Single-Dose Ciprofloxacin Versus 3 Days of Norfloxacin in Uncomplicated Urinary Tract Infections in Women

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CONCISE COMMUNICATION

Single-dose ciprofloxacin versus 3 days of norfloxacin in uncomplicated urinary tract infections in women F. Auquer1, F. Cordoń1 , E. Gorina2, J. C. Caballero3, C. Adalid1, J. Batlle4 and the Urinary Tract Infection Study Group

1Subdivisio´ d’Atencio´ Prima`ria, Institut Catala` de la Salut, Unitat Docent de Medicina de Famı´lia i Comunita`ria, c/Santa Clara, 33–35 Girona 17001, 2Medical Department, Q.F. Bayer S.A. Barcelona, 3Garraf Primary Rural Health Area, Barcelona, 4Microbiology Laboratory, ‘Josep Trueta’ Hospital, Girona, Spain

Tel: þ34 972 20 00 04 Fax: þ34 972 20 39 18 E-mail: [email protected]

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: 50–54

INTRODUCTION PATIENTS AND METHODS Twenty per cent of women will experience urinary Study population infections during their lifetime. Although a num- Women aged 18–65 years attending primary care ber of single-dose antibacterial treatment studies centers with symptoms of uncomplicated lower [1–5] have shown efficacy in this indication, this urinary tract infection (UTI), and positive dipstick approach is seldom used in primary healthcare, as (Multistix 10 SG; Ames Division Bayer Diagnos- it is perceived as a cause of relapse [4,6]. Single-dose tics, Slough, UK) and urine culture, were enrolled treatments could have clear advantages over longer in the study, being randomly assigned to one of ones, including improved compliance, lower cost, the study treatments. The exclusion criteria were: fewer adverse effects and less probability of alter- pregnancy or lactation, symptoms of UTI lasting ing the normal flora and, thus, of inducing drug for more than 7 days, recurrent UTI in the last resistance [7]. Ciprofloxacin, due to its broad anti- year, allergy to quinolones, weight under 45 kg, bacterial spectrum and kinetic profile, with sus- background of abnormalities of the urinary tained urinary concentrations for over 24 h [8], is tract, renal lithiasis, urinary catheters, renal or ideal for use in single-dose administration [5,9,10]. hepatic failure, suspicion of upper UTI, ongoing A multicenter, double-blind, double-dummy, ran- treatment with medications that could interfere domized, controlled clinical trial was performed, with quinolones, having received antibiotic treat- comparing single-dose ciprofloxacin (500 mg) with ment in the 48 h prior to inclusion, and having 3 days of norfloxacin (400 mg) every 12 hours in participated in a clinical trial in the previous uncomplicated urinary tract infections in women. 30 days.

ß 2002 Copyright by the European Society of Clinical Microbiology and Infectious Diseases Concise Communication 51

A double-blind, double-dummy technique was Bacterial eradication was considered successful used to mask the different number of tablets of when <105 CFU/mL of Gram-negative bacteria or each treatment. Informed consent was obtained <104 CFU/mL of Gram-positive bacteria were iso- before initiating any study tests. lated in the culture at day 7.

Urine collection and processing Data analysis Mid-micturition urine samples were obtained Homogeneity of baseline data and patient char- using the clean-catch technique. Samples were acteristics in the two treatment groups was ana- analyzed by dipstick and immediately refrigerated lyzed by ANOVA for the continuous variables and by (between 2 8C and 4 8C) for a maximum duration of the w2-test for the categorical variables. For the prin- 48 h—in most cases, less than 24 h—before being cipal analysis, estimates of the proportion of suc- cultured in one of two centralized microbiology cess in each of the two treatment groups were laboratories. compared in a unilateral hypothesis test, based ¼ on the formula [11]: Z (Pn Pc 0.10)/SE, with ¼ þ 1/2 SE [Pn (1 Pn)/Nn Pc (1 Pc)/Nc] , where Bacteriologic techniques Pn and Pc are the proportions of successes in each Urine samples were cultivated on blood agar, treatment group, and Nn and Nc are the sample CLED agar and MacConkey agar. Antibiograms, sizes. Efficacy was analyzed both for the patients MIC90s and inhibitory zones were measured for considered valid, meeting all protocol require- both treatments. Bacteriuria was considered sig- ments, and for the intention-to-treat population. nificant if 105 CFU/mL of Gram-negative or All patients receiving at least one dose of either 104 CFU/mL of Gram-positive organisms were study medication were included in the safety found. analysis. This trial was performed in accordance with GCP guidelines and with the Declaration of Visit schedule Helsinki. Informed consent was obtained from Patients were assessed at baseline and at 3, 7 and all patients prior to their participation. This trial 28 days after treatment. The day 3 control included was also approved by each center’s Ethical Com- assessment of treatment compliance, exclusion of mittee and by the Spanish Ministry of Health. clinical symptomatology of upper UTI, evaluation of subjective clinical response, and a second dip- RESULTS stick analysis. On day 7, clinical evaluation and urine dipstick analysis and culture for microbio- Three hundred and twenty-five patients were ran- logical assessment were performed. On day 28, domized: 164 received ciprofloxacin, and 161 nor- clinical follow-up and microbiological assessment floxacin. Twelve cases were excluded because they were carried out. Any adverse event was noted did not attend the subsequent control visits. Of the and investigated at each study visit. remainder, 87 were considered invalid: in 71, there was no bacterial growth in the initial culture; in three, the cultures were contaminated; eight cases Sample size did not meet other diagnostic criteria; four cases The sample size was calculated at 160 patients per did not comply with the therapeutic schedule; and, treatment arm, including a 30% drop-out rate, in one case, the symptoms had been present for allowing equivalence between treatments to be more than 7 days. Thus, 226 patients were consid- demonstrated at a level of 80% power. ered valid for the main efficacy analysis (114 receiving ciprofloxacin and 112 receiving norfloxacin). The most frequent microorganisms isolated in Definitions of clinical and microbiological the initial culture were Escherichia coli in 153 success patients (65.7%), Proteus mirabilis in 32 (13.7%), A patient was considered clinically cured (resolu- Enterococcus faecalis in 10 (4.3%), Proteus vulgaris tion) signs and symptoms of infection disappeared in seven (3.0%), Staphylococcus saprophyticus in completely. seven (3.0%), Staphylococcus epidermidis in six

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(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 dis- tribution 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 Figure 1 Clinical and microbiological responses at day 7. was withdrawn due to in vitro resistance to norfloxacin or ciprofloxacin. The equivalence test resulted in a P-value of 95% confidence interval of 4.33–9.37, lower than 0.01632, rejecting the null hypothesis in favor of the 10% value defined as the limit of equivalence in the alternative hypothesis of at least equivalence of this study. Furthermore, analysis on the intention- the two treatments. As contemplated in the study to-treat population (n ¼ 313) gave the same results design, the analysis was repeated using alternative as found in the valid patient subpopulation; 91.5% tests based on the normal approach with and for norfloxacin and 89.38% for ciprofloxacin, with without correction for continuity. All tests yielded a P-value of 0.00536. significant results in favor of the hypothesis of at No differences in efficacy were found when least equivalence. In particular, the Dunnet–Gent analyzing the results stratified by the two most w2-test with correction for continuity gave a P- frequently isolated microorganisms, E. coli and P. value of 0.0062. The point estimate establishing mirabilis. the difference in the proportion of successes At day 28, 97 of the 104 patients in the cipro- between the two treatments (norfloxacin minus floxacin group remained asymptomatic. Of the ciprofloxacin) was 93.75 91.23 ¼ 2.52%, with a seven remaining cases, six had recurrence of

Table 1 Safety and tolerability: adverse events

Patients with adverse events Intensity Relation to Type of n (%) (%) study druga adverse event

Ciprofloxacin 21 (12.7) Mild 76% 17 Gastrointestinal 14/17 Moderate 19% Other 3/17b Severe 5% Norfloxacin 18 (11.3) Mild 65% 13 Gastrointestinal 8/13 Moderate 35% CNS 3/13 Other 2/13c aNo. of adverse events with possible or probable relation to study drug. CNS, central nervous system. bVulvar itching (possible); Pyelonephritis (possible); Candidiasis (possible). cPyelonephritis (possible); Candidiasis (possible).

ß 2002 Copyright by the European Society of Clinical Microbiology and Infectious Diseases, CMI, 8, 50–54 Concise Communication 53 urinary symptoms with positive culture and one in this trial, the requirements were increased, was lost to follow-up. In the norfloxacin group, particularly regarding the number of colonies in 98 of the 103 patients remained asymptomatic; the cultures, in order to avoid the inclusion of four had symptoms compatible with UTI and patients without clear evidence of infection ac- positive culture, and one patient was lost to cording to more stringent, widely accepted stan- follow-up. dards. This gave rise to a subgroup of patients with All patients receiving at least one dose of any probable lower UTI but in whom, for whatever study drug (n ¼ 324) entered the safety assessment reason, the growth of microorganisms in the cul- (159 for norfloxacin and 165 for ciprofloxacin). The tures did not reach the accepted limits. These results are displayed in Table 1. patients were included, however, in the intention-to-treat analysis, giving the same conclusions. In contrast to other studies, we have not found DISCUSSION differences in the efficacy of both study regimens The results of this study show that both treatments for the subgroups of microorganisms with at least are effective in the treatment of uncomplicated 10 isolated cases [18]. UTIs in women. The same conclusion may be As previously described, both treatments were drawn from analysis of the intention-to-treat generally well tolerated [19,20]. Few adverse population. The cure rates for ciprofloxacin and events were drug related, and most were mild. norfloxacin at day 7 (91.2 and 92%, respectively) The most frequent adverse events were gastroin- were similar to those found in other studies testinal, and all resolved. [12,13]. No in vitro resistance to the test drugs To summarize, although a literature review [21] was found in the initial cultures, in those cases revealed that single-dose treatments appear to be in which cure was not achieved, or in subsequent less effective than longer treatments with regard to re-infections or relapses. This has also been ob- bacterial eradication, the results of this study sug- served in other studies of single-dose treatment gested that a single-dose treatment with ciproflox- with fluoroquinolones [12,13]. This finding can be acin was equally effective as a 3-day regimen with explained by the study exclusion criteria, and thus, norfloxacin. Accordingly, we recommend the use by the relatively healthy background of the en- of ciprofloxacin in single-dose treatment in rolled patients. Epidemiological studies performed uncomplicated UTI in women, due to ease of in the same geographic areas which included a administration, low incidence of adverse affects, wider range of patient conditions revealed a low and lower cost than a 3-day treatment regimen. percentage of microbiological resistance to fluoroquinolones [14,15]. MEMBERS OF THE URINARY TRACT It is worth noting that this study has been con- INFECTION STUDY GROUP ducted in line with regular primary care practice for a patient with clinical symptoms and a dipstick The participant investigators in the ‘Urinary Tract urine test compatible with an uncomplicated UTI; Infection Study Group’ who made patients avail- empirical treatment would normally be given able for the trial and were as follows. C. A. P. without awaiting microbiological confirmation. Salvador Maluquer: N. Salleras, C. Adalid, E. Such patients would usually be treated empirically Simo´, L. L. Vicenç, R. Meleńdez, C. Corominas, with norfloxacin for 3 days in accordance with M. Costa, C. Rodrı´guez, N. Payola`, P. Ferrer, F. the understanding that single-dose treatments Anguera. C. A. P. Roquetes: J. M. Benet, A. Pe´rez, J. increase the number of relapses due to a failure Hernańdez, O. Figueres, J. Castro. C. A. P. Platja to eliminate the vaginal reservoir of coliforms d’Aro: J. Casablanca, F. Planelles, B. Lluch. A. B. S. [6,16]. In this study, no significant differences were Sant Feliu de Guixols: J. F. Rovira, L. Beltran, J. A. found in the relapse rates after 4 weeks in the two Bravo, J. Gay, I. Legazpi, R. L. L. Ortigosa, M. groups being compared, challenging the above Ciurana, C. Armengol, L. Cinos, R. Herrero, M. understanding. Pujiula. A. B. S. Santa Coloma de Farners: N. Xifro´, Some authors suggest that symptoms of uncom- F. Barrot. A. B. S. Sarria` de Ter: R. Creus, P. Pe´rez, plicated UTI associated with 103 CFU/mL of C. de Castro, E. Marco, J. Taberner. A. B. S. ‘El uropathogens on urine culture establishes the Fondo’ Sta Coloma de Gramanet: M. J. Martinez diagnosis of uncomplicated UTI [17]. However, Vicente, C. de Febrer, M. Corominola, M. del Pozo,

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J. Font, C. Lisicio, A. Figueredo, J. Romero. A. B. S. 10. Van Poppel H, Chysky´ V, Hullmann R, Baert L. La Jonquera: J. Isart, J. Dome`nech, J. Lecumberri, F. Clinical experience with ciprofloxacin in the treat- Iriarte. A. B. S. Torroella de Montgrı´: C. Gonza´lez, ment of urinary tract infections: a review. Infection J. Lafont, J. Vinyet, M. Vidal, C. Iglesias, A. Saénz. 1988; 16: 337–44. 11. Blackwelder WC. ‘Proving the null hypothesis’ in clinical trials. Control Clin Trials 1982; 3: 345–53. 12. Pfau A, Sacks TG. Single dose quinolone treatment ACKNOWLEDGEMENTS in acute uncomplicated urinary tract infection in The trial was supported by a grant from Q. F. women. J Urol 1993; 149: 532–4. Bayer, S.A., Barcelona, Spain. 13. Raz R, Rottensterich E, Hefter H, Kennes Y, Potasman I. Single-dose ciprofloxacin in the treatment of uncomplicated urinary tract infection REFERENCES in women. Eur J Clin Microbiol Infect Dis 1989; 8: 1040–2. 1. Fihn SD, Johnson C, Roberts PL, Running K, Stamm 14. Ponce de Leoń Roca M, Caballero Domeńech JC, WE. Trimethoprim–sulfamethoxazole for acute Aguilar Saćhez M, Leoń Sanroma´ M, Fenańdez dysuria in women: a single-dose or 10-day course. Ferre´ ML. Infeccioń urinaria extrahospitalaria acti- Ann Intern Med 1988; 108: 350–7. vidad in vitro de trimetoprin y cotrimoxazol. Aten 2. Guibert J, Capron MH, Giacomino A. Treatment of Primaria 1991; 8: 41–4. uncomplicated acute lower urinary tract infections 15. Vinyes-Miralpeix A, Targa X. Urinary tract infec- in women: lomefloxacin versus pefloxacin. Presse tions. Antibiotic hospital sensibility in Girona. Aten Med 1996; 25: 1271–5. Primaria 1992; 10: 22–6. 3. Iravani A. Multicenter study of single-dose and 16. Wilkei ME, Almond MK, Marsh FP. Diagnosis and multiple-dose fleroxacin versus ciprofloxacin in the management of urinary tract infection in adults. treatment of uncomplicated urinary tract infections. BMJ 1992; 305: 1137–41. Am J Med 1993; 94(suppl 3): 89–96. 17. Stamm WE. Criteria for the diagnosis of urinary 4. Leibovici L, Wysenbeek AJ. Single-dose antibiotic tract infection and for the assessment of therapeutic treatment for symptomatic urinary tract infections effectiveness. Infection 1992; 20(suppl 3): 151–4. in women: a meta-analysis of randomized trials. QJ 18. Saginur R, Nicolle LE. Single dose compared with Med 1991; 285: 43–57. 3-day norfloxacin treatment of uncomplicated 5. Iravani A, Tice AD, McCarty J et al. Short-course urinary tract infection in women. Canadian Infec- ciprofloxacin treatment of acute uncomplicated tious Diseases Society Clinical Trials Study Group. urinary tract infection in women. The minimum Arch Intern Med 1992; 152: 1233–7. effective dose. Arch Intern Med 1995; 155: 485–94. 19. Bailey RR. Single oral dose treatment of uncompli- 6. Kunin CM. Urinary tract infections in females. Clin cated urinary tract infection in women. Chemother- Infect Dis 1994; 18: 1–12. apy 1996; 42(suppl 1): 10–16. 7. Wolfson JS, Hooper DC. Bacterial resistance to 20. Schaeffer AJ, Anderson RU. Efficacy and tolerabil- quinolones: mechanisms and clinical importance. ity of norfloxacin versus ciprofloxacin in compli- Rev Infect Dis 1989; 11(suppl 5): 960–8. cated urinary tract infection. Urology 1992; 40: 8. Brittain DC, Scully BE, McElrath MJ, Steinman R, 446–9. Labthavikul P, Neu HC. The pharmacokinetics and 21. Warren JW, Abrutyn E, Hebel JR, Johnson JR, serum and urine bactericidal activity of ciproflox- Schaeffer AJ, Stamm WE. Guidelines from the acin. J Clin Pharmacol 1985; 25: 82–8. Infectious Diseases Society of America. Guidelines 9. Andriole VT. Use of quinolones in treatment of for Antimicrobial Treatment of Uncomplicated prostatitis and lower urinary tract infections. Eur J Acute Bacterial Cystitis and Acute Pyelonephritis Clin Microbiol Infect Dis 1991; 10: 342–50. in Women. Clin Infect Dis 1999; 29: 745–58.

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