Urinary tract infections (UTIs) are among the most common bacterial infections, representing a massive burden on healthcare systems and accounting for significant morbidity and healthcare expenditure. As bacteria generally cause UTIs, the primary therapy is defined by antibiotics, whose wide use can cause antibiotic resistance. In this scenario, using nutraceuticals to manage UTIs is an attractive alternative.
This study aims to test the in vitro efficacy of a new food supplement for treating UTIs containing D-mannose, palmitoylethanolamide, HibCyn® (hibiscus extract), N-acetylcysteine and microencapsulated Lactobacillus rhamnosus LR04.
The activity of the product was evaluated in terms of antimicrobial, antibiofilm, cytotoxic, antiinflammatory, and synergic activity with fosfomycin with respect to the main microorganisms responsible for UTIs, specifically Klebsiella pneumoniae, Enterococcus faecium, and Escherichia coli.
“UTIVAL” food supplement has an action on both the inhibition and eradication of the biofilms formed by all the microorganisms. In the in vitro tests performed in this study, the activity of the product was effective at a concentration of 0.78 g/l.
It was also possible to affirm that the product has an inhibiting effect on inflammation mediated by tumor necrosis factor αlfa (TNFα) in a concentration range of 0.04 to 0.625 mg/ml.
Foxman B. The epidemiology of urinary tract infection. Nature Reviews Urology 2010; 7: 653-60. https://doi.org/10.1038/nrurol.2010.190
Griebling TL. Urologic diseases in america project: trends in resource use for urinary tract infections in women. Journal of Urology 2005; 173: 1281-7. https://doi.org/10.1097/01.ju.0000155596.98780.82
Foxman B, Brown P. Epidemiology of urinary tract infections: transmission and risk factors, incidence, and costs. Infectious Disease Clinics of North America 2003; 17: 227-41. https://doi.org/10.1016/S0891-5520(03)00005-9
Sannathimmappa MB, Nambiar V, Aravindakshan R. Antibiotics at the crossroads - Do we have any therapeutic alternatives to control the emergence and spread of antimicrobial resistance? Journal of Education and Health Promotion 2021; 10: 438.
Ventola CL. The antibiotic resistance crisis: part 1: causes and threats. P & T : A Peer-Reviewed Journal for Formulary Management 2015; 40: 277-83.
Foxman B. Epidemiology of urinary tract infections: incidence, morbidity, and economic costs. The American Journal of Medicine 2002; 113: 5-13. https://doi.org/10.1016/S0002-9343(02)01054-9
Mazzulli T. Resistance trends in urinary tract pathogens and impact on management. The Journal of Urology 2002; 168: 1720-2. https://doi.org/10.1016/S0022-5347(05)64397-2
Yarnell E. Botanical medicines for the urinary tract. World Journal of Urology 2002; 20: 285-93. https://doi.org/10.1007/s00345-002-0293-0
Das S. Natural therapeutics for urinary tract infections—a review. Future Journal of Pharmaceutical Sciences 2020; 6: 64. https://doi.org/10.1186/s43094-020-00086-2
Forster CS, Hsieh MH, Cabana MD. Perspectives from the Society for Pediatric Research: Probiotic use in urinary tract infections, atopic dermatitis, and antibiotic-associated diarrhea: an overview. Pediatric Research 2021; 90: 315-27. https://doi.org/10.1038/s41390-020-01298-1
Aragón IM, Herrera-Imbroda B, Queipo-Ortuño MI, Castillo E, del Moral JS-G, Gómez-Millán J, et al. The Urinary Tract Microbiome in Health and Disease. European Urology Focus 2018; 4: 128-38. https://doi.org/10.1016/j.euf.2016.11.001
Hanson L, VandeVusse L, Jermé M, Abad CL, Safdar N. Probiotics for Treatment and Prevention of Urogenital Infections in Women: A Systematic Review. Journal of Midwifery & Women’s Health 2016; 61: 339-55. https://doi.org/10.1111/jmwh.12472
Beerepoot MAJ, Geerlings SE, van Haarst EP, van Charante NM, ter Riet G. Nonantibiotic Prophylaxis for Recurrent Urinary Tract Infections: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Journal of Urology 2013; 190: 1981-9. https://doi.org/10.1016/j.juro.2013.04.142
Fraile B, Alcover J, Royuela M, Rodríguez D, Chaves C, Palacios R, et al. Xyloglucan, hibiscus and propolis for the prevention of urinary tract infections: results of in vitro studies. Future Microbiology 2017; 12: 721-31. https://doi.org/10.2217/fmb-2017-0015
Munita JM, Arias CA. Mechanisms of Antibiotic Resistance. Microbiology Spectrum 2016; 4. https://doi.org/10.1128/microbiolspec.VMBF-0016-2015
Flores-Mireles AL, Walker JN, Caparon M, Hultgren SJ. Urinary tract infections: epidemiology, mechanisms of infection and treatment options. Nature Reviews Microbiology 2015; 13: 269-84. https://doi.org/10.1038/nrmicro3432
Stamm WE, Norrby SR. Urinary Tract Infections: Disease Panorama and Challenges. The Journal of Infectious Diseases 2001; 183: S1-4. https://doi.org/10.1086/318850
Xia J, Yang C, Xu D, Xia H, Yang L, Sun G. Consumption of cranberry as adjuvant therapy for urinary tract infections in susceptible populations: A systematic review and meta-analysis with trial sequential analysis. PLOS ONE 2021; 16: e0256992. https://doi.org/10.1371/journal.pone.0256992
Altarac S, Papeš D. Use of d-mannose in prophylaxis of recurrent urinary tract infections (UTIs) in women. BJU International 2014; 113: 9-10. https://doi.org/10.1111/bju.12492
LoVerme J, la Rana G, Russo R, Calignano A, Piomelli D. The search for the palmitoylethanolamide receptor. Life Sciences 2005; 77: 1685-98. https://doi.org/10.1016/j.lfs.2005.05.012
Kelly GS. Clinical applications of N-acetylcysteine. Alternative Medicine Review : A Journal of Clinical Therapeutic 1998; 3: 114-27.
Allameh Z, Salamzadeh J. Use of antioxidants in urinary tract infection. Journal of Research in Pharmacy Practice n.d.; 5: 79-85. https://doi.org/10.4103/2279-042X.179567
Margiotta G, Ferretti S, Graglia B, Gatto A, Capossela L, Bersani G, et al. Effect of Lactobacillus reuteri LRE02-Lactobacillus rhamnosus LR04 combination and gastrointestinal functional disorders in an Emergency Department pediatric population. European Review for Medical and Pharmacological Sciences 2021; 25: 3097-104.
Giacometti A, Cirioni O, Barchiesi F, del Prete MS, Fortuna M, Caselli F, et al. In vitro Susceptibility Tests for Cationic Peptides: Comparison of Broth Microdilution Methods for Bacteria That Grow Aerobically. Antimicrobial Agents and Chemotherapy 2000; 44: 1694-6. https://doi.org/10.1128/AAC.44.6.1694-1696.2000
Mann CM, Markham JL. A new method for determining the minimum inhibitory concentration of essential oils. Journal of Applied Microbiology 1998; 84: 538-44. https://doi.org/10.1046/j.1365-2672.1998.00379.x
Munoz-Price LS, Poirel L, Bonomo RA, Schwaber MJ, Daikos GL, Cormican M, et al. Clinical epidemiology of the global expansion of Klebsiella pneumoniae carbapenemases. The Lancet Infectious Diseases 2013; 13: 785-96. https://doi.org/10.1016/S1473-3099(13)70190-7
Mitsuya Y, Kawai S, Kobayashi H. Influence of macrolides on guanosine diphospho-d-mannose dehydrogenase activity in Pseudomonas biofilm. Journal of Infection and Chemotherapy 2000; 6: 45-50. https://doi.org/10.1007/s101560050049
Al Zuhairi JJMJ, Jookar Kashi F, Rahimi-Moghaddam A, Yazdani M. Antioxidant, cytotoxic and antibacterial activity of Rosmarinus officinalis L. essential oil against bacteria isolated from urinary tract infection. European Journal of Integrative Medicine 2020; 38: 101192. https://doi.org/10.1016/j.eujim.2020.101192
Lee S-J, Park S-S, Cho Y-H, Park K, Kim E-J, Jung K-H, et al. Activation of matrix metalloproteinase-9 by TNF-α in human urinary bladder cancer HT1376 cells: The role of MAP kinase signaling pathways. Oncology Reports 2008. https://doi.org/10.3892/or.19.4.1007
