New insights into UTI and its management

Annually more than 150 million individuals suffer from urinary tract infection (UTI) worldwide, which is considered to be the most common bacterial infection affecting humans.¹Renuart AJ, Goldfarb DM, et al. PLoS ONE 2013;8(3): e57776.   UTI acts as a public burden each year in terms of direct medical expenses, decreased quality of life and lost productivity. Urinary tract infections (UTIs) are common, affect men and women of all ages, and vary dramatically in their presentation and sequelae. Women, the elderly and persons with underlying illnesses, such as urologic abnormalities or diabetes mellitus, are at increased risk and many of these persons will develop an UTI at some point in their lives.

UTI can be classified by the site of infection (anatomical classification. Box 1), and also based on clinical symptoms. Dysuria, frequency, urgency, suprapubic pain and/or hematuria all indicate the presence of bladder infection (cystitis or lower UTI); fever or chills, flank pain, nausea and vomiting reflect kidney infection (pyelonephritis of upper UTI) which is considered an ascending lower UTI. In men, fever or chills, myalgia, dysuria, pelvic or perineal pain may reflect infection of the prostate (prostatitis).

Uropathogenic Escherichia coli (UPEC) is the most common etiological agent responsible for uncomplicated UTI. After E. coli, less common causative organisms include

Uncomplicated UTI 

other Enterobacteriaceae, Pseudomonas aeruginosa, group B streptococci, Klebsiella pneumoniae and enterococci.²Rijal A, Ghimire G, Gautam K, Barakoti A. J Nepal Health Res Counc. 2012 Jan;10(1):24-7.   Most community-acquired UTIs are due to infection by uropathogenic Escherichia coli (UPEC) that elicit an inflammatory response in the bladder during acute bacterial cystitis.

Pre-disposing factors

Lactobacilli, coagulase negative staphylococci and streptococci are found normally around the vaginal introitus, periurethral region and urethra. These microoragnsims form a barrier against pathogenic colonization. Any change in vaginal pH and alterations in vaginal mucosa plays a significant role in growth and development of pathological strains in UTI. Spermicidal and antimicrobial agents alter the normal flora and induce increased receptivity for uropathogens. Five times increased incidence of pyelonephritis is observed among diabetic patients when compared to non-diabetics and also female patients with diabetes mellitus are 3 times more likely to develop pyelonephritis compared to male patients with the condition.³Nicolle LE, Friesen D, Harding GK, Roos LL. Clin Infect Dis 1996; 22(6):1051-6.  

UTI in specific populations

Increased incidence of UTI has been observed in specific populations like in women, elderly people, children as well as catheterized patients.

Pediatric UTIs

Urinary tract infections remain the most common bacterial infection in childhood. Escherichia coli is responsible for over 80% of pediatric UTIs. Signs and symptoms vary greatly by age of the patient becoming more specific as the child grows older. Even in the absence of specific signs UTI should be included in the differential diagnosis of high grade fever. Depending on patient’s clinical symptoms and tolerance, therapy can be oral or parenteral as they have both been found equally efficacious.

Management of vesicoureteric reflux

Dysfunctional voiding syndromes and constipation should be considered in young children and adolescents with UTIs.

Dysfunctional voiding if unrecognized and not managed properly could lead to reflux nephropathy.

Vesicoureteric reflux (VUR) is initially managed with antibiotic prophylaxis. The prophylaxis is continued till 1 year of age in patients with VUR grades I and II, and till 5 years in those with higher grades of reflux or until it resolves. If needed, the common antimicrobials used are trimethoprim sulfamethoxazole, trimethoprim, nitrofurantoin, and first generation cephalosporins in a one nightly dose. In children less than two months of age, amoxicillin is generally used as prophylaxis.⁴Habib S. International Journal of Pediatrics. Volume 2012, Article ID 943653, 6 pages doi:10.1155/2012/943653.  

Surgical Treatment of VUR

VUR often undergoes spontaneous resolution. The time from first UTI to resolution of VUR is 6-7 years. Surgical treatment for vesicoureteric reflux is reserved for patients with high grade and unilateral reflux, recurrent UTIs despite antibiotic prophylaxis, and noncompliance with antibiotics persistence beyond 9 years of age. Endoscopic management involves subureteral or intraureteral injection of bulking agent with dextranomer/hyaluronic acid is suggested as first line of treatment.⁴Habib S. International Journal of Pediatrics. Volume 2012, Article ID 943653, 6 pages doi:10.1155/2012/943653.  

Nitrofurantoin in pediatric UTI

A study was conducted to characterize current national patterns of antibiotic resistance in outpatient pediatric urinary tract infection (UTI).⁵Edlin RS, Shapiro DJ, Hersh AL, Copp HL. J Urol. 2013 Jan 28.   Outpatient urinary isolates from children ® (TSN^®), a database with antibiotic susceptibility results and patient demographic data from 195 US hospitals was examined. Prevalence and antibiotic resistance patterns were determined for the six most common uropathogens: Escherichia coli, Proteus mirabilis, Klebsiella, Enterobacter, Pseudomonas aeruginosa, and Enterococcus.

E. Coli was the most prevalent pathogen with increased prevalence among females (83%) when compared to males (50%). Other common species were Enterococcus (17%), Proteus mirabilis (11%), and Klebsiella (10%). E.Coli demonstrated highest resistance to trimethoprim/ sulfamethoxazole (TMP/SMX) (24%) but lower for (<1%) for nitrofurantoin and cephalothin (15%) (Figure 1). This study concluded that Nitrofurantoin and first-generation cephalosporins are appropriate narrow-spectrum alternatives given their low resistance rates in pediatric UTIs.

In pediatric UTI management, flouroquinolones are usually not recommended because of concerns regarding induction of arthropathy.⁶Jonhnson JR. Flouroquinolones in urinary tract infections. In:Ronald AR, Low DE(eds) Fluoroquinolone antibiotics. Germany. Springer 2003 : 107-119.  

Nelson textbook of pediatrics, recommends Nitrofurantoin as the first line of treatment for the effective management of UTI in children.⁷Kliegman RM, Behrman RE, Jenson HB, Stanton BF. Nelson Textbook of Pediatrics, 19th edition.  

Recurrent urinary tract infections in women

Recurrent urinary tract infections (UTIs) are common in women and associated with considerable morbidity and health care use. The clinical features, diagnostic testing, and causative organisms are often similar to those of single cases of UTI, although there are additional treatment strategies and prevention measures to consider with recurrent UTIs. In symptomatic women, predictors of recurrent UTIs include symptoms following intercourse, signs or symptoms of pyelonephritis, and prompt resolution of symptoms with antibiotics. Nocturia and persistence of symptoms between UTI episodes are strong negative predictors for recurrent infection. Recurrent UTIs are common among women with dysfunctional voiding.⁸Kodner CM, Gupton EKT. Am Fam Physician. 2010 Sep 15;82(6):638-643.  

Patients with recurrent UTIs should be counseled about risk factors such as spermicide use, frequent sexual intercourse, and new sex partners, as well as about preventive measures.

Antimicrobial prophylaxis has proved effective in reducing the risk of recurrent UTIs in women with two episodes of infection in the previous year. Continuous prophylaxis for six to 12 months reduces the rate of UTIs during the prophylaxis period, with no difference between the six-month and 12-month treatment groups after cessation of prophylaxis.

Catheter- Associated Urinary Tract Infection (CAUTI)

Catheter-associated (CA) bacteriuria is the most common health care-associated infection worldwide and is a result of the widespread use of urinary catheterization, much of which is inappropriate, in hospitals and long term care facilities (LTCFs). CAUTI in patients with indwelling urethral, indwelling suprapubic, or intermittent catheterization is defined by the presence of symptoms or signs compatible with UTI with no other identified source of infection along with ≥10³ colony forming units (cfu)/mL of ≥1 bacterial species in a single catheter urine specimen or in a midstream voided urine specimen from a patient whose urethral, suprapubic, or condom catheter has been removed within the previous 48 hour.

Signs and symptoms compatible with CAUTI include new onset or worsening of fever, rigors, altