Randomized, double-blind study of short-course (5 day) grepafloxacin versus 10 day clarithromycin in patients with acute bacterial exacerbations of chronic bronchitis

C. E. Langana, P. Zuckb, F. Vogelc, A. McIvord, W. Pierzchalae, M. Smakalf, H. Staleyg and C. Marrg,*

a Baillieston Health Centre, 20 Muirside Rd, Glasgow G69AD, UK b Hôpital Notre Dame de Bon Secours, Service Médecine Interne-Pneumologie 1, Place Phillippe de Vigneulles, 57000 Metz, France c Kliniken des Main-Taunus-Kreises, Lindenstrasse 10, 65719 Hofheim, Germany d Sunnybrook Health Science Centre, A456-2075 Bayview Ave, Toronto, Canada, M4N 3M5 e Katerda i Klinika Pneumonologii SLAM, ul. Medykow 4, 40-752 Katowice, Poland f Ke stacirne 608, 149 00 Praha 4, Czech Republic g Glaxo Wellcome R&D Greenford Rd, Greenford, Middlesex UB6 0HE, UK


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
The efficacy and safety of grepafloxacin were compared with clarithromycin in a randomized, double-blind, multicentre clinical trial of 805 patients with acute bacterial exacerbations of chronic bronchitis (ABECB). Patients were randomized to receive grepafloxacin 400 mg od for either 5 (n = 273) or 10 days (n = 268) or clarithromycin 250 mg bd for 10 days (n = 261). Patients were assessed pre-treatment, 3–5 days during treatment, 1–3 days post-treatment and at follow-up (21–28 days post-treatment). The clinical success rates for the evaluable patients were 91% in the 5 day grepafloxacin group, 95% in the 10 day grepafloxacin group and 86% in the clarithromycin group. At follow-up, respective rates were 72%, 81% and 73%. A total of 513 pathogens were isolated from the pre-treatment sputum specimens of 400 (49%) patients. The primary pathogens were Haemophilus influenzae (36% of isolates), Haemophilus parainfluenzae(27%), Moraxella catarrhalis (12%), Streptococcus pneumoniae (11%) and Staphylococcus aureus (3%). Pathogens were eradicated or presumed eradicated at post-treatment in 85%, 91% and 58% of evaluable patients treated with grepafloxacin for 5 days, grepafloxacin 10 days and clarithromycin 10 days, respectively. The eradication rates in both grepafloxacin groups were significantly greater than the clarithromycin group (P< 0.001). All treatments were well tolerated and incidence of drug-related adverse events in each group was comparable. This study demonstrates that both a 5 and a 10 day regimen of grepafloxacin 400 mg od are as clinically and bacteriologically effective as in the treatment of ABECB clarithromycin 250 mg bd for 10 days.


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Chronic bronchitis afflicts between 3% and 17% of the population in most developed countries.1 Individuals with chronic bronchitis frequently experience acute bacterial exacerbations (ABECB) that are characterized by increased cough and sputum production, and dyspnoea.2 Haemophilus influenzae, Streptococcus pneumoniaeand Moraxella catarrhalisare the major bacterial pathogens identified in ABECB.3,4 Bacterial exacerbations are sometimes associated with acute decreases in lung function and increases in morbidity and mortality. Antimicrobial therapy has been shown to play a role in reducing the morbidity and mortality associated with ABECB and in preventing suppurative complications sometimes associated with these bacterial infections in patients with chronic pulmonary disease.2,5

Most cases of ABECB are treated empirically with a course of a broad-spectrum antibiotic. Traditional empirical antibiotic therapy with someß-lactam and macrolide antibiotics may be compromised by the rise in incidence of penicillin resistance andß-lactamase-producing strains among the common respiratory pathogens.6 Although there is considerable variability in the national, regional and local incidence of penicillin resistance andß-lactamase production, predictive models indicate trends for emergence of resistance, even in areas where current prevalence is low. This study also reported increases in cross-resistance of S. pneumoniae isolates to other antibiotics.7 The incidence of multidrug-resistant S. pneumoniae is increasing, resulting in decreased susceptibility of these strains to macrolides and some other antibiotics.8 Therefore, patients with ABECB require effective and well tolerated antimicrobial agents for empirical therapy and in cases where resistant organisms are suspected.

