Scand J Infect Dis 24: 773-780. 1092
Lomefloxacin versus Norfloxacin in the Treatment of Un co mpIicat ed Urina ry Tract Inf ect io ns : T hree- Day v e rsus Seven-Day Treatment RUNE NERINGER', ARNE FORSGREN', CHRISTER HANSSON'. BJORN ODE4,+and THE SOUTH SWEDISH LOLEX STUDY GROUP
'
Scand J Infect Dis Downloaded from informahealthcare.com by Monash University on 11/02/14 For personal use only.
From the Deparrments of Infectious Diseases Central Hospital, Karlskronu. ' < 'etirrul Hospriul, Kristiansrad. 'General Hospital. Malmo und rhe ' 1)eparrrrretri 01 C'litrrcul Microbiology, General Hospital, Mulmo, Sweden This randomised, double-blind, multicenter study compared the safety and efficacy of lomefloxacin and norfloxacin in adult female outpatients with uncomplicated urinary tract infections. Patients were randomly assigned to one of 3 treatment groups: 400 mg lomefloxacin once daily for 3 days (L3), 400 mg lomefloxacin once daily for 7 days (L7), or 400 mg norfloxacin twice daily for 7 days (N7). A total of 703 patients (age 17-75 years) were enrolled at 21 investigative sites in southern Sweden. Clinical and microbiological evaluations were conducted at the start, 5-9 days and 3 4 weeks post therapy. Patients with quantitative urine cultures of 2 10' CFU/ml of a susceptible pathogen were considered evaluable for efficacy. Escherichia coli and Staphylococcus saprophyticus were the most commonly isolated pathogens. In both L3 and L7 groups, 196 patients and in the N7 group 195 patients met the criteria for efficacy evaluation. At the 5-9 day post-treatment evaluation, 88% of the pathogens were eradicated in the L3 group, 93% in the L7 group and 93% in the N7 group. At the 3 4 week post-treatment evaluation, 8l%, 82%, and 85% of urine cultures remained negative in the L3, L7, and N7 groups, respectively. No statistically significant differences between the 3 treatment groups were noted with the exception of eradication of S. saprophyticus. for which the 7 day courses were more effective at 4-9 days post treatment. No persistent pathogen developed resistance to the study drugs. All 3 treatment regimens were equally well tolerated, except for photosensitivity reactions, which were more frequently reported in patients in the lomefloxacin groups. R . Neringer, MD, Department of Infectious Diseases, Central Hospital, S-371 85 Karlskrona, Sweden
INTRODUCTION The duration of treatment in uncomplicated lower urinary tract infections UTIs in women has been discussed for at least a decade (1, 2). The discussions have focused o n short term treatment, including single-dose therapy. The advantages of single-dose or %day treatment seem obvious: better patient compliance, reduced costs and a reduced exposure to the drug. However, the advantages of a shorter duration of treatment could be outweighed if there is an unacceptable risk of treatment failure. Effective short-term treatment has been reported with several antimicrobial drugs in a number of clinical trials. However. many of these studies included too few patients to allow conclusions as to equivalence between the regimens studied. Differences among various antibiotics, in terms of both efficacy and safety, when used for
t Deceased SO'
Scand J Infect Dis Downloaded from informahealthcare.com by Monash University on 11/02/14 For personal use only.
774 R. Neringer et al.
Scand J Infect Dis 24
different treatment duration was noted by Norrby in a review ( 2 ) of 28 UTI trials. All antibiotics tested were less effective in eradicating bacteriuria used in a single-dose regimen than used for 1 3 days of treatment.This difference was most pronounced for beta-lactam antibiotics, which were more effective when administered for 2 5 days than when given as a 3-day course. Both single-dose and 3-day regimens of trimethoprimlsulfamethoxazolewere considerably more effective than beta-lactams given for the same duration. With trimethoprim/sulfamethoxazole no apparent therapeutic benefit in extending therapy past 3 days was noted; instead a higher frequency of adverse events were noted with the longer regimens. Thus, it is not possible to extrapolate results from one antibiotic to another. The efficacy and safety of each antimicrobial drug must be individually documented. Lomefloxacin is a new fluoroquinolone with excellent activity against a broad spectrum of Gram-negative and Gram-positive bacteria and a half-life sufficiently long to allow once-aday dosing. The concentration of lomefloxacin in urine during the 12-24 h period after a single oral dose of 400 mg is > 50 mgA (3), which greatly exceeds the minimum inhibitory concentration for 90% of pathogens (MIC,) commonly associated with UTIs,such as Escherichia coli, other Enterobacteriaceae and Staphylococcus saprophyticus (4). The purpose of this study was t o compare the efficacy and safety of lomefloxacin administered once daily for 3 or 7 days to the comparable dose of norfloxacin administered twice daily for 7 days in the treatment of adult female outpatients with uncomplicated UTIs.
MATERIAL AND METHODS Study design Outpatients were randomly assigned to one of the 3 treatment regimens according to a computergenerated randomisation schedule: lomefloxacin400 mg once daily for 3 days (L3), lomefloxacin 400 mg once daily for 7 days (L7) or norfloxacin 400 mg twice daily for 7 days (N7). Double-blinding was assured by the double dummy technique. All patients received pouches of medication designated for morning and evening doses for 7 days. Patients in the lomefloxacin groups received 2 capsules of 200 mg active drug for the morning dose and 2 placebo capsules for the evening dose. The L3 group received placebo capsules for all doses after the third day. Patients in the norfloxacin group received 2 capsules of 200 mg norfloxacin for all doses.
Study population The study was conducted in 21 community health centers in 3 counties in southern Sweden. Female patients, 18-65 years of age, with symptomatic, uncomplicated lower UTIs were enrolled in the study between August 1988 and January 1990. Exclusion criteria were pregnancy, signs of upper UTI, septicaemia or concomitant infection that may have confused interpretation of therapy results, concomitant antimicrobial therapy, known impairment of kidney or liver function, history of allergy to quinolones, or convulsive disorder. Patients requiring a chronic indwelling catheter or having an ileal loop conduit were excluded, as well as patients who demonstrated a favourable response to previous antimicrobial therapy for this episode of infection. The study protocol was approved by the Swedish National Board of Health and Welfare and by the Ethics Committee of the Medical Faculty at the University of Lund. Patients were given oral and written information about the study and all provided informed consent.
Investigational methods Infections were classified as sporadic (< 2 previous episodes of UTI during the past 6 months or < 3 during the past year) or recurrent. Midstream urine samples were obtained for culture before the first dose, 5-9 days and 3 4 weeks post-treatment. Significant bacteriuria was defined as 2 lo4 colonyforming units (CFU)/ml urine. Isolated organisms were identified by standard procedures. Sensitivity testing was performed using a disk diffusion technique ( 5 ) . The breakpoint for resistance for both drugs was 16 mg/l. All bacterial strains isolated before, during and after treatment were kept for determina-
Lornefloxnciri vs norfloxacin in UVI 175
Scand J Infect Di5 24
Table I. Patient demographics Lomefloxacin 400 mg QD 3 days ( n = 235)
Scand J Infect Dis Downloaded from informahealthcare.com by Monash University on 11/02/14 For personal use only.
Median age, years (range) Type of UTI. “/o Sporadic Recurrent Symptoms present at start, YO Dysuria Frequency Urgency Suprapubic pain Hematuria
38 ( 17-65)
Lomefloxacin 400 mg OD 7 days (r1 = 241)
Norfloxacin 400 mg BID 7 days ( n = 227)
40 ( 17-75)
93 7
95 5
96 94 88 57 50
92 94 83 62
55
tion of minimal inhibitory concentrations (MICs) for lomefloxacin and norfloxacin by the agar dilution method. To differentiate relapses from reinfections similarity between strains o f E. coli was estimated by comparing their hehaviour in 16 biochemical tests in which strains of the species are known to differ. Serotyping was not carried out.
Bacteriologic evaluation The bacteriologic outcome was classified as eradication. initial pathogen eliminated (< lo4 CFU/ml) with no other pathogen isolated; persistence, initial pathogen not eliminated ( 2 10‘ CFUlml) during therapy or at first follow-up; relapse, initial pathogen eliminated (< 10‘CFU/ml) but later reisolated ( 2 10‘ CFU/ml); or reinfection. significant growth of a new pathogen ( 2 lo4 CFU/ml) after eradication of the original one (< lo4 CFU/ml). Results are given for short-term efficacy (results 5-9 days posttreatment) and accumulated efficacy (worst possible result up to 3 4 weeks post-treatment).
Clinical evaluation Clinical symptoms were recorded initially and at the follow-up visits. The clinical outcome was classified as cure (complete disappearance of all baseline symptoms). improvemen1 (satisfactory remission but one symptom remains with a maximum intensity of “mild”) or failure (either persistence. defined as signs and symptoms remaining, or recurrence, defined as improvement of signs and symptoms during treatment but reappearance after stopping treatment). If the result was considered a failure at 5-9 days post-treatment, the result was also considered a failure at -3-4 weeks post-treatment.
Safety evaluation All patients who had received at least 1 dose and for whom data were available were included in the analysis of adverse events. The information was derived by spontaneous statements by the patient during follow-up and after a non-leading question, “How have you felt since the start of treatment?”
Statistical analysis The study was designed to be able to detect a difference of 10% in cure rates between the treatment groups based on an estimated cure rate of 90% and a power of 80%. Treatment group comparisons were performed using chi-square tests and Fisher’s exact test and 95% confidence intervals for single proportions as well as for differences between proportions were calculated. Two-tailed p-values c 0.05 were considered statistically significant.
776 R. Neringer et al.
Scand J Infect DIs 24
Table 11. Bacteriologic outcome in % of patients in treatment groups (95% confidence intervals) Lomefloxacin 400 mg QD 3 days (n = 196)
Lomefloxacin 40(1 rng QD
7 days (n = 196)
Norfloxacin 400 rng BID 7 days (n = 195)
5-9 days post-treatment
Scand J Infect Dis Downloaded from informahealthcare.com by Monash University on 11/02/14 For personal use only.
Eradication Reinfection Persistence Unknown
88 (84-92) 4 8 0
93 (89-97) 4 3 1
93 (89-97) 2 3 3
82 (77-87) 10 8 1
85 (8(&90) 6 9 1
Accumulated results at 3-4 weeks post-treatment
Eradication Reinfection Relapse + persistence Unknown
81 (76-86) 5 14 1
RESULTS
Patients A total of 703 patients were enrolled and randomised to treatment groups. 235 patients were randomised to L3, 241 to L7, and 227 to N7. There were no differences in demographic parameters between the 3 treatment groups (Table I). The median age in the 3 groups was 38-40 years. The majority of UTIs were classified as sporadic. Dysuria and frequency were the most frequent symptoms, followed by urgency. Bacteriologic outcome Efficacy was assessed for patients with confirmed baseline pathogens with colony counts P 10' CFUlml. Bacteriologic outcome is shown in Table 11. Differences between the 3 treatment groups were not statistically significant. The 2-tailed 95% confidence intervals (CI) for the differences in eradication proportions were L3 vs L7 -0.051 (-0.109-0.007), L3 vs N7 -0.050 (-0.108-0.008) and L7 vs N7 0.002 (-0.050-0.052). The aetiology and outcome in relation to causative bacterial species are shown in Table 111. All baseline pathogens were evaluated as susceptible or intermediate to the study drugs by routine disc diffusion tests for antibiotic susceptibility. For E. coli, no differences in bacteriologic outcome between the treatment groups were seen. However, at 5-9 days, there was a statistically significant difference in eradication of