Antimicrobial Stewardship: Promoting Optimal Management for Patients with Uncomplicated Cystitis

ASSESSMENT OF UNCOMPLICATED CYSTITIS

Urinary tract infection (UTI) is an exceptionally common reason for infection-related primary care visits¹. More than half of women will experience a UTI in their lifetime with an 11% annual incidence.^2,3 Urinary tract infection is defined by anatomic site and complexity. In this review, we focus on lower urinary tract disease, namely cystitis (infection of the bladder) in the uncomplicated patient population.

Symptoms of Cystitis

1) Acute dysuria (pain while urinating)
2) New urinary urgency
3) New urinary frequency
4) Suprapubic pain (pain in the lower abdomen)

Signs of Cystitis

1) Hematuria (blood in the urine)
2) Urine Turbidity (cloudy urine)
3) Leukocyte esterase positive urine (indicating presence of white blood cells in the urine, seen on urine dipstick testing)
4) Nitrites present in the urine (indicating gram negative bacteria in the urine and reflecting the ability of some bacteria to reduce nitrates to nitrites, seen on urine dipstick testing)

The initial assessment of urinary tract infection is based on presenting symptoms and signs, (performing a urinary dipstick assessment if available), and exclusion of other infections/complicating factors⁴ No single symptom or sign is diagnostic and patient history and clinical judgement are key to diagnosing cystitis. Urine culturing is not recommended for first episode uncomplicated cystitis but should be considered for recurrent/worsening disease.⁴ If cultures are sent, keep in mind that turnaround times for results will likely be equal to or longer than the anticipated treatment duration. If the culture is positive for bacteria (bacteriuria) but the patient is asymptomatic (termed asymptomatic bacteriuria), no further treatment is warranted.

Uncomplicated UTI:

1) Non-pregnant adult females (without any complicated criteria below)

Complicated UTI

1) Urologic or neurologic abnormality
2) Upper tract or systemic disease
3) Immunocompromised patients
4) Catheter use
5) Males

MANAGEMENT OF UNCOMPLICATED CYSTITIS

Many cases of uncomplicated cystitis self-resolve.⁵ Despite this, symptoms can be significant and concern exists for progression to the upper urinary tract or systemic infection.<sup>6</sup> A balanced approach to education and waiting, culturing and empiric therapy is essential. No one approach (waiting, immediate treatment, etc.) will work for all patients and shared decision making with patients is vital.

Place in therapy	Antimicrobial	Dose	Rate of E. Coli Resistance	Dosage adjustments in renal dysfunction
1st line	Nitrofurantoin macrocrystals	100mg PO BID x 5 days	~3%	Should not be used in CrCl<40ml/min
2nd line	Trimethoprim-Sulfamethoxazole (TMP-SMX)	160mg/800mg PO BID x 3 days	~20%	Requires dosage adjustment in significant renal dysfunction
3rd line	Ciprofloxacin Note: higher risk for ADR and C.difficile	250-500mg PO BID x 3 days	~15%	Requires dosage adjustment in significant renal dysfunction
4th line	Amoxicillin/Clavulanate Note: broad spectrum, B-lactams require longer therapy	875mg/125mg PO BID x 5-7 days	~10%	Requires dosage adjustments in significant renal dysfunction

When treating with antimicrobial therapy, the following drugs and dosages are recommended based on resistance patterns in Ontario and assuming normal renal function.

While fosfomycin has activity against most urinary pathogens, a recent study found it inferior to nitrofurantoin7. However, fosfomycin may be an alternative to the above in those with organisms resistant to more common antimicrobial agents.

If cultures are available prior to starting treatment, targeting the choice of drug to the sensitivity pattern of the organism should be done with the goal of using the narrowest appropriate therapy.

STEWARDSHIP OPPORTUNITIES FOR THE COMMUNITY PHARMACIST

Despite the clinical frequency of cystitis and the widespread availability of practice guidelines^4,8, management frequently does not adhere to guidelines. More than half of antimicrobial prescriptions for UTI are for a non-first line antibiotic choice or for a duration longer than recommended.^9-11 Unnecessary antimicrobial treatment can place patients at risk for adverse events (ADRs) and C.difficile infection. Additionally, antimicrobial usage will increase the likelihood for antimicrobial resistance and treatment failure.^12,13

Examples of proactive strategies to address cystitis management in community pharmacy practice

Prescriber:

 Academic detailing on local resistance rates and optimal treatment for cystitis
 Feedback antibiotic prescription data (if available)
 Reinforce avoidance of antibiotics for asymptomatic bacteriuria (ASB)

