Skip to main content
F1000Research logoLink to F1000Research
. 2018 Dec 21;7:F1000 Faculty Rev-1964. [Version 1] doi: 10.12688/f1000research.16245.1

Recent advances in managing lower urinary tract infections

Seung-Ju Lee 1,a
PMCID: PMC6305210  PMID: 30613378

Abstract

Urinary tract infections (UTIs) are among the most common bacterial infections. Traditionally, all symptomatic UTIs are tested and treated. The use of antibiotics has resulted in an antibiotic resistance crisis, and we have limited options for managing UTIs. Currently, we live in the era of antimicrobial resistance and may live in other eras like the era of the microbiome. New insights might provide an opportunity to prevent the overuse and misuse of antibiotics and could enable the development of innovate managing strategies.

Keywords: Urinary tract infections, antimicrobial resistance, microbiome

Introduction

The world is changing rapidly; there is hardly anything in life that is not changing. Technological advancements have enriched our lives, but others have created fear and anxiety. The number of antibiotic-resistant pathogens is rapidly increasing, and many pathogens are becoming multidrug resistant (MDR) with the attendant increased risk of failure of standard therapies 1. Several decades ago, the first antibiotic saved our lives from bacterial infection, but now bacterial infections have again become a threat. The overuse and misuse of antibiotics, along with the development of few new drugs by the pharmaceutical industry, are the most important causes of the antibiotic resistance crisis 2.

Urinary tract infections (UTIs) are among the most common bacterial infections managed by clinicians 3. Traditionally, a UTI is defined as microbial infiltration of the normally sterile urinary tract, and most clinicians think all symptomatic UTIs should be treated 4, 5. Recently, however, the paradigm for the management of infectious diseases started to shift as the concept of the microbiome has been established 6.

Stop the overuse and misuse of antibiotics

Asymptomatic pyuria and bacteriuria are very common in the elderly, especially in women residing in long-term care facilities or in patients who use a urinary catheter, with a prevalence of 25–50% 7, 8. In older residents of long-term care facilities, diagnostic testing and the initiation of antibiotics should be reserved for residents with fever, dysuria, gross hematuria, worsening urinary frequency and incontinence, costovertebral angle tenderness, or suspected bacteremia. Non-specific symptoms and altered mental status are no longer part of the recommended evaluation for a possible UTI 9, 10. Asymptomatic bacteriuria also occurs in an estimated 1–5% of healthy pre-menopausal females, increasing to 0.7–27% of patients with diabetes, 2–10% of pregnant women, and 23–89% of patients with spinal cord injuries 11, 12. Asymptomatic bacteriuria does not cause systemic disorders, such as renal damage 13. Thus, the treatment of asymptomatic bacteriuria is not recommended in patients without risk factors 11. Avoiding antibiotic administration in cases where the urine culture does not indicate UTI may be the first step to decreasing antibiotic misuse 14.

For patients with non-febrile uncomplicated UTIs, active pain control and minimal use of antibiotics should be prioritized. Uncomplicated cystitis can be a self-limiting disease in some cases. Pain in acute cystitis is a natural consequence of the inflammatory response, and pain-mediated urinary frequency or urgency is the chief complaint of patients. Therefore, for this self-limited disease, painkillers, including NSAIDs, may be a good option for symptomatic care as well as reducing the consumption of antibiotics 15, 16. Delaying antibiotic treatment with a back-up prescription to see if symptoms will resolve without antibiotic treatment, or delaying the antibiotic until microbiological results are available, may be an option for antibiotic sparing 17.

Recently, multiplex PCR assays for the detection of sexually transmitted infection (STI) agents became commonplace in Eastern Europe, Western Europe, South America, and Asia 1820. However, the use of unnecessary antibiotics has increased by including strains other than “true” STIs such as Mycoplasma hominis, Ureaplasma urealyticum (previously U. urealyticum biovar 2), and Ureaplasma parvum (earlier U. urealyticum biovar 1) 21. M. hominis, U. urealyticum, and U. parvum are commonly detected in the urogenital tract of both healthy and symptomatic individuals 22, 23. Testing for M. hominis and U. parvum and subsequent antimicrobial treatment of positive men or women are currently not recommended. Instead, “true” STIs and bacterial vaginosis in symptomatic women should be diagnosed and treated 21. Bacterial vaginosis, sexually transmitted diseases (STDs), and pelvic inflammatory disease can mimic symptoms of UTIs. In fact, a recent study showed that approximately one-third of STD cases were misdiagnosed as UTIs 24.

The era of antimicrobial resistance

There are limited oral options for the treatment of antibiotic-resistant uropathogens associated with lower UTIs (acute cystitis). Co-trimoxazole was a typical antibiotic used to treat UTIs, but the resistance of Escherichia coli to this drug has markedly increased. According to the literature published in the past decade, the resistance rates of E. coli to co-trimoxazole varied but were usually over 15–30% 2528. However, there was an interesting report wherein the authors emphasized the role of co-trimoxazole in empirical antibiotics because of the recent decrease in the resistance rate to co-trimoxazole in several European countries owing to its low prescription rate 29. Nevertheless, it may not be possible to reuse the drug worldwide within the next few years, and close observation of surveillance data will be required.

With respect to fluoroquinolones, the increase of resistance in uropathogens has occurred at an alarming rate in relation to increased prescribing practices 27, 28. Fluoroquinolones are no longer recommended as first-line therapy for uncomplicated UTIs 11. Similar to what was seen with co-trimoxazole, there is evidence that escape from exposure to this antibiotic will increase antimicrobial susceptibility in UTIs. According to Lee et al., the susceptibility of Gram-negative bacteria to ciprofloxacin was much higher in patients younger than 20 years old than in patients older than 20 years old. The reason for this observation may be the lower exposure to fluoroquinolones in young individuals because these drugs are not recommended for use in those under 20 years old 30.

One recent issue of importance is the increasing prevalence of extended spectrum beta lactamase (ESBL)-producing uropathogens. Before 2010, the vast majority of countries showed less than a 5–10% prevalence of ESBL-producing E. coli, whereas the prevalence exceeded 10% in the local communities of many countries after 2010 3135. Therefore, the increase in ESBL-producing E. coli is no different to that of co-trimoxazole-resistant E. coli or fluoroquinolone-resistant E. coli, and the prevalence of ESBL-producing E. coli is likely to increase soon.

Use of re-emerging older antibiotics

Fosfomycin is an oral antibiotic agent that has broad activity against MDR uropathogens including ESBL-producing E. coli. Fosfomycin prevents peptidoglycan synthesis earlier than do beta-lactam or glycopeptide antibiotics and is broadly active against several Gram-positive and Gram-negative organisms, including methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus spp.. Fosfomycin has been shown to have advantages in the treatment of UTIs owing to its high concentration in the urinary tract, which exceeds 2,000 mg/L after the initial administration and remains at high levels for a prolonged period, over 24 hours. However, oral fosfomycin should not be used for pyelonephritis or in patients with bacteremia because of inadequate concentrations within the bloodstream 36, 37. Fosfomycin susceptibility in uropathogens, including E. coli, is currently greater than 90%, even in ESBL-producing E. coli 3840. It is safe to use in pregnancy 41. The drug is likely to be excreted in low levels in breast milk, but would not be expected to cause any adverse effects in breastfed infants, especially if the infant is older than two months. 42.

Another oral antimicrobial agent that can be considered for the treatment of ESBL-producing E. coli cystitis is nitrofurantoin. Nitrofurantoin is a drug that has been used since the 1950s to treat uncomplicated UTIs and works by damaging bacterial DNA in its highly active reduced form. Now, and even in earlier eras of widespread use, the baseline resistance to nitrofurantoin is low (0–10%) 43, 44. Nitrofurantoin should be used only for lower UTIs, and its use should be avoided in patients with a creatinine clearance of less than 60 mL/minute, as reduced renal function results in decreased active drug within the urine 45. Nitrofurantoin is one of the few drugs that can be used during pregnancy 46. A recent retrospective, matched-cohort study in older adults concluded that long-term use of nitrofurantoin is associated with greater risk of lung injury than acute exposure 47.

Role for non-antimicrobial prophylaxis

The active use of non-antimicrobial prophylaxis is often indicated and does not result in an increase in antimicrobial resistance of the commensal flora. Immunoactive agents, probiotics ( Lactobacillus spp.), cranberry-based products, D-mannose, methenamine hippurate, hormonal replacement (in post-menopausal women), and other options have been studied as non-antimicrobial prophylaxis 4853. Evidence for the use of non-antimicrobial prophylaxis is hampered by considerable heterogeneity, and further placebo-controlled randomized trials of these agents are needed. However, trials investigating these options have produced promising results and combining these agents may offer the best route to lowering the rate of recurrent UTIs without needing to use antimicrobials 54.

Among these modalities, the urinary immunopotentiator is now well documented and strongly recommended in the guidelines 11. The oral immunostimulant OM-89 (Uro-Vaxom ®), an extract of 18 different serotypes of heat-killed uropathogenic E. coli, stimulates innate immunity by increasing non-specific and specific humoral and cellular immune responses via the induction of interferon-γ and tumor necrosis factor-γ production as well as the activities of lymphocytes and macrophages 5557. Uro-Vaxom ® is a safe and effective medicine that can reduce recurrent UTI episodes 48, 5860 and can effectively reduce the repeated use of antibiotics 61. Uromune ® is a sublingual spray consisting of equal amounts of four common UTI-causing bacteria in a suspension of 10 9 inactivated whole bacteria/mL: E. coli; Klebsiella pneumoniae, Proteus vulgaris, and Enterococcus faecalis 54. The data from European prospective and retrospective studies suggest that Uromune ® is a viable alternative therapy for treating recurrent UTIs in women 62, 63.

The lower estrogen state found in postmenopausal women is linked with decreased innate immunity via the loss of the commensal bacteria Lactobacillus and the loss of the acidic pH microenvironment within the vagina. Although specific mechanisms are still poorly understood, estrogen plays a key role in modulating the natural defense of the lower urinary tract against UTIs 64. The role for topical (intravaginal cream, vaginal rings, impregnated pessary rings, vaginal pessaries, and vaginal tablets) estrogen in averting recurrent UTIs in postmenopausal women compared with placebo is clear, and guidelines for this population recommend their use 11, 65, 66. Currently, there is evidence that CO 2 ablative vaginal lasers may help rejuvenate this microenvironment, much like topical estrogen therapy, restoring the lactic acid synthesis of commensal bacteria and the innate vaginal defense against UTIs 6769. For postmenopausal women, vaginal estrogen therapy has been considered often as an adjunct to antimicrobial-based prophylaxis 70. However, combination therapy with both immunostimulants and vaginal therapy (laser rejuvenation or estrogen) may provide better effectiveness at preventing UTI recurrence in postmenopausal women and is a potentially novel avenue for further research.

Paradigm shifting in the era of the microbiome

The microbiota is defined as the microorganisms in a particular environment. The microbiome refers to their genomes that are revealed using molecular techniques such as 16S ribosomal RNA (rRNA) sequencing 71. Recently, more sensitive diagnostic tests demonstrated that urine is not sterile 72. The urinary tract is inhabited by a unique urinary microbiota, and standard bacteriuria represents a fraction of the diverse microbiota hosted by the urinary tract 73. In the past, the notion that UTI was the detection of organisms as a standard culture in sterile urine has changed in the era of the microbiome. The fact that we diagnosed UTIs through standard culture and antibiotic susceptibility ignored the dozens of bacterial species and intracellular bacterial colonies known to reside in the urinary tract 72. As expected, in the era of the microbiome, stable bacterial communities are generally beneficial and this condition is referred to as symbiosis. In this sense, patients with urinary tract symptoms would be more likely to be classified as having urinary tract dysbiosis rather than a UTI 73. If the full array of microbes resident in the human urinary tract is identified in the near future, some treatment of UTIs by antibiotics may turn into a correction of dysbiosis. In the gut microbiome, treatments of Clostridium difficile infections through fecal transplants have been investigated 74, 75. In the urinary tract, the instillation of non-pathogenic E. coli safely reduced the risk of symptomatic UTI in patients with spinal cord injury. All of these efforts are ultimately related to preventing the overuse and misuse of antibiotics. The paradigm of managing UTIs has shifted from diagnosing UTIs and antibiotic treatment to screening for patients who really need antibiotics.

Conclusions

A clear achievement in recent oncology is the emergence of immunotherapy, a type of treatment that helps our immune system fight cancer and that marks an entirely different way of treating cancer by targeting the immune system, not the tumor itself. If the immune system also helps our body fight infections, why not use our body’s immune system instead of antibiotics to treat UTIs? This paradigm shift seems to be beginning in the management of UTIs. Further understanding of the microbiome in the urogenital system is expected to stimulate this shift. Eventually, the spread of antibiotic resistance can be reduced if antibiotics are used only when they are needed.

Editorial Note on the Review Process

F1000 Faculty Reviews are commissioned from members of the prestigious F1000 Faculty and are edited as a service to readers. In order to make these reviews as comprehensive and accessible as possible, the referees provide input before publication and only the final, revised version is published. The referees who approved the final version are listed with their names and affiliations but without their reports on earlier versions (any comments will already have been addressed in the published version).

The referees who approved this article are:

  • Florian Wagenlehner, Clinic & Policlinic for Urology, Pediatric Urology & Andrology, Justus-Liebig University, Giessen, Germany

  • Linda Cardozo, Department of Urogynaecology, King's College London, London, UK

Funding Statement

The author(s) declared that no grants were involved in supporting this work.

