Effect of lactobacillus in preventing post-antibiotic vulvovaginal candidiasis: a randomised controlled trial
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《英国医生杂志》
1 Department of General Practice, 200 Berkeley Street, Carlton, Victoria, Australia, 3053, 2 Royal Women's Hospital, Women's and Children's Health, 132 Grattan Street, Carlton, Victoria, 3 School of Population Health, University of Melbourne, Swanston Street, Carlton, Victoria
Correspondence to: M Pirotta m.pirotta@unimelb.edu.au
Abstract
The use of many complementary and alternative medicines remains controversial. In Australia and the United States, the estimated annual expenditure associated with use of such treatments is $A2.3bn (￡0.9bn) and $27.1bn (￡15bn) respectively, which is more than that spent on prescription drugs.1 2
Probiotics, microorganisms that have antagonist activity against pathogens in vivo, have long been promoted as health enhancing in general and specifically as useful for vaginal problems.3 Probiotics are commonly used4-6 and recommended7 for vulvovaginitis that develops after antibiotic treatment—a condition of concern to many women4 and usually caused by Candida albicans.8 Lactobacilli are a genus of bacteria, many species of which have been evaluated for their probiotic potential and may be found in yoghurt. Our previous study found that 40% of a sample of 751 women with a history of vulvovaginitis had used yoghurt or lactobacillus orally or vaginally to prevent post-antibiotic vulvovaginitis,4 but no published trials have tested the effectiveness of this treatment.
The aim of our present study was to test whether oral or vaginal lactobacillus can prevent post-antibiotic vulvovaginitis.
Participants and methods
Viability of the lactobacilli and correct labelling of the interventions were confirmed in three independent tests. After the second interim analysis showed no evidence of effect with active treatment, the Data Monitoring Committee recommended terminating the trial early. At this stage, the committee had 62% of the expected data, and stochastic curtailment methods showed that if the trial proceeded to full enrolment the chances of detecting a significant reduction in vulvovaginitis with oral or vaginal lactobacillus treatment were less than 0.032 and 0.0006 respectively.
A total of 278 women were randomised (26 while awaiting the second interim analysis results). Because of the recruitment method used, it was not practical to document the entire eligible population. However, an audit of 132 eligible women by 13 recruiters showed that 25% agreed to randomisation and that non-participants were similar to participants in key characteristics (age, use of oestrogen based drugs, and antibiotic prescribed) (results not shown).
Complete data for the main outcomes were available for 235 women; partial data were available for 29 (report of symptoms but no vaginal swab at follow up), of whom six reported symptoms of vulvovaginitis; and no outcome data were available for 14 women. The figure shows the numbers of participants by treatment group. Table 1 shows the reasons for women's withdrawal from the trial and non-compliance with treatment. Table 2 shows participants' key baseline characteristics, which were reasonably balanced between the treatment groups.
Table 1 Reasons for withdrawal from trial of oral and vaginal lactobacillus for preventing post-antibiotic vulvovaginitis among 278 women and levels of poor compliance. Values are numbers of women
Table 2 Baseline characteristics of 278 women in trial of oral and vaginal lactobacillus for preventing post-antibiotic vulvovaginitis by treatment group. Values are numbers (percentages*) unless stated otherwise
Women who did not supply complete outcome data were more likely to be younger, to smoke, and not to have completed tertiary education than those who supplied full data (table 3). Among the 234 participants who gave the information, good compliance ("most" or "all" treatments taken) was reported by 225 (96%) for prescribed antibiotics, by 201 (86%) for the oral intervention, and by 184 (79%) for the vaginal intervention, with no significant difference across factorial groups. More than half the participants answered "Don't know" to the question of which treatment group they were assigned to; 64/231 (28%) correctly guessed they were in the active oral group, 46/230 (20%) correctly guessed they were in the active pessary group, and 21/228 (9%) correctly guessed their factorial group.
Table 3 Comparison of baseline characteristics of women with and women without complete outcome data from trial of oral and vaginal lactobacillus for preventing post-antibiotic vulvovaginitis. Values are numbers (percentages*) unless stated otherwise
Effects of the interventions
Overall, 55/235 of the participants (23% (95% confidence interval 18% to 29%)) developed post-antibiotic vulvovaginitis. Table 4 shows the results for the factorial groups. The odds ratios for developing vulvovaginitis while taking oral lactobacillus was 1.06 (95% confidence interval 0.58 to 1.94) and while taking vaginal lactobacillus was 1.38 (0.75 to 2.54).
Table 4 Number of cases of post-antibiotic vulvovaginitis in women taking oral and vaginal lactobacillus, by treatment group
Sensitivity analysis
Table 5 shows the sensitivity analyses for women without complete outcome data, assuming either all such women were not affected or that those reporting symptoms and those with unknown outcomes had vulvovaginitis. There was no evidence of an interaction between oral and vaginal treatments (results not shown). Only three of the 29 asymptomatic women with a positive follow up swab for candida reported symptoms of vaginitis after the end of the trial.
Table 5 Sensitivity analyses for numbers of cases of post-antibiotic vulvovaginitis in women taking oral and vaginal lactobacillus. Participants who did not give complete outcome data were either viewed as all non-cases, or those who reported symptoms or had unknown outcomes were viewed as cases
Discussion
MacLennan A, Wilson D, Taylor A. The escalating cost and prevalence of alternative medicine. Prev Med 2002;35: 166-73.
Eisenberg D, Davis R, Ettner S, Appel S, Wilkey S, Van Rompay M, et al. Trends in alternative medicine use in the United States, 1990-1997. JAMA 1998;280: 1569-75.
Mombelli B, Gismondo MR. The use of probiotics in medical practice. Int J Antimicrob Agents 2000;16: 531-6.
Pirotta M, Gunn J, Chondros P. "Not thrush again!" Women's experience of post-antibiotic vulvovaginitis. Med J Aust 2003;179: 43-6.
Nyirjesy P, Weitz M, Grody T, Lorber B. Over-the-counter and alternative medicines in the treatment of chronic vaginal symptoms. Obstet Gynecol 1997;90: 50-3.
Chapple A, Hassell K, Nicolson M, Cantrill J. `You don't really feel you can function normally': women's perceptions and personal management of vaginal thrush. J Reprod Infant Psychol 2000;18: 309-19.
Pizzorno L, Pizzorni J, Murray M. Natural medicine instructions for patients. Edinburgh: Churchill Livingstone, 2002.
Bluestein D, Rutledge C, Lumsden L. Predicting the occurrence of antibiotic-induced candidal vaginitis (AICV). Fam Pract Res J 1991;11: 319-26.
Pirotta M, Gunn J, Chondros P, Grover S, Hurley S, Garland S. Study protocol. The PAV trial: does lactobacillus prevent post-antibiotic vulvovaginal candidiasis? Protocol of a randomised controlled trial . BMC Fam Pract 2004;5: 5.
Bernal S, Mazuelos EM, Garcia M, Aller AI, Martinez MA, Gutierrez MJ. Evaluation of CHROMagar candida medium for the isolation of presumptive identification of species of candida of clinical importance. Diagn Microbiol Infect Dis 1996;24: 201-4.
Hospenthal DR, Murray CK, Beckius ML, Green JA, Dooley D. Persistence of pigment production by yeast isolates grown on CHROMagar candida medium. J Clin Microbiol 2002;40: 4768-70.
O'Brien P, Fleming T. A multiple testing procedure for clinical trials. Biometrics 1979;35: 549-56.
Jennison C, Turnbull B. Group sequential methods with applications to clinical trials. Boca Raton: Chapman and Hall/CRC, 2000.
Nelson D, Bellamy S, Gray T, Nachamkin I. Self-collected versus provider-collected vaginal swabs for the diagnosis of bacterial vaginosis: an assessment of validity and reliability. J Clin Epidemiol 2003;56: 862-6.
Pocock S. When to stop a clinical trial. BMJ 1992;305: 235-6.
Redondo-Lopez V, Cook RL, Sobel JD. Emerging role of lactobacilli in the control and maintenance of the vaginal bacterial microflora. Rev Infect Dis 1990;12: 856-72.
McGroarty JA. Probiotic use of lactobacilli in the human female urogenital tract. FEMS Immunol Med Microbiol 1993;6: 251-64.
Klebanoff SJ, Hillier SL, Eschenbach DA, Waltersdorph AM. Control of the microbial flora of the vagina by H2O2-generating lactobacilli. J Infect Dis 1991;164: 94-100.
Sobel JD, Faro S, Force RW, Foxman B, Ledger WJ, Nyirjesy PR, et al. Vulvovaginal candidiasis: epidemiologic, diagnostic, and therapeutic considerations. Am J Obstet Gynecol 1998;178: 203-11.
Sobel JD, Chaim W. Vaginal microbiology of women with acute recurrent vulvovaginal candidiasis. J Clin Microbiol 1996;34: 2497-9.
Fidel PL Jr. The protective immune response against vaginal candidiasis: lessons learned from clinical studies and animal models. Int Rev Immunol 2002;21: 515-48.
