Author's Accepted Manuscript Does stone removal help patients with recurrent urinary tract infections? Mohamed Omar , Abdullahi Abdulwahab-Ahmed , Hemant Chaparala , Manoj Monga

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S0022-5347(15)03896-3 10.1016/j.juro.2015.04.096 JURO 12579

To appear in: The Journal of Urology Accepted Date: 13 April 2015 Please cite this article as: Omar M, Abdulwahab-Ahmed A, Chaparala H, Monga M, Does stone removal help patients with recurrent urinary tract infections?, The Journal of Urology® (2015), doi: 10.1016/ j.juro.2015.04.096. DISCLAIMER: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our subscribers we are providing this early version of the article. The paper will be copy edited and typeset, and proof will be reviewed before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to The Journal pertain.

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Title: Does stone removal help patients with recurrent urinary tract infections? Authors:

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Mohamed Omar, MD Abdullahi Abdulwahab-Ahmed, MD Hemant Chaparala, (MS4)

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Manoj Monga, MD

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Affiliations: Glickman Urological & Kidney Institute – Cleveland Clinic Foundation, Cleveland, OH, United States

Corresponding author: Manoj Monga, MD

Director, Stevan Streem Center for Endourology & Stone Disease

The Cleveland Clinic

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Glickman Urological & Kidney Institute

9500 Euclid Avenue, Q10-1

PH: 216-445-8678

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Cleveland OH 44195

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Email: [email protected]

Running head: Infectious outcomes after stone extraction Word count: (abstract) 249; (text) 2062 Keywords: Urolithiasis, recurrent, urinary tract infection, eradication

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Abstract PURPOSE:

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To evaluate the impact of surgical extraction of non-obstructing asymptomatic stones on recurrent urinary tract infections, and identify predictors of patients who may be rendered infection-free. MATERIALS AND METHODS:

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A retrospective chart review identified patients with recurrent UTIs that underwent surgical stone extraction and were rendered stone-free. Demographic variables as well as procedure, infectious etiology, stone composition, and SIRS rate were also recorded. Patients were divided into two groups; the 1st group had no evidence of recurrent infection following surgery while the 2nd group developed recurrent infection. Univariate analysis was performed using Wilcoxon’s signed-rank test and Fisher’s exact test. Logistic regression was used for multivariate analysis. RESULTS:

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CONCLUSIONS:

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120 patients with recurrent UTIs and a non-obstructive renal stone were identified. Surgical management included SWL (32%), URS (7%), and PCNL (61%). 48% (58/120) remained infection-free after surgery, while 52% (62/120) had a recurrence of infection. Factors associated with a higher risk of recurrent infections included type 2 DM (OR 1.73, p=0.01), hypertension (OR 2.8, p=0.007), and African-American ethnicity (OR13.7, p=0.009). E.coli infections were more likely to resolve (OR 0.34, p=0.01). In contrast, Enterococcus infections were more likely to persist (OR 2.5, p=0.04). Upon analysis via multiple logistic regression analysis, only race, HTN, and presence of E. coli infections were significant predictors of infection clearance.

50% patients with recurrent UTIs and asymptomatic renal calculi may be rendered stone-free following extraction. Patients with risk factors for recurrent infections after surgery should be counseled that stone extraction might not eradicate their infection.

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Introduction.

Urinary tract infections (UTIs) are the most common bacterial infection affecting the

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general population1. 1 in 3 women will have at least 1 UTI requiring medical evaluation by 24 years of age. The annual incidence of UTIs in the US is estimated to be 3% in men and 12% in women2. A certain subset of individuals are affected by recurrent

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urinary tract infection, defined as ≥ 3 UTIs/year or ≥ 2 UTIs/6 months.3

The relationship between nephrolithiasis and UTI is unclear. Traditionally, infectious

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stones were believed to be caused by urease-producing bacteria leading to the formation of struvite stones3,4. However, recent studies demonstrate that 35% of stones associated with infection are calcium stones4,5. Additionally, studies looking for UTI during renal colic episodes have demonstrated prevalence rates of 7-28%5,6,7. UTI may

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develop as a consequence of urinary stasis secondary to obstruction by the stone. Alternatively, UTIs may promote the formation of stones.

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A specific challenge facing the urologist is the patient with recurrent urinary tract infections and asymptomatic non-obstructing renal calculi. Often it is proposed that

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management of the associated UTI is contingent on removal of the stone as the stone acts as a nidus or collecting surface for recurrent infections.

The objective of this study was to evaluate the likelihood of resolution of recurrent urinary tract infections after successful removal of asymptomatic non-obstructing renal calculi.

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Materials and Methods

A retrospective chart review of patients who presented to our stone clinic with renal

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calculi and recurrent UTIs prior to surgery for stone removal was performed. Patients were referred to the stone clinic after diagnosis of a non-obstructing and asymptomatic

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renal stone. Imaging, typically US followed by a confirmatory NCCT, was obtained as part of the evaluation for recurrent urinary tract infections by the referring primary care physician, infectious disease specialist, or urologist. Post-operative recurrent urinary tract infections were defined as documented positive urine cultures, obtained due to symptoms or surveillance, following successful removal of all stones at surgery with no

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residual stones on post-operative imaging. Charts were reviewed to correctly identify baseline demographic variables as well as the type of surgery, type of infection, stone

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composition, and the incidence rate of SIRS. SIRS was diagnosed when patients demonstrated two of the following: heart rate greater than ninety beats per minute, a

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respiratory rate greater than twenty respirations per minute, a serum WBC greater than 12,000/HPF,or less than 4000 / HPF , and a temperature either greater than thirty eight degrees or less than thirty six degrees Celsius. Patients with UTIs within one month post-surgery were excluded as the infection may have been secondary to the procedure itself. Patients were separated into two groups. The 1st group showed no evidence of recurrence of infection one year after stone removal. The 2nd group still showed evidence of recurrent urinary tract infection within one year after stone removal. 4

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Univariate analysis was performed using Wilcoxon’s signed-rank test and Fisher’s exact test comparing different variables then a Logistic regression was used to test variables

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during multivariate analysis.

Results

48% (58/120) of patients were rendered infection-free after their surgery, with a mean

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follow-up of 14±3 months while 52% (62/120) of patients continued to have infections, with a mean time to the first UTI recurrence of 12±2 months. Sex and age were not

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significantly associated with repeat infections post-procedure (Table 1). on Univariate analysis (p= 0.1, p=0.1) respectively. African American ethnicity was associated with repeat infections after stone procedure (OR13.7, p=0.0004). Existing hypertension also demonstrated a significant association with recurrent UTIs (OR 2.8, p=0.007). Presence

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of diabetes mellitus did not demonstrate an association with recurrent UTIs (p=0.2). However, when the grouping was stratified by sex, males with diabetes mellitus were more likely to have recurrent infection (OR 1.73, p=0.01). Neither stone composition nor

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type of stone removal procedure were significantly associated with repeat infections on univariate analysis (p=0.4, p=0.3 respectively). Infection with solely E. coli bacteria was

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associated with successful clearance of infection (p=0.01). In contrast, infection with Enterococcus was associated with failed clearance (p=0.04) (Table 2). Immunosuppression, steroid usage, cancer, hospital stay, pH, SIRS incidence, GFR, creatinine were not significantly associated with repeat infections

On multivariate analysis, HTN and African American ethnicity maintained an association with unsuccessful clearance of infection (p=0.01), (p=0.003) respectively. Solely E. coli 5

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also maintained an association with clearance of infections on multivariate analysis (p=0.01). Age did demonstrate an association with recurrent infection on multivariate

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analysis (p=0.3) (Table 3).

Quinolone-resistance was more common in the preoperative cultures for patients who had recurrent UTI's after stone removal (48% of cultures) compared to those who

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remained infection-free after stone removal (27%, p=0.02). For those with

Enterococcus, multi-drug resistance was noted preoperatively in 37% of those who

post-operative infections (p=0.9)

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remained infection free after surgery, compared to 40% in those who had recurrent

For those patients in whom infections recurred or persisted after surgery, there was no significant differences between the preoperative and postoperative cultures with regards

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to quinolone resistance (48% vs. 57%, p=0.3), beta-lactamase resistance (28% vs. 19%, p=0.08) or multi-drug resistance (48% vs. 47%, p=0.9).

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For those patients with recurrent urinary tract infections post-operatively, 82% continued to have infections with the same preoperative organism while in 18% of patients there

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was a change in bacterial species cultured.

DISCUSSION

Urinary tract infections (UTIs) are among the most prevalent infectious diseases with a substantial financial burden on society. In the USA, UTIs are responsible for over 7

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million physician visits annually, with approximately 15% of all community-prescribed antibiotics and an estimated annual cost of over US $1 billion.

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Numerous studies have reported that voided urine cultures do not often correlate with cultures from the renal pelvis or with stone cultures at the time of percutaneous

nephrolithotomy8,9. To our knowledge; no studies have looked at renal pelvis or stone

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cultures at the time of shockwave lithotripsy or ureteroscopy. Our study did not evaluate stone cultures. However, the objective of the study was to evaluate pre-operative

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predictors of success; stone cultures are not available until 48 hours after surgery.

Unfortunately the likelihood that recurrent UTIs will be eradicated with removal of asymptomatic renal calculi approaches 50%, and this study identifies specific risk

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factors for failure to eradicate infections.

Genitourinary infections account for approximately 25% of all infections amongst the

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non-institutionalized elderly2. Factors associated with an increased UTI risk amongst the elderly include cognitive impairment, incontinence, history of a previous UTI, and

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impairment of daily activities7,10. Diabetes, a common comorbidity amongst the elderly, has also been demonstrated to increase the risk of UTI10,11. However, our study did not demonstrate an association between diabetes and UTI recurrence, except in males only which was not confirmed by the multivariate analysis. It is difficult to discern the underlying pathophysiology of the higher risk of recurrent UTIs in males with DM. Differences may relate to the uroepithelial adherence of bacteria. Alternatively, there may be differences in the microbe of the urinary calculus in diabetic males, which we 7

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did not evaluate in this study. Lastly, we did not evaluate the tightness of diabetic control in subjects.

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As such, though diabetes may be associated with UTIs, it does not predict who may be rendered infection-free with stone extraction.

Urinary tract infections are an established risk factor for ESRD and those patients at

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high risk for acquiring kidney damage associated with UTIs are those with

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vesicoureteric reflux (VUR) and recurrent febrile UTIs11.

Hypertension has been reported to be a complication of chronic upper urinary tract infection, although It is very difficult to establish this in elderly as atherosclerosis is also commonly incriminated in the pathophysiology of hypertension in this age group12.

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In our study we identified that HTN is a risk factor for having recurrent urinary tract infection (p=0.0134). Renal function may play a role in this association, as those with no HTN had a higher GFR (114.5±95) than those with hypertension (mean GFR

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(67.6±28, P value (0.04))

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Enterococcus is emerging as a common cause of hospital-acquired urinary tract infections. Enterococci is clinically significant due to a relative resistance to antimicrobials, rapid acquisition of additional resistances, and the ability to form protective biofilms13,14. Moreover, Enterococcus has been demonstrated to be a common pathogen in patients with chronic and repeatedly medicated urinary tract infections14,15,16. Recent studies indicate that Enterococcus may be capable of intracellular invasion of urothelial cells. Intracellular invasion of urothelial cells may lead 8

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to more difficult eradication and explain the increased prevalence of Enterococcus amongst patients with recurrent UTIs, however, intracellular survival and formation of intracellular bacterial communities is also commonly observed with uropathogenic E.

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coli. In this case, the stone may not be the sole nidus of infection; indeed the urothelium may be the culprit.

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Struvite and secondarily infected calcium stones can manifest clinically as recurrent urinary tract infections16,17,18. PCNL has been demonstrated to be the preferred option in

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the clearance of recurrent bacteriuria from infected stones16,17. PCNL has a superior stone clearance rate which precludes residual stone fragments from continuing to act as a nidus for repeat infections16,17. ESWL’s bactericidal effect has been studied in the hopes of utilizing the shockwaves for clearance of recurrent infections associated with stones. Results of in-vivo studies have ranged from a 0-82% decrease in bacterial

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viability, though differences in experimental models make direct comparisons difficult. In our study, we there no difference between PCNL and ESWL however, we excluded

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patients with residual stones from our study. The association between ESWL and recurrent infections may be secondary to the residual fragments present after

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shockwave therapy.

E. coli is the most common bacteria associated with urinary tract infections, and traditionally has not been considered to be associated with “infection stones”, as it is not a urease-producing organism. As such, clinicians often counsel patients that the stone may not be associated with their recurrent infections. Our study suggests that stone

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removal should be offered to patients with recurrent E. coli UTI’s as E. coli infection was associated with a higher rate of eradication after stone extraction than other organisms.

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All patients received preoperative antibiotics prior to surgical intervention in an attempt to render the urine sterile. It is possible that the antibiotics administered played a role in resolution of the infection rather than the surgery to remove the stone as a nidus. In this

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event, E. coli may have been more susceptible to antibiotic eradication due to the higher resistance rate of Enterococcus. However, all of these patients had a history of

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persistent / recurrent urinary tract infections with multiple attempts at medical eradication prior to undergoing surgery, making it unlikely that the preoperative antibiotic course played a significant role in our results.

It has been reported that African American infants had a lower rate of UTI (4%)

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(p=0.007) compared with Asians (22%), Caucasians (16%), and Hispanics (16%) 19 Others have reported that between 1999 and 2001 the overall prevalence of UTI as a primary diagnosis in veterans seeking outpatient care was 2.3 to 2.48 times greater in

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women than in men and that UTI rates increased with age in this cohort and they were higher in black men than in other racial/ethnic groups20. In our study African American

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demonstrated a higher incidence for the recurrence of UTI after stone removal (p=0.0035).

Post-operative imaging to document the absence of residual stones typically consisted of a combination of KUB and US within 3 months of surgery. NCCT was utilized to confirm findings on initial KUB and US, since routine use of NCCT in the postoperative course carries an unacceptable burden of radiation. The decreased sensitivity of KUB

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and US compared to CT is a limitation of our study, though it does reflect the standard of practice. For patients with a struvite component to their stone, we commonly utilized NCCT to evaluate for residual fragments. As such, our practice may provide an element

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of selection bias that attributes to our observation that struvite stones did not correlate with a higher incidence of recurrent infections; the level of scrutiny for inclusion based

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on absence of residual fragments was higher.

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CONCLUSION

Only half of patients with recurrent urinary tract infections and asymptomatic renal calculi may be rendered stone free with stone extraction. Patients with risk factors for recurrent infections after stone extraction, such as Hypertension, and African American descent, should be counseled that stone extraction may not eradicate their infections.

by E. coli.

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.

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An attempt at stone clearance should be offered to patients with recurrent UTI caused

REFERENCES

1. Foxman B. Epidemiology of urinary tract infections: incidence, morbidity, and economic costs. Am. J. Med. 2002; 113:5-13.

2. Foxman B, Brown P. Epidemiology of urinary tract infections: Transmission and risk factors, incidence, and costs. Infect. Dis. Clin. North Am. 2003; 17:227–241.

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3.Dason S, Dason JT, Kapoor A. Guidelines for the diagnosis and management of recurrent urinary tract infection in women Can Urol Assoc J. 2011;5(5): 316-322.

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4. Miano R, Germani S, Vespasiani G. Stones and Urinary Tract Infections. Urol Int. 2007; 79:32–36. 5. Hugosson J, Grenabo L, Hedelin H, et al. Chronic urinary tract infection and renal stones. Scand. J. Urol. Nephrol. 1989; 23:61–66.

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6. Holmgren K, Danielson BG, Fellstrom B, et al. The relation between urinary tract infections and stone composition in renal stone formers. Scand. J. Urol. Nephrol. 1989; 23:131–136. 7. Ohkawa M, Tokunaga S, Nakashima T, et al. Composition of urinary calculi related to urinary tract infection. J. Urol. 1992;148:995–997.

8. Lei M1, Zhu W, Wan SP et al. The outcome of urine culture positive and culture negative staghorn calculi after minimally invasive percutaneous nephrolithotomy. Urolithiasis. 2014 Jun;42(3):235-40.

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9. Mariappan P1, Smith G, Bariol SV et al. Stone and pelvic urine culture and sensitivity are better than bladder urine as predictors of urosepsis following percutaneous nephrolithotomy: a prospective clinical study.J Urol. 2005 May;173(5):1610-4.

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10. Caljouw MA, den Elzen WP, Cools HJ, et al. Predictive factors of urinary tract infections among the oldest old in the general population. A population-based prospective follow-up study. BMC Med. 2007; 9:57.

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11. Jacobson SH, Eklof O, Eriksson CG, et al. Development of hypertension and uraemia after pyelonephritis in childhood: 27 year follow up. BMJ. 1989; 299: 703706. 12. Pacurari A, Serban C, Narita A, et al. IS URINARY TRACT INFECTION A RISK FACTOR FOR HYPERTENSION IN ELDERLY?. J of Hypertension. 2010; 28:512. 13. Boyko EJ, Fihn SD, Scholes D, et al. Diabetes and the risk of acute urinary tract infection among postmenopausal women. Diabetes Care. 2002; 25:1778–1783.

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14. Mohamed JA, Huang DB. Biofilm formation by enterococci. J. Med. Microbiol. 2007; 56:1581–1588.

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15. Guiton PS, Hannan TJ, Ford B, et al. Enterococcus faecalis Overcomes Foreign Body-Mediated Inflammation To Establish Urinary Tract Infections. Infect. Immun. 2013l; 81:329–339.

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16. Poulsen LL, Bisgaard M, Son NT et al. Enterococcus and Streptococcus spp. associated with chronic and self-medicated urinary tract infections in Vietnam. BMC Infect. Dis. 2012; 12:320.

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17. Riad EM, Roshdy M, Ismail MAA, et al. Extracorporeal Shock wave Lithotripsy (ESWL) Versus Percutaneous Nephrolithotomy (PCNL) in the Eradication of Persistent Bacteruria Associated with Infected Stones. Aust. J. Basic Appl. Sci. 2008; 2:672-676. 18. Schwartz BF, Stoller ML. Nonsurgical management of infection-related renal calculi. Urol. Clin. North Am. 1999; 26: 765–778.

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19. Chen L, Baker MD. Racial and ethnic differences in the rates of urinary tract infections in febrile infants in the emergency department. Pediatr Emerg Care. 2006; 7:485-487.

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20. Griebling TL. UROLOGIC DISEASES IN AMERICA PROJECT: TRENDS IN RESOURCE USE FOR URINARY TRACT INFECTIONS IN MEN J Urol. 2005;173:1288-1294.

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Results: TABLE 1: DEMOGRAPHIC VARIABLES Infection Cleared (58)

Mean Age Sex

57±17.1 Male: 15 (26%) Female: 43 (74%) African American: 1 Caucasian: 56 Other: 1

Recurrent Infections (62) 62±19.1 Male: 23 (37%) Female: 39 (63%) African American: 13 Caucasian: 47 Other: 2

DM

12 (21%)

20 (31%)

HTN Immunosuppression

16 (27.5%) 4 (10%)

Cancer Steroid Usage Type of surgery

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Race

p-value

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Variable

0.1158 0.1861

0.0009*

0.2682 0.0073* 0.6308

9 (16%) 11 (19%) URS: 3 (5%) PCNL: 39 (67%) ESWL: 16 (28%)

10 (16%) 12 (19%) URS: 5 (8%) PCNL: 34 (55%) ESWL: 23 (37%)

0.9269 0.9568

3.1 ±3.5 6.2 ±0.8 6/25 (24%) Calcium Oxalate: 14 Calcium Phosphate: 22 Struvite: 1 Uric Acid: 5 Mixed: 1 0.9 ±0.47 86 ±46.6

2.8 ±4.3 6.2 ±0.8 10/35 (29%) Calcium Oxalate: 15 Calcium Phosphate: 25 Struvite: 5 Uric Acid: 2 Mixed: 1 1 ±0.64 90 ±73

0.2025 0.7900 0.6930 0.4126

BMI

28.9 ± 8.2

29.5 ±6.7

0.3146

Stone Size

14.1 ±8.4

15.2 ±9.8

0.4759

Hounsfield Units

862 ±330

813 ±260

0.4789

DM in males

1/15 (7%)

10/23 (43%)

0.0145

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Creatinine GFR

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Hospital stay pH SIRS Stone Composition

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32 (52%) 3 (5%)

0.3739

0.2230 0.4832

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Group 1 31/58 (53%)

Group 2 31/62 (50%)

p-value 0.7056

E. coli (only)

21/58 (36%)

10/62 (16%)

0.0114*

K. pneumonia

12/58 (21%)

12/62 (19%)

0.8551

P. mirabilis

6/58 (10%)

7/62 (11%)

0.8677

Urease producing bacteria

19/58 (33%)

23/62 (37%)

0.6184

P. aeruginosa

6/58 (10%)

11/62 (18%)

0.2455

Lactose fermenting bacteria

45/58 (78%)

43/62 (69%)

0.3069

Citrobacter

5/58 (9%)

1/62 (2%)

0.0676

Enterococcus

8/58 (14%)

18/62 (29%)

0.0405*

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Infecting organism E. coli

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TABLE 2: PREVALENCE OF INFECTING ORGANISM

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p-value 0.3344 0.8414 0.0035* 0.4788 0.0134*

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0.574 0.3095 0.9600 0.4925 0.0116* 0.7121

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Variable Age Sex Race DM HTN Immunosuppression & Steroids Type of Surgery GFR/MDRD Stone Size (mm) E. coli only Enterococcus

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TABLE 3: MULTIVARIATE ANALYSIS

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STANDARD ABBREVIATIONS URS: Ureteroscopy SWL: shockwave lithotripsy

E.coli: Escherichia coli OR: Odds Ratio UTIs: Urinary tract infections SIRS: Systemic Inflammatory Response Syndrome

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HPF: High Power Field

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PCNL : Percutaneous Nephrolithotomy

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Does Stone Removal Help Patients with Recurrent Urinary Tract Infections?

We evaluated the impact of surgical extraction of nonobstructing asymptomatic stones on recurrent urinary tract infections and identified predictors o...
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