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Keywords:

  • Co-amoxiclav;
  • community-acquired pneumonia;
  • gatifloxacin

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Study design and number of patients
  6. Patients
  7. Diagnostic procedures
  8. Study medication
  9. Clinical efficacy assessment
  10. Bacteriological efficacy assessment
  11. Safety assessment
  12. Statistical analyses
  13. Results
  14. Patient population
  15. Baseline microbiology
  16. Clinical outcome
  17. Bacteriological outcome
  18. Clinical and bacteriological outcome for patients with bacteraemia
  19. Safety
  20. Discussion
  21. Acknowledgements
  22. References

A double-blind, double-dummy, multicentre, multinational, parallel-group study was designed to establish proof of equivalence between oral gatifloxacin and oral co-amoxiclav in the treatment of 462 patients with mild-to-moderate community-acquired pneumonia. Eligible patients were randomised equally to either gatifloxacin 400 mg once-daily plus matching placebo for 5–10 days, or amoxycillin 500 mg + clavulanic acid  125 mg three-times-daily for 5–10 days. The primary efficacy endpoint was clinical response (clinical cure plus improvement) at the end of treatment. Overall, a successful clinical response was achieved in 86.8% of gatifloxacin-treated patients, compared with 81.6% of those receiving co-amoxiclav, while corresponding rates of bacteriological efficacy (eradication plus presumed eradication) were 83.1% and 78.7%, respectively. The safety and tolerability profile of gatifloxacin was comparable to that of co-amoxiclav, with adverse gastrointestinal events, e.g., diarrhoea and nausea, being the most common treatment-related adverse events in both groups. The study showed no evidence of gatifloxacin-induced phototoxicity, musculoskeletal disorders, or hepatic and renal problems. Overall, this study showed that gatifloxacin was equivalent clinically to a standard course of co-amoxiclav in patients with community-acquired pneumonia, and that gatifloxacin was safe and well-tolerated.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Study design and number of patients
  6. Patients
  7. Diagnostic procedures
  8. Study medication
  9. Clinical efficacy assessment
  10. Bacteriological efficacy assessment
  11. Safety assessment
  12. Statistical analyses
  13. Results
  14. Patient population
  15. Baseline microbiology
  16. Clinical outcome
  17. Bacteriological outcome
  18. Clinical and bacteriological outcome for patients with bacteraemia
  19. Safety
  20. Discussion
  21. Acknowledgements
  22. References

Community-acquired pneumonia (CAP) is a significant cause of morbidity and mortality, especially among the elderly. In the USA alone, over four million cases of CAP are diagnosed each year, of which some 600 000 require hospitalisation [1]. With annual costs of about $23 billion, the economic burden posed by this disease is considerable [2].

Antimicrobial therapy plays a vital role in the treatment of CAP, with studies showing that prompt administration of antibiotic therapy can have a significant effect in reducing morbidity and mortality associated with the disease [3]. There is a need to initiate antibiotic therapy early, so treatment is usually empirical and coincident with an initial clinical diagnosis of CAP. Therefore, to be effective, first-line antimicrobial agents must provide adequate coverage of the pathogens likely to be isolated from patients with CAP, and should include both typical and atypical respiratory pathogens in their spectrum of activity. While Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis are the most common pathogens isolated in patients with CAP, atypical intracellular pathogens, such as Legionella pneumophila, Mycoplasma pneumoniae and Chlamydia pneumoniae, are now being isolated with increasing frequency [4–7].

Traditionally, patients with CAP have been treated with oral penicillins, cephalosporins and tetracyclines. Although these agents are still used widely, the additional use of modern macrolides is now recommended because of their activity against atypical respiratory pathogens [8]. The choice of first-line antimicrobial treatment is also complicated by the increasing prevalence of resistant strains of respiratory pathogens, such as penicillin-resistant pneumococci and β-lactamase-producing strains of H. influenzae and M. catarrhalis, which render ineffective some of the traditional antimicrobial agents, such as penicillins, cephalosporins and macrolides, used to treat patients with CAP. The broad-spectrum fluoroquinolones have therefore been recommended for empirical therapy of CAP because of their activity against both Gram-positive and Gram-negative respiratory pathogens, including strains of penicillin-resistant S. pneumoniae and β-lactamase-producing strains of H. influenzae and M. catarrhalis[8–10].

Gatifloxacin is an advanced-generation 8-methoxyfluoroquinolone with a broad spectrum of antibacterial activity which covers all the common typical and atypical pathogens of CAP. Its superior in-vitro activity, compared with many standard agents, against common respiratory pathogens [11–17] is accompanied by a favourable pharmacokinetic profile, which includes excellent tissue penetration and a long plasma half-life, enabling once-daily dosing. Following oral dosing, high and sustained concentrations of gatifloxacin are achieved in the respiratory tract that are above the MICs for most infecting pathogens encountered in CAP [18]. High drug concentrations at the site of infection are considered essential for effective eradication of bacteria from the lungs [19].

The primary objective of the present study was to determine the efficacy and safety in adult patients with CAP of a once-daily oral dose of gatifloxacin 400 mg in comparison with three-times-daily oral co-amoxiclav (amoxycillin 500 mg  + clavulanic acid 125 mg).

Study design and number of patients

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Study design and number of patients
  6. Patients
  7. Diagnostic procedures
  8. Study medication
  9. Clinical efficacy assessment
  10. Bacteriological efficacy assessment
  11. Safety assessment
  12. Statistical analyses
  13. Results
  14. Patient population
  15. Baseline microbiology
  16. Clinical outcome
  17. Bacteriological outcome
  18. Clinical and bacteriological outcome for patients with bacteraemia
  19. Safety
  20. Discussion
  21. Acknowledgements
  22. References

This was a randomised, double-blind, double-dummy, multicentre, multinational, parallel-group study, designed to compare the efficacy and safety of oral gatifloxacin with oral co-amoxiclav in the treatment of over 400 patients with typical CAP. The protocol complied with the Guidelines for the Clinical Evaluation of Anti-infective Products [20]. Written informed consent was obtained from all patients before the start of the study, which was approved by the appropriate Ethics Committee in each country and conducted in accordance with the current Declaration of Helsinki.

Patients

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Study design and number of patients
  6. Patients
  7. Diagnostic procedures
  8. Study medication
  9. Clinical efficacy assessment
  10. Bacteriological efficacy assessment
  11. Safety assessment
  12. Statistical analyses
  13. Results
  14. Patient population
  15. Baseline microbiology
  16. Clinical outcome
  17. Bacteriological outcome
  18. Clinical and bacteriological outcome for patients with bacteraemia
  19. Safety
  20. Discussion
  21. Acknowledgements
  22. References

Adult (aged ≥ 18 years) ambulatory or hospitalised male and female patients with a primary diagnosis of CAP of mild-to-moderate intensity were eligible for enrolment. The diagnosis required evidence of new and persistent infiltrates on chest X-ray, indicative of bacterial pneumonia, within 48 h of the start of therapy, as well as signs and symptoms of pneumonia, such as cough, dyspnoea, chills, sputum production and chest pain. Other inclusion criteria included evidence of fever > 38 °C, or a white blood cell count of > 10 000/mm3, or microbiological evidence of bacterial pneumonia. Pregnant and nursing mothers were excluded from the study, but female patients of childbearing age could be included if they had a negative pregnancy test and used reliable contraception throughout the study period.

Patients were excluded if they were receiving current antibiotic therapy for other infectious diseases, had extrathoracic symptoms, needed additional antibiotic or intravenous treatment for pneumonia or antibiotic therapy for > 10 days, had concomitant pulmonary or respiratory tract disease, or had pneumonia requiring ventilation. Other exclusion criteria included intolerance or hypersensitivity to quinolone or β-lactam antibiotics, the need for immunosuppressive therapy, or participation in another study within the previous 4 weeks or in a current parallel study. Severe hepatic, renal or coronary dysfunction, HIV infection, epilepsy, severe allergic or haematological disease, severe dehydration or blood donation (> 500 mL) within the previous 3 months, were also criteria for exclusion. Patients with a history of psychiatric illness or suicide risk within the previous 2 years, a history of alcohol, substance or drug abuse, or any condition likely to affect the disposition of study medication, were also excluded.

Diagnostic procedures

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Study design and number of patients
  6. Patients
  7. Diagnostic procedures
  8. Study medication
  9. Clinical efficacy assessment
  10. Bacteriological efficacy assessment
  11. Safety assessment
  12. Statistical analyses
  13. Results
  14. Patient population
  15. Baseline microbiology
  16. Clinical outcome
  17. Bacteriological outcome
  18. Clinical and bacteriological outcome for patients with bacteraemia
  19. Safety
  20. Discussion
  21. Acknowledgements
  22. References

Respiratory secretions for Gram's stain, culture and susceptibility testing were obtained from spontaneously expectorated sputum, or by transtracheal or endotracheal aspiration, bronchoscopic procedures or lung biopsy. These tests were carried out within 48 h before the start of treatment, on days 4–6 during treatment, 1–3 days after the end of treatment, and 14–28 days post-treatment. Two venous blood samples were also cultured for aerobes and anaerobes at study admission, and this was repeated at subsequent visits if the admission blood culture was positive or if indicated clinically. Culture was only done if purulent respiratory secretions contained > 25 polymorphonuclear leukocytes and < 10 squamous epithelial cells/low-power (× 100) magnification field. Susceptibility of cultured pathogens to gatifloxacin and co-amoxiclav was determined by the disk diffusion method.

Diagnosis of pneumonia associated with atypical respiratory pathogens was based on serological tests for C. pneumoniae, Chlamydia psittaci, Coxiella burnettii, M. pneumoniae and L. pneumophila, in which a four-fold rise in antibody titre in paired sera taken 14–28 days apart was considered a current definite infection. Single high titres against atypical pathogens were considered to be indicative only of possible infection.

Study medication

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Study design and number of patients
  6. Patients
  7. Diagnostic procedures
  8. Study medication
  9. Clinical efficacy assessment
  10. Bacteriological efficacy assessment
  11. Safety assessment
  12. Statistical analyses
  13. Results
  14. Patient population
  15. Baseline microbiology
  16. Clinical outcome
  17. Bacteriological outcome
  18. Clinical and bacteriological outcome for patients with bacteraemia
  19. Safety
  20. Discussion
  21. Acknowledgements
  22. References

Patients were assigned randomly to one of two treatment groups, in a ratio of 1:1, in which they received either a once-daily oral dose of gatifloxacin 400 mg plus matching placebo for 5–10 days, or oral amoxycillin 500 mg + clavulanic acid 125 mg three-times-daily for 5–10 days.

Clinical efficacy assessment

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Study design and number of patients
  6. Patients
  7. Diagnostic procedures
  8. Study medication
  9. Clinical efficacy assessment
  10. Bacteriological efficacy assessment
  11. Safety assessment
  12. Statistical analyses
  13. Results
  14. Patient population
  15. Baseline microbiology
  16. Clinical outcome
  17. Bacteriological outcome
  18. Clinical and bacteriological outcome for patients with bacteraemia
  19. Safety
  20. Discussion
  21. Acknowledgements
  22. References

Before administration of the study drugs, all patients gave a detailed medical history and underwent a complete physical examination for clinical signs and symptoms of pneumonia, together with an assessment of vital signs, a chest X-ray and laboratory analyses. Repeated physical examinations, together with an assessment of vital signs, as well as clinical signs and symptoms of pneumonia, were carried out during treatment (days 4–6), at the end of treatment (days 1–3 post-treatment), and at the end of the study (14–28 days post-treatment). Chest X-rays were performed at the end of treatment and, if clinically indicated or not done at previous visits, at the end of the study.

Clinical response (clinical cure plus improvement) at the end of treatment was the primary efficacy endpoint in this study. Clinical cure was defined as a complete resolution of acute signs and symptoms of pneumonia, together with improvement or lack of progression of imaging, and no reason for clinical failure. Clinical improvement was defined as resolution of > 50% of all signs and symptoms of pneumonia, together with improvement or lack of progression of imaging, resolution of fever if elevated at enrolment, and no reason for clinical failure. Clinical failure was defined as persistence or progression of all signs and symptoms of pneumonia after 3–5 days of treatment, a lack of improvement in any signs and symptoms of pneumonia and in chest X-ray at the end of treatment, or a lack of resolution of > 50% of signs and symptoms of pneumonia. Additional reasons for clinical failure included fever at follow-up or end of the study, progression of pneumonia-related radiographical abnormalities, development of an active infection, a change in or use of additional antibiotics, withdrawal because of treatment-related adverse events, or death caused by pneumonia.

Analyses were based primarily on the modified intent-to-treat population (mITT), which included all patients who had received at least one dose of study medication and had the study disease. Analyses were also carried out on the efficacy analysable population (EAP), a subset of the mITT population. This comprised patients who had completed 72 h of treatment, had complied fully with the dosing regimen, were assessed within the specific time windows required by the study protocol, did not develop concurrent illnesses likely to interfere with treatment effectiveness, and had received no other antibiotics except for topical agents.

Bacteriological efficacy assessment

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Study design and number of patients
  6. Patients
  7. Diagnostic procedures
  8. Study medication
  9. Clinical efficacy assessment
  10. Bacteriological efficacy assessment
  11. Safety assessment
  12. Statistical analyses
  13. Results
  14. Patient population
  15. Baseline microbiology
  16. Clinical outcome
  17. Bacteriological outcome
  18. Clinical and bacteriological outcome for patients with bacteraemia
  19. Safety
  20. Discussion
  21. Acknowledgements
  22. References

Bacteriological response at the end of treatment and the end of the study was a secondary efficacy endpoint. Patients were considered to have responded to treatment if eradication or presumed eradication of the causative organism was achieved, with or without colonisation. Eradication was defined as elimination of the original causative organism(s) from the same site; presumed eradication was defined as the absence of appropriate material for culture because the patient had improved clinically and did not produce sputum, or because repeated aspiration of pleural fluid was clinically unjustified. Colonisation was defined as the development of a positive sputum culture, with a bacterial strain other than the primary causative organism, that appeared > 48 h after initiation of therapy and persisted in at least two repeated cultures in the absence of fever, leukocytosis, persistence or progression of pneumonia, or evidence of infection at a distant site.

Bacteriological response was considered unsatisfactory if the outcome was persistence, presumed persistence, relapse, superinfection or reinfection. Persistence was defined as a failure to eradicate the causative organism from the site of infection, irrespective of the presence or absence of signs of infection. Presumed persistence was defined as a failure in the absence of material for culture, or change of therapy because of inadequate efficacy, or discontinuation because of inadequate efficacy. Relapse was defined as initial eradication of the original pathogen isolated at baseline, followed by reinfection with the same pathogen at the end of the study. Superinfection was defined as the development of a new lower respiratory tract infection caused by a new or resistant pathogen not identified as the original causative organism. Reinfection was defined as infection with a new pathogen at the end of the study.

