Session Vl L. E. Nicolle
Prophylaxis: Recurrent Urinary Tract Infection in Women Summary: Long-term, low-dose antimicrobial prophylaxis is effective for the prevention of acute uncomplicated, urinary tract infection in women. Selected new antimicrobials should be assessed to determine their efficacy for this clinical use. Recommended guidelines for future studies of prophylactic therapy need to address several issues. The study population must be limited to women with recurrent symptomatic uncomplicated urinary tract infection. Antimicrobials studied should be excreted in the urine, with an in vitro spectrum that includes the common uropathogens. An extended half-life may be beneficial. Monitoring during the study should include monthly urine cultures and vaginal, periurethral and rectal colonization studies. The primary outcome measurement is symptomatic urinary tract infection. Secondary outcomes would include asymptomatic bacteriuria, adverse antimicrobial effects, colonization with potential uropathogens, and development of resistance. The comparative regimen should be one of the current standard regimens, trimethoprim/ sulphamethoxazole, nitrofurant0in, or trimethoprim.
Zusammenfassung:Prophylaxe der rezidivierenden Hamwegsinfektion bei Frauen. Langdauernde niedrig dosierte Antibiotikaprophylaxe kann akute unkomplizierte Harnwegsinfektionen (HWI) bei Frauen verhindern. Dazu geeignete neue Antibiotika sollten auf ihre klinische Wirksamkeit untersucht werden. Die for kfinftige Studien empfohlenen Richtlinien sollten verschiedene Gesichtspunkte beachten. Die untersuchte Gruppe sollte nur Patientinnen mit rezidivierenden HWI einschlieBen. Die Antibiotika sollten fiber den Urin ausgeschieden werden, wobei das in vitro Spektrum die fiblichen Erreger von HWI effassen sollte. Eine verl~ngerte Halbwertszeit mag dabei gfinstig sein. Die Untersuchungen w~ihrend der Studie sollten monatliche Urinkulturen sowie Studien zur vaginalen, periurethralen und rektalen Kolonisation beinhalten. Das Hauptuntersuchungsziel ist die symptomatische HWI. Weitere Untersuchungsziele beinhalten die asymptomatische Bakteriurie, antibakterielle Nebenwirkungen, die Kolonisation mit potentiell uropathogenen Erregern und die Resistenzentwicklung. Zur Kontrolle sollte eine der g/ingigen Standardbehandlungen herangezogen werden, Trimethoprim/Sulfamethoxazol, Nitrofurantoin oder Trimethoprim.
recurrent urinary infection are both genetic and behavourial. Women who are nonsecretors of blood group substances have an increased occurrence of recurrent urinary infection [2], and women with recurrent infection have an increased frequency of urinary infection in first degree female relatives [3]. In addition, Escherichia coli, the most common uropathogen, adheres more readily to epithelial cells in women with recurrent infection [4,5]. Behavourial factors associated with recurrent urinary infection include sexual activity, with a particularly high risk in those who use spermicides as a birth control method [6-9]. Individual episodes of acute uncomplicated urinary infection are easily treated. Short courses of a single dose or three days of antimicrobial therapy are generally successful and are the recommended therapeutic regimens [9]. The major management problem for patients with acute uncomplicated urinary infection is the frequency of recurrence [10,11]. Reinfection rates are highly variable and, at present, not predictable. Some women have multiple, very closely spaced recurrent infections, whereas others will have recurrent infection separated by infection-free periods of months or years.
Prophylactic Regimens One approach repeatedly documented to be effective for the management of recurrent uncomplicated urinary infection is the prevention of infection through the use of long-term, low-dose prophylactic antimicrobials taken at bedtime [12]. A summary of different regimens is given in Table 1. Generally, the occurrence of infections is decreased by 95% by the use of prophylaxis. The initial duration of prophylactic therapy is usually six months or Table 1: Antimicrobial regimens of documented prophylactic efficacy for prevention of acute uncomplicated urinary infection in women.
Standard regimens* Trimethoprim/sulphamethoxazole Trimethoprim Nitrofurantoin Nitrofurantoin macrocrystals Others Cephalexin Norfloxacin
40/200 mg/dayor three times weekly 100 rag/day 50 mg/day 100 mg/day 125 or 250 mg/day 200 rag/day
* Taken at bedtime.
Background Between 1O and 20% of women experience recurrent uncomplicated urinary infection [1]. Risk factors for
Lindsav E. Nicolte, M. D., FRCPC, Dept. of Medical Microbiology, University of Manitoba, MS-675 D, Health Sciences Centre, 820 Sherbrook Street, Winnipeg, Manitoba R 3A 1R9, Canada.
Infection 20 (1992) Suppl. 3 © MMV Medizin Verlag GmbH Miinchen, Miinchen 1992
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L. E. Nicolle: Prophylaxis of Uncomplicated Urinary Tract Infection one year. However, for co-trimoxazole, continuous prophylaxis for as long as two [13] or five years [14] has remained efficacious. Prophylaxis does not appear to modify the natural history of recurrent urinary infection. When discontinued, even after extended periods, approximately 60% of women will reinfect within three to four months. Prophylactic antimicrobials appear to be effective through at least two mechanisms. Some antimicrobials eradicate the aerobic gram-negative flora of the gut which serves as the principal reservoir for urinary infection. This is the case for co-trimoxazole [15] and norfloxacin [16]. Nitrofurantoin, however, is as effective for the prophylaxis of acute uncomplicated urinary infection as these agents, but has minimal impact on the gut flora [15]. It appears to be efficacious through the intermittent sterilization of the urine. Thus, both urinary concentration and suppressive effect on gram-negative gut flora may be considered predictors of potential prophylactic efficacy. An alternate prophylactic approach to continuous low-dose antimicrobial therapy is post-intercourse prophylaxis for women in whom episodes of infection are associated with sexual intercourse [17,18]. This has not been so well studied. However, the limited data available and considerable therapeutic experience support this as an alternative approach.
Problems and Remaining Issues In compliant patients, the failure of prophylactic therapy is usually due to the acquisition of gut, vaginal, and periurethral flora resistant to the prophylactic antimicrobial [12]. These resistant organisms may then serve as a reservoir for urinary infection. It is of note, however, that while uropathogens generally emerge from the colonizing flora of the gut and genitourinary tract, identification of colonization has not, to date, been shown to be predictive of infection. Thus, the efficacy of prophylaxis will be related to and limited by the prevalence of resistant organisms in the community. This has been well documented for trimethoprim, in particular, where it has been shown not to be an effective regimen in a community with a high prevalence of trimethoprim resistance [19,20]. Antimicrobiat resistance in a population is dynamic, and the emergence of colonizing organisms resistant to commonly used outpatient antimicrobials would be anticipated. Thus, there is a need for ongoing monitoring and assessment of the efficacy of prophylaxis as it relates to community levels of antimicrobial resistance. Newly marketed antimicrobials which appear likely to be effective for prophylaxis should be tested individually to determine their respective roles in prophylactic therapy. Finally, issues with respect to the minimum effective dosage regimen of antimicrobial therapy still need to be addressed. Cost and adverse effects are related to the dose given. However, lower antimicrobial doses may also be S 204
associated with an increased emergence and colonization with resistant organisms. Thus, while tong-term, low-dose prophylactic antimicrobial therapy has been well studied and is of documented efficacy, there is a need for continuing clinical trials to further refine therapy and test the efficacy of newer antimicrobials.
Clinical Evaluation of Drug Efficacy Requirements for future studies examining prophylactic antimicrobial therapy would include: Study population: A defined patient population of women with recurrent symptomatic uncomplicated urinary infection. The potential of a subject for enrolment into the study should be identified on the basis of the frequency of infection in the recent past. A useful rule is two infections in the previous six months or three within the previous 12 months. Women should not be excluded on the basis of age. However, stratification on the basis of age should be considered in the analysis. The appropriate cut-off age for this stratification - 40 years, 50 years or 60 years - is not clear. Therapeutic regimens: Oral antimicrobials appropriate for study would include those with the following characteristics: (I) excreted primarily in the urine as an active drug; (II) associated with eradication of gram-negative flora from the gut without significant impact on the anaerobic flora; (III) an extended half-life, to facilitate minimal dosing; (IV) an /n vitro spectrum effective for common uropathogens (E. coli, Staphylococcus saprophyticus, Klebsiellapneumoniae, Proteus mirabilis). Whether there is any benefit for agents that include Enterococcusfaecalis or other gram-positive organisms in their spectrum is not clear at present. Monitoring: Study subjects should be monitored for urinary symptoms and bacteriuria, potential adverse effects of antimicrobials, and colonization of the gut, periurethral area and vagina with potential uropathogens. Post-therapy follow-up at one and three months should be obtained as most reinfections wilt occur by three months. Further post-prophylaxis monitoring would not be warranted unless a specific study question is whether the prophylactic regimen has an impact on long-term post-prophylaxis infection frequency. Outcome measurements: I) The primary outcome parameter must be the occurrence of s)~nptomatic urinary infection. This may be expressed as a life table analysis to time of first symptomatic infection, or differences in incidence between study groups. II) Secondary outcome parameters to be analyzed would include asymptomatic bacteriuria, occurrence of adverse antimicrobial effects, and colonization with potential uropathogens, including those resistant to the prophylactic agent.
Infection 20 (1992) Suppl. 3 © MMV Medizin VerlagGmbH Mfinchen, Mfinchen 1992
L. E. Nicolle: Prophylaxis of Uncomplicated Urinary Tract Infection
Comparative regimen: As the efficacy of prophylactic therapy is well documented for a number of different regimens, a placebo study arm is likely to be unethical. The comparative arm • should be one of the accepted standard regimens such as trimethoprim/ sulphamethoxazole 40/200 mg daily or three times weekly,
References 1. Sanford, J. P.: Urinary tract symptoms and infection. Ann. Rev. Med. 26 (1975) 485.
2. Kinane, D. F, Blaekwell, C. C., Brettle, R. P., Weir, D. M, Winstanley, F. P , Eltor, IL A.: ABO blood group, secretor state and susceptibility to recurrent urinary tract infection in women. Br. Med. J. 285 (1982) 7. 3. Fennell, R. S, Wilson, S. G., Garin, E. H., Pryor, N. D., Sorgen, C. P , Walker, R. D., Richard, G. A.: Bacteriuria in families of girls with recurrent bacteriuria. Clin. Pediatr. 16 (1977) 1132. 4. Schaeffer, A. J., Jones, J., Dunn, J. K.: Association of in vitro Escherichia coli adherence to vaginal and buccal epithelial cells with susceptibility of women to recurrent urinary tract infections. N. Engl. J. Med. 304 (1981) 1062-1066.
5. Kozody, N. L, Harding, G. K. M., Nicolle, L E., Kelly, K., Ronald, A. R.: Adherence of Escherichia coli to epithelial cells in the pathogenesis of urinary tract infection. Clin. Invest. Med. 8 (1985) 121- 125. 6. Nieolle, L E., Hardin, G. IL M., Preiksaitis, J , Ronald, A. It.: The association of urinary tract infection with sexual intercourse. J. Infect. Dis. 146 (1982) 579-583. 7. Foxman, B., Freriehs, IL It.: Epidemiology of urinary tract infections: I. Diaphragm use and sexual intercourse. Amer. J. Public Health 75 (1985) 1308-1313.
8. Fihn, S. D., Latham, R. H., Roberts, P., Running, K., Stamm, W. E.: Association between diaphragm use and urinary tract infection. JAMA 254 (1985) 240-245. 9. Johnson, J. R., Stature, W. E.: Diagnosis and treatment of acute urinary tract infections. Infect. Dis. Clin. North Am. 1 (1987) 773791. 10. Kraft, J. I¢_, Stamey, T. A.: The natural history of symptomatic recurrent bacteriuria in women. Medicine 56 (1977) 55--60. 11. Stature, W. E, McKevitt, M, Roberts, P. L., White, N. J.: Natural
trimethoprim 100 mg daily, or nitrofurantoin 50 mg or, as macrocrystals, 100 mg daily. The remarkable effectiveness of antimicrobial prophylaxis means that, when comparing new antimicrobial agents to standard therapy, large study numbers may be required to demonstrate a difference in outcome measured by symptomatic infection.
history of recurrent urinary tract infections in women. Rev. Infect. Dis. 13 (t99t) 77-84. 12. Nieolle, L E., Ronaid, A. R.: Recurrent urinary tract infection in adult women: diagnosis and treatment. Inf. Dis. Clin. North Am. 1 (1987) 793-806.
13. Harding, G. K. M., Ronald, A. R. Nieolle, L. E., Thomson, M. J., Gray, G. J.: Long-term antimicrobial prophylaxis for recurrent urinary tract infection in women. Rev. Infect. Dis 4 (1982) 438-443. 14. Nicoile, L E., Harding, G. K. M., Thomson, M, Kennedy, J., Urias, B., Ronald, A. R.: Efficacy of five ),ears of continuous low dose cotrimoxazole prophylaxis for prevention of urinary tract infection. J. Infect. Dis. 157 (1988) 1239-1242. 15. Stamey, R. A., Condy, M., Mehara, G,: Prophylactic efficacy of nitrofurantoin macrocrystals and trimethoprim-sulfamethoxazole in urinary infections: biologic effects on the vaginal and rectal flora. N. Engt. J. Med. 296 (1977) 780--783. 16. Nicolle, L E., Harding, G: K. M., Thompson, M, Kennedy, J., Ulnas, B., Ronald, A. R.: A prospective, randomized placebo controlled trial of norfloxacin for the prophylaxis of recurrent urinary infection in women. Antimicrob. Agents Chemother. 33 (1989) 1032-1035. 17. Vosti, K. L.: Recurrent urinary tract infections: prevention by prophylactic antibiotics after sexual intercourse. JAMA 231 (1975) 934- 940. 18. Stapleton, A., Latham, 17,.H., Johnson, C., Stamm, W. E.: Post-coital antimicrobial prophylaxis for recurrent urinary infection. JAMA 264 (1990) 703-706.
19. Brumfitt, W., Hamilton-Miller, J. M. T., Gargon, R. A., Cooper, J., Smith, G. W.: Long-term prophylaxis of urinary infections in women: comparative trial of trimethoprim, methenamine hippurate, and topical povidone-iodine. J. Urol. 130 (1983) 1110-1114.
20. Brumfitt, W., Smith, G. W., Hamilton-Miller, J. M. T., Gargan, R. A.: A clinical comparison between macrodantin and trimethoprim for prophylaxis in women with recurrent urinary infection. J. Antimicrob. Agents Chemother. 16 (1985) 111-120.
Infection 20 (1992) Suppl. 3 @ MMV Medizin Verlag GmbH Miinchen, Miinchen 1992
S 205
Prophylaxis: Recurrent Urinary Tract Infection in Women Summary: Long-term, low-dose antimicrobial prophylaxis is effective for the prevention of acute uncomplicated, urinary tract infection in women. Selected new antimicrobials should be assessed to determine their efficacy for this clinical use. Recommended guidelines for future studies of prophylactic therapy need to address several issues. The study population must be limited to women with recurrent symptomatic uncomplicated urinary tract infection. Antimicrobials studied should be excreted in the urine, with an in vitro spectrum that includes the common uropathogens. An extended half-life may be beneficial. Monitoring during the study should include monthly urine cultures and vaginal, periurethral and rectal colonization studies. The primary outcome measurement is symptomatic urinary tract infection. Secondary outcomes would include asymptomatic bacteriuria, adverse antimicrobial effects, colonization with potential uropathogens, and development of resistance. The comparative regimen should be one of the current standard regimens, trimethoprim/ sulphamethoxazole, nitrofurant0in, or trimethoprim.
Zusammenfassung:Prophylaxe der rezidivierenden Hamwegsinfektion bei Frauen. Langdauernde niedrig dosierte Antibiotikaprophylaxe kann akute unkomplizierte Harnwegsinfektionen (HWI) bei Frauen verhindern. Dazu geeignete neue Antibiotika sollten auf ihre klinische Wirksamkeit untersucht werden. Die for kfinftige Studien empfohlenen Richtlinien sollten verschiedene Gesichtspunkte beachten. Die untersuchte Gruppe sollte nur Patientinnen mit rezidivierenden HWI einschlieBen. Die Antibiotika sollten fiber den Urin ausgeschieden werden, wobei das in vitro Spektrum die fiblichen Erreger von HWI effassen sollte. Eine verl~ngerte Halbwertszeit mag dabei gfinstig sein. Die Untersuchungen w~ihrend der Studie sollten monatliche Urinkulturen sowie Studien zur vaginalen, periurethralen und rektalen Kolonisation beinhalten. Das Hauptuntersuchungsziel ist die symptomatische HWI. Weitere Untersuchungsziele beinhalten die asymptomatische Bakteriurie, antibakterielle Nebenwirkungen, die Kolonisation mit potentiell uropathogenen Erregern und die Resistenzentwicklung. Zur Kontrolle sollte eine der g/ingigen Standardbehandlungen herangezogen werden, Trimethoprim/Sulfamethoxazol, Nitrofurantoin oder Trimethoprim.
