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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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 59 days and 46 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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Materials and methods |
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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:
Early follow-up (EFU) (59 days after treatment) and late follow-up (LFU) visits (46 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 MantelHaenszel 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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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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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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Discussion |
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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 1020%, 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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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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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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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 x 2 tables in equivalence studies using Cochran's statistic. Controlled Clinical Trials 24, 37889.[CrossRef][ISI][Medline]
6 . Iravani, A., Tice, A. D., McCarty, J. et al. (1995). Short-course ciprofloxacin treatment of acute uncomplicated urinary tract infection in women. Archives of Internal Medicine 155, 48594.[Abstract]
7 . Auquer, F., Cordon, F., Gorina, E. et al. (2002). Single-dose ciprofloxacin versus 3 days of norfloxacin in uncomplicated urinary tract infections in women. Clinical Microbiology and Infection 8, 504.[CrossRef][ISI][Medline]
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, 74558.[ISI][Medline]
9 . Kunin, C. M. (1994). Urinary tract infections in females. Clinical Infectious Diseases 18, 112.[ISI][Medline]
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.
11 . Nivón-Bolán, I., García, X., Amábile-Cuevas, C. F., et al. (1998). Phenotypic resistance patterns associated to ciprofloxacin 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.