Safety assessment

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Study design and number of patients
  6. Patients
  7. Diagnostic procedures
  8. Study medication
  9. Clinical efficacy assessment
  10. Bacteriological efficacy assessment
  11. Safety assessment
  12. Statistical analyses
  13. Results
  14. Patient population
  15. Baseline microbiology
  16. Clinical outcome
  17. Bacteriological outcome
  18. Clinical and bacteriological outcome for patients with bacteraemia
  19. Safety
  20. Discussion
  21. Acknowledgements
  22. References

All patients who received at least one dose of study medication were included in the safety analyses. These were based on the incidence and severity of all adverse events and their relationship to study medication, as well as changes from baseline in vital signs and clinical chemistry, haematology and urinalysis parameters.

Statistical analyses

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Study design and number of patients
  6. Patients
  7. Diagnostic procedures
  8. Study medication
  9. Clinical efficacy assessment
  10. Bacteriological efficacy assessment
  11. Safety assessment
  12. Statistical analyses
  13. Results
  14. Patient population
  15. Baseline microbiology
  16. Clinical outcome
  17. Bacteriological outcome
  18. Clinical and bacteriological outcome for patients with bacteraemia
  19. Safety
  20. Discussion
  21. Acknowledgements
  22. References

The sample size of 456 patients assumed that the probability of a successful clinical response (primary efficacy endpoint) was 80% for both treatments, and that the maximal acceptable difference was 15% with a type II error probability of 20%. Allowance was also made for 15% dropout and an assumption that 33% of patients would have bacteriological confirmation of CAP.

Demographic and baseline data for the two treatment groups were compared by the Cochran–Mantel–Haenszel test with adjustment for centre, or the F-test adjusting for centre, and centre-by-treatment, as appropriate. A two-sided 95% confidence interval (CI) for the difference in clinical response to oral gatifloxacin and co-amoxiclav was calculated, in which the procedure described by Farrington and Manning was used to compute the CIs [21]. For equivalence to be shown, the lower bound of the two-sided 95% CIs for the observed difference between treatments must not exceed − 15%. Clinical cure rates in each group were summarised, with 95% CI calculated according to the Pearson and Clopper method [22].

Bacteriological response was compared by analysing the patient and pathogen response to treatment in patients with bacteriological confirmation at admission. The absolute and relative frequencies for bacteriological response and the 95% CI for patient response rate within treatment was calculated, as well as the 95% CI for the difference in patient response rates to treatments. The same statistical procedures were applied to other secondary endpoints, such as clinical response at the end of the study and clinical cure rate at the end of treatment and study, while the remaining secondary endpoints, which included treatment duration and chest X-ray findings, were compared using descriptive statistics.

Patient population

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Study design and number of patients
  6. Patients
  7. Diagnostic procedures
  8. Study medication
  9. Clinical efficacy assessment
  10. Bacteriological efficacy assessment
  11. Safety assessment
  12. Statistical analyses
  13. Results
  14. Patient population
  15. Baseline microbiology
  16. Clinical outcome
  17. Bacteriological outcome
  18. Clinical and bacteriological outcome for patients with bacteraemia
  19. Safety
  20. Discussion
  21. Acknowledgements
  22. References

In total, 462 patients from 73 centres in 16 countries, most of which were in Europe, were randomised to treatment, of whom 228 received gatifloxacin 400 mg and 234 received co-amoxiclav. The two treatment groups were comparable with respect to baseline demographic characteristics and respiratory status such as underlying chronic obstructive pulmonary disease and smoking history (Table 1). Of these, 456 patients were included in the primary mITT (228 each in the gatifloxacin and co-amoxiclav groups). Six patients were excluded from the co-amoxiclav group because they did not have the disease being studied.

Table 1.  Summary of patient demographics and smoking history
CharacteristicsGatifloxacin group n = 228Co-amoxiclav group n = 234
  1. COPD, chronic obstructive pulmonary disease.

Male148 (64.9%)141 (60.3%)
Female 80 (35.1%) 93 (39.7%)
Race
 Caucasian171 (75.0%)175 (74.8%)
 Black 52 (22.8%) 53 (22.7%)
 Asian  1 (< 1.0%)  2 (< 1%)
 Other  4 (1.8%)  4 (1.7%)
Mean age in years (SD) (range) 49.2 (16.70) (18–89) 50.2 (17.28) (18–88)
Mean weight in kg (SD) (range) 70.5 (15.45) (38–129) 70.2 (14.38) (36–125)
Smoking history
 Never smoked 93 (41.0%) 91 (39.1%)
 Current smoker 88 (38.8%) 80 (34.3%)
 Ex-smoker 46 (20.3%) 62 (26.6%)
 Missing  1  1
History of COPD 18 (7.9%) 16 (6.8%)
Alcohol consumption
 Not done  0  1
 None 95 (41.7%)110 (47.0%)
 Rarely 92 (40.4%) 89 (38.0%)
 Often 33 (14.5%) 24 (10.3%)
 Daily  8 (3.5%) 10 (4.3%)

Baseline microbiology

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Study design and number of patients
  6. Patients
  7. Diagnostic procedures
  8. Study medication
  9. Clinical efficacy assessment
  10. Bacteriological efficacy assessment
  11. Safety assessment
  12. Statistical analyses
  13. Results
  14. Patient population
  15. Baseline microbiology
  16. Clinical outcome
  17. Bacteriological outcome
  18. Clinical and bacteriological outcome for patients with bacteraemia
  19. Safety
  20. Discussion
  21. Acknowledgements
  22. References

As is usual in community-based clinical trials, most bacteriological samples at admission were from sputum cultures (92% in the gatifloxacin group vs. 95% in the co-amoxiclav group, while 0.7% vs. 0.9% were from transtracheal aspiration, 2.9% vs. 0.9% from endotracheal aspiration, and 4.3% vs. 3.6% were bronchoalveolar lavage samples).

The most common pathogens isolated at baseline were consistent with a diagnosis of CAP, and were mainly isolates of S. pneumoniae (n = 61) and H. influenzae (n = 48) (Table 2). Seven patients in the gatifloxacin group and five in the co-amoxiclav group had positive blood cultures. In the gatifloxacin group, S. pneumoniae was isolated in five cases and Staphylococcus aureus in two cases, while in the co-amoxiclav group, S. pneumoniae, Staph. aureus and Klebsiella pneumoniae were isolated in three cases, one case and one case, respectively. Pneumonia caused by atypical pathogens (M. pneumoniae, L. pneumophila, C. psittaci) was diagnosed definitively in only 35 patients (19 gatifloxacin group; 16 co-amoxiclav group), while 36 patients had a possible diagnosis of pneumonia caused by atypical pathogens, as defined by a single high-titre antibody result.

Table 2.  Causative pathogens isolated from patients at baseline
 Gatifloxacin group n = 228Co-amoxiclav group n = 228
Patients with pathogen75 84
 Single pathogen61 (26.8%) 68 (29.8%)
 Multiple pathogens14 (6.1%) 16 (7.0%)
Causative pathogens90 (100%)104 (100%)
Gram-positive organisms
 Streptocoocus pneumoniae28 (31.1%) 33 (31.7%)
  Penicillin-susceptible19 (21.1%) 17 (16.3%)
  Penicillin-intermediate 2 (2.2%)  3 (2.9%)
  Penicillin susceptibility unknown 7 (7.8%) 13 (12.5%)
 Staphylococcus aureus 7 (7.8%)  6 (5.8%)
 Streptococcus viridans group 4 (4.4%)  4 (3.8%)
 Streptococcus pyogenes 4 (4.4%)  3 (2.9%)
Gram-negative organisms
 Haemophilus influenzae26 (28.9%) 22 (21.2%)
 Moraxella catarrhalis 3 (3.3%) 10 (9.6%)
 Haemophilus parainfluenzae 3 (3.3%)  3 (2.9%)
Non-fermenting bacteria
 Pseudomonas aeruginosa 3 (3.3%)  1 (< 1.0%)
Enterobacteriaceae
 Klebsiella pneumoniae 2 (2.2%)  4 (3.8%)
 Escherichia coli 4 (4.4%)  1 (< 1.0%)
 Other enteric bacteria 0 13 (12.5%)

With regard to patients with chronic obstructive pulmonary disease, 12 of the 18 patients in the gatifloxacin group and six of the 16 in the co-amoxiclav group had no pathogen at admission. The remaining six patients in the gatifloxacin group yielded an isolate of S. pneumoniae (n = 3), H. influenzae (n = 3) or K. pneumoniae (n = 1), while patients in the co-amoxiclav group yielded four S. pneumoniae isolates, two H. influenzae isolates, and one isolate each of Haemophilus parainfluenzae, Pseudomonas aeruginosa, Pseudomonas fluorescens, M. catarrhalis and K. pneumoniae.

Clinical outcome

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Study design and number of patients
  6. Patients
  7. Diagnostic procedures
  8. Study medication
  9. Clinical efficacy assessment
  10. Bacteriological efficacy assessment
  11. Safety assessment
  12. Statistical analyses
  13. Results
  14. Patient population
  15. Baseline microbiology
  16. Clinical outcome
  17. Bacteriological outcome
  18. Clinical and bacteriological outcome for patients with bacteraemia
  19. Safety
  20. Discussion
  21. Acknowledgements
  22. References

Within the limits of treatment duration of 5–10 days, 9% of gatifloxacin-treated patients and 11% of co-amoxiclav-treated patients received < 7 days of treatment; 89% and 85%, respectively, received treatment for 7–10 days; and 2% and 4%, respectively, received treatment for > 10 days. Overall, the average therapy duration of 9 days was the same in the two treatment groups.

At the end of treatment, a successful clinical response was achieved in 86.8% of gatifloxacin-treated patients, compared with 81.6% of those receiving co-amoxiclav. The two-sided 95% CI for the difference between the two treatments was well within the specified limit, indicating clinical equivalence for the two treatments (Table 3). These results were mirrored by those of the EAP, in which clinical response at the end of treatment for gatifloxacin and co-amoxiclav was 89.6% (190/212) and 84.8% (173/204), respectively.

Table 3.  Assessment of clinical response to treatment with gatifloxacin or co-amoxiclav at end of treatment and end of study in the mITT population
OutcomeGatifloxacinCo-amoxiclav
  • a

    95% confidence intervals: gatifloxacin 400 mg vs. co-amoxiclav (− 1.80%; 12.33%).

