Efficacy and safety of gemifloxacin in the treatment of community-acquired pneumonia: a randomized, double-blind comparison with trovafloxacin

T. M. File, Jra,*, B. Schlemmerb, J. Garauc, M. Cupod, C. Youngd and the 049 Clinical Study Group{dagger}

a Summa Health System, Akron Infectious Disease Inc., 75 Arch Street, Suite 105 Akron, OH 44304, USA; b Hôpital St Louis, Paris, France; c Hospital Mutua de Terassa, Barcelona, Spain; d SmithKline Beecham, Collegeville, PA, USA


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
This multicentre, randomized, double blind, parallel group study compared the efficacy and safety of gemifloxacin (320 mg once daily) with trovafloxacin (200 mg once daily) in 571 patients with community-acquired pneumonia (CAP). Although treatment was given routinely for 7 days it could be extended to 14 days; two-thirds of patients were treated for 7 days. High clinical success rates were noted at follow-up in the per-protocol population in both the gemifloxacin group (95.8%) and the trovafloxacin group (93.6%), non-inferiority with 95% CI. In the intentto-treat population, the clinical success rate at follow-up was significantly superior for gemifloxacin (87.6%) compared with trovafloxacin (81.1%; 95% CI 0.5, 12.4). The pathogens identified most commonly at presentation were Mycoplasma pneumoniae and Streptococcus pneumoniae. Gemifloxacin eradicated 100% of S. pneumoniae. One bacteraemic isolate of S. pneumoniae was associated with clinical failure in the trovafloxacin group (MIC of trovafloxacin 8 mg/L). Gemifloxacin was well tolerated and the incidence of transient liver function abnormalities was very low. Gemifloxacin is an effective and well-tolerated treatment for patients with CAP.


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Community-acquired pneumonia (CAP) is a common and serious disease that causes considerable morbidity and mortality.13 Initial therapy for CAP is usually empirical. In the majority of cases, particularly for patients treated as outpatients, the causative organism remains unidentified.4 In those cases where a pathogen is identified, the most common is Streptococcus pneumoniae.4 Other common agents include Haemophilus influenzae and ‘atypical’ pathogens, such as Mycoplasma pneumoniae, Chlamydia pneumoniae and Legionella pneumophila.35

The choice of appropriate empirical therapy for CAP is increasingly complicated by the emergence of antibiotic-resistant organisms. Penicillin-resistant strains of S. pneumoniae have been identified worldwide.6,7 Resistance to other antibiotics such as macrolides is increasing among penicillin-resistant strains8,9 and in a recent North American surveillance study, 33% and 92% of community-acquired respiratory tract isolates of H. influenzae and Moraxella catarrhalis, respectively, were ß-lactamase producers.10 New agents with a broad spectrum of activity against the range of organisms implicated in CAP are therefore needed.

The quinolones have been accepted widely for the treatment of many infections because of their high antimicrobial potency and bioavailability.11 Older quinolones, such as ciprofloxacin, have not been recommended for the treatment of CAP because of their limited activity against S. pneumoniae.4 However, the newer agents in this class, such as levofloxacin and trovafloxacin, have significantly improved activity against S. pneumoniae.4,12 These newer quinolones have been recommended as an option for treatment of patients with CAP, especially if infection with drug-resistant S. pneumoniae is a consideration.4 At the time of the development of this study, trovafloxacin was considered to be the most potent quinolone for S. pneumoniae and a very effective antimicrobial for therapy of CAP. Problems with hepatotoxicity have led to the marketing authorization for trovafloxacin being suspended in Europe13 and to use being restricted to one of ‘last resort’ in the USA.14 A need has arisen, therefore, for a new quinolone agent with the clinical efficacy of trovafloxacin, but with a more favourable tolerability profile. Clinical data have recently been presented on two such new quinolones, moxifloxacin and gatifloxacin, demonstrating their safety and efficacy in the treatment of CAP.15,16

Gemifloxacin (SB-265805; FACTIVETM, SmithKline Beecham, Harlow, UK) is an enhanced-affinity quinolone that has excellent in vitro activity against both Gramnegative and -positive organisms.17,18 Gemifloxacin is the most potent member of the quinolone class against isolates of S. pneumoniae with reduced susceptibility to ciprofloxacin.19 Additionally, gemifloxacin has activity against atypical pathogens such as M. pneumoniae, C. pneumoniae and L. pneumophila.2022

In this study the clinical and antibacterial efficacy of oral gemifloxacin was compared with that of oral trovafloxacin in the treatment of CAP.