Grepafloxacin is a broad-spectrum fluoroquinolone with good activity against Gram-positive bacteria as well as Gram-negative and atypical organisms.9,10 Grepafloxacin demonstrates extensive respiratory tissue distribution and has an extended half-life (12 h) in humans.11,12 These pharmacokinetic parameters allow once-daily dosing, which is considered an important consideration in optimizing patient compliance.13,14 Current indications for grepafloxacin include ABECB and community acquired pneumonia. Grepafloxacin has been shown to be well tolerated.15,16

The current grepafloxacin dosing regimen in ABECB is 400 mg od for up to 10 days. Recent trials with other classes of antibiotics, including the cephalosporins, have shown that shorter courses of antibiotic therapy are as efficacious as the standard 10 day dosing regimen in lower respiratory tract infections.16,17,18 Shorter courses of antibiotic therapy in ABECB potentially have the advantage of reducing adverse effects, increasing patient compliance and improving cost management.

Clarithromycin is an extended-spectrum macrolide antibiotic currently approved for use in the treatment of upper and lower respiratory tract infections. Clarithromycin demonstrates good bioavailability and tissue distribution.19

The present study compares the efficacy and safety of a 10 day course of grepafloxacin 400 mg od with a shorter 5 day course of grepafloxacin and with a 10 day treatment of clarithromycin 250 mg bd in patients with ABECB.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
This study was a randomized, double-blind, multicentre study (protocol number GFXB3002) conducted at 78 centres in nine countries (Belgium, Canada, Czech Republic, France, Germany, Poland, Portugal, Spain and the UK). All patients gave written informed consent before entry in the study, and the study protocol was approved in accordance with local Ethics Committees in each country.

Patient selection

Male and female outpatients aged 18 years or older with an established diagnosis of chronic bronchitis were eligible to participate in the study. Patients were screened at a pre-treatment visit within 48 h of initiating treatment. Patients were required to have purulent changes in their sputum and at least two of the following six signs and symptoms compatible with ABECB: increased frequency and/or severity of cough, increase in sputum volume, dyspnoea or increased dyspnoea, increased chest congestion as indicated by adventitious sounds, and chills and/or fever. Enrolment necessitated collection of an acceptable expectorated sputum sample for culture before initiation of treatment.

Patients were not enrolled if they presented with severe acute exacerbations of chronic bronchitis requiring hospitalization and/or parenteral antibiotics, with active bronchiectasis, cystic fibrosis, lung cancer, pneumonia (excluded by chest X-ray), lung abscess, tuberculosis, uncontrolled bronchial asthma or were known to have severe chronic lung disease. Patients were excluded from the study if they presented with a history of hypersensitivity or phototoxicity reaction to any quinolone or macrolide antibiotic; were neutropenic; were receiving theophylline, warfarin or any other anticoagulant, carbamazepine, terfenadine, astemizole, digoxin, ergotamine, dihydroergotamine, triazolam, cisapride, ketoconazole, class Ia or class III anti-arrhythmic drugs, or other drugs which prolong the QT interval (delayed ventricular repolarization).

Patients with significant cardiac disease, congenital or acquired QT interval prolongation, clinically relevant congestive heart failure, immune deficiency, AIDS, uncontrolled diabetes mellitus, seizure disorder, hepatic disease, splenectomy or gastrointestinal disease were excluded from the study. Patients who had received any systemic antimicrobial agent within the previous 7 days or who had failed treatment for the current ABECB were also excluded. Pre-menopausal female patients were eligible to participate only if they were not pregnant or lactating and were using acceptable methods of contraception.

Study treatments

Patients were randomly assigned to one of three treatment regimens: grepafloxacin 400 mg od for 5 days, grepafloxacin 400 mg od for 10 days or clarithromycin 250 mg bd for 10 days. Patients received matched grepafloxacin and/or clarithromycin placebo in order to blind the study. Study medication was administered without regard to meals.

