28 Mar 2022  Empiric Antibiotic Therapy for Uncomplicated Lower Urinary Tract Infections
Urinary tract infections (UTIs) are one of the most common clinical conditions of women in primary care. This Letter describes antimicrobial best practices for the treatment of symptomatic, uncomplicated lower UTI in British Columbia (BC), Canada.
UTIs in most healthy women who are not pregnant and have no major abnormality of urinary tract structure and function, can be considered “uncomplicated.”1,2 This Letter does not discuss complicated lower UTI (e.g. in men), upper urinary tract infections (e.g. pyelonephritis), recurrent UTI, nor asymptomatic bacteriuria.
Diagnose by symptoms, not tests
A diagnosis of lower uncomplicated UTI (or “acute cystitis”) can be made with > 90% probability if a patient is experiencing two or more of dysuria, urgency, or frequency, and no vaginal discharge.3 As women age, genitourinary symptoms less reliably predict uncomplicated UTI.2
If the clinical symptoms are uncertain, a urine dipstick test showing the presence of nitrites and moderate pyuria may help rule-in the diagnosis.4 However, dipstick tests are less helpful for ruling-in the diagnosis in older women; asymptomatic bacteriuria, and corresponding dipstick abnormalities, increase with age.4
Culture seldom required
Fewer than 2% of urine cultures meaningfully impact choice of treatment or need for follow-up.5 Thus, most major guidelines recommend against culture for symptomatic uncomplicated UTI.5,6 In one randomized controlled trial (RCT) neither a urine dipstick nor a culture, compared with empiric therapy, improved symptom outcomes or time to re-consultation; serious outcomes were not reported.7
The BC Centre for Disease Control (BCCDC) recommends urine cultures prior to treatment only in specific situations: suspicion of complicated and upper UTI (i.e. pyelonephritis), previous UTI with specific resistant organisms, recent travel outside of Canada/USA, recent quinolone or cephalosporin use, and recent hospitalization.8 (see Bugs and Drugs www.bugsanddrugs.org for further detail) Post-treatment urine cultures are not recommended after achieving clinical cure.9
Treat with regard to regional resistance patterns
A Cochrane systematic review found that various antibiotics achieve similar resolution of symptoms of uncomplicated UTIs and recommended that antibiotic treatment should reflect local bacterial resistance patterns.10
E. coli is the pathogen in about 80% of uncomplicated UTIs.11 In BC during 2019, only 3.5% of E. coli isolated from urine were nitrofurantoin resistant.12 More frequent use of nitrofurantoin has not increased E. coli resistance in BC or other jurisdictions.12,13
In contrast, E. coli resistance to ciprofloxacin and trimethoprim-sulfamethoxazole (TMP-SMX) in BC exceeds 20%. Amoxicillin resistance (based on ampicillin resistance, which is equivalent) exceeds 40%, and cephalexin resistance exceeds 50%.12 The Infectious Diseases Society of America (IDSA) recommends against using antibiotics for organisms with resistance rates to specific drug classes over 20%, or over 10% in the case of fluoroquinolones. The IDSA states that fluoroquinolones have a propensity for collateral damage and should be reserved for important uses other than acute cystitis.1
Nitrofurantoin for 5-7 days best for uncomplicated UTI in BC
Nitrofurantoin (MacroBID 100 mg BID or MacroDantin 50 mg qid) provides the best combination of clinical effectiveness, low bacterial resistance, and infrequent adverse events. Courses of 5 to 7 days have superior efficacy (~79 to 92%) compared with 3 days (~61 to 70%). Two meta-analyses focusing on nitrofurantoin for uncomplicated UTI both demonstrated that nitrofurantoin achieves symptom resolution equivalent to other antibiotics, with similar or fewer adverse events.14,15
Common adverse effects of nitrofurantoin include discolouration of urine, nausea (8%), and headache (6%).16 No severe irreversible outcomes were noted with up to 14 days of treatment in RCTs (N=4807).14 Observational studies and models report acute, reversible interstitial pneumonitis in 1 per 5000 people, usually beginning within 3-8 days of first use, and resolving shortly after stopping.17,18
Hepatotoxicity and pulmonary fibrosis occured almost exclusively in people taking nitrofurantoin for > 6 months.19
What is the alternative for patients unable to take nitrofurantoin?
The BCCDC recommends a single oral dose of fosfomycin 3 g as the preferred alternative to nitrofurantoin. It reaches high urinary but low systemic concentration and is effective even in patients with decreased creatinine clearance.22,23
A systematic review of fosfomycin compared with other antibiotics found equivalent clinical cure and no significant differences in adverse effects.24
In BC, the majority of E. coli are considered susceptible to fosfomycin, although current susceptibility testing methods are unable to detect all mechanisms of resistance. There is concern that overuse of fosfomycin in uncomplicated UTI may promote more widespread resistance, but to date this has not been demonstrated.25 Fosfomycin is costlier for a therapeutic course (PharmaCare pays $12.64 for a 3-gram packet) than nitrofurantoin ($6.44 for 5 days of therapy).
Antibiotic treatment failure
Observational studies in the United Kingdom found that 12 to 16% of patients treated for uncomplicated UTI returned within a month with urinary symptoms, regardless of the initial antibiotic.26 They may require a detailed history, urine culture, and other investigations to determine best care.
Spontaneous improvement of uncomplicated UTI occurs in 33-50% of women.27 While some RCTs have assessed the use of cranberry supplements and increased hydration for prevention of UTI, none assessed them as therapies for UTI.28
Shared decision-making can include options for delayed antibiotic prescriptions or symptom management with NSAIDs. A meta-analysis of antibiotic treatment versus placebo found no difference in pyelonephritis in the two RCTs that reported this outcome.29 However, two subsequent RCTs comparing NSAID versus antibiotic treatment in outpatients reported worse results for the NSAID groups.30,31
- Urine dipstick/urinalysis and/or urine cultures are not recommended for diagnosing most uncomplicated lower urinary tract infections. [corrected July 2022]
- Empiric prescription of nitrofurantoin for 5 to 7 days is recommended.
- The BCCDC recommends one oral dose of fosfomycin 3 g when CrCl is ≤ 30mL/min or when there is allergy/intolerance to nitrofurantoin.
- TMP-SMX, fluoroquinolones, and beta-lactams are unsuitable for empiric therapy in BC due to bacterial resistance.
- 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. Clinical Infectious Diseases 2011; 52(5):e103-20. DOI: 1093/cid/ciq257
- Grabe M, Bishop MC, Bjerklund-Johansen TE, et al. Guidelines on urological infections. European Association of Urology Guidelines, Arnhem, The Netherlands. European Association of Urology 2010; 1–110. Available from: https://www.medinovis.nl/pdf/EAU_guidelines_Urological_Infections.pdf (accessed Aug 24, 2021)
- Bent S, Nallamothu BK, Simel DL, et al. Does this woman have an acute uncomplicated urinary tract infection? JAMA 2002; 287(20):2701-10. DOI: 1001/jama.287.20.2701
- Little P, Turner S, Rumsby K, et al. Validating the prediction of lower urinary tract infection in primary care: sensitivity and specificity of urinary dipsticks and clinical scores in women. British Journal of General Practice 2010; 60(576):495-500. DOI: 3399/bjgp10X514747
- Johnson JD, O’Mara HM, Durtschi HF, Kopjar B. Do urine cultures for urinary tract infections decrease follow-up visits? Journal of the American Board of Family Medicine: JABFM 2011; 24(6):647-55. DOI: 3122/jabfm.2011.06.100299
- Long B, Koyfman A. Urine Culture and Uncomplicated Cystitis: The Minuses Outweigh the Pluses. Annals of Emergency Medicine 2019; 73(3):309-311. DOI: 1016/j.annemergmed.2018.06.008
- 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. DOI: 1136/bmj.c199
- BC Centre for Disease Control. Do Bugs Need Drugs? Treatment Recommendations: Cystitis. Available from: http://www.bugsanddrugs.org/7399B374-C9F6-4044-9E03-86B1D11F2874 (accessed Aug 24, 2021)
- Winickoff RN, Wilner SI, Gall G, et al. Urine culture after treatment of uncomplicated cystitis in women. Southern Medical Journal 1981; 74(2):165-9. DOI: 1097/00007611-198102000-00010
- Zalmanovici Trestioreanu A, Green H, Paul M, et al. Antimicrobial agents for treating uncomplicated urinary tract infection in women. Cochrane Database of Systematic Reviews 2010, Issue 10. Art. No.: CD007182. DOI: 1002/14651858.CD007182.pub2
- Echols RM, Tosiello RL, Haverstock DC, Tice AD. Demographic, clinical, and treatment parameters influencing the outcome of acute cystitis. Clinical Infectious Diseases 1999; 29(1):113-9. DOI: 1086/520138
- Communicable Disease Prevention and Control Services, British Columbia Centre for Disease Control. British Columbia Antimicrobial Resistance Dashboard. 2021; Available from: http://www.bccdc.ca/health-professionals/data-reports/antimicrobial-resistance-utilization/antimicrobial-resistance-dashboard (Accessed Aug 24, 2021)
- Pedela RL, Shihadeh KC, Knepper BC, et al. Preferential Use of Nitrofurantoin Over Fluoroquinolones for Acute Uncomplicated Cystitis and Outpatient Escherichia coli Resistance in an Integrated Healthcare System. Infection Control & Hospital Epidemiology 2017; 38(4):461-468. DOI:1017/ice.2016.315
- Huttner A, Verhaegh EM, Harbarth S, et al. Nitrofurantoin revisited: a systematic review and meta-analysis of controlled trials. Journal of Antimicrobial Chemotherapy 2015; 70(9):2456-64. DOI: https://doi.org/10.1093/jac/dkv147
- Porreca A, D’Agostino D, Romagnoli D, et al. The Clinical Efficacy of Nitrofurantoin for Treating Uncomplicated Urinary Tract Infection in Adults: A Systematic Review of Randomized Control Trials. Urologia Internationalis 2021; 105(7-8):531-540. DOI: 1159/000512582
- Pharmascience Inc. Product Monograph: Prpms-Nitrofurantoin BID. Nitrofurantoin Capsules, House Standard (nitrofurantoin monohydrate/macrocrystals) 100 mg, Urinary Tract Antibacterial. Health Canada Drug Product Database 2020; Submission Control No: 237005. Available from: https://pdf.hres.ca/dpd_pm/00057835.PDF (Accessed August 24, 2021)
- Jick SS, Jick H, Walker AM, Hunter JR. Hospitalizations for pulmonary reactions following nitrofurantoin use. Chest 1989; 96(3):512-5. DOI: 1378/chest.96.3.512
- Kabbara WK, Kordahi MC. Nitrofurantoin-induced pulmonary toxicity: A case report and review of the literature. Journal of Infection and Public Health 2015; 8(4):309-13. DOI: 1016/j.jiph.2015.01.007
- LeBras M, Gauthier A. What is the risk of pulmonary toxicity with nitrofurantoin (MACROBID)? Rx Files. 2017; Available at: https://www.rxfiles.ca/rxfiles/uploads/documents/Nitrofurantoin-Pulmonary-Toxicity.pdf (Accessed Aug 24, 2021)
- By the 2019 American Geriatrics Society Beers Criteria R Update Expert Panel. American Geriatrics Society 2019 Updated AGS Beers Criteria R for Potentially Inappropriate Medication Use in Older Adults. Journal of the American Geriatrics Society. 2019; 67(4):674-694. DOI: 1111/jgs.15767
- Hoang P, Salbu RL. Updated Nitrofurantoin Recommendations in the Elderly: A Closer Look at the Evidence. Consultant Pharmacist 2016; 31(7):381-4. DOI: 4140/TCP.n.2016.381
- Gardiner BJ, Stewardson AJ, Abbott IJ, Peleg AY. Nitrofurantoin and fosfomycin for resistant urinary tract infections: old drugs for emerging problems. Australian Prescriber 2019; 42(1):14-19. DOI: 18773/austprescr.2019.002
- Ten Doesschate T, van Haren E, Wijma RA, et al. The effectiveness of nitrofurantoin, fosfomycin and trimethoprim for the treatment of cystitis in relation to renal function. Clinical Microbiology & Infection 2020; 26(10):1355-1360. DOI: 1016/j.cmi.2020.03.001
- Cai T, Tamanini I, Tascini C, et al. Fosfomycin Trometamol versus Comparator Antibiotics for the Treatment of Acute Uncomplicated Urinary Tract Infections in Women: A Systematic Review and Meta-Analysis. Journal of Urology 2020; 203(3):570-578. DOI: 1097/JU.0000000000000620
- Mowlaboccus S, Daley DA, Birdsall J, et al. Molecular characterisation of fosfomycin-resistant Escherichia coli urinary tract infection isolates from Australia. Clinical Microbiology & Infection 2021; S1198-743X(21)00217-2. DOI: 1016/j.cmi.2021.04.029
- Lawrenson RA, Logie JW. Antibiotic failure in the treatment of urinary tract infections in young women. Journal of Antimicrobial Chemotherapy 2001; 48(6):895–901. DOI: 1093/jac/48.6.895
- Hoffmann T, Peiris R, Mar CD, et al. Natural history of uncomplicated urinary tract infection without antibiotics: a systematic review. British Journal of General Practice 2020; 70(699):e714-e722. DOI: 3399/bjgp20X712781
- Jepson RG, Mihaljevic L, Craig JC. Cranberries for treating urinary tract infections. Cochrane Database of Systematic Reviews 1998, Issue 4. Art. No.: CD001322. DOI: 1002/14651858.CD001322
- Falagas ME, Kotsantis IK, Vouloumanou EK, Rafailidis PI. Antibiotics versus placebo in the treatment of women with uncomplicated cystitis: a meta-analysis of randomized controlled trials.Journal of Infection 2009;58(2):91–102. DOI: 1016/j.jinf.2008.12.009
- 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. DOI: 1136/bmj.h6544
- Kronenberg A, Bütikofer L, Odutayo A, et al. Symptomatic treatment of uncomplicated lower urinary tract infections in the ambulatory setting: randomised, double blind trial. BMJ 2017; 359:j4784. DOI: 1136/bmj.j4784