JAC Advance Access originally published online on September 3, 2004
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Journal of Antimicrobial Chemotherapy 2004 54(4):840-843; doi:10.1093/jac/dkh414
JAC vol.54 no.4 © The British Society for Antimicrobial Chemotherapy 2004; all rights reserved
Comparison of short-term treatment regimen of ciprofloxacin versus long-term treatment regimens of trimethoprim/sulfamethoxazole or norfloxacin for uncomplicated lower urinary tract infections: a randomized, multicentre, open-label, prospective study
1 Instituto Nacional de Perinatología, Mexico City; 2 Hospital General de México, Mexico City; 3 Hospital Clínica del Parque, Chihuahua; 8 Fundación Lusara, Apartado Postal 102-006, 08930, Mexico City; 9 Bayer de México, Dirección Médica, Mexico City, Mexico; 4 Hospital Eugenio Espejo, Quito; 5 Hospital del Sur, Quito, Ecuador; 6 Hospital de Maternidad, San Salvador, El Salvador; 7 Hospital Vargas de Caracas, Caracas, Venezuela; 10 Química Farmacéutica Bayer, Barcelona, Spain
Received 30 June 2004; accepted 24 July 2004
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Abstract |
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Objective: To compare the bacteriological and clinical efficacy of three treatments for uncomplicated cystitis in ambulatory pre-menopausal women: ciprofloxacin 250 mg orally twice daily for 3 days, trimethoprim/sulfamethoxazole 160/800 mg orally twice daily for 7 days, and norfloxacin 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 ciprofloxacin, 150 received trimethoprim/sulfamethoxazole, and 154 received norfloxacin. Bacteriological cure and clinical resolution were evaluated 5–9 days and 4–6 weeks after completion of treatment.
Results: There was no significant difference among the three treatment groups: overall efficacy ranged from 78.5% for the trimethoprim/sulfamethoxazole group, to 84.5% for the ciprofloxacin 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 ciprofloxacin is at least as clinically and bacteriologically effective as 7 day treatments with trimethoprim/sulfamethoxazole and norfloxacin for uncomplicated lower urinary tract infections.
Keywords: fluoroquinolones , clinical trials , cystitis , Latin America
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Introduction |
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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 patterns.3 Therapy of UTIs has not changed significantly 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.
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Materials and methods |
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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.
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: Ciprofloxacin (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: Norfloxacin (Merck, Sharp and Dohme, Mexico City, Mexico) 400 mg every 12 h for 7 days.
- Group 2: Trimethoprim/sulfamethoxazole (Roche, Mexico City, Mexico) 160/800 mg every 12 h for 7 days.
Early follow-up (EFU) (5–9 days after treatment) and late follow-up (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.
Statistical approach and analysis
The primary efficacy analysis was carried out upon combined outcomes at EFU in the per protocol (PP) population. Two-sided 95% confidence intervals of the differences between the success rates (ciprofloxacin minus trimethoprim/sulfamethoxazole, and ciprofloxacin minus norfloxacin) were calculated with Mantel–Haenszel weighting.5 For ciprofloxacin to be considered as not less effective than any of the comparator drugs, the lower limit of each one of these confidence 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.
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Results |
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A total of 455 patients were randomly assigned to the three treatment groups: 151 to the ciprofloxacin group, 150 to the trimethoprim/sulfamethoxazole group, and 154 to the norfloxacin 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 ciprofloxacin, trimethoprim/sulfamethoxazole and norfloxacin 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 significant differences between treatment groups (data not shown). Resistance/intermediate susceptibility were, for all isolates, 2%/2% for norfloxacin, 15%/3% for trimethoprim/sulfamethoxazole (ranging from 8% resistant isolates in Venezuela, to 38% in Colombia), and 1%/5% for ciprofloxacin; for E. coli isolates, 1.4%/0.9% for norfloxacin, 18.3%/2.8% for trimethoprim/sulfamethoxazole, and 0.9%/2.3% for ciprofloxacin.
Evaluation of the PP population at EFU showed that 88.7% of the patients treated with ciprofloxacin, 86.4% of those treated with trimethoprim/sulfamethoxazole, and 84.1% of those treated with norfloxacin were successfully cured. Clinical cure at LFU remained similar in the ciprofloxacin (83.5%), trimethoprim/sulfamethoxazole (81.5%) and norfloxacin (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 ciprofloxacin, trimethoprim/sulfamethoxazole and norfloxacin, respectively.
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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 ciprofloxacin (89.0% and 80.5% cure at EFU and LFU, respectively) and norfloxacin (83.3% and 78.6%) was also observed, whereas the difference between ciprofloxacin and trimethoprim/sulfamethoxazole (76.3% and 71.2%) suggests superiority of ciprofloxacin at LFU.
A combined clinical and bacteriological response was matched to obtain the overall efficacy 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 ciprofloxacin, trimethoprim/sulfamethoxazole and norfloxacin, respectively (Table 2). When combining both visits, the efficacy result for ciprofloxacin 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 norfloxacin.
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Twenty-five 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 drug-related AEs were dyspepsia, headache and dizziness. Patients receiving trimethoprim/sulfamethoxazole showed AEs more frequently (8.7%, compared to 4.0% of those receiving ciprofloxacin and 3.9% of those receiving norfloxacin), and those AEs were more frequently related to the drug (7.3%, compared to 0.7% and 2.6% of ciprofloxacin and norfloxacin, respectively). However, since trimethoprim/sulfamethoxazole (as well as norfloxacin) was administered for 7 days, it is possible that the more frequent AEs were simply the result of the extended treatment.
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Discussion |
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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 efficacies 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 ciprofloxacin (twice daily for 3 days) was as effective a treatment as conventional trimethoprim/sulfamethoxazole or norfloxacin 7 day treatments for the therapy 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 efficacy of fluoroquinolones 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 fluoroquinolone 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 norfloxacin and ciprofloxacin is still low, it is becoming troublesome for countries like Mexico, where multiple-drug (ciprofloxacin, 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 ciprofloxacin against community-acquired UTI was as effective clinically and microbiologically as longer treatments with trimethoprim/sulfamethoxazole or norfloxacin, with the inherent advantages of a shorter regimen. Despite the fact that trimethoprim/sulfamethoxazole is recommended as a first-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.
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Acknowledgements |
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This work was completed with financial support from Bayer AG (Germany) and Bayer de México, SA de CV.
The uUTI Latin American Study Group members are as follows: Mexico: P. Leal del Rosal, J.A. Leal del Rosal, R.E. Urbina Rodríguez, J. Jaspersen Gastelum, A. Valle Gay, M. Leal, L. Aguirre Chávez, R. Ortega Rosas, D. Akle, A. Torres y Gutiérrez Rubio, R. Orrantia Gradín, J.J. Ceja Rodríguez, C. Lara Pérez Soto, D. Hurley, D. Sotres, R. Ponce de Leon, I. León, R. Villanueva, J.J. Manrique; Guatemala: C. Erdmenger, E. Hidalgo Portillo, J.D. Solano; Colombia: J.C. Mendoza Rocancio, J.R. Castañeda, B.M. Santos, A.C. Jaramillo-Tobón; Ecuador: F. Cornejo Proaño, N. Paz y Miño, F. Castellanos; Venezuela: B. Gallegos, M. Marcano, I. Arocha.
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Footnotes |
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* Corresponding author. Tel/Fax: +52-55-52195855; Email: carlos.amabile{at}lusara.org
Present address. Unidad de Apoyo a la Investigación Clínica, Instituto Nacional de Pediatría, Mexico City, Mexico. 
Present address. Hospital CIMA, Chihuahua, Mexico.
Members of the uUTI Latin American Study Group are listed in the Acknowledgements.
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References |
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