[version 1; referees: 2 approved]

References

  • 1. Tillotson GS, Zinner SH: Burden of antimicrobial resistance in an era of decreasing susceptibility. Expert Rev Anti Infect Ther. 2017;15(7):663–76. 10.1080/14787210.2017.1337508 [DOI] [PubMed] [Google Scholar]; F1000 Recommendation
  • 2. Morehead MS, Scarbrough C: Emergence of Global Antibiotic Resistance. Prim Care. 2018;45(3):467–84. 10.1016/j.pop.2018.05.006 [DOI] [PubMed] [Google Scholar]; F1000 Recommendation
  • 3. Tandogdu Z, Wagenlehner FM: Global epidemiology of urinary tract infections. Curr Opin Infect Dis. 2016;29(1):73–9. 10.1097/QCO.0000000000000228 [DOI] [PubMed] [Google Scholar]; F1000 Recommendation
  • 4. Barber AE, Norton JP, Spivak AM, et al. : Urinary tract infections: current and emerging management strategies. Clin Infect Dis. 2013;57(5):719–24. 10.1093/cid/cit284 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5. Sobel JD: Urinary tract infections.In: Mandell GL, Douglas RG Jr, Bennett JE, Dolin R, eds. Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases 7th ed. Philadelphia, PA: Elsevier Churchill Livingstone;2009:957–985. [Google Scholar]
  • 6. Whiteside SA, Razvi H, Dave S, et al. : The microbiome of the urinary tract--a role beyond infection. Nat Rev Urol. 2015;12(2):81–90. 10.1038/nrurol.2014.361 [DOI] [PubMed] [Google Scholar]; F1000 Recommendation
  • 7. Hooton TM, Bradley SF, Cardenas DD, et al. : Diagnosis, prevention, and treatment of catheter-associated urinary tract infection in adults: 2009 International Clinical Practice Guidelines from the Infectious Diseases Society of America. Clin Infect Dis. 2010;50(5):625–63. 10.1086/650482 [DOI] [PubMed] [Google Scholar]
  • 8. Ducharme J, Neilson S, Ginn JL: Can urine cultures and reagent test strips be used to diagnose urinary tract infection in elderly emergency department patients without focal urinary symptoms? CJEM. 2007;9(2):87–92. 10.1017/S1481803500014846 [DOI] [PubMed] [Google Scholar]
  • 9. Yin P, Kiss A, Leis JA: Urinalysis Orders Among Patients Admitted to the General Medicine Service. JAMA Intern Med. 2015;175(10):1711–3. 10.1001/jamainternmed.2015.4036 [DOI] [PubMed] [Google Scholar]
  • 10. Daley P, Penney C, Wakeham S, et al. : Urinary tract infection diagnosis and response to therapy in long-term care: A prospective observational study. Can J Infect Dis Med Microbiol. 2015;26(3):133–6. 10.1155/2015/830415 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11. Bonkat G, Pickard R, Bartoletti R, et al. : European Association of Urology (EAU) Guidelines Office.Guidelines on urological infections.2017;8–9. [Google Scholar]
  • 12. Nicolle LE, Bradley S, Colgan R, et al. : Infectious Diseases Society of America guidelines for the diagnosis and treatment of asymptomatic bacteriuria in adults. Clin Infect Dis. 2005;40(5):643–54. 10.1086/427507 [DOI] [PubMed] [Google Scholar]
  • 13. Tencer J: Asymptomatic bacteriuria--a long-term study. Scand J Urol Nephrol. 1988;22(1):31–4. 10.1080/00365599.1988.11690380 [DOI] [PubMed] [Google Scholar]
  • 14. Lee MJ, Kim M, Kim NH, et al. : Why is asymptomatic bacteriuria overtreated?: A tertiary care institutional survey of resident physicians. BMC Infect Dis. 2015;15:289. 10.1186/s12879-015-1044-3 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15. Vik I, Bollestad M, Grude N, et al. : Ibuprofen versus mecillinam for uncomplicated cystitis--a randomized controlled trial study protocol. BMC Infect Dis. 2014;14:693. 10.1186/s12879-014-0693-y [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16. Gágyor I, Bleidorn J, Kochen MM, et al. : Ibuprofen versus fosfomycin for uncomplicated urinary tract infection in women: randomised controlled trial. BMJ. 2015;351:h6544. 10.1136/bmj.h6544 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17. Little P, Moore MV, Turner S, et al. : Effectiveness of five different approaches in management of urinary tract infection: randomised controlled trial. BMJ. 2010;340:c199. 10.1136/bmj.c199 [DOI] [PMC free article] [PubMed] [Google Scholar]; F1000 Recommendation