Patient:

 Educate on preventative measures for patients at risk of recurrent cystitis
 Increase fluid intake to >1.5L/day (if appropriate)¹³
 Encourage optimal hygiene practices and consider¹⁴

 Post-coital voiding
 Avoidance of spermicides

Examples of reactive strategies to address cystitis management in community pharmacy practice

Patients, prior to visit to prescriber:

 Assessment of symptoms and referral to appropriate level of care
 Consider providing a list of the patients recent antibiotics, if available, for presentation to the prescriber

Patient and Prescriber, after visit to prescriber:

 Confirm indication for antimicrobial prescription (cystitis versus pyelonephritis/other)
 Review the antimicrobial order for appropriateness
 Choice of antibiotic (for condition, allergy history and renal function)
 Duration of therapy
 Intervene as appropriate with prescriber
 Follow up with the patient in 48-72 hours to establish efficacy and safety of the prescribed medication

Generally, these interventions should not preclude the provision of antimicrobial therapy to patients but can prompt an initial discussion and follow-up with the prescriber and then patient for modification after dispensing. If therapy does change, encourage patients to return the unused antibiotic supply to the pharmacy.

Though intervening with antimicrobials may seem difficult at first, there are many opportunities to make a difference in your daily practice. We encourage you to be the best stewardship pharmacist you can be and keep antibiotics working for everyone. More information and resources are available at our website: www.antimicrobialstewardship.com.

REFERENCES

Foxman B. Epidemiology of urinary tract infections: incidence, morbidity, and economic costs. Am J Med. 2002;113 Suppl 1A:5S-13S.
Butler CC, Hawking MK, Quigley A, McNulty CA. Incidence, severity, help seeking, and management of uncomplicated urinary tract infection: a population-based survey. Br J Gen Pract. 2015;65(639):e702-707.
Hooton TM. Clinical practice. Uncomplicated urinary tract infection. N Engl J Med. 2012;366(11):1028-1037.
Beahm NP, Nicolle LE, Bursey A, Smyth DJ, Tsuyuki RT. The assessment and management of urinary tract infections in adults: Guidelines for pharmacists. Can Pharm J (Ott). 2017;150(5):298-305.
Gagyor I, Bleidorn J, Kochen MM, Schmiemann G, Wegscheider K, Hummers-Pradier E. Ibuprofen versus fosfomycin for uncomplicated urinary tract infection in women: randomised controlled trial. BMJ. 2015;351:h6544.
Little P, Merriman R, Turner S, et al. Presentation, pattern, and natural course of severe symptoms, and role of antibiotics and antibiotic resistance among patients presenting with suspected uncomplicated urinary tract infection in primary care: observational study. BMJ. 2010;340:b5633.
Huttner A, Kowalczyk A, Turjeman A, et al. Effect of 5-day nitrofurantoin vs single-dose fosfomycin on clinical resolution of uncomplicated lower urinary tract infection in women: A randomized clinical trial. JAMA. 2018;319(17):1781-1789.
Gupta K, Hooton TM, Naber KG, et al. 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;52(5):e103-120.
Kabbara WK, Meski MM, Ramadan WH, Maaliki DS, Salameh P. Adherence to International Guidelines for the Treatment of Uncomplicated Urinary Tract Infections in Lebanon. Can J Infect Dis Med Microbiol. 2018;2018:7404095.
Durkin MJ, Keller M, Butler AM, et al. An Assessment of Inappropriate Antibiotic Use and Guideline Adherence for Uncomplicated Urinary Tract Infections. Open Forum Infect Dis. 2018;5(9):ofy198.
Hecker MT, Fox CJ, Son AH, et al. Effect of a stewardship intervention on adherence to uncomplicated cystitis and pyelonephritis guidelines in an emergency department setting. PLoS One. 2014;9(2):e87899.
van Hecke O, Wang K, Lee JJ, Roberts NW, Butler CC. Implications of Antibiotic Resistance for Patients’ Recovery From Common Infections in the Community: A Systematic Review and Meta-analysis. Clin Infect Dis. 2017;65(3):371-382.
Hooton TM, Vecchio M, Iroz A, et al. Effect of increased daily water intake in premenopausal women with recurrent urinary tract infections: A randomized clinical trial. JAMA Internal Medicine. 2018.
Dason S, Dason JT, Kapoor A. Guidelines for the diagnosis and management of recurrent urinary tract infection in women. Can Urol Assoc J. 2011;5(5):316-322.