Uncomplicated Urinary Tract Infections: Lomefloxacin versus Trimethoprim/ Sulphamethoxazole J GUIBERT AND M
H
CAPRON
Saint Joseph Hospital, Paris, France
Data were collected from 14 French centres which participated in a randomized study to compare the safety and efficacy of 400 mg lomefloxacin taken orally once daily by 62 patients with 160/800 mg trimethopriml sulphamethoxazole (TMP/SMX) taken orally twice daily by 64 patients with uncomplicated urinary tract infections. Most patients were infected with Escherichia coli at baseline (72.4% in the lomefloxacin group and 69.0% in the TMP/SMX group) and all patients were treated for 5 days. At 5 - 9 days post-treatment, lomefloxacin had eradicated the causative organism of infection in 100% of evaluable patients treated with lomefloxacin compared with 86.7% of those treated with TMP/SMX. At 4 - 6 weeks post-treatment, there were no marked differences in eradication rates between the two treatment groups: 83.3% and 80.0% for the lomefloxacin and TMP/SMX groups, respectively. Clinical cure rates showed no marked differences between treatment groups at 5 - 9 days or at 4 - 6 weeks post-treatment. At 5 - 9 days post-treatment, lomefloxacin achieved a clinical cure rate of 78.6% compared with 86.7% for TMP/SMX evaluable patients. At 4 - 6 weeks post-treatment, the clinical cure rates were 66.7% and 86.7% for the evaluable lomefloxacin- and TMP/SMXtreated patients, respectively. Both treatment regimens were well tolerated with a low incidence of adverse events.
467
In conclusion, once-daily oral dosing with lomefloxacin is a safe and efficacious alternative to twice-daily dosing with TMPI SMX in the treatment ofuncomplicated urinary tract infections.
KEYWORDS: LOMEFLOXACIN; TRIMETHOPRIM/SULPHAMETHOXAZOLE; UNCOMPLICATED URINARY TRACT INFECTIONS; CYSTITIS
INTRODUCTION Lomefloxacin hydrochloride (NY-198, SC 47111) is a synthetic difl uoroquinolone antimicrobial agent, which in in vitro studies has been demonstrated to have a broad antibacterial spectrum with comparable activity to that of other quinolones.' -, The antibacterial activity of lomefloxacin, in common with other quinolones, is due to its ability to inhibit bacterial DNA synthesis by inhibiting DNA gyrase.' Lomefloxacin has demonstrated antimicrobial activity against Gram-negative and some Gram-positive bacteria.' The minimum inhibitory concentrations (MICs) of lomefloxacin against most pathogens responsible for urinary tract infections are well below the concentrations achieved in the urine with the 400 mg once-daily dosing regimen. This oncedaily dosing regimen is based on the relationship of the MICs to achievable serum and urine concentrations, the long half-life of lomefloxacin (8 h) and a very high bioavailability of more than 98% following an oral dose, indicating complete absorption of lomefloxacin.' A multicentre, open-label, prospectively randomized, comparative trial was conducted in France, Ireland and the UK to evaluate the safety and efficacy of 400 mg lomefloxacin taken orally once daily versus that of 160/ 800 mg trimethoprim/sulphamethoxazole (TMP/SMX) taken orally twice daily for 5 - 7 days in the treatment of uncomplicated urinary tract infections in patients with normal
urinary tracts and normal renal function. This paper presents results from 126 patients enrolled by the 14 centres in France that participated in the international trial with patients receiving therapy for 5 days.
PATIENTS AND METHODS PATIENTS In order to participate in the study patients had to satisfy certain inclusion criteria regarding the presence of significant bacteriuria, defined as a pretreatment culture of ~ 10 5 colony forming units/ml (CFU/ml), and at least one of the following signs or symptoms of urinary tract infection: dysuria; frequency; haematuria; fever (> 38°C); suprapubic pain. Informed consent was obtained from all patients taking part in the study. Pregnant and lactating women were excluded, as were patients with complicated urinary tract infections, bacteraemia, terminal illness, low back pain or costovertebral angle tenderness, a history of quinolone sensitivity or convulsive disorders, epilepsy, or those receiving other systemic antimicrobial therapy. Patients with abnormal liver function tests or serum creatinine concentrations, or those requiring antacid or fenbufen therapy during the study were also excluded. On bacteriological examination, patients with initial baseline pathogens that were resistant
468
to either lomefloxacin or TMP/SMX were withdrawn from the study.
