1. UTI 101: Antimicrobial agents, duration and prophylaxis April 30, 2012
Jennifer J. Schimmel, MD
Baystate Medical Center
Division of Infectious Diseases and Antimicrobial Stewardship
Focus on older patients, especially in a facility

2. Objectives
Describe the agents used for treating bacterial urinary tract infections (UTI’s) and understand how to choose the most appropriate agent
Understand the appropriate duration of therapy and monitoring
Understand the options for prophylaxis of recurrent UTI
Focus on the elderly in long term care

3. Background
UTI is one of the most common infections in the elderly in the community and in long-term care
Two problems: overdiagnosis and overtreatment
Subsequent issues:
C. difficile
Antibiotic resistance
What’s important?
Proper diagnosis
Appropriate antibiotic choice and duration

4. Defining the Problems Lower UTI: infection in bladder and/or urethra
Uncomplicated UTI: lower UTI AND
Not pregnant
No urinary tract abnormalities
No indwelling urinary device
Complicated UTI:
Upper UTI (systemic symptoms, extension beyond urethra/bladder)
Functional or structural urinary tract abnormality
UTI in men
Urinary catheter (CA-UTI)
Older female patients
Many have functional or structural abnormalities
Bacter: usu 10 to the 5..unlikely to be contaminated, but still doesn’t mean clinically significant. May be asymptomatic and not need rx % of women and 15-40% of men without catheters in NH have asymptomatic bacteriuria Furthermore, lower levels may be significant.
Pyuria: doesn’t represent disease, can be seen with or w/o bacteria. Associated with urinary catheter, stone, tumor, infection.
Lower UTI: not associated with signs of systemic infection
Uncomplicated UTI: this is where 3 day short course recs are applicable, SO NOT MALES, NOT CA-UTI and not systemic symptoms
CA-UTI: greatest risk for infection with catheter is the duration of catheterization. Indwelling ur cath almost universally leads to bacteriuria within 3-4 days due to formation of biofilm between catheter and urethral mucosa.
Rates of infection are high in postmenopausal women because of bladder or uterine prolapse causing incomplete bladder emptying; loss of estrogen with attendant changes in vaginal flora (notably, loss of lactobacilli), which allows periurethral colonization with gram-negative aerobes, such as E coli; and higher likelihood of concomitant medical illness, such as diabetes.

5. Most Common Organisms E.coli Other gram-negatives
Klebsiella pneumoniae
Proteus mirabilis
Staphylococcus saprophyticus
Enterococcus faecalis
In the elderly: Ecoli
E coli causes 70-95% of both upper and lower UTIs. Various organisms are responsible for the remainder of infections, including S saprophyticus, Proteus species, Klebsiella species, Enterococcus faecalis, other Enterobacteriaceae, and yeast
Where do bacteria come from that cause urinary tract infections?
GI tract
Perineum
Manipulation (catheter/procedure)

6. Microbiology in Nursing Homes
New Haven, CT
5 Nursing Homes May
551 patients, presumed UTI
Das ICHE Nov 2009
Das R et al. ICHE 2009;30(11):

7. Case 1
75 year old woman s/p recent vertebral fracture, in NH for past 2 weeks, no prior UTI’s
Now several days of urinary frequency, urgency, burning
No fevers or back pain
U/a with significant pyuria
Started empirically on ciprofloxacin

8. What to use empirically?
Take into account most likely uropathogens
Patient Factors
Other medications/interactions
Allergies
Other past infections
Other medical problems (renal insufficiency, C.diff, etc)
Threshold for failure
Local epidemiology
Cost
Empirically: define

9. Antibiogram Helps to determine best choices for empiric therapy
Helps with empiric choices, but still need to take into account the clinical picture
Mostly concerned about Gram-negative bacteria
For example for Bactrim for acute cystitis (TRIM-SULFA), if local resistance rates of uropathogens causing UTI do not exceed 20% (or if sensitivity of organism know). Threshold of 20% is based on expert opinion derived from clinical, in vitro and mathematical modeling studies.
BUT for pyelonephritis, threshold is lower, if 10% resistance to cipro, expert opinion recommends additional or alternative agent

10. Antimicrobial Susceptibilities from Nursing Home Residents in New Haven, CT
Das R et al. ICHE 2009;30(11):

11. Case 1: Culture Data What can you do now?
Collect date: 04/15/12 08:35
Result Status: Auth (Verified)
Result Date: 04/17/12 09:33
SPECIMEN DESCRIPTION : URINE CLEAN CATCH/MIDSTREAM
SPECIAL REQUESTS : NONE
CULTURE : >100,000 COL/ML ESCHERICHIA COLI
TEST PERFORMED AT BAYSTATE MEDICAL CENTER, SPRINGFIELD, MA
REPORT STATUS : FINAL 04/17/2012
ORGANISM >100,000 COL/ML ESCHERICHIA COLI
METHOD MIN. INHIB. CONC. (MCG/ML)
AMPICILLIN RESISTANT
AMPICILLIN/SULBACTAM INTERMEDIATE
AMOXICILLIN/CLAVULAN SUSCEPTIBLE
CEFAZOLIN SUSCEPTIBLE
CEFEPIME SUSCEPTIBLE
CEFTRIAXONE SUSCEPTIBLE
CIPROFLOXACIN SUSCEPTIBLE
ERTAPENEM SUSCEPTIBLE
GENTAMICIN SUSCEPTIBLE
LEVOFLOXACIN SUSCEPTIBLE
MEROPENEM SUSCEPTIBLE
NITROFURANTOIN SUSCEPTIBLE
PIPERACILLIN/TAZOBAC SUSCEPTIBLE
TRIMETH/SULFAMETHOX SUSCEPTIBLE
TETRACYCLINE SUSCEPTIBLE
Help with narrowing/finalizing therapy

12. Seeking the perfect antibiotic…
Needs to get into urinary tract
And sometimes the prostate
Treat specific organism
Narrowest spectrum possible
Minimize adverse effects
Avoid drug interactions
No allergy
Compliance
Cost
Oral option?

13. Case 2
75 year old woman with well-controlled Crohn’s disease on mesalamine, admitted with syncopal event
Found to have conduction abnormality
Allergy to penicillin (unknown)
Has pacemaker placed (perioperative Clindamycin)
2 days after procedure still has unexplained leukocytosis with WBC 13
no obvious source of infection, no urinary symptoms, no diarrhea, CXR unremarkable, u/a with 1 wbc

14. Case 2 Urine culture pending at the time of discharge to rehab
What would be the next best step?
A) Discharge on 5 days of Levofloxacin for possible UTI
B) Follow off antibiotics
C) Keep her in the hospital and repeat u/a tomorrow
D) Treat with Ceftriaxone 1g IV and additional antibiotics base on culture data
E) Treat with Tobramycin 5mg/kg and additional antibiotics based on culture data
B is best option…but what really happened is A. Culture negative, unclear if result followed up at NH. Then readmitted within 2 weeks for Cdiff (and I just saw this week with her probably 3rd recurrence…

15. C. diff-o-genicity High risk Medium risk Low risk Carbapenems
2nd – 4th generation cephalosporins
Fluoroquinolones
Clindamycin
Medium risk
Penicillins
1st generation cephalosporins
Macrolides
Aztreonam
Low risk
Aminoglycosides
Vancomycin
Daptomycin
Nitrofurantoin
Linezolid
Trimethoprim/
sulfamethoxazole
Tetracyclines
Rifampin
Colistin
Fosfomycin
Mullane et al. Clin Infect Dis. 2011;53:

16. Recommendations from the Guidelines
In this case, there was no UTI to treat, but what if there is a UTI to treat?
Unfortunately, no specific guidelines for post-menopausal, NH population.

18. Uncomplicated UTI: Lower Tract
Brings up several issues in the elderly and LTC:
Are elderly/postmenopausal women uncomplicated?
What about if diabetes without urologic issues? No clear answers from the guidelines, so probably depends on clinical factors/illness/host, etc…
Take home: trying to avoid so much FQ use..
March NEJM
Author also of IDSA guidelines
Provides simple clearly uncomplicated case
Addresses that “complicated UTI” is a heterogeneous group: risks of infection and treatment failure vary. Current classification schemes are overly simplistic.
Suggests that Short course regimens are likely to be effective for mild-mod cystitis in healthy, ambulatory, compliant women who are elderly, have CA-UTI, pregnant or mild DM
NF and fosfomycin: minimal resistance (possibly because of limited effects on fecal flora), minimal collateral damage “ecological effects”: such as the selection of drug-resistant organism and colonization or infection with multidrug resistant organisms.
Collateral damage is important to consider esp with uUTI: minimal risk of progression to tissue invasion or sepsis (25-50% will get better if not treated or if treated with drug that doesn’t have in vitro activity vs pathogen)
NF: and Fosfomycin avoid if early pyelonephritis.
Pivmecillinam: beta lactam with specificity for urinary tract, minimal resistance and collateral damage, not available in US or Canada
Gupta K et al. Clinical Infectious Diseases 2011;52(5):e

19. Nitrofurantoin (Macrobid, Macrodantin)
Minimal “collateral” damage
DRUG INTERACTIONS
Minimal
Concomitant administration of a magnesium trisilicate antacid may decrease the absorption of nitrofurantoin
Nitrofurantoin may reduce the effect of quinolone antibiotics
Fluconazole: increased risk of pulmonary and hepatic toxicity
Avoid if creatinine clearance less than 60
Due to potentiation of adverse effects
Common side effects: nausea, headache
Other serious adverse effects:
Peripheral neuropathy
Pulmonary hypersensitivity
Hepatoxicity
Decreased renal function
Hemolytic anemia
Pulm hypersens: maybe more in elderly, esp 1st week and with chronic rx (>6mos)
Example of cr cl <60 pretty much any women over age 70 even with nl cr (1).

