CONCISE COMMUNICATION

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1 CONCISE COMMUNICATION Single-dose ciprofloxacin versus 3 days of norfloxacin in uncomplicated urinary tract infections in women F. Auquer 1, F. Cordón 1, E. Gorina 2, J. C. Caballero 3, C. Adalid 1, J. Batlle 4 and the Urinary Tract Infection Study Group 1 Subdivisió d Atenció Primària, Institut Català de la Salut, Unitat Docent de Medicina de Família i Comunitària, c/santa Clara, Girona 17001, 2 Medical Department, Q.F. Bayer S.A. Barcelona, 3 Garraf Primary Rural Health Area, Barcelona, 4 Microbiology Laboratory, Josep Trueta Hospital, Girona, Spain Tel: þ Fax: þ p416ufcg@pstaclara.scs.es A double-blind, randomized controlled study to evaluate the efficacy and safety of a single dose of 500 mg of ciprofloxacin versus 3 days 400 mg twice-daily of norfloxacin in uncomplicated urinary tract infection in women was designed. Patients underwent four visits: baseline, and at 3, 7 and 28 days. The main efficacy variables were clinical and microbiological outcome at day 7. Analyses on both valid patients and intention-to-treat populations were performed. Two hundred and twenty-six patients (114 receiving ciprofloxacin and 112 receiving norfloxacin) were considered valid for efficacy evaluation. Bacteriologic cure was 91.2% in the ciprofloxacin group and 91.9% in the norfloxacin group. Clinical resolution was 91.2 and 93.8%, respectively. Both treatments were equally efficacious (P ¼ 0.016). Keywords ciprofloxacin, norfloxacin, urinary tract infection Accepted 1 August 2001 Clin Microbiol Infect 2002; 8: INTRODUCTION Twenty per cent of women will experience urinary infections during their lifetime. Although a number of single-dose antibacterial treatment studies [1 5] have shown efficacy in this indication, this approach is seldom used in primary healthcare, as it is perceived as a cause of relapse [4,6]. Single-dose treatments could have clear advantages over longer ones, including improved compliance, lower cost, fewer adverse effects and less probability of altering the normal flora and, thus, of inducing drug resistance [7]. Ciprofloxacin, due to its broad antibacterial spectrum and kinetic profile, with sustained urinary concentrations for over 24 h [8], is ideal for use in single-dose administration [5,9,10]. A multicenter, double-blind, double-dummy, randomized, controlled clinical trial was performed, comparing single-dose ciprofloxacin (500 mg) with 3 days of norfloxacin (400 mg) every 12 hours in uncomplicated urinary tract infections in women. PATIENTS AND METHODS Study population Women aged years attending primary care centers with symptoms of uncomplicated lower urinary tract infection (UTI), and positive dipstick (Multistix 10 SG; Ames Division Bayer Diagnostics, Slough, UK) and urine culture, were enrolled in the study, being randomly assigned to one of the study treatments. The exclusion criteria were: pregnancy or lactation, symptoms of UTI lasting for more than 7 days, recurrent UTI in the last year, allergy to quinolones, weight under 45 kg, background of abnormalities of the urinary tract, renal lithiasis, urinary catheters, renal or hepatic failure, suspicion of upper UTI, ongoing treatment with medications that could interfere with quinolones, having received antibiotic treatment in the 48 h prior to inclusion, and having participated in a clinical trial in the previous 30 days. ß 2002 Copyright by the European Society of Clinical Microbiology and Infectious Diseases

2 Concise Communication 51 A double-blind, double-dummy technique was used to mask the different number of tablets of each treatment. Informed consent was obtained before initiating any study tests. Bacterial eradication was considered successful when <10 5 CFU/mL of Gram-negative bacteria or <10 4 CFU/mL of Gram-positive bacteria were isolated in the culture at day 7. Urine collection and processing Mid-micturition urine samples were obtained using the clean-catch technique. Samples were analyzed by dipstick and immediately refrigerated (between 2 8C and 4 8C) for a maximum duration of 48 h in most cases, less than 24 h before being cultured in one of two centralized microbiology laboratories. Bacteriologic techniques Urine samples were cultivated on blood agar, CLED agar and MacConkey agar. Antibiograms, MIC 90 s and inhibitory zones were measured for both treatments. Bacteriuria was considered significant if 10 5 CFU/mL of Gram-negative or 10 4 CFU/mL of Gram-positive organisms were found. Visit schedule Patients were assessed at baseline and at 3, 7 and 28 days after treatment. The day 3 control included assessment of treatment compliance, exclusion of clinical symptomatology of upper UTI, evaluation of subjective clinical response, and a second dipstick analysis. On day 7, clinical evaluation and urine dipstick analysis and culture for microbiological assessment were performed. On day 28, clinical follow-up and microbiological assessment were carried out. Any adverse event was noted and investigated at each study visit. Sample size The sample size was calculated at 160 patients per treatment arm, including a 30% drop-out rate, allowing equivalence