TREATMENT Patients were randomized to receive either 400 mg lomefloxacin once daily or 160/ 800 mg TMP/SMX twice daily for 5 days.
EVALUATION OF PATIENTS Quantitative urine cultures were obtained before therapy, during therapy on day 3 of treatment and after therapy (5 - 9 days and 4 - 6 weeks post-treatment). An evaluation of the clinical signs and symptoms of urinary tract infection was performed during therapy (48 h after the initial dose) and after treatment (5 - 9 days and 4 - 6 weeks post-treatment). Clinical laboratory evaluation for safety was carried out before therapy and at 5 - 9 days posttreatment. Blood counts were performed on samples from all patients. Serum creatinine concentrations and liver enzyme activities were measured before inititation of therapy and at 5 - 9 days post-treatment.
pathogen, i.e. :0;103 CFU/ml, and the appearance of a different pathogen (;::: 10 5 CFU/ml); 'relapse', reappearance of the same baseline pathogen initially eradicated; 'failure', persistence of the baseline pathogen; and 'unknown', no information available at the post-treatment visit. Only eradication of the baseline pathogen was considered to be a satisfactory bacteriological response to therapy.
RESULTS Of the 126 patients initially enrolled, 62 were randomized to the lomefloxacin treatment group and 64 to the TMP/SMX treatment group. Patients had a median age of 57 years (range 18 - 97 years) in the lomefloxacin group and 60 years (range 18 - 87 years) in the TMP/SMX group. Both treatment groups consisted mostly of females: 92% and 80%, respectively, in the lomefloxacin and TMP/ SMX groups. Bacteriological and clinical results were evaluated by subgroup analysis as follows: intent-to-treat patients, all randomized patients; modified intent-to-treat patients, all randomized patients with a baseline pathogen colony count z 10 5 CFU/ml; and evaluable patients, all randomized patients with a baseline colony count z 10 5 CFU/ml and who had provided a baseline urine specimen and had a clinical evaluation within the 48 h prior to initiation of treatment. In addition, evaluable patients had a baseline pathogen that was susceptible/ moderately susceptible to both study drugs; had one or more signs or symptoms of uncomplicated urinary tract infection at baseline, had a culture taken and were clinically observed at 5 - 9 days post-treatment, took the study medication for 5 days, had not taken any concomitant systemic antimicrobial, mineral antacid, or fenbufen during treatment, and had no concomitant infections that would confuse the results of therapy.
EFFICACY Clinical efficacy was based on the comparison of signs and symptoms assessed before and after treatment (5 - 9 days and 4 - 6 weeks) and was defined as follows: 'cure', disappearance of all clinical signs and symptoms relevant to the acute episode; 'failure', the presence of any remaining baseline sign or symptom; and 'unknown', no information available at the post-treatment visits. Bacteriological efficacy was determined by comparing results obtained before and after treatment (at 5 - 9 days and 4 - 6 weeks posttreatment). The definitions used to assess bacteriological outcome were as follows: 'eradication', disappearance of the baseline pathogen(s), i.e. colony count :0; 10' CFU/ml, and the absence of other pathogens; 'reinfection', disappearance of the baseline
469
for lomefloxacin compared with 80.0% for TMP!SMX (Table 3). Reinfections occurred in two patients (16.7%) treated with lomefloxacin and one (6.7%) treated with TMP! SMX. There were no treatment failures with lomefloxacin in the evaluable patient group and one failure (6.7%) in the TMP/SMXgroup. No relapses occurred in evaluable patients treated with lomefloxacin but one relapse (6.7%) occurred in the TMP!SMX group. Clinical outcomes at 5 - 9 days and 4 - 6 weeks post-treatment are shown in Tables 4 and 5, respectively. There were no marked differences in cure rates between the two treatment groups. At 5 - 9 days post-treatment, clinical cure was achieved in 78.6% of evaluable patients treated with lomefloxacin and in 86. 7% of those treated with TMP!SMX (Table 4). Treatment failures occurred in three patients (21.4%) treated with lomefloxacin and two (13.3%) treated with TMP/SMX. At4-6weeks post-treatment, clinical cure had been achieved by lomefloxacin in 66.7% of evaluable patients in the lomefloxacin group and by TMP !SMX in 86.7%.
The baseline pathogens in both treatment groups are shown in Table 1. The majority of patients were infected with Escherichia coli (72.4% in the lomefloxacin group and 69.0% in the TMP!SMX group). Bacteriological outcomes at 5 - 9 days posttreatment and at 4 - 6 weeks post-treatment are shown in Tables 2 and 3, respectively. There were no marked differences between treatment groups in eradication rates at 5 - 9 days post-treatment or at 4 - 6 weeks posttreatment. At 5 - 9 days post-treatment, 100% of baseline pathogens were eradicated by lomefloxacin in the evaluable patient subgroup compared with 86.7% ofthose treated with TMP!SMX (Table 2). Of the evaluable patients treated with lomefloxacin, none developed reinfections compared with one patient (6.7%) treated with TMP!SMX. There were no treatment failures with lomefloxacin in the evaluable patient group and one failure (6.7%) in the TMP/SMX group. At 4 - 6 weeks post-treatment, eradication rates in the 27 evaluable patients were 83.3%
Baseline pathogens in patients with uncomplicated urinary tract infections treated once daily with 400 mglday lomefloxacin or twice daily with 1601800 mg trimethoprimlsulphamethoxazole (TMPISMX) for 5 days
No. of patients Pathogen Escherichia coli Proteus species Klebsiella pneumoniae Others Total
Lomefloxacin 42 6 4 6
58
470
(72.4%) (10.3%) (6.9%) (10.3%)
TMP/SMX 40 (69.0%) 8 (13.8%) o (0%) 10 (17.2%)
58
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Bacteriological outcome at 5 - 9 days post-treatment of once-daily treatment with 400 mglday lomefloxacin or twice-daily treatment with 1601800mg trimethoprimlsulphamethoxazole (TMPISMX) for 5 days in patients with uncomplicated urinary tract infections
No. of patients Treatment
Eradication Reinfection
Failure
Intent-to-treat Lomefloxacin TMP/SMX
43 (86.0%) 45 (81.8%)
5 (10.0%) 2 (3.6%)
Modified intent-to-treat Lomefloxacin TMP/SMX
43 (86.0%) 45 (81.8%)
Evaluable Lomefloxacin TMP/SMX
14 (100%) 13 (86.7%)
Total
P-value
2 (4.0%) 8 (14.5%)
50 55
0.986
5 (10.0%) 2 (3.6%)
2 (4.0%) 8 (14.5%)
50 55
0.882
0(0.0%) 1 (6.7%)
0(0.0%) 1 (6.7%)
14 15
0.141
Bacteriological outcome at 4 - 6 weeks post-treatment of once-daily treatment with 400 mglday lomefloxacin or twice-claily treatment with 160/800 mg trimethoprimlsulphamethoxazole (TMPISMX) for 5 days in patients with uncomplicated urinary tract infections
No. of patients Eradication
Reinfection
Failure
Intent-to-treat Lomefloxacin TMP/SMX
36 (81.8%) 39 (70.9%)
5 (11.4%) 1 (1.8%)
2 (4.5%) 8 (14.5%)
Modified intent-to-treat Lomefloxacin TMP/SMX
36 (81.8%) 39 (70.9%)
5 (11.4%) 1 (1.8%)
Evaluable Lomefloxacin TMP/SMX
10 (83.3%) 12 (80.0%)
2 (16.7%) 1 (6.7%)
Treatment
471
Total
P-value
1 (2.3%) 7 (12.7%)
44 55
0.774
2 (4.5%) 8 (14.5%)
1 (2.3%) 7 (12.7%)
44 55
0.564
0(0.0%) 1 (6.7%)
0(0.0%) 1 (6.7%)
12 15
0.484
Relapse
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H
CAPRON
Saint Joseph Hospital, Paris, France
Data were collected from 14 French centres which participated in a randomized study to compare the safety and efficacy of 400 mg lomefloxacin taken orally once daily by 62 patients with 160/800 mg trimethopriml sulphamethoxazole (TMP/SMX) taken orally twice daily by 64 patients with uncomplicated urinary tract infections. Most patients were infected with Escherichia coli at baseline (72.4% in the lomefloxacin group and 69.0% in the TMP/SMX group) and all patients were treated for 5 days. At 5 - 9 days post-treatment, lomefloxacin had eradicated the causative organism of infection in 100% of evaluable patients treated with lomefloxacin compared with 86.7% of those treated with TMP/SMX. At 4 - 6 weeks post-treatment, there were no marked differences in eradication rates between the two treatment groups: 83.3% and 80.0% for the lomefloxacin and TMP/SMX groups, respectively. Clinical cure rates showed no marked differences between treatment groups at 5 - 9 days or at 4 - 6 weeks post-treatment. At 5 - 9 days post-treatment, lomefloxacin achieved a clinical cure rate of 78.6% compared with 86.7% for TMP/SMX evaluable patients. At 4 - 6 weeks post-treatment, the clinical cure rates were 66.7% and 86.7% for the evaluable lomefloxacin- and TMP/SMXtreated patients, respectively. Both treatment regimens were well tolerated with a low incidence of adverse events.
467
In conclusion, once-daily oral dosing with lomefloxacin is a safe and efficacious alternative to twice-daily dosing with TMPI SMX in the treatment ofuncomplicated urinary tract infections.
KEYWORDS: LOMEFLOXACIN; TRIMETHOPRIM/SULPHAMETHOXAZOLE; UNCOMPLICATED URINARY TRACT INFECTIONS; CYSTITIS
INTRODUCTION Lomefloxacin hydrochloride (NY-198, SC 47111) is a synthetic difl uoroquinolone antimicrobial agent, which in in vitro studies has been demonstrated to have a broad antibacterial spectrum with comparable activity to that of other quinolones.' -, The antibacterial activity of lomefloxacin, in common with other quinolones, is due to its ability to inhibit bacterial DNA synthesis by inhibiting DNA gyrase.' Lomefloxacin has demonstrated antimicrobial activity against Gram-negative and some Gram-positive bacteria.' The minimum inhibitory concentrations (MICs) of lomefloxacin against most pathogens responsible for urinary tract infections are well below the concentrations achieved in the urine with the 400 mg once-daily dosing regimen. This oncedaily dosing regimen is based on the relationship of the MICs to achievable serum and urine concentrations, the long half-life of lomefloxacin (8 h) and a very high bioavailability of more than 98% following an oral dose, indicating complete absorption of lomefloxacin.' A multicentre, open-label, prospectively randomized, comparative trial was conducted in France, Ireland and the UK to evaluate the safety and efficacy of 400 mg lomefloxacin taken orally once daily versus that of 160/ 800 mg trimethoprim/sulphamethoxazole (TMP/SMX) taken orally twice daily for 5 - 7 days in the treatment of uncomplicated urinary tract infections in patients with normal
urinary tracts and normal renal function. This paper presents results from 126 patients enrolled by the 14 centres in France that participated in the international trial with patients receiving therapy for 5 days.
PATIENTS AND METHODS PATIENTS In order to participate in the study patients had to satisfy certain inclusion criteria regarding the presence of significant bacteriuria, defined as a pretreatment culture of ~ 10 5 colony forming units/ml (CFU/ml), and at least one of the following signs or symptoms of urinary tract infection: dysuria; frequency; haematuria; fever (> 38°C); suprapubic pain. Informed consent was obtained from all patients taking part in the study. Pregnant and lactating women were excluded, as were patients with complicated urinary tract infections, bacteraemia, terminal illness, low back pain or costovertebral angle tenderness, a history of quinolone sensitivity or convulsive disorders, epilepsy, or those receiving other systemic antimicrobial therapy. Patients with abnormal liver function tests or serum creatinine concentrations, or those requiring antacid or fenbufen therapy during the study were also excluded. On bacteriological examination, patients with initial baseline pathogens that were resistant
468
to either lomefloxacin or TMP/SMX were withdrawn from the study.
