Short-course Methenamine Hippurate for Prevention of Post-operative UTI (NO-UTI)

The Efficacy and Cost-effectiveness of a 24-hour Course of metheNamine Hippurate for Preventing Post-Operative Urinary Tract Infection

The investigators will determine the efficacy of an innovative short regimen of methenamine hippurate on prevention of post-operative UTI in patients requiring short-term catheterization after pelvic reconstructive surgery through a single-blind, randomized controlled trial. Primary outcome will be the rate of symptomatic UTI within 3 weeks of catheter removal. The investigators will study cost-effectiveness, antibiotic resistance profiles, and adverse drug effects. Findings may reduce antibiotic use and nosocomial UTIs.

Study Overview

• Status: Completed
• Conditions: Urinary Tract Infections; Catheter-Related Infections
• Intervention / Treatment: Drug: methenamine hippurate; Drug: Ciprofloxacin

Detailed Description

Prevention of post-operative urinary tract infections (UTI) is becoming important for both the individual patient and the health system. Complications of UTI include pyelonephritis and bacteremia, requiring hospitalization and parenteral antibiotics. Additionally, recurrent exposure to antibiotics commonly given for UTIs increases the risk of antibiotic resistance to uropathogens. UTIs also increase economic burdens on the health care system, with each episode costing nearly 600 dollars. UTIs associated with catheterization are particularly costly for hospitals, resulting in decreased hospital quality measures and lack of compensation.

This is particularly important after pelvic reconstructive surgery, as reported rates of UTI reach up to 20-25%. Urinary retention requiring short-term indwelling catheterization, common in these women, contributes to the risk of UTIs by increasing the risk of bacteriuria by 5-10% per day and through the dislodging of bacterial colonies during catheter removal. Balancing prevention and resistance and cost is key. A meta-analysis by Marschall et al indicated the benefit of a short dose of antibiotic prophylaxis at catheter removal in general post-surgical patients. However, data is lacking on the effects of daily antibiotic prophylaxis on resistance and cost.

A possible alternative to antibiotics presents itself in methenamine hippurate, a urinary antiseptic which forms formaldehyde in the presence of acidic urine. It is relatively inexpensive, and does not induce resistance in vivo. Prior studies have shown that daily use of methenamine can decrease the risk of post-operative UTI.

The purpose of our study was to investigate the efficacy of a short course of methenamine hippurate at catheter removal to that of a short course of ciprofloxacin in prevention of UTIs after short-term indwelling catheterization. Additionally, we investigated factors that influence post-operative UTIs, the rate of culture-proven UTIs after prophylaxis, the antibiotic resistance profile of those undergoing prophylaxis, and the cost effectiveness of prophylaxis.

• Study Type: Interventional
• Enrollment (Actual): 201
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Hospital of the University of Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Penn Presbyterian Medical Center
    • Philadelphia, Pennsylvania, United States, 19107
      • Pennsylvania Hospital
    • Philadelphia, Pennsylvania, United States, 19118
      • Chestnut Hill Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• female;
• patients who are able to read and write English;
• 18 years of age or older;
• underwent surgery for pelvic organ prolapse, urinary incontinence, or both;
• require post-operative short-term transurethral catheterization for greater than 24 hours.

Exclusion Criteria:

• patients undergoing surgical intervention for sacral neuromodulation, or mesh excision;
• patients requiring long-term catheterization secondary to injury to the urinary tract;
• patients who pass their post-operative trial void and thus, do not require additional catheterization;
• patients requiring catheterization for less than 24 hours;
• pregnant patients;
• patients who are breast-feeding;
• allergy to methenamine hippurate or fluroquinolones (either ciprofloxacin or levofloxacin);
• impaired renal or hepatic function;
• pre-operative urinary retention;
• patients who are currently using sulfonamides;
• patients who have severe dehydration;
• patients using tizanidine;
• patients sensitive to quinolones class;
• patients using theophylline; patients with myasthenia gravis;
• patients with prolongation of QT interval.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Methenamine; Methenamine hippurate is a medication that exhibits antibacterial activity by converting to formaldehyde in the presence of acidic urine. It is currently FDA approved for the prophylaxis of recurrent urinary tract infections. It has been previously used in studies for prevention of UTI after gynecologic surgery. Dosage will be methenamine hippurate 1g, 1 tablet by mouth every 12 hours for 24 hours (total of two doses), with the first dose taken at least one hour prior to catheter removal.	Drug: methenamine hippurate; A urinary antiseptic used for prevention of UTI; Other Names: Hiprex
Active Comparator: Ciprofloxacin; Ciprofloxacin is a commonly used antibiotic commonly used for prevention of UTI after catheterization. It belongs to a class of antibiotics known as the fluoroquinolones. Dosage will be ciprofloxacin 500 mg, 1 tablet by mouth every 12 hours for 24 hours (total of two doses), with the first dose taken at least one hour prior to catheter removal.	Drug: Ciprofloxacin; An antibiotic used for treatment and prevention of UTI; Other Names: Cipro

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Treatment of Clinically Suspected UTI - Using Intent to Treat Analysis	This is defined as any symptomatic UTI requiring treatment with antibiotics as determined by the development of 2 or more of the following symptoms, in the absence of vaginal symptoms: urinary frequency; urinary urgency; dysuria; fever over 38oC/100.4oF; suprapubic, flank, or back pain; and/or chills.	3 weeks post-operative
Treatment of Clinically Suspected UTI - Per Protocol	This is defined as any symptomatic UTI requiring treatment with antibiotics as determined by the development of 2 or more of the following symptoms, in the absence of vaginal symptoms: urinary frequency; urinary urgency; dysuria; fever over 38oC/100.4oF; suprapubic, flank, or back pain; and/or chills.	3 weeks post-operative

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Culture-positive Symptomatic UTI	All patients will be encouraged to submit urine cultures prior to treatment, but this is not always possible. Amongst patients who undergo urine culture as part of standard of care for UTI, the rate of positive cultures will be identified.	3 weeks post-operative
Antibiotic Resistance of Culture-positive Symptomatic UTI	All patients who submit urine cultures that are positive will have sensitivities performed as per standard care. The prevalence of bacterial species and sensitivities will be collected	3 weeks post-operative
Cost-effectiveness of Prophylaxis With Methenamine Hippurate for Prevention of Post-operative UTI Compared to Prophylaxis With Fluoroquinolones	Routine costs of prevention of UTI with methenamine hippurate prophylaxis will be compared with costs of prevention of UTI with fluoroquinolone prophylaxis. We plan to capture costs for each direct medical service use, direct non-medical items, and indirect items related to post-operative UTIs in each arm of the trial.	3 weeks post-operative
Prevalence of Side Effects	Adverse effects from the administration of methenamine and fluoroquinolones will be collected.	within 24 hours of administration

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of UTI Consistent With NHSN Criteria	We plan to analyze the prevalence of UTI in this population that meet the definitions of symptomatic UTI and catheter-associated UTI according to the National Healthcare Safety Network criteria.	3 weeks post-operative

Collaborators and Investigators

• Sponsor: University of Pennsylvania
• Investigators: Principal Investigator: Christine M Chu, MD, University of Pennsylvania; Study Director: Lily Arya, MD, MS, University of Pennsylvania; Principal Investigator: Daniel Lee, MD, University of Pennsylvania

Publications and helpful links

General Publications

• Schiotz HA. Comparison of 1 and 3 days' transurethral Foley catheterization after retropubic incontinence surgery. Int Urogynecol J Pelvic Floor Dysfunct. 1996;7(2):98-101. doi: 10.1007/BF01902381.
• Schiotz HA, Guttu K. Value of urinary prophylaxis with methenamine in gynecologic surgery. Acta Obstet Gynecol Scand. 2002 Aug;81(8):743-6. doi: 10.1080/j.1600-0412.2002.810810.x.
• Anger JT, Litwin MS, Wang Q, Pashos CL, Rodriguez LV. Complications of sling surgery among female Medicare beneficiaries. Obstet Gynecol. 2007 Mar;109(3):707-14. doi: 10.1097/01.AOG.0000255975.24668.f2.
• Hakvoort RA, Elberink R, Vollebregt A, Ploeg T, Emanuel MH. How long should urinary bladder catheterisation be continued after vaginal prolapse surgery? A randomised controlled trial comparing short term versus long term catheterisation after vaginal prolapse surgery. BJOG. 2004 Aug;111(8):828-30. doi: 10.1111/j.1471-0528.2004.00181.x.
• Harding GK, Nicolle LE, Ronald AR, Preiksaitis JK, Forward KR, Low DE, Cheang M. How long should catheter-acquired urinary tract infection in women be treated? A randomized controlled study. Ann Intern Med. 1991 May 1;114(9):713-9. doi: 10.7326/0003-4819-114-9-713.
• Saint S. Clinical and economic consequences of nosocomial catheter-related bacteriuria. Am J Infect Control. 2000 Feb;28(1):68-75. doi: 10.1016/s0196-6553(00)90015-4.
• Warren JW. Catheter-associated urinary tract infections. Infect Dis Clin North Am. 1987 Dec;1(4):823-54.
• Wazait HD, van der Meullen J, Patel HR, Brown CT, Gadgil S, Miller RA, Kelsey MC, Emberton M. Antibiotics on urethral catheter withdrawal: a hit and miss affair. J Hosp Infect. 2004 Dec;58(4):297-302. doi: 10.1016/j.jhin.2004.06.012.
• Wolf JS Jr, Bennett CJ, Dmochowski RR, Hollenbeck BK, Pearle MS, Schaeffer AJ; Urologic Surgery Antimicrobial Prophylaxis Best Practice Policy Panel. Best practice policy statement on urologic surgery antimicrobial prophylaxis. J Urol. 2008 Apr;179(4):1379-90. doi: 10.1016/j.juro.2008.01.068. Epub 2008 Feb 20. Erratum In: J Urol. 2008 Nov;180(5):2262-3.
• ACOG practice bulletin No. 104: antibiotic prophylaxis for gynecologic procedures. Obstet Gynecol. 2009 May;113(5):1180-1189. doi: 10.1097/AOG.0b013e3181a6d011. No abstract available.
• Ghezzi F, Serati M, Cromi A, Uccella S, Salvatore S, Bolis P. Prophylactic single-dose prulifloxacin for catheter-associated urinary tract infection after tension-free vaginal tape procedure. Int Urogynecol J Pelvic Floor Dysfunct. 2007 Jul;18(7):753-7. doi: 10.1007/s00192-006-0233-4. Epub 2006 Nov 21.
• Rogers RG, Kammerer-Doak D, Olsen A, Thompson PK, Walters MD, Lukacz ES, Qualls C. A randomized, double-blind, placebo-controlled comparison of the effect of nitrofurantoin monohydrate macrocrystals on the development of urinary tract infections after surgery for pelvic organ prolapse and/or stress urinary incontinence with suprapubic catheterization. Am J Obstet Gynecol. 2004 Jul;191(1):182-7. doi: 10.1016/j.ajog.2004.03.088.
• Baertschi U, Kunz J. [Comparative study on the question of systemic chemoprophylaxis following gynecological surgery]. Schweiz Med Wochenschr. 1976 Mar 13;106(11):380-5. German.
• Gordon KA, Jones RN; SENTRY Participant Groups (Europe, Latin America, North America). Susceptibility patterns of orally administered antimicrobials among urinary tract infection pathogens from hospitalized patients in North America: comparison report to Europe and Latin America. Results from the SENTRY Antimicrobial Surveillance Program (2000). Diagn Microbiol Infect Dis. 2003 Apr;45(4):295-301. doi: 10.1016/s0732-8893(02)00467-4.
• Tyreman NO, Andersson PO, Kroon L, Orstam S. Urinary tract infection after vaginal surgery. Effect of prophylactic treatment with methenamine hippurate. Acta Obstet Gynecol Scand. 1986;65(7):731-3. doi: 10.3109/00016348609161491.
• Knoff T. [Methenamine hippurate. Short-term catheterization in gynecologic surgery. A double-blind comparison of Hiprex and placebo]. Tidsskr Nor Laegeforen. 1985 Mar 10;105(7):498-9. No abstract available. Norwegian.
• Ladehoff P, Jacobsen JC, Olsen H, Pedersen GT, Sorensen T. [The preventive effect of methenamine hippurate (Haiprex) on urinary infections after short-term catheterization. A clinical study]. Ugeskr Laeger. 1984 May 7;146(19):1433-4. No abstract available. Danish.
• Strom JG Jr, Jun HW. Effect of urine pH and ascorbic acid on the rate of conversion of methenamine to formaldehyde. Biopharm Drug Dispos. 1993 Jan;14(1):61-9. doi: 10.1002/bdd.2510140106.
• Marschall J, Carpenter CR, Fowler S, Trautner BW; CDC Prevention Epicenters Program. Antibiotic prophylaxis for urinary tract infections after removal of urinary catheter: meta-analysis. BMJ. 2013 Jun 11;346:f3147. doi: 10.1136/bmj.f3147. Erratum In: BMJ. 2013;347:f5325.
• Sutkin G, Alperin M, Meyn L, Wiesenfeld HC, Ellison R, Zyczynski HM. Symptomatic urinary tract infections after surgery for prolapse and/or incontinence. Int Urogynecol J. 2010 Aug;21(8):955-61. doi: 10.1007/s00192-010-1137-x. Epub 2010 Mar 31.
• Dieter AA, Amundsen CL, Edenfield AL, Kawasaki A, Levin PJ, Visco AG, Siddiqui NY. Oral antibiotics to prevent postoperative urinary tract infection: a randomized controlled trial. Obstet Gynecol. 2014 Jan;123(1):96-103. doi: 10.1097/AOG.0000000000000024. Erratum In: Obstet Gynecol. 2014 Mar;123(3):669.
• Turck M, Stamm W. Nosocomial infection of the urinary tract. Am J Med. 1981 Mar;70(3):651-4. doi: 10.1016/0002-9343(81)90590-8.
• Duclos JM, Larrouturou P, Sarkis P. Timing of antibiotic prophylaxis with cefotaxime for prostatic resection: better in the operative period or at urethral catheter removal? Am J Surg. 1992 Oct;164(4A Suppl):21S-23S. doi: 10.1016/s0002-9610(06)80053-x.
• Lusardi G, Lipp A, Shaw C. Antibiotic prophylaxis for short-term catheter bladder drainage in adults. Cochrane Database Syst Rev. 2013 Jul 3;2013(7):CD005428. doi: 10.1002/14651858.CD005428.pub2.
• Lee BS, Bhuta T, Simpson JM, Craig JC. Methenamine hippurate for preventing urinary tract infections. Cochrane Database Syst Rev. 2012 Oct 17;10(10):CD003265. doi: 10.1002/14651858.CD003265.pub3.

Helpful Links

• Methenamine. In: Lexi-Drugs Online. Hudson, OH: Lexi-Comp, Inc. [updated 2/1/14; accessed 2/21/14].
• Ciprofloxacin (systemic). In: Lexi-Drugs Online. Hudson, OH: Lexi-Comp, Inc. [updated 2/19/14; accessed 2/21/14].
• Nitrofurantoin. In: Lexi-Drugs Online. Hudson, OH: Lexi-Comp, Inc. [updated 2/14/14; accessed 2/21/14].
• Sulfamethoxazole and Trimethoprim. In: Lexi-Drugs Online. Hudson, OH: Lexi-Comp, Inc. [updated 2/1/14; accessed 2/21/14].
• Methenamine. In: Micromedex 2.0. Martindale - The Complete Drug Reference. Ann Arbor, MI: Truven Health Analytics. [updated 8/20/2010; accessed 2/21/14].
• Nitrofurantoin. In: Micromedex 2.0. Martindale - The Complete Drug Reference. Ann Arbor, MI: Truven Health Analytics. [updated 8/20/2010; accessed 2/21/14].
• Ciprofloxacin. In: Micromedex 2.0. Martindale - The Complete Drug Reference. Ann Arbor, MI: Truven Health Analytics. [updated 8/20/2010; accessed 2/21/14].
• Sulfamethoxazole/Trimethoprim. In: Micromedex 2.0. Martindale - The Complete Drug Reference. Ann Arbor, MI: Truven Health Analytics. [updated 8/20/2010; accessed 2/21/14].

Study record dates

Study Major Dates

• Study Start (Actual): December 1, 2014
• Primary Completion (Actual): September 30, 2020
• Study Completion (Actual): September 30, 2020

Study Registration Dates

• First Submitted: February 3, 2015
• First Submitted That Met QC Criteria: February 6, 2015
• First Posted (Estimate): February 9, 2015

Study Record Updates

• Last Update Posted (Actual): February 25, 2022
• Last Update Submitted That Met QC Criteria: February 3, 2022
• Last Verified: February 1, 2022

More Information

Terms related to this study

• Keywords: Urinary Tract Infections; Urogynecology; Urinary catheterization; Catheter-Related Infections; Pelvic Reconstructive Surgery; Post-operative Infections; Methenamine hippurate
• Additional Relevant MeSH Terms: Pathologic Processes; Urologic Diseases; Disease Attributes; Infections; Communicable Diseases; Urinary Tract Infections; Catheter-Related Infections; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antineoplastic Agents; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Anti-Bacterial Agents; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 CYP1A2 Inhibitors; Anti-Infective Agents, Urinary; Renal Agents; Ciprofloxacin; Methenamine; Methenamine hippurate; Methenamine mandelate
• Other Study ID Numbers: 820117

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided