Journal of Antimicrobial Chemotherapy (2004) 54, 840843 DOI: 10.

1093/jac/dkh414 Advance Access publication 3 September 2004

JAC

Comparison of short-term treatment regimen of ciprooxacin versus long-term treatment regimens of trimethoprim/ sulfamethoxazole or noroxacin for uncomplicated lower urinary tract infections: a randomized, multicentre, open-label, prospective study
Luis Arredondo-Garc n1, Alejandro Rosas2, a1, Ricardo Figueroa-Damia Jose uregui3, Mauricio Corral4, Alexis Costa5, Roberto Mauricio Merlos6, Arturo Ja bile-Cuevas8*, Gerardo M. Herna ndez-Oliva9, os-Fabra7, Carlos F. Ama Antonio R n9, Oscar Carden osa-Guerra10 on behalf of the uUTI Latin American Study Group Jorge Olgu
1

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a, Mexico City; 2Hospital General de Me xico, Mexico City; 3Hospital Cl nica Instituto Nacional de Perinatolog 8 n Lusara, Apartado Postal 102-006, 08930, Mexico City; 9Bayer de Me xico, del Parque, Chihuahua; Fundacio n Me dica, Mexico City, Mexico; 4Hospital Eugenio Espejo, Quito; 5Hospital del Sur, Quito, Ecuador; Direccio 6 Hospital de Maternidad, San Salvador, El Salvador; 7Hospital Vargas de Caracas, Caracas, Venezuela; 10 mica Farmace utica Bayer, Barcelona, Spain Qu
Received 30 June 2004; accepted 24 July 2004

Objective: To compare the bacteriological and clinical efcacy of three treatments for uncomplicated cystitis in ambulatory pre-menopausal women: ciprooxacin 250 mg orally twice daily for 3 days, trimethoprim/sulfamethoxazole 160/800 mg orally twice daily for 7 days, and noroxacin 400 mg orally twice daily for 7 days. Materials and methods: A total of 455 women were randomly assigned to three treatment groups: 151 received ciprooxacin, 150 received trimethoprim/sulfamethoxazole, and 154 received noroxacin. Bacteriological cure and clinical resolution were evaluated 59 days and 46 weeks after completion of treatment. Results: There was no signicant difference among the three treatment groups: overall efcacy ranged from 78.5% for the trimethoprim/sulfamethoxazole group, to 84.5% for the ciprooxacin group. The highest overall incidence of drug-related adverse effects occurred in the trimethoprim/sulfamethoxazole patients. Conclusions: These data indicate that a 3 day treatment with ciprooxacin is at least as clinically and bacteriologically effective as 7 day treatments with trimethoprim/sulfamethoxazole and noroxacin for uncomplicated lower urinary tract infections. Keywords: uoroquinolones, clinical trials, cystitis, Latin America

Introduction
Uncomplicated urinary tract infections (UTIs) are among the most common bacterial infections seen in general practice in

women.1,2 Current management of these infections is made empirically, without any prior urine culture or susceptibility tests. The rationale for this approach is based on the narrow and predictable variety of pathogens and their susceptibility

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*Corresponding author. Tel/Fax: +52-55-52195855; E-mail: carlos.amabile@lusara.org n Cl nica, Instituto Nacional de Pediatr a, Mexico City, Mexico. Present address. Unidad de Apoyo a la Investigacio Present address. Hospital CIMA, Chihuahua, Mexico. Members of the uUTI Latin American Study Group are listed in the Acknowledgements.
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JAC vol.54 no.4 q The British Society for Antimicrobial Chemotherapy 2004; all rights reserved.

Short-term ciprooxacin for urinary tract infections

patterns.3 Therapy of UTIs has not changed signicantly during the last decade. However, shorter treatment regimens are preferred over the longer ones in terms of cost-effectiveness, patient compliance, and lower incidence of adverse events (AEs).2 In order to address the effectiveness of a short versus a long treatment regimen in an area where resistance to currently approved drugs for the treatment of UTI is increasing dramatically, we carried out a multicentre, randomized, open-label clinical trial to compare a short (3 day) versus a long (7 day) therapy regimen in ambulatory pre-menopausal women with acute uncomplicated cystitis.

Statistical approach and analysis

The primary efcacy analysis was carried out upon combined outcomes at EFU in the per protocol (PP) population. Two-sided 95% condence intervals of the differences between the success rates (ciprooxacin minus trimethoprim/sulfamethoxazole, and ciprooxacin minus noroxacin) were calculated with Mantel Haenszel weighting.5 For ciprooxacin to be considered as not less effective than any of the comparator drugs, the lower limit of each one of these condence intervals had to be greater than 10%. The three treatment groups were also assessed for homogeneity of their demographic and baseline medical characteristics. Adverse events and laboratory data were analysed by descriptive statistics.

Materials and methods

Study population
All patients were ambulatory pre-menopausal women, over 18 years of age, with a clinical diagnosis of acute uncomplicated cystitis. Patients were enrolled in 28 Latin American outpatient centres between July 1995 and June 1999: Mexico (9), Colombia (7), Ecuador (5), Venezuela (5), El Salvador (1) and Guatemala (1). Eligible patients should have experienced urinary clinical symptoms of infection for less than 10 days. A urine culture was done for every patient. Patients with structural or functional abnormalities of the genitourinary tract; with prior administration of any antibiotic within 30 days of enrolment or under treatment with immunosuppressive drugs; with a history of more than three UTIs during the previous 12 months; with vaginitis or cervicitis of any aetiology; with known or suspected liver or renal failure; with neutropenia of <1000 cells/mL; or with diabetes mellitus were not accepted to participate in this trial.

Results
A total of 455 patients were randomly assigned to the three treatment groups: 151 to the ciprooxacin group, 150 to the trimethoprim/sulfamethoxazole group, and 154 to the noroxacin group. All 455 randomized patients were valid for the safety analysis. Ninety-three patients were excluded, thus, a total of 362 patients were included in the intention-to-treat (ITT) analysis; 77 additional patients did not comply with criteria for the PP analysis, giving a total of 285, distributed evenly in the three treatment groups (97, 81 and 107 for the ciprooxacin, trimethoprim/sulfamethoxazole and noroxacin groups, respectively). All patients were female, primarily mestizo, mainly in their early thirties and with vital signs within normal ranges. There were no differences in the symptoms and signs of UTI among the patients in the three treatment groups. Dysuria was the most frequent symptom reported (>95%), followed by polyuria (>81%), tenesmus (>67%), and lower abdominal pain (>60%). The most frequently isolated microorganism was Escherichia coli: 185 isolates (64.9% of the PP population). Staphylococcus spp. (18.9%) and Proteus spp. (11.2%) accounted for most other isolates. There were no signicant differences between treatment groups (data not shown). Resistance/intermediate susceptibility were, for all isolates, 2%/2% for noroxacin, 15%/3% for trimethoprim/sulfamethoxazole (ranging from 8% resistant isolates in Venezuela, to 38% in Colombia), and 1%/5% for ciprooxacin; for E. coli isolates, 1.4%/0.9% for noroxacin, 18.3%/2.8% for trimethoprim/sulfamethoxazole, and 0.9%/2.3% for ciprooxacin. Evaluation of the PP population at EFU showed that 88.7% of the patients treated with ciprooxacin, 86.4% of those treated with trimethoprim/sulfamethoxazole, and 84.1% of those treated with noroxacin were successfully cured. Clinical cure at LFU remained similar in the ciprooxacin (83.5%), trimethoprim/ sulfamethoxazole (81.5%) and noroxacin (82.2%) treatment groups (Table 1). For the ITT population, clinical response at EFU was achieved in 84.7%, 72.0% and 79.4% of patients, and at LFU, 81.4%, 67.8%, and 78.6% of patients, for ciprooxacin, trimethoprim/sulfamethoxazole and noroxacin, respectively. Bacteriological cure was also measured at EFU (Table 1). For the bacteriology analysis at LFU, an analysis of the patients with bacterial cure at visit 2 and continued negative results at visit 3 was compared to those with reinfection or superinfection at visit 3. In the ITT population, equivalence between ciprooxacin (89.0% and 80.5% cure at EFU and LFU, respectively) and noroxacin (83.3% and 78.6%) was also observed, whereas

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Study procedures
This was a prospective, randomized, open-label clinical trial that included a selection visit, and two follow-up visits, as described below. Selection visit (visit 1). Prospective patients supplied their medical history and underwent a physical examination focusing on the signs and symptoms of urinary tract infection, routine haematological tests, urinalysis and a urine culture. Patients were randomly distributed to three treatment groups, as follows: Group 1: Ciprooxacin (Bayer, Mexico City, Mexico) 250 mg every 12 h for 3 days. Group 2: Trimethoprim/sulfamethoxazole (Roche, Mexico City, Mexico) 160/800 mg every 12 h for 7 days. Group 3: Noroxacin (Merck, Sharp and Dohme, Mexico City, Mexico) 400 mg every 12 h for 7 days. Comparator medication was conditioned and labelled accordingly in Bayer-Mexico facilities. Early follow-up (EFU) (5 9 days after treatment) and late followup (LFU) visits (4 6 weeks after treatment). Urinalysis and a urine culture were carried out in each. AEs, concomitant medications, and treatment compliance were recorded. Patients presenting persistent infection or superinfection were treated accordingly.

Microbiological methods
Urine collected at every visit was cultured to identify organisms present at a concentration of >105 cfu/mL using standard microbiological techniques,4 and antimicrobial susceptibility was tested by disc diffusion.

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a et al. J. L. Arredondo-Garc
Table 1. Clinicala and bacteriological response at EFU and LFU in PP population EFU ciprooxacin n (%) No. of patients Resolution Resolution rates estimated differenceb 95% condence interval Bacteriological cure Bacteriological rates estimated differenceb 95% condence interval 97 86 (88.7) 89 (91.8) SXT n (%) 81 70 (86.4) +3.4 5.3, 12.1 69 (85.2) +7.9 0.9, 16.6 noroxacin n (%) 107 90 (84.1) +3.5 5.2, 12.2 93 (86.9) +6.1 2.1, 14.2 ciprooxacin n (%) 97 81 (83.5) 81 (83.5) LFU SXT n (%) 81 66 (81.5) +3.9 6.3, 14.2 66 (81.5) +1.7 9.4, 14.8 noroxacin n (%) 107 88 (82.2) +2.1 7.6, 11.8 87 (81.3) +1.0 9.3, 11.4

SXT, trimethoprim/sulfamethoxazole. a Signs and symptoms of infection disappeared (resolution), persisted or reappeared (failure) or were not evaluable (indeterminate). Indeterminate and missing assessments were counted as non-success. b MantelHaenszel weighted difference.

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Table 2. Overall efcacy outcomea at EFU and LFU EFU ciprooxacin n (%) No. of patients Success Failure Indeterminate Success rates weighted differenceb 95% condence interval 97 81 (83.5) 14 (14.4) 2 (2.1) SXT n (%) 81 66 (81.5) 14 (17.3) 1 (1.2) +5.4 4.5, 15.3 noroxacin n (%) 107 84 (78.5) 17 (15.9) 6 (5.6) +4.6 5.1, 14.3 ciprooxacin n (%) 97 75 (77.3) 13 (13.4) 9 (9.3) LFU SXT n (%) 81 61 (75.3) 11 (13.6) 9 (11.1) +3.7 8.1, 15.4 noroxacin n (%) 107 86 (80.4) 7 (6.5) 14 (13.1) 2.4 13.2, 8.3

SXT, trimethoprim/sulfamethoxazole. a Bacteriological cure and clinical resolution = success; bacteriological persistence or superinfection and/or clinical failure = failure; indeterminate or missing evaluation = indeterminate. Indeterminate and missing assessments were counted as non-success. b MantelHaenszel weighted difference.

the difference between ciprooxacin and trimethoprim/ sulfamethoxazole (76.3% and 71.2%) suggests superiority of ciprooxacin at LFU. A combined clinical and bacteriological response was matched to obtain the overall efcacy outcome. For the PP population, the results were similar among the three treatment groups: 83.5%, 81.5% and 78.5% for EFU, and 77.3%, 75.3% and 80.4% for LFU, for ciprooxacin, trimethoprim/sulfamethoxazole and noroxacin, respectively (Table 2). When combining both visits, the efcacy result for ciprooxacin was 84.5%, compared with 79.0% (success rates difference of +5.4; 95% CI 6.0, 16.9) for trimethoprim/sulfamethoxazole and 78.5% (+4.9; 5.7, 15.5) for noroxacin. Twenty-ve patients (5.5%) presented with moderate to severe AEs during the duration of this study. Of these, 16 were assessed as drug-related (category 3). The predominant drugrelated AEs were dyspepsia, headache and dizziness. Patients receiving trimethoprim/sulfamethoxazole showed AEs more frequently (8.7%, compared to 4.0% of those receiving ciprooxacin and 3.9% of those receiving noroxacin), and those AEs were more frequently related to the drug (7.3%, compared

to 0.7% and 2.6% of ciprooxacin and noroxacin, respectively). However, since trimethoprim/sulfamethoxazole (as well as noroxacin) was administered for 7 days, it is possible that the more frequent AEs were simply the result of the extended treatment.

Discussion
Community-acquired UTIs are among the most common bacterial infections in healthy women with a normal urinary tract. During the last two decades, a large number of studies have stressed the advantages of a shorter regimen versus a longer regimen for the treatment of uncomplicated UTI. The clinical and bacteriological efcacies of shorter treatment regimens are equivalent to those achieved with a treatment regimen of 7 days or longer, but shorter regimens involve fewer side effects, lower costs, and better patient compliance.1,6 Our study demonstrated that a shorter course of ciprooxacin (twice daily for 3 days) was as effective a treatment as conventional trimethoprim/ sulfamethoxazole or noroxacin 7 day treatments for the therapy

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Short-term ciprooxacin for urinary tract infections

of acute uncomplicated cystitis in pre-menopausal women. These longer therapeutic schemes are often used in Latin American countries even nowadays, and were therefore chosen for the purposes of this study. Clinical and antibacterial efcacy of uoroquinolones has been extensively documented in short-course therapy of UTI.6,7 Treatment guidelines from the Infectious Diseases Society of America state that patients having an uncomplicated UTI should be treated empirically with trimethoprim/sulfamethoxazole, unless the resistance among community uropathogens exceeds 10 20%, in which case a uoroquinolone is recommended.8,9 Manges et al.10 state that UTI management becomes complicated due to the increasing incidence of infections caused by strains of E. coli that are resistant to commonly used antimicrobials. Although resistance to noroxacin and ciprooxacin is still low, it is becoming troublesome for countries like Mexico, where multiple-drug (ciprooxacin, ampicillin, trimethoprim/ sulfamethoxazole, chloramphenicol and tetracycline)11 resistance among community-acquired uropathogens was found in 20 out of 100 isolates. In conclusion, a 3 day treatment with ciprooxacin against community-acquired UTI was as effective clinically and microbiologically as longer treatments with trimethoprim/ sulfamethoxazole or noroxacin, with the inherent advantages of a shorter regimen. Despite the fact that trimethoprim/sulfamethoxazole is recommended as a rst-line drug by some guidelines used in various countries, our study showed that this medication is no longer as effective as it was considered some time ago. Careful prescription of the quinolone drugs should be made to avoid or at least delay fostering resistance, which is increasing day by day and becoming a worrisome problem. C. Erdmenger, E. Hidalgo Portillo, J.D. Solano; Colombia: eda, B.M. Santos, J.C. Mendoza Rocancio, J.R. Castan n; Ecuador: F. Cornejo Proan o, N. Paz y A.C. Jaramillo-Tobo o, F. Castellanos; Venezuela: B. Gallegos, M. Marcano, Min I. Arocha.

References
1. Jancel, T. & Dudas, V. (2002). Management of uncomplicated urinary tract infections. Western Journal of Medicine 176, 515. 2. Huang, E. S. & Stafford, R. S. (2002). National patterns in the treatment of urinary tract infections in women by ambulatory care physicians. Archives of Internal Medicine 162, 417. 3. Gupta, K., Hooton, T. M. & Stamm, W. E. (2001). Increasing antimicrobial resistance and the management of uncomplicated community-acquired urinary tract infections. Annals of Internal Medicine 135, 4150. 4. Pezzlo, M. (1992). Urine culture procedure. In Clinical Microbiology Procedures Handbook (Isenberg, H. D., Ed.), pp. 1.17.11.17.15. American Society for Microbiology, Washington, DC, USA. 5. Song, J. X. & Wassell, J. T. (2003). Sample size for K 2 2 tables in equivalence studies using Cochrans statistic. Controlled Clinical Trials 24, 378 89. 6. Iravani, A., Tice, A. D., McCarty, J. et al. (1995). Short-course ciprooxacin treatment of acute uncomplicated urinary tract infection in women. Archives of Internal Medicine 155, 485 94. 7. Auquer, F., Cordon, F., Gorina, E. et al. (2002). Single-dose ciprooxacin versus 3 days of noroxacin in uncomplicated urinary tract infections in women. Clinical Microbiology and Infection 8, 50 4. 8. Warren, J. W., Abrutyn, E., Hebel, J. R. et al. (1999). Guidelines for antimicrobial treatment of uncomplicated acute bacterial cystitis and acute pyelonephritis in women. Clinical Infectious Diseases 29, 745 58. 9. Kunin, C. M. (1994). Urinary tract infections in females. Clinical Infectious Diseases 18, 112. 10. Manges, A. R., Johnson, J. R., Foxman, B. et al. (2001). Widespread distribution or urinary tract infections caused by a multidrug-resistant Escherichia coli clonal group. New England Journal of Medicine 345, 100713. n-Bola n, I., Garc bile-Cuevas, C. F., et al. (1998). a, X., Ama 11. Nivo Phenotypic resistance patterns associated to ciprooxacin resistance in community uropathogenic strains from Mexico City, In Program and Abstracts of the 8th International Congress on Infectious Diseases, Boston, MA, 1998, p. 235. International Society for Infectious Diseases, Boston, MA, USA.

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Acknowledgements
This work was completed with nancial support from Bayer AG xico, SA de CV. (Germany) and Bayer de Me The uUTI Latin American Study Group members are as follows: Mexico: P. Leal del Rosal, J.A. Leal del Rosal, guez, J. Jaspersen Gastelum, A. Valle Gay, R.E. Urbina Rodr vez, R. Ortega Rosas, D. Akle, A. M. Leal, L. Aguirre Cha rrez Rubio, R. Orrantia Grad n, J.J. Ceja Torres y Gutie guez, C. Lara Pe rez Soto, D. Hurley, D. Sotres, R. Ponce Rodr n, R. Villanueva, J.J. Manrique; Guatemala: de Leon, I. Leo

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