Hilton E, Isenberg HD, Alperstein P, France K, Borenstein MT. Ingestion of yogurt containing Lactobacillus acidophilus as prophylaxis for candidal vaginitis. Ann Intern Med 1992;116: 353-7.(Marie Pirotta, senior lec)
Correspondence to: M Pirotta m.pirotta@unimelb.edu.au
Abstract
The use of many complementary and alternative medicines remains controversial. In Australia and the United States, the estimated annual expenditure associated with use of such treatments is $A2.3bn (￡0.9bn) and $27.1bn (￡15bn) respectively, which is more than that spent on prescription drugs.1 2
Probiotics, microorganisms that have antagonist activity against pathogens in vivo, have long been promoted as health enhancing in general and specifically as useful for vaginal problems.3 Probiotics are commonly used4-6 and recommended7 for vulvovaginitis that develops after antibiotic treatment—a condition of concern to many women4 and usually caused by Candida albicans.8 Lactobacilli are a genus of bacteria, many species of which have been evaluated for their probiotic potential and may be found in yoghurt. Our previous study found that 40% of a sample of 751 women with a history of vulvovaginitis had used yoghurt or lactobacillus orally or vaginally to prevent post-antibiotic vulvovaginitis,4 but no published trials have tested the effectiveness of this treatment.
The aim of our present study was to test whether oral or vaginal lactobacillus can prevent post-antibiotic vulvovaginitis.
Participants and methods
Viability of the lactobacilli and correct labelling of the interventions were confirmed in three independent tests. After the second interim analysis showed no evidence of effect with active treatment, the Data Monitoring Committee recommended terminating the trial early. At this stage, the committee had 62% of the expected data, and stochastic curtailment methods showed that if the trial proceeded to full enrolment the chances of detecting a significant reduction in vulvovaginitis with oral or vaginal lactobacillus treatment were less than 0.032 and 0.0006 respectively.
A total of 278 women were randomised (26 while awaiting the second interim analysis results). Because of the recruitment method used, it was not practical to document the entire eligible population. However, an audit of 132 eligible women by 13 recruiters showed that 25% agreed to randomisation and that non-participants were similar to participants in key characteristics (age, use of oestrogen based drugs, and antibiotic prescribed) (results not shown).
Complete data for the main outcomes were available for 235 women; partial data were available for 29 (report of symptoms but no vaginal swab at follow up), of whom six reported symptoms of vulvovaginitis; and no outcome data were available for 14 women. The figure shows the numbers of participants by treatment group. Table 1 shows the reasons for women's withdrawal from the trial and non-compliance with treatment. Table 2 shows participants' key baseline characteristics, which were reasonably balanced between the treatment groups.
Table 1 Reasons for withdrawal from trial of oral and vaginal lactobacillus for preventing post-antibiotic vulvovaginitis among 278 women and levels of poor compliance. Values are numbers of women
Table 2 Baseline characteristics of 278 women in trial of oral and vaginal lactobacillus for preventing post-antibiotic vulvovaginitis by treatment group. Values are numbers (percentages*) unless stated otherwise
Women who did not supply complete outcome data were more likely to be younger, to smoke, and not to have completed tertiary education than those who supplied full data (table 3). Among the 234 participants who gave the information, good compliance ("most" or "all" treatments taken) was reported by 225 (96%) for prescribed antibiotics, by 201 (86%) for the oral intervention, and by 184 (79%) for the vaginal intervention, with no significant difference across factorial groups. More than half the participants answered "Don't know" to the question of which treatment group they were assigned to; 64/231 (28%) correctly guessed they were in the active oral group, 46/230 (20%) correctly guessed they were in the active pessary group, and 21/228 (9%) correctly guessed their factorial group.
Table 3 Comparison of baseline characteristics of women with and women without complete outcome data from trial of oral and vaginal lactobacillus for preventing post-antibiotic vulvovaginitis. Values are numbers (percentages*) unless stated otherwise
Effects of the interventions
Overall, 55/235 of the participants (23% (95% confidence interval 18% to 29%)) developed post-antibiotic vulvovaginitis. Table 4 shows the results for the factorial groups. The odds ratios for developing vulvovaginitis while taking oral lactobacillus was 1.06 (95% confidence interval 0.58 to 1.94) and while taking vaginal lactobacillus was 1.38 (0.75 to 2.54).
Table 4 Number of cases of post-antibiotic vulvovaginitis in women taking oral and vaginal lactobacillus, by treatment group
Sensitivity analysis
Table 5 shows the sensitivity analyses for women without complete outcome data, assuming either all such women were not affected or that those reporting symptoms and those with unknown outcomes had vulvovaginitis. There was no evidence of an interaction between oral and vaginal treatments (results not shown). Only three of the 29 asymptomatic women with a positive follow up swab for candida reported symptoms of vaginitis after the end of the trial.
