OCTOBER 2017 DRUG ANTIBIOTICS. Presence of bacteria in the urine with no symptoms or clinical signs.

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1 OCTOBER 2017 DRUG ANTIBIOTICS This optimal usage guide is mainly intended for primary care health professionnals. It is provided for information purposes only and should not replace the clinician s judgement. The recommendations were developed using a systematic approach and are supported by the scientific literature and the knowledge and experience of Quebec clinicians and experts. They do not apply to pregnant women or to severe urinary tract infections requiring parenteral therapy. For more details, go to inesss.qc.ca. GENERAL CONSIDERATIONS TERMINOLOGY Uncomplicated urinary tract infection Acute, sporadic or recurrent urinary tract infection (cystitis or pyelonephritis) in a healthy woman, regardless of her age. Complicated or at risk of becoming complicated Recurrent urinary tract infection Any other urinary tract infection, particularly in a pregnant woman, a man, any individual with an anatomical or functional abnormality of the urinary system, a urinary catheter, a previous urologic manipulation or uncontrolled diabetes, or any immunosuppressed individual. A urinary tract infection that occurs more than 2 times every 6 months or more than 3 times a year. Most cases are a reinfection, i.e., another infection of the urinary system. It may also be a persistent infection due to bacterial resistance, inadequate treatment or an anatomical or functional abnormality of the urinary system, which recurs usually very quickly, i.e., within 2 to 4 weeks maximum after initial treatment. Asymptomatic bacteriuria Presence of bacteria in the urine with no symptoms or clinical signs. PATHOGENS Common Escherichia coli Klebsiella pneumoniae Staphylococcus saprophyticus Enterococcus Rare (may require further investigation) Examples : Enterobacter spp. Proteus mirabilis Pseudomonas aeruginosa Staphylococcus aureus

2 DIAGNOSIS SYMPTOMATOLOGY Diagnosis is based on the combination of symptoms and clinical signs and on the absence of clinical manifestations, which may point to another diagnosis. Signs and symptoms 1 Cystitis Dysuria Urinary frequency Burning sensation and pain when urinating Pyelonephritis Hematuria Suprapubic pain Cloudy or foul-smelling urine! If isolated, cloudy or foul-smelling urine should be considered carefully as it is not specific to urinary tract infections. Fever Chills Nausea, vomiting Costovertebral angle tenderness (Murphy s punch sign) Cystitis symptoms (often present) 1. Elderly patient : Atypical and non-specific symptomatology (e.g., confusion, incontinence). Consider a differential diagnosis except if specific urinary tract infection symptoms appear or persist (with abnormal urine analysis and culture results). Signs and symptoms pointing to another diagnosis Women Men Vaginal discharge, vulvar itching, pregnancy symptoms. Pain elicited by prostatic or testicular examination. Cystitis is not associated with altered vital signs or elevated temperature. DIFFERENTIAL DIAGNOSIS Women Vaginal or pelvic infections, gynecological pathologies (e.g., pelvic inflammatory disease, ectopic pregnancy, ruptured ovarian cyst). Men All patients URINE ANALYSIS AND CULTURE Prostatitis, epididymo-orchitis. Sexually transmitted infections, urinary calculus with or without urosepsis, other intra-abdominal infections (e.g., appendicitis, diverticulitis). Urine dipstick Simple, low-cost and reliable : recommended for any type of suspected urinary tract infection. Presence of leukocyte esterase, nitrites and de novo urinary symptoms : good positive predictive value ( 90 %). Absence of leukocyte esterase and/or nitrites in a symptomatic patient : good negative predictive value ( 90 %). Urine culture Optional in cases of uncomplicated cystitis or documented recurrent cystitis (except if a recurrence occurred within one month). Recommended in the following cases : - Uncomplicated acute pyelonephritis (APN), complicated or at risk of becoming complicated urinary tract infection, persisting symptoms or failed antibiotic treatment. - Combination of symptoms and clinical signs but negative urine analysis. - Recent trip to an area at risk for multidrug-resistant bacteria and urinary symptoms. To be avoided in patients with an indwelling urinary catheter with no symptoms or clinical signs of urinary tract infection, except in certain cases (e.g., urosepsis).

