Advances in the Management of Acute and Recurrent Urinary Tract Infections Caused by Resistant Pathogens – What’s Next? - European Medical Journal

Advances in the Management of Acute and Recurrent Urinary Tract Infections Caused by Resistant Pathogens – What’s Next?

12 Mins
Flagship Journal
Urology
Download PDF
Speakers:
Debra Fromer,1 Vik Khullar,2,3 Florian Wagenlehner4
Disclosure:

Fromer is a legal consultant for Johnson & Johnson, and a speaker and advisor for GSK. Khullar is a consultant and researcher for AbbVie, and consultant and speaker for GSK. Wagenlehner has worked as a consultant for Achaogen, Astellas, Eumedica, Janssen, Klosterfrau, Leo-Pharma, Merlion, Shionogi, Quiagen, Sysmex, and VenatoRX. As a consultant and speaker for Bionorica, GSK, MSD, Rosen Pharma, and OM/Vifor-Pharma. As a speaker for AstraZeneca and Pfizer, and as a researcher for Helperby, Phagomed and Saxonia R&D. The speakers have no conflicts of interest relating to this presentation.

Acknowledgements:

This symposium review article was proposed by EMJ and was written by Caroline E. Cross, Reading, UK. All speakers were given the opportunity to review the article.

Disclaimer:

The opinions expressed in this article belong solely to the named speakers and do not necessarily reflect those of GSK. GSK was provided with the opportunity to review this publication prior to submission to EMJ, for the sole purpose of ensuring its data is accurately stated herein. Not all medicines and/or indications presented in this webinar may be approved for use in all countries. This medical education activity is intended for healthcare professionals only.

Support:

The symposium and publication of this article was funded by GSK.

Citation
EMJ. ;7[3]:23-29. DOI/10.33590/emj/10081330. https://doi.org/10.33590/emj/10081330.

Each article is made available under the terms of the Creative Commons Attribution-Non Commercial 4.0 License.

Meeting Summary

Uncomplicated urinary tract infections (uUTI) are one of the most common infections in the community, affecting >150 million people each year worldwide, and being responsible for large amounts of antibiotic prescribing.1,2 Up to 80% of females will experience at least one uUTI in their lifetime, and 45% will have recurrent uUTI.3 The debilitating symptoms that accompany urinary tract infections (UTI), including pain and urinary urgency, coupled with the unpredictability of recurrence, negatively impact quality of life (QoL).1,3

The GSK Industry Symposium took place on 1st July 2022 as part of the European Association of Urology (EAU) Conference in Amsterdam, the Netherlands, and focused on the challenges surrounding the diagnosis and management of uUTIs and recurrent UTIs in the context of increasing antimicrobial resistance.

During the presentations, speakers Debra Fromer, Vik Khullar, and Florian Wagenlehner, all specialists in urology, outlined the challenges facing clinicians and patients in treating UTIs effectively whilst maintaining good antibiotic stewardship. The wide-ranging discussions included questions around differential diagnosis, personalised approaches to treatment, and the challenges of treating recurrent UTIs.

The panel also discussed the need for new strategies to manage such infections, and highlighted alternatives to antibiotics that are under development and could help to slow the rise in antimicrobial resistance. The symposium finished on a positive note with discussions around new and emerging therapies, such as immune stimulation, vaccination, and fulguration, that could help many females to break the debilitating cycle of recurrent UTIs.

INTRODUCTION

At least 60% of females worldwide will experience at least one UTI in their lifetime.4 An array of pathogenic bacteria, both gram-negative and gram-positive, can cause the infections, although in uUTIs, Escherichia coli (E. coli) is the predominant pathogen.5

Symptoms are debilitating, and include urinary urgency, dysuria, and frequency. More than 25% of females who experience a UTI will go on to have further infections, often within 3 months, increasing anxiety levels with feelings of helplessness and dread, and reducing QoL.6,7

Oral antibiotics are the mainstay of treatment, and medications to treat UTIs currently account for 15% of all antibiotic prescriptions in the USA and Europe.2 Increasingly, patients are experiencing UTIs that are resistant to first line antibiotics,8 contributing to the global threat of antimicrobial resistance. Clinical guidelines for the treatment of UTIs recommend that first line antibiotics be chosen based on local antimicrobial resistance patterns.9

During this symposium, the speakers highlighted the complexities of both uncomplicated and recurrent UTIs that mean a more personalised approach to treatment could be beneficial. They also discussed the increasing prevalence of antibiotic resistant uropathogens, and what clinicians should consider when prescribing antimicrobial medications. Discussions also covered recent clinical studies that demonstrate the value of a more clinically informed approach to treatments, and show the potential of novel treatment approaches with antibiotics and other alternatives.

This article captures the main questions discussed during the symposium and draws attention to novel therapeutic strategies that can help clinicians apply appropriate antibiotic prescribing when treating patients with uncomplicated and recurrent UTIs.

How is the Differential Diagnosis of Urinary Tract Infection Done in Female Patients Presenting at Clinic, and What Is the Impact of These Infections on the Patient?

Most young females (>90%) who present at clinic with urinary urgency and pain whilst passing urine (dysuria) will have a UTI,10 explained Fromer, who sees hundreds of females with uncomplicated and recurrent UTIs in her clinics. She commonly sees females in their mid-thirties with previous history of culture-proven uUTIs who present with dysuria, frequency, urgency, and suprapubic pain. “However, it’s also possible that patients presenting with UTI symptoms could instead have overactive bladder or bladder pain syndrome.”11

Wagenlehner concurred, saying: “Diagnosis is not always straightforward. For a long time the gold standard has been lab culture of the urinary bacteria. However, in more than a third of cases, we do not get a positive culture, sometimes because the culture test is not sufficiently sensitive, and in others, the bacteria is not culturable in the lab.” It has also become increasingly clear that bacteria can be present in the healthy bladder.5

The panel members agreed that the impact of UTIs on females can be pervasive. Some females have as many as six recurrent infections in a year, and the impact on individuals are significant. As Fromer outlined: “The infections are sudden, unforeseeable and distressing, taking a toll on mental health and sense of wellbeing.”12 Fromer drew attention to a study of 575 patients with recurrent UTIs, in which 61.9% of patients with a UTI suffered some degree of depression, and almost three quarters of females experienced anxiety. A reduction in UTIs correlated with improvements in QoL.12

Khullar added that other impacts of recurrent UTIs on patients’ lives include sleep disruption, persistent fatigue, negative impacts on intimate relationships, and the financial consequences of taking time off work.13

Referring to one of his own studies, Wagenlehner said: “Using a self-administered anonymous web-based survey across five countries, we demonstrated that recurrent UTIs had a significant impact on QoL and are associated with mental stress for a high proportion of women.”14 Other studies also report negative QoL impacts associated with treatment failure, often caused by antimicrobial resistant strains.15,16

Antibiotic Resistance in Common Bacteria Has Reached Alarming Levels in Many Parts of the World Indicating that Many of the Available Treatment Options for Common Infections in Some Settings are Becoming Ineffective.8 How does this Impact the Management of Patients with Urinary Tract Infections?

Uropathogens such as E. coli and Klebsiella pneumoniae (K. pneumoniae) feature prominently in the World Health Organization (WHO)’s 2014 report on emerging resistant pathogens.8 As Fromer explained: “There is now a high frequency of resistance to third generation cephalosporins commonly used to treat UTIs. This can lead to a reliance on carbapenems to treat severe infections, which really should be used only as a last resort.”

The speakers emphasised the need for clinicians to consider antimicrobial resistance when treating patients for UTIs. “Often, when taking a patient’s recent history we find that the patient has had multiple courses of antibiotics, for example for dental work. It is important to understand the resistance patterns for the individual at the time of symptom onset and prior to treatment,”17 Fromer said.