S. saprophyticus between the L3 and the other groups (p = 0.0253). This difference did not persist in the accumulated results for elimination at 3-4 weeks post-treatment due to reinfections in the 7-day groups with predominantly E. coli, while n o relapses with S. saprophyticus were seen. N o persistent or recurrent pathogen developed resistance to the study drugs during treatment or during the follow-up period. No difference in bacteriological outcome was seen between the groups having intermediate colony counts (104-105 CFU/ml) and to those patients fulfilling the standard criterion for significant bacteriuria, i.e. 2 lo5 CFU/ml. This holds true also on the species level. MICs for norfloxacin and lomefloxacin were determined from initial cultures and fol-
Lomefloxacin
S a n d J Infect Dis 24
IJS
norfloxacin in UVI 777
Table 111. Bacteriologic outcome b y pathogens Eradication. ‘b Lomefloxacin 400 mg OD 3 days
Lomefloxacin 400 mg OD 7 days
89
95
15
91
93
90
100
70
Norfloxacin 400 mg BID 1 days
5-9 days post-treatment E. coli 148; 136; 136) S. saprophyticus ( n = 28; 29; 27) Other Gram-negatives ( n = 14; 20; 13) Other Gram-positives (ti = 6 ; 10; 15)
Scand J Infect Dis Downloaded from informahealthcare.com by Monash University on 11/02/14 For personal use only.
(PZ
=
Accumulated results 3-4 weeks post-treatment
E. coli ( n = 147; 135; 137) S. saprophyticus ( n = 28; 29; 29) Other Gram-negatives (n = 14: 20; 13) Other Gram-positives ( n = 6; 1 0 ; 15)
82
86
86
75
83
86
79
80
92
83
4(t
13
low-up cultures. The MIC values (agar dilution) for 472/487 (97%) E.coli strains were 0.0W.25 and 0.12-0.25 mg/l for norfloxacin and lomefloxacin. respectively. 15 (E. coli) strains (3%) were intermediate with MIC values between 2 4 (norfloxacin) and 4-8 mg/l (lomefloxacin). Regional differences were observed as 14 of these strains were isolated from 1 of the 3 counties (Kristianstad) where the study was conducted. This corresponds to 14% of all E. coli strains included in the study from this county. All intermediately sensitive E. coli strains were eradicated during treatment. The MIC values for other isolated pathogens were: Enterobacter 0.12, Klebsiella 0.12-0.25. S. saprophyticus 2 4 , S. aureus 0 . 5 4 , Streptococcus group B 4-8 and enterococci 4-8 mg/l for both norfloxacin and lomefloxacin.
Clinical outcome There were no differences in clinical outcome observed between the treatment groups. The clinical cure rates 5-9 days after treatment were 84 , 87 and 85% for the L3, L7 and N7 groups, respectively. Corresponding percentages for the P I week follow-up were 72,73 and 73.
Safety Adverse event data were recorded for all patients receiving 2 1 doses of study drug (Table IV). There was a statistically significant higher incidence of photosensitivity reactions in patients treated with lomefloxacin, most pronounced in the L7 group. The photosensitivity reactions caused 10/10 withdrawals in the L7 group, both withdrawals in the L3 group, and the only withdrawal in the N7 group. Five of the photosensitivity reactions in the L7 group
778 R. Neringer et al.
Scand J Infect Dis 24
Table IV. Adverse events occurring in 2 1% of patients regardless of attribution to treatment regimen
Scand J Infect Dis Downloaded from informahealthcare.com by Monash University on 11/02/14 For personal use only.
p-values are from Chi*-test or if expected values < 5 Fisher’s exact test Lomefloxacin 400 mg QD 3 days (n = 228) L3, %
Lomefloxacin 400 mg QD 7 days (n = 235) L7, ‘A
Norfloxacin 400 mg BID 7 days ( n ~ 2 2 3 N7, ) %
Any event” Any severe event Event causing withdrawalh
25
Lomefloxacin versus Norfloxacin in the Treatment of Un co mpIicat ed Urina ry Tract Inf ect io ns : T hree- Day v e rsus Seven-Day Treatment RUNE NERINGER', ARNE FORSGREN', CHRISTER HANSSON'. BJORN ODE4,+and THE SOUTH SWEDISH LOLEX STUDY GROUP
'
Scand J Infect Dis Downloaded from informahealthcare.com by Monash University on 11/02/14 For personal use only.