Clinical and bacteriological evaluations

Patients were evaluated on days 3–5 of treatment (during treatment visit), 1–3 days (post-treatment visit) and 21–28 days (follow-up visit) following cessation of treatment. Clinical assessments were made on the basis of frequency and/or severity of cough, volume of sputum production, qualitative changes in sputum, dyspnoea, chest congestion, chills and/or fever (oral temperature >=100.0°F or >=37.5°C).

The clinical response was classified as: (i) cure (clinical signs and symptoms of ABECB improved or resolved at the post-treatment visit and absent at the follow-up visit); (ii) improvement (improved but with incomplete resolution of the clinical signs and symptoms of ABECB by the follow-up visit); (iii) failure (no apparent improvement of clinical signs and symptoms of ABECB in response to therapy during treatment or by the post-treatment visit, or patient withdrawn due to a study drug-related adverse event); (iv) recurrence (resolution or improvement of clinical signs and symptoms of ABECB at the post-treatment visit with recurrence of clinical symptoms by the follow-up visit). Study patients were considered clinically unevaluable if they received a concurrent non-study systemic antimicrobial agent, if they failed to complete any of the study visits, if there was evidence of poor compliance, if the patient was withdrawn due to a non-study drug-related adverse event, or if there was any violation of selection criteria or any other significant deviation from the study protocol.

Sputum samples were collected before beginning treatment and when available, at all subsequent clinical visits. Sputum samples were sent to a local laboratory for Gram's stain, culture and susceptibility testing. The most commonly reported pathogens were considered as primary pathogens in this study, including H. influenzae, Haemophilus parainfluenzae, S. pneumoniae, M. catarrhalis and Staphylococcus aureus. Pathogens were isolated in local laboratories and were subsequently shipped to a central laboratory (Covance, Geneva, Switzerland), and were tested for susceptibility to grepafloxacin and clarithromycin via a tube or agar dilution MIC determination using breakpoints established by the NCCLS. All S. pneumoniae isolates were also tested for penicillin susceptibility; ß-lactamase production was determined for all Haemophilusspp. and M. catarrhalis isolates using a nitrocefin base test.

Bacteriological efficacy was assessed as one of nine possible categories including: (i) cure (initial pathogen eradicated during or at completion of therapy); (ii) presumed bacteriological cure (clinical cure or improvement as defined above but where an appropriate sputum specimen could not be obtained or cultured at the during-treatment or post-treatment visits); (iii) bacteriological cure with superinfection (bacteriological cure as defined above plus the isolation of one or more new pathogens); (iv) bacteriological cure with colonization (bacteriological cure as defined above plus the isolation of one or more new organisms not considered pathogenic); (v) bacteriological recurrence (bacteriological cure as defined above plus the isolation of the original pathogen at follow-up); (iv) bacteriological failure (initial pathogen was not eradicated from cultures after at least 3 days of therapy, requiring additional or alternative treatment); (vii) presumed bacteriological failure (clinical failure or recurrence as defined above but where a sputum specimen could not be obtained or cultured); (viii) bacteriological failure with superinfection (bacteriological failure as defined above plus the isolation of one or more new pathogens); (ix) bacteriological failure with resistance (bacteriological failure as defined above with initial pathogen(s) developing resistance to the study drug during the course of therapy).

In cases where more than one pathogen was isolated from a single sample, each bacterial isolate was evaluated separately. A study patient was considered bacteriologically unevaluable if any of the circumstances applying to clinical unevaluability existed or if there was inability to culture a pretreatment bacterial pathogen. The patients with negative cultures remained in the trial for clinical assessment, and sputum samples were taken from these patients at subsequent visits.

Safety assessment

Blood was collected for haematology and clinical chemistry screens at pre- and post-treatment visits. A urine specimen was obtained at the during-treatment visit and screened using a qualitative biological assay for the presence of antibiotic, in order to confirm compliance. Adverse events were assessed for severity, frequency, outcome and relationship to study drug at all clinical visits.