Table 5 Sensitivity analyses for numbers of cases of post-antibiotic vulvovaginitis in women taking oral and vaginal lactobacillus. Participants who did not give complete outcome data were either viewed as all non-cases, or those who reported symptoms or had unknown outcomes were viewed as cases
Discussion
MacLennan A, Wilson D, Taylor A. The escalating cost and prevalence of alternative medicine. Prev Med 2002;35: 166-73.
Eisenberg D, Davis R, Ettner S, Appel S, Wilkey S, Van Rompay M, et al. Trends in alternative medicine use in the United States, 1990-1997. JAMA 1998;280: 1569-75.
Mombelli B, Gismondo MR. The use of probiotics in medical practice. Int J Antimicrob Agents 2000;16: 531-6.
Pirotta M, Gunn J, Chondros P. "Not thrush again!" Women's experience of post-antibiotic vulvovaginitis. Med J Aust 2003;179: 43-6.
Nyirjesy P, Weitz M, Grody T, Lorber B. Over-the-counter and alternative medicines in the treatment of chronic vaginal symptoms. Obstet Gynecol 1997;90: 50-3.
Chapple A, Hassell K, Nicolson M, Cantrill J. `You don't really feel you can function normally': women's perceptions and personal management of vaginal thrush. J Reprod Infant Psychol 2000;18: 309-19.
Pizzorno L, Pizzorni J, Murray M. Natural medicine instructions for patients. Edinburgh: Churchill Livingstone, 2002.
Bluestein D, Rutledge C, Lumsden L. Predicting the occurrence of antibiotic-induced candidal vaginitis (AICV). Fam Pract Res J 1991;11: 319-26.
Pirotta M, Gunn J, Chondros P, Grover S, Hurley S, Garland S. Study protocol. The PAV trial: does lactobacillus prevent post-antibiotic vulvovaginal candidiasis? Protocol of a randomised controlled trial . BMC Fam Pract 2004;5: 5.
Bernal S, Mazuelos EM, Garcia M, Aller AI, Martinez MA, Gutierrez MJ. Evaluation of CHROMagar candida medium for the isolation of presumptive identification of species of candida of clinical importance. Diagn Microbiol Infect Dis 1996;24: 201-4.
Hospenthal DR, Murray CK, Beckius ML, Green JA, Dooley D. Persistence of pigment production by yeast isolates grown on CHROMagar candida medium. J Clin Microbiol 2002;40: 4768-70.
O'Brien P, Fleming T. A multiple testing procedure for clinical trials. Biometrics 1979;35: 549-56.
Jennison C, Turnbull B. Group sequential methods with applications to clinical trials. Boca Raton: Chapman and Hall/CRC, 2000.
Nelson D, Bellamy S, Gray T, Nachamkin I. Self-collected versus provider-collected vaginal swabs for the diagnosis of bacterial vaginosis: an assessment of validity and reliability. J Clin Epidemiol 2003;56: 862-6.
Pocock S. When to stop a clinical trial. BMJ 1992;305: 235-6.
Redondo-Lopez V, Cook RL, Sobel JD. Emerging role of lactobacilli in the control and maintenance of the vaginal bacterial microflora. Rev Infect Dis 1990;12: 856-72.
McGroarty JA. Probiotic use of lactobacilli in the human female urogenital tract. FEMS Immunol Med Microbiol 1993;6: 251-64.
Klebanoff SJ, Hillier SL, Eschenbach DA, Waltersdorph AM. Control of the microbial flora of the vagina by H2O2-generating lactobacilli. J Infect Dis 1991;164: 94-100.
Sobel JD, Faro S, Force RW, Foxman B, Ledger WJ, Nyirjesy PR, et al. Vulvovaginal candidiasis: epidemiologic, diagnostic, and therapeutic considerations. Am J Obstet Gynecol 1998;178: 203-11.
Sobel JD, Chaim W. Vaginal microbiology of women with acute recurrent vulvovaginal candidiasis. J Clin Microbiol 1996;34: 2497-9.
Fidel PL Jr. The protective immune response against vaginal candidiasis: lessons learned from clinical studies and animal models. Int Rev Immunol 2002;21: 515-48.
Hilton E, Isenberg HD, Alperstein P, France K, Borenstein MT. Ingestion of yogurt containing Lactobacillus acidophilus as prophylaxis for candidal vaginitis. Ann Intern Med 1992;116: 353-7.(Marie Pirotta, senior lec)