TREATMENT Patients were randomized to receive either 400 mg lomefloxacin once daily or 160/ 800 mg TMP/SMX twice daily for 5 days.
EVALUATION OF PATIENTS Quantitative urine cultures were obtained before therapy, during therapy on day 3 of treatment and after therapy (5 - 9 days and 4 - 6 weeks post-treatment). An evaluation of the clinical signs and symptoms of urinary tract infection was performed during therapy (48 h after the initial dose) and after treatment (5 - 9 days and 4 - 6 weeks post-treatment). Clinical laboratory evaluation for safety was carried out before therapy and at 5 - 9 days posttreatment. Blood counts were performed on samples from all patients. Serum creatinine concentrations and liver enzyme activities were measured before inititation of therapy and at 5 - 9 days post-treatment.
pathogen, i.e. :0;103 CFU/ml, and the appearance of a different pathogen (;::: 10 5 CFU/ml); 'relapse', reappearance of the same baseline pathogen initially eradicated; 'failure', persistence of the baseline pathogen; and 'unknown', no information available at the post-treatment visit. Only eradication of the baseline pathogen was considered to be a satisfactory bacteriological response to therapy.
RESULTS Of the 126 patients initially enrolled, 62 were randomized to the lomefloxacin treatment group and 64 to the TMP/SMX treatment group. Patients had a median age of 57 years (range 18 - 97 years) in the lomefloxacin group and 60 years (range 18 - 87 years) in the TMP/SMX group. Both treatment groups consisted mostly of females: 92% and 80%, respectively, in the lomefloxacin and TMP/ SMX groups. Bacteriological and clinical results were evaluated by subgroup analysis as follows: intent-to-treat patients, all randomized patients; modified intent-to-treat patients, all randomized patients with a baseline pathogen colony count z 10 5 CFU/ml; and evaluable patients, all randomized patients with a baseline colony count z 10 5 CFU/ml and who had provided a baseline urine specimen and had a clinical evaluation within the 48 h prior to initiation of treatment. In addition, evaluable patients had a baseline pathogen that was susceptible/ moderately susceptible to both study drugs; had one or more signs or symptoms of uncomplicated urinary tract infection at baseline, had a culture taken and were clinically observed at 5 - 9 days post-treatment, took the study medication for 5 days, had not taken any concomitant systemic antimicrobial, mineral antacid, or fenbufen during treatment, and had no concomitant infections that would confuse the results of therapy.
EFFICACY Clinical efficacy was based on the comparison of signs and symptoms assessed before and after treatment (5 - 9 days and 4 - 6 weeks) and was defined as follows: 'cure', disappearance of all clinical signs and symptoms relevant to the acute episode; 'failure', the presence of any remaining baseline sign or symptom; and 'unknown', no information available at the post-treatment visits. Bacteriological efficacy was determined by comparing results obtained before and after treatment (at 5 - 9 days and 4 - 6 weeks posttreatment). The definitions used to assess bacteriological outcome were as follows: 'eradication', disappearance of the baseline pathogen(s), i.e. colony count :0; 10' CFU/ml, and the absence of other pathogens; 'reinfection', disappearance of the baseline
469
for lomefloxacin compared with 80.0% for TMP!SMX (Table 3). Reinfections occurred in two patients (16.7%) treated with lomefloxacin and one (6.7%) treated with TMP! SMX. There were no treatment failures with lomefloxacin in the evaluable patient group and one failure (6.7%) in the TMP/SMXgroup. No relapses occurred in evaluable patients treated with lomefloxacin but one relapse (6.7%) occurred in the TMP!SMX group. Clinical outcomes at 5 - 9 days and 4 - 6 weeks post-treatment are shown in Tables 4 and 5, respectively. There were no marked differences in cure rates between the two treatment groups. At 5 - 9 days post-treatment, clinical cure was achieved in 78.6% of evaluable patients treated with lomefloxacin and in 86. 7% of those treated with TMP!SMX (Table 4). Treatment failures occurred in three patients (21.4%) treated with lomefloxacin and two (13.3%) treated with TMP/SMX. At4-6weeks post-treatment, clinical cure had been achieved by lomefloxacin in 66.7% of evaluable patients in the lomefloxacin group and by TMP !SMX in 86.7%.