20. Fosfomycin Issues: Minimal resistance Minimal collateral damage
High urinary levels
Prolonged bactericidal effect
Minimal drug interactions
Not always available
Susceptibility data not routinely available
Role for treatment of resistant organisms such as ESBL’s, VRE, MRSA
Maybe less effective than other short-course regimens
Drug interaction: Metoclopramide (Reglan) increases FF excretion

21. Trimethoprim/Sulfamethoxazole TMP/SMX (Bactrim)
DRUG INTERACTIONS
Warfarin
Methotrexate
Fluconazole (incr QT)
TCA, antipsychotics, antiarrhythmics
Antihyperglycemics
Common side effects: nausea, vomiting, rash
Other serious adverse effects:
Bone marrow suppression
Hepatic necrosis
Severe rash
Hyperkalemia
Hypoglycemia (esp with renal and liver disease)
Increased creatinine…may be falsely elevated
In contrast to NF and Fosfo, more effect on fecal flora and more issues with antimicrobial resistance with TMP/SMX, quinolones (and amp).
Other issues: resistance right around 20%.....but local resistance rates reported in hospital antibiogram may be skewed by cultures of samples from inpts/those with complicated infection and may not predict susceptibilities in women with uncomplicated comm acq UTI in whom resistance rates tend to be lower And it remins very effective (with est clinical cure 85% even in regions with 30% resistance)
And some evidence that if used in the preceding 3-6 mos, that is an independent RF for TMP/SMX resistance

22. Quinolones: Ciprofloxacin and Levofloxacin
Highly efficacious in a 3-day regimen
Numerous issues with collateral damage: C.difficile and resistance
Save for other uses
Black Box Warning: tendonitis/tendon rupture esp. over age 60, steroids, transplant
Interactions:
calcium, aluminum, magnesium, iron, and zinc (antacids, nutritional supplements, multivitamin and mineral supplements), sucralfate
Warfarin
Antihyperglycemics
Other issues:
QT prolongation esp. in elderly
Decreased seizure threshold
Also Moxifloxacin: Many uses, but doesn’t get in to urinary tract
FQ: linked to infection with MRSA, increasing R to FQ in GNB such as Pseudomonas.

23. Hooton, TM. NEJM 2012;366:

24. Alternatives Amoxicillin-clavulanate Cefdinir (Omnicef)
Cefpodoxime-proxetil (Vantin)
Cefaclor (Ceclor)
Not for empiric therapy due to poor efficacy and resistance: amoxicillin and ampicillin
Cefdinir: 3rd gen ceph
Cefaclor: 2nd gen ceph
Cefpodoxime: 3rd, but some properties that are more like 2nd
Down side: collateral damage:
Ceph linked to subsequent VRE, ESBL K pneumo, Betalactam resistant acinetobacter, Cdiff

25. Upper Tract Infection: Acute Pyelonephritis
Not requiring hospitalization (and resistance less than 10%):
Ciprofloxacin 500mg PO BID for 7 days
Ciprofloxacin 1000mg ER for 7 days
Levofloxacin 750mg for 5 days
Bactrim DS BID for 14 days (if pathogen susceptible)
Alternative initial IV antibiotic: Ceftriaxone 1g IV or Aminoglycoside
Alternative: Oral b-lactam (initial IV dose Ceftriaxone) and days
Hospitalized:
IV regimen:
Fluoroquinolone
Aminoglycoside +/- ampicillin
2nd or 3rd generation cephalosporin +/- aminoglycoside
Extended spectrum penicillin +/- aminoglycoside
Carbapenem
NRH: initial IV dose (Cipro)
Also 1 dose IV CTX then oral cefixime (3rd gen ceph)(Suprax) 400mg BID for 2 days and then 7 more days oral abx based on susceptibilities was comp to CTX 1g for 3 days
Gupta K et al. Clinical Infectious Diseases 2011;52(5):e

26. Catheter-Associated UTI (CA-UTI)
Most common health care-associated infection worldwide
40% of hospital-acquired infections
5-10% of LTCF residents with long-term indwelling catheters
Almost all have bacteriuria
Single organism in short-term catheter
Multiple organisms in long-term catheterization
Hooton TM et al. Clinical Infectious Diseases 2010;50:

