Probiotics vs. Antibiotics for Prevention of UTIs: Inferiority Complex?
Women’s Health
Probiotics vs. Antibiotics for Prevention of UTIs: Inferiority Complex?
Abstract & Commentary
By Donald J. Brown, ND
Managing Director, Natural Product Research Consultants, Seattle, WA
Dr. Brown reports no financial relationships relevant to this field of study.
Synopsis: In this non-inferiority clinical trial, 1-year prophylaxis with an oral lactobacilli probiotic combination proved less effective than trimethoprim-sulfamethoxazole for preventing recurrence of urinary tract infections in postmenopausal women. However, although women in the antibiotic group had a dramatic increase in antibiotic resistance, there was no increase noted in the probiotic group.
Source: Beereport MAJ, et al. Lactobacilli vs. antibiotics to prevent urinary tract infections: A randomized, double-blind, noninferiority trial in postmenopausal women. Arch Intern Med 2012;172:704-712.
Growing concerns about antibiotic resistance have led to increased interest in non-antibiotic therapies for recurrent urinary tract infections (UTIs). In this randomized, double-blind, non-inferiority clinical trial, postmenopausal women with a history of at least three self-reported UTIs in the year preceding the study were recruited through advertisements or referred by Dutch family physicians. Women were randomized to: 1) trimethoprim-sulfamethoxazole (TMP-SMX), 480 mg, one tablet at night and one placebo capsule twice daily or 2) one capsule containing Lactobacillus rhamnosus GR-1 and Lactobacillus reuteri RC-14 (1 x 109 colony forming units [CFU] of each strain) twice daily and one placebo tablet at night. The treatment period was 12 months. Immediately before the study medication was started and monthly thereafter, until 3 months after discontinuation of the study medication, the women were asked to collect urine and fecal samples and also a vaginal swab specimen. During these times, women also completed a questionnaire regarding UTI symptoms, adverse events, infections other than UTIs, and antibiotic use. In case of a symptomatic UTI, women were instructed to collect urine using a dipslide and to send it to the study laboratory for culture. Urine and stool samples were used to measure antibiotic resistance of commensal Esherichia coli, and urine samples also were tested for antibacterial activity associated with TMP-SMX or other antibacterial substances.
The primary clinical outcomes were the mean number of symptomatic UTIs (clinical recurrences [CR]) during 12 months, the proportion of patients with at least one CR during 12 months of prophylaxis, and the median time to the first CR. The primary outcome evaluating the development of antibiotic resistance was the percentage of TMP-SMX-resistant E. coli isolates from asymptomatic women at 1 and 12 months. Additionally, antibiotic susceptibility of these E. coli isolates to trimethoprim, nitrofurantoin, amoxicillin, amoxicillin-clavulanic acid, gentamicin, ciproflaxin, and norfloxacin was analyzed. An additional analysis of these measures was repeated 3 months after discontinuation of the study medications. Secondary outcomes included the mean number of microbiologically confirmed UTIs (microbiological recurrences [MRs]) during the 12 months of prophylaxis and in the 3 months after its discontinuation, the proportion of women with at least one MR during this period, and the time to the first MR. An MR was defined as a UTI based on the combination of clinical symptoms and bacteriuria (≥ 103 CFU/mL bacteria in midstream urine). Preplanned subgroup analyses included the mean number of CRs in women with complicated vs uncomplicated UTIs. To establish non-inferiority of the probiotics compared to TMP-SMX, the upper limit of the 95% confidence interval (CI) for the between-groups difference in the mean number of CRs at 12 months had to lie below a predefined 10% non-inferiority margin.
The study included 252 postmenopausal women, with 127 randomized to receive TMP-SMX (mean age 65.4 years) and 125 to receive probiotics (mean age 63.2 years). After 12 months of prophylaxis, the mean number of CRs was 2.9 (95% CI, 2.3 to 3.6) in the TMP-SMX group and 3.3 for the probiotic group (95% CI, 2.7 to 4.0). The between-group difference in the mean number of CRs after 12 months was 0.4 (95% CI, -0.4 to 1.5), which equated to a difference of 13.8%. The percentage of women with at least one CR at 12 months was 69.3% in the TMP-SMX group and 79.1% in the probiotic group. The median times to first recurrence were 6 and 3 months, respectively (P = 0.02). The number of CRs during the 3 months following discontinuation of prophylaxis did not differ significantly between groups. After 1 month of TMP-SMX prophylaxis, resistance to TMP-SMX and amoxicillin increased from approximately 20-40% to approximately 80-95% in the feces and urine of asymptomatic women. After 12 months of TMP-SMX, all urinary E. coli isolates of asymptomatic women were resistant to TMP-SMX and trimethoprim. Resistance rates for ciproflaxcin and norflaxacin in urinary E. coli isolates increased from 16-18% at baseline to 34% 1 month after TMP-SMX prophylaxis was stopped. Resistance remained unchanged in the probiotic group.
After 12 months of prophylaxis, the mean number of MRs was 1.2 (95% CI, 0.9 to 1.6) in the TMP-SMX group and 1.8 (95% CI, 1.4 to 2.3) in the probiotic group. The percentage of women with at least one MR at 12 months was 49.4% in the TMP-SMX group and 62.9% in the probiotic group. Median times to first MR were 12 and 6 months, respectively (P = 0.02). The number of MRs 3 months after treatment discontinuation did not differ significantly between groups. Resistance percentages of E. coli isolates in these symptomatic women were similar to that found for asymptomatic women. At 1 month, 39.6% of women in the TMP-SMX group and 44.7% of those in the probiotic group had asymptomatic bacteriuria. At 12 months, these percentages were 38.5% and 53.2%, respectively. The mean number of CRs after 12 months of prophylaxis in women with uncomplicated UTIs was 1.9 (95% CI, 1.4 to 2.6) in the TMP-SMX group and 3.2 (95% CI, 2.5 to 4.2 in the probiotic group. In women with complicated UTIs, these numbers were 4.4 (95% CI, 3.4 to 5.7) and 3.4 (95% CI, 2.6 to 4.5), respectively (P < 0.001). No significant differences in AEs were noted between the two groups.