Fromer reinforced the point by describing data from a retrospective study of 908 female patients with UTIs from an outpatient clinic in the USA, which identified E. coli as the most common organism causing UTIs (complicated UTI [cUTI] and uncomplicated UTI [uUTI]). More than a third of patients had experienced three or more UTIs in the previous year (2015–2016), and rates of resistance to three or more oral antibiotics were as high as 30%.18 Antibiotic resistant infections were more prevalent in females with recurrent UTIs, and who were older.19

The speakers outlined how clinicians can support good antimicrobial stewardship and reduce inappropriate use of antibiotics. Strategies include not treating asymptomatic bacteriuria,17 avoiding use of broad-spectrum fluoroquinolones,9 using the shortest possible effective course of antibiotics,17 and raising awareness among patients of the dangers of ‘self-starting’ antibiotics, and not adhering to recommended dosage.11,17,20

Wagenlehner also emphasised the complexities of diagnosing UTIs and the need for clinicians to rule out other underlying causes where possible, and to consider alternative strategies before prescribing antibiotics. Non-antibiotic interventions include behavioural changes, antiadhesive treatments, local antiseptics, topical oestrogens, and immunomodulation.21 “We use symptom questionnaires that are also used in other conditions and can provide quantitative information to help clinicians to rule out complicated UTI and assess risk factors such as treatment failure and risk of recurrence.”

What can be Done in Clinical Practice to Assess the Risk of Antimicrobial Resistance In Patients with Urinary Tract Infection?

Wagenlehner believes we need a more personalised approach to the treatment of UTI patients, to identify patients who are more likely to have resistant pathogens. His team studied antibiotic sensitivity in 386 females with uUTIs and found that two-thirds (n=259) had infections that were susceptible to all antibiotics, but almost one-third (n=112) had infections that were resistant to one or two antibiotics, and 15 patients had infections that were resistant to multiple antibiotics.22 The patients with multiple drug resistant infections were generally older, and with history of recurrent infections.

Physical examination and history taking are important in supporting UTI diagnosis. “If resistance is suspected and the patient can tolerate the symptoms until a positive culture is returned, that is preferable. But for many the symptoms are unbearable, even with increased fluids and pain medication, and sometimes there is concern over more serious infection. In these cases, empiric antibiotics are necessary,” stated Fromer. “At this point we must rely on knowledge of local uropathogen resistance patterns and any history of antibiotic allergy or intolerance when deciding which antibiotic to prescribe.9,17 It is also important to consider the patient’s prior antibiotic use and previous culture results to clarify any history of antimicrobial resistance,”17,23 she reiterated. Avoiding use of broad-spectrum antibiotics and fluoroquinolones, and keeping the duration of therapy to a minimum also help to reduce the chances of further resistance developing.9,17

Khullar reiterated the importance of checking for local uropathogen resistance patterns as they can vary considerably between regions and countries, with fluoroquinolone resistance common in southern Europe,24 and penicillin resistance common in the UK.25 The speakers unanimously referred the audience to international clinical practice guidelines for the treatment of acute uncomplicated cystitis in the context of local resistance patterns.9

What are the Potential Roles of the Urinary Microbiota in Homeostasis of the Urinary Tract, and How does that Influence the Host Bacterial and Inflammatory Interactions in Patients with Urinary Tract Infections?

The human microbiome consists of trillions of bacteria, viruses, and fungi that are found in the human body, and outnumber human cells by 10:1.26 The intimate and complex relationships that exist between the microbiome and human cells are vital for homeostasis.26 The symbiotic ecosystem which results, influences both health and disease. For example, as Khullar explained, in the bladder, ‘beneficial bacteria’ such as some Lactobacilli sp, can attack pathogenic organisms, communicate with the bladder, control neurological function, and destroy chemicals in the urine.26

Patients who experience recurrent UTIs often have repeated courses of antibiotics which can change the balance of microbiota in the gut and bladder. Older, post-menopausal females with low oestrogen levels had lower levels of beneficial Lactobacilli in their urinary tract compared to younger females.27 When the DNA of bacteria in urine was analysed in both females with urgency urinary incontinence (UUI) and those without, females with UUI had more Gardnerella and Enterobacteriaceae, and fewer Lactobacilli.5 The differences were confirmed when bacteria were cultured from bladder biopsies.5 Khullar also highlighted a study that suggests Lactobacillus crispatus, one of the beneficial Lactobacilli, when given as a probiotic intravaginally, may help to reduce recurrent UTIs (rUTI).28

Khullar also drew attention to experimental models of bladder infection that demonstrate that E. coli can invade superficial bladder epithelium, mature into biofilms, and create pod-like bulges on the bladder surface.29 These ‘pods’ allow bacteria to evade the host’s immune system defences, and can be a source of rUTI. In translational work, a study of urine sediments, prepared from females with acute episodes of rUTI caused by uropathogenic E. coli, found evidence of intracellular bacterial colonies in almost a fifth of cases.30

“Some people get an infection and it is cleared by the immune system, or they may have asymptomatic infection. Others have frequent painful infections and have an abnormal response to infection causing inflammation with bacteria entering the bladder wall,” Khullar explained. When epithelial cells collected from the bladder lining of females without active UTI were lysed, bacteria were found inside cells. Further analysis from both cultures of the samples showed Staphylococcus and Enterococci in both groups, with more E. coli, Proteus sp, and Micrococcus sp in the bladder walls,31 reinforcing the likelihood that bacteria in the bladder wall that are not killed by antibiotics are a source of recurrent UTIs.

With increasing evidence that microbial biofilms play a role in causing recurrent UTIs, cystoscopic electrofulguration as an experimental treatment has been used as a way to clear resistant bacteria from the bladder lining by cauterising inflammatory lesions. Fromer described a study of 95 females who received the treatment. Five-year follow up showed an 88% cure rate.32

What are the Risk Factors Associated with Uncomplicated Urinary Tract Infection Recurrence?

The risk of recurrent uUTIs is higher for females over 55 years old.33 These females have diminishing levels of oestrogen as they enter the menopause. Other risk factors include diabetes, particularly more advanced Type 2 diabetes when the patient is receiving insulin,34 vaginal atrophy, urinary incontinence, vaginal wall prolapse, and increased post-void residual volume.35

Khullar shared his clinical experience and practice, reiterating that in older, post-menopausal patients, it is important to attempt urine culture while the patient has symptoms, while taking account of patient’s history and previous antibiotic use. Additional assessments, such as urinary flow rate and post-void residual volume, will help the clinician to assess risk of recurrence. Also, if haematuria is present, cystoscopy should be carried out, and if needed, a CT urogram to examine the upper urinary tract. Additional factors that increase the risk of UTI recurrence include constipation rather than diarrhoea, and recent antibiotic use.36

What is the Current Guidance in the Management of Recurrent Urinary Tract Infections in Female Patients?

Based on clinical experience and practice, Khullar recommends antimicrobial prophylaxis for up to 6 months for patients with recurrent UTIs. “We tend to use nitrofurantoin or fosfomycin in line with EAU guidelines,”26 he outlined. Also, postcoital prophylaxis can be used, or the antiseptic methenamine hippurate, 1 g twice daily for 6 months, which has been shown to reduce recurrent infections.37 Fromer emphasised that there are currently no evidence-based guidelines for the use of antibiotic prophylaxis for recurrent UTIs, and that it should be seen as a last resort option.

There is also evidence that non-antimicrobial prophylactics are effective. For example, an oestrogen-releasing vaginal ring,38 intravaginal probiotics (L. rhamnosus, L. reuteri),39 or immunoactive prophylaxis.40,41L. crispatus given intravaginally as a probiotic, shows promise at reducing recurrent UTIs.28 Topical oestrogens can help to decrease vaginal pH, while increasing glycogen production and Lactobacillus concentrations42 and antibacterial peptide secretions.43

What are the Emerging Targets and Therapies In Urinary Tract Infections?

For the millions of females worldwide who live with the uncertainty of when their next debilitating UTI will strike, there is some hope. “Vaccine therapy is showing promise, although as yet, the mechanism of action is not clearly understood,” enthused Wagenlehner. Recent data is strong, said Fromer, who presented data from a trial of a sublingual vaccine of whole-cell inactivated bacteria (E. coli, K. pneumoniae, E. faecalis, and P. vulgaris).41 The study showed vaccination reduced the recurrence of UTIs at 9-months post-vaccination. Also encouraging, was that the time to first UTI post-vaccine was 275 days in the vaccine group, versus 48 days in the placebo group. Females also reported improved QoL.41 Fromer added: “Interestingly, all women had similar microbiota in their bladder, despite the reduction in UTIs, and the study authors suggest that the vaccine boosts local innate immune mechanisms that might be deficient in women who experience recurrent UTIs.” Wagenlehner supported this viewpoint, suggesting that the host response to the bacteria might be more important in causing disease, rather than the bacteria themselves. “Sublingual vaccines help to boost the innate immune system and this might help to prevent severe disease,” he surmised.

The panel also discussed the potential of bacteriophages to target and kill specific bacterial species, such as specific E. coli isolates and Klebsiella.44 Wagenlehner explained that these are already available in Georgia as a ‘cocktail’ of bacteriophages, but are not sufficiently tested clinically. He suggested that there is still a lot of preclinical and clinical work to be done until bacteriophages might in future provide an alternative to antibiotics. Novel β-lactam and β-lactamase inhibitors are also currently being tested in clinical phases as oral treatments for patients with UTIs.45

The panel also discussed novel antibiotics that are in the pipeline, such as Gepotidacin, which is currently in Phase III clinical developement.46,47 New oral carbapenems, Tebipenem48 and sulopenem,49 are also under development for complicated UTIs and uUTIs, respectively. The speakers emphasised that these new antibiotics could be very helpful to patients who have uropathogens that are resistant to orally administered antibiotics. However, it will be important to ensure they are only used under appropriate antibiotic prescribing stewardship.

NX-GBL-UTI-ADVR-220002
July 2022

References
Flores-Mireles AL et al. Urinary tract infections: epidemiology, mechanisms of infection and treatment options. Nat Rev Microbiol. 2015;13(5):269-84. Öztürk R, Murt A. Epidemiology of urological infections: a global burden. World J Urol. 2020;38(11):2669-79. Wagenlehner F et al. A global perspective on improving patient care in uncomplicated urinary tract infection: expert consensus and practical guidance. J Glob Antimicrob Resist. 2022;28:18-29 Foxman B. Urinary tract infection syndromes: occurrence, recurrence, bacteriology, risk factors, and disease burden. Infect Dis Clin North Am. 2014;28(1):1-13. Pearce MM et al. The female urinary microbiome: a comparison of women with and without urgency urinary incontinence. mBio. 2014;5(4):e01283-14. Grigoryan L et al. The emotional impact of urinary tract infections in women: a qualitative analysis. BMC Womens Health. 2022;22(1):182. McLellan LK, Hunstad DA. Urinary tract infection: pathogenesis and outlook. Trends Mol Med. 2016;22(11):946-57. World Health Organization (WHO). Antimicrobial resistance: global report on surveillance. 2014. Available at: https://apps.who.int/iris/handle/10665/112642. Last accessed: 1 August 2022. Gupta K et al.; Infectious Diseases Society of America; European Society for Microbiology and Infectious Diseases. International clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women: a 2010 update by the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases. Clin Inf Dis. 2011;52(5);103-20. Bent S et al. Does this woman have an acute uncomplicated urinary tract infection? JAMA. 2002;287(20):2701-10. Kodner CM, Thomas Gupton EK. Recurrent urinary tract infections in women: diagnosis and management. Am Fam Physician. 2010;82(6):638-43. Renard J et al. Recurrent lower urinary tract infections have a detrimental effect on patient quality of life: a prospective, observational study. Infect Dis Ther. 2014;4(1):125-35. Flower A et al. How women manage recurrent urinary tract infections: an analysis of postings on a popular web forum. BMC Fam Pract. 2014;15:162. Wagenlehner F et al. Social and economic burden of recurrent urinary tract infections and quality of life: a patient web-based study (GESPRIT). Exp Rev Pharmacoecon Outcomes Res. 2018:18(1):107-17. Abrahamian FM et al. The association of antimicrobial resistance with cure and quality of life among women with acute uncomplicated cystitis. Infection. 2011;39(6):507-14. Ernst EJ et al. Women's quality of life is decreased by acute cystitis and antibiotic adverse effects associated with treatment. Health Qual Life Outcomes. 2005;3:45. Anger J et al. Recurrent uncomplicated urinary tract infections in women: AUA/CUA/SUFU guideline. J Urol. 2019;202(6):282-9. Kirkpatrick G et al. Poster #NM123: Patterns and risk factors for antimicrobial resistance in female urological patients with urinary tract infections in the New York/New Jersey metropitan area outpatient setting. Society of Urodynamics, Female Pelvic Medicine and Urogenital Reconstruction (SUFU) Winter Meeting, 27 February-3 March 3, 2018. Cunningham M et al. Abstract #NM36: The prevalence of antimicrobial resistant pathogens causing recurrent urinary tract infections amongst women in the outpatient urology setting. Society of Urodynamics, Female Pelvic Medicine and Urogenital Reconstruction (SUFU) Winter Meeting, February 25-27, 2021. Forbes R et al. Alternatives to prophylactic antibiotics for the treatment of recurrent urinary tract infection in women (ALTAR): study protocol for a multicentre, pragmatic, patient-randomised, non-inferiority trial. Trials. 2018;19(1):616. Zare M et al. Management of uncomplicated recurrent urinary tract infections. BJU Int. 2022;129(6):668-78. Naber KG et al. Poster presentation 00655: Antimicrobial resistance patterns and patient characteristics among females with uncomplicated urinary tract infection in Germany: A physician-based chart review. 32nd European Congress of Clinical Microbiology and Infectious Diseases (ECCMID), 23-26 April, 2022. Ny S et al.; NoDARS UTIStudy Group. Antimicrobial resistance of Escherichia coli isolates from outpatient urinary tract infections in women in six European countries including Russia. J Glob Antimicrob Resist. 2019;17:25-34. Kresken M et al. Comparative in vitro activity of oral antimicrobial agents against Enterobacteriaceae from patients with community-acquired urinary tract infections in three European countries. Clin Microbiol Infect. 2016;22(1):63. Watts V et al. Routine laboratory surveillance of antimicrobial resistance in community-acquired urinary tract infections adequately informs prescribing policy in England. JAC Antimicrob Resist. 2020;2(2):dlaa022. Whiteside SA et al. The microbiome of the urinary tract--a role beyond infection. Nat Rev Urol. 2015;12(2):81-90. Thomas-White KJ et al. Evaluation of the urinary microbiota of women with uncomplicated stress urinary incontinence. Am J Obstet Gynecol. 2017;216(1);55. Stapleton AE et al. Randomized, placebo-controlled phase 2 trial of a Lactobacillus crispatus probiotic given intravaginally for prevention of recurrent urinary tract infection. Clin Infect Dis. 2011;52(10):1212-7. Anderson GG et al. Intracellular bacterial biofilm-like pods in urinary tract infections. Science. 2003;301(5629):105-7. Hannan TJ et al. Host-pathogen checkpoints and population bottlenecks in persistent and intracellular uropathogenic Escherichia coli bladder infection. FEMS Microbiol Rev. 2012;36(3):616-48. Khasriya R et al. Spectrum of bacterial colonization associated with urothelial cells from patients with chronic lower urinary tract symptoms. J Clin Microbiol. 2013;51(7):2054-62. Crivelli JJ et al. Electrofulguration in the advanced management of antibiotic-refractory recurrent urinary tract infections in women. Int J Urol. 2019;26(6):662-8. Ikäheimo R et al. Recurrence of urinary tract infection in a primary care setting: analysis of a 1-year follow-up of 179 women. Clin Infect Dis. 1996;22(1);91-9. Gorter KJ et al. Risk of recurrent acute lower urinary tract infections and prescription pattern of antibiotics in women with and without diabetes in primary care. Fam Pract. 2010;27(4):379-85. Storme O et al. Risk factors and predisposing conditions for urinary tract infection. Ther Adv Urol. 2019;2;11:1756287218814382. Cai T. Recurrent uncomplicated urinary tract infections: definitions and risk factors. GMS Infect Dis. 2021;9:Doc03. Harding C et al. Alternative to prophylactic antibiotics for the treatment of recurrent urinary tract infections in women: multicentre, open label, randomised, non-inferiority trial. BMJ. 2022;376:e068229. Eriksen B. A randomized, open, parallel-group study on the preventive effect of an estradiol-releasing vaginal ring (Estring) on recurrent urinary tract infections in postmenopausal women. Am J Obstet Gynecol. 1999;180(5):1072-9. Ng QX et al. Use of Lactobacillus spp. to prevent recurrent urinary tract infections in females. Med Hypotheses. 2018;114:49-54. Bauer HW et al.; Multicenter UTI Study Group. A long-term, multicenter, double-blind study of an Escherichia coli extract (OM-89) in female patients with recurrent urinary tract infection. Eur Urol. 2005;47(4):542-8. Lorenzo-Gomez M et al. Sublingual MV140 for prevention of recurrent urinary tract infections. NEJM Evid. 2022;1(4). Sihra N et al Nonantibiotic prevention and management of recurrent urinary tract infection. Nat Rev Urol. 2018;15(12):750-76. Lüthje P et al. Estrogenic action on innate defense mechanisms in the urinary tract. Maturitas. 2014;77(1):32-6. Zalewska-Piątek B, Piątek R. Phage therapy as a novel strategy in the treatment of urinary tract infections caused by E. Coli. Antibiotics (Basel). 2020;9(6):304. Veeraraghavan B et al. Oral antibiotics in clinical development for community-acquired urinary tract infections. Infect Dis Ther. 2021;10(4);1815-35. Overcash JS et al. Phase 2a pharmacokinetic, safety, and exploratory efficacy evaluation of oral gepotidacin (GSK2140944) in female participants with uncomplicated urinary tract infection (acute uncomplicated cystitis). Antimicrob Agents Chemother. 2020;64(7):e00199-20. Scangarella-Oman NE et al. Dose selection for phase iii clinical evaluation of gepotidacin (GSK2140944) in the treatment of uncomplicated urinary tract infections. Antimicrob Agents Chemother. 2022;66(3):e0149221. Eckburg PB et al. Oral tebipenem pivoxil hydrobromide in complicated urinary tract infection. N Engl J Med. 2022;386(14):1327-38. Dunne MW et al. LB-1: Efficacy and safety of oral sulopenem etzadroxil/probenecid versus oral ciprofloxacin in the treatment of uncomplicated urinary tract infections (uUTI) in adult women: results from the SURE-1 trial. ID week, 21-25 October 2020.

Join our mailing list

To receive the EMJ updates straight to your inbox free of charge, please click the button below.
Join Now