between treatments to be demonstrated at a level of 80% power. Definitions of clinical and microbiological success A patient was considered clinically cured (resolution) signs and symptoms of infection disappeared completely. Data analysis Homogeneity of baseline data and patient characteristics in the two treatment groups was analyzed by ANOVA for the continuous variables and by the w 2 -test for the categorical variables. For the principal analysis, estimates of the proportion of success in each of the two treatment groups were compared in a unilateral hypothesis test, based on the formula [11]: Z ¼ (P n P c 0.10)/SE, with SE ¼ [P n (1 P n )/N n þ P c (1 P c )/N c ] 1/2, where P n and P c are the proportions of successes in each treatment group, and N n and N c are the sample sizes. Efficacy was analyzed both for the patients considered valid, meeting all protocol requirements, and for the intention-to-treat population. All patients receiving at least one dose of either study medication were included in the safety analysis. This trial was performed in accordance with GCP guidelines and with the Declaration of Helsinki. Informed consent was obtained from all patients prior to their participation. This trial was also approved by each center s Ethical Committee and by the Spanish Ministry of Health. RESULTS Three hundred and twenty-five patients were randomized: 164 received ciprofloxacin, and 161 norfloxacin. Twelve cases were excluded because they did not attend the subsequent control visits. Of the remainder, 87 were considered invalid: in 71, there was no bacterial growth in the initial culture; in three, the cultures were contaminated; eight cases did not meet other diagnostic criteria; four cases did not comply with the therapeutic schedule; and, in one case, the symptoms had been present for more than 7 days. Thus, 226 patients were considered valid for the main efficacy analysis (114 receiving ciprofloxacin and 112 receiving norfloxacin). The most frequent microorganisms isolated in the initial culture were Escherichia coli in 153 patients (65.7%), Proteus mirabilis in 32 (13.7%), Enterococcus faecalis in 10 (4.3%), Proteus vulgaris in seven (3.0%), Staphylococcus saprophyticus in seven (3.0%), Staphylococcus epidermidis in six

3 52 Clinical Microbiology and Infection, Volume 8 Number 1, January 2002 (2.6%), and various other bacteria in the remaining 18 (7.7%). Tests for homogeneity of the baseline variables between the two treatment groups revealed no statistically significant differences in terms of symptoms and signs or in the urine culture analysis. The clinical follow-up on day 3 revealed that 74.6% of the patients receiving ciprofloxacin and 70.5% receiving norfloxacin were already asymptomatic; the remaining patients showed clinical improvement, and none was considered to be a clinical failure. At day 7, there was a similar distribution of the clinical response in both groups; clinical resolution was found in 104 of the 114 (91.2%) cases assigned to ciprofloxacin, and in 105 of the 112 (93.8%) assigned to norfloxacin (Figure 1). Microbiological resolution was found in 104 cases (91.2%) in the ciprofloxacin group and in 103 (92.0%) in the norfloxacin group. No patient was withdrawn due to in vitro resistance to norfloxacin or ciprofloxacin. The equivalence test resulted in a P-value of , rejecting the null hypothesis in favor of the alternative hypothesis of at least equivalence of the two treatments. As contemplated in the study design, the analysis was repeated using alternative tests based on the normal approach with and without correction for continuity. All tests yielded significant results in favor of the hypothesis of at least equivalence. In particular, the Dunnet Gent w 2 -test with correction for continuity gave a P- value of The point estimate establishing the difference in the proportion of successes between the two treatments (norfloxacin minus ciprofloxacin) was ¼ 2.52%, with a Figure 1 Clinical and microbiological responses at day 7. 95% confidence interval of , lower than the 10% value defined as the limit of equivalence in this study. Furthermore, analysis on the intentionto-treat population (n ¼ 313) gave the same results as found in the valid patient subpopulation; 91.5% for norfloxacin and 89.38% for ciprofloxacin, with a P-value of No differences in efficacy were found when analyzing the results stratified by the two most frequently isolated microorganisms, E. coli and P. mirabilis. At day 28, 97 of the 104 patients in the ciprofloxacin group remained asymptomatic. Of the seven remaining cases, six had recurrence of Table 1 Safety and tolerability: adverse events Patients with adverse events n (%) Intensity (%) Relation to study drug a Type of adverse event Ciprofloxacin 21 (12.7) Mild 76% 17 Gastrointestinal 14/17 Moderate 19% Other 3/17 b Severe 5% Norfloxacin 18 (11.3) Mild 65% 13 Gastrointestinal 8/13 Moderate 35% CNS 3/13 Other 2/13 c a No. of adverse events with possible or probable relation to study drug. CNS, central nervous system. b Vulvar itching (possible); Pyelonephritis (possible); Candidiasis (possible). c Pyelonephritis (possible); Candidiasis (possible).

4 Concise Communication 53 urinary symptoms with positive culture and one was lost to follow-up. In the norfloxacin group, 98 of the 103 patients remained asymptomatic; four had symptoms compatible with UTI and positive culture, and one patient was lost to follow-up. All patients receiving at least one dose of any study drug (n ¼ 324) entered the safety assessment (159 for norfloxacin and 165 for ciprofloxacin). The results are displayed in Table 1. DISCUSSION The results of this study show that both treatments are effective in the treatment of uncomplicated UTIs in women. The same conclusion may be drawn from analysis of the intention-to-treat population. The cure rates for ciprofloxacin and norfloxacin at day 7 (91.2 and 92%, respectively) were similar to those found in other studies [12,13]. No in vitro resistance to the test drugs was found in the initial cultures, in those cases in which cure was not achieved, or in subsequent re-infections or relapses. This has also been observed in other studies of single-dose treatment with fluoroquinolones [12,13]. This finding can be explained by the study exclusion criteria, and thus, by the relatively healthy background of the enrolled patients. Epidemiological studies performed in the same geographic areas which included a wider range of patient conditions revealed a low percentage of microbiological resistance to fluoroquinolones [14,15]. It is worth noting that this study has been conducted in line with regular primary care practice for a patient with clinical symptoms and a dipstick urine test compatible with an uncomplicated UTI; empirical treatment would normally be given without awaiting microbiological confirmation. Such patients would usually be treated empirically with norfloxacin for 3 days in accordance with the understanding that single-dose treatments increase the number of relapses due to a failure to eliminate the vaginal reservoir of coliforms [6,16]. In this study, no significant differences were found in the relapse rates after 4 weeks in the two groups being compared, challenging the above understanding. Some authors suggest that symptoms of uncomplicated UTI associated with 10 3 CFU/mL of uropathogens on urine culture establishes the diagnosis of uncomplicated UTI [17]. However, in this trial, the requirements were increased, particularly regarding the number of colonies in the cultures, in order to avoid the inclusion of patients without clear evidence of infection according to more stringent, widely accepted standards. This gave rise to a subgroup of patients with probable lower UTI but in whom, for whatever reason, the growth of microorganisms in the cultures did not reach the accepted limits. These patients were included, however, in the intention-to-treat analysis, giving the same conclusions. In contrast to other studies, we have not found differences in the efficacy of both study regimens for the subgroups of microorganisms with at least 10 isolated cases [18]. As previously described, both treatments were generally well tolerated [19,20]. Few adverse events were drug related, and most were mild. The most frequent adverse events were gastrointestinal, and all resolved. To summarize, although a literature review [21] revealed that single-dose treatments appear to be less effective than longer treatments with regard to bacterial eradication, the results of this study suggested that a single-dose treatment with ciprofloxacin was equally effective as a 3-day regimen with norfloxacin. Accordingly, we recommend the use of ciprofloxacin in single-dose treatment in uncomplicated UTI in women, due to ease of administration, low incidence of adverse affects, and lower cost than a 3-day treatment regimen. MEMBERS OF THE URINARY TRACT INFECTION STUDY GROUP The participant investigators in the Urinary Tract Infection Study Group who made patients available for the trial and were as follows. C. A. P. Salvador Maluquer: N. Salleras, C. Adalid, E. Simó, L. L. Vicenç, R. Meléndez, C. Corominas, M. Costa, C. Rodríguez, N. Payolà, P. Ferrer, F. Anguera. C. A. P. Roquetes: J. M. Benet, A. Pérez, J. Hernández, O. Figueres, J. Castro. C. A. P. Platja d Aro: J. Casablanca, F. Planelles, B. Lluch. A. B. S. Sant Feliu de Guixols: J. F. Rovira, L. Beltran, J. A. Bravo, J. Gay, I. Legazpi, R. L. L. Ortigosa, M. Ciurana, C. Armengol, L. Cinos, R. Herrero, M. Pujiula. A. B. S. Santa Coloma de Farners: N. Xifró, F. Barrot. A. B. S. Sarrià de Ter: R. Creus, P. Pérez, C. de Castro, E. Marco, J. Taberner. A. B. S. El Fondo Sta Coloma de Gramanet: M. J. Martinez Vicente, C. de Febrer, M. Corominola, M. del Pozo,

5 54 Clinical Microbiology and Infection, Volume 8 Number 1, January 2002 J. Font, C. Lisicio, A. Figueredo, J. Romero. A. B. S. La Jonquera: J. Isart, J. Domènech, J. Lecumberri, F. Iriarte. A. B. S. Torroella de Montgrí: C. González, J. Lafont, J. Vinyet, M. Vidal, C. Iglesias, A. Sáenz. ACKNOWLEDGEMENTS The trial was supported by a grant from Q. F. Bayer, S.A., Barcelona, Spain. REFERENCES 1. Fihn SD, Johnson C, Roberts PL, Running K, Stamm WE. Trimethoprim sulfamethoxazole for acute dysuria in women: a single-dose or 10-day course. Ann Intern Med 1988; 108: Guibert J, Capron MH, Giacomino A. Treatment of uncomplicated acute lower urinary tract infections in women: lomefloxacin versus pefloxacin. Presse Med 1996; 25: Iravani A. Multicenter study of single-dose and multiple-dose fleroxacin versus ciprofloxacin in the treatment of uncomplicated urinary tract infections. Am J Med 1993; 94(suppl 3): Leibovici L, Wysenbeek AJ. Single-dose antibiotic treatment for symptomatic urinary tract infections in women: a meta-analysis of randomized trials. QJ Med 1991; 285: Iravani A, Tice AD, McCarty J et al. Short-course ciprofloxacin treatment of acute uncomplicated urinary tract infection in women. The minimum effective dose. Arch Intern Med 1995; 155: Kunin CM. Urinary tract infections in females. Clin Infect Dis 1994; 18: Wolfson JS, Hooper DC. Bacterial resistance to quinolones: mechanisms and clinical importance. Rev Infect Dis 1989; 11(suppl 5): Brittain DC, Scully BE, McElrath MJ, Steinman R, Labthavikul P, Neu HC. The pharmacokinetics and serum and urine bactericidal activity of ciprofloxacin. J Clin Pharmacol 1985; 25: Andriole VT. Use of quinolones in treatment of prostatitis and lower urinary tract infections. Eur J Clin Microbiol Infect Dis 1991; 10: Van Poppel H, Chyský V, Hullmann R, Baert L. Clinical experience with ciprofloxacin in the treatment of urinary tract infections: a review. Infection 1988; 16: Blackwelder WC. Proving the null hypothesis in clinical trials. Control Clin Trials 1982; 3: Pfau A, Sacks TG. Single dose quinolone treatment in acute uncomplicated urinary tract infection in women. J Urol 1993; 149: Raz R, Rottensterich E, Hefter H, Kennes Y, Potasman I. Single-dose ciprofloxacin in the treatment of uncomplicated urinary tract infection in women. Eur J Clin Microbiol Infect Dis 1989; 8: Ponce de León Roca M, Caballero Doménech JC, Aguilar Sáchez M, León Sanromá M, Fenández Ferré ML. Infección urinaria extrahospitalaria actividad in vitro de trimetoprin y cotrimoxazol. Aten Primaria 1991; 8: Vinyes-Miralpeix A, Targa X. Urinary tract infections. Antibiotic hospital sensibility in Girona. Aten Primaria 1992; 10: Wilkei ME, Almond MK, Marsh FP. Diagnosis and management of urinary tract infection in adults. BMJ 1992; 305: Stamm WE. Criteria for the diagnosis of urinary tract infection and for the assessment of therapeutic effectiveness. Infection 1992; 20(suppl 3): Saginur R, Nicolle LE. Single dose compared with 3-day norfloxacin treatment of uncomplicated urinary tract infection in women. Canadian Infectious Diseases Society Clinical Trials Study Group. Arch Intern Med 1992; 152: Bailey RR. Single oral dose treatment of uncomplicated urinary tract infection in women. Chemotherapy 1996; 42(suppl 1): Schaeffer AJ, Anderson RU. Efficacy and tolerability of norfloxacin versus ciprofloxacin in complicated urinary tract infection. Urology 1992; 40: Warren JW, Abrutyn E, Hebel JR, Johnson JR, Schaeffer AJ, Stamm WE. Guidelines from the Infectious Diseases Society of America. Guidelines for Antimicrobial Treatment of Uncomplicated Acute Bacterial Cystitis and Acute Pyelonephritis in Women. Clin Infect Dis 1999; 29: