Urinary Tract Infection and Prevention of Recurrent UTI Dobie Giles, MD, MS Chief, Female Pelvic Medicine and Reconstructive Surgery Division of Gynecology Assistant Professor 3/12/2014 Disclosures  None Objectives  Discuss the incidence of Urinary Tract Infections  Discuss the diagnosis and treatment of Urinary Tract Infections  Discuss treatment and prevention strategies for Recurrent Urinary Tract Infections Case:  A 30 y/o woman calls you to report a 2-day history of worsening dysuria, urinary urgency, and frequency. She denies fever, chills, back pain, vaginal irritation or discharge.  One month ago, you treated her with a 3-day course of trimethoprim-sulfamethoxazole for presumptive cystitis, and her symptoms resolved.  She is otherwise healthy, but this is her 2nd episode in the past year. How would you manage this patient? Case  Diagnosis? Uncomplicated UTI Incidence - UTI  Most common bacterial infection encountered in the ambulatory care setting in the U.S.  8.6 million office visits in 2007 (84% were women)  $3,500,000,000.00/year  By age 32, 50% of women will have had a UTI  Infection recurs in 25% of women within 6 months of the first UTI  3-5% have multiple recurrences  Acute uncomplicated pyelonephritis is less common (1 case pyelo per 28 cases of cystitis) Definitions  Asymptomatic bacteriuria: Bacteriuria with no symptoms  Cystitis: infection limited to lower UT with symptoms of dysuria, frequency, urgency, and suprapubic tenderness  Acute pyelonephritis: infection of the renal parenchyma and pelvicaliceal system accompanied by significant bacteriuria, usually with fever and back pain  Relapse: Recurrent UTI with same organism after adequate therapy within two weeks of treatment  Reinfection: Recurrent UTI caused by bacteria previously isolated after adequate treatment or new isolate, with negative intervening UCx “Uncomplicated” Classification  Healthy, premenopausal, non-pregnant women with no history suggestive of an abnormal urinary tract.  All others are complicated  Distinction guides choice and duration of antimicrobial treatment Features of Uncomplicated vs. Complicated Cystitis and Pyelo Variable Uncomplicated Complicated Typical patient Healthy female with no history suggestive of anatomical or functional urinary tract abnormality Men, women, children with function, metabolic, or anatomical condition that increase risk of treatment failure or serious outcome Clinical spectrum Mild cystitis to severe pyelo Mild cystitis to lifethreatening pyelo Diagnosis On the basis of typical symptoms; UA/C&S not routinely needed for cystitis but recc’d for pyelo Typical symptoms or atypical symptoms, UA/C&S indicated Pathogenesis  Urinary pathogens from bowel or vagina colonize the periurethral mucosa and ascend through the urethra to the bladder and in some cases through the ureter and kidney  E. coli – predominant pathogen – 75-95%  Potential for enhanced virulence (fimbriae, flagella, adhesins, toxins, etc)  Staphylococcus saphrophyticus, Proteus, Klebsiella, Pseudomonas, Enterococcus, Morganella Risk Factors Sporadic or Recurrent • • • • • Sexual intercourse Use of spermicides New sex partner Previous UTI FH of UTI in first degree female relative • Urethra to anus distance • Postmenopausal NOT associated • Coital voiding patterns • Daily beverage consumption • Frequency of urination • Wiping patterns • Tampon use • Douching • Use of hot tubs • Type of underwear Diagnosis Symptoms Cystitis Pyelonephritis • • • • • • • • • • • Dysuria Frequency Urgency Suprapubic pain Hematuria Fever > 38 Chills Flank pain CVA-tenderness Nausea/vomiting +/- cystitis symptoms Cystitis vs. Vaginitis  Women with symptoms of dysuria and frequency AND NO vaginal discharge or irritation, had > 90% probability of acute cystitis  Do we need to do a urinalysis?  Do we need a urine culture? • Bent S, et al. JAMA. 2002;287(20):2701-2710. Differential Diagnosis Symptoms DDx Suprapubic tenderness Cystitis, symphysitis Dysuria Urethritis, cystitis, cervicitis, bacterial vaginitis, atrophic vaginitis, urethral diverticulum Frequency Cystitis, urethritis, IC, foreign body (stone, mesh) Flank pain Pyelonephritis, nephrolithiasis Hematuria Hemorrhagic cystitis, pyelonephritis, IC, nephrolithiasis, neoplasm Urine Dip  Leukocyte esterase – enzyme released from leukocytes  PPV: 19-88%  NPV: 97-99%  Nitrites – some bacteria (Enterococcus) reduce nitrates to nitrites  PPV: 94%  NPV: Low  Together –  Both +: Specificity: 98-99.5%; PPV:90+%  Both -: NPV: 80-90% Diagnosis – Putting it together  Woman with symptoms