UTIs:

Advice about lifestyle/behavioural measures is required as is symptomatic treatment with pain relief and, in most cases, treatment with an antibiotic, writes Donna Cosgrove PhD MPSI

Urinary tract infections (UTIs) are the result of bacterial proliferation in the otherwise sterile urinary tract.^1,2 There are usually symptoms involving the bladder (cystitis), ureters, or kidneys (pyelonephritis). In acute simple cystitis, the most common form of UTI, uropathogens from faecal flora ascend via the urethra into the bladder. In the case of pyelonephritis, these pathogens extend further, up to the kidneys via the ureters.^1,3

Escherichia coli causes most uncomplicated UTIs (up to 95 per cent). Proteus, Klebsiella and Providentia bacterial species are sometimes implicated.^4,5 The most common complication of lower UTIs is ascending infection which leads to upper UTI, ie, acute pyelonephritis. Prostate involvement is common in men with lower UTI.⁴

UTI symptoms include:¹

• Dysuria;

• Cloudy urine (pyuria);

• Urgency;

• Frequency;

• Haematuria;

• New onset urinary incontinence.

Where a patient shows symptoms of a UTI suggestive of pyelonephritis or systemic illness, this is considered to be a complicated UTI.³ Symptoms of acute pyelonephritis/upper UTI include:^1,6

• Flank/back pain;

• Sudden onset general systemic disturbance with fever, rigours;

• Tenderness and guarding over the kidney;

• Nausea and/or vomiting;

• General ill feeling.

Many people experience a single UTI episode in their life (at least 50 per cent of women), but about 15-25 per cent of adults and children have chronic symptomatic UTIs that may be recurrent, persistent, re-infected, or relapsed.⁵ UTIs are 50 times more likely to occur in young women compared to young men, likely due to the shorter urethra allowing bacteria from faecal flora to ascend more easily into the bladder. About 30 per cent of women have recurrent UTI (with an average of two to three per year). Children who have UTIs tend to present with a fever and non-specific symptoms like lethargy, vomiting, or poor feeding.¹  Urethral syndrome refers to an experience in about 50 per cent of women, who have symptoms of acute cystitis with little or no evidence of bacterial growth in their urine sample.²

Management of UTIs

• Management of lower UTI requires treatment with an antibiotic in most cases;⁴

• For cystitis treatment, paracetamol or ibuprofen for pain relief and ensuring sufficient hydration may be sufficient;

• Prophylactic treatment options include antibiotics, topical oestrogen, urine alkalisers, dietary supplements, and lifestyle/behavioural measures (altered sexual activity, personal hygiene, and clothing);⁵

• NICE guidance⁴ advises that there is no evidence for cranberry products or alkalinising products in treating lower UTIs;

• Some people with UTIs are asymptomatic and generally do not need to be treated, except in cases where there is a high risk of developing complications (eg, pregnant women, the elderly;)¹

• If a urine sample has been given, empiric antibiotic choice must be reviewed once culture/susceptibility results are available;⁴

• If symptoms do not start to improve within 48 hours of taking an antibiotic, the patient should be reassessed for pyelonephritis, or antibiotic resistance, for example;

• STIs should also be considered in any young person presenting with lower UTI symptoms.⁶

Treatment of UTIs in men

When UTIs occur in men, pre-treatment mid-stream urine (MSU) samples should always be sent to confirm diagnosis and antibiotic susceptibility.⁶ In general, dipstick analysis is not recommended because this is poor at ruling out diagnosis in males. Empirical treatment in the meantime should reflect previous results (if available). In males >50 years, acute prostatitis might be an issue. If this is suspected, avoid nitrofurantoin as a treatment option, as this has poor penetration in the prostate. Recurrent UTI in men should always be referred for specialist treatment.

Many people experience a single UTI episode in their life (at least 50% of women), but about 15-25% of adults and children have chronic symptomatic UTIs that may be recurrent, persistent, re-infected, or relapsed

• First choice empiric antibiotic treatment for uncomplicated lower UTI in adult males is nitrofurantoin (four times daily for seven days, or prolonged release (PR) capsules twice daily). Resistance rates for nitrofurantoin remain low in the community in Ireland;

• Alternatives recommended by the HSE are cefalexin or trimethoprim. For systemic infections and pyelonephritis, nitrofurantoin is not suitable due to its low tissue concentrations;

• Data indicates a high resistance to trimethoprim in community samples of E coli, especially in residential settings, and as a result it is no longer recommended, unless nitrofurantoin is not suitable and risk of resistance is low;

• Fosfomycin is not licensed for use in male patients with UTIs;

• Amoxicillin is not recommended as empiric treatment due to high levels of resistance in community samples of E coli;

• Co-amoxiclav resistance is also high. Furthermore, it is a systemic medication, so should not be used in uncomplicated cystitis if a locally acting pharmacotherapy can be successfully used instead;

• Ciprofloxacin is broad spectrum, linked with C difficile infection, and multiple side effects including GIT disturbances, psychiatric reactions, QT prolongation, and musculoskeletal and joint pain (including tendon rupture). It is not recommended for the empiric treatment of uncomplicated cystitis but may be considered for targeted therapy of multi-resistant infections, where there are no other appropriate options.^{7, 8}

Treatment of UTIs in women

In women with signs of a UTI, dipstick urinalysis may be useful to aid diagnosis. A positive result for nitrite, leukocyte, and red blood cells indicates the presence of a UTI.⁹ It has been shown that women with culture-negative UTIs still respond
to antibiotics.

• The preferred first choice empiric antibiotic treatment for uncomplicated lower UTI in women is nitrofurantoin (four times daily for seven days, or PR capsules twice daily) due to low levels of resistance throughout Ireland;¹⁰

• If unsuitable, cefalexin (500mg twice daily for three days) is an alternative first choice option;

• Trimethoprim is another alternative but only when the risk of resistance is low;

• Fosfomycin is a second choice option or alternative when other treatments are not suitable.

Uncomplicated UTIs often resolve spontaneously without antibiotic treatment. In some cases, delaying the start of antibiotic treatment to see if symptoms resolve after symptomatic treatment with NSAIDs only may be an option (taking into consideration symptom severity and patient factors).^4,11

Treatment of UTIs in pregnancy

• In pregnant women, MSU should be sent for culture;¹²

• Treatment recommendations are similar to those for non-pregnant women (nitrofurantoin, cefalexin, and fosfomycin are all appropriate), except that nitrofurantoin should be avoided after 36 weeks (due to risk of neonatal haemolysis). Trimethoprim is not recommended;

• Amoxicillin can be used as first line but only if known to be susceptible.

Treatment of UTIs in children

• Upper UTI (pyelonephritis) is diagnosed in children presenting with fever ?38 degrees and bacteriuria, or fever <38C, loin pain/tenderness and bacteriuria;¹³

• Lower UTI (cystitis) is diagnosed in children with bacteriuria, lower abdominal pain, dysuria, urinary frequency/urgency, and no systemic symptoms;

• The first choice option for treating upper UTIs in children is cefalexin (seven to 10 days) or co-amoxiclav. For lower UTIs, trimethoprim, nitrofurantoin, or cefalexin is recommended.

Uncomplicated UTIs often resolve spontaneously without antibiotic treatment. In some cases, delaying the start of antibiotic treatment to see if symptoms resolve after symptomatic treatment with NSAIDs only may be an option (taking into consideration symptom severity and patient factors)

Cranberries and UTIs

The cranberry has been associated historically with urinary tract health. The mechanism behind this beneficial effect was previously thought to be due to acidification of urine, making the environment less hospitable to microorganisms. It now appears to prevent adhesion of E coli to the uroepithelial cells of the bladder wall, without which the bacteria cannot infect the mucosal surface.¹

Two components of cranberry contribute to this effect: Fructose, which inhibits the adherence of type 1 fimbriated (fringed) E coli, and proanthocyanidins (PACs), which inhibit p fimbriated E coli. PACs are found in other dietary sources like apple and grape juices, and dark chocolate, but only the PACs in cranberry have the specific A-type linkages that prevents
E coli adhesion to the bladder wall.

Cranberry products for UTI prophylaxis

A Cochrane review¹ of the use of cranberry products for UTI prophylaxis (updated in 2023) found that, overall, cranberry products reduce the risk of symptomatic, culture-verified UTIs.
More specifically, they probably reduce the risk of repeat symptomatic, culture-verified UTIs in women with recurrent UTIs, in children, and in people at risk
of UTIs following an intervention (such as bladder radiotherapy). They may not, however, be effective in UTI prevention in elderly adults in institutions, pregnant women, or those with incomplete bladder emptying.

Authors of the review could not establish whether tablets differ from juice in efficacy, or recommend an optimal dose of cranberry for UTI prevention. One study indicated that PAC levels between 36 to 72mg may be recommended. Due to the duration of bacterial anti-adhesion effect, cranberry supplements should be taken twice daily to maintain effective concentrations.

Cranberry products for UTI treatment

A Cochrane review (updated 2023) found that there is no evidence to suggest that cranberry products are effective in treating UTIs (as opposed to preventing) because, remarkably, no RCTs have been performed to assess this.²

D-Mannose products for UTI teatment and prophylaxis

D-Mannose is a sugar found in most diets with a role in metabolism, and is available as a supplement. The theoretical mechanism behind its effect in UTI prevention, like cranberries, is that it prevents bacterial adherence to uroepithelial cells.⁵ When ingested, D-Mannose (found in grapes, watermelon, cranberries, apples) is absorbed into the bloodstream and excreted out via the renal tubular cells in the urine, reducing bacterial adhesion. Authors of a Cochrane review,⁵ however, found no clear evidence to support (or refute) the use of D-Mannose for preventing or treating UTIs, highlighting the lack of research in this area.

Urinary alkalisers for UTI treatment

Dysuria is often treated with urinary alkalisers (citrate or bicarbonate salts), either alone or along with antibiotics. Use of urinary alkalisers for symptomatic treatment of UTIs or cystitis is common even though the evidence for use is unclear, and NICE guidelines specifically do not recommend their use.⁴ Urinary alkalisers increase urine pH, which, in theory, reduces symptom severity in
the bladder and urethral mucosa, although an observational study found no correlation between UTI symptoms and urine pH. Alkalisation of the urine has been suggested by some studies to reduce pain and urinary frequency associated with UTIs, although a Cochrane review¹¹ did not find sufficient evidence to recommend the use of urinary alkalisers for uncomplicated UTIs.

Conclusion

Management of UTIs requires advice about lifestyle/behavioural measures, symptomatic treatment with pain relief, and in most cases, treatment with an antibiotic. Pharmacists, as well as doctors, need to be aware of HSE UTI antibiotic-prescribing advice to ensure patients are given effective and safe treatments. OTC interventions for UTI treatment and prophylaxis should be recommended based on evidence-based research where possible.

Author: Dr Donna Cosgrove PhD. Donna’s overall aim is to improve patient outcomes through education. After graduating with a BSc in Pharmacy, she returned to university to complete a MSc in Neuropharmacology. This led to a PhD investigating the genetics of schizophrenia, followed by
a postdoctoral research position in the same area. She has worked in hospital, research, and community pharmacy settings and is currently a community pharmacist in Galway and a clinical writer.

References

1. Williams, G, Stothart, CI, Hahn, D, et al. (2023). Cranberries for preventing urinary tract infections. Cochrane database of systematic reviews, (11). Available at: www. cochrane.org/CD001321/RENAL_cranber- ries-preventing-urinary-tract-infections.

2. Jepson, RG, Mihaljevic, L, & Craig, JC (2023). Cranberries for treating urinary tract infections. Cochrane database of systematic reviews, (12). Available at: www.cochraneli- brary.com/cdsr/doi/10.1002/14651858. CD001322.pub2/epdf/full.
3. O’Kane, DB, Dave, SK, Gore, N, et al. (2016). Urinary alkalisation for symptomat-
ic uncomplicated urinary tract infection in women. Cochrane database of systematic reviews, (4). Available at: www.cochraneli- brary.com/cdsr/doi/10.1002/14651858. CD010745.pub2/references.
4. National Institute for Health and Care Ex- cellence. (2018). Urinary tract infection (low- er): antimicrobial prescribing. Available at: www.nice.org.uk/guidance/ng109/resources/ urinary-tract-infection-lower-antimicrobi- al-prescribing-pdf-66141546350533.
5. Cooper, TE, Teng, C, Howell, M,
et al (2022). D?mannose for preventing and

treating urinary tract infections. Cochrane database of systematic reviews, (8). Available at: www.cochranelibrary.com/ cdsr/doi/10.1002/14651858.CD013608. pub2/epdf/full.

6. HSE Guidelines Health Service Executive. (2023). Antibiotic prescribing. Uncomplicated UTI in adult male, ie, no fever or flank pain. Available at: www.hse.ie/eng/services/ list/2/gp/antibiotic-prescribing/condi- tions-and-treatments/urinary/adult-uncom- plicated-uti/.

7. Health Products Regulatory Authori- ty. (2019). Summary of product charac- teristics. Ciprofloxacin 2mg/ml infusion. Available at: www.hpra.ie/img/uploaded/ swedocuments/Licence_PA2299-034- 001_16092019092404.pdf.

8. HSE Guidelines Health Service Executive. (2023). Antibiotic prescribing. Fluoroquino- lone warnings. Available at: www.hse.ie/ eng/services/list/2/gp/antibiotic-prescribing/ drug-interactions/fluoroquinolone-warn- ing-2019.html.

9. Health Service Executive. (2021). Position statement: Use of dipstick urinalysis to assess for evidence of urinary tract infection in adults. Available at: www.hse.ie/eng/

services/list/2/gp/antibiotic-prescribing/con- ditions-and-treatments/urinary/position%20 statements%20dipstick%20urinalysis%20 for%20utis%20in%20adults/position-state- ments-dipstick-urinalysis-for-utis.pdf.

10. HSE Guidelines Health Service Executive. (2023). Antibiotic prescribing. Uncomplicated UTI in adult non-pregnant females. Available at: www.hse.ie/eng/services/list/2/gp/antibi- otic-prescribing/conditions-and-treatments/ urinary/adult-female-uti/adult-female-non- pregnant-uncomplicated-uti-i-e-no-fever-or- flank-pain.html.

11. Kavanagh, ON (2022). Alkalising agents in urinary tract infections: theoretical con- traindications, interactions and synergy. Therapeutic Advances in Drug Safety, 13, 20420986221080794.

12. Health Service Executive. (2022). Antibiotic prescribing. UTI in pregnancy. Available at: www.hse.ie/eng/services/list/2/gp/antibiot- ic-prescribing/conditions-and-treatments/uri- nary/uti-in-pregnancy/uti-in-pregnancy.html. 13. Health Service Executive. (2022). Antibi- otic prescribing. UTI in children. Available at: www.hse.ie/eng/services/list/2/gp/antibiot- ic-prescribing/conditions-and-treatments/ urinary/uti-in-children/uti-in-children.html.