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

This was a randomized, multicentre, double blind, parallel group study carried out in the USA, Mexico and Spain. Eligible patients were randomized to receive either oral gemifloxacin 320 mg (equivalent to 400 mg of the mesylate salt) once daily or oral trovafloxacin 200 mg once daily for 7 days. Patients could be treated on an outpatient basis or in the hospital, but all antimicrobial therapy was administered orally. The treatment duration could be extended to 14 days if the patient had severe infection, a confirmed or probable diagnosis of infection with an atypical pathogen, or at the investigator's discretion (i.e. if the infection was considered serious enough to require longer treatment).

The study was conducted according to Good Clinical Practice guidelines and the Declaration of Helsinki; approval was obtained from the ethics review committee of each participating centre according to the local regulations of the particular country. Informed consent was obtained from all patients enrolled in the study.

Patients

Adult patients with a radiological and clinical diagnosis of CAP were eligible to participate in the study. Radiological diagnosis was defined as the presence of new or progressive infiltrates, consolidation or pleural effusion consistent with pneumonia. The clinical diagnosis of CAP was defined as the presence of at least two of the following signs or symptoms: new or increased cough; purulent sputum or change in sputum characteristics; presence of rales or evidence of pulmonary consolidation; dyspnoea, tachypnoea or hypoxaemia; or pleuritic chest pain. Patients were also required to have one of the following: fever (>38°C, oral); an elevated total white blood cell count >10 000 cells/mm3, >15% immature neutrophils or leucopenia with a total white blood cell count of <4500 cells/mm3.

Exclusion criteria included: hypersensitivity to quinolones or a history of tendonitis while taking fluoroquinolones; bronchial obstruction or a history of post-obstructive pneumonia; aspiration pneumonia; cystic fibrosis; active tuberculosis; bronchiectasis; active lung malignancies; hospital-acquired pneumonia; or hospitalization within 2 weeks before entry into the study. Patients requiring parenteral antibiotic therapy and those who had received >24 h of treatment with any other antibacterial agent for the current episode of CAP were not included in the study. Women who were pregnant or lactating were ineligible for inclusion and women of childbearing potential had to be using an accepted method of birth control.

Clinical outcome

Clinical outcome was assessed at the end of therapy (2–4 days post-therapy) and at follow-up (14–21 days posttherapy). The investigator compared the signs and symptoms of CAP at pre-treatment baseline with those at the end of therapy and at follow-up to evaluate the patient's clinical outcome. Clinical outcome was classified as clinical success (sufficient improvement such that no further antibiotic therapy was required for CAP), clinical failure (insufficient improvement such that further antibiotic therapy was required for CAP) or unable to determine (an assessment of clinical outcome could not be made). Patients with an outcome of clinical failure at the end of therapy were also considered clinical failures at the follow-up visit.

Bacteriological outcome

Samples of sputum or other respiratory tract secretions were obtained at baseline, at the end of therapy and at follow-up. Sputum samples were considered evaluable for routine bacterial pathogens based on the presence of 25 or more white blood cells and 10 or less epithelial cells per field at 100x magnification.

Nasopharyngeal and throat swab samples were collected for culture of C. pneumoniae and M. pneumoniae, respectively. Blood cultures were performed at baseline and, if these were positive, repeated at subsequent visits after 2–4 days of study medication. Blood samples for serological evaluation of atypical pathogens (M. pneumoniae, enzyme immune assay; L. pneumophila, indirect fluorescent antibody; C. pneumoniae, microimmunofluorescent antibody; and Coxiella burnetii, indirect fluorescent antibody) were taken at baseline and at follow-up (equivalent to 21–35 days after baseline). M. pneumoniae IgM was detected by serology at screening and/or follow-up with an immune status ratio (ISR) >=1.1, or M. pneumoniae IgG was detected at follow-up with an ISR >=1.1 and there was a rise in M. pneumoniae IgG ISR of >=46% between screening and follow-up. C. pneumoniae was detected by serology and met one or more of the following criteria: (i) there was at least a four-fold rise in C. pneumoniae IgG titre between the screening and follow-up visit; or (ii) there was a C. pneumoniae IgM titre of >=1:10 at screening and/or follow-up. C. burnetii was detected by serology and met one of the following criteria: an IgG phase II titre of >=1:256 at screening and/or follow-up; or an IgG or IgM titre of >1:16 (phase I and phase II) and phase II titres > phase I titres at the screening and/or follow-up visit; or there was at least a four-fold rise in C. burnetii IgG or IgM phase II titre between the screening and follow-up visit, with a follow-up phase II titre >=1:64. L. pneumophila was detected by a four-fold rise in IgG titre.

