Levofloxacin versus cefuroxime axetil in the treatment of acute exacerbation of chronic bronchitis: results of a randomized, double-blind study

P. M. Shaha,*, F. P. V. Maesenb, A. Dolmannc, N. Vetterd, E. Fisse and R. Weschf

a Klinikum der Johann Wolfgang Goethe-Universitaet, Zentrum der Inneren Medizin, Medizinische Klinik III, Schwerpunkt Infektiologie, D-60590 Frankfurt, Germany b De Wever Ziekenhuis, Department of Pneumology, Henri-Dunant 5, NL-6401 CX Heerlen, The Netherlands c Hospital Antonio Cetrangolo, Italia 1750, RA-1602 Florida, Buenos Aires, Argentina d Pulmonologisches Zentrum der Stadt Wien, Sanatoriumstraat 2, A-1145, Vienna, Austria e Hospital Oswaldo Cruz, Departamento de Pneumologia, Rua Joao Juliao 331, BR-01323-903, São Paulo, Brazil f Hoechst Marion Roussel, D-65926, Frankfurt, Germany


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
A randomized, double-blind, double-dummy, three-arm parallel design, multicentre study was conducted among adult patients with acute exacerbation of chronic bronchitis (AECB) in order to compare the efficacy and safety of two different doses of levofloxacin with cefuroxime axetil. A total of 832 patients were randomized to receive oral levofloxacin (250 mg od or 500 mg od) or oral cefuroxime axetil (250 mg bd) for 7- 10 days. The primary efficacy analysis was based on the clinical response in patients with bacteriologically confirmed AECB, determined 5- 14 days after the end of therapy (per-protocol population). Of 839 patients enrolled (at 71 centres in 14 countries), seven were not treated, giving an intention-to-treat (ITT) population of 832. In total, 281 patients received levofloxacin 250 mg, 280 received levofloxacin 500 mg and 271 received cefuroxime axetil. The cure rates in the ITT population were: levofloxacin 250 mg, 70% (196/281); levofloxacin 500 mg, 70% (195/280); cefuroxime axetil, 61% (166/271); those in the per-protocol population were: 78% (121/156), 79% (108/137) and 66% (88/134), respectively. Both doses of levofloxacin were at least as effective as cefuroxime axetil and were active against the main pathogens of clinical relevance (Haemophilus influenzae, Streptococcus pneumoniae and Moraxella catarrhalis). All three treatment regimens were equally well tolerated. In conclusion, the results show that levofloxacin (250 mg and 500 mg) od is effective and well tolerated in the treatment of AECB in adult patients.


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Acute bronchitis, an inflammatory condition of the tracheobronchial mucosa, is caused by a variety of irritants and infectious agents. Patients with chronic bronchitis frequently experience episodes of acute disease that is superimposed on the chronic condition. These acute exacerbations are characterized by factors such as a worsening cough and respiratory distress and an increase in sputum volume and purulence. However, objective signs of an exacerbation are not always present and diagnosis is therefore reliant on the patient's observations.

Bacteria are thought to be responsible for about 70% of these exacerbations (the remainder being viral), most commonly Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis. 1 However, Haemophilus parainfluenzae, ß-haemolytic streptococci, strains of Enterobacteriaceae and Staphylococcus aureus are also often cultured from the sputum. Therapeutic options for the treatment of acute exacerbations include steroids, bronchodilators and antibiotics, depending on the extent of inflammation and bronchial obstruction and the nature of the infection.

The newer fluoroquinolones, such as levofloxacin, are effective against a broad range of respiratory tract pathogens, including S. pneumoniae and H. influenzae, and have good tolerability and pharmacokinetic profiles. 2,3 Of the older fluoroquinolones, both ciprofloxacin and ofloxacin have proved effective in the treatment of respiratory exacerbations in patients with cystic fibrosis. 4 Levofloxacin has a broad spectrum of activity including Gram-positive aerobic bacteria, e.g. S. pneumoniae and S. aureus, Gram-negative bacteria, e.g. H. influenzae, Escherichia coli, Klebsiella spp. and Pseudomonas aeruginosa, and atypical bacteria, e.g. Mycoplasma pneumoniae, Chlamydia pneumoniae and Legionella pneumophila. 2,5,6

The pharmacokinetic profile of levofloxacin is characterized by rapid absorption, almost 100% bioavailability, relatively slow elimination (6- 8 h) and good tissue penetration, including lung and bronchial secretions. 2,7,8,9,10 Previous studies have demonstrated its utility in the treatment of lower respiratory tract infections including acute exacerbation of chronic bronchitis (AECB). 11,12,13 These data suggest that levofloxacin is a promising therapeutic option in the treatment of respiratory tract infections.