recurrent urinary infection are both genetic and behavourial. Women who are nonsecretors of blood group substances have an increased occurrence of recurrent urinary infection [2], and women with recurrent infection have an increased frequency of urinary infection in first degree female relatives [3]. In addition, Escherichia coli, the most common uropathogen, adheres more readily to epithelial cells in women with recurrent infection [4,5]. Behavourial factors associated with recurrent urinary infection include sexual activity, with a particularly high risk in those who use spermicides as a birth control method [6-9]. Individual episodes of acute uncomplicated urinary infection are easily treated. Short courses of a single dose or three days of antimicrobial therapy are generally successful and are the recommended therapeutic regimens [9]. The major management problem for patients with acute uncomplicated urinary infection is the frequency of recurrence [10,11]. Reinfection rates are highly variable and, at present, not predictable. Some women have multiple, very closely spaced recurrent infections, whereas others will have recurrent infection separated by infection-free periods of months or years.
Prophylactic Regimens One approach repeatedly documented to be effective for the management of recurrent uncomplicated urinary infection is the prevention of infection through the use of long-term, low-dose prophylactic antimicrobials taken at bedtime [12]. A summary of different regimens is given in Table 1. Generally, the occurrence of infections is decreased by 95% by the use of prophylaxis. The initial duration of prophylactic therapy is usually six months or Table 1: Antimicrobial regimens of documented prophylactic efficacy for prevention of acute uncomplicated urinary infection in women.
Standard regimens* Trimethoprim/sulphamethoxazole Trimethoprim Nitrofurantoin Nitrofurantoin macrocrystals Others Cephalexin Norfloxacin
40/200 mg/dayor three times weekly 100 rag/day 50 mg/day 100 mg/day 125 or 250 mg/day 200 rag/day
* Taken at bedtime.
Background Between 1O and 20% of women experience recurrent uncomplicated urinary infection [1]. Risk factors for
Lindsav E. Nicolte, M. D., FRCPC, Dept. of Medical Microbiology, University of Manitoba, MS-675 D, Health Sciences Centre, 820 Sherbrook Street, Winnipeg, Manitoba R 3A 1R9, Canada.
Infection 20 (1992) Suppl. 3 © MMV Medizin Verlag GmbH Miinchen, Miinchen 1992
S 203
L. E. Nicolle: Prophylaxis of Uncomplicated Urinary Tract Infection one year. However, for co-trimoxazole, continuous prophylaxis for as long as two [13] or five years [14] has remained efficacious. Prophylaxis does not appear to modify the natural history of recurrent urinary infection. When discontinued, even after extended periods, approximately 60% of women will reinfect within three to four months. Prophylactic antimicrobials appear to be effective through at least two mechanisms. Some antimicrobials eradicate the aerobic gram-negative flora of the gut which serves as the principal reservoir for urinary infection. This is the case for co-trimoxazole [15] and norfloxacin [16]. Nitrofurantoin, however, is as effective for the prophylaxis of acute uncomplicated urinary infection as these agents, but has minimal impact on the gut flora [15]. It appears to be efficacious through the intermittent sterilization of the urine. Thus, both urinary concentration and suppressive effect on gram-negative gut flora may be considered predictors of potential prophylactic efficacy. An alternate prophylactic approach to continuous low-dose antimicrobial therapy is post-intercourse prophylaxis for women in whom episodes of infection are associated with sexual intercourse [17,18]. This has not been so well studied. However, the limited data available and considerable therapeutic experience support this as an alternative approach.
Problems and Remaining Issues In compliant patients, the failure of prophylactic therapy is usually due to the acquisition of gut, vaginal, and periurethral flora resistant to the prophylactic antimicrobial [12]. These resistant organisms may then serve as a reservoir for urinary infection. It is of note, however, that while uropathogens generally emerge from the colonizing flora of the gut and genitourinary tract, identification of colonization has not, to date, been shown to be predictive of infection. Thus, the efficacy of prophylaxis will be related to and limited by the prevalence of resistant organisms in the community. This has been well documented for trimethoprim, in particular, where it has been shown not to be an effective regimen in a community with a high prevalence of trimethoprim resistance [19,20]. Antimicrobiat resistance in a population is dynamic, and the emergence of colonizing organisms resistant to commonly used outpatient antimicrobials would be anticipated. Thus, there is a need for ongoing monitoring and assessment of the efficacy of prophylaxis as it relates to community levels of antimicrobial resistance. Newly marketed antimicrobials which appear likely to be effective for prophylaxis should be tested individually to determine their respective roles in prophylactic therapy. Finally, issues with respect to the minimum effective dosage regimen of antimicrobial therapy still need to be addressed. Cost and adverse effects are related to the dose given. However, lower antimicrobial doses may also be S 204
associated with an increased emergence and colonization with resistant organisms. Thus, while tong-term, low-dose prophylactic antimicrobial therapy has been well studied and is of documented efficacy, there is a need for continuing clinical trials to further refine therapy and test the efficacy of newer antimicrobials.
Clinical Evaluation of Drug Efficacy Requirements for future studies examining prophylactic antimicrobial therapy would include: Study population: A defined patient population of women with recurrent symptomatic uncomplicated urinary infection. The potential of a subject for enrolment into the study should be identified on the basis of the frequency of infection in the recent past. A useful rule is two infections in the previous six months or three within the previous 12 months. Women should not be excluded on the basis of age. However, stratification on the basis of age should be considered in the analysis. The appropriate cut-off age for this stratification - 40 years, 50 years or 60 years - is not clear. Therapeutic regimens: Oral antimicrobials appropriate for study would include those with the following characteristics: (I) excreted primarily in the urine as an active drug; (II) associated with eradication of gram-negative flora from the gut without significant impact on the anaerobic flora; (III) an extended half-life, to facilitate minimal dosing; (IV) an /n vitro spectrum effective for common uropathogens (E. coli, Staphylococcus saprophyticus, Klebsiellapneumoniae, Proteus mirabilis). Whether there is any benefit for agents that include Enterococcusfaecalis or other gram-positive organisms in their spectrum is not clear at present. Monitoring: Study subjects should be monitored for urinary symptoms and bacteriuria, potential adverse effects of antimicrobials, and colonization of the gut, periurethral area and vagina with potential uropathogens. Post-therapy follow-up at one and three months should be obtained as most reinfections wilt occur by three months. Further post-prophylaxis monitoring would not be warranted unless a specific study question is whether the prophylactic regimen has an impact on long-term post-prophylaxis infection frequency. Outcome measurements: I) The primary outcome parameter must be the occurrence of s)~nptomatic urinary infection. This may be expressed as a life table analysis to time of first symptomatic infection, or differences in incidence between study groups. II) Secondary outcome parameters to be analyzed would include asymptomatic bacteriuria, occurrence of adverse antimicrobial effects, and colonization with potential uropathogens, including those resistant to the prophylactic agent.
Infection 20 (1992) Suppl. 3 © MMV Medizin VerlagGmbH Mfinchen, Mfinchen 1992
L. E. Nicolle: Prophylaxis of Uncomplicated Urinary Tract Infection
Comparative regimen: As the efficacy of prophylactic therapy is well documented for a number of different regimens, a placebo study arm is likely to be unethical. The comparative arm • should be one of the accepted standard regimens such as trimethoprim/ sulphamethoxazole 40/200 mg daily or three times weekly,
References 1. Sanford, J. P.: Urinary tract symptoms and infection. Ann. Rev. Med. 26 (1975) 485.
2. Kinane, D. F, Blaekwell, C. C., Brettle, R. P., Weir, D. M, Winstanley, F. P , Eltor, IL A.: ABO blood group, secretor state and susceptibility to recurrent urinary tract infection in women. Br. Med. J. 285 (1982) 7. 3. Fennell, R. S, Wilson, S. G., Garin, E. H., Pryor, N. D., Sorgen, C. P , Walker, R. D., Richard, G. A.: Bacteriuria in families of girls with recurrent bacteriuria. Clin. Pediatr. 16 (1977) 1132. 4. Schaeffer, A. J., Jones, J., Dunn, J. K.: Association of in vitro Escherichia coli adherence to vaginal and buccal epithelial cells with susceptibility of women to recurrent urinary tract infections. N. Engl. J. Med. 304 (1981) 1062-1066.
5. Kozody, N. L, Harding, G. K. M., Nicolle, L E., Kelly, K., Ronald, A. R.: Adherence of Escherichia coli to epithelial cells in the pathogenesis of urinary tract infection. Clin. Invest. Med. 8 (1985) 121- 125. 6. Nieolle, L E., Hardin, G. IL M., Preiksaitis, J , Ronald, A. It.: The association of urinary tract infection with sexual intercourse. J. Infect. Dis. 146 (1982) 579-583. 7. Foxman, B., Freriehs, IL It.: Epidemiology of urinary tract infections: I. Diaphragm use and sexual intercourse. Amer. J. Public Health 75 (1985) 1308-1313.
8. Fihn, S. D., Latham, R. H., Roberts, P., Running, K., Stamm, W. E.: Association between diaphragm use and urinary tract infection. JAMA 254 (1985) 240-245. 9. Johnson, J. R., Stature, W. E.: Diagnosis and treatment of acute urinary tract infections. Infect. Dis. Clin. North Am. 1 (1987) 773791. 10. Kraft, J. I¢_, Stamey, T. A.: The natural history of symptomatic recurrent bacteriuria in women. Medicine 56 (1977) 55--60. 11. Stature, W. E, McKevitt, M, Roberts, P. L., White, N. J.: Natural
trimethoprim 100 mg daily, or nitrofurantoin 50 mg or, as macrocrystals, 100 mg daily. The remarkable effectiveness of antimicrobial prophylaxis means that, when comparing new antimicrobial agents to standard therapy, large study numbers may be required to demonstrate a difference in outcome measured by symptomatic infection.
history of recurrent urinary tract infections in women. Rev. Infect. Dis. 13 (t99t) 77-84. 12. Nieolle, L E., Ronaid, A. R.: Recurrent urinary tract infection in adult women: diagnosis and treatment. Inf. Dis. Clin. North Am. 1 (1987) 793-806.
13. Harding, G. K. M., Ronald, A. R. Nieolle, L. E., Thomson, M. J., Gray, G. J.: Long-term antimicrobial prophylaxis for recurrent urinary tract infection in women. Rev. Infect. Dis 4 (1982) 438-443. 14. Nicoile, L E., Harding, G. K. M., Thomson, M, Kennedy, J., Urias, B., Ronald, A. R.: Efficacy of five ),ears of continuous low dose cotrimoxazole prophylaxis for prevention of urinary tract infection. J. Infect. Dis. 157 (1988) 1239-1242. 15. Stamey, R. A., Condy, M., Mehara, G,: Prophylactic efficacy of nitrofurantoin macrocrystals and trimethoprim-sulfamethoxazole in urinary infections: biologic effects on the vaginal and rectal flora. N. Engt. J. Med. 296 (1977) 780--783. 16. Nicolle, L E., Harding, G: K. M., Thompson, M, Kennedy, J., Ulnas, B., Ronald, A. R.: A prospective, randomized placebo controlled trial of norfloxacin for the prophylaxis of recurrent urinary infection in women. Antimicrob. Agents Chemother. 33 (1989) 1032-1035. 17. Vosti, K. L.: Recurrent urinary tract infections: prevention by prophylactic antibiotics after sexual intercourse. JAMA 231 (1975) 934- 940. 18. Stapleton, A., Latham, 17,.H., Johnson, C., Stamm, W. E.: Post-coital antimicrobial prophylaxis for recurrent urinary infection. JAMA 264 (1990) 703-706.
19. Brumfitt, W., Hamilton-Miller, J. M. T., Gargon, R. A., Cooper, J., Smith, G. W.: Long-term prophylaxis of urinary infections in women: comparative trial of trimethoprim, methenamine hippurate, and topical povidone-iodine. J. Urol. 130 (1983) 1110-1114.
20. Brumfitt, W., Smith, G. W., Hamilton-Miller, J. M. T., Gargan, R. A.: A clinical comparison between macrodantin and trimethoprim for prophylaxis in women with recurrent urinary infection. J. Antimicrob. Agents Chemother. 16 (1985) 111-120.
Infection 20 (1992) Suppl. 3 @ MMV Medizin Verlag GmbH Miinchen, Miinchen 1992
S 205
