolated pathogens (31.8%) was lower than expected, especially given Anthonisen type 1 criteria and macroscopic sputum purulence,41 but it is within the range reported in previous studies of AECB.42– 46 This might be ex-
Table 7—Clinical Results by Degree of Airway Obstruction 7 to 10 Days After Therapy* ITT Population Variables Clinical success FEV1 ⬍ 50% FEV1 ⱖ 50% Clinical cure FEV1 ⬍ 50% FEV1 ⱖ 50%
PP Population
Moxifloxacin
Comparator
p Value
Moxifloxacin
Comparator
p Value
124/149 (83.2) 186/205 (90.7)
126/159 (79.3) 186/217 (85.7)
0.37 0.11
98/119 (82.4) 141/155 (91.0)
105/130 (80.8) 146/168 (86.9)
0.75 0.25
89/149 (59.7) 162/205 (79.0)
85/159 (53.5) 151/217 (69.6)
0.27 0.03
70/119 (58.8) 121/155 (78.1)
69/130 (53.1) 116/168 (69.1)
0.36 0.07
*Data are presented as No./Total (%). www.chestjournal.org
CHEST / 125 / 3 / MARCH, 2004
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Figure 3. Life-table analysis of time to the first composite event (treatment failure, and/or new exacerbation and/or any further antibiotic treatment) stratified according to the time of the last exacerbation prior to randomization.
plained by the stringency of sputum assessment and an additional 30.3% proportion of patients who had respiratory pathogens without any stringent criteria. The a priori stratification according to steroid use was meant to avoid imbalance in steroid allocation to study treatment groups, therefore ensuring that the comparison between moxifloxacin and the comparator was not biased by the concomitant use of steroids. However, no inference on the clinical efficacy of steroids treatments can be drawn from this study since the allocation of steroids was not randomized. In that light, caution is needed in interpreting the
Table 8 —Incidence of More Frequent Drug-Related Adverse Events* Variables
Moxifloxacin (n ⫽ 354)
Comparator (n ⫽ 376)
Any adverse event Abdominal pain Headache Diarrhea Gastritis Nausea Dizziness Nervousness Taste perversion
25 (7.1) 3 (0.8) 4 (1.1) 9 (2.5) 2 (0.6) 3 (0.8) 3 (0.8) 2 (0.6) —
18 (4.8) 2 (0.5) 3 (0.8) 3 (0.8) — 2 (0.5) — — 3 (0.8)
*At least two patients reporting a possible or probable drug-related adverse event. Data are presented as No. of patients (%). 962
data for clinical success with moxifloxacin vs comparator in patients who did not concomitantly receive steroids for the presenting AECB or had no change in their long-term corticosteroids treatment. Further research will be needed, possibly using factorial study designs analyzing the correlations among several variables, to document whether there is a potential for treatment interaction between antibiotic and corticosteroid use. Corticosteroids might have an effect per se. Alternatively, their use may simply signal a more severe subgroup of the CB population with a different clinical prognosis. These considerations are also relevant to the lack of a difference between the two treatment groups in those patients with the most severe airflow obstruction, who would be more likely to receive corticosteroids, and the superiority of moxifloxacin over comparator in those patients with less severe airflow obstruction (clinical cure in ITT population), who would not. When factorial designs are not applicable, consideration should be given to excluding corticosteroid use in clinical trials seeking to investigate differences between antibiotics. One recent study47 included a long-term observational period after treatment follow-up to determine whether fluoroquinolone treatment prolongs the time to next AECB compared to a standard therapy. In that study,47 a significantly greater proportion of Clinical Investigations
patients receiving a 5-day course of gemifloxacin remained free of AECB over a 26-week period than those receiving a 7-day course of clarithromycin. In our study, the time to next exacerbation was significantly longer in the moxifloxacin arm, with an approximately 13% and 27% benefit for mean and median times, respectively. The superiority of moxifloxacin over standard antibiotic treatment in terms of the percentage of patients who had not failed during the first exacerbation or had a further exacerbation requiring antibiotic treatment was seen up to 5 months after randomization. Moxifloxacin was also superior over comparator therapy when considering those patients whose previous exacerbation had occurred within six months of randomization. These patients are likely to have more frequent exacerbations. Adverse events were usually mild to moderate in intensity and reported at comparable rates in both treatment arms. In line with the known safety profile of moxifloxacin, most of these events in the moxifloxacin arm were related to the digestive or nervous system.48 Taken together, this study demonstrated that moxifloxacin was equivalent to the comparator regimen for the primary outcome measure, ie, clinical success at 7 to 10 days after therapy. Superiority with moxifloxacin was shown for both short-term and long-term efficacy variables including cure rate, need for additional antimicrobial treatment of AECB, rate of bacteriologic eradication, and time to next exacerbation. All study treatments were safe and well tolerated. In conclusion, these consistent data support the use of moxifloxacin for the treatment of AECB. The methods of this study should be taken into consideration in the design of future clinical studies of AECB, and the results of this study should be considered for possible re-evaluation of current AECB treatment guidelines. Appendix MOSAIC Study Group members Argentina: Horacio Ariza, Luis Horacio Marquez, Lucia Cristina Marzoratti; Australia: David Mackenzie, Charles Mitchell, Matthew Peters, Martin Phillips, Anne-Marie Southcott; Austria: Norbert Vetter; Belgium: Guido Creytens, Jean-Benoit Martinot; Brazil: Alberto Cukier, Luiz Carlos Correˆ a Da Silva; Finland: Tuomo Kava, Esko Kurttila, Pekka Saarelainen, Anja Suontausta, Martti Torkko, Kari Venho; France: Nathan Abenhaim, Jacques Allix, Robert Arnou, Martial Boucheret, Nicolas Breton, Pierre Causse, Salam Farhat, Robert Francon, Jean-Paul Grazzini, Eric Mascherpa, Miche`le Pithon, Alain Simmons, Gilles Sorbe, JeanYves Vogel; Germany: Klaus Bo¨ ge, Manfred Bo¨ hm, Eduard Chesin, Klaus Colberg, Rolf Dichmann, Thomas Ginko, Klaus Harzbecker, Reinhard Hu¨ ting, Ina Itzigehl, Josef Junggeburth, Helmut Leiner, Karin Liebscher, Anneliese Linnhoff, Mechthild Otto, Beate Rosenblum, Johannes Rumpf, So¨ ren Schmidtmann, www.chestjournal.org
Renita Schnorr, Thomas Schultz, Peter Stutz, Harald Sudhoff, Ilona Szasz, Lutz Volgmann, Walter Vorderstrasse, Heinrich Weber; Greece: Harry Bassaris, Paul Nikolaidis, Emmanouel Papadakis; Hungary: Eleonora Babinszky, Eva Bauknecht, Agnes Forrai, Zoltan Kuberka, Katalin Major, Miklos Namenyi, Maria Poncsak, Katalin Rajkay, Amalia Weltner; Israel: Abraham Eliraz, Joel Greif, Robert Shiner, Daniel Weiler; Mexico: Raul Bates Flores, Ricardo Bujanos, Rodolfo Posadas Valay, Gerardo Rico Mendez, Raul Sansores; Norway: Kjell Langaker, Jetmund Ringstad; Poland: Małgorzata Czajkowska-Malinowska, Małgorzata Jeˆdrzejczak, Iwona Grzelewska-Rzymowska, Władysław Pierzchała, Tadeusz Płusa, Paweł Sliwin˜ski, Hanna Szelerska-Twardosz, Teresa Wilewska-Kłubo; Portugal: Cecı´lia Ba´rbara Louro Robalo Nunes Sousa, Joa˜o Manuel De Sousa Almeida; Slovenia: Ema Musˇic, Renato Er en; Spain: Cristian Domingo, Jose Maria Ignacio, Jose Morera, Santiago Romero, Candelaria Santana, Rafael Zalacain; Switzerland: Ju¨rg Baradun, Urs Honegger; United Kingdom: Gary Barlow, Neil Barnes, Barry Glekin, Charles Langan, R. Macleod, Gerry Mackaig, Robert Wilson.
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