Statistical analyses

This trial was designed to test for statistical equivalence between the 5 day and 10 day grepafloxacin treatment groups and between each grepafloxacin group and the clarithromycin group. For satisfactory outcomes >=80% and <90%, treatment equivalence was established if the lower limit of the 95% confidence interval around the difference in response rates was greater than or equal to –15% and if the confidence interval included the value of zero. The primary study endpoint was the satisfactory clinical response rate (cure plus improvement) in the clinically evaluable patient population. Secondary endpoints were the satisfactory bacteriological outcome (cure, presumed cure and cure with colonization) and incidence of adverse events. Other efficacy measures included a subgroup summary of age, gender, race and underlying risk factors to compare informally the rates of satisfactory clinical response between treatment groups at the follow-up assessment. A two-tailed Fisher's exact test was used to compare differences between treatment groups in clinical and bacteriological efficacies and incidences of the most common drug-related adverse events (defined as an incidence of the specified adverse event of >=5% in any group). The significance level for all tests was 0.05.


    Results
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
A total of 805 patients were enrolled in the study. Of the 802 patients randomized, 273 received 5 days of grepafloxacin, 268 received 10 days of grepafloxacin and 261 received 10 days of clarithromycin. Participant progress through the trial is shown in Figure 1. Demographic characteristics in the three groups were comparable (Table I).



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Figure 1. Progress of patients through the trial.

 

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Table I. Summary of demographic characteristics of patients in the intent-to-treat population
 
Clinical symptoms at the pre-treatment visit occurred with a similar frequency and severity in all treatment groups. The majority of patients showed moderate or severe cough (95%), mild or moderate chest congestion (77%), mild or moderate dyspnoea (83%) and moderate or severe increase in sputum volume (92%). Most patients were producing mucopurulent (56%) or purulent (44%) sputum. Chills and fever occurred in fewer than 40% of patients. Seven (<1%) patients were classified as unevaluable and excluded from the clinically evaluable population due to chest X-ray findings suggesting the presence of pneumonia.

All 802 patients were included in the intent-to-treat population and safety analyses. Two hundred and twenty (27%) patients withdrew prematurely from the study: 85 (31%) in the 5 day grepafloxacin group, 61 (23%) in the 10 day grepafloxacin group and 74 (28%) in the 10 day clarithromycin group. No differences in overall withdrawal rates were seen when comparing the two grepafloxacin groups with clarithromycin. More patients withdrew from the 5 day grepafloxacin group and the 10 day clarithromycin group due to a lack of efficacy (15% in each group) than the 10 day grepafloxacin group (7%).

The urine of 97% of patients (685/708) was positive for the presence of antibiotic: 226 (96%) in the 5 day grepafloxacin group, 232 (97%) in the 10 day grepafloxacin group and 227 (97%) in the 10 day clarithromycin group. Ninety per cent of patients took study medication according to protocol.

Four hundred and seventy-three patients were clinically evaluable: 156 (57%) in the 5 day grepafloxacin group, 157 (59%) in the 10 day grepafloxacin group and 160 (61%) in the clarithromycin group. A large percentage of the patients (178, 22%) in this study were unevaluable, primarily due to the lack of an acceptable sputum sample. This was due in part to the large numbers of patients entered by investigators in primary care centres without direct access to laboratory facilities. These patients were entered into the study based on visual evidence of sputum purulence, since it was not considered appropriate for ethical reasons to delay treatment until receipt of laboratory confirmation of an acceptable sputum sample. Patients with an acceptable sputum but with negative cultures (194/473, 41% of evaluable population) remained in the trial for clinical assessment.

Clinical outcome

Patients in all treatment groups demonstrated marked improvement by 3–5 days after initiation of therapy (during-treatment visit), as judged by the reduction in the proportion of patients with clinical symptoms of bronchitis, as well as the decrease in severity of the symptoms which were present, including productive cough, chest congestion, dyspnoea and sputum purulence. The majority of patients in all treatment groups showed resolution or improvement at follow-up.

No statistically significant differences were seen when comparing clinical efficacy between the three treatment groups at the during-treatment assessment in either the clinically evaluable or the intent-to-treat populations. The numbers of patients showing cure or improvement at the post-treatment assessment were 142/156 (91%), 149/157 (95%) and 137/160 (86%) in the 5 day grepafloxacin, 10 day grepafloxacin and 10 day clarithromycin groups, respectively. There were no statistically significant differences between the 5 day grepafloxacin group and the 10 day grepafloxacin group. A significantly greater number of patients showed a satisfactory response in the 10 day grepafloxacin group compared with the 10 day clarithromycin group (P = 0.01). Cure or improvement at the follow-up assessment were 113 (72%), 127 (81%) and 117 (73%) of clinically evaluable patients treated with 5 or 10 days grepafloxacin or 10 days of clarithromycin, respectively (Figure 2).



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Figure 2. Satisfactory clinical response at the post-treatment and follow-up assessments of the clinically evaluable patients.

 
Clinical efficacy was analysed by pre-treatment organism for the five primary pathogens (H. influenzae, S. pneumoniae, M. catarrhalis, H. parainfluenzae and S. aureus) isolated from patients enrolled in the trial (Table II). The satisfactory clinical response rate in the microbiologically and clinically evaluable population for all organisms was 70% in the 5 day grepafloxacin group, 73% in the 10 day grepafloxacin group and 67% in the 10 day clarithromycin group. For H. influenzaeisolates, cure or improvement was highest for the 10 day grepafloxacin group. For S. pneumoniae, patients in both grepafloxacin groups showed a higher cure or improvement rate than those in the 10 day clarithromycin group. The proportion of patients showing cure or improvement was comparable across treatment groups for those with M. catarrhalis isolated at pre-treatment.


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Table II. Satisfactory clinical and bacteriological response by pre-treatment pathogen at follow-up in the microbiologically and clinically evaluable population
 
Bacteriologial outcome

Five hundred and thirteen pre-treatment pathogens were isolated from 400 (49%) patients. Of these, 279 patients were both microbiologically and clinically evaluable. The most common pathogens isolated were H. influenzae (36% of isolates), Haemophilus parainfluenzae(27%), M. catarrhalis (12%), S. pneumoniae (11%) and S. aureus (3%) (Figure 3). Eleven per cent of the H. influenzae isolates, 16% of the H. parainfluenzaeand 83% of the M. catarrhalis isolates were positive for ß-lactamase production. All primary pathogens isolated at pre-treatment were susceptible to grepafloxacin and 85% were susceptible to clarithromycin. Both ß-lactamase positive and negative strains of H. influenzae, M. catarrhalisand H. parainfluenzae were equally susceptible to grepafloxacin and clarithromycin. All the S. pneumoniae isolates demonstrated susceptibility to grepafloxacin while eight (15%) isolates were resistant to clarithromycin.



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Figure 3. Distribution of pre-treatment pathogens.

 
The bacteriological response at follow-up for the primary pathogens isolated at pre-treatment varied across the three treatment groups (Table II). For H. influenzae, both the 5 and 10 day grepafloxacin groups (68% and 79%) showed a higher eradication rate than the clarithromycin group (54%). Similarly the eradication rate of S. pneumoniae was higher in the 5 and 10 day grepafloxacin groups (57% and 44%) than in the clarithromycin group (22%). The proportion of satisfactory responses for M. catarrhalis was highest in the clarithromycin group. Overall, the satisfactory bacteriological responses in the 5 and 10 day grepafloxacin groups (65% and 68%, respectively), were higher than that seen in the clarithromycin group (57%).

The proportions of patients with a satisfactory bacteriological response during treatment, post-treatment and at the follow-up assessment are summarized in Table III. At the during-treatment assessment, the response rates in the grepafloxacin groups were equivalent (96% and 94%) and both showed significantly higher satisfactory bacteriological response rates than clarithromycin (62%; P < 0.001). This trend continued at the post-treatment assessment, where the bacteriological success rates for 5 and 10 day grepafloxacin (85% and 91%) were significantly greater than the success rate with clarithromycin (58%; P < 0.001). At the follow-up visit, all pair-wise statistical comparisons of the bacteriological response rates showed equivalence.


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Table III. Satisfactory bacteriological response during treatment, post-treatment and at follow-up in the microbiologically and clinically evaluable population
 
Safety evaluations

No adverse event occurred in >=5.0% of the patients in any treatment group (Table IV). The adverse events most often reported were nausea and abnormal/unusual taste. Of the 36 patients who discontinued due to adverse events 21 experienced events that were considered related to study drug (five in the 5 day grepafloxacin group; five in the 10 day grepafloxacin group and 11 in the 10 day clarithromycin group). Seventeen patients experienced adverse events considered serious; eight patients in the 5 day grepafloxacin group, three patients in the 10 day grepafloxacin group and six patients in the clarithromycin group. Two patients in the clarithromycin group had drug-related adverse events (gastroenteritis/pre-cordial pain and exacerbation of bronchitis) that were considered serious. None of the serious adverse events reported in the grepafloxacin groups were considered related to treatment. Three deaths occurred during the study (one in each treatment group, due to respiratory failure, cardiogenic shock and dissecting aortic aneurysm), none of which were considered to be related to study drug.


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Table IV. Summary of drug-related adverse events among patients in the intent-to-treat population(incidence >1.0% in any treatment group)
 

    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
The results of this study indicate that both 5 and 10 day regimens of grepafloxacin 400 mg od are as clinically and bacteriologically effective as 10 days of clarithromycin 250 mg bd in patients with ABECB. Success rates in all three treatment groups were maintained in the majority of patients for up to 4 weeks following cessation of treatment. Treatment in all three groups was well tolerated, with few patients withdrawing from the study due to drug-related adverse events.

The shorter course regimen of grepafloxacin met two important criteria for antimicrobial therapy in ABECB: rapid resolution of the infection (91% clinical success at end of treatment) and maintain cured (72% clinical success at 21–28 days post-treatment). Patients in the 5 day treatment group demonstrated marked improvement as noted by substantial decreases in the severity of symptoms within 3–5 days of initiation of therapy, and continued to improve throughout the study. These improvements were comparable with those observed in the 10 day grepafloxacin and clarithromycin groups. The results from the present study are similar to a recent clinical trial conducted in the USA which demonstrated that a 5 day regimen of grepafloxacin 400 mg od was as clinically and bacteriologically effective as the standard 10 day regimen,20 and support the role for a grepafloxacin short course in ABECB antimicrobial therapy.

The clinical responses reported at follow-up in this study are similar to those observed in previous clinical comparisons of 10 day treatments for ABECB with grepafloxacin and amoxycillin (82% versus 85%)16 grepafloxacin and ciprofloxacin (87% versus 80%)15 and grepafloxacin and clarithromycin (89% versus 88%).21 Collectively, these studies confirm the clinical efficacy of grepafloxacin in the treatment of ABECB.

The overall bacteriological success rates were significantly higher in both the grepafloxacin groups during treatment and post-treatment than the clarithromycin group, and were equivalent in the three treatment groups at the follow-up assessment. The most common organisms isolated from patients enrolled in the study were H. influenzae, H. parainfluenzae, S. pneumoniae, M. catarrhalis and S. aureus. These results are consistent with recent grepafloxacin clinical studies of patients with lower respiratory infections.15,22 The clinically and bacteriologically satisfactory outcomes assessed by organism varied among the three treatment groups, but in general, clinical outcomes correlated with bacteriological outcomes.

All treatment regimens were well tolerated in this study, with most drug-related adverse events categorized as mild to moderate. Common drug-related adverse events included gastrointestinal disturbance and abnormal/unusual taste. There were slightly fewer incidences of these adverse events in the 5 day grepafloxacin treatment group. Decreased incidence of adverse events with antimicrobial therapy has been associated with increased patient acceptance of treatment and improved compliance.23 Furthermore, frequency of daily dosing and the duration of treatment are also factors influencing patient adherence to treatment. Compliance with regimens of oral antibiotic therapy correlates with dosing frequency (mean compliance rates of 80%, 60% and 38% for administration once, twice and three times a day, respectively).24 Therefore, a 5 day treatment course of grepafloxacin once daily is likely to have positive effects on patient adherence to therapy.

In deciding the appropriate duration of therapy the physician should consider the benefits of short-course therapy and the risk factors of the individual patient, such as clinical history, concurrent illnesses and presenting illness severity. The potential benefits of efficacious short-course antimicrobial therapy include reduction in the emergence of bacterial resistance due to premature cessation of medication, fewer adverse events, as well as lower costs to payers. In clinical practice a 5 day course of treatment with grepafloxacin 400 mg administered od has significant advantages over antibiotics requiring longer duration of treatment and multiple daily doses. It could provide an effective treatment for the majority of patients with the option of a longer treatment duration for patients with more severe disease.


    Acknowledgments
 
The authors thank the following investigators for their participation in the study: Dr Wilfried De Backer, Dr Paul Reynders, Dr Daniel Rozen, Dr Luc Siemons and Dr G. Vandermoten, Belgium; Dr Geeta Achyuthan, Dr Fred Aoki, Dr Jacques Bouchard, Dr Robert Cowie, Dr Anthony {Delta}rquote Urzo, Dr Donald Eddy, Dr Noel Lampron, Dr Robert Luton, Dr Frank Onuska, and Dr Michael Weinstock in Canada; Dr Jan Cerny, Dr Jaromir Musil and Dr Petr Prusa, Czech Republic; Dr Philippe Angeli, Dr Jean Pierre Astruc, Dr Paul Bauzon, Dr Stéphane Beaujot, Dr Michel Behar, Dr Michel Benady, Dr Richard Benady, Dr Etienne Blot, Dr André Cohen, Dr Patrick Daine, Dr Patrick Deleporte, Dr Alain Devaux, Dr Sylvaine Dumas, Dr Jules Fineltain, Dr Jacques Franck, Dr Bernard Gontharet, Dr Marc Hindamian, Dr Max Labyod, Dr Jérôme Lefrançois, Dr Edouard Lichtblau, Dr Patrick Machin, Dr Robert Melka, Dr Benoît Paty, Dr Jean Louis Poignonec, Dr Joseph Rebot, Dr Jean Michel Retaux and Dr Bernard Soriano, France; Dr Oswald-Joerg Brückner, Dr Hubertus Grygier, Dr Lutz Jestel, Dr Hans-Otto Kühl, Dr Ernst Radermacher, Dr Werner Reimann, Dr Dietlinde Schmikale, Dr Gerhard Scholz, Dr Susanne Tomingas, Dr Hans-Christian Weber and Dr Walter Weede, Germany; Prof. Sabina Chyrek-Borowska, Prof. W. Droszcz, Prof. Pawal Gorski, Prof. K. Oklek, Prof. Edmund Rogala, Prof. A. Szczeklik and Prof. J. Zielinski, Poland; Dr Maria Carmos Neves, Portugal; Dr Evelio Perea and Dr Carlos Villasante, Spain; Dr Louis Glekin, Dr James Hosie, Dr Iain McColl, Dr Gerry McKaig, Dr Carol McKinnon, Dr Roderick McLeod and Dr Richard Quigley, UK. We also thank Patrice C. Ferriola, Ph.D., Glaxo Wellcome Inc. for editorial assistance. Funding for the studies was provided by a grant from Glaxo Wellcome R & D. Grepafloxacin is licensed from Otsuka Pharmaceutical Co. Ltd, Japan.


    Notes
 
* Corresponding author. Tel: +44-181-966-3962; Fax: +44-181-966-3988; E-mail: CLPM0454{at}glaxowellcome.co.uk Back


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
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Received 11 January 1999; returned 15 March 1999; revised 30 April 1999; accepted 25 June 1999