27. CA-UTI
E.coli (30%), Klebsiella species, Serratia species, Citrobacter species, Enterobacter species, Pseudomonas aeruginosa, coagulase-negative staphylococci, Enterococcus species
Long-term catheters: the organisms above and: Proteus mirabilis, Morganella morganii, Providencia stuartii
Choice of abx will depend on local epi, prior infections, how ill……
May choose a broader agent empirically and then narrow once culture data

28. CA-UTI Duration: Other issues Prompt resolution of symptoms: 7 days
Delayed response: days
Not severely ill: 5 day Levofloxacin may be considered
Women aged 65 or under with CA-UTI and no upper tract symptoms, with removal of catheter: consider 3 days of therapy
Other issues
De-escalation/narrowing of therapy as soon as possible
If catheter in place for >2 weeks and is still needed, catheter should be replaced
More rapid resolution of symptoms
Decrease risk of subsequent CA-bacteriuria and CA-UTI
Urine culture specimens should ideally be obtained from freshly placed catheter if in place for 2 weeks and still needed
Choice of drug more complicated, depends on prior hx, cultures.
Hooton TM et al. Clinical Infectious Diseases 2010;50:

29. Case 3
68 yo woman with poorly-controlled diabetes, dysuria, fever and chills
Prior history of UTI’s with resistant Klebsiella
No allergies
WBC 18K
Cr 2.6
U/a with >182 wbc, 2 rbc, 1 sq epith cell
Guideline Wish List
Complicated UTI
UTI Management for Patients in Long-Term Care
Post-menopausal UTI

30. Limited Therapeutic Options
URINE CULTURE Final Organism 1 KLEBSIELLA PNEUMO SSP PNEUMO. COLONY COUNT >100,000 CFU/ml RESULT COMMENT: ** DRUG RESISTANT ORGANISM ** Drug Resistant Organism KLEBSIELLA PNEUMO. SSP PNEUMO. MULTIPLE DRUG RESISTANCE TRIMETHOPRIM/SULFAMETHOXAZOLE R >=320 AMPICILLIN R >=32 AMPICILLIN/SULBACTAM R >=32 CEFAZOLIN R >=64 CEFOXITIN R >=64 CEFTAZIDIME R >=64 CEFTRIAXONE R >=64 CEFEPIME R >=64 CIPROFLOXACIN R >=4 GENTAMICIN R >=16 LEVOFLOXACIN R >=8 IMIPENEM R >=16 NITROFURANTOIN R >=512 TOBRAMYCIN R >=16 AMIKACIN R >=64 PIPERACILLIN/TAZOBACTAM R >=128
What are the antibiotic options in this case?
None
Colistin
Gatifloxacin
Ertapenem
Other ideas?

31. New FDA Antibiotic Approvals
Increasing Resistant Organisms
14 new classes of antibiotics between 1935 and 2003
Since 1998, only 11 new antibiotics approved\
Decreasing antimicrobial drug development
Significant lag time between discovery of molecules and introduction into clinical use
Increasing multi-drug resistant organisms
Boucher HW et al. Clinical Infect Diseases 2009;48:1-12.

32. Answers Colistin Tigecycline Fosfomycin
Reasonable to have ID consultant involved

33. Case 3, Part 2
Patient is treated with colistin, has resolution of her symptoms, leukocytosis and eventually improved renal function.
Which of the following should be done?
A) Repeat u/a 7 days after therapy completed
B) Repeat urine culture 7 days after therapy completed
C) A and B
D) Repeat u/a and culture are not indicated

34. Test of Cure Not routinely recommended
Except in pregnant women, certain cases for urologic intervention

35. Case 4
70 year old woman with 4 E.coli UTI’s in the past 6 months, urologist notes a mild cystocele and atrophic vaginal mucosa on exam
What do you recommended?
A) Nothing
B) Bactrim DS BID indefinitely
C) Cranberry juice 8 oz daily
D) Topical estrogen
D) Cipro 500mg weekly
Depends: but topical estrogen is probably the most reasonable to start with. Also, little down side to cranberry juice.

36. Recurrent UTI: Risk Factors
Post-menopausal:
estrogen deficiency
urogenital surgery
incontinence, cystocele, post-void residuals
Men:
Prostatic disease
Both Men and Women:
Obstruction: stones, tumor
Complicated UTI:
MDRO, obstruction, stasis, foley catheter, stent, diabetes, pregnancy, renal failure, transplant, immunosuppression
Young healthy women: recurrent infection in 25% within 6mos of first infection
??data for postmenopausal/elderly?
Franco AV. Best Pract & Res Clin Obstet & Gynec 2005;19(6):

37. What else other than antibiotics?
Fluids to promote a dilute urine flow
Topical estrogen
In some postmenopausal women it can normalize the vaginal flora and reduce recurrent UTI
Methenamine
Adhesion blockers (D-mannose)
Not evaluated in clinical trials
Drinking cranberry juice or cranberry tablets
Clinical Data Cochrane Review 2008
Recent studies
Pilot Study in LTC
ESTROGEN
A randomized, double-blind, placebo-controlled trial in 93 postmenopausal women found that estriol in a vaginal cream (0.5 mg nightly for 2 weeks, then twice weekly for 8 months) significantly reduced the incidence of recurrent UTI.[8] The effect probably is related to the restoration of lactobacilli, which replace Enterobacteriaceae and decrease the vaginal pH. Raz R, Stamm WE. A controlled trial of intravaginal estriol in postmenopausal women with recurrent urinary tract infections. N Engl J Med. Sep ;329(11): [Medline]. [Full Text
Methenamine salts: lack of selection for resistant organisms
Salts are hydrolyzed to (ammonia and) formaldehyde. Formaldehyde denatures proteins and nucleic acids: antimicrobial activity. Activity depends on urinary concentration of formaldehyde, which depends on methenamine concentration, urine pH and time the drug is in the bladder.
Vit C at 4-12 g per day to acidify urine
2007 Oct 17;(4):CD
COCHRANE:
Methenamine hippurate for preventing urinary tract infections.
Lee BB, Simpson JM, Craig JC, Bhuta T.
Source
Prince of Wales Hospital, Spinal Injuries Unit, High St, Randwick, NSW, Australia,
Abstract
BACKGROUND:
Methenamine salts are often used as an alternative to antibiotics for the prevention of urinary tract infection (UTI).
OBJECTIVES:
To assess the benefits and harms of methenamine hippurate in preventing UTI.
SEARCH STRATEGY:
We searched the Cochrane Central Register of Controlled Trials (CENTRAL in The Cochrane Library), MEDLINE (from 1950), EMBASE (from 1980), reference lists of articles and abstracts from conference proceedings without language restriction. Manufacturers' of methenamine salts were contacted for unpublished studies and contact was made with known investigators. Date of last search: September 2006
SELECTION CRITERIA:
Randomised controlled trials (RCT) and quasi-RCTs of methenamine hippurate used for the prevention of UTIs in all population groups were eligible. A comparison with a control/no treatment group was a prerequisite for selection.
DATA COLLECTION AND ANALYSIS:
Two authors independently assessed study quality and extracted data. Statistical analyses were performed using the random effects model and the results expressed as relative risk (RR) for dichotomous outcomes with 95% confidence intervals (CI). An exploration of heterogeneity and a detailed description of results, grouped by population, was undertaken.
MAIN RESULTS:
Thirteen studies (2032 participants) were included. Six studies (654 patients) reported symptomatic UTI and eight studies (796 patients) reported bacteriuria. Overall, study quality was mixed. The overall pooled estimates for the major outcome measures were not interpretable because of underlying heterogeneity. Subgroup analyses suggested that methenamine hippurate may have some benefit in patients without renal tract abnormalities (symptomatic UTI: RR 0.24, 95% CI 0.07 to 0.89; bacteriuria: RR 0.56, 95% CI 0.37 to 0.83), but not in patients with known renal tract abnormalities (symptomatic UTI: RR 1.54, 95% CI 0.38 to 6.20; bacteriuria: RR 1.29, 95% CI 0.54 to 3.07). For short-term treatment duration (1 week or less) there was a significant reduction in symptomatic UTI in those without renal tract abnormalities (RR 0.14, 95% CI 0.05 to 0.38). The rate of adverse events was low.
AUTHORS' CONCLUSIONS:
Methenamine hippurate may be effective for preventing UTI in patients without renal tract abnormalities, particularly when used for short-term prophylaxis. It does not appear to work in patients with neuropathic bladder or in patients who have renal tract abnormalities. The rate of adverse events was low, but poorly described. There is a need for further large well-conducted RCTs to clarify this question, particularly for longer term use for people without neuropathic bladder
Cranberry prevents adhesion of bacteria (esp E. coli) to uroepithelial cells.
Cochrane review cranberry: Jan 23;(1):CD
Cranberries for preventing urinary tract infections.
Jepson RG, Craig JC.
University of Stirling, Cancer Care Research Centre, Unit 1, Scion House, Innovation Park, Stirling, UK FK9 4LA.
Cranberries have been used widely for several decades for the prevention and treatment of urinary tract infections (UTIs).
To assess the effectiveness of cranberry products in preventing UTIs in susceptible populations.
We searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL in The Cochrane Library) and the Internet. We contacted companies involved with the promotion and distribution of cranberry preparations and checked reference lists of review articles and relevant studies. Date of last search: January 2007.
All randomised controlled trials (RCTs) or quasi-RCTs of cranberry products for the prevention of UTIs in all populations.
Two authors independently assessed and extracted information. Information was collected on methods, participants, interventions and outcomes (UTIs - symptomatic and asymptomatic, side effects, adherence to therapy). Relative risk (RR) were calculated where appropriate, otherwise a narrative synthesis was undertaken. Quality was assessed using the Cochrane criteria.
Ten studies (n = 1049, five cross-over, five parallel group) were included. Cranberry/cranberry-lingonberry juice versus placebo, juice or water was evaluated in seven studies, and cranberries tablets versus placebo in four studies (one study evaluated both juice and tablets). Cranberry products significantly reduced the incidence of UTIs at 12 months (RR 0.65, 95% CI 0.46 to 0.90) compared with placebo/control. Cranberry products were more effective reducing the incidence of UTIs in women with recurrent UTIs, than elderly men and women or people requiring catheterisation. Six studies were not included in the meta-analyses due to methodological issues or lack of available data. However, only one reported a significant result for the outcome of symptomatic UTIs. Side effects were common in all studies, and dropouts/withdrawals in several of the studies were high.
There is some evidence that cranberry juice may decrease the number of symptomatic UTIs over a 12 month period, particularly for women with recurrent UTIs. It's effectiveness for other groups is less certain. The large number of dropouts/withdrawals indicates that cranberry juice may not be acceptable over long periods of time. It is not clear what is the optimum dosage or method of administration (e.g. juice, tablets or capsules). Further properly designed studies with relevant outcomes are needed.

38. Mayo Clinic Proceedings 2012 Feb;87(2):143-50
Recurrent urinary tract infection and urinary Escherichia coli in women ingesting cranberry juice daily: a randomized controlled trial.
Stapleton AE, Dziura J, Hooton TM, Cox ME, Yarova-Yarovaya Y, Chen S, Gupta K.
Source
Department of Medicine, University of Washington, Seattle, USA.
Abstract
OBJECTIVE:
To compare the time to urinary tract infection (UTI) and the rates of asymptomatic bacteriuria and urinary P-fimbriated Escherichia coli during a 6-month period in women ingesting cranberry vs placebo juice daily.
PATIENTS AND METHODS:
Premenopausal women with a history of recent UTI were enrolled from November 16, 2005, through December 31, 2008, at 2 centers and randomized to 1 of 3 arms: 4 oz of cranberry juice daily, 8 oz of cranberry juice daily, or placebo juice. Time to UTI (symptoms plus pyuria) was the main outcome. Asymptomatic bacteriuria, adherence, and adverse effects were assessed at monthly visits.
RESULTS:
A total of 176 participants were randomized (120 to cranberry juice and 56 to placebo) and followed up for a median of 168 days. The cumulative rate of UTI was 0.29 in the cranberry juice group and 0.37 in the placebo group (P=.82). The adjusted hazard ratio for UTI in the cranberry juice group vs the placebo group was 0.68 (95% confidence interval, ; P=.29). The proportion of women with P-fimbriated urinary E coli isolates during the intervention phase was 10 of 23 (43.5%) in the cranberry juice group and 8 of 10 (80.0%) in the placebo group (P=.07). The mean dose adherence was 91.8% and 90.3% in the cranberry juice group vs the placebo group. Minor adverse effects were reported by 24.2% of those in the cranberry juice group and 12.5% in the placebo group (P=.07).
CONCLUSION:
Cranberry juice did not significantly reduce UTI risk compared with placebo. The potential protective effect we observed is consistent with previous studies and warrants confirmation in larger, well-powered studies of women with recurrent UTI. The concurrent reduction in urinary P-fimbriated E coli strains supports the biological plausibility of cranberry activity.
RECENT STUDIES
1) Barbosa-Cesnik C et al. Cranberry Juice Fails to Prevent Recurrent Urinary Tract Infection: Results from a Randomized Placebo-Controlled Trial. Clinical Infectious Diseases 2011;52(1);23-30.
2) Mayo Clinic Proceedings 2012 Feb;87(2):143-50
Recurrent urinary tract infection and urinary Escherichia coli in women ingesting cranberry juice daily: a randomized controlled trial.
Stapleton AE, Dziura J, Hooton TM, Cox ME, Yarova-Yarovaya Y, Chen S, Gupta K.
Source
Department of Medicine, University of Washington, Seattle, USA.
Abstract
OBJECTIVE:
To compare the time to urinary tract infection (UTI) and the rates of asymptomatic bacteriuria and urinary P-fimbriated Escherichia coli during a 6-month period in women ingesting cranberry vs placebo juice daily.
PATIENTS AND METHODS:
Premenopausal women with a history of recent UTI were enrolled from November 16, 2005, through December 31, 2008, at 2 centers and randomized to 1 of 3 arms: 4 oz of cranberry juice daily, 8 oz of cranberry juice daily, or placebo juice. Time to UTI (symptoms plus pyuria) was the main outcome. Asymptomatic bacteriuria, adherence, and adverse effects were assessed at monthly visits.
RESULTS:
A total of 176 participants were randomized (120 to cranberry juice and 56 to placebo) and followed up for a median of 168 days. The cumulative rate of UTI was 0.29 in the cranberry juice group and 0.37 in the placebo group (P=.82). The adjusted hazard ratio for UTI in the cranberry juice group vs the placebo group was 0.68 (95% confidence interval, ; P=.29). The proportion of women with P-fimbriated urinary E coli isolates during the intervention phase was 10 of 23 (43.5%) in the cranberry juice group and 8 of 10 (80.0%) in the placebo group (P=.07). The mean dose adherence was 91.8% and 90.3% in the cranberry juice group vs the placebo group. Minor adverse effects were reported by 24.2% of those in the cranberry juice group and 12.5% in the placebo group (P=.07).
CONCLUSION:
Cranberry juice did not significantly reduce UTI risk compared with placebo. The potential protective effect we observed is consistent with previous studies and warrants confirmation in larger, well-powered studies of women with recurrent UTI. The concurrent reduction in urinary P-fimbriated E coli strains supports the biological plausibility of cranberry activity.
3)MCMURDO relevant b/c in elderly: Cranberry juice tolerable, need larger trials pts males and females in hospital, low infection rate so underpowered, but did have fewer ecoli infections in cranberry juice group.
4)PILOT: Juthani-Mehta Oct 2010, small study: 56 pts Sept 2007-July Cranberry capsules 2 doses and placebo. Time to first positive cx and incidence were not signif diff. Basically demonstrated tolerability. Difficulties with followup and contamination of samples. ?appropriate dose.
Juthani-Mehta M et al. Journal of the American Geriatric Socety 2010;58(10):

39. Cranberry juice and Warfarin?
Case reports of cranberry juice or cranberry sauce potentiating the effects of warfarin by elevating the INR
Clinical trials evaluating this interaction have failed to demonstrate a significant effect on an INR +

40. Cochrane Review/Meta-analysis
Beerepoot MA, ter Riet G, Nys S, van der Wal WM, de Borgie CA, de Reijke TM, et al. Cranberries vs antibiotics to prevent urinary tract infections: a randomized double-blind noninferiority trial in premenopausal women. Arch Intern Med. Jul ;171(14): [Medline].
Jepson RG, Craig JC. Cranberries for preventing urinary tract infections. Cochrane Database Syst Rev. Jan ;CD [Medline].
Kontiokari T, Sundqvist K, Nuutinen M, Pokka T, Koskela M, Uhari M. Randomised trial of cranberry-lingonberry juice and Lactobacillus GG drink for the prevention of urinary tract infections in women. BMJ. Jun ;322(7302):1571. [Medline]. [Full Text].
Wojnicz D, Sycz Z, Walkowski S, Gabrielska J, Aleksandra W, Alicja K, et al. Study on the influence of cranberry extract Zuravit S·O·S(®) on the properties of uropathogenic Escherichia coli strains, their ability to form biofilm and its antioxidant properties. Phytomedicine. Feb ;[Medline].
Cochrane Review/Meta-analysis
RR 0.21 compared to placebo (95%CI ) NNT 1.85
Adverse events: RR 1.78 (95%CI ) NNT for ADR 13.5
Rate of recurrence returns to baseline after prophylaxis stopped
Risk for the development of antibiotic resistance is real
Exhaust all non-pharmacologic methods for UTI prevention prior to resorting to antibiotic prophylaxis, due to cost, risk of adverse effects, and development of antibiotic resistance
Point out that 6 month trial recommended then discontinued and observed…..