The second-generation cephalosporin, cefuroxime axetil, is a semi-synthetic broad-spectrum oral antibiotic which is widely used for the treatment of respiratory tract infections. 14,15,16,17 An open, multicentre, randomized study of 456 patients with community-acquired pneumonia showed that treatment with levofloxacin was superior to ceftriaxone and/or cefuroxime axetil treatment in the management of community-acquired pneumonia in adults. 12 In a previous study in AECB— also an open, multicentre, randomized design— DeAbate et al. 11 showed that levofloxacin 500 mg od was as effective and well tolerated as cefuroxime axetil 250 mg bd. The aim of this randomized, double-blind study was to compare the efficacy and tolerability of two different doses of levofloxacin (250 or 500 mg od) with cefuroxime axetil 250 mg bd in the treatment of AECB in adult patients.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Study design and patients

This randomized, double-blind study was carried out in 71 centres in 14 countries in Europe, Africa and South America. The study was double-dummy, with a three-arm parallel design, and was conducted in hospitalized patients or out-patients of either sex, aged >=18 years. Randomization was performed by centre, with each centre assigned a sequence of patient numbers. Study medication was randomly assigned to the patient numbers in advance by Hoechst Marion Roussel and labelled with the patient number. Patients were numbered consecutively in the order in which they entered the study. Levofloxacin (250 and 500 mg) and cefuroxime axetil were randomized on a 1:1:1 basis. Study medication was supplied on blister cards consisting of a transparent strip and an opaque, plain, silver-foil strip and packed for 7 days' treatment in 24 h periods. For each 24 h period, the first dose consisted of one active tablet and two matching placebo tablets and the second dose comprised either one cefuroxime axetil tablet or, for levofloxacin patients, one placebo tablet matching cefuroxime axetil.

The patients recruited had experienced chronic cough and sputum production for >2 consecutive years and on most days for 3 consecutive months. Their symptoms and signs were compatible with the usual diagnosis criteria for AECB (e.g. increased cough, dyspnoea, increased sputum volume and increased sputum purulence); the patients also had to be appropriate candidates for oral therapy.

Patients were excluded if they were pregnant or of childbearing potential and not taking adequate contraceptive measures or if they had pneumonia or bronchopneumonia (shown by acute infiltrations on admission chest X-ray), cystic fibrosis, active tuberculosis, lung cancer/metastases; unstable chronic pulmonary disease, severe bronchiectasis, severe malabsorption syndrome, neutropenia, AIDS, progressively fatal disease, renal impairment, severe hepatic disease, a lowered seizure threshold, a history of epilepsy or hypersensitivity to ofloxacin or other fluoroquinolones or penicillin/ß-lactams. Patients were also excluded if they required probenecid or a systemic antibiotic for another infection or if they had received antibiotic treatment in the 72 h before entry to the study or azithromycin in the 7 days before study entry.

All patients provided informed consent, and the study protocol was approved for all centres by the local ethics committee. The study was conducted according to the Good Clinical Practice Guidelines of the European Union and the Declaration of Helsinki. Patients were randomized to receive oral levofloxacin 250 mg od or 500 mg od (Hoechst Marion Roussel, Frankfurt, Germany), or cefuroxime axetil 250 mg bd (Glaxo Wellcome Ltd, Uxbridge, UK) for 7- 10 days. The primary analysis of efficacy was based on the clinical response in patients with bacteriologically confirmed AECB, determined at the clinical endpoint, 5- 14 days after the end of therapy (per-protocol population).

Assessments

A total of 832 patients were randomized to receive oral levofloxacin (250 mg od or 500 mg od) or oral cefuroxime axetil (250 mg bd) for 7- 10 days. Assessments were performed after 3- 6 days of treatment and within 2 days (post-treatment), 5- 14 days (clinical endpoint) and 21- 28 days (follow-up) after the end of treatment. Assessments were made both by computer (protocol assessment) and by the investigator. All patients provided a detailed medical history and underwent a full physical examination and a postero-anterior chest X-ray (to rule out pneumonia and bronchopneumonia) at inclusion. Clinical signs and symptoms of infection (cough, peak flow spirometry, dyspnoea, sputum volume, sputum purulence and peak body temperature in febrile patients) and bacteriological variables (patient response, baseline pathogen response and pathogen sensitivity) were documented at each visit. Baseline sputum cultures were obtained from 3 days before to 2 days after the start of treatment in order to isolate and identify the causative pathogen and to examine for the presence of polymorphonuclear leucocytes and squamous epithelial cells. Follow-up cultures were obtained at each visit.

Peak flow spirometry was performed with the Vitalograph peak flow meter (Vitalograph GmbH, Hamburg, Germany). Haematology and serum chemistry were performed according to standard methods used at individual centres. Safety was assessed at each visit by adverse events and vital signs; another physical examination was performed within 2 days after the end of treatment and laboratory parameters were assessed after 3- 6 days of treatment and within 2 days after the end of treatment. Adverse events were classified by the investigators according to their intensity (mild, moderate or severe), nature (serious or non-serious) and possible relationship to the study drug. In the case of a serious adverse event possibly related to the study drug (investigator assessment), patients were immediately withdrawn from the study if still on the study drug. An adverse event was serious if it was fatal or life-threatening, permanently or significantly disabling, required prolonged hospitalization, involved cancer or congenital anomaly, occurred as a result of overdose or suggested a significant hazard.

Analyses

Analyses were performed on the intention-to-treat (ITT) population (all patients who received at least one dose of medication) and the per-protocol population (all patients with clinical signs and symptoms of infection and bacteriologically proven infection, excluding major protocol violators). Major protocol violators were defined as: incorrect entry diagnosis, insufficient treatment duration, non- compliance, antibiotic pre-treatment, no clinical post-treatment evaluation or broken randomization code. The primary efficacy variable was the clinical response in bacteriologically confirmed cases of AECB determined 5- 14 days after the last day of treatment. Efficacy assessments were performed by a computerized evaluation programme and by the investigators. The definitions of clinical response were based on the European Guidelines for the Clinical Evaluation of Anti-infective Drugs. 18

Cure was defined as the disappearance of all infection signs and symptoms or their return to preinfection state, or the improvement of at least one infection-related sign or symptom, with the patient afebrile and no subsequent antibiotic treatment started. Treatment failure was defined according to one or more of the following criteria: all infection-related symptoms remained unchanged or worsened; the patient was febrile, even if any other symptom improved; the patient developed new clinical findings consistent with active infection; the patient died owing to infectious disease for which the study drug was given; the study drug was discontinued because of clinical and/or bacteriological treatment failure; one or more antibiotics were added to the study drug because of treatment failure; at least one infection-related sign or symptom had improved but antibiotic treatment was subsequently started. If assessment circumstances precluded classification (e.g. follow-up information was missing), the clinical response was regarded as indeterminate.

The bacteriological response was also assessed. Patients were eligible for bacteriological evaluation if a causative pathogen was isolated from the baseline culture and there was no major protocol violation. A satisfactory bacteriological response was defined as eradication (the baseline causative pathogen was eradicated), presumed eradication (the patient had improved clinically to such an extent that a proper follow-up culture could not be obtained) or colonization (a new organism other than the baseline pathogen was present at any site without clinical evidence of infection).

An unsatisfactory response was recorded in the following circumstances: persistence (the baseline causative pathogen was still present whether or not signs of infection were present), relapse (the absence of the baseline causative pathogen was documented, but the same pathogen appeared in cultures of specimens obtained 21- 28 days after the end of treatment), superinfection (a new causative pathogen emerged at any site during therapy or <3 days after treatment had been completed, together with clinical evidence of infection), eradication and reinfection (the eradication of the baseline causative pathogen was followed by replacement with a new pathogen at the same site with clinical evidence of infection >3 days after completion of treatment), persistence and reinfection (the persistence of the baseline pathogen was accompanied by a new pathogen at the same site with clinical evidence of infection >=4 days after completion of treatment), persumed persistence (a new or additional antibiotic treatment was given due to clinical evidence of infection at the original site without adequate microbiological data), resistance (a new or additional antibiotic treatment was given because the responsible baseline pathogen was resistant to one of the study drugs in vitro).

The bacteriological response was regarded as indeterminate if it was not possible to categorize the microbiological response because of a lack of opportunity to obtain further cultures or because the patient had been treated with a systemic antibiotic in addition to the study drug. A hierarchy was established within the categories `satisfactory' and `unsatisfactory' to ensure that patients with more than one responsible pathogen were only included once; the worse assessment of a pathogen was retained for each patient.

Bacteriology

Susceptibility testing of isolates to the study drugs was carried out using the disc diffusion test according to the NCCLS method. 19 Levofloxacin (5 µg disc): inhibition zone >=16 mm, susceptible; 13- 15 mm, intermediate; <=12 mm, resistant. Cefuroxime (30 µg disc) (inhibition zones for Haemophilus spp. in parentheses): inhibition zone >=23 mm (>=24 mm), susceptible; 15- 22 mm (21- 23 mm), intermediate; <=14 mm (<=20 mm), resistant.

Statistical analysis

The SAS program package version 6.09 was used for all evaluations. The primary analysis of efficacy was based on the clinical cure rate in patients with bacteriologically confirmed AECB (per-protocol population), determined 5- 14 days after the end of treatment (clinical endpoint), comparing both levofloxacin 250 and 500 mg with cefuroxime axetil 500 mg. For each of these comparisons, a two-sided 95% confidence interval (CI) was calculated. Levofloxacin was considered equivalent to cefuroxime axetil if the upper and lower bounds of the 95% CI were >0% and >15%, respectively. Assuming a success rate of 70% in the three treatment arms of a {delta} of 15% (the maximum difference between treatments to be accepted as equivalent), 160 evaluable patients per group were needed to provide an 80% chance (power = 80%) for showing equivalence in each of the two comparisons. 20,21,22 It was assumed that 60% of the patients treated would be evaluable for efficacy and, therefore, a total of 800 patients were to be enrolled. In addition, the clinical success rate and bacteriological response rate, the 95% CIs of these rates and the 95% CIs for the difference in success rates between the treatment groups were determined for all the population analyses at post-treatment, clinical endpoint and follow-up.


    Results
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
A total of 839 patients were enrolled at 71 centres in 14 countries, of whom seven were not treated, giving an ITT population of 832. The study population was representative of moderate-to-high-risk patients with AECB with a clear need for antibiotic treatment. More than 50% of the study patients were elderly (median age 65, range 23- 100 years) and 69% (574/832) were male. A history of disease and/or concomitant illness was reported in 817/832 (98%) patients, the most common being respiratory diseases (753/832, 91%; excluding chronic bronchitis, since this was the condition required for entry to the study), cardiovascular (308/832, 37%), gastrointestinal (251/832, 30%) and hypertension (190/832, 23%). The most frequently reported risk factors for respiratory disease, other than chronic bronchitis, were emphysema (312/832, 38%), bronchial obstruction other than cancer (208/832, 25%) and asthma (167/832, 20%). Most patients were smokers or ex-smokers (624/832, 75%). The most frequently prescribed concomitant medications were bronchodilators (616/832, 74%), corticosteroids (424/832, 51%) and theophylline (358/832, 43%).

Symptoms of the current exacerbation were present for <4 days in 483/832 patients (58%) at study entry. Peak flow was impaired (any value <=400 L/min) in 705/832 patients (85%). Six hundred and thirty patients (76%) were classified as having moderate or severe disease, and 263/832 (32%) were judged to be in poor or critical condition. The source of infection for almost all patients was community acquired (785/832, 94%) and nearly half the patients were hospitalized on admission (362/832, 44%). The most frequently isolated pathogens were H. influenzae, S. pneumoniae and M. catarrhalis. The baseline characteristics, i.e. demographics, hospitalization status, infection characteristics, and baseline pathogens, were similar for all three treatment groups.

The number of patients included in each analysis is shown in Table I. The median treatment duration was 7 days in all three groups. A total of 112 patients were with- drawn prematurely from the study. The reason for withdrawal (patients could have more than one reason for withdrawal) was given as clinical failure for 20 patients, bacteriological failure for four patients, safety reasons for 44 (35 due to adverse events, nine due to death) and other reasons for 59 patients. Major protocol violations occurred in 110 patients and no pathogen was isolated at baseline in 285 patients, giving a per-protocol population of 437 patients.