Bacteriological response at the end of therapy was defined as successful if all original pathogens were eradicated (elimination of pathogen from sputum or blood culture) or presumed eradicated (if no sputum produced or for an organism identified by serological means clinical success) with no superinfection. Bacteriological failure was defined as persistence or presumed persistence (in the absence of culture in a patient who was classified as a clinical failure, it was presumed there was persistence of the original pathogen) of an original pathogen, superinfection or the outcome for one or more pathogens could not be determined. At follow-up, the bacteriological response was defined as success if there was continued absence of the original pathogen and no new infection requiring antibiotic treatment, or failure if there was a recurrence of one or more of the original pathogens, the appearance of a new pathogen requiring treatment or the outcome for one or more pathogens could not be determined.

All susceptibility testing was conducted in accordance with National Committee for Clinical Laboratory Standards (NCCLS).23

Therapeutic response

The therapeutic response was defined as the combined clinical and bacteriological responses.

Safety assessments

Clinical chemistry, haematology and urinalysis were performed at baseline, on day 2–4 of therapy and at end of therapy. Adverse events, defined as any new sign or symptom or an exacerbation of the pre-existing condition occurring at any time during the study, were recorded. An adverse event was classified as serious if it was fatal, life-threatening, disabling or incapacitating, resulted in prolonged hospitalization, or was associated with congenital abnormality, cancer or overdose. Adverse events were classified as severe if they prevented normal everyday activities.

Patient withdrawals

Patients could be withdrawn from the study for the following reasons: an adverse event deemed sufficiently severe to warrant withdrawal; insufficient therapeutic effect of study medication; non-compliance with study medication; pregnancy; or at the patient's or physician's request.

Data evaluation

The primary efficacy variable was clinical response at follow-up for the clinical per-protocol (PP) population. Secondary efficacy variables included clinical response at end of therapy, bacteriological response at end of therapy and at follow-up, and radiological response at end of therapy and at follow-up. Therapeutic response (combined clinical and bacteriological response) was an additional efficacy variable.

The primary efficacy analysis was based on an unstratified comparison of proportions between treatment groups. Two-sided 95% CIs were used to estimate the difference in the proportion of clinical successes between the two groups (gemifloxacin minus trovafloxacin), with a conclusion of non-inferior efficacy of gemifloxacin drawn if the lower limit of the confidence interval was –10% or greater.

For the analysis of safety data, if an adverse event occurred in 5% or more of patients in either of the treatment groups, the proportions of patients reporting that adverse event were compared between treatment groups using Fisher's exact test. Two-sided 95% confidence intervals were used to estimate the difference in proportions between the two groups.

All confidence intervals for differences in proportions were calculated using the normal approximation to the binomial distribution.


    Results
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Patients

A total of 573 patients were randomized to receive study medication and 571 received at least one dose of medication and comprised the intent-to-treat (ITT) population; 290 received gemifloxacin and 281 received trovafloxacin. At follow-up, there were 216 and 207 patients in the gemifloxacin and trovafloxacin groups, respectively, who had adhered to the entire study protocol; these patients comprised the clinical PP population.

The baseline demographic characteristics of the two treatment groups were similar (Table IGo). A total of 152 patients (26.6%) were hospitalized at the time of study entry. Most patients (two-thirds) were treated for 7 days and the percentage of patients who had treatment extended to 14 days was similar in the two treatment groups (gemifloxacin, 36.9%; trovafloxacin, 33.8%), the main reason being serious infection as judged by the investigator to warrant longer duration. In the ITT population, 498 patients completed the study: 256 (88.3%) in the gemifloxacin group and 242 (86.1%) in the trovafloxacin group.


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Table I. Patient characteristics at study baseline (ITT population)
 
Pathogens isolated

Of the ITT population, 120 (41.4%) patients from the gemifloxacin group and 102 (36.3%) from the trovafloxacin group had at least one pathogen identified at screening; these patients comprised the bacteriology ITT population. The pathogens most commonly identified were M. pneumoniae and S. pneumoniae. S. pneumoniae and other ‘typical bacterial’ pathogens were isolated by culture methods; the ‘atypical pathogens’, i.e. M. pneumoniae, were identified by serological methods. Table IIGo shows the susceptibilities of the bacterial isolates to gemifloxacin, trovafloxacin and a range of other antibacterial agents commonly used to treat respiratory tract infections. The minimum inhibitory concentrations against 90% of strains tested (MIC90s) were generally lower for gemifloxacin than for the other antibacterial agents.


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Table II. Activity [MIC90 (MIC range) in mg/L] of selected antibacterials against pathogens isolated from patients at screening (bacteriology ITT population)
 
Of 47 S. pneumoniae isolates tested, four were resistant to penicillin, six were resistant to clarithromycin, five were azithromycin resistant and 10 were trimethoprim/sulphamethoxazole resistant. Eight isolates of S. pneumoniae had evidence of multidrug resistance; however, the MIC of gemifloxacin for these isolates was low (0.008–0.015 mg/L). One S. pneumoniae isolate was resistant to ofloxacin (64 mg/L), ciprofloxacin (>16 mg/L), grepafloxacin (8 mg/L), levofloxacin (16 mg/L) and trovafloxacin (8 mg/L). In contrast, the MIC of gemifloxacin for this isolate was low (0.25 mg/L). For ß-lactamase-producing H. influenzae the gemifloxacin MICs were 0.002 and 0.015 mg/L.

In the PP population there was a total of 232 pathogens identified. The pathogens most commonly identified in this group were: S. pneumoniae 33; H. influenzae 11; S. aureus 10; M. pneumoniae 88; C. pneumoniae 29; C. burnetii 20; and L. pneumophila 11. There were no marked differences between treatment groups in the prevalence of any of the most common pathogens associated with CAP.

Clinical response

At the end of therapy study visit, high clinical success rates were demonstrated in the gemifloxacin and trovafloxacin treatment groups for both the ITT and PP populations (Table IIIGo). For the primary efficacy parameter, the clinical response rate at follow-up in the clinical PP population, gemifloxacin was shown to be at least as effective as trovafloxacin (95.8% versus 93.6%, respectively; treatment difference 2.2%, 95% CI –1.8, 6.3). In addition, the clinical success rate at follow-up in the ITT population was significantly greater in the gemifloxacin group (87.6%) compared with the trovafloxacin group (81.1%) (treatment difference of 6.4%, 95% CI 0.5, 12.4).


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Table III. Clinical and bacteriological responses by patient at end of therapy and follow-up in the ITT and PP populations
 
Bacteriological response

At the end of therapy, high bacteriological response success rates were demonstrated for gemifloxacin and trovafloxacin (Table IVGo).


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Table IV. Initial pathogen outcome at end of therapy (bacteriological PP population)
 
Gemifloxacin treatment was associated with eradication or presumed eradication of approximately 94% of key initial pathogens (including 100% of S. pneumoniae isolates) in the bacteriology PP population at end of therapy as shown in Table IVGo. In the gemifloxacin group there were seven organisms that persisted or were presumed to have persisted. There were one isolate each of Pseudomonas aeruginosa and group G Streptococcus that persisted at the end of therapy visit. There was no increase in MICs of gemifloxacin for these organisms (prescreening MIC was 0.25 mg/L for P. aeruginosa and 0.015 mg/L for group G Streptococcus). There were two isolates of H. parainfluenzae and three cases with M. pneumoniae identified as presumed persistence. In the trovafloxacin group there were five pathogens that it was presumed persistent. This included two cases of M. pneumoniae, one blood culture isolate of S. pneumoniae, one isolate of B. cepacia and one isolate of H. influenzae. The pre-therapy MIC of trovafloxacin for the S. pneumoniae isolate with presumed persistence was 8 mg/L (the MIC for gemifloxacin of this isolate was 0.25 mg/L). The MIC of the B. cepacia for trovafloxacin was 0.03 mg/L. No superinfecting pathogens were identified at follow-up in the PP or ITT populations. No new infections were identified at follow-up in either population.