  • b

    95% confidence intervals: gatifloxacin 400 mg vs. co-amoxiclav (0.98%; 16.09%).

End of treatmentan = 228n = 228
 Clinical response   (cure + improvement)198 (86.8%)186 (81.6%)
 Clinical cure123 (53.9%)108 (47.4%)
 Clinical improvement 75 (32.9%) 78 (34.2%)
 Clinical non-response   (failure + indeterminate) 30 (13.2%) 42 (18.4%)
End of studybn = 211n = 211
 Clinical response   (cure + improvement)184 (87.2%)166 (78.7%)
 Clinical cure141 (66.8%)133 (63.0%)
 Clinical improvement 43 (20.4%) 33 (15.6%)
 Clinical non-response   (failure + indeterminate) 27 (12.8%) 45 (21.3%)

Equivalence was also demonstrated for secondary clinical endpoints, although there was a trend towards higher rates of clinical cure with gatifloxacin at both the end of treatment and at the end of the study, which was also seen in the primary endpoint analysis (Table 3). Of the small number of patients with a definitive diagnosis of pneumonia caused by atypical pathogens (M. pneumoniae, L. pneumophila, Chlamydia spp.), all but one of those who received gatifloxacin were treated successfully at both the end of treatment and at the end of the study. The one case classified as a clinical failure at the end of treatment, because of continuing clinical signs and symptoms, resolved by the end of the study without further therapeutic measures. In contrast, only 12 of the 16 co-amoxiclav-treated patients had a successful clinical outcome at the end of treatment, and only 11 out of 16 at the end of the study.

Clinical failure occurred with 30 (13.2%) and 42 (18.4%) of cases in the gatifloxacin and co-amoxiclav treatment groups, respectively. Clinical failure was caused primarily by the need for additional or new antibiotics for pneumonia (nine gatifloxacin vs. 19 co-amoxiclav patients), as well as incomplete resolution of symptoms (11 gatifloxacin vs. six co-amoxiclav patients), premature withdrawal because of treatment-related adverse events (five patients in each group), complete lack of improvement (one gatifloxacin vs. three co-amoxiclav patients), and progression of radiographical abnormalities (two gatifloxacin vs. one co-amoxiclav patient).

In the mITT population, clinical success was accompanied by a marked improvement in clinical symptoms, and evidence of resolution of infection on chest X-ray, in both treatment groups at the end of treatment and at the end of the study.

Bacteriological outcome

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Study design and number of patients
  6. Patients
  7. Diagnostic procedures
  8. Study medication
  9. Clinical efficacy assessment
  10. Bacteriological efficacy assessment
  11. Safety assessment
  12. Statistical analyses
  13. Results
  14. Patient population
  15. Baseline microbiology
  16. Clinical outcome
  17. Bacteriological outcome
  18. Clinical and bacteriological outcome for patients with bacteraemia
  19. Safety
  20. Discussion
  21. Acknowledgements
  22. References

Within the mITT population, the bacteriological outcome was evaluated for 65 patients treated with gatifloxacin and 75 with co-amoxiclav. Treatment was successful in 54 (83.1%) and 59 (78.7%) patients at the end of treatment, respectively. Corresponding rates at the end of the study were 78.7% and 75.0%, respectively. The two-sided 95% CI for the difference between the two treatments at the end of treatment (− 9.29%; 18.11%) and at the end of the study (− 11.36%; 18.74%) indicated equivalent bacteriological efficacy for the two antibiotic regimens. The favourable bacteriological results for gatifloxacin in the mITT population were similar in the EAP, with bacteriological response at the end of treatment in 50 (84.7%) and 54 (80.6%) patients, respectively. Overall, there was no bacteriological response in 11 (16.9%) and 16 (21.3%) patients, respectively, which, in most cases (ten vs. 15), was caused by persistence or presumed persistence of infection.

For bacteriologically evaluable patients in the mITT population, gatifloxacin successfully eradicated 91.7% of S. pneumoniae at the end of treatment compared with 100% with co-amoxiclav, a difference that was not statistically significant. Activity was also similar against strains of H. influenzae, M. catarrhalis and Staph. aureus(Table 4).

Table 4.  Assessment of bacteriological response to treatment with gatifloxacin or co-amoxiclav at end of treatment and end of study for the baseline pathogens isolated most frequently (mITT population)
 Gatifloxacin n = 228Co-amoxiclav n = 228
Total pathogens90104
All pathogens
 End of treatment67/78 (85.9%)78/94 (83%)
 End of study59/72 (81.9%)64/80 (80%)
Streptococcus pneumoniae
 End of treatment22/24 (91.7%)30/30 (100%)
 End of study18/23 (78.3%)19/21 (90.5%)
Haemophilus influenzae
 End of treatment21/22 (95.5%)16/19 (84.2%)
 End of study18/20 (90%)14/18 (77.8%)
Moraxella catarrhalis
 End of treatment2/2 (100%)9/10 (90%)
 End of study2/2 (100%)7/8 (87.5%)
Staphylococcus aureus
 End of treatment7/7 (100%)3/5 (60%)
 End of study7/7 (100%)3/5 (60%)
Haemophilus parainfluenzae
 End of treatment3/3 (100%)2/2 (100%)
 End of study3/3 (100%)3/3 (100%)

