|Year : 2017 | Volume
| Issue : 3 | Page : 347-354
Recurrent urinary tract infections in women: How promising is the use of probiotics?
Varsha Gupta, Deepika Nag, Pratibha Garg
Department of Microbiology, Government Medical College Hospital, Chandigarh, India
|Date of Web Publication||12-Oct-2017|
Department of Microbiology, Government Medical College Hospital, Sector 32-B, Chandigarh - 160 030
Source of Support: None, Conflict of Interest: None
Urinary tract infections (UTIs) currently rank amongst the most prevalent bacterial infections, representing a major health hazard. UTIs in females usually start as vaginal infections and ascend to the urethra and bladder. Recurrent UTIs (rUTIs) can be defined as at least three episodes of UTI in 1 year or two episodes in 6 months. Various antibiotics have been the mainstay of therapy in ameliorating the incidence of UTIs, but recurrent infections continue to afflict many women. It necessitates the exploitation of alternative antimicrobial therapy. Probiotics have been shown to be effective in varied clinical trials for long-term preventions of rUTI. Because Escherichia coli is the primary pathogen involved in UTIs which spreads from the rectum to vagina and then ascends up the sterile urinary tract, improving the gut or vaginal flora will thus impact the urinary tract. Since a healthy vaginal microbiota is mainly dominated by Lactobacillus species, in this context, exogenously administered probiotics containing Lactobacilli play a pivotal role in reducing the risk of rUTI. The concept of artificially boosting the Lactobacilli numbers through probiotic administration has long been conceived but has been recently shown to be possible. Lactobacilli may especially be useful for women with a history of recurrent, complicated UTIs or on prolonged antibiotic use. Probiotics do not cause antibiotic resistance and may offer other health benefits due to vaginal re-colonisation with Lactobacilli. However, more comprehensive research is still needed, to recommend for probiotics as an alternative to antibiotics.
Keywords: Lactobacillus, probiotics, recurrent urinary tract infections
|How to cite this article:|
Gupta V, Nag D, Garg P. Recurrent urinary tract infections in women: How promising is the use of probiotics?. Indian J Med Microbiol 2017;35:347-54
|How to cite this URL:|
Gupta V, Nag D, Garg P. Recurrent urinary tract infections in women: How promising is the use of probiotics?. Indian J Med Microbiol [serial online] 2017 [cited 2018 Apr 25];35:347-54. Available from: http://www.ijmm.org/text.asp?2017/35/3/347/216616
| ~ Urinary Tract Infections|| |
Urinary tract infection (UTI) is an acute, bacterial infection of the urinary tract, which is accounting for around 8 million patient visits annually.,, It is very common in females where the infection seems to colonise the vagina and ascend into the urinary system. It is estimated that 1 in 3 women will have had a UTI by the age of 26 years. 25%–30% of adult women with the first episode of UTI have a recurrence and the risk factors associated with an increased likelihood of UTI in women include urinary tract obstruction, urinary catheterisation, neurologic malfunction, pregnancy and use of spermicides, a diaphragm or anticholinergic agents. UTIs are generally diagnosed based on the presence of a microorganism with a count of ≥105 CFU/mL in a clean-catch midstream urine specimen. Escherichia More Details coli is the predominant pathogen in UTIs followed by Staphylococcus saprophyticus, Enterococcus faecalis and occasionally Klebsiella pneumoniae and Proteus mirabilis.
| ~ Recurrent Urinary Tract Infection in Women|| |
Mabeck found in his study that nearly one-half of the women whose uncomplicated UTIs resolved spontaneously developed a recurrent UTI (rUTI) within the 1st year. A rUTI is common and significant healthcare problem worldwide amongst women and even more so in specific patient populations which include the ones with spinal cord injury and neurogenic bladder as well as patients with long-term urinary catheter. The rUTI is symptomatic UTI, presenting as increased frequency of micturition, dysuria or irritative voiding symptoms and is most commonly caused by reinfection with the original bacterial isolate in healthy women with no anatomic or functional abnormalities of the urinary tract which follows UTI resolved clinically. A study reported that about 27% of young college-going females experienced at least one culture-confirmed recurrence within the 6 months following the initial infection and 2.7% had the second recurrence over this time period. A study by Ikäheimo et al. has been reported that women aged 17–82 years had E. coli cystitis, 44% had a recurrence within 1 year, 53% in women older than 55 years and 36% in younger women showing that older women are more prone to recurrences. Although it is not documented, it is estimated that about 10%–15% of women over 60 years of age have frequent recurrences. Further, no studies on large-scale population have been conducted to determine the pattern of high-frequency recurrence among women with UTI. It has been hypothesised that the vast majority of recurrences of cystitis are reinfections by the strains present in the faecal flora which after elimination from the urinary tract recolonise it and cause the recurrent infections and also that these strains by colonising into the epithelium of the bladder resist host defences and cause rUTI. Recurrence of UTI occurs because of either relapse or reinfection. From clinical and therapeutic point of view, it is useful to distinguish between relapse and reinfection as a vast majority of population is thought to represent relapses, although mostly they are reinfections. A reinfection is termed as recurrence when it is caused by a strain different from that causing the original infection and is difficult to distinguish from relapse. Thus, clinically a recurrence is often defined as a relapse if it is caused by the same species of organism as that causing the original UTI and if it occurs within 2 weeks after treatment. It is considered as reinfection if it occurs after >2 weeks treatment of the original UTI. It would be an exceptional situation where the urine culture after treatment shows no growth and again the infection is caused by the same organism, and is thus counted as reinfection, most of which appear to occur in first 3 months after initial UTI with exception in some studies., In a study, done on college women with uncomplicated cystitis who were treated with a variety of antimicrobial agents, only about 6% had persistent infection (relapse) which occurred within a week of the start of the therapy whereas in others having 'complicating factors', around 80% of the recurrences were episodes of reinfection and were months apart.,, Antibiotic prophylaxis with agents such as trimethoprim/sulfamethoxazole, nitrofurantoin and fluoroquinolones has been associated with decreasing the rate of recurrence, from 2 to 3 cases per patient-year to 0.1–0.2 cases per patient-year, which also leads to the disruption of normal flora of the urinary tract and increase the development of resistance in uropathogens. The emergence of the problematic resistance like extended spectrum beta-lactamases and carbapenem-resistant E. coli warrants the need to explore the novel agents which have less side effects and promise long-term antimicrobial prophylaxis.
| ~ Probiotics|| |
Nobel laureate Elie Metchnikoff in the early 1900s proposed that the long life of Bulgarian Peasants resulted from their consumption of fermented milk products. He also observed the positive role of some bacteria, which further suggested that these bacteria could be administered into the host and could be promising in the replacement of harmful microbes with them. They were further given the term 'probiotics'. The term 'probiotics' was derived from the Greek word, meaning 'for life' which was first coined in the 1960s by Lilly and Stillwell., Food and FAO/WHO later defined probiotic as 'live microorganisms', which when administered in adequate amounts confers a health benefit on the host. Various bacterial genera most commonly used in probiotic preparations are Lactobacillus, Bifidobacterium, Escherichia, Enterococcus, Bacillus and Streptococcus, as well as certain non-pathogenic strains of E. coli, and some fungal strains belonging to Saccharomyces., The strains, which are able to implant inside the body and are further able to tolerate the harsh conditions, are considered as ideal probiotics and are the ones who have received the most clinical attention., The probiotic organisms enhance the body's immunity by increasing the number of immunoglobulins (IgA) and other immunoglobulin-secreting cells in the mucosal membranes, stimulating local release of interferons and facilitating antigen transport to underlying lymphoid cells, which serves to increase antigen uptake in Peyer's patches.
| ~ Why Probiotics?|| |
The flora of the skin and mucosal surfaces acts as an important barrier to infection, and within this normal bacterial flora, host defence is ensured through a balance between non-pathogenic commensals and pathogenic bacteria. In immunocompromised host as well as those who undergo antibiotic treatment, the natural protective biofilm of bacteria and surface-cells is disrupted. This correlates with human immunodeficiency virus positive (HIV+) patients in whom Lactobacillus colonisation of the urogenital tract is diminished and which leads to the shedding of HIV into the tract. Disruption of the natural flora renders patients prone to severe infection that could involve several pathogenic microorganisms. A strategy to restore a host-supportive bacterial flora involves the use of probiotics.
There are two main scientific concepts associated with probiotics:
- i. First is competitive theory where live microorganisms administered orally or applied to the genital area overgrow pathogenic flora and restore an environment resistant to infections. Moreover, probiotics can exhibit a synergistic effect with antibiotics
- And, the second which is little controversial is based on modulation of the immune system where live microorganisms are known to influence production of immunoglobulins, thus altering the body's immune defence and contribute to a specific immune response against pathogenic bacteria.,
The term 'friendly bacteria' is often used as an alternative term for 'probiotics' and is widely used nowadays instead of chemotherapeutic agents in yoghurts and probiotics drinks. Lactobacillus and Bifidobacterium species are the potential candidates of probiotics therapy. They have generally regarded as safe status. Probiotics are used for their protective properties such as antimicrobial, antioxidant, antidiarrheal, anticancerous, antilipidemic and also for their lactose intolerance activity and helps in the treatment and prevention of diseases. Probiotics exert beneficial effects by various protective mechanisms such as maintaining the acidic pH, bacteriocins, production of hydrogen peroxide, prevention of colonisation of pathogen, antimicrobial activity, degrading the toxins and stimulation of immunity of the host.
The dominant presence of Lactobacilli in the urogenital microflora of healthy women and the obliteration of Lactobacilli in patients who develop UTI, bacterial vaginosis (BV) and many other genital infections including candidiasis has led to a focus on these bacteria.,, Lactobacilli are Gram-positive rods, primarily facultative or strict anaerobes that generally have a fastidious growth requirement. They prefer an acidic environment and help create one by producing lactic and other acids. In general, Lactobacilli have not been associated with disease and for >100 years have been regarded as non-pathogenic members of the intestinal and urogenital floras. Lactobacilli have long been of interest to the dairy and agriculture industries., Over the past century, studies in relation to human health were sporadic and often inconclusive. Some examples can be found in which lactic acid bacteria have been used to treat or prevent infections of the intestinal and genital tracts with different degrees of success.,
| ~ How Vaginal Lactobacilli Exert Their Health Promoting Effects|| |
Since Lactobacilli appear to be a hallmark of a healthy vaginal ecosystem, it is important to understand how they can exert important health-promoting effects, because knowledge on the exact molecular mediators can also promote the discovery and implementation of biomarkers. Postulated direct and indirect anti-pathogenic mechanisms of Lactobacilli include
- Production of lactic acid and bacteriocins that directly kill or inhibit bacterial and viral pathogens
- Formation of microcolonies that adhere to the epithelial cell receptors and form a physical barrier against pathogen adhesion and
- Stimulation of host defence mechanisms against pathogens.
Yet again, although the health benefits of vaginal Lactobacilli are widely recognised, they have been poorly substantiated by molecular studies.
[TAG:2]Probiotics– Lactobacillus Strains To Restore Vaginal Health[/TAG:2]
Since a healthy vaginal microbiota is mainly dominated by Lactobacillus species, the perspective of using exogenously applied Lactobacillus probiotics to restore and/or maintain vaginal health becomes feasible [Figure 1]. Various studies have been performed to investigate the role of single or a combination of probiotics for the treatment of BV as the most common vaginal disorder. Furthermore, several studies also showed the potential of exogenously administered probiotics for the treatment of another common vaginal disorder, namely, candidiasis. For reasons not yet understood, not all Lactobacilli are able to colonise the vagina. The three strains, Lactobacillus brevis CD2, Lactobacillus salivarius FV2 and Lactobacillus gasseri MB335, have been selected for their ability to adhere to vaginal epithelial cells, production of H2O2 and co-aggregation with pathogens. The same strains were later used in a study against Chlamydia trachomatis infection which suggested that a healthy vaginal microbiota can reduce the risk of acquiring C. trachomatis infection and counteract the development of persistent chlamydial forms. Another recent study has reported that the vaginal tablets containing Lactobacilli can cure BV and reduce vaginal inflammatory response. The effect on vaginal malodours could be ascribed to the strain L. brevis CD2 producing high levels of arginine deaminase (US patent No. 6572854). The enzyme downregulates the polyamine synthesis.