From the Deparrments of Infectious Diseases Central Hospital, Karlskronu. ' < 'etirrul Hospriul, Kristiansrad. 'General Hospital. Malmo und rhe ' 1)eparrrrretri 01 C'litrrcul Microbiology, General Hospital, Mulmo, Sweden This randomised, double-blind, multicenter study compared the safety and efficacy of lomefloxacin and norfloxacin in adult female outpatients with uncomplicated urinary tract infections. Patients were randomly assigned to one of 3 treatment groups: 400 mg lomefloxacin once daily for 3 days (L3), 400 mg lomefloxacin once daily for 7 days (L7), or 400 mg norfloxacin twice daily for 7 days (N7). A total of 703 patients (age 17-75 years) were enrolled at 21 investigative sites in southern Sweden. Clinical and microbiological evaluations were conducted at the start, 5-9 days and 3 4 weeks post therapy. Patients with quantitative urine cultures of 2 10' CFU/ml of a susceptible pathogen were considered evaluable for efficacy. Escherichia coli and Staphylococcus saprophyticus were the most commonly isolated pathogens. In both L3 and L7 groups, 196 patients and in the N7 group 195 patients met the criteria for efficacy evaluation. At the 5-9 day post-treatment evaluation, 88% of the pathogens were eradicated in the L3 group, 93% in the L7 group and 93% in the N7 group. At the 3 4 week post-treatment evaluation, 8l%, 82%, and 85% of urine cultures remained negative in the L3, L7, and N7 groups, respectively. No statistically significant differences between the 3 treatment groups were noted with the exception of eradication of S. saprophyticus. for which the 7 day courses were more effective at 4-9 days post treatment. No persistent pathogen developed resistance to the study drugs. All 3 treatment regimens were equally well tolerated, except for photosensitivity reactions, which were more frequently reported in patients in the lomefloxacin groups. R . Neringer, MD, Department of Infectious Diseases, Central Hospital, S-371 85 Karlskrona, Sweden
INTRODUCTION The duration of treatment in uncomplicated lower urinary tract infections UTIs in women has been discussed for at least a decade (1, 2). The discussions have focused o n short term treatment, including single-dose therapy. The advantages of single-dose or %day treatment seem obvious: better patient compliance, reduced costs and a reduced exposure to the drug. However, the advantages of a shorter duration of treatment could be outweighed if there is an unacceptable risk of treatment failure. Effective short-term treatment has been reported with several antimicrobial drugs in a number of clinical trials. However. many of these studies included too few patients to allow conclusions as to equivalence between the regimens studied. Differences among various antibiotics, in terms of both efficacy and safety, when used for
t Deceased SO'
Scand J Infect Dis Downloaded from informahealthcare.com by Monash University on 11/02/14 For personal use only.
774 R. Neringer et al.
Scand J Infect Dis 24
different treatment duration was noted by Norrby in a review ( 2 ) of 28 UTI trials. All antibiotics tested were less effective in eradicating bacteriuria used in a single-dose regimen than used for 1 3 days of treatment.This difference was most pronounced for beta-lactam antibiotics, which were more effective when administered for 2 5 days than when given as a 3-day course. Both single-dose and 3-day regimens of trimethoprimlsulfamethoxazolewere considerably more effective than beta-lactams given for the same duration. With trimethoprim/sulfamethoxazole no apparent therapeutic benefit in extending therapy past 3 days was noted; instead a higher frequency of adverse events were noted with the longer regimens. Thus, it is not possible to extrapolate results from one antibiotic to another. The efficacy and safety of each antimicrobial drug must be individually documented. Lomefloxacin is a new fluoroquinolone with excellent activity against a broad spectrum of Gram-negative and Gram-positive bacteria and a half-life sufficiently long to allow once-aday dosing. The concentration of lomefloxacin in urine during the 12-24 h period after a single oral dose of 400 mg is > 50 mgA (3), which greatly exceeds the minimum inhibitory concentration for 90% of pathogens (MIC,) commonly associated with UTIs,such as Escherichia coli, other Enterobacteriaceae and Staphylococcus saprophyticus (4). The purpose of this study was t o compare the efficacy and safety of lomefloxacin administered once daily for 3 or 7 days to the comparable dose of norfloxacin administered twice daily for 7 days in the treatment of adult female outpatients with uncomplicated UTIs.
MATERIAL AND METHODS Study design Outpatients were randomly assigned to one of the 3 treatment regimens according to a computergenerated randomisation schedule: lomefloxacin400 mg once daily for 3 days (L3), lomefloxacin 400 mg once daily for 7 days (L7) or norfloxacin 400 mg twice daily for 7 days (N7). Double-blinding was assured by the double dummy technique. All patients received pouches of medication designated for morning and evening doses for 7 days. Patients in the lomefloxacin groups received 2 capsules of 200 mg active drug for the morning dose and 2 placebo capsules for the evening dose. The L3 group received placebo capsules for all doses after the third day. Patients in the norfloxacin group received 2 capsules of 200 mg norfloxacin for all doses.
Study population The study was conducted in 21 community health centers in 3 counties in southern Sweden. Female patients, 18-65 years of age, with symptomatic, uncomplicated lower UTIs were enrolled in the study between August 1988 and January 1990. Exclusion criteria were pregnancy, signs of upper UTI, septicaemia or concomitant infection that may have confused interpretation of therapy results, concomitant antimicrobial therapy, known impairment of kidney or liver function, history of allergy to quinolones, or convulsive disorder. Patients requiring a chronic indwelling catheter or having an ileal loop conduit were excluded, as well as patients who demonstrated a favourable response to previous antimicrobial therapy for this episode of infection. The study protocol was approved by the Swedish National Board of Health and Welfare and by the Ethics Committee of the Medical Faculty at the University of Lund. Patients were given oral and written information about the study and all provided informed consent.
Investigational methods Infections were classified as sporadic (< 2 previous episodes of UTI during the past 6 months or < 3 during the past year) or recurrent. Midstream urine samples were obtained for culture before the first dose, 5-9 days and 3 4 weeks post-treatment. Significant bacteriuria was defined as 2 lo4 colonyforming units (CFU)/ml urine. Isolated organisms were identified by standard procedures. Sensitivity testing was performed using a disk diffusion technique ( 5 ) . The breakpoint for resistance for both drugs was 16 mg/l. All bacterial strains isolated before, during and after treatment were kept for determina-
Lornefloxnciri vs norfloxacin in UVI 175
Scand J Infect Di5 24
Table I. Patient demographics Lomefloxacin 400 mg QD 3 days ( n = 235)
Scand J Infect Dis Downloaded from informahealthcare.com by Monash University on 11/02/14 For personal use only.
Median age, years (range) Type of UTI. “/o Sporadic Recurrent Symptoms present at start, YO Dysuria Frequency Urgency Suprapubic pain Hematuria
38 ( 17-65)
Lomefloxacin 400 mg OD 7 days (r1 = 241)
Norfloxacin 400 mg BID 7 days ( n = 227)
40 ( 17-75)
93 7
95 5
96 94 88 57 50
92 94 83 62
55
tion of minimal inhibitory concentrations (MICs) for lomefloxacin and norfloxacin by the agar dilution method. To differentiate relapses from reinfections similarity between strains o f E. coli was estimated by comparing their hehaviour in 16 biochemical tests in which strains of the species are known to differ. Serotyping was not carried out.
Bacteriologic evaluation The bacteriologic outcome was classified as eradication. initial pathogen eliminated (< lo4 CFU/ml) with no other pathogen isolated; persistence, initial pathogen not eliminated ( 2 10‘ CFUlml) during therapy or at first follow-up; relapse, initial pathogen eliminated (< 10‘CFU/ml) but later reisolated ( 2 10‘ CFU/ml); or reinfection. significant growth of a new pathogen ( 2 lo4 CFU/ml) after eradication of the original one (< lo4 CFU/ml). Results are given for short-term efficacy (results 5-9 days posttreatment) and accumulated efficacy (worst possible result up to 3 4 weeks post-treatment).
Clinical evaluation Clinical symptoms were recorded initially and at the follow-up visits. The clinical outcome was classified as cure (complete disappearance of all baseline symptoms). improvemen1 (satisfactory remission but one symptom remains with a maximum intensity of “mild”) or failure (either persistence. defined as signs and symptoms remaining, or recurrence, defined as improvement of signs and symptoms during treatment but reappearance after stopping treatment). If the result was considered a failure at 5-9 days post-treatment, the result was also considered a failure at -3-4 weeks post-treatment.
Safety evaluation All patients who had received at least 1 dose and for whom data were available were included in the analysis of adverse events. The information was derived by spontaneous statements by the patient during follow-up and after a non-leading question, “How have you felt since the start of treatment?”
Statistical analysis The study was designed to be able to detect a difference of 10% in cure rates between the treatment groups based on an estimated cure rate of 90% and a power of 80%. Treatment group comparisons were performed using chi-square tests and Fisher’s exact test and 95% confidence intervals for single proportions as well as for differences between proportions were calculated. Two-tailed p-values c 0.05 were considered statistically significant.
776 R. Neringer et al.
Scand J Infect DIs 24
Table 11. Bacteriologic outcome in % of patients in treatment groups (95% confidence intervals) Lomefloxacin 400 mg QD 3 days (n = 196)
Lomefloxacin 40(1 rng QD
7 days (n = 196)
Norfloxacin 400 rng BID 7 days (n = 195)
5-9 days post-treatment
Scand J Infect Dis Downloaded from informahealthcare.com by Monash University on 11/02/14 For personal use only.
Eradication Reinfection Persistence Unknown
88 (84-92) 4 8 0
93 (89-97) 4 3 1
93 (89-97) 2 3 3
82 (77-87) 10 8 1
85 (8(&90) 6 9 1
Accumulated results at 3-4 weeks post-treatment
Eradication Reinfection Relapse + persistence Unknown
81 (76-86) 5 14 1
RESULTS
Patients A total of 703 patients were enrolled and randomised to treatment groups. 235 patients were randomised to L3, 241 to L7, and 227 to N7. There were no differences in demographic parameters between the 3 treatment groups (Table I). The median age in the 3 groups was 38-40 years. The majority of UTIs were classified as sporadic. Dysuria and frequency were the most frequent symptoms, followed by urgency. Bacteriologic outcome Efficacy was assessed for patients with confirmed baseline pathogens with colony counts P 10' CFUlml. Bacteriologic outcome is shown in Table 11. Differences between the 3 treatment groups were not statistically significant. The 2-tailed 95% confidence intervals (CI) for the differences in eradication proportions were L3 vs L7 -0.051 (-0.109-0.007), L3 vs N7 -0.050 (-0.108-0.008) and L7 vs N7 0.002 (-0.050-0.052). The aetiology and outcome in relation to causative bacterial species are shown in Table 111. All baseline pathogens were evaluated as susceptible or intermediate to the study drugs by routine disc diffusion tests for antibiotic susceptibility. For E. coli, no differences in bacteriologic outcome between the treatment groups were seen. However, at 5-9 days, there was a statistically significant difference in eradication of S. saprophyticus between the L3 and the other groups (p = 0.0253). This difference did not persist in the accumulated results for elimination at 3-4 weeks post-treatment due to reinfections in the 7-day groups with predominantly E. coli, while n o relapses with S. saprophyticus were seen. N o persistent or recurrent pathogen developed resistance to the study drugs during treatment or during the follow-up period. No difference in bacteriological outcome was seen between the groups having intermediate colony counts (104-105 CFU/ml) and to those patients fulfilling the standard criterion for significant bacteriuria, i.e. 2 lo5 CFU/ml. This holds true also on the species level. MICs for norfloxacin and lomefloxacin were determined from initial cultures and fol-
Lomefloxacin
S a n d J Infect Dis 24
IJS
norfloxacin in UVI 777
Table 111. Bacteriologic outcome b y pathogens Eradication. ‘b Lomefloxacin 400 mg OD 3 days
Lomefloxacin 400 mg OD 7 days
89
95
15
91
93
90
100
70
Norfloxacin 400 mg BID 1 days
5-9 days post-treatment E. coli 148; 136; 136) S. saprophyticus ( n = 28; 29; 27) Other Gram-negatives ( n = 14; 20; 13) Other Gram-positives (ti = 6 ; 10; 15)
Scand J Infect Dis Downloaded from informahealthcare.com by Monash University on 11/02/14 For personal use only.
(PZ
=
Accumulated results 3-4 weeks post-treatment
E. coli ( n = 147; 135; 137) S. saprophyticus ( n = 28; 29; 29) Other Gram-negatives (n = 14: 20; 13) Other Gram-positives ( n = 6; 1 0 ; 15)
82
86
86
75
83
86
79
80
92
83
4(t
13
low-up cultures. The MIC values (agar dilution) for 472/487 (97%) E.coli strains were 0.0W.25 and 0.12-0.25 mg/l for norfloxacin and lomefloxacin. respectively. 15 (E. coli) strains (3%) were intermediate with MIC values between 2 4 (norfloxacin) and 4-8 mg/l (lomefloxacin). Regional differences were observed as 14 of these strains were isolated from 1 of the 3 counties (Kristianstad) where the study was conducted. This corresponds to 14% of all E. coli strains included in the study from this county. All intermediately sensitive E. coli strains were eradicated during treatment. The MIC values for other isolated pathogens were: Enterobacter 0.12, Klebsiella 0.12-0.25. S. saprophyticus 2 4 , S. aureus 0 . 5 4 , Streptococcus group B 4-8 and enterococci 4-8 mg/l for both norfloxacin and lomefloxacin.
Clinical outcome There were no differences in clinical outcome observed between the treatment groups. The clinical cure rates 5-9 days after treatment were 84 , 87 and 85% for the L3, L7 and N7 groups, respectively. Corresponding percentages for the P I week follow-up were 72,73 and 73.
Safety Adverse event data were recorded for all patients receiving 2 1 doses of study drug (Table IV). There was a statistically significant higher incidence of photosensitivity reactions in patients treated with lomefloxacin, most pronounced in the L7 group. The photosensitivity reactions caused 10/10 withdrawals in the L7 group, both withdrawals in the L3 group, and the only withdrawal in the N7 group. Five of the photosensitivity reactions in the L7 group
778 R. Neringer et al.
Scand J Infect Dis 24
Table IV. Adverse events occurring in 2 1% of patients regardless of attribution to treatment regimen
Scand J Infect Dis Downloaded from informahealthcare.com by Monash University on 11/02/14 For personal use only.
p-values are from Chi*-test or if expected values < 5 Fisher’s exact test Lomefloxacin 400 mg QD 3 days (n = 228) L3, %
Lomefloxacin 400 mg QD 7 days (n = 235) L7, ‘A
Norfloxacin 400 mg BID 7 days ( n ~ 2 2 3 N7, ) %
Any event” Any severe event Event causing withdrawalh
25