Clinical and bacteriological outcome for patients with bacteraemia

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Study design and number of patients
  6. Patients
  7. Diagnostic procedures
  8. Study medication
  9. Clinical efficacy assessment
  10. Bacteriological efficacy assessment
  11. Safety assessment
  12. Statistical analyses
  13. Results
  14. Patient population
  15. Baseline microbiology
  16. Clinical outcome
  17. Bacteriological outcome
  18. Clinical and bacteriological outcome for patients with bacteraemia
  19. Safety
  20. Discussion
  21. Acknowledgements
  22. References

Of the seven patients in the gatifloxacin group who had positive blood cultures, six responded to gatifloxacin therapy. This included four cases of S. pneumoniae and two cases of Staph. aureus bacteraemia. One patient with a gatifloxacin-susceptible S. pneumoniae blood isolate was considered as a clinical failure because of discontinuation of therapy caused by nausea and stomachache on the second day of treatment after two doses of gatifloxacin. Notably, this patient had a history of duodenal ulcer.

In the co-amoxiclav group, four of five patients with bacteraemia responded to treatment. One case with concomitant Staph. aureus bacteraemia needed a change in antibiotic therapy after 2 days and was thus considered a clinical failure.

Safety

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Study design and number of patients
  6. Patients
  7. Diagnostic procedures
  8. Study medication
  9. Clinical efficacy assessment
  10. Bacteriological efficacy assessment
  11. Safety assessment
  12. Statistical analyses
  13. Results
  14. Patient population
  15. Baseline microbiology
  16. Clinical outcome
  17. Bacteriological outcome
  18. Clinical and bacteriological outcome for patients with bacteraemia
  19. Safety
  20. Discussion
  21. Acknowledgements
  22. References

Overall, both antibiotics were well-tolerated by patients in this study, with the adverse event profile being similar for gatifloxacin and co-amoxiclav. From the start of dosing to the end of treatment, gastrointestinal disturbances were the most common treatment-related adverse events, although only diarrhoea occurred with a frequency of > 5% in both groups (Table 5). Most adverse events were mild-to-moderate in intensity. Serious adverse events occurred with similar frequency in the two groups, affecting 17 (7.4%) gatifloxacin-treated patients and 16 (6.8%) of those treated with co-amoxiclav, but in only one patient in each group was this attributed to study medication. Additional safety assessments (of special relevance to the fluoroquinolones) showed no evidence of phototoxicity, cardiotoxicity, adverse effects on the musculoskeletal system, or renal or hepatic toxicity, in either treatment group. There were also no treatment-related cases of crystalluria.

Table 5.  Summary of the most frequent (≥ 1% patients in either group) treatment-related adverse events following administration of gatifloxacin or co-amoxiclav (from start to end of treatment)
 No. (%) of patients experiencing adverse event (WHO-ARD terms)
Gatifloxacin n = 228Co-amoxiclav n = 234
Diarrhoea13 (5.7%)16 (6.8%)
Nausea10 (4.4%) 6 (2.6%)
Thrush 6 (2.6%) 3 (1.3%)
Vomiting 4 (1.8%) 4 (1.7%)
Abdominal pain 4 (1.8%) 1 (< 1%)
Abnormal hepatic function 2 (< 1.0%) 3 (1.3%)
Increased serum alkaline phosphatase 3 (1.3%) 1 (< 1.0%)
Leukopenia 2 (< 1.0%) 3 (1.3%)

Premature discontinuation because of adverse events occurred in ten (4.4%) and 11 (4.7%) patients in the gatifloxacin and co-amoxiclav groups, respectively; in eight cases, the adverse events were considered to be serious. Three patients in each treatment group died within 30 days of the last dose of study medication. Five of these deaths were unrelated to study medication, while the sixth, a death in the co-amoxiclav group, was caused by hepatic failure. Overall, no clinically meaningful changes from baseline were observed in relation to clinical chemistry, haematology and urinalysis parameters. Changes in vital signs were consistent with improvement in disease state.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Study design and number of patients
  6. Patients
  7. Diagnostic procedures
  8. Study medication
  9. Clinical efficacy assessment
  10. Bacteriological efficacy assessment
  11. Safety assessment
  12. Statistical analyses
  13. Results
  14. Patient population
  15. Baseline microbiology
  16. Clinical outcome
  17. Bacteriological outcome
  18. Clinical and bacteriological outcome for patients with bacteraemia
  19. Safety
  20. Discussion
  21. Acknowledgements
  22. References

The results of this study demonstrate that once-daily gatifloxacin 400 mg is clinically and bacteriologically equivalent to a standard course of three-times-daily co-amoxiclav in the treatment of CAP. The study population consisted of patients with mild-to-moderate bacterial CAP, in whom the infecting pathogens are most commonly S. pneumoniae, H. influenzae and M. catarrhalis and, to a lesser extent, Staph. aureus, K. pneumoniae and other Enterobacteriaceae [23]. Consistent with the bacterial aetiology of the disease, the pathogens isolated most frequently from patients at admission were, in order of frequency, S. pneumoniae, H. influenzae, M. catarrhalis and Staph. aureus. Relatively few patients in this study were infected with atypical respiratory pathogens.