| ~ Probiotics Enhance The Immune Response In Host|| |
Innate immune system is the first line of defence against microorganisms. Epithelial cells also secrete an array of chemokines and cytokines, which are crucial for the recruitment and activation of innate immune cells., In spite of these mechanisms, there are some receptors known as TLRs, which are a class of proteins, spanning and non-catalytic entities. They recognise structurally conserved molecules derived from microbes. TLRs are now regarded as the key molecules that alert the immune system in the presence of microbial infections. It has been reported that oral probiotic supplementation is able to influence the mucosal sites different from intestine microorganisms due to the existence of the common mucosal immune system. In this sense, after delivering the intestinal antigens to Peyer's patches, both B and T cells can migrate from Peyer's patches to mucosal membranes of the respiratory, gastrointestinal and genitourinary tract, as well as to exocrine glands such as the lacrimal, salivary, mammary and prostatic glands. Previous studies have shown that Lactobacillus species in the form of probiotics reduce the incidence of UTI and vaginal infections. However, downregulating the production of proinflammatory cytokines (interleukin-6 [IL-6], IL-8, tumour necrosis factor alpha) seems to constitute the important mechanisms for partial amelioration of UTI in various models.,,
In a study done to see the effectiveness of Lactobacilli on vaginal health and proinflammatory cytokines, Lactobacilli tablet was found to be better than the pH tablet in preventing BV in healthy subjects. A significant reduction in IL-1 β and IL-6 vaginal cytokines was observed after treatment with Lactobacilli, while the active comparator did not have any effect on local proinflammatory cytokines.
Commensal bacteria such as Lactobacillus species and Bifidobacterium species are known to produce immune-regulatory factors that may enhance infection in the host by modulating immune responses. Such immune modulins may have important roles in maintaining intestinal health and quenching systemic inflammatory responses. It has been observed that the two major bacterial cell wall components, peptidoglycan in the case of Gram-positive bacteria and lipopolysaccharides (LPSs) in Gram-negative bacteria, are important molecular markers recognised by the immune system. It has been observed that intestinal epithelium and uroepithelium contain several TLRs such as TLR2, TLR3, TLR4 and TLR5.,
TLRs recognise microbial antigens commonly referred to as pathogen-associated molecular patterns. TLRs recognise various microbial products such as LPS, peptidoglycan, lipoprotein and DNA. Stimulation of these receptors is responsible for the induction of acute inflammatory responses. It also improves the capacity of professional antigen-presenting cells to stimulate T cells. Hence, the system of pathogen recognition receptors including the TLRs is able to sense danger signalling and thus activate the host immune system of the genitourinary tract., TLRs are expressed on immune cells such as lymphocytes, macrophages and dendritic cells as well as found in close proximity of epithelial cells. TLRs differentially activate distinct signalling events via cofactors and adaptor proteins, which leads to the activation and nuclear translocation of transcription factors. These factors modulate the expression of pro- and anti-inflammatory cytokines and chemokines, which in turn regulate the activities of the innate and the adaptive immune responses. It has been observed that TLR4 activates a sequence of intracellular signals, which further results in activation of the transcriptional factor, NF-kβ, and the production of several NF-kβ dependent cytokines including some chemoattractants, reactive oxygen species that manages the phagocytic cells to clear the infection or infectious particles.,, TLR4 stimulates a complex array of events that may lead to cell death and even cell proliferation in others.
| ~ Trials With Probiotics|| |
Because the potential of certain probiotic strains to balance the intestinal microbiota improves the mucosal barrier function and restores the vaginal health, numerous trials have been conducted to check the efficacy of probiotics in UTI patients. A few trials examined the effect of oral probiotic administration on UTI patients which have been proved to be more effective with compared to vaginal suppositories. There are small studies where the use of probiotics in renal calculi due to enteric hyperoxaluria, recurrent candida vulvo-vaginitis as well as UTIs has been conducted.,, Other studies have shown encouraging results on patients with neurogenic bladder where non-pathogenic E. coli as probiotic organism was used., No trials with probiotics on rUTI female patients have been performed or reported in India till date. In a study, Darouiche et al. tested the topical use of probiotics in patients with neurogenic bladder and used the benign strains of E. coli, and found decreased rates of rUTI especially in those, where the bladder was successfully colonised. Also, the rate of symptomatic UTI was reduced in patients where the urinary catheters were coated with probiotic microorganisms in contrast to catheters, which were coated with antimicrobials. In a pilot study, women were given Lactobacilli in the form of vaginal suppository, resulted in the reduction of E. coli positive cultures from 5.0 ± 1.6 episodes to 1.3 ± 1.2, P < 0.0007 over a 12-month period. In a trial with oral probiotics, using two strains Lactobacillus rhamnosus and Lactobacillus reuteri, 280 post-menopausal women were randomised to receive either oral probiotics or standard antibiotic treatment for rUTI. Treatment was given for 12 months with a follow-up of 3 months. In another trial in the US, 100 pre-menopausal women were randomised to receive either placebo or topical Lactobacilli (Lactobacillus crispatus) as a vaginal capsule for 3 months with a follow-up of 6 months. Neither of these trials compared pre-menopausal to post-menopausal treatment with probiotics and it was concluded that probiotics are not expected to completely eradicate infections, but they lower the rate of recurrence and prevent development of bacterial resistance to antimicrobials. In a recent randomised, double-blind study, the effectiveness of vaginal tablets containing Lactobacilli versus pH tablets was checked on vaginal health and inflammatory cytokines, and they concluded that those Lactobacilli containing vaginal tablets were able to cure vaginal infection and reduce vaginal inflammatory response. In a recent meta-analysis done by Grin et al., the trials with probiotics on pre-menopausal females with rUTI were evaluated. It concluded that probiotic strains of Lactobacillus are safe and effective in preventing rUTI in adult women, but more randomised controlled trials (RCTs) are required before making any definitive recommendation since the patient population contributing data to this meta-analysis were small. In 2011, Stapleton et al. demonstrated the randomised, placebo-controlled phase 2 trial that 100 pre-menopausal women with rUTI randomised to an intravaginal probiotic, L. crispatus, for 10 weeks, reported significantly lower recurring UTIs in women achieving high-level vaginal L. crispatus, in contrast women in placebo group shown a non-significant reduction in UTIs. They found that L. crispatus was associated with reduced symptomatic UTIs. The study from Abdulwahab et al. has been reported that culture of vaginal swabs of 200 (100 healthy women and isolates from 100 women with rUTIs) of asymptomatic women identified Lactobacilli and inhibitory effect of Lactobacilli isolates on uropathogenic E. coli could be seen. The oral adjuvant capacity of probiotics (L. rhamnosus GR-1 and L. reuteri RC-14) has been demonstrated by Beerepoot et al. Probiotics can be regarded as the single most powerful alternative option under clinical development for the prevention and treatment of chronic infection. Given the enormous burden on patients, as well as the scientific and economic problem caused by rUTI, the studies on probiotics are of potentially crucial importance for patient benefit and clinical science. Laboratory and clinical research on live microorganisms have opened a major research field for more investigations and trials. The interaction of complex human bacterial population with the human body has not been studied extensively. From evolutionary point of view, live microorganisms have provided the human body with crucial functions in digestion and immune modulation. The human body did not have to develop these functions and has been employing the hosted flora of microorganisms as a metabolic organ exquisitely tuned to our physiology on its outer surfaces. The bacterial flora of the gut has a weight of approximately 1–2 kg and is thought to be metabolically as important as the liver. As the live microorganisms used in probiotics are often isolated from the human flora, trials with specific probiotics will help elucidate the role of these bacteria in the human body's eco-system. Lactobacilli species present in healthy vagina of women in India have been found to be different from those reported from other countries. This information is useful in the development of probiotic tablets seeking to replenish the missing Lactobacilli in the vagina of females and might help in the prevention and treatment of different infections by foreign pathogens.,
