BERKELEY, CA (UroToday.com) - Recurrent urinary tract infections (UTIs) are a common problem affecting both women and men.[1,2] In light of the increasing prevalence of resistance of uropathogens against antimicrobial agents,[3,4] an alternative treatment against UTIs is warranted.
Recent studies have suggested that uropathogenic Escherichia coli are invasive to bladder epithelial cells, which facilitates the formation of a quiescent intracellular reservoir. Such bacteria that form this reservoir can persist for months following initial infection, resist antibiotic treatment, and can cause recurrent UTIs.[5, 6] In animal studies, it has been shown that statins can interfere with this bacterial invasion, possibly by inhibiting Rac1 membrane expression;[7, 8, 9, 10, 11, 12] however, epidemiological evidence is from non-randomized studies and is controversial.[13, 14] Therefore, we investigated the effect of statins on the occurrence of recurrent UTIs conducting a post-hoc analysis of the PREVEND-IT trial.
The PREVEND-IT trial is a randomized, placebo-controlled trial that was designed to assess whether pravastatin, fosinopril, or both might prevent cardiovascular and renal disease in non-hypertensive, non-hypercholesterolaemic adults with persistent microalbuminuria. We linked the clinical data with a large prescription database and used UTI antibiotic prescriptions (nitrofurantoin, trimethoprim, sulphonamide) as a proxy measure for UTIs.
In intention-to-treat analysis, pravastatin was associated with a reduction in the total number of UTIs (relative risk 0.43, 95% confidence interval 0.21-0.88) and second UTIs, but not the number of first UTIs compared with placebo.
In the placebo group, 34 subjects received a first UTI antibiotic prescription, while based on age- and gender-specific figures from the general Dutch population, 22 first UTIs would be expected. The difference can be explained because all trial participants had persistent microalbuminuria and they were at increased risk of developing de novo renal function impairment. Moreover, since an increased Rac1 activity can cause microalbuminuria,[17, 18] the study population most likely had an elevated Rac1 membrane expression which elevates the risk for recurrent UTIs.
This post hoc analysis has some potential limitations. We used specific antibiotic prescriptions obtained from a pharmacy prescription database as a proxy for UTIs. Although misclassification of the clinical outcome UTI may have occurred, we expect this to be random, because we used the same objective outcome definition for each treatment group. Since random misclassification generally biases the results to a null finding, using a proxy has not likely resulted in an overestimation of the effect of pravastatin. Moreover, prescription rates for other antibiotics used to treat UTIs were similar across the different groups.
The study sample was predominantly healthy and male, and we excluded patients with UTIs in the previous 6 months (n=16), which could have limited the generalizability of our results.
In summary, this post-hoc analysis suggests that pravastatin can reduce the risk of recurrent UTIs. Given the mechanism involved, future studies should preferably be performed in patients with elevated Rac1 membrane expression in the urinary tract.
- Hundstad DA, Justice SS. Intracellular lifestyles and immune evasion strategies of uropathogenic Escherichia coli. Annu Rev Microbiol 2010;64:203-21.
- Lipsky BA. Urinary tract infections in men: epidemiology, pathophysiology, diagnosis, and treatment. Ann Intern Med 1989;110:138-50.
- Sanchez GV, Master RN, Karlowsky JA, Bordon JM. In vitro antimicrobial resistance of urinary Escherichia coli isolates among U.S. outpatients from 2000 to 2010. Antimicrob Agents Chemother 2012;56:2181-3.
- Swami SK, Liesinger TJ, Shah N, Baddour LM, Banerjee R. Incidence of antibiotic-resistant Escherichia coli bacteriuria according to age and location of onset: a population-based study from omsted county, Minnesota. Mayo Clin Proc 2012;87:753-759.
- Mulvey MA, Schilling JD, Hultgren SJ. Establishment of a persistent Escherichia coli reservoir during the acute phase of a bladder infection. Infect Immun 2001;69:4572-9.
- Schilling JD, Mulvey MA, Vincent CD et al. Bacterial invasion augments epithelial cytokine responses to Escherichia coli through a lipopolysaccharide-dependent mechanism. J Immunol 2001;166:1148-55.
- Martinez JJ, Hultgren SJ. Requirement of rho-family GTPases in the invasion of type 1-piliated uropahtogenic Escherichia coli. Cell Host Microbe 2002;4:19-28.
- Burnham CA, Shokoples SE, Tyrrell GJ. Rac1, RhoA, and Cdc42 participate in HeLa cell invasion by group B streptococcus. FEMS Microbiol Lett 2007;272:8-14.
- Dechend R, Gieffers J, Dietz R et al. Hydroxymethylglutaryl coenzyme A reductase inhibition reduces chlamydia pneumoniae-induced cell interaction and activation. Circulation 2003;108:261-5.
- Zaas DW, Duncan M, Rae Wright J et al. The role of lipid rafts in the pathogenesis of bacterial infections. Biochim Biophys Acta 2005;1746:305-13.
- Horn MP, Knecht SM, Rushing FL et al. Simvastatin inhibits staphylococcus aureus host cell invasion through modulation of isoprenoid intermediates. J Pharmacol Exp Ther 2008;326:135-43.
- Rosch JW, Boyd AR, Hinojosa E et al. Statins protect against fulminant pneumococcal infection and cytolysin toxicity in a mouse model of sickle cell disease. J Clin Invest. 2010;120:627-35.
- Fleming DM, Verlander NQ, Elliot AJ et al. An assessment of the effect of statin use on the incidence of acute respiratory infections in england during winters 1998-1999 to 2005-2006. Epidemiol Infect 2010;138:1281-8.
- Smeeth L, Douglas I, Hall AJ et al. Effect of statins on a wide range of health outcomes: A cohort study validated by comparison with randomized trials. Br J Clin Pharmacol 2009;67:99-109.
- Pouwels KB, Visser ST, Hak E. Effect of pravastatin and fosinopril on recurrent urinary tract infections. J Antimicrob Chemother 2013;68:708-14.
- Verhave JC, Gansevoort RT, Hillege HL et al. An elevated urinary albumin excretion predicts de novo development of renal function impairment in the general population. Kidney Int Suppl. 2004;(92):S18-21.
- Mundel P, Reiser J. Proteinuria: an enzymatic disease of the podocyte? Kidney Int 2010;77:571-80.
- Shibata S, Nagase M, Yoshida S et al. Modification of mineralocorticoid receptor function by Rac1 GTPase: implication in proteinuric kidney disease. Nat Med 2008;14:1370-6.
Koen Pouwels, MSc and Eelko Hak, PhD as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.
Unit of PharmacoEpidemiology and PharmacoEconomics, Department of Pharmacy, University of Groningen, Groningen, The Netherlands