of UTI (acute onset dysuria, frequency, or urgency)  No complicating conditions (pregnant, known voiding abnormalities, co-morbid conditions -> complicated UTI)  No back pain (if present -> consider pyelonephritis)  No vaginal discharge (if present -> consider STD, vaginitis) → then > 90% probability of acute cystitis  If hx not clear  Use dipstick • positive = 90% cystitis (consider tx for UTI) • negative = 20% cystitis (dipstick not very specific so 1/5th of these cases might still have real UTI – consider urine cx, close f/u, other diagnoses) • Bent S, et al. JAMA. 2002;287(20):2701-2710 Urine Specimen  Midstream, Catheterized, Suprapubic aspiration  Midsteam  Least invasive  Give clear instructions to minimize contamination  Cath/SP aspiration  Physically disabled, obese, unable to comply with instructions  Aseptic technique to minimize introducing infection Urinalysis / Microscopy  Micro:  PPV 100% when pyuria (>8 WBC/mm) and bacteriuria +  NPV 100% when absent  Casts and crystals provide information about renal involvement Urine Culture  Gold standard in diagnosing UTI  Number, type, and sensitivity/resistance of bacteria  Paramount in complicated UTI’s  Limitation: 1-2 days for results  Bacteriuria: >10x5, although if positive symptoms, 10x3 can be considered positive Culture vs. No-Culture  Complicated UTI: Anatomic, functional or metabolic abnormality of the urinary tract  Pregnant  Diabetes, immunocompromised, post-menopausal, elderly  Catheter, calculi, neurogenic bladder  h/o Multi-drug resistance  Pyelonephritis (even if uncomplicated)  Get a urine culture; start empiric antibiotics; tailor therapy based on culture Imaging  Useful if:  Recurrent or severe symptoms, conventional treatment has failed, unusual organism (Proteus), compromised condition, history of calculi, childhood UTI, or non-pregnant pyelo  Renal ultrasound:  Hydronephrosis, nephrolithiasis, perinephric abscess  CT:  Study of choice, best identification of extent of disease, image renal parenchyma Cystoscopy  Used for recurrent UTI evaluation  Risk factors for abnormalities:        Proteus Calculi Hematuria Obstructive symptoms Pyelo Age > 50yo Previous surgery (TVT) Mesh in the Bladder Management Management  Benign condition  25-42% spontaneously resolve  Rare progression to pyelo  Antimicrobial resistance  E. coli resistance to amoxicillin, bactrim > 20%  Fluoroquinolones, cephalosporins, amoxicillinclavulanate <10% resistance  Nitrofurantoin, fosfomycin, pivmecillinam – lowest rates of resistance  Infectious Diseases Society of America (IDSA) Guidelines - “Collateral Damage” , ecologic adverse effects Collateral Damage  “Collateral damage” is a term used to refer to ecological adverse effects of antibiotic therapy:  Selection of drug-resistant organisms - VRE, MRSA  Unwanted development of colonization or infection with multidrug-resistant organisms  Clostridium difficile (do you know how they are treating this?) • Paterson DL. 2004; 38 Suppl 4:S341-S345. Resistance Rates Empirical Treatment of Cystitis Antimicrobials Efficacy Comments Nitrofurantoin 93% for 5-7d Avoid if pyelo suspected TMP-SMX 93% for 3d Avoid if sulfa allergy, OR if resistance >20% or used in prior 3-6m Fosfomycin 91% single dose Avoid if pyelo suspected. Most labs do not check resistances Pivmecillinam 55-82% for 3-7d Not available in US Fluoroquinolones 90% for 3d Ecologic adverse events Beta-lactams 89% for 3-5d Avoid empiric amoxicillin or ampicillin First Line Therapy Second Line Therapy Empirical Treatment of Cystitis  Choice of agent should be individualized based on patient’s allergy and compliance history, local practice patterns/resistance prevalence, availability, cost, patient/provider threshold for failure  IF a 1st line agent is not a good choice based on these factors, use fuoroquinolone or beta lactam  Preferable to minimize due to ecologic adverse effects and resistances  Unfortunately, 2nd line therapies are most commonly used for UTI in ambulatory settings Nitrofurantoin  Macrobid  100mg twice daily for 5-7d  Inhibits several bacterial enzyme systems including acetyl CoA interfering with metabolism and possibly cell wall synthesis  Minimal ecologic adverse effects  Common side effects: nausea, headache, flatulence  Monitor use in elderly due to potential for pulmonary toxicity, increased risk of hepatic toxicity and peripheral neuropathy TMP-SMX  Bactrim  Interferes with bacterial folic acid synthesisDS 160/800mg bid x 3d  Fewer ecologic effects than fluoroquinolones  Bacterial resistance and sulfa allergy are