125 mg BID for ten days for treatment of acute bacterial exacerbation of chronic bronchitis: A post hoc analysis of data from severely ill patients

Clinical Therapeutics/Volume 28, Number 8, 2006

Research Letter

Levofloxacin 750 mg QD for Five Days Versus Amoxicillin/ Clavulanate 875 mg/125 mg BID for Ten Days for Treatment of Acute Bacterial Exacerbation of Chronic Bronchitis: A Post Hoc Analysis of Data from Severely Ill Patients Ronald F. Grossman, MD1; Mary E. Ambrusz, RN2; Alan C. Fisher, DrPH2; Mohammed M. Khashab, MBA3; and James B. Kahn, MD 3

1University of Toronto, Credit Valley Hospital, Toronto, Ontario, Canada; 20rtho-McNeilJanssen Scientific Affairs, L.L.C., Raritan, NewJersey; and 3PriCara, Unit of Ortho-McNeil, Inc., Raritan, NewJersey ABSTRACT This post hoc analysis of data from a previous randomized, blinded, multicenter, parallel, noninferiority study assessed the bacterial etiology, symptom resolution, and tolerability of severe acute bacterial exacerbation of chronic bronchitis (ABECB) patients treated with either levofloxacin 750 mg QD for 5 days or amoxicillin/clavulanate 875 mg/125 mg BID for 10 days. Severe ABECB was defined as ABECB and forced expiratory volume in 1 second (FEV1) <50% of the predicted value, or FEV 1 of 50% to 65% of the predicted value plus comorbidities, or _>4 exacerbations per year. A total of 369 patients were included in the intent-totreat (ITT) population (187 treated with levofloxacin and 182 treated with amoxicillin/clavulanate), and 175 patients were microbiologically assessable (MA) (86 treated with levofloxacin and 89 treated with amoxicillin/clavulanate). In the ITT population, the mean age was 58.7 years, 49.1% were male, and 48.2% were current smokers. At the on-treatment visit, a significantly higher proportion of MA patients in the levofloxacin group resolved purulent sputum production (57.5% vs 35.6%; P < 0.006), sputum production (65.4% vs 45.3%; P < 0.013), and cough (60.0% vs 44.0%; P < 0.045), compared with the amoxicillin/ clavulanate group. However, no significant betweengroup differences were observed at posttreatment. A total of 341 pathogens were isolated, of which 143 (41.9%) were traditional ABECB flora, 181 (53.1%) were other gram-negative organisms, and 17 (5.0%) were gram-positive organisms. Overall susceptibility of the pathogens was 97.1% for levofloxacin and 90.6% for amoxicillin/clavulanate (P < 0.001). The August 2006

prevalence of treatment-emergent adverse events was 42.1% in patients who received levofloxacin and 48.6% in those who received amoxicillin/clavulanate (95% CI, -4.0 to 17.0). (Clin Ther. 2006;28:1175-1180) Copyright © 2006 Excerpta Medica, Inc. Key words: acute bacterial exacerbation of chronic bronchitis, levofloxacin, amoxicillin/clavulanate, tolerability, short-course.

DISCUSSION Antimicrobial treatment has been found to provide beneficial clinical effects for patients with acute bacterial exacerbation of chronic bronchitis (ABECB), leading to earlier symptom resolution and lower relapse rates. 1,2 Some guidelines recommend patient stratification to guide selection of a first-line agent for those who would most likely benefit from antimicrobial treatment and/or are at greater risk for treatment failure. 3,4 Patients with severe ABECB have risk factors associated with treatment failure or hospitalization, such as forced expiratory volume in 1 second (FEV1) <50% of the predicted value, >4 exacerbations per year, cardiopulmonary disease, use of home oxygen, long-term (maintenance) steroid use, and antimicrobial use within the previous 3 months. 3,5,6 The potential pathogens in patients with severe ABECB might differ from those in patients with mild Accepted for publication July 1O, 2006. doi: 10.1016/].clinthera.2006.08.013 0149-2918/06/$19.00 Printed in the USA. Reproduction in whole or part is not permitted. Copyright © 2006 Excerpta Medica, Inc.

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conditions. Studies suggest that patients with declining lung function are more likely to harbor gramnegative pathogens, such as Pseudomonas aeruginosa and Enterobacteriaceae. 7-9 Many of these organisms are resistant to traditional first-line agents, such as amoxicillin, doxycycline, trimethoprim/sulfamethoxazole, azalides, and macrolides. 1° Of additional concern is the frequent use of antimicrobials by patients with severe ABECB, a practice that may increase the risk for selecting resistant pathogens. For these reasons, traditional first-line agents might not be adequate, and fluoroquinolones or ]3-1actarrd]3-1actamase inhibitor agents have been recommended as an appropriate initial choice for their management. 3 The results from a randomized, blinded, multicenter, clinical trial comparing levofloxacin 750 mg versus azithromycin or amoxicillin/clavulanate in the treatment of ABECB were recently published, u This communication provides a more detailed assessment of the bacterial etiology, symptom resolution, and tolerability in a subset of the patient population diagnosed with severe ABECB and treated with either levofloxacin 750 mg PO QD for 5 days, or amoxicillin/ clavulanate 875 mg/125 mg PO BID for 10 days. The study design and statistical analyses have been previously described, u Severe ABECB was defined as ABECB and an FEV 1 value <50% of that predicted, or an FEV 1 value in the range of 50% to 65% of the predicted value in association with significant comorbidity (eg, diabetes mellitus, congestive heart failure, chronic kidney or liver disease), or _>4 exacerbations per year. Clinical signs and symptoms were assessed at study entry (day 0) and during treatment (days 3-6 after the first dose), posttreatment (days 17-26), and poststudy (days 40-45) visits. The protocol was approved by the participating institutional review boards and written informed consent was obtained before any study procedures were initiated. This study was conducted in accordance with the principles of the Declaration of Helsinki 12 and Good Clinical Practice. 13 Microbiologically assessable (MA) patients were defined as those who were clinically assessable and had a pathogen identified at study entry. Sputum samples were collected from each patient and assessed for adequacy at each institution as well as a central laboratory for confirmation, u Susceptibility testing and antimicrobial breakpoints were based on the Clinical and Laboratory Standards Institute protocols using broth microdilution techniques. 14,15 Differences in sus1176

ceptibility to levofloxacin or amoxicillinMavulanate were assessed for statistical significance using the Fisher exact test. A total of 369 patients with severe ABECB were enrolled in the study and comprised the intent-to-treat (ITT) population (all randomized patients who received _>1 dose of study drug), with 187 patients in the levofloxacin group and 182 patients in the amoxicillin/ clavulanate group. In the ITT population, the mean age was 58.7 years (36.9% were age _>65years), 49.1% were male, 48.2% of patients were current smokers, and 41.7% were ex-smokers (a mean of 42.2 packyears for all current and ex-smokers). The MA population consisted of 175 patients (86 in the levofloxacin group and 89 in the amoxicillin/clavulanate group). The presence of ABECB-related symptoms was recorded at each patient visit. At the on-treatment visit, significantly higher proportions of MA patients in the levofloxacin group had resolved purulent sputum production (57.5% vs 35.6%; P < 0.006), sputum production (65.4% vs 45.3%; P < 0.013), and cough (60.0% vs 44.0%; P < 0.045) compared with those in the amoxicillin/clavulanate group (Figure 1). No significant between-group differences were observed among the other symptoms tested at this visit (shortness of breath, fever, and chills). By the posttreatment visit, there were no significant between-group differences for any of the symptoms (Figure 2). A total of 341 pathogens were isolated from 248 (67.2%) ITT patients (125 in the levofloxacin group and 123 in the amoxicillin/clavulanate group). One hundred forty-three (41.9%) of the isolates were considered to be traditional ABECB pathogens16: Haemophilus influenzae (65 isolates), Moraxella catarrhalis (42 isolates), and Streptococcus pneumoniae (36 isolates). The majority of the remaining pathogens consisted of Haemophilus parainfluenzae (66 isolates), other Haemophilus spp (13 isolates), and other gramnegative organisms (102 isolates). Among gramnegative species, 56 isolates were Enterobacteriaceae and 32 isolates were Pseudomonas spp. The remaining 17 (5.0%) isolates were gram-positive organisms, including 13 isolates of Staphylococcus aureus (including one methicillin-resistant S aureus isolate). Isolates were tested for resistance to each of the study drugs. Overall, 97.1% (297/306) were susceptible to levofloxacin, whereas 90.6% (242/267) were susceptible to amoxicillin/clavulanate (P < 0.001). Thirty-nine isolates (32 isolates of Pseudomonas spp Volume 28 Number 8

R.F. Grossman et al.

• Levofloxacin [] Amoxicillin/clavulanate 46/80

Purulent sputum production

P < 0.006 31/87

53/81 P< 0.013

Sputum production 39/86 48/80

Cough

P < 0.045

37/84 43/71

Shortness of breath 40/82 13/17 Fever 17/21

22/30 Chills

19/21 0

I

I

I

I

I

20

40

60

80

100

% Patients

of symptoms from the baseline visit to the on-treatment visit (days 3-6 after the administration of the first dose of active drug) in the microbiologically assessable population (n = 175) of 362 patients receiving levofloxacin 750 mg QD for 5 days (n = 86) or amoxicillin/clavulanate 875 rag/125 mg BID for 10 days (n = 89) for the treatment of severe acute bacterial exacerbation of chronic bronchitis. Resolution was defined as symptom presence at study entry and absence at on-treatment visit.

Figure 1. Resolution

and 7 isolates of Acinetobacter spp) were not included in susceptibility testing for amoxicillin/clavulanate because the organisms are nonsusceptible to this agent. Additionally, of the 34 S pneumoniae isolates for which susceptibility to penicillin was reported, 11 (32.4%) were resistant to penicillin (all demonstrated a MIC of >2 pg/mL). All patients that received >1 dose of study drug were included in the evaluation for tolerability (183 in the levofloxacin group, and 179 in the amoxicillin/ clavulanate group). The prevalence of treatmentemergent adverse events (AEs) was 42.1% in the levofloxacin-treated group and 48.6% in those treated with amoxicillin/clavulanate (95% C I , - 4 . 0 to 17.0). The most commonly reported AEs in both groups were diarrhea (11 [6.0%] in the levofloxacin group, 15 [8.4%] in the amoxicillin/clavulanate group), nausea (10 [5.5%] and 8 [4.5%], respectively), and headache (9 [4.9%] and 7 [3.9%], respectively) August 2006

(Table). Drug-related AEs, as determined by the investigator, were observed in 16 (8.7%) levofloxacintreated patients and 16 (8.9%) amoxicillin/clavulanatetreated patients (95% CI, -5.9 to 6.3). Eleven (6.0%) patients in the levofloxacin treatment group and 13 (7.3%) patients in the amoxicillin/clavulanate treatment group experienced >1 serious AE (95% CI,-3.5 to 7.1). Serious AEs observed in the levofloxacin group, regardless of their relationship to the study drug, included exacerbation of condition (7 patients), cardiac failure (2), respiratory insufficiency/disorder (2), and 1 occurrence of each of the following: airway obstruction, bronchitis, cholelithiasis, dyspnea, gastrointestinal hemorrhage, hyperglycemia, thrombophlebitis, and vein distention. Serious AEs observed in the amoxicillin/ clavulanate group included exacerbation of condition (7 patients), pneumonia (5), and 1 occurrence of each of the following: aggravated depression, anemia, cardiac failure, fungal infection, pneumothorax, sar1177

Clinical Therapeutics

• Levofloxaci n [] Amoxicillin/clavulanate

67/83

Purulent sputum production 70/89 69/84 Sputum production 71/88

67/83

Cough 65/85 59/74

Shortness o f breath 64/84 17/17

Fever

20/21

28/30

Chills 20/21

0

20

40

60

80

100

% Patients Figure 2. Resolution of symptoms from the baseline visit to the posttreatment visit (days 17-26 after the administration of the first dose of study drug) in the microbiologically assessable population (n = 175) of 362 patients receiving levofloxacin 750 mg QD for 5 days (n = 86) or amoxicillin/clavulanate 875 mg/125 mg BID for 10 days (n = 89) for the treatment of severe acute bacterial exacerbation of chronic bronchitis. Resolution was defined as symptom presence at study entry and absence at posttreatment visit.

coidosis, and tachycardia. The only serious AE assessed by the investigator to be possibly related to the study drug in either treatment group was aggravated depression in 1 amoxicillin/clavulanate-treated patient. No deaths or cases of Clostridium difficile-associated diarrhea were observed in either treatment group during this study. The goals of antimicrobial treatment for ABECB include resolution of symptoms, eradication of the causative pathogen, and a decreased risk for recurrence. 17 Early recognition and treatment of an exacerbation might reduce the risk for hospitalization, is Reducing the severity, duration, and frequency of exacerbations might reduce the rate of lung function decline and improve overall quality of life in these patients. 19,2° Several factors associated with an increased risk for treatment failure in patients with ABECB have been identified, including the frequency of exacerbations, FEV 1 percentage of predicted values, presence 1178

of comorbidities, age, and long-term (maintenance) use of steroids or home oxygen. 3,5,<8 Patient stratification schemes have incorporated these factors to provide a targeted approach in antimicrobial selection, thereby attempting to reduce the risk for treatment failure and possible hospitalization in patients with severe ABECB. Because treatment failure and hospitalization can be significant factors for increased health care costs, choosing an appropriate first-line agent might also have important pharmacoeconomic benefits. This post hoc analysis revealed that patients receiving the 750-mg, 5-day regimen of levofloxacin were more likely to experience resolution of symptoms by days 3-6 of therapy compared with patients receiving the 10-day course of amoxicillin/clavulanate. The patients included in this analysis presented with >1 risk factor for severe ABECB. Approximately 80% of the patients in each treatment group experienced clinical and microbiological success after antimicrobial treatVolume 28 Number 8

R.F. Grossman et al.

Table. Treatment-emergent adverse events (AEs)* that were observed in _>2% of patients with severe acute bacterial exacerbation of chronic bronchitis (N = 362). Values are no. (%) o f patients.