For patients with bacteraemia, 5/5 were therapeutic successes at follow-up in the gemifloxacin group patients (four S. pneumoniae; one M. catarrhalis) compared with 8/10 patients in the trovafloxacin group (eight S. pneumoniae; one S. aureus; one B. cepacia). Of the two pathogens that were not successfully treated in the trovafloxacin group, one was a B. cepacia strain and one was a S. pneumoniae strain as described in the previous paragraph.

Therapeutic response

Therapeutic response (combined clinical and bacteriological response) rates at end of therapy or at follow-up in the ITT and PP populations were similar in the two treatment groups. In the ITT population, therapeutic success rates at end of therapy were 92.5% in the gemifloxacin group and 87.3% in the trovafloxacin group. At follow-up, the success rates were 84.2% and 80.4%, respectively.

Adverse events

During the study and 30 day follow-up, the incidence of adverse events, with a suspected or probable relationship to study medication, was 20.0% for gemifloxacin and 25.6% for trovafloxacin. Most of these events were mild to moderate in severity. The most frequently reported adverse events with suspected or probable relationship to study medication were rash, headache and diarrhoea in the gemifloxacin group and dizziness, nausea and headache in the trovafloxacin group (Table VGo).


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Table V. Number (%) of patients reporting adverse events with a suspected or probable relationship to study medication during the treatment period and 30 days post-treatment (adverse events reported by >2% of patients)
 
The incidence of adverse events involving the central and peripheral nervous system (regardless of relationship to treatment) was 12.4% for gemifloxacin and 19.9% for trovafloxacin.

Serious adverse events were reported by 3.8% of patients in the gemifloxacin group and 5.3% in the trovafloxacin group. One patient in the gemifloxacin group and one in the trovafloxacin group died during the study, due to myocardial infarction and suicide, respectively. Neither death was considered to be of suspected or probable relationship to study medication.

The incidence of treatment-associated adverse events leading to withdrawal was low and comparable for the two groups: 5.5% of patients in the gemifloxacin group and 4.6% in the trovafloxacin group. The most common reason for withdrawal was rash (2.8%) for gemifloxacin and dizziness (1.1%) for trovafloxacin.

Laboratory tests

The incidence of treatment-emergent haematology, clinical chemistry and urinalysis abnormalities was low in both treatment groups, as was the incidence of abnormal liver function values. At end of therapy there was no difference between the treatment groups in the incidence of abnormal liver function values. Six patients in the trovafloxacin group experienced increased serum glutamic–oxaloacetic transaminase (SGOT) and/or serum glutamic pyruvic transaminase (SGPT) compared with only one patient in the gemifloxacin group. The largest increase in the gemifloxacin group was an increase of 139 IU/L for SGPT, which was considered by the investigator to have resolved. The largest increase in the trovafloxacin group was 184 IU/L for SGPT. This was also considered by the investigator to have resolved after 13 days.


    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
The recent development of new quinolone agents with enhanced activity against Gram-positive organisms, whilst maintaining Gram-negative activity, offers the promise of significant advantages over standard agents, including a broader spectrum of activity, higher bioavailability and low potential for selection of resistant organisms.24 In addition, these newer quinolones also offer shorter courses of therapy leading to enhanced compliance and potential economic savings.

This randomized, double-blind study, designed to evaluate the efficacy and safety of gemifloxacin, demonstrated that gemifloxacin 320 mg once daily was as effective as trovafloxacin 200 mg once daily for 7 or 14 days in the treatment of CAP. With regard to bacteriological response, gemifloxacin was shown to be at least as effective as trovafloxacin, while for clinical response, gemifloxacin was significantly superior to trovafloxacin in the ITT population. At the time that this study was undertaken, trovafloxacin was widely considered to be the most potent quinolone based on its in vitro potency versus community-acquired respiratory tract infection pathogens.

In this study, the pathogen most frequently identified was M. pneumoniae, identified by serological methods. This finding is in common with other studies of predominantly ambulatory patients.25 The most commonly isolated ‘pyogenic’ respiratory pathogen was S. pneumoniae. Multidrug-resistant S. pneumoniae was observed in 17% of isolates. All of these isolates were, however, susceptible to gemifloxacin. In addition, one isolate of S. pneumoniae that was resistant to all of the other quinolones tested was susceptible to gemifloxacin. The small number of bacteriological failures could not be attributed to elevated gemifloxacin or trovafloxacin MICs for the initial pathogens.

In this study, the overall tolerability of both gemifloxacin and trovafloxacin was good. Most adverse events were mild to moderate in intensity and occurred generally within the first week of treatment.

The Infectious Diseases Society of America (IDSA) has included the quinolones, which have enhanced activity against S. pneumoniae, in the list of generally preferred options for empirical therapy because of their activity against common pathogens and atypical organisms.4 These guidelines specify that a quinolone may be a preferred choice for patients with risks for drug-resistant S. pneumoniae (DRSP), the elderly, or those with underlying disease, but ‘some authorities prefer to reserve quinolones for such patients’.4 A recently published CDC statement is similar but stresses more strongly that quinolones should be reserved for cases associated with failure due to, or because of allergy to other agents or cases due to, documented DRSP, because of concerns about the development of resistance.26

Ciprofloxacin-resistant pneumococci have emerged recently in Canada, Hong Kong and Spain.19,27,28 The appearance of these strains may be related to the ability of different quinolones to select for quinolone-resistant mutants of S. pneumoniae. Resistance to the older quinolones appears to occur in a single step, whereas for the newer agents at least two mechanisms are required to induce high-level resistance. Acquisition of two mutations is unlikely to occur frequently.29 In addition, the quinolones with the greatest potency against initially susceptible organisms are expected to retain activity against mutants that have been selected by the use of the older quinolones.30 The initial use of the most potent antimicrobial agent is theoretically likely to prevent or decrease selection of resistance. The once-daily dosing regimen of the newer quinolones should also be given preference as patients are more likely to be compliant with treatment requiring once-daily dosing, thus reducing the risk of antibiotic resistance developing.31


    Acknowledgments
 
This study was funded by SmithKline Beecham Pharmaceuticals, Harlow, UK.

Members of the 049 Clinical Study Group: P. Ball (University of St Andrews, Fife, Scotland); R. Wilson (Consultant Physician, Royal Brompton Hospital; Reader in Respiratory Medicine, Imperial College of Science, Technology and Medicine at National Heart and Lung Institute, London, UK); L. Mandell (Division of Infectious Diseases, Department of Medicine, McMaster University, Hamilton, Ontario, Canada); J. Davies, T. Henkel, D. McKay (SmithKline Beecham, Harlow, UK); L. Aguilar (Hospital Clínico Universitario, Zaragoza, Spain); B. Siquer (Hospital Son Dureta, Palma de Mallorca, Spain); K. Hendrick (McLaren Family Practice, Flushing, MI, USA).

The authors wish to acknowledge the following international study investigators: Mexico: M. Garcia-Guillen, A. Rodreguez Toledo; Spain: J. Garau, B. Siquier, J. Custardoy, E. Llorca, J. Mensa, R. Pallares, J. Viejo, E. Bouza, A. Gil-Aguado, J. Santos, S. Moreno, J. Martinez, G. Zubillaga, R. Aguero, J. Pachon, R. Blanquer, J. Caminero, J. Duran; USA: K. Hendrick, J. Tan/T. File, R. Ovetsky, S. Simon, H. Hassman, J. Sanford, R. Tidman, D. McConnehey, J. Kearney, A. Ross, R. Kaplan, D. Mikolich, J. Adelglass, B. Moran, M. Abramson, J. Hopland, M. Sperling, S. D'Amico, S. Singh, B. Harrison, E. Anderson, T. Smith, J. Applestein, M. Perlman, E. Wong, T. Chiambretti, R. Wunderink, K. Warren, T. Anderson, W. Sokol, M. Patel, J. Felicetta, E. Riffer, C. Yamada, D. Henry, J. Macpherson, J. Rhudy, M. Suchyta, D. Brandon, M. Drehobl, B. Spitz, J. Morales-Ramirez, D. Campbell, C. Fogarty, D. Hammond, T. Hyers, P. Korenblat, J. Morelli, M. Otruba, J. Taylor, M. Finneran, E. Skobeloff.


    Notes
 
* Corresponding author. Tel: +1-330-375-3894: Fax: +1-330-375-3161; E-mail: filet{at}summa-health.org Back

{dagger} Members of the 049 Clinical Study Group are listed in the Acknowledgements. Back


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
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Received 11 September 2000; returned 17 November 2000; revised 28 February 2001; accepted 28 March 2001