Guidance: Uncomplicated Cystitis

Eminent pharmacy academics from the Queensland University of Technology reported outcomes of the Urinary Tract Infection Pharmacy Pilot - Queensland (UTIPP-Q) identifying that pharmacists have appropriate skills, competencies, and training, and reinforced their value to the health care system and patients, in the safe and appropriate care in community pharmacy of uncomplicated urinary tract infection. [1]

Following this Pilot, Queensland became the first state in Australia to authorise a pharmacist to supply medicine without a prescription for the treatment of urinary tract infection (in accordance with state- based legislation Extended Practice Authority).

For state- and territory-based training, requirements and legislation please refer to the following.

Pharmacist Treatment Guidance: Uncomplicated Cystitis (Queensland v1.0)

Purpose+

Supporting Resources & Training+

Setting for Service Delivery+

Background+

Definitions & Acronyms+

Criteria for Treatment+

Eligible patients are females, 18 to 65 years old, presenting with uncomplicated cystitis and no other relevant history. Table 1 provides a more detailed summary of the inclusion criteria for pharmacists to supply antimicrobials for uncomplicated cystitis and exclusion criteria for patients requiring referral for further assessment under the guidance.

Table 1: Summary of inclusion and exclusion criteria for pharmacist treatment of uncomplicated cystitis

Criteria	Inclusion	Exclusion (requires referral)
Cystitis	Uncomplicated	Complicated
Sex (biological)*	Female	Male
Age	18-65 years	18 years 65 years
Pregnancy status	Not pregnant	Pregnant Postpartum (commonly 4-6 weeks after birth)
Symptoms	Presenting with 2 or more symptoms of cystitis: Dysuria Urinary frequency Urinary urgency Suprapubic pain	Presenting with only 1 symptom of cystitis Fever (>38^◦C) Chills Nausea Vomiting Back/side pain Vaginal itch and/or discharge (consider appropriateness of S3 Pharmacist Only thrush or bacterial vaginosis treatment or refer to a medical practitioner)
UTI history		Recurrent UTI 2 or more UTIs in previous 6 months; OR 3 or more UTIs in previous 12 months Reoccurrence of UTI symptoms within 2 weeks of completing appropriate antimicrobial treatment Any other prior non-responsiveness to UTI treatment Multidrug resistant infection within the previous 3 months
Medicines		Antimicrobial use within the previous 3 months Frequent antimicrobial use Intrauterine device in situ Immunosuppressant medicines Medicines that increase the risk of UTI e.g. SGLT2 inhibitors
Other relevant medical history		Any STI risk Immunocompromise History of: Urinary tract obstruction Pyelonephritis urinary tract abnormality Urolithiasis Urinary catheterisation (last 48 hours) Nephrostomy tube Ureteral stent Renal disease or impairment Spinal cord injury Asplenia Diabetes Any overseas travel within the previous 3 months Overseas travel within the previous 6 months in regions with high prevalence of antibiotic resistance# Recent inpatient of a hospital (within previous 4 weeks) or other health care facility (within previous 3 months) or frequent or long-term care facility resident

*Anatomical characteristics

#E.g. from Southeast Asia and South Asia, particularly if they received medical care or treatment with antibiotics in that region.

Empirical Antimicrobial Cystitis Therapy+

Recommendation of empirical therapy for UTI is ideally guided by antimicrobial susceptibility testing of organisms recently isolated from a patient urine sample. Or, if antibiotic susceptibility is not available, likely susceptibility from local antibiogram data. [7] Choice of empirical therapy is also based on efficacy, convenience, cost, availability, and potential for harm (e.g. adverse effects and risk of development of antimicrobial resistance). [2]

Table 2 describes the empirical antimicrobial regimens used to treat patients included in the guidance (based on Australian and international guidelines – See Appendix 2, Table 4 for more information).

The potential benefits versus risks, including adverse effects and drug interactions, should be considered before recommending empirical antimicrobial treatment in each patient. Key contraindications and some precautions when treating cystitis with antimicrobials are included in Table 2.

Pharmacists should note this is not an exhaustive list and are advised to consider all relevant safe use of medicine precautions when recommending empirical UTI therapy. Precautions for use of antimicrobials may exclude some patients from the service.

All symptoms should respond within 48 hours of commencing antimicrobial therapy. [8]

Table 2: Empirical antimicrobial regimens used to treat patients with uncomplicated cystitis included in the guidance (refer to Table 1 for inclusion and exclusion criteria)

Antimicrobial	Dose	Contraindications and precautions [9,10]
First line - Trimethoprim Excluding patients who have taken trimethoprim in the previous 3 months Although ≈ 20% of E. coli urine isolates from adults in the community are resistant to trimethoprim, it continues to be recommended as empirical therapy for acute cystitis as the risk of adverse outcomes from treatment failure is low. [2]	300mg daily (at night) for 3 nights	Contraindications Previous serious adverse reaction to trimethoprim containing medicines Megaloblastic anaemia due to folate deficiency Other severe blood disorders Renal impairment (CrCl < 15mL/min) Porphyria Pregnancy Precautions Hepatic impairment Dose adjustment should be considered for creatinine clearance of 15-30mL/min Hyperkalaemia – Trimethoprim causes retention of potassium. Concomitant renal impairment, potassium supplements, and other medicines that cause potassium retention may increase the risk of hyperkalaemia (average onset 4-5 days, therefore less likely with 3-day course) May worsen folate deficiency and blood dyscrasias
Second line - Nitrofurantoin When trimethoprim is contraindicated	100mg q6h for 5 days	Contraindications Previous serious adverse reaction to nitrofurantoin Renal impairment (CrCl < 60mL/min) Glucose-6-phosphate dehydrogenase (G6PD), enolase, or glutathione peroxidase deficiency (may lead to haemolytic anaemia) Anuria or oliguria Avoid in breastfeeding if infant is < 4 weeks old or has G6PD deficiency Precautions Risk of polyneuropathy increases in renal failure (often accompanied by diabetes, electrolyte imbalance and vitamin B deficiency) Medicines that alkalinise (e.g. antacids, urinary alkalinisers) reduce efficacy Medicines that acidify (e.g. probenecid) may reduce excretion of nitrofurantoin leading to toxicity
Third line - Cefalexin When both trimethoprim and nitrofurantoin are contraindicated	500mg q12h for 5 days	Contraindications Previous hypersensitivity to cephalosporins or immediate or severe hypersensitivity to penicillins

Symptom Management+

Symptoms of cystitis including pain and dysuria are commonly managed with non-prescription treatments and other self-care strategies. The evidence for their effectiveness is summarised in Table 3.

Table 3: Evidence for common symptomatic management of cystitis

Treatment	Proposed mechanism in cystitis	Evidence and comments
Urinary alkalinisers e.g. sodium bicarbonate	Reduce discomfort of dysuria by reducing acidity of urine	Evidence for efficacy and safety of urinary alkalinisers for cystitis symptoms is lacking [2] Consider patient preferences when recommending urinary alkalinisers Avoid use with nitrofurantoin
Analgesics e.g. NSAIDs and paracetamol	The symptoms of UTI are mostly due to the inflammatory effects of prostaglandins on the urinary mucosa	Where appropriate, patients should be offered analgesia to manage symptoms of acute cystitis [2]
Cranberry juice or tablets	Inhibition of bacterial (mainly E. coli) adhesion to uroepithelial cells	Evidence is conflicting and clinical trials are often small and of variable design [11] Outcomes of systematic reviews are contradictory [11] Unlikely to be effective at preventing recurrent UTI [11] eTG states cranberry products are not effective for UTI treatment [2]
Methenamine hippurate	Methenamine salts are converted in acidic urine to the antibacterial formaldehyde	Methenamine hippurate may be effective for preventing UTI in patients without renal tract abnormalities, but there is a need for further large well‐conducted randomised controlled trials [12] Contraindicated in renal impairment eTG states methenamine hippurate is not effective for UTI treatment [2]
D-mannose	Prevents bacterial adherence to uroepithelial cells	Evidence is conflicting Systematic reviews find that there is some support for the use of D-mannose in treating cystitis symptoms [13] and that there is currently little to no evidence to support or refute the use of D-mannose to prevent or treat UTIs [14]
Probiotics	Restoration of bowel and vaginal microbiota may decrease UTI risk	Clinical trials suggest probiotic supplements may reduce episodes of recurrent UTI [11] However systematic reviews find the evidence to be limited and inconsistent [15,16]
Other self-care strategies and behavioural changes to reduce recurrent UTI episodes	Increased fluid intake Avoid spermicide use Post-coital bladder voiding Wiping from front to back when toileting	Mostly clinically untested [17] Increasing fluid intake above 1.5L per day is supported by clinical trial [17] Evidence supporting behavioural changes such as post-coital voiding and hygiene practices is commonly anecdotal with the likelihood of strong bias [17]

Counselling, Documentation & Follow Up+

Appendix 1+

Appendix 2+

Summary of Australian and international UTI guidelines

Table 4: Summary of empirical antimicrobial treatment regimens for uncomplicated cystitis from Australian and international guidelines

Guideline	Year	Region	Organisation	Antimicrobial
Treatment guideline for pharmacists Cystitis [18]	2022	Australia	Pharmaceutical Society of Australia	Trimethoprim 300mg daily (night) for 3 nights OR Nitrofurantoin 100mg q6h for 5 days OR Cefalexin 500mg q12h for 5 day
Acute cystitis in adults [2]	2019	Australia	Therapeutic Guidelines	Trimethoprim 300mg daily for 3 days OR Nitrofurantoin 100mg q6h for 5 days OR Cefalexin 500mg q12h for 5 days (if both above are not appropriate)
Urinary tract infections (adult): empirical treatment guideline [19]	2022	South Australia	SA Health Department	Trimethoprim 300mg daily (night) for 3 days OR Nitrofurantoin 100mg qid for 7 days OR Cefalexin 500mg bd for 7 days
EAU guidelines on urological infections [6]	2022	Europe	European Association of Urology	Fosfomycin 3g as a single dose OR Nitrofurantoin 50-100mg qid for 5 days or Pivmecillinam* 400mg tds for 3-5 days OR Cephalosporins 500 mg bd for 3 days OR Trimethoprim^ 200mg bd for 5 days OR Trimethoprim/sulfamethoxazole^ 160/800mg bd for 3 days
Urinary tract infection (lower): antimicrobial prescribing [20]	2018	United Kingdom	NICE Guideline	Nitrofurantoin 100mg bd for 3 days OR Trimethoprim 200mg bd for 3 days (if low risk of resistance)
International clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women [21]	2011	United States of America	Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases	Nitrofurantoin 100mg bd for 5 days OR Trimethoprim/sulfamethoxazole 160/800mg bd for 3 days OR Fosfomycin 3g as a single dose OR Pivmecillinam* 400mg tds for 3-5 days Fluoroquinolones and other β-lactams should be used with caution in uncomplicated cystitis

*Not registered on the Australian Register of Therapeutic Goods [Accessed 12/09/2022]

^When resistance pattern for Escherichia coli is less than 20%

Comments+

References+

1. Nissen, Lisa, Lau, Esther, & Spinks, Jean (2022) The management of urinary tract infections by community pharmacists: A state-wide trial: Urinary Tract Infection Pharmacy Pilot- Queensland (Outcome Report). Queensland University of Technology, Brisbane, Qld.

2. eTG complete. (2019). Acute cystitis in adults. Therapeutic Guidelines Ltd. Melbourne. Published April 2019 [Accessed 09/09/2022]

3. Kidney Health Australia. Urinary tract infections Fact sheet. [Last Review December 2018, Accessed September 2022].

4. Australian Institute of Health and Welfare. (2020). Disparities in potentially preventable hospitalisations across Australia: Exploring the data.

5. Australian Commission on safety and quality in Healthcare. (2021). The Fourth Australian Atlas of Healthcare Variation. 2.4 Kidney and urinary tract infections.

6. Bonkat et al. European Association of Urology. (2022). EUA Guidelines Urological infections.

7. Sullivan and Nicolaides. Community antibiogram report (Jan-Dec 2020).

8. Hooton TM and Gupta K. UptoDate. (2021). Acute simple cystitis in women. Updated 15 March 2021. Available at: uptodate.com

9. Rossi S, ed. Australian medicines handbook. Australian Medicines Handbook Pty Ltd. Adelaide. July 2022. [Accessed 13/09/2022].

10. eMIMS. MIMS Australia. Sydney. 2022. [Accessed 13/09/2022]

11. Wawrysiuk S, Naber K, Rechberger T, Miotla P. Prevention and treatment of uncomplicated lower urinary tract infections in the era of increasing antimicrobial resistance-non-antibiotic approaches: a systemic review. Arch Gynecol Obstet. 2019 Oct;300(4):821-828.

12. Lee BS, Bhuta T, Simpson JM, Craig JC. Methenamine hippurate for preventing urinary tract infections. Cochrane Database Syst Rev. 2012 Oct 17;10(10):CD003265.

13. Parazzini F, Ricci E, Fedele F, Chiaffarino F, Esposito G, Cipriani S. Systematic review of the effect of D-mannose with or without other drugs in the treatment of symptoms of urinary tract infections/cystitis (Review). Biomed Rep. 2022 Jun 15;17(2):69.

14. Cooper TE, Teng C, Howell M, Teixeira-Pinto A, Jaure A, Wong G. D-mannose for preventing and treating urinary tract infections. Cochrane Database Syst Rev. 2022 Aug 30;8(8):CD013608.

15. Abdullatif VA, Sur RL, Eshaghian E, Gaura KA, Goldman B, Panchatsharam PK, Williams NJ, Abbott JE. Efficacy of Probiotics as Prophylaxis for Urinary Tract Infections in Premenopausal Women: A Systematic Review and Meta-Analysis. Cureus. 2021 Oct 17;13(10):e18843.

16. New FJ, Theivendrampillai S, Juliebø-Jones P, Somani B. Role of Probiotics for Recurrent UTIs in the Twenty-First Century: a Systematic Review of Literature. Curr Urol Rep. 2022 Feb;23(2):19-28. doi: 10.1007/s11934-022-01085-x. Epub 2022 Feb 14. Erratum in: Curr Urol Rep. 2022 Jul 13;: PMID: 35156175.

17. Gupta K. UptoDate. (2022). Recurrent simple cystitis in women. Updated 29 April 2022. Available at: uptodate.com

18. Guidance for provision of antibiotics for acute uncomplicated cystitis in females (2020). Pharmaceutical Society of Australia Ltd. Endorsed April 2020, amended August 2022.

19. SA Health. Government of South Australia. Urinary tract infections (adult): Empirical treatment clinical guideline. V2.1. Approved 25/08/2022. [Accessed 08/09/2022]

20. National Institute for Health and Care Excellence. (2018). Urinary tract infection (lower): antimicrobial prescribing. NICE Guideline [NG109]. Published 31 October 2018. [Accessed 09/09/2022].

21. 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 Infect Dis. 2011 Mar 1;52(5):e103-20.