limiting factors  Common side effects: N/v, rash, urticaria, hematologic complications, photosensitivity Fosfomycin      Monurol Phosphonic acid derivative Inhibits cell wall synthesis Oral sachet – 3g single oral dose Active against wide spectrum of GP and GN organisms, including ESBL, VRE  Resistance is chromosomally encoded rather than plasmid – little cross-reactivity with R to other agents  Minimal ecologic adverse effects  Common side effects: nausea, diarrhea, headache, vaginitis Fluoroquinolones  Cipro 250mg bid x 3d; Levo 250mg daily x 3d  Inhibits DNA-gyrase in susceptible organisms  Propensity for ecologic adverse effects, recommended for uses other than cystitis when possible  Common side effects: n/v/d, headache, drowsiness  Adverse effects (tendon rupture, QT changes) may be increased in the elderly Beta-lactams  Amoxicillin-clavulanate, cefdinir, cefaclor, etc  Amoxicillin, cephalosporins inhibits bacterial cell wall synthesis, Clavulanic acid inhibits betalactamases  Probably fewer ecologic adverse effects than parenteral broad spectrum cephalosporins  Common side effects: n/v/d, rash, urticaria UW Resistance Rates Inpatient Outpatient TMP/SMX 26% 32% Cipro 22% 15% Nitro 4% 3% Amoxicillin 23% 15% Empirical Treatment of Pyelonephritis  Most pyelo now treated in outpatient setting  Urine culture and susceptibilities should be performed  Inpatient therapy if severe, hemodynamic instability, complicating factor (stones, pregnancy, DM), if oral meds unable to be tolerated, or concern for non-adherence to treatment Empirical Treatment of Pyelonephritis Antimicrobials Efficacy Comments Fluoroquinolones 96% for cipro 500mg bid Drug of choice x 7d 86% for levo 750mg qday x 5d TMP-SMX 83% for 14d Inferior choice due to high rates of resistance unless culture confirmed susceptibility Oral beta lactams 10-14d, Inferior to above Use only when other recommended agents cannot be used Follow-up  Repeat culture unnecessary after uncomplicated cystitis/pyelo if symptoms resolve, except in pregnant women  Consider further eval if early recurrences with same bacteria, persistent hematuria or cystitis symptoms Special Topics Recurrent UTI asymptomatic bacturia Recurrent UTI  If symptoms persist or recur in 1-2 wks of treatment, resistance likely, therefore use broad spectrum, fluoroquinolone  If symptoms recur >1m, repeat short-course firstline treatment, using another 1st line drug, especially if Bacrim was used  Goal for long-term recurrent UTI: improve QOL while minimizing antimicrobial exposure  Antimicrobial prophylaxis reduces risk by 95%  Use only if >3 culture proven UTI/1yr and if nonantimicrobial strategies have not been effective  Self-diagnosis and treatment also useful Non-antimicrobial Prevention of Recurrent UTI Strategy Comments Behavioral Abstinence Often not feasible No spermicides Strong risk factor, especially if used with a diaphragm Urinate after intercourse, drink fluids liberally, wipe front to back, avoid douching, tight fitting underwear Not effective in case control studies, but low risk and maybe effective so reasonable to suggest Biologic Cranberry Inhibition of uropathogen adherence to uroepithelial cells, RCT showed no benefit Topical estrogen Normalizes vaginal flora, effective in postmenopausal. RCT showed benefit Adhesin blockers D-mannose, blocks E.coli adhesion to uroepitelium. No studies Antimicrobial Management of Recurrent UTI Strategy Comments Self-diagnosis and treatment First line anti-microbials rx’ed for future use at onset of UTI symptoms Women w h/o cystitis can accurately self diagnose 85-95% of time, leads to higher patient satisfaction and less antimicrobial exposure Antimicrobial prophylaxis Postcoital – single dose -Nitrofurantoin 50-100mg -TMP-SMX 40/200 -Cephalexin 250mg Continuous – qhs -Nitrofurantoin 50-100mg -TMP-SMX 3x/wk or qday -Cephalexin 250mg -Fosfomycin 3g q 10d Useful if UTI’s are temporally related to coitus. Beneficial in 92% Reduce cystitis by 95%, 6-month trial recommended Asymptomatic Bacteriuria  Definition: culture with >10x5 cfu/ml in 2 consecutive voided specimens or > 100 cfu/ml in a cath specimen from a patient without associated symptoms  Treatment debatable  Abx may make an avirulent strain  virulent strain  Allergic or adverse reaction to abx  ISDA currently does not recommend treating: Catheter-associated Urinary Tract Infections (CaUTI)  Among UTI’s acquired in the hospital  75% are associated with a catheter  15-25% of hospitalized patients receive a catheter Catheter-associated Urinary Tract Infections (CaUTI)  Only use if necessary  Take out as soon as possible  UWHC  2011 - 169  2013 - 99 Case:  A 30 y/o woman calls you to report a 2-day history of worsening dysuria, urinary urgency, and frequency. She denies fever, chills, back pain, vaginal irritation or discharge.  One month ago, you treated her with a 3-day course of trimethoprim-sulfamethoxazole for presumptive cystitis, and her symptoms resolved. She is otherwise healthy, but this is her 2nd episode in the past year.  How would you manage this patient? Case:  Given recent exposure to TMP-SMX, offer another first line antimicrobial agent (nitrofurantoin)  Counsel regarding non-antimicrobial preventive approaches  If recurrences continue, consider selfdiagnosis/self-treatment, postcoital or continuous antimicrobial prophylaxis Conclusions  UTI is a common problem for women  Knowledge of community bacterial resistance rates and prescribing recommendations is key According to the 2010 American Urologic Associate Guidelines, all of the following are acceptable treatment regimens for acute pyelonephritis, EXCEPT:  A) Amoxicillin 500mg three times daily for 14 days with initial dose of 3gm fosfomycin  B) Oral ciprofloxacin 500mg twice daily, for 7 days with initial 400mg dose of intravenous ciprofloxacin  C) Oral ciprofloxacin 500mg twice daily, for 7 days without initial 400mg dose of intravenous ciprofloxacin  D) Oral levofloxacin 750mg daily for 5 days According to the 2010 American Urologic Associate Guidelines, all of the following are acceptable treatment regimens for acute pyelonephritis, EXCEPT:  A) Amoxicillin 500mg three times daily for 14 days with initial dose of 3gm fosfomycin  B) Oral ciprofloxacin 500mg twice daily, for 7 days with initial 400mg dose of intravenous ciprofloxacin  C) Oral ciprofloxacin 500mg twice daily, for 7 days without initial 400mg dose of intravenous ciprofloxacin  D) Oral levofloxacin 750mg daily for 5 days Select the most accurate statement regarding prevention of recurrent urinary tract infection in non-pregnant women.  A) Continuous antibiotic prophylaxis for 6-12 months DOES NOT reduce the rate of UTI during prophylaxis compared to placebo  B) Continuous antibiotic prophylaxis for 6-12 months reduces the rate of UTI during prophylaxis compared to placebo  C) Continuous daily cranberry juice intake for 612 months reduces the rate of UTI  D) Continuous daily cranberry powder intake for 6-12 months reduces the rate of UTI Select the most accurate statement regarding prevention of recurrent urinary tract infection in non-pregnant women.  A) Continuous antibiotic prophylaxis for 6-12 months DOES NOT reduce the rate of UTI during prophylaxis compared to placebo  B) Continuous antibiotic prophylaxis for 6-12 months reduces the rate of UTI during prophylaxis compared to placebo  C) Continuous daily cranberry juice intake for 612 months reduces the rate of UTI  D) Continuous daily cranberry powder intake for 6-12 months reduces the rate of UTI Which of the following has NOT been shown to increase the risk of urinary tract infection? A) Sexual activity B) Urethra-to-anus distance C) Hormonal status D) Use of spermicide combined with diaphragm for contraception  E) Voiding habits before or after intercourse     Which of the following has NOT been shown to increase the risk of urinary tract infection? A) Sexual activity B) Urethra-to-anus distance C) Hormonal status D) Use of spermicide combined with diaphragm for contraception  E) Voiding habits before or after intercourse     What is the recommended first-line antibiotic therapy for uncomplicated cystitis?  A) ciprofloxacin 250mg PO BID for 5 days  B) cephalexin 500mg QID PO for 3 days  C) nitrofurantoin monohydrate/macrocrystals 100mg PO for 5 days  D) amoxicillin 500mg PO TID for 7 days What is the recommended first-line antibiotic therapy for uncomplicated cystitis?  A) ciprofloxacin 250mg PO BID for 5 days  B) cephalexin 500mg QID PO for 3 days  C) nitrofurantoin monohydrate/macrocrystals 100mg PO for 5 days  D) amoxicillin 500mg PO TID for 7 days Which of the following antibiotics is currently associated with the highest rate of bacterial resistance in the United States?      A) Nitrofuratoin monohydrate/macrocystals B) Rocephin C) Trimethoprim-sulfamethoxazole D) Ciprofloxacin E) Amoxicillin Which of the following antibiotics is currently associated with the highest rate of bacterial resistance in the United States?      A) Nitrofuratoin monohydrate/macrocystals B) Rocephin C) Trimethoprim-sulfamethoxazole D) Ciprofloxacin E) Amoxicillin Questions?