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Table I. Number of patients included in each analysis
 
Clinical efficacy

The clinical success rates for the primary efficacy analysis (clinical endpoint, 5- 14 days after the end of treatment) were similar for both levofloxacin treatment groups and these were higher than for the cefuroxime axetil group. The results of the analysis of the ITT population revealed a lower cure rate in the cefuroxime axetil group than in either levofloxacin group; the cure rate in both levofloxacin groups was 70% (250 mg: 196/281; 500 mg: 195/280) whereas the corresponding value for the cefuroxime axetil group was 61% (166/271). The 95% CI values for 250 mg levofloxacin vs cefuroxime axetil and 500 mg levofloxacin vs cefuroxime axetil were 0.2%, 16.8% and 0.1%, 16.7% respectively. Thus, both levofloxacin doses were at least equivalent to cefuroxime axetil. As expected, the cure rates for all treatment groups in the ITT population were lower than in the per-protocol population due to the higher number of indeterminate cases, mainly due to protocol violations (Table II).


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Table II. Clinical success rates
 
The clinical response in the per-protocol population 5- 14 days after the end of therapy, as assessed by the computerized evaluation programme, is shown in Table III. The clinical cure rate was considerably lower in the cefuroxime axetil group (88/134, 66%) than in either the 250 mg or 500 mg levofloxacin groups (121/156, 78% and 108/137, 79%, respectively). This was due to the higher number of withdrawals due to failure (16 in the cefuroxime axetil) group compared with three in the 250 mg levofloxacin group and one in the 500 mg levofloxacin group) and the higher number of patients for whom subsequent antibiotic treatment was indicated. The two-sided 95% CI for the differences in cure rates revealed that both 250 mg and 500 mg levofloxacin were at least equivalent to cefuroxime axetil (0.8%, 23.0% and 1.9%, 24.5%, respectively).


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Table III. Clinical response in the per-protocol populations 5–14 days after the end of treatment (clinical endpoint)
 
There were more patients who received subsequent antibiotic therapy in the cefuroxime axetil group than in either of the levofloxacin groups in both the ITT (51, 45 and 64 patients in the 250 mg levofloxacin, 500 mg levofloxacin and cefuroxime axetil groups, respectively) and per- protocol populations (31, 22 and 40 patients in the 250 mg levofloxacin, 500 mg levofloxacin and cefuroxime axetil groups, respectively). Most of the successful subsequent antibiotic treatments were penicillins, with or without ß-lactamase inhibitors, and cephalosporins.

The clinical response 5- 14 days after the end of therapy as assessed by the investigator revealed that levofloxacin treatment at both doses was as effective as cefuroxime axetil treatment. In the ITT population, the clinical cure rate was 76% (190/249), 79% (195/248) and 74% (173/233) in the 250 mg levofloxacin, 500 mg levofloxacin and the cefuroxime axetil groups, respectively. Similar findings were observed in the per-protocol population, with cure rates of 82% (112/136), 88% (104/118) and 82% (91/111) in the 250 mg levofloxacin, 500 mg levofloxacin, and cefuroxime axetil groups, respectively. The corresponding 95% CI values for 250 mg levofloxacin vs cefuroxime axetil and 500 mg levofloxacin vs cefuroxime axetil were -10.0%, 10.8% and -3.9%, 16.3%, respectively.

The cure rates in the investigator assessment were higher for all three treatment groups compared with the protocol assessment. The difference between the protocol and investigator assessment was highest for cefuroxime axetil, which resulted in similar clinical success rates for all three treatment groups as assessed by the investigator. The protocol and investigator assessments were in agreement for 82% (601/730) of patients in the ITT population who had both assessments and 77% (330/429) of patients in the per-protocol population who had both assessments.

Cure rates for all treatment groups in both the ITT and per-protocol populations were lower at follow-up (21- 28 days after the end of therapy) than at clinical endpoint (5- 14 days after the end of therapy). In contrast to the clinical endpoint assessment, where the cure rates for both levofloxacin treatments were higher than for cefuroxime axetil, the cure rates at follow-up were similar for all three treatments (Table II).