Commentary
Approximately 50-60% of women have a UTI during their lifetime, and recurrence occurs in approximately 25-30%.1 Recurrent UTIs are most common in sexually active women 20-40 years old and postmenopausal women. Standard therapy for postmenopausal women with at least three UTIs per year is vaginal application of estrogens or low-dose antibiotic prophylaxis.2 The first choice is increasingly unpopular with women and the second, while an effective prevention, has led to an increased prevalence of antibiotic resistance. Probiotics have joined cranberry as one of the popular, non-antibiotic alternatives for women with recurrent UTIs.
Like bacterial vaginosis, an imbalance in the normal vaginal flora is associated with recurrent UTIs. Vaginal colonization with E. coli has been linked to a depletion of vaginal H2O2-producing lactobacilli in women with recurrent UTIs.3 Postmenopausal women have been found to have reduced concentrations of vaginal lactobacilli, most likely the result of decreased estrogen levels.4 Research to date using probiotics as prophylaxis for recurrent UTIs has focused largely on premenopausal women using vaginal suppositories and primarily has been negative.5 Promising results recently have been shown with the intravaginal application of a new probiotic strain, L. crispatus CTV-05, but the study focused only on premenopausal women following antibiotic treatment.6 The current study is the first to focus on postmenopausal women using an oral probiotic combination7,8 and an active control. It did not address the effect of prophylaxis following standard antibiotic therapy for an acute UTI.
So, what to make of the results? Based solely on efficacy, one would conclude that TMP-SMX prophylaxis is superior to the oral probiotic combination in preventing UTI recurrence in postmenopausal women. The results correspond roughly to 1.5 additional UTIs in women choosing to take the probiotic combination instead of TMP-SMX. Interestingly, the only exceptions were those women with complicated UTIs, where probiotics outperformed TMP-SMX. However, it is important to factor in the difference in antibiotic resistance between the two treatments. Although the probiotic group showed no increase in resistance, the TMP-SMX group had a more than two-fold increase in resistance to both TMP-SMX and amoxicillin. The investigators sum it up best by stating, “Lactobacilli may be an acceptable alternative for prevention of UTIs, especially in women who dislike taking antibiotics.” Unfortunately, that conclusion comes at the very end of the Discussion section of the paper. I look forward to an upcoming paper by the investigators that will offer an economic evaluation weighing the pros and cons of both regimens.
Non-inferiority clinical trials have a number of inherent weaknesses that superiority trials do not but are often used when a placebo group cannot be ethically included.9 These weaknesses include lack of protection from bias by blinding and difficulty in specifying the non-inferiority margin. It is interesting to note that this is the second of these trials by this group from the Netherlands. The earlier study was a noninferiority study comparing cranberry (in capsules) and TMP-SMX in premenopausal women with recurrent UTIs.10 The difference in recurrence was similar to that found in this probiotic study, while the antibiotic resistance findings at 1 month were similar for TMP-SMX but slightly higher for cranberry (approximately 28%) compared to the probiotic findings in the current study. Perhaps a combination of probiotics and cranberry might be superior when considering the downside of antibiotic prophylaxis for prevention of UTIs.
References
1. Foxman B, Brown P. Epidemiology of urinary tract infections: Transmission and risk factors, incidence, and costs. Infect Dis Clin North Am 2003;17:227-241.
2. Hooton TM. Recurrent urinary tract infection in women. Int J Antimicrob Agents 2001;17:259-268.
3. Gupta K, et al. Inverse association of H2O2-producing lactobacilli and vaginal Eschericia coli colonization in women with recurrent urinary tract infections. J Infect Dis 1998;178:446-450.
4. Pabich WL, et al. Prevalence and determinants of vaginal flora alterations in postmenopausal women. J Infect Dis 2003;188:1054-1058.
5. Barrons R, Tassone D. Use of Lactobacillus probiotics for bacterial genitourinary tract infections in women: A review. Clin Therapeutics 2008;30:453-468.
6. Stapleton AE, et al. Randomized, placebo-controlled phase 2 trial of a Lactobacillus crispatus probiotic given intravaginally for prevention of recurrent urinary tract infections. CID 2011;52:1212-1217.
7. Reid G, et al. Oral use of Lactobacillus rhamnosus GR-1 and Lactobacillus fermentum RC-14 significantly alters vaginal flora: Randomized, placebo-controlled trial in 64 healthy women. FEMS Immunol Med Microbiol 2003;35:131-134.
8. Morelli L, et al. Utilization of the intestinal tract as a delivery system for urogenital probiotics. J Clin Gastroenterol 2004;38(suppl2): S1-S4.
9. Sanpinn SM. Noninferiority trials. Curr Control Trials Cardiovasc Med 2000;1:19-21.
10. Beerepoot MAJ, et al. Cranberries vs. antibiotics to prevent urinary tract infections: A randomized, double-blind, noninferiority trial in premenopausal women. Arch Intern Med 2011;171:1270-1278.
In this non-inferiority clinical trial, 1-year prophylaxis with an oral lactobacilli probiotic combination proved less effective than trimethoprim-sulfamethoxazole for preventing recurrence of urinary tract infections in postmenopausal women. However, although women in the antibiotic group had a dramatic increase in antibiotic resistance, there was no increase noted in the probiotic group.Subscribe Now for Access
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