3 TREATMENT PRINCIPLES Asymptomatic bacteriuria should not be treated, except before urology interventions. When selecting a medication, local antibiotic resistance should be taken into account. It should never exceed 20 % (except if there is no alternative treatment). Data on Escherichia coli resistance to certain antibiotics in Québec 1 Antibiotics Fosfomycin tromethamine Nitrofurantoin Ciprofloxacin Trimethoprimsulfamethoxazole Resistance Less than 5 % 5 10 % % % 1. Regional variations exist. Fluoroquinolones should not be prescribed to treat uncomplicated cystitis (except if there is no alternative treatment). Recent use of antibiotics, a trip to an area at high risk for antibiotic resistance (e.g., Middle East, Far East, Indian sub-continent, Sub-Saharan Africa) and a recent hospital stay increase the risk of bacterial resistance. In case of failed hygienic and dietary measures (e.g., sufficient hydration, personal hygiene, postcoital voiding) and after urinary system exploration (identification of anatomical or functional abnormalities), recurrent uncomplicated cystitis may be treated with the following : Postcoital antibiotic prophylaxis for 6 months detected by the patient) Continuous antibiotic prophylaxis for 3 to 6 months Self-start antibiotic therapy (if signs or symptoms are Follow-up is recommended after 6 months to reassess treatment relevance for recurrent uncomplicated cystitis and check what changes the patient has made, if any (e.g., contraceptive method, sexual activity). Current knowledge does not support, as non-antibiotic prophylaxis for urinary tract infections, the use of cranberries or intravaginal probiotics, for which efficacy data is contradictory; using oral estrogen, whose efficacy has not been proven; or vaginal estrogen, as there is no statistically significant data on their use in menopausal women.

4 ANTIBIOTIC TREATMENT ANTIBIOTIC TREATMENT OF UNCOMPLICATED CYSTITIS FIRST-LINE RECURRENT CYSTITIS 2,3 Antibiotics 1 Dosage Duration Nitrofurantoin monohydrate/ macrocrystals Nitrofurantoin, macrocrystals only Fosfomycin tromethamine Trimethoprimsulfamethoxazole 100 mg PO BID 5 days 50 mg PO QID 7 days Postcoital (6 months) or continuous (3 to 6 months) antibiotic prophylaxis mg PO : within 2 hours of sexual intercourse or DIE if continuous 3 g PO In a single dose N/A 160/800 mg PO BID (1 DS tablet) 3 days 80/400 mg PO : within 2 hours of sexual intercourse or DIE or 3 times/week if continuous ALTERNATIVE TREATMENT IN CASE OF CONTRAINDICATION TO ALL FIRST-LINE ANTIBIOTICS (medication allergy, intolerance, resistance or interaction) Trimethoprim 100 mg PO BID 3 days 100 mg PO : within 2 hours if postcoital or DIE if continuous Beta-lactams 4,5 Amoxicillin-clavulanate 875/125 mg PO BID 6 Cefadroxil Cefixime Cephalexin 500 mg PO BID 400 mg PO DIE 500 mg PO QID 7 days N/A SECOND-LINE (if all first-line antibiotics fail or have adverse effects) Antibiotics Dosage Duration Fluoroquinolones 7 Norfloxacin Ciprofloxacin Ciprofloxacin XL Levofloxacin 400 mg PO BID 250 mg PO BID 500 mg PO DIE 250 mg PO DIE 1. Antibiotics are presented based on Escherichia coli resistance (least to most) and cost (lowest to highest). 2. Cystitis is considered recurrent when there are more than 2 episodes over 6 months or more than 3 a year; self-start antibiotic therapy is similar to first-line treatment. 3. Fosfomycin, beta-lactams and fluoroquinolones are usually not recommended as antibiotic prophylaxis options. 4. Beta-lactams are presented in alphabetical order of generic name. 5. Although cefuroxime and cefprozil are indicated for the treatment of uncomplicated cystitis, there is limited evidence supporting this use. 6. The 7:1 formulation (875/125 mg) PO BID of amoxicillin-clavulanate is preferred due to its higher digestive tolerance. 7. Fluoroquinolones are presented based on cost (lowest to highest). 3 days N/A : Not applicable; DS : Double strength.

5 ANTIBIOTIC TREATMENT OF UNCOMPLICATED APN AND COMPLICATED OR AT RISK OF BECOMING COMPLICATED INFECTIONS FIRST-LINE Antibiotics Fluoroquinolones 2 Ciprofloxacin Ciprofloxacin XL Levofloxacin Dosage 500 mg PO BID mg PO DIE 500 mg PO DIE ANTIBIOTIC TREATMENT FOLLOWING ANTIBIOTIC SENSITIVITY TESTING ONLY Duration Cystitis APN 1 Women : 7 days Men : 10 to 14 days Trimethoprimsulfamethoxazole 160/800mg PO BID 7 to 10 days 10 to 14 days Beta-lactams 3,4 Amoxicillin-clavulanate 875/125 mg PO BID 5 Cefadroxil Cefixime Cephalexin 500 mg PO BID 400 mg PO DIE 500 mg PO QID 1. For the treatment of uncomplicated, complicated or at risk of becoming complicated APN. 2. Fluoroquinolones are presented based on cost (lowest to highest). 3. Beta-lactams are presented in alphabetical order of generic name. 4. Although cefuroxime is indicated for the treatment of urinary tract infections, there is limited evidence supporting this use. 5. The 7:1 formulation (875/125 mg) PO BID of amoxicillin-clavulanate is preferred due to its higher digestive tolerance. 10 to 14 days APN : Acute pyelonephritis; XL : Extended release. FOLLOW-UP Patient follow-up is performed mainly in the following situations : After urine culture If symptoms persist despite treatment If symptoms reappear quickly (within 2 to 4 weeks) After antibiotic prophylaxis is initiated, to assess its relevance and determine if it should be continued In case of recurrence or treatment failure, a urine culture should be performed before a new treatment is prescribed. Some anatomical conditions (e.g., lithiasis, significant residual urine) may contribute to maintaining a persistent bacteria colony, which increases the number of recurring infections. These conditions can be detected with first-line investigations (ultrasound, computed tomography of the urinary system).

6 CRITERIA FOR SPECIALIST REFERRAL Referral to a specialist is indicated in the following cases : Anatomical or functional abnormality of the urinary system Recurrence caused by an unusual pathogen (e.g., Pseudomonas aeruginosa, Proteus mirabilis) Hydronephrosis or persistent post-void residual urine of more than 150 ml in the lower urinary system Recurrent uncomplicated APN or any recurrent complicated or at risk of becoming complicated urinary tract infection MAIN REFERENCES Beerepoot MA, Geerlings SE, van Haarst EP, van Charante NM, ter Riet G. Nonantibiotic prophylaxis for recurrent urinary tract infections: A systematic review and metaanalysis of randomized controlled trials. The Journal of Urology 2013;190(6): Bonkat G, Pickard R, Bartoletti R, Bruyère F, Geerlings SE, Wagenlehner F, Wullt B, et al. Urological Infections. European Association of Urology; Accessible at: Dason S, Dason JT, Kapoor A. Guidelines for the diagnosis and management of recurrent urinary tract infection in women Gupta K, Hooton TM, Naber KG, Wullt B, Colgan R, Miller LG, et al. International clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelo nephritis 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-e20. Michigan Medicine, University of Michigan. Urinary Tract Infection Guidelines for Clinical Care Ambulatory Accessible at: practiceguides/uti/uti.pdf. Scottish Intercollegiate Guidelines Network (SIGN). Management of suspected bacterial urinary tract infection in adults (SIGN 88). Edinburgh: SIGN; Accessible at: Société de Pathologie Infectieuse de Langue Française (SPILF). Diagnostic et antibiothérapie des infections urinaires bactériennes communautaires de l'adulte Please note that other references have been consulted. Any reproduction of this document in whole or in part for non-commercial use is permitted on condition that the source is mentioned.