Understanding and Treating Urinary Tract Infections

1 Urinary Tract Infections Su Lee, Pharm.D., MS, BCIDP, BCPS 3 Epidemiology of UTIs in the United States • 8 million physician visits/year • 10.8 % annual prevalence • 40-50% lifetime prevalence in women • 1 in 3 women will require antimicrobial therapy before 24 years of age • 0.5-0.7 episodes/person/year in sexually active women • $1 billion/year for evaluation and treatment 4 • Bacterial virulence Pathogenesis • Ascending Route • Urethra is colonized with bacteria • Female urethra is short and close proximity to vulvar and perianal area, making contamination likely • Sexual Intercourse can force bacteria into the female bladder • Bacteria ascend through urethra to bladder • G(-) or enterococcus • Hematogenous Route o Bacteremia or endocarditis o G(+) • Lymphatic Route o Increased pressure in the bladder can cause lymphatic flow Most commonly d/t E. coli • Behavioral factors • Host biologic factors 5 Host Defenses • Urinary tract is resistant to colonization • Rapidly eliminates bacteria by several mechanisms • Urine properties : osmolality, pH, organic acids • Urine flow • Presence of bactericidal activity, peptides, cytokines in urinary tract mucosa • Urinary inhibitors of bacterial adherence • Inflammatory response : PMNs, cytokines • Immune system : Cell-mediated, humoral immunity • Prostatic secretions 6 Behavioral Risk Factors in Adults • Female o Sexual intercourse o Lack of urination after intercourse o Spermicidal use o Diaphragm use o Pregnancy o Diabetes • Male o Insertive rectal intercourse o Vaginal colonization with E.coli in partner o https://www.google.com/search?q=diaphragm&safe=active&source=lnms&tbm=isch&sa=X&ved=0ah UKEwifpYyE4rnWAhXiw1QKHfXiCo4Q_AUICigB&biw=1920&bih=950#imgrc=u1Tf2YvbZReLQM:Access ed on 9/22/17 7 Etiology of UTI Setting/Host Factor Likely Organisms Outpatient, acute UTI E.coli Recurrent UTIs E.coli Proteus, Pseudomonas, Klebsiella, Enterobacter spp., Enterococci and Staphylococcus spp. Hospital/LTCF E.coli Proteus, Pseudomonas, Klebsiella, Enterobacter spp., Enterococcus and Staphylococcus spp. Young female, sexually active E.coli Staphylococcus saprophyticus Catheter associated E.coli Candida spp. Immunosuppressed or Renal Transplants E.coli Corynebacterium urealyticum 8 Urinary Tract Infection • Upper kidneynfion • Pyelonephritis (±bacteremia) • Lower • Cystitis • Asymptomatic bacteriuria (ASB) • Urethral pain syndrome 9 10 Clinical Characteristics Uncomplicated UTI Complicated UTI =Cystitis Uncomplicated Pyelonephritis Age/Gender You women in childbearing age Young women in childbearing age Men, post-menopausal women, pregnant, elderly women Etiology Community -acquired Community-acquired Community acquired or hospital acquired Comorbid Conditions Healthy Healthy Functional, metabolic, or structural abnormality Symptoms Localized Localized, Systemic S/S (Fever) , Flank pain Localized or Systemic (fever, delirium or AMS; altered mental status) Bacteremia Bacteremia Consequences/complicat Self-limited or pyelonephritis ions Example crack paint Men Catheter associated UTI stone Nephrolithiasis a kidney Pregnant women Hooton TM, Stamm WE, Infect Dis Clin North Amer, 1997;11:551-581, Stam WE, Hooton TM, NEJM, 1993;329:1328-1334 11 uncomplicatedugh CASE AA 12 Laboratory Diagnosis of UTI • Urine analysis • Not required for uncomplicated UTI • Avoid contamination, by mid-stream sample after disinfection of adjacent mucosa o Pyuria (> 10 WBC/mm3 or leukocyte esterase) o Bacteriuria (>105 CFU/ml urine) • 102 with symptoms o (+) Nitrite dipstick : G(-) bacteria, E. coli convert Nitrate to Nitrite • False negative (G(+) as enterococci, or pseudomonas) o Hematuria (app. 1/3 gross hematuria) o Elevated pH (6.5-8) • Bacteria produce urease: catalyzes the hydrolysis of urea in urine -> ammonia