Levofloxacin (n = 183)

Amoxicillin/ Clavulanate (n = 179)

All body systemsf Diarrhea

77 (42.1) 11 (6.0)

87 (48.6) 15 (8.4)

Nausea Headache Exacerbation of

10 (5.5) 9 (4.9)

8 (4.5) 7 (3.9)

AE

condition Dyspnea Rhinitis Constipation Dizziness Dyspepsia Skeletal pain Abdominal pain Sinusitis Moniliasis genital

7 6 5 4 4 4 4 3 2 1

(3.8) (3.3) (2.7) (2.2) (2.2) (2.2) (2.2) (1.6) (1.1) (0.5)

3 4 7 3 1 1 1 6 4 4

(1.7) (2.2) (3.9) (1.7) (0.6) (0.6) (0.6) (3.4) (2.2) (2.2)

*AEs that began on-treatment or up to 14 days after administration of the last close of study drug. fNo significant between-group difference for overall AE rate was Found.

ment. These observations were made among a group of patients with a relatively high yield of baseline respiratory pathogens (67.2% of the ITT population), contrary to previous studies where pathogens were isolated from only 17% to 32% of the ITT population. 21,22 The results from the present post hoc study are consistent with those from previous studies that suggest that patients with severe ABECB are more likely to be infected with difficult-to-treat pathogens, such as enteric gram-negatives. Antimicrobial resistance is also a major consideration when choosing an appropriate first-line agent for severe ABECB patients due to frequent antimicrobial use in this patient population. Among all isolates in this study, 97.1% were susceptible to levofloxacin, whereas 90.6% were susceptible to amoxicillin/clavulanate, though Pseudomonas and Acinetobacter spp were not tested against the latter agent. However, a correlation between in vitro susceptibility and clinical efficacy August 2006

was not apparent in this study. Significant differences favoring levofloxacin were observed in the proportions of patients who experienced resolution of symptoms, such as purulent sputum production, sputum production, and cough by the on-treatment visit, but not the posttreatment visit. The significantly higher proportion of patients who resolved symptoms with levofloxacin might be associated with a more rapid eradication of the causative pathogen, although additional studies are required to support this hypothesis. The results from this post hoc analysis suggest that levofloxacin 750 QD for 5 days was at least as effective in symptom resolution and as tolerable as amoxicillin/clavulanate 875/125 mg BID for 10 days in these patients with severe ABECB. ACKNOWLEDGM

ENT

The design, conduct, and analysis of this study were supported by PriCara, Unit of Ortho-McNeil, Inc., Raritan, New Jersey. REFERENCES 1. Anthonisen NR, Manfreda J, Warren CP, et al. Antibiotic therapy in exacerbations of chronic obstructive pulmonary disease. Ann Intern Med. 1987;106:196-204. 2. Adams SG, Melo J, Luther M, Anzueto A. Antibiotics are associated with lower relapse rates in outpatients with acute exacerbations of COPD. Chest. 2000;117:1345-1352. 3. Baker MS, La Forge J, Low DE, et al, for the Canadian Thoracic Society and the Canadian Infectious Disease Society. Canadian guidelines for the management of acute exacerbations of chronic bronchitis. Can RespirJ. 2003;10(SuppI B):3B-32B. 4. Grossman RF. Guidelines for the treatment of acute exacerbations of chronic bronchitis. Chest. 1997;112:310S313S. 5. Miravitlles M, Murio C, Guerrero T, for the DAFNE Study Group. Factors associated with relapse after ambulatory treatment of acute exacerbations of chronic bronchitis. Eur RespirJ. 2001 ;17:928-933. 6. Dewan NA, Rafique S, Kanwar B, et al. Acute exacerbation of COPD: Factors associated with poor treatment outcome. Chest. 2000;117:662-671. 7. Soler N, Torres A, Ewig S, et al. Bronchial microbial patterns in severe exacerbations of chronic obstructive pulmonary disease (COPD) requiring mechanical ventilation. AmJ Respir Crit Care Med. 1998; 157:1498-1505. 8. Miravitlles M, Espinosa C, Fernandez-Laso E, et al, for the Study Group of Bacterial Infection in COPD. Relationship between bacterial flora in sputum and functional impairment in patients with acute exacerbations of COPD. Chest. 1999;116:40-46. 1179

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A d d r e s s c o r r e s p o n d e n c e to: J a m e s B. K a h n , M D , P r i C a r a , Unit of O r t h o M c N e i l , Inc., 1000 R o u t e 202, P O B o x 300, R a r i t a n , N J 0 8 8 6 9 - 0 6 0 2 . E-mail: j k a h n @ o m p u s . j n j . c o m V o l u m e 28 N u m b e r 8