Bacteriological efficacy

As shown in Table IV, a total of 577 bacterial isolates were obtained at baseline. Distribution between the treatment groups was similar. The most commonly isolated pathogens were H. influenzae (208/577, 36%), S. pneumoniae (105/577, 18%) and M. catarrhalis (92/577, 16%). Resistance to levofloxacin was observed in 10/555 isolates (1.8%), including six resistant P. aeruginosa isolates; resistance to cefuroxime was considerably more common, occurring in 74/558 isolates (13%), including 36 resistant P. aeruginosa isolates and 18 resistant H. influenzae isolates. Only two Gram-positive pathogens were resistant to levofloxacin and one to cefuroxime. In total, 2.5% (5/200) and 0.5% (1/183) of isolates in the 250 mg and 500 mg levofloxacin groups were resistant to levofloxacin and 12% (20/173) of isolates in the cefuroxime axetil group were resistant to cefuroxime.


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Table IV. Pathogens isolated at baseline
 
The bacteriological response 5- 14 days after the end of treatment in the per-protocol population, as assessed by the computerized evaluation programme, is shown in Table V. As seen with the clinical success rate, the bacteriological response rate was lower with cefuroxime axetil (68/114, 60%) than with 250 mg or 500 mg levofloxacin (88/127, 69% and 82/107, 77%, respectively). The corresponding 95% CI values for 250 mg levofloxacin vs cefuroxime axetil and 500 mg levofloxacin vs cefuroxime axetil were -3.3%, 22.5% and 4.0%, 30.0%, respectively. The bacteriological response assessed by the investigator also showed that levofloxacin was as effective as cefuroxime axetil. In the per-protocol analysis, the bacteriological and clinical response were in agreement for 66% (289/437) of patients who had data for both assessments.


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Table V. Bacteriological response in the per-protocol population 5–14 days after the end of treatment (clinical endpoint)
 
The bacteriological eradication rate by pathogen 5- 14 days after the end of treatment in the per-protocol population, as assessed by the computerized evaluation programme, is shown in Table VI. The higher eradication rate in the levofloxacin groups was due to better eradication of Gram-negative pathogens. A total of 71 causative pathogens persisted in 67 patients (23, 15 and 33 in the 250 mg levofloxacin, 500 mg levofloxacin and cefuroxime axetil groups, respectively); the most common persistent pathogens were S. pneumoniae and P. aeruginosa in the levofloxacin groups, and H. influenzae and P. aeruginosa in the cefuroxime axetil group. Fifteen pathogens in 15 patients were responsible for superinfections (six, three, and six in the 250 mg levofloxacin, 500 mg levofloxacin and cefuroxime axetil groups, respectively), and 16 pathogens in 15 patients were responsible for reinfection (five, four, and six in the 250 mg levofloxacin, 500 mg levofloxacin and cefuroxime axetil groups, respectively).


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Table VI. Bacteriological eradication rate by pathogen in the per-protocol population 5–14 days after the end of treatment (clinical endpoint)
 
Similar to the clinical response at follow-up, the bacteriological response rates at follow-up were also lower than at clinical endpoint, with a satisfactory response in 48% (46/96), 56% (40/67) and 36% (31/87) of patients in the 250 mg levofloxacin, 500 mg levofloxacin and cefuroxime axetil groups, respectively.

Subgroup efficacy analysis

Analyses of the clinical and bacteriological responses were performed separately at clinical endpoint (5- 14 days after the end of treatment) in subgroups of patients in the per-protocol population, including elderly patients (>=65 years), hospitalized patients, smokers, patients taking concomitant corticosteroids and patients taking concomitant theophylline. The cure rates were generally similar to those in the overall population, although hospitalized patients and those taking concomitant corticosteroids or theophylline showed higher response rates with 500 mg levofloxacin than with 250 mg levofloxacin or cefuroxime axetil (clinical cure rates were 47.68, 69%; 48/63, 76% and 34.57, 60% in the levofloxacin 250 mg, levofloxacin 500 mg and cefuroxime axetil groups, respectively). The clinical cure rate in patients with more severe disease (peak flow <=300 L/min) was 75% in both the levofloxacin groups (99/132 in the 250 mg group, 84/112 in the 500 mg group) and 63% (74/117) in the cefuroxime axetil group.

The bacteriological response rates for elderly, hospitalized patients and smokers were similar to those of the overall population for both levofloxacin groups. Patients on 500 mg levofloxacin, with either of the concomitant medications, had similar bacteriological response rates to the overall population whereas the 250 mg levofloxacin and cefuroxime axetil patients had lower response rates.

Safety evaluation

All 832 patients in the ITT population were included in the safety evaluation. All three treatment regimens were equally well tolerated; adverse events were reported by 50% (140/281) of patients in the 250 mg levofloxacin group, 47% (131/280) in the 500 mg levofloxacin group and 42% (115/271) in the cefuroxime axetil group. The number of patients with adverse events by body system is shown in Table VII. The most commonly affected body systems were similar for all three groups: respiratory, digestive, nervous and body as a whole. The only between-group comparison that achieved statistical significance was the incidence of respiratory tract adverse events in the 500 mg levofloxacin group versus the incidence in the cefuroxime axetil group (P = 0.043). However, the majority of these events in both groups were considered by the investigator to be due to the underlying disease and not related to treatment.


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Table VII. Number of patients with adverse events (AEs), by body system
 
Adverse events possibly related to the study drug were reported in 163 patients, 57 in both levofloxacin groups and 49 in the cefuroxime axetil group (Table VII). The type of adverse events possibly related to the study were the same as those irrespective of causal relationship except for respiratory events which were obviously related to the study indication. Thus, the frequency of respiratory events was reduced from 16- 23% for all events to 2.2- 2.5% for possibly related events. There were no relevant differences between the treatment groups.

Adverse events accounted for the premature discontinuation of treatment in 42 patients, 14 patients in each treatment group; events associated with the digestive system were the most common. Serious adverse events (not drug related) occurred in 112 patients: 39 patients (13.9%) in the 250 mg levofloxacin group, 43 (15.4%) in the 500 mg levofloxacin group and 30 (11.1%) in the cefuroxime axetil group (see Table VIII). The respiratory tract was most commonly associated with serious adverse events in all three groups (31, 36 and 24 patients, respectively). There were a total of 18 deaths during the study, four in the 250 mg levofloxacin group, 10 in the 500 mg levofloxacin group and four in the cefuroxime axetil group. Only three deaths occurred during or shortly after treatment; the remaining 15 occurred >=8 days after the end of treatment. The adverse events associated with the deaths were largely severe pre-existing conditions and none was considered by the investigator to be causally related to the study treatment. The most common laboratory variables with abnormalities reported as adverse events were eosinophilia, SGOT/SGPT increases, hyperglycaemia and bilirubinaemia. The frequency of laboratory adverse events was similar for all three treatment groups. There were no differences between the groups for any of the vital sign variables.


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Table VIII. Number of patients with serious adverse events (not drug related), by body system
 

    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
The results from this double-blind, multicentre study show that levofloxacin, at a dose of 250 or 500 mg od for 7- 10 days, was at least as effective as cefuroxime axetil (250 mg bd) in the treatment of AECB in adult patients. The higher clinical cure rates and bacteriological response rates seen with levofloxacin were probably a result of the enhanced activity of fluoroquinolone antibacterials compared with cephalosporins against Gram-negative pathogens, which comprised three-quarters of the causative pathogens in this study. Relatively higher cure rates were achieved with the computerized evaluation programme than with the investigator assessments. This may have been because the strict definitions of cure within defined time points were unlikely to correspond absolutely to subjective clinical impressions in such a chronically ill patient group.

The results of our study are similar to those of previous studies and confirm the efficacy of levofloxacin in the treatment of AECB. 11,13 DeAbate et al. 11 also compared levofloxacin (500 mg od) with cefuroxime axetil (250 mg bd) in adults. The study was a randomized, multicentre open-label design among 492 adult out-patients (248 levofloxacin, 244 cefuroxime axetil) treated for a mean of 10 days. Clinical success and bacteriological eradication rates were 95% and 97%, respectively, for levofloxacin and 93% and 95%, respectively, for cefuroxime axetil. The authors concluded that levofloxacin was as effective and well tolerated as cefuroxime axetil. Levofloxacin 500 mg od for 5- 7 days was compared with cefaclor 250 mg tds for 7- 10 days in the study by Habib et al. 13 This was a randomized, multicentre, active-control design among 373 adult out-patients. Clinical success rates and bacteriological eradication rates were 92% and 95%, respectively, for levofloxacin and 92% and 87%, respectively, for cefaclor. Levofloxacin was concluded to be as effective and well tolerated as cefaclor.