The baseline pathogens in both treatment groups are shown in Table 1. The majority of patients were infected with Escherichia coli (72.4% in the lomefloxacin group and 69.0% in the TMP!SMX group). Bacteriological outcomes at 5 - 9 days posttreatment and at 4 - 6 weeks post-treatment are shown in Tables 2 and 3, respectively. There were no marked differences between treatment groups in eradication rates at 5 - 9 days post-treatment or at 4 - 6 weeks posttreatment. At 5 - 9 days post-treatment, 100% of baseline pathogens were eradicated by lomefloxacin in the evaluable patient subgroup compared with 86.7% ofthose treated with TMP!SMX (Table 2). Of the evaluable patients treated with lomefloxacin, none developed reinfections compared with one patient (6.7%) treated with TMP!SMX. There were no treatment failures with lomefloxacin in the evaluable patient group and one failure (6.7%) in the TMP/SMX group. At 4 - 6 weeks post-treatment, eradication rates in the 27 evaluable patients were 83.3%
Baseline pathogens in patients with uncomplicated urinary tract infections treated once daily with 400 mglday lomefloxacin or twice daily with 1601800 mg trimethoprimlsulphamethoxazole (TMPISMX) for 5 days
No. of patients Pathogen Escherichia coli Proteus species Klebsiella pneumoniae Others Total
Lomefloxacin 42 6 4 6
58
470
(72.4%) (10.3%) (6.9%) (10.3%)
TMP/SMX 40 (69.0%) 8 (13.8%) o (0%) 10 (17.2%)
58
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Bacteriological outcome at 5 - 9 days post-treatment of once-daily treatment with 400 mglday lomefloxacin or twice-daily treatment with 1601800mg trimethoprimlsulphamethoxazole (TMPISMX) for 5 days in patients with uncomplicated urinary tract infections
No. of patients Treatment
Eradication Reinfection
Failure
Intent-to-treat Lomefloxacin TMP/SMX
43 (86.0%) 45 (81.8%)
5 (10.0%) 2 (3.6%)
Modified intent-to-treat Lomefloxacin TMP/SMX
43 (86.0%) 45 (81.8%)
Evaluable Lomefloxacin TMP/SMX
14 (100%) 13 (86.7%)
Total
P-value
2 (4.0%) 8 (14.5%)
50 55
0.986
5 (10.0%) 2 (3.6%)
2 (4.0%) 8 (14.5%)
50 55
0.882
0(0.0%) 1 (6.7%)
0(0.0%) 1 (6.7%)
14 15
0.141
Bacteriological outcome at 4 - 6 weeks post-treatment of once-daily treatment with 400 mglday lomefloxacin or twice-claily treatment with 160/800 mg trimethoprimlsulphamethoxazole (TMPISMX) for 5 days in patients with uncomplicated urinary tract infections
No. of patients Eradication
Reinfection
Failure
Intent-to-treat Lomefloxacin TMP/SMX
36 (81.8%) 39 (70.9%)
5 (11.4%) 1 (1.8%)
2 (4.5%) 8 (14.5%)
Modified intent-to-treat Lomefloxacin TMP/SMX
36 (81.8%) 39 (70.9%)
5 (11.4%) 1 (1.8%)
Evaluable Lomefloxacin TMP/SMX
10 (83.3%) 12 (80.0%)
2 (16.7%) 1 (6.7%)
Treatment
471
Total
P-value
1 (2.3%) 7 (12.7%)
44 55
0.774
2 (4.5%) 8 (14.5%)
1 (2.3%) 7 (12.7%)
44 55
0.564
0(0.0%) 1 (6.7%)
0(0.0%) 1 (6.7%)
12 15
0.484
Relapse
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