Both study drugs achieved high and sustained clinical response rates that were, in general, accompanied by a decrease in signs and symptoms of pneumonia, together with improved radiographical findings. The antibacterial activity of gatifloxacin against the main typical respiratory pathogens was confirmed by the bacteriological outcome, which correlated closely with clinical findings, and was comparable to eradication rates achieved with other broad-spectrum fluoroquinolones [23–27]. Against S. pneumoniae, including strains of intermediate penicillin susceptibility, gatifloxacin eradicated > 90% of isolates successfully.

The results of the present study are consistent with those of other studies in which gatifloxacin has been used to treat patients with CAP, where clinical cure rates of > 95% have been reported [28–31]. This includes patients infected with multiresistant strains of S. pneumoniae, H. influenzae and M. catarrhalis, the presence of which can jeopardise treatment outcome seriously if older standard antimicrobial agents, such as penicillins, cephaloporins and macrolides, are used as first-line agents for empirical therapy of CAP.

In the present study, high rates of clinical and bacteriological efficacy were accompanied by good drug safety and tolerability, with the frequency and nature of adverse events being similar in the two treatment groups. Concerns have been raised about the safety of broad-spectrum fluoroquinolones following the discovery of serious drug-related side effects with some agents in this class. This has led to the withdrawal or restricted clinical use of certain broad-spectrum fluoroquinolones, and a cautious approach to drug licensing by the regulatory authorities.

To address potential concerns about the safety and tolerability of gatifloxacin, extensive post-marketing surveillance studies have been carried out following its approval in the USA for the treatment of respiratory tract and other infections. Results from a Phase IV post-marketing surveillance trial carried out in 2000, involving over 15 000 patients treated with gatifloxacin for respiratory tract infections, have shown gatifloxacin to be safe and well-tolerated when used in routine clinical practice for the treatment of CAP and other infections of the upper and lower respiratory tract [32–34].

Results from the present Phase III study are in accordance with these findings, with the incidence and nature of adverse events observed with gatifloxacin being within the incidence range reported elsewhere [35]. Gatifloxacin had a safety and tolerability profile comparable to that of co-amoxiclav, with adverse gastrointestinal events being the most common treatment-related adverse events in both groups. The study also showed no evidence that gatifloxacin induced phototoxicity, musculoskeletal disorders or the hepatic, cardiac and renal problems that have been reported for some of the other broad-spectrum fluoroquinolones [36–39].

Discontinuations associated with adverse events were similar in the two treatment groups, reflecting the good tolerability of both agents. Based on the current medical literature, the discontinuation rates for gatifloxacin were comparable to rates of < 4.1% reported for other fluoroquinolones [40]. Compared with co-amoxiclav, the long elimination half-life of gatifloxacin permits once-daily dosing, which provides a convenient dosage schedule for patients with CAP, and may offer advantages over the three-times-daily dosing schedule for co-amoxiclav.

In conclusion, the results of this multicentre, double-blind, randomised, double-dummy, parallel-group study have shown that a once-daily dose of gatifloxacin 400 mg administered for 5–10 days was a safe and effective treatment for patients with CAP.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Study design and number of patients
  6. Patients
  7. Diagnostic procedures
  8. Study medication
  9. Clinical efficacy assessment
  10. Bacteriological efficacy assessment
  11. Safety assessment
  12. Statistical analyses
  13. Results
  14. Patient population
  15. Baseline microbiology
  16. Clinical outcome
  17. Bacteriological outcome
  18. Clinical and bacteriological outcome for patients with bacteraemia
  19. Safety
  20. Discussion
  21. Acknowledgements
  22. References

We acknowledge the members of the Gatifloxacin International Study Group for their participation in this study: N. F. Alberts, Randfontein, South Africa; D. M. Allin, Birmingham, UK; D. F. Botha, Potgietersrus, South Africa; M. Cmakalova, Prague, Czech Republic; J. Geyser, Conera, South Africa; S. Gruszka, Otwock, Poland; V. Jensovsky, Lovosice, Czech Republic; G. Koratzanis, Athens, Greece; Dr Matthews, South Africa; Dr Mills, Hamilton, New Zealand; A. Nusch, Essen, Germany; J. Pretorius, Potgietersrus, South Africa; M. Reguiski, Otwock, Poland; Z. Rott, Matrahaza, Hungary; A. J. Schreurs, Amsterdam, The Netherlands; Dr van Rendsberg, South Africa; and many others, including centres also in Australia, France, Iceland, Belgium, Austria and Switzerland. The study was supported by an educational grant from Grünenthal GmbH, Germany.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Study design and number of patients
  6. Patients
  7. Diagnostic procedures
  8. Study medication
  9. Clinical efficacy assessment
  10. Bacteriological efficacy assessment
  11. Safety assessment
  12. Statistical analyses
  13. Results
  14. Patient population
  15. Baseline microbiology
  16. Clinical outcome
  17. Bacteriological outcome
  18. Clinical and bacteriological outcome for patients with bacteraemia
  19. Safety
  20. Discussion
  21. Acknowledgements
  22. References
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