The cure rates observed in our study (ITT population: levofloxacin 70%; cefuroxime axetil 61%; per-protocol population: levofloxacin 78% and 79%; cefuroxime axetil 66%) were within the expected range of 50- 70% given in the European Guidelines for Clinical Evaluation of Anti-infectives. 18 In a study of the effects of broad-spectrum antibiotic therapy in patients with AECB of similar severity, a success rate of 68% was reported. 23 The success rates commonly reported for antibiotic studies in AECB are often higher (80- 90%), but the patients in these studies tended to have fewer complicating conditions and the studies had less stringent protocols than the present study. 24,25,26 Similarly, DeAbate et al. 11 and Habib et al. 13 reported success rates of >90%. The lower cure rates reported in our study could be due to the patient population, which had a high degree of complications and the stricter definition of clinical failure. For example, bacteriological failure as a reason for subsequent antibiotic therapy was considered clinical failure, as were all determinate cases in the ITT population.

Both levofloxacin doses were clinically effective against the main pathogens of clinical relevance in AECB: H. influenzae, S. pneumoniae and M. catarrhalis. In general, the causative pathogens were more commonly resistant to cefuroxime than to levofloxacin, mainly due to the presence of resistant Gram-negative pathogens such as H. influenzae and P. aeruginosa. Only two Gram-positive pathogens were resistant to levofloxacin and one to cefuroxime.

Evaluation of patient subgroups revealed that the 250 mg dose of levofloxacin was less effective than the 500 mg dose in hospitalized patients and those treated with concomitant theophylline or corticosteroids. Thus, these patients might require the higher dose of levofloxacin. The effectiveness of the two doses did not vary, however, in the total patient population. The clinical cure rate in patients with more severe disease (peak flow <=300 L/min) was higher in levofloxacin than in cefuroxime axetil treated patients.

Both levofloxacin and cefuroxime axetil were well tolerated. The most common adverse events in both groups were those associated with the respiratory tract (mainly due to worsening of symptoms associated with the underlying disease) and the digestive system (well-recognized side-effects of antibacterial treatments). The high number of patients experiencing respiratory adverse events was not unexpected given the severity of the disease in the majority of patients. That these adverse events were largely related to the underlying disease is shown by the much lower numbers of patients with such events that were considered to be related to the study drug. Despite the tendency for fluoroquinolone antibacterials to be associated with effects on the nervous system, the incidence of such adverse events did not differ between the three treatment groups.

In conclusion, the results of our study show that 250 mg or 500 mg levofloxacin od was at least as effective and as well tolerated as cefuroxime axetil bd in the treatment of AECB in adults. Levofloxacin was active against the main pathogens of clinical relevance, H. influenzae, S. pneumoniae and M. catarrhalis. Thus, levofloxacin 500 mg od is an effective and well-tolerated treatment for AECB in adults.


    Acknowledgments
 
The authors would like to thank the following members of the international study group for their assistance in conducting this study: Argentina: C. Piovano; Belgium: W. de Backer, D. Galdermans; Brazil: M. R. A. A. Lima, A. Chibante; Denmark: J. I. Jensen; Finland: K. Aemmaelae, K. Alanko, R. Kauppinen, L. Miettinen, E. R. Salomaa, R. Valta; France: B. Blaive, G. de Lafond, J. Gallet, P. Godard, J. P. Homasson, G. Lamarque, M. E. Lamouliatte, E. Lemarie, V. Macquet, J. P. Orlando, Y. Pacheco, R. Parlente; Germany: T. Anke, O. J. Brueckner, M. Eff, H. T. Heidemann, W. Kersten, K. H. Krause, P. Kleine, R. Lohmueller; Italy: S. Amaducci, A. Ciaccia, R. Cogo, R. Corsico, C. Donner, L. Gandola, G. Morandini, G. M. Massaglia, A. Rossi, G. Scarpazza; South Africa: A. Foden, J. Janssen, M. Plit, M. Plit, G. Richards, P. Willcox; Spain: R. Blanquer, J. M. G. del Rio, F. Manresa, J. Morera, J. M. Pardo, V. Sobradillo, J. M. S. Valet; Sweden: H. Grip, C. Hansson, J. Ziegler; UK: P. Barber, G. S. Basran, D. Bell, R. J. Davies, W. McNee, K. R. Patel, R. D. Stevenson, R. Stockley, J. H. Winter. The study was supported by a grant from Hoechst Marion Roussel.


    Notes
 
* Corresponding author. Tel: +49-69-6301-6614; Fax: +49-69-6301-7717; E-mail: shah{at}em.uni-frankfurt.de Back


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
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Received 23 June 1998; returned 26 August 1998; revised 26 October 1998; accepted 30 November 1998