and CO2 • Especially Proteus or Providencia Hooton TM, Stamm WE, Infect Dis Clin North Amer, 1997;11:551-581 Falagas ME, Gorbach SL, Infect Dis clin Prac. 1995;4:241 13 CASE AA dean sample 14 Risk Factors of UTI • Risk factors • Sexual activity with different partners • Diaphragm or spermicide use • History of prior UTI • Urologic instrumentation or surgery • Urethral catheterization • Urinary tract obstruction • Neurogenic bladder • Renal transplant • Functional Mental impairment • Estrogen deficiency (loss of vaginal lactobacilli) • Lack of circumcision (children and young men) • Prostatic enlargement 15 Antibiotic Selection Considerations BasedonAnti program • Local antibiotic resistance patterns • Pharmacokinetics o Drug concentration in urinary tract • Tissue level of active drug : TMP/SMX or Fluoroquinolones (Cipro or Levo, NOT moxi) o Once-daily vs. multiple daily doses • Effects on normal enteric and vaginal flora • Safety (adverse events, allergies) • Patient age • Prior antibiotic use 16 senseof Bacteriaintheurine pre ye Asymptomatic Bacteriuria (ASB) • Asymptomatic defined as lack of S/S • Fever, urgency, frequency, dysuria, suprapubic tenderness, costovertebral angle pain • IDSA recommend against screening for or/and treatment for ASB except pregnant women or patients who undergo urologic procedures • In older patients with functional and/or cognitive impairment with bacteriuria and delirium (acute mental status change, confusion) and without local genitourinary symptoms or other systemic signs of infection (eg, fever or hemodynamic instability) • Recommend assessment for other causes and careful observation rather than antimicrobial treatment (strong recommendation, very low-quality evidence). • In patients with high-risk neutropenia (absolute neutrophil count <100, > 7 days) • No recommendation (Knowledge gab) • Bacteriuria defined as : • Women • 2 consecutive voided urine specimens with isolation of the same bacterial strain in quantitative counts ≥105 cfu/mL • Men • A single, clean-catch voided urine specimen with 1 bacterial species isolated in a quantitative count ≥105 cfu/mL • A single Catheterized Urine specimen with 1 bacterial species isolated in ≥ 102 cfu/mL in men or women 17 Asymptomatic bacteriuria (ASB) • Pregnant woman o should be treated for 3-7 days with periodic screening for ASB after therapy o Untreated bacteriuria result in pyelonephritis, Increased rate of prematurity, low birth weight, preeclampsia o Tx : Nitrofurantoin, or Beta-lactams • Those who will have urology procedures • Suggest that a urine culture be obtained prior to the procedure and targeted antimicrobial therapy of a short course (1 or 2 doses) at 30–60 minutes before the procedure. • Recommend against screening for nor treatment of ASB o Premenopausal, non-pregnant woman o DM, spinal cord injury, solid organ transplant patients o Older persons in a community setting, The institutionalized elderly o Patients with urologic device o Catheter Associated Asymptomatic Bacteriuria (CA-ASB) Hooton TM et al., CID 2010:50:625 18 Antibiotic Resistance (%) of E. coli in US https://resistancemap.cddep.org/AntibioticResistance.php accessed 9/22/2017 Antibiotics 2012 2014 2021 AHG* Aminopenicillins 55 56 Amoxicillin-clavulanate 18 43 Carbapenems 1 1 0 Cephalosporins, 3rd 12 16 24 Fluoroquinolones (Cip/Lev) 30 35 37/39 Piperacillin-tazobactam 3 7 Nitrofurantoin (urine) 3 TMP/SMX 33 Gentamicin/Tobramycin *2020 Adventist Health Glendale Antibiogram 14/17 19 pain Bak infectio kidney 20 Acute Cystitis in Uncomplicated UTI • Symptoms : • Absence of complicated UTI, pyelonephritis, or structural obstruction • fever, flank pain, or other suspicion for • Diagnosis : LeukocyteWBC • Pyuriaso • Urinary dipstick • Leukocyte esterase pyelonephritis • Dysuria • Frequent, painful urination • Turbid urine • Hematuria Gupta K. et al., CID 2011;52:e103 21 Treatment of Uncomplicated Cystitis • Able to take oral medication →Outpatient treatment • Primary Options Browncolor st 1 line: Nitrofurantoin (Macrobid) 100 mg BID x 5 days OR To Eon A notuseitpthave systemic sightympt • Avoid if early pyelonephritis suspected • Only for normal renal function, avoid CRCL<30 ml/min • Beers criteria recommends avoiding use in elderly≥65 YO with a CRCL < 30ml/min TMP/SMX DS (Bactrim 160/800) BID x 3 days OR Ight • Avoid if resistance > 20% or if used within previous 3 months (Not in AHG) Only when necessary: Fosfomycin 3 gm single dose • • • • Avoid early pyelonephritis suspected $$$ Susceptibility not routinely performed Consider for E. coli or E. faecalis if no other PO options (Other organisms may be resistant) Pivmecillinam (Pivya) 185 mg Q 8 H x 3-7 days, with/without food for female adult with uncomplicated UTI  A pivalate ester prodrug that is well abosorbed and rapidly hydrolyzed to mecillinam (the active agent) by mecillinam preferentially targets PBP-2 in the bacterial cell wall  Approved in May 2024  Pivmecillinam 185 mg = pivmecillinam hydrochloride 200 mg Gupta K. et al., CID 2011;52:e103 22 • Alternative Options o Fluoroquinolones x 3 days • • • • Yao QI prolongation Tendon Ciprofloxacin 250 mg PO BID CNS Hepatotoxity Levofloxacin 250 mg PO Daily FQs NOT recommended in community resistance > 10% (same for uncomplicated UTI) Avoid FQs for cystitis unless no alternatives, due to collateral damage and adverse event risk o Beta-Lactams in 5-7 days • Amoxicillin-clavulanate • Cefdinir (3rd) • Cefaclor (2nd) • Cefpodoxime-proxetil (3rd) • Avoid ampicillin or amoxicillin alone (50% resistant) • Lower efficacy than other available agents 23 Recurrent Uncomplicated UTI : Pathogenesis and Epidemiology • Pathogenesis • Most cases of recurrent UTI due to re-infection are caused by usually E. coli (not always from the same strains as the original infection) • Epidemiology • 20-30% of young women with uncomplicated cystitis have recurrent UTI • Risk factors : sexual intercourse, spermicide, first UTI at early age, maternal history of UTI • Cf. Recurrent vs. Relapse • Recurrent : infection at least 2 weeks after the previous infections – different pathogens, considered as different episode • Relapse : a revival of infection from an existing episode, within 2 weeks – usually same pathogens 24 Recurrent Uncomplicated UTI in Women: AUA/CUA/SUFU Guideline (2019) https://www.auanet.org/guidelines/guidelines/recurrent-uti, retrieved on 10/3/21 25 Recurrent Uncomplicated UTI, 2019 AUA • Antibiotic Treatment • Should use 1st line therapy (ie, nitrofurantoin, TMP/SMX, Fosfomycin) depend on the local antibiogram for the treatment of symptomatic UTI in women (strong recommendation: evidence level grade B) • Should treat with as short a duration of antibiotics as reasonable, generally no longer than seven days (Moderate, Grade B) • If Ucxs resistant to oral Abx, treat with culture directed IV Abx for short course, no longer than 7 days (Expert Opinion) • Antibiotic Prophylaxis • May prescribe antibiotic prophylaxis to decrease the risk of future UTIs in all women after discussing the risks, benefits, and alternatives (Moderate, Grade B) • Non-Antibiotic Prophylaxis • May offer cranberry prophylaxis for women with rUTI (Conditional Recommendation: Grade C) • Follow-up Evaluation • Should NOT perform a post-treatment test of cure UA or Ucx in asymptomatic patients (Expert Opinion) • Should repeat urine cultures to guide further management when UTI symptoms persist following antimicrobial therapy (Expert Opinion) • Estrogen • In peri-and post-menopausal women with rUTI, should recommend vaginal estrogen therapy to reduce the risk of future UTIs if there is no contraindication to estrogen therapy (Moderate, Grade B) 26 Recurrent Uncomplicated UTI in Women: AUA/CUA/SUFU Guideline (2019) https://www.auanet.org/guidelines/guidelines/recurrent-uti, retrieved on 10/3/21 28 Preventing UTIs Patient Education • Empty your bladder every 3 hrs while awake, whether you feel an urge to do so; avoid • • • • long intervals between urination Drink at least 6-8 glasses of water daily Shower instead of taking a bath; avoid using bubble bath or other cosmetic bath product Avoid using any feminine hygiene sprays, scented douches, or a vaginal diaphragm if you are prone to UTIs Empty your bladder after sexual intercourse; sexual relations may cause UTIs 30 AHGL Continuing Education, retrieved on 10/15/24 31 Pyelonephritis infection Kidney • Symptoms develop rapidly (< 24hrs) and may include: • Fever > 38C, chills • Flank pain (Costovertebral angle tenderness) • Nausea/vomiting/diarrhea • Symptoms of cystitis • Increased urinary frequency, urgency, and dysuria 32 Empiric Treatment of Pyelonephritis combat Outpatient Abx (uncomplicated) • Urine culture and sensitivity • Ciprofloxacin (+/- initial IV Cipro) • 500 mg PO BID x 7 days or 1000 mg PO qday x 7 days • Levofloxacin 750 mg PO qday x 5 days • TMP/SMX DS PO BID x 14 days • Caution with hyperkalemia when CrCL<30 or with ACEI/ARBs, K-sparing diuretics, aliskiren • PO Beta-lactams x 10-14 days • Comment • Add an initial one-time IV dose of long-acting antimicrobials (1Gm ceftriaxone or 5 mg/kg once daily Aminoglycosides) recommended • TMP/SMX NOT recommended in community resistance > 20 % (same for uncomplicated UTI) see • FQs NOT recommended in community resistance > 10% (same for uncomplicated UTI) • Nitrofurantoin and Fosfomycin are NOT appropriate for pyelonephritis • • • • Inpatient Abx (complicated) Initial IV abx: broad spectrum Fluoroquinolones Aminoglycoside +/-ampicillin 3rd gen (Ceftriaxone) or broad spectrum cephalosporins • Extended spectrum penicillin (eg, ampicillin/sulbactam or pip/tazo) • Carbapenem • Should be based on local resistance data, and the regimen should be tailored based on susceptibility results 33 Duration of Therapy of Acute Pyelonephritis • 7-14 days • De-escalation • PO TMP/SMX can be used if susceptible • PO FQs can be used if susceptible • PO ampicillin or nitrofurantoin should be avoided due to low site of infection concentration • Moxifloxacin should be avoided due uncertainty of urinary concentration • Oral Beta-lactam agents are less effective than other available agents • Conversion to PO antimicrobials is appropriate once afebrile and clinically stable 34 Complicated UTIs • Depends on status, may need to admit • Severely ill • Direct therapy towards bacteremia/sepsis • Hospitalize + IV abx • Prompt initiation of broad- spectrum antibiotics • Immediate urinary tract decompression in patients with evidence of obstruction Nicolle LE, Drugs Aging. 2001;18:243-254 35 Treatment of Complicated UTI 2009 IDSA Catheter associated UTI treatment guidelines • Duration (5-14 days (3days)) • Regardless if patient is catheterized • 7 days for quick resolution of symptoms • 10 to 14 days for a delayed response • May use levofloxacin for 5 days in not severely ill patients (unknown about other fluoroquinolones) • 3 days of treatment may be appropriate for women ≤ 65 years old with Catheter Associated-UTI without upper UTI symptoms after indwelling catheter removal Hooton TM et al., CID 2010:50:625 36 Treatment of Acute Complicated UTI • Low risk of MDR GNB • Primary Treatment Fyi • Levofloxacin 750 mg IV/PO qday for 5 days (or 250 mg IV/PO for 10 days), Cipro 400 mg IV Q 12h • Ceftriaxone 1 G IV q 24 hrs • Alternatives • Nitrofurantoin (Macrobid) 100 mg PO BID (if without signs or symptoms of systemic infection - fever, flank pain) • TMP/SMX DS 1 T PO BID (If local prevalence of resistance to TMP/SMX is < 20%) • cUTI with previous Pseudomonas infection and/or Sepsis • • • • Ceftazidime 0.5-1 g IV q 8h Cefepime 0.5-1 G IV q 12 hrs for 7-10 days ( or severe : 2 G IV q 12 hrs for 10 days) Piperacillin/Tazobactam 3.375 G IV Q 4-6 h Pen allergy • Aztreonam 0.5-1 G IV q 8-12 h • Gentamicin 5 mg/kg IV qday • Cipro or levo • MDR GNB • • • • • Meropenem or Ertapenem (ESBL) Ceftolozane-tazobactam (MDR-pseudomonas) 1.5 G IV q8h if CRCL > 50 ml/min Ceftazidime-avibactam (KPC) 2.5 G IV q8h Meropenem-vaborbactam (KPC) 4 G IV q 8h with 3 hr infusion Plazomicin 15 mg/kg IV q24h Modified from Sanford Guide Web edition, https://webedition.sanfordguide.com/sanford-guide-online, accessed on 10/3/21 37 UTI in Pregnancy • Treatment • Beta-Lactams (B) • Amoxicillin-clavulanate 500 mg PO q8h 3-7 days (or Amoxicillin: Resistance 50%, not in CA) • Cephalexin 500 mg PO Q6h x 3-7 days(71% E.coli sensitive in 2020 AHG) • Cefdinir (3rd) • Cefaclor (2nd) • Cefpodoxime-proxetil (3rd) • Nitrofurantoin [B, but contraindicated at term, 38-42 weeks, avoid first trimester if there is a safer alternative, G6PD Deficiency(hemolytic anemia)] • Fosfomycin • Avoid : TMP/SMX [1st trimester (congenital malformations), 3rd Trimester(kernicterus), G6PD deficiency(Hemolytic anemia)], Aminoglycosides(D), Fluoroquinolones(C), TCs • Follow up in 1-2 weeks required to confirm pathogen eradication Lexicomp, accessed on 9/22/17 Uptodate, retrieved on 10/13/21 38 Treatment of Complicated UTI Durationoftherapyislonger was • UTI in males • TMP/SMX, Fluoroquinolones, or Ceftriaxone • 7-14 days of cystitis (uncomplicated) • Acute cystitis or pyelonephritis in young men is very rare • Single organism, no significant obstruction, a normal urinary function, and the absence of prostatic involvement • 10 days to 4-6 weeks of treatment in Prostatitis or epididymitis (deep tissue infection, permeability issue) • Prostatitis occurs in young and middle-aged men • Prostatitis S/S : fever/chills, pelvic pain or perineal pain • Follow up: repeat urinalysis and culture • 1-2 weeks after completion of antibiotic therapy 39 Acute Prostatitis Etiologies • Age < 35 years • N. gonorrhea • C. trachomatis • Age ≥35 years • Enterobacterales • Coliforms • Enterococcus sp. Primary Regimens • Uncomplicated, with risk of STD • Ceftriaxone 500 mg IM x 1 dose Then Doxycycline 100 mg PO BID x 10d • Uncomplicated with low risk of STD • At least 10-14 days of therapy • Levofloxacin 500-750 mg IV/PO qday • Ciprofloxacin (500-750 mg PO or 400 mg IV) BID • TMP-SMX 1 DS tablet PO BID • Some authorities recommend 4 to 6 weeks of therapy 40 Uncomplicated UTI =Cystitis Pyelonephritis Complicated UTI Etiology Community -acquired Community-acquired Community acquired or hospital acquired Comorbid Conditions Healthy Healthy Functional, metabolic, or structural abnormality Symptoms Localized Localized, Systemic S/S (Fever) , Flank pain Systemic (fever, delirium or AMS; altered mental status) Consequences/com plications Self-limited or pyelonephritis Bacteremia Bacteremia Treatment Nitrofurantoin TMP/SMX Fosfomycin Alternatives: FQs or B-lactams Outpts: FQs, TMP/SMX Inpts: broad spectrum Abx (Ceftriaxone, Ags, FQ…) Outpts: FQ, TMP/SMX Inpts: broad spectrum Abx (Ceftriaxone, risk factors for PSA or sepsis, MDR) Duration 3 days, 5 days, 1 dose, 7 days 5-14 days 5-14 days 41 orangediva AZO RxPrep retrieved on 4/15/24 42 Summary • Pathogens/Diagnosis • Various UTIs and Treatment Options • Asymptomatic bacteriuria : No except pregnant or urology survey • Uncomplicated UTI : Nitrofurantoin (5d), TMP/SMX (3d), Fosfomycin(1) • Alternatives : FQ, B-lactams • Achieves high concentration in urine • 3-7 days : uncomplicated UTI • 7-14 days : complicated UTI or acute pyelonephritis • 10 to 4 - 6 weeks : Prostatitis • 6 Months : recurrent UTI > 3 times/year or >2 times/6 months