Moazzezy N, Asadi Karam MR, Rafati S, Bouzari S, Oloomi M. A Synthetic Peptide 2Abz23S29 Reduces Bacterial Titer and Induces Proinflammatory Cytokines in a Murine Model of Urinary Tract Infection. Drug Design, Development and Therapy 2020; 14: 2797-807. https://doi.org/10.2147/DDDT.S259937
Gonzalez S. TNF-$alpha; $minus; 308A promoter polymorphism is associated with enhanced TNF-$alpha; production and inflammatory activity in Crohn?s patients with fistulizing disease. The American Journal of Gastroenterology 2003; 98: 1101-6. https://doi.org/10.1016/S0002-9270(03)00134-5
Rand KH, Houck HJ, Brown P, Bennett D. Reproducibility of the microdilution checkerboard method for antibiotic synergy. Antimicrobial Agents and Chemotherapy 1993; 37: 613-5. https://doi.org/10.1128/AAC.37.3.613
Chen M, Li Y, Li S, Tang L, Zheng J, An Q. Genomic identification of nitrogen-fixing Klebsiella variicola, K. pneumoniae and K. quasipneumoniae. Journal of Basic Microbiology 2016; 56: 78-84. https://doi.org/10.1002/jobm.201500415
Ng ZJ, Zarin MA, Lee CK, Phapugrangkul P, Tan JS. Isolation and characterization of Enterococcus faecium DSM 20477 with ability to secrete antimicrobial substance for the inhibition of oral pathogen Streptococcus mutans UKMCC 1019. Archives of Oral Biology 2020; 110: 104617. https://doi.org/10.1016/j.archoralbio.2019.104617
Pinto L, Poeta P, Radhouani H, Coelho C, Carvalho C, Rodrigues J, et al. Proteomic evaluation of Escherichia coli isolates from human clinical strains. Journal of Integrated OMICS 2011; 1. https://doi.org/10.5584/jiomics.v1i1.20
Ellner PD. The Inhibitory Quotient. JAMA 1981; 246: 1575. https://doi.org/10.1001/jama.1981.03320140063033
Falagas ME, Vouloumanou EK, Samonis G, Vardakas KZ. Fosfomycin. Clinical Microbiology Reviews 2016; 29: 321-47. https://doi.org/10.1128/CMR.00068-15
Richards DM, Heel RC, Brogden RN, Speight TM, Avery GS. Ceftriaxone A Review of its Antibacterial Activity, Pharmacological Properties and Therapeutic Use. Drugs 1984; 27: 469-527. https://doi.org/10.2165/00003495-198427060-00001
Gupta A. Original Research Article Biofilm Quantification and Comparative Analysis of MIC (Minimum Inhibitory Concentration) & MBIC (Minimum Biofilm Inhibitory Concentration) Value for Different Antibiotics against E. coli. vol. 4. 2015.
Verma P. Minimum Biofilm Eradication Concentration (MBEC) Assay of Silver and Selenium Nanoparticles against Biofilm forming Staphylococcus aureus. Journal of Medical Science And Clinical Research 2017; 05. https://doi.org/10.18535/jmscr/v5i4.77
Okuda T, Kokubu E, Kawana T, Saito A, Okuda K, Ishihara K. Synergy in biofilm formation between Fusobacterium nucleatum and Prevotella species. Anaerobe 2012; 18: 110-6. https://doi.org/10.1016/j.anaerobe.2011.09.003
Namivandi-Zangeneh R, Sadrearhami Z, Bagheri A, Sauvage-Nguyen M, Ho KKK, Kumar N, et al. Nitric Oxide-Loaded Antimicrobial Polymer for the Synergistic Eradication of Bacterial Biofilm. ACS Macro Letters 2018; 7: 592-7. https://doi.org/10.1021/acsmacrolett.8b00190
Marks DC, Belov L, Davey MW, Davey RA, Kidman AD. The MTT cell viability assay for cytotoxicity testing in multidrug-resistant human leukemic cells. Leukemia Research 1992; 16: 1165-73. https://doi.org/10.1016/0145-2126(92)90114-M
Palin K, Bluthé R-M, McCusker RH, Levade T, Moos F, Dantzer R, et al. The type 1 TNF receptor and its associated adapter protein, FAN, are required for TNFα-induced sickness behavior. Psychopharmacology 2009; 201: 549-56. https://doi.org/10.1007/s00213-008-1331-4
Tsurufuji S, Sugio K, Takemasa F. The role of glucocorticoid receptor and gene expression in the antiinflammatory action of Dexamethasone. Nature 1979; 280: 408-10. https://doi.org/10.1038/280408a0
Clark MF, Lister RM, Bar-Joseph M. ELISA techniques, 1986; pp. 742-66. https://doi.org/10.1016/0076-6879(86)18114-6
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