  • 18. Kim Y, Kim J, Lee KA: Prevalence of sexually transmitted infections among healthy Korean women: implications of multiplex PCR pathogen detection on antibiotic therapy. J Infect Chemother. 2014;20(1):74–6. 10.1016/j.jiac.2013.08.005 [DOI] [PubMed] [Google Scholar]
  • 19. Fernández G, Martró E, González V, et al. : Usefulness of a novel multiplex real-time PCR assay for the diagnosis of sexually-transmitted infections. Enferm Infecc Microbiol Clin. 2016;34(8):471–6. 10.1016/j.eimc.2015.10.014 [DOI] [PubMed] [Google Scholar]; F1000 Recommendation
  • 20. Del Prete R, Ronga L, Lestingi M, et al. : Simultaneous detection and identification of STI pathogens by multiplex Real-Time PCR in genital tract specimens in a selected area of Apulia, a region of Southern Italy. Infection. 2017;45(4):469–77. 10.1007/s15010-017-1002-7 [DOI] [PubMed] [Google Scholar]; F1000 Recommendation
  • 21. Horner P, Donders G, Cusini M, et al. : Should we be testing for urogenital Mycoplasma hominis, Ureaplasma parvum and Ureaplasma urealyticum in men and women? - a position statement from the European STI Guidelines Editorial Board. J Eur Acad Dermatol Venereol. 2018;32(11):1845–51. 10.1111/jdv.15146 [DOI] [PubMed] [Google Scholar]; F1000 Recommendation
  • 22. Robertson JA, Stemke GW, Davis JW, Jr, et al. : Proposal of Ureaplasma parvum sp. nov. and emended description of Ureaplasma urealyticum (Shepard et al. 1974) Robertson et al. 2001. Int J Syst Evol Microbiol. 2002;52(Pt 2):587–97. 10.1099/00207713-52-2-587 [DOI] [PubMed] [Google Scholar]
  • 23. Taylor-Robinson D: Mollicutes in vaginal microbiology: Mycoplasma hominis, Ureaplasma urealyticum, Ureaplasma parvum and Mycoplasma genitalium. Res Microbiol. 2017;168(9–10):875–81. 10.1016/j.resmic.2017.02.009 [DOI] [PubMed] [Google Scholar]; F1000 Recommendation
  • 24. Tomas ME, Getman D, Donskey CJ, et al. : Overdiagnosis of Urinary Tract Infection and Underdiagnosis of Sexually Transmitted Infection in Adult Women Presenting to an Emergency Department. J Clin Microbiol. 2015;53(8):2686–92. 10.1128/JCM.00670-15 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25. Yang B, Yang F, Wang S, et al. : Analysis of the spectrum and antibiotic resistance of uropathogens in outpatients at a tertiary hospital. J Chemother. 2018;30(3):145–9. 10.1080/1120009X.2017.1418646 [DOI] [PubMed] [Google Scholar]; F1000 Recommendation
  • 26. Seo MR, Kim SJ, Kim Y, et al. : Susceptibility of Escherichia coli from community-acquired urinary tract infection to fosfomycin, nitrofurantoin, and temocillin in Korea. J Korean Med Sci. 2014;29(8):1178–81. 10.3346/jkms.2014.29.8.1178 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27. Chervet D, Lortholary O, Zahar JR, et al. : Antimicrobial resistance in community-acquired urinary tract infections in Paris in 2015. Med Mal Infect. 2018;48(3):188–92. 10.1016/j.medmal.2017.09.013 [DOI] [PubMed] [Google Scholar]; F1000 Recommendation
  • 28. Seitz M, Stief C, Waidelich R: Local epidemiology and resistance profiles in acute uncomplicated cystitis (AUC) in women: a prospective cohort study in an urban urological ambulatory setting. BMC Infect Dis. 2017;17(1):685. 10.1186/s12879-017-2789-7 [DOI] [PMC free article] [PubMed] [Google Scholar]; F1000 Recommendation
  • 29. Caron F, Wehrle V, Etienne M: The comeback of trimethoprim in France. Med Mal Infect. 2017;47(4):253–60. 10.1016/j.medmal.2016.12.001 [DOI] [PubMed] [Google Scholar]; F1000 Recommendation
  • 30. Lee DS, Choe HS, Kim HY, et al. : Role of age and sex in determining antibiotic resistance in febrile urinary tract infections. Int J Infect Dis. 2016;51:89–96. 10.1016/j.ijid.2016.08.015 [DOI] [PubMed] [Google Scholar]
  • 31. Toner L, Papa N, Aliyu SH, et al. : Extended-spectrum beta-lactamase-producing Enterobacteriaceae in hospital urinary tract infections: incidence and antibiotic susceptibility profile over 9 years. World J Urol. 2016;34(7):1031–7. 10.1007/s00345-015-1718-x [DOI] [PubMed] [Google Scholar]; F1000 Recommendation
  • 32. Arpin C, Quentin C, Grobost F, et al. : Nationwide survey of extended-spectrum {beta}-lactamase-producing Enterobacteriaceae in the French community setting. J Antimicrob Chemother. 2009;63(6):1205–14. 10.1093/jac/dkp108 [DOI] [PubMed] [Google Scholar]
  • 33. Martin D, Fougnot S, Grobost F, et al. : Prevalence of extended-spectrum beta-lactamase producing Escherichia coli in community-onset urinary tract infections in France in 2013. J Infect. 2016;72(2):201–6. 10.1016/j.jinf.2015.11.009 [DOI] [PubMed] [Google Scholar]; F1000 Recommendation
  • 34. Hoban DJ, Nicolle LE, Hawser S, et al. : Antimicrobial susceptibility of global inpatient urinary tract isolates of Escherichia coli: results from the Study for Monitoring Antimicrobial Resistance Trends (SMART) program: 2009-2010. Diagn Microbiol Infect Dis. 2011;70(4):507–11. 10.1016/j.diagmicrobio.2011.03.021 [DOI] [PubMed] [Google Scholar]
  • 35. Doi Y, Park YS, Rivera JI, et al. : Community-associated extended-spectrum β-lactamase-producing Escherichia coli infection in the United States. Clin Infect Dis. 2013;56(5):641–8. 10.1093/cid/cis942 [DOI] [PMC free article] [PubMed] [Google Scholar]; F1000 Recommendation
  • 36. Raz R: Fosfomycin: an old--new antibiotic. Clin Microbiol Infect. 2012;18(1):4–7. 10.1111/j.1469-0691.2011.03636.x [DOI] [PubMed] [Google Scholar]
  • 37. Naber KG, Thyroff-Friesinger U: Fosfomycin trometamol versus ofloxacin/co-trimoxazole as single dose therapy of acute uncomplicated urinary tract infection in females: a multicentre study. Infection. 1990;18 Suppl 2:S70–6. 10.1007/BF01643431 [DOI] [PubMed] [Google Scholar]
  • 38. Oteo J, Orden B, Bautista V, et al. : CTX-M-15-producing urinary Escherichia coli O25b-ST131-phylogroup B2 has acquired resistance to fosfomycin. J Antimicrob Chemother. 2009;64(4):712–7. 10.1093/jac/dkp288 [DOI] [PubMed] [Google Scholar]
  • 39. Honderlick P, Cahen P, Gravisse J, et al. : [Uncomplicated urinary tract infections, what about fosfomycin and nitrofurantoin in 2006?]. Pathol Biol (Paris). 2006;54(8–9):462–6. 10.1016/j.patbio.2006.07.016 [DOI] [PubMed] [Google Scholar]
  • 40. Cho YH, Jung SI, Chung HS, et al. : Antimicrobial susceptibilities of extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiella pneumoniae in health care-associated urinary tract infection: focus on susceptibility to fosfomycin. Int Urol Nephrol. 2015;47(7):1059–66. 10.1007/s11255-015-1018-9 [DOI] [PubMed] [Google Scholar]
  • 41. Deck D, Winston L: Beta-Lactam and other cell wall- and membrane-active antibiotics.In: Basic & clinical pharmacology 12th edition. New York: McGraw-Hill;2012. [Google Scholar]
  • 42. Deck D, Winston L: Sulfonamides, trimethoprim, quinolones.In: Basic and clinical pharmacology 12th edition. New York: McGraw-Hill;2012. [Google Scholar]
  • 43. Melekos MD, Naber KG: Complicated urinary tract infections. Int J Antimicrob Agents. 2000;15(4):247–56. 10.1016/S0924-8579(00)00168-0 [DOI] [PubMed] [Google Scholar]
  • 44. Huttner A, Verhaegh EM, Harbarth S, et al. : Nitrofurantoin revisited: a systematic review and meta-analysis of controlled trials. J Antimicrob Chemother. 2015;70(9):2456–64. 10.1093/jac/dkv147 [DOI] [PubMed] [Google Scholar]
  • 45. Oplinger M, Andrews CO: Nitrofurantoin contraindication in patients with a creatinine clearance below 60 mL/min: Looking for the evidence. Ann Pharmacother. 2013;47(1):106–11. 10.1345/aph.1R352 [DOI] [PubMed] [Google Scholar]