The harmful effects of antibiotics have always been somewhat overlooked. The scientific importance of trials with probiotics is not only to investigate their potential use in recurrent infection but also the containment and therapy of the side effects of antimicrobial chemotherapy itself. A major concept in urological therapy is to prevent the recurrence of UTI. Investigations on live microorganisms derived from the human gut flora will drive forward the field of preventive medicine in the therapy of rUTI. Similar to nutritional aspects in medicine, probiotics acknowledge the complex nature of infection. Despite longstanding knowledge of immunosuppressive effects of poor nutrition, the introduction of perioperative enteral nutrition has only recently been developed. Perioperative enteral nutrition has a major impact on the body's ability to resist infection. This view and treatment strategy has now been added to antibiotic therapy for infection in most surgical specialties, giving evidence of the need for complementary anti-infective prevention and treatment., Despite definitive clinical evidence on the positive effects of probiotics, so far sufficiently powered studies using probiotics in rUTI have only recently been commenced., The cited studies have not been reported any serious side effects or intolerance, but suggested that severely immunocompromised hosts may only be trialed with caution. Previous studies have been reported that patients experienced no side effects on administering Lactobacillus probiotics orally. In addition, L. rhamnosus GR-1 has been shown to colonise the vagina after oral administration of >109 CFU twice daily for 14 days in a different study. Therefore, oral administration might be a feasible solution to the occurrence of side effects and could result in better patient compliance. The risk factors that lead to UTI in pre-menopausal women are different from those in other groups which include recent sexual intercourse, use of a diaphragm with spermicide or spermicidal condoms, prior history of UTI and recent antimicrobial use. These factors and others appear to either cause or result into the depletion of Lactobacilli in the vaginal microbiome, which further allows uropathogens to colonise the vagina and later ascend into the urinary tract. This further suggests that the use of Lactobacillus suppositories could reduce the risk caused by these factors by simply restoring the normal vaginal microbiota, and maintaining a healthy vaginal acidic pH by producing lactic acid thus restoring protection against uropathogens at the point of entry and further inhibiting their survival. Some other probiotic strains such as L. rhamnosus GR-1 and L. crispatus CTV-05 produce H2O2, a strong antimicrobial that induces membrane stress on uropathogenic bacteria. This further leads to a stress condition which further prevents the growth of E. coli and prevents its adhesion to the vaginal epithelium. Along with L. rhamnosus GR-1 and L. crispatus CTV-05, Lactobacillus fermentum B-54 has also shown in clinical trials to be highly capable of colonisation and survival within the vaginal environment.,
| ~ Conclusion|| |
rUTI is a challenging condition among women of all ages. The frequent and indiscriminate use of antibiotics has led to the development of increased antibiotic resistance, thus warranting a need to explore the novel therapeutic agents for prevention and reduce the incidence of rUTI. Although promising, the current literature is inconclusive regarding the use of probiotics for preventing rUTIs since no large clinical trials have been performed. Several recent reviews suggested that Lactobacillus probiotics are safe and effective in preventing rUTIs, but cannot be recommended clinically due to absence of evidence from large clinical trial. In addition, the trial designs do not describe precautions or scenarios on the use of probiotics in episodes of UTI severe enough to require additional treatment. The studies we reviewed confirm that Lactobacillus suppositories could be used safely; some patients experienced only mild side effects. We also found that no serious adverse events have been caused by Lactobacillus in studies involving healthy pre-menopausal women, which supports the case for carrying out additional clinical trials. Until further research is completed, the probiotic strains of Lactobacillus delivered in suppositories may be considered, but not definitively recommended. They could be regarded as a safe alternative to antimicrobials for UTI prophylaxis in high-risk women when antimicrobial resistance is the issue. This issue needs to be explored further in reference to the UTIs. Therefore, future RCTs should study these strains, for longer period, to build upon the existing evidence for efficacy of these probiotics in prevention of rUTI.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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