Urinary Tract Infections 2023_Handout.pdf

Urinary Tract Infections Elizabeth Coyle, Pharm.D., BCPS, FCCM Email: [email protected] Objectives • Recognize the signs and symptoms of uncomplicated and complicated UTIs. • Know the pathogens associated with uncomplicated and complicated UTIs. • Design a therapeutic regimen for someone with an uncom...

Urinary Tract Infections Elizabeth Coyle, Pharm.D., BCPS, FCCM Email: [email protected] Objectives • Recognize the signs and symptoms of uncomplicated and complicated UTIs. • Know the pathogens associated with uncomplicated and complicated UTIs. • Design a therapeutic regimen for someone with an uncomplicated or complicated UTI. • Design a therapeutic regimen for special populations and UTIs such as asymptomatic bacteriuria, pregnancy, recurrent infections, antimicrobial resistance, etc. Urinary Tract Infections MN is a 22 year old female who presents to her doctor’s office complaining of dysuria urinary frequency over the past 4 days. She denies fever or flank pain. She is an otherwise healthy female, no history of UTIs and with no known allergies. Urinalysis reveals: hazy urine WBC of 107/mm3 nitrite positive leukocyte esterase positive positive protein 105 CFU/mL gram-negative rods How would you treat MN’s uncomplicated cystitis? Urinary Tract Infections • Most common indication for antimicrobials in women of childbearing age. • Cystitis/Pyelonephritis • Cystitis: lower UTIs involving bladder • Pyelonephritis: upper UTIs – kidney • Uncomplicated: usually girls ages 15 – 45 years • Complicated • • • • Structural abnormalities Men Pregnancy Children Urinary Tract Infections • Additional factors associated with complicated UTIs:      Male sex Hospital-acquired Pregnancy Anatomical abnormality of the urinary tract Poorly controlled diabetes     Recent antimicrobial use Indwelling urinary catheter Recent urinary tract instrumentation Immunosuppression Complicated and Uncomplicated Cystitis • Uncomplicated cystitis • Complicating factors • Often community onset • Indwelling Foley catheter — Dehydration — Sexual intercourse — Poor hygiene — Duration dependent • Patient factors — No obstruction or intrinsic disease — Non-pregnant females — Controlled diabetes mellitus • Neurogenic bladder — Increased storage pressure — Vesico-uretero-renal reflux • Obstruction/intrinsic disease — Prostatic hyperplasia — Tissue invasion — Nephropathies/cancer Urinalysis • Bacterial Count • ≥ 105 CFU/mL • Can present with symptoms with lower bacterial count • Microscopic Exam • Pyuria: WBC > 102 /mm • Hematuria often present (not specific) • Proteinuria common (not specific) • Chemistry • Nitrite (produced by bacteria that reduce nitrate in urine) • Leukocyte esterase (indicates presence of pyuria) Urinary Tract Infections • Etiology _ Community • E. coli (75 – 95%) • Enterobacteriacea • Proteus mirabilis • Klebsiella pneumoniae • Staphylococcus saprophyticus Urinary Tract Infections  Community-acquired UTI organisms K. pneumoniae Enterococcus P. mirabilis S. saprophyticus E. coli Urinary Tract Infections • Consideration of E. coli Resistance • Need to be cognizant of local resistant patterns • General Resistance Rates • • • • • Amoxicillin > 20% Trimethoprim/Sulfamethoxazole ~ >20% Fluoroquinolones <10% Amoxicillin-clavulanate, 2nd generation oral cephalosporins <10% Nitrofurantion & fosfomycin relatively good in vitro susceptibility Treatment Uncomplicated Cystitis • Trimethoprim/Sulfamethoxazole 160/800 mg BID 3 day treatment • Fluoroquinolones • Ciprofloxacin 500mg extended release daily or 250mg twice/day • Levofloxacin 250mg daily 3 day treatment • Nitrofurantion 100mg BID 5 day treatment • Fosfomycin 3 grams Single dose • Beta-lactam (Not Amoxicillin) 5 – 7 day treatment Maximizing PK/PD against UTIs • T>MIC • Proportion of time the dose-interval drug concentration remained above MIC • Describes beta-lactams and nitrofurantoin: influenced by Vd and half-life • Clinical implication: give doses more frequently or infused over longer duration • Cmax/MIC • Ratio of peak concentration to MIC • Describes aminoglycosides: influenced primarily by Vd • Clinical implication: give larger doses less often • AUC/MIC • Ratio of integrated exposure to MIC • Describes fluoroquinolones, vancomycin: influenced by Vd and half-life • Clinical implication: maximize total exposure by increasing 24-hr dose/CL ratio PK Considerations in UTI • Antibiotics frequently used in UTI • Percent of dose recovered in urine — Amoxicillin — Cephalexin — Cefadroxil — Ciprofloxacin — Fosfomycin — Levofloxacin — Nitrofurantoin — TMP/SMX 60% 90% 90% 50-70% 38% 87% 20-25% 65-85% (respectively) • Achievable urinary concentrations — Amoxicillin 250 mg — Cephalexin 500 mg — Cefadroxil 500 mg — Ciprofloxacin 500 mg — Fosfomycin 3 g — Levofloxacin 500 mg — Nitrofurantoin 100 mg — TMP/SMX 160/800mg ~ 650-1500 mg/L ~ 2200 mg/L ~ 1800 mg/L ~ 200 mg/L ~ 700 mg/L ~ 500-700 mg/L ~ 50-200 mg/L ~ 200 / 75 mg/L Package inserts available at Drugs@FDA. https://www.accessdata.fda.gov/scripts/cder/daf/. Novelli A, Rosi E. J Chemother. 2017; 29(suppl 1):10-18. IDSA Guideline Treatment Algorithm Woman with acute uncomplicated cystitis, can take oral meds & no suspicion for pyelonephritis NO Consider alternate diagnosis such as pyelonephritis or complicated UTI YES Can one of following be recommended Fluoroquinolones for 3 days (be (allergy, availability, tolerance): aware of local resistance) Nitrofurantoin 100mg BID X 5 days NO OR (avoid if pyelonephritis suspected) Β-lactams for 5 – 7 days (avoid TMP/SMX 160/800mg BID X 3 days (avoid if local resistance >20% or used in last 3 months) ampicillin or amoxicillin alone; requires close follow-up) Fosfomycin 3 grams single dose (lower efficacy, avoid if pyelonephritis suspected) Adapted from algorithm in CID 2011; 52(5): e103-e120. Urinary Tract Infections MN is a 22 year old female who presents to her doctor’s office complaining of dysuria urinary frequency over the past 4 days. She denies fever or flank pain. She is an otherwise healthy female, no history of UTIs and with no known allergies. Urinalysis reveals: hazy urine WBC of 107/mm3 nitrite positive leukocyte esterase positive positive protein 105 CFU/mL gram-negative rods How would you treat MN’s uncomplicated cystitis? Urinary Tract Infections How would you treat MN’s acute cystitis? A. B. C. D. Levofloxacin 250mg once/day X 3 days Fosfomycin 3 gram X 3 doses Nitrofurantoin 100mg BID X 5 days TMP/SMX 160/800mg X one dose Urinary Tract Infections • Recurrent and Relapse infections • Recurrent Infections – infecting organism is different than original/preceding infection • Risks: sexual intercourse, diaphragm & spermicide use • Treatment options • • • • Self/administered/initiated therapy at onset of symptoms Postcoital therapy Continuous low-dose prophylaxis (when >3 episodes/year) In postmenopausal women, topical estrogen • Relapse Infections – persistence of original infection after treatment • May indicate renal involvement, structural abnormality • May require longer treatment or use of alternative agent Urinary Tract Infections MN returns to the clinic 8 months later with dysuria and increases urinary frequency the last 2 days. This is her second UTI in the past 8 months. Otherwise she is in very good health, and her only drug is a multivitamin daily and loratadine as needed for seasonal allergies. She is very concerned about the frequency of her UTIs and would like to know whether there is any way she can prevent these. Urinary Tract Infections • Which intervention is best for MN? A. B. C. D. Drink a glass of cranberry juice daily Daily topical estrogen cream applied vaginally Self-administered short-course therapy Nitrofurantoin 100mg orally 2 times/day for 6 months Management of urinary tract infections in females. Citation: Urinary Tract Infections and Prostatitis, DiPiro JT, Yee GC, Posey L, Haines ST, Nolin TD, Ellingrod V. Pharmacotherapy: A Pathophysiologic Approach, 11e; 2020. Available at: https://accesspharmacy.mhmedical.com/content.aspx?bookid=2577&sectionid=219307238 Accessed: October 17, 2019 Copyright © 2019 McGraw-Hill Education. All rights reserved Outpatient Antimicrobial Therapy for UTIs Indications Uncomplicated UTIs Complicated UTIs in nonpregnant women Prophylaxis for recurrent infections Antibiotic Dose Trimethoprim/sulfamethoxazole One double-strength tablet twice daily for 3 days Ciprofloxacin 250 mg twice daily for 3 days Levofloxacin 250 mg once daily for 3 days Amoxicillin/clavulanate 500/125 mg twice daily for 5–7 days Trimethoprim 100 mg twice daily for 3–5 days Nitrofurantoin monohydrate 100 mg twice daily for 5 days Fosfomycin 3-g single dose Trimethoprim/sulfamethoxazole One double-strength tablet twice daily for 7–10 days Ciprofloxacin 250–500 mg twice daily for 7–10 days Levofloxacin 250-500 mg/day for 7–10 days Nitrofurantoin 50 mg/day for 6 months Trimethoprim/sulfamethoxazole ½ single-strength tablet daily for 6 months Asymptomatic Bacteriuria (ASB) • Defined by lack of symptoms and — Women: ≥105 cfu/mL from 2 specimens — Men: ≥105 cfu/mL from 1 specimen — Men/Women: ≥102 cfu/mL from catheter • Bacteriuria varies by population — Comorbidities and devices increase rate • Pyuria also varies by population • In the absence of symptoms, usually does not require antibiotic treatment Population Bacteriuria Pyuria Prevalence Prevalence Pregnancy 2-10% 30-70% Elderly females 11-16% 90% Diabetic females 9-27% 70% Short-term catheter 9-23% 30-75% Hemodialysis requirement 28% 90% SCI with intermittent catheterization* 23-89% ~100% Long-term catheter 100% 50-100% *SCI = spinal cord injury Nicolle LE et al. Clin Infect Dis. 2019; 68:83-110. Peterson JR, Roth EJ. Arch Phys Med Rehabil. 1989; 70:839-41. Asymptomatic Bacteriuria (ASB) • Routine screening not recommended • • • • • • Young non-pregnant females Diabetic females Older community-dwelling patients Elderly long-term care facility patients Spinal-cord injury patients Indwelling-catheter patients Nicolle LE et al. Clin Infect Dis. 2019; 68:83-110. Asymptomatic Bacteriuria (ASB) • Screening currently recommended for: • Pregnant female patients • Patients undergoing urologic procedures Nicolle LE et al. Clin Infect Dis. 2019; 68:83-110. Treating Asymptomatic Bacteriuria in Pregnancy • Goals of therapy: • Decrease incidence of pyelonephritis (30% if untreated) • Reduce the rate of preterm delivery (20 to 50% if untreated) • Recommendations: • Screening at least once early in pregnancy • Prompt treatment for at least 3 to 7 days • Screening periodically for recurrence Nicolle LE et al. Clin Infect Dis. 2019; 68:83-110. Widmer M, et al. Cochrane Database Syst Rev. 2015; 11:CD000491. Benefits of Treating Asymptomatic Bacteriuria in Pregnancy* Pyelonephritis • Antibiotics: 48/1000 • Control: 208/1000 • RR 0.23 (95% CI 0.13 to 0.41) Birth < 37 weeks gestational age • Antibiotics: 60/1000 • Control: 221/1000 • RR 0.27 (95% CI 0.11 to 0.62) Birth weight < 2500 g • Antibiotics: 87/1000 • Control: 136/1000 • RR 0.64 (95% CI 0.43 to 0.93) *Majority of studies used short course with 3-7 days of treatment. The benefit of single-dose therapy is less clear. Smaill FM, Vazquez JC. Cochrane Database Syst Rev. 2015; 8:CD000490. Widmer M, et al. Cochrane Database Syst Rev. 2015; 11:CD000491. Treatment Options for ASB in Pregnancy Antibiotic Dose Notes Amoxicillin 500 to 875 mg PO every 12 hours Be familiar with local resistance patterns Nitrofurantoin 100 mg PO every 12 hours Some literature says to avoid in 1st trimester. Good choice for penicillin allergy. Trimethoprim/sulfamethoxazole 1 DS tablet PO (800/160 mg) every 12 hours Avoid in 1st trimester and right before delivery Cephalexin 500 mg PO every 12 hours Cefpodoxime 100 mg PO every 12 hours Cefuroxime 250 mg PO every 12 hours Fosfomycin 3 grams PO as a single dose Safe in pregnancy Kazemier BM, et al. Lancet Infect Dis. 2015; 15:1324-33. Urinary Tract Infections SB is a 35 year-old pregnant female who presents to the OB clinic for her 10-week appointment. She is otherwise healthy. She denies urinary frequency, dysuria, or costovertebral angle tenderness. She has no known drug allergies. Here urinalysis shows WBCs 102 cells/mm3, No RBCs, nitrite positive, leukocyte esterase positive, trace protein, and 104 CFU/mL gram-negative rods. Urinary Tract Infections Which of the following is the most appropriate recommendation for BA at this time? A. B. C. D. Amoxicillin 875mg po BID for 7 days Levofloxacin 500mg po QD for 3 days No antimicrobial therapy indicated at this time Trimethoprim/sulfamethoxazole 160/800mg po BID for 7 days Common Treatment for cUTIs & Pyelonephritis Indications Complicated UTIs in non-pregnant women Oral Therapy Acute pyelonephritis Oral therapy Complicated UTIs and Acute pyelonephritis Antibiotic Dose Trimethoprim/sulfamethoxazole One double-strength tablet twice daily for 7–10 days Ciprofloxacin 250–500 mg twice daily for 7–10 days Levofloxacin 250-500 mg/day for 7–10 days Trimethoprim/sulfamethoxazole One double-strength tablet twice daily for 14 days Ciprofloxacin 500 mg twice daily for 14 days Levofloxacin 250 mg/day for 10 days 750 mg/day for 5 days Ciprofloxacin 400 mg IV every 12 hours for 7 – 14 days Levofloxacin 500 – 700 mg IV every 24 hours for 7 – 14 days Piperacillin/tazobactam 3.375 grams IV every 6 hours for 7 – 14 days Ceftriaxone 1 gram IV every 24 hours for 7 – 14 days Cefepime 1 gram IV every 8 hours for 7 – 14 days Ceftazidime 2 grams IV every 8 hours for 7 – 14 days Imipenem 500 mg IV every 6 hours for 7 – 14 days Meropenem 500 mg IV every 8 hours for 7 – 14 days Doripenem 500 mg IV every 8 hours for 7 – 14 days Ertapenem 1 gram IV every 24 hours for 7 – 14 days Cystitis and Pyelonephritis • Cystitis • Pyelonephritis • History is essential • Urinary symptoms — Urgency — Incontinence — Frequency — Dysuria • Uncomplicated • Complicated • Urinary symptoms AND • Systemic symptoms — Fever — Chills — Flank pain — CVA tenderness Gupta K, et al. Clin Infect Dis. 2011; 52:e103-20. U.S. Food and Drug Administration. Center for Drug Evaluation and Research. Guidance for Industry: Complicated Urinary Tract Infections. February 2015. https://www.fda.gov/downloads/Drugs/.../Guidances/ucm070981.pdf. Cystitis and Pyelonephritis • Cystitis • Pyelonephritis • Urinary symptoms • Urinary symptoms • Systemic symptoms — Urgency — Incontinence — Frequency — Dysuria — Fever — Chills — Flank pain — CVA tenderness • Uncomplicated • Complicating factors — Indwelling catheter — Neurogenic bladder — Obstruction/intrinsic disease Gupta K, et al. Clin Infect Dis. 2011; 52:e103-20. U.S. Food and Drug Administration. Center for Drug Evaluation and Research. Guidance for Industry: Complicated Urinary Tract Infections. February 2015. https://www.fda.gov/downloads/Drugs/.../Guidances/ucm070981.pdf. Complicated Urinary Tract Infections  Nosocomial UTI organisms Fungi Enterococcus E. coli P. mirabilis S. aureus K. pneumoniae P. aeruginosa Other Gram-negative Acute Pyelonephritis • Subset of complicated UTI (cUTI) • Ascending (progressive cUTI) — More common • Descending (hematogenous) — Less common • Complication of cystitis • Signs & Symptoms • More systemic – High fever (>100.9◦F), flank pain, nausea, etc • Treatment • Mild (outpatient) – oral therapy • Moderate to Severe/Complicated – IV therapy first, then switch to oral • Total treatment should be 7-14 days Common Treatment for cUTIs & Pyelonephritis Indications Complicated UTIs in non-pregnant women Oral Therapy Acute pyelonephritis Oral therapy Complicated UTIs and Acute pyelonephritis Antibiotic Dose Trimethoprim/sulfamethoxazole One double-strength tablet twice daily for 7–10 days Ciprofloxacin 250–500 mg twice daily for 7–10 days Levofloxacin 250-500 mg/day for 7–10 days Trimethoprim/sulfamethoxazole One double-strength tablet twice daily for 14 days Ciprofloxacin 500 mg twice daily for 14 days Levofloxacin 250 mg/day for 10 days 750 mg/day for 5 days Ciprofloxacin 400 mg IV every 12 hours for 7 – 14 days Levofloxacin 500 – 700 mg IV every 24 hours for 7 – 14 days Piperacillin/tazobactam 3.375 grams IV every 6 hours for 7 – 14 days Ceftriaxone 1 gram IV every 24 hours for 7 – 14 days Cefepime 1 gram IV every 8 hours for 7 – 14 days Ceftazidime 2 grams IV every 8 hours for 7 – 14 days Imipenem 500 mg IV every 6 hours for 7 – 14 days Meropenem 500 mg IV every 8 hours for 7 – 14 days Doripenem 500 mg IV every 8 hours for 7 – 14 days Ertapenem 1 gram IV every 24 hours for 7 – 14 days