41. Antimicrobial Prophylaxis
Point out that 6 month trial recommended then discontinued and observed…..
Cochrane Review/Meta-analysis
RR 0.21 compared to placebo (95%CI ) NNT 1.85
Adverse events: RR 1.78 (95%CI ) NNT for ADR 13.5
Rate of recurrence returns to baseline after prophylaxis stopped
Risk for the development of antibiotic resistance is real
Exhaust all non-pharmacologic methods for UTI prevention prior to resorting to antibiotic prophylaxis, due to cost, risk of adverse effects, and development of antibiotic resistance
Hooton, TM. NEJM 2012;366:

42. What about for CA-UTI? Reduce indwelling catheter use
Remove catheters the as soon as they are no longer clinically necessary
Catheters
Care
Insertion with aseptic technique/sterile equipment
Closed drainage systems, with drainage bag and tube always below bladder level
Antimicrobial coating
May delay onset of CA-bacteriuria in short-term
Data insufficient to say if antimicrobial-coated catheters reduce CA-UTI in short-term or CA-bacteriuria/CA-UTI in long-term catheterization
Hooton TM et al. Clinical Infectious Diseases 2010;50:

43. What about for CA-UTI?
Methenamine not recommended in long-term catheterization
Data unconvincing that it is effective
May be effective with intermittent catheterization and short-term catheterization (studied in specific population)
Methenamine hippurate 1 g BID
Methenamine mandelate 1g 4 times daily
And it may help to acidify urine when using these agents (Vit C?)
Cranberry
3/4 double-blind placebo controlled trials: no effect
Studies are poor, mostly negative
Antimicrobial prophylaxis can reduce CA-ASB, but not CA-UTI
Not recommended because of cost, potential for adverse effects and development of antimicrobial resistance
Methenamine salts: lack of selection for resistant organisms
Salts are hydrolyzed to (ammonia and) formaldehyde. Formaldehyde denatures proteins and nucleic acids: antimicrobial activity. Activity depends on urinary concentration of formaldehyde, which depends on methenamine concentration, urine pH and time the drug is in the bladder.
Vit C at 4-12 g per day to acidify urine
And antimicrobial proph increases antimicrob-resistant bacteria
Hooton TM et al. Clinical Infectious Diseases 2010;50:

44. In Summary Decide if treatment is necessary
Appropriate antibiotic and duration
Choice based on patient (allergies/comorbidities/prior history), epidemiologic factors, organism
Minimize adverse effects, minimize development of resistance, avoid C.difficile
Narrowest spectrum possible
If empiric therapy is more broad than needed, narrow after culture data
Prophylaxis
Several options that do not affect antimicrobial resistance
Avoid antimicrobial agents if possible
If such an agent is chosen, would re-evaluate after several months
If antimicrob agent chosen for proph, then would re-evaluate after a certain period of time…..

45. Questions?

46. References
Barbosa-Cesnik C et al. Cranberry Juice Fails to Prevent Recurrent Urinary Tract Infection: Results from a Randomized Placebo-Controlled Trial. Clinical Infectious Diseases 2011;52(1);23-30.
Beerepoot MAJ et al. Cranberries vs Antibiotics to Prevent Urinary Tract Infections. Archives of Internal Medicine 2011;171(14):
Beveridge LA et al. Optimal Management of Urinary Tract Infections in Older People. Clinical Interventions in Aging 2011;6:
Boucher HW et al. Bad bugs, no drugs: no ESKAPE! An update from the Infectious Diseases Society of AmericaClinical Infect Diseases 2009;48:1-12.
Das R et al. Antimicrobial Susceptibility of Bacteria Isolated from Urine Samples Obtained from Nursing Home Residents. ICHE 2009;30(11):
Franco AV. Recurrent Urinary Tract Infections. Best Pract & Res Clin Obstet & Gynec 2005;19(6):861-73
Gupta K 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 of Microbiology and Infectious Diseases. Clinical Infectious Diseases 2011;52(5):e
Hooton, TM. Uncomplicated Urinary Tract Infection. NEJM 2012;366:
Hooton TM et al. Diagnosis, Prevention, and Treatment of Catheter-Associated Urinary Tract Infection in Adults: Internation Clinical Practice Guidelines from the Infectious Diseases Society of America. Clinical Infectious Diseases 2010;50:
Jepson RG et al. Cranberries for preventing urinary tract infections. Cochrane Review 2008.
Juthani-Mehta M et al. Feasibility of Cranberry Capsule Administration and Clean-Catch Urine Collection in Long-Term Care Residents. Journal of the American Geriatric Socety 2010;58(10):
Mcmurdo MET et al. Does Ingestion of Cranberry Juice Reduce Urinary Tract Infections in Older People in Hospital? A Double-Blind Placebo-Controlled Trial. Age and Aging 2005;34:
Mullane et al. Clin Infect Dis. 2011;53:
Nicolle LE et al. Infectious Diseases Society of America Guidelines for the Diagnosis and Treatment of Asymptomatic Bacteriuria in Adults. Clinical Infectious Diseases 2005;40:
Stapleton AE et al. Recurrent Urinary Tract Infection and Urinary Escherichia coli in Women Ingesting Cranberry Juice Daily: A Randomized Controlled Trial. Mayo Clinic Proceedings 2012;87(2):