  • 46. Lee M, Bozzo P, Einarson A, et al. : Urinary tract infections in pregnancy. Can Fam Physician. 2008;54(6):853–4. [PMC free article] [PubMed] [Google Scholar]
  • 47. Santos JM, Batech M, Pelter MA, et al. : Evaluation of the Risk of Nitrofurantoin Lung Injury and Its Efficacy in Diminished Kidney Function in Older Adults in a Large Integrated Healthcare System: A Matched Cohort Study. J Am Geriatr Soc. 2016;64(4):798–805. 10.1111/jgs.14072 [DOI] [PubMed] [Google Scholar]; F1000 Recommendation
  • 48. Beerepoot MAJ, Geerlings SE, van Haarst EP, et al. : Nonantibiotic prophylaxis for recurrent urinary tract infections: a systematic review and meta-analysis of randomized controlled trials. J Urol. 2013;190(6):1981–9. 10.1016/j.juro.2013.04.142 [DOI] [PubMed] [Google Scholar]; F1000 Recommendation
  • 49. Schwenger EM, Tejani AM, Loewen PS: Probiotics for preventing urinary tract infections in adults and children. Cochrane Database Syst Rev. 2015; (12):CD008772. 10.1002/14651858.CD008772.pub2 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 50. Kontiokari T, Sundqvist K, Nuutinen M, et al. : Randomised trial of cranberry-lingonberry juice and Lactobacillus GG drink for the prevention of urinary tract infections in women. BMJ. 2001;322(7302):1571. 10.1136/bmj.322.7302.1571 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 51. Kranjčec B, Papeš D, Altarac S: D-mannose powder for prophylaxis of recurrent urinary tract infections in women: a randomized clinical trial. World J Urol. 2014;32(1):79–84. 10.1007/s00345-013-1091-6 [DOI] [PubMed] [Google Scholar]
  • 52. Lo TS, Hammer KD, Zegarra M, et al. : Methenamine: a forgotten drug for preventing recurrent urinary tract infection in a multidrug resistance era. Expert Rev Anti Infect Ther. 2014;12(5):549–54. 10.1586/14787210.2014.904202 [DOI] [PubMed] [Google Scholar]
  • 53. Raz R, Stamm WE: A controlled trial of intravaginal estriol in postmenopausal women with recurrent urinary tract infections. N Engl J Med. 1993;329(11):753–6. 10.1056/NEJM199309093291102 [DOI] [PubMed] [Google Scholar]
  • 54. Sihra N, Goodman A, Zakri R, et al. : Nonantibiotic prevention and management of recurrent urinary tract infection. Nat Rev Urol. 2018;15(12):750–776. 10.1038/s41585-018-0106-x [DOI] [PubMed] [Google Scholar]; F1000 Recommendation
  • 55. Wybran J, Libin M, Schandene L: Activation of natural killer cells and cytokine production in man by bacterial extracts. Immunopharmacol Immunotoxicol. 1989;11(1):17–32. 10.3109/08923978909082140 [DOI] [PubMed] [Google Scholar]
  • 56. van Pham T, Kreis B, Corradin-Betz S, et al. : Metabolic and functional stimulation of lymphocytes and macrophages by an Escherichia coli extract (OM-89): in vitro studies. J Biol Response Mod. 1990;9(2):231–40. [PubMed] [Google Scholar]
  • 57. Bosch A, Benedi VJ, Pares R, et al. : Enhancement of the humoral immune response and resistance to bacterial infection in mice by the oral administration of a bacterial immunomodulator (OM-89). Immunopharmacol Immunotoxicol. 1988;10(3):333–43. 10.3109/08923978809041425 [DOI] [PubMed] [Google Scholar]
  • 58. Bauer HW, Rahlfs VW, Lauener PA, et al. : Prevention of recurrent urinary tract infections with immuno-active E. coli fractions: a meta-analysis of five placebo-controlled double-blind studies. Int J Antimicrob Agents. 2002;19(6):451–6. 10.1016/S0924-8579(02)00106-1 [DOI] [PubMed] [Google Scholar]
  • 59. Naber KG, Cho YH, Matsumoto T, et al. : Immunoactive prophylaxis of recurrent urinary tract infections: a meta-analysis. Int J Antimicrob Agents. 2009;33(2):111–9. 10.1016/j.ijantimicag.2008.08.011 [DOI] [PubMed] [Google Scholar]
  • 60. Bauer HW, Alloussi S, Egger G, et al. : A long-term, multicenter, double-blind study of an Escherichia coli extract (OM-89) in female patients with recurrent urinary tract infections. Eur Urol. 2005;47(4):542–8; discussion 548. 10.1016/j.eururo.2004.12.009 [DOI] [PubMed] [Google Scholar]
  • 61. Muzzi-Bjornson L, Macera L: Preventing infection in elders with long-term indwelling urinary catheters. J Am Acad Nurse Pract. 2011;23(3):127–34. 10.1111/j.1745-7599.2010.00588.x [DOI] [PubMed] [Google Scholar]
  • 62. Lorenzo-Gómez MF, Padilla-Fernández B, García-Cenador MB, et al. : Comparison of sublingual therapeutic vaccine with antibiotics for the prophylaxis of recurrent urinary tract infections. Front Cell Infect Microbiol. 2015;5:50. 10.3389/fcimb.2015.00050 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 63. Yang B, Foley S: First experience in the UK of treating women with recurrent urinary tract infections with the bacterial vaccine Uromune ®. BJU Int. 2018;121(12):289–92. 10.1111/bju.14067 [DOI] [PubMed] [Google Scholar]; F1000 Recommendation
  • 64. Hannan TJ, Hooton TM, Hultgren SJ: Estrogen and recurrent UTI: what are the facts? Sci Transl Med. 2013;5(190):190fs23. 10.1126/scitranslmed.3006423 [DOI] [PubMed] [Google Scholar]
  • 65. Perrotta C, Aznar M, Mejia R, et al. : Oestrogens for preventing recurrent urinary tract infection in postmenopausal women. Cochrane Database Syst Rev. 2008; (2):CD005131. 10.1002/14651858.CD005131.pub2 [DOI] [PubMed] [Google Scholar]; F1000 Recommendation
  • 66. Suckling J, Lethaby A, Kennedy R: Local oestrogen for vaginal atrophy in postmenopausal women. Cochrane Database Syst Rev. 2006; (4):CD001500. 10.1002/14651858.CD001500.pub2 [DOI] [PubMed] [Google Scholar]
  • 67. Salvatore S, Leone Roberti Maggiore U, Athanasiou S, et al. : Histological study on the effects of microablative fractional CO2 laser on atrophic vaginal tissue: an ex vivo study. Menopause. 2015;22(8):845–9. 10.1097/GME.0000000000000401 [DOI] [PubMed] [Google Scholar]
  • 68. Zerbinati N, Serati M, Origoni M, et al. : Microscopic and ultrastructural modifications of postmenopausal atrophic vaginal mucosa after fractional carbon dioxide laser treatment. Lasers Med Sci. 2015;30(1):429–36. 10.1007/s10103-014-1677-2 [DOI] [PubMed] [Google Scholar]
  • 69. YANG BOB, Foley S: MP23-05 USING FEMTOUCH™ IN THE TREATMENT OF WOMEN WITH RECURRENT URINARY TRACT INFECTIONS: FIRST EXPERIENCE IN THE UNITED KINGDOM. J Urol. 2017;197(4):e294–e295. 10.1016/j.juro.2017.02.733 [DOI] [Google Scholar]
  • 70. Hooton TM, Gupta K: UpToDate.Waltham, MA: [accessed 5 June 2016]. Recurrent urinary tract infection in women.2016. [Google Scholar]
  • 71. Ursell LK, Metcalf JL, Parfrey LW, et al. : Defining the human microbiome. Nutr Rev. 2012;70 Suppl 1:S38–44. 10.1111/j.1753-4887.2012.00493.x [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 72. Hilt EE, McKinley K, Pearce MM, et al. : Urine is not sterile: use of enhanced urine culture techniques to detect resident bacterial flora in the adult female bladder. J Clin Microbiol. 2014;52(3):871–6. 10.1128/JCM.02876-13 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 73. Finucane TE: 'Urinary Tract Infection' and the Microbiome. Am J Med. 2017;130(3):e97–e98. 10.1016/j.amjmed.2016.08.018 [DOI] [PubMed] [Google Scholar]; F1000 Recommendation
  • 74. Vrieze A, Van Nood E, Holleman F, et al. : Transfer of intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome. Gastroenterology. 2012;143(4):913–6.e7. 10.1053/j.gastro.2012.06.031 [DOI] [PubMed] [Google Scholar]
  • 75. Youngster I, Sauk J, Pindar C, et al. : Fecal microbiota transplant for relapsing Clostridium difficile infection using a frozen inoculum from unrelated donors: a randomized, open-label, controlled pilot study. Clin Infect Dis. 2014;58(11):1515–22. 10.1093/cid/ciu135 [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from F1000Research are provided here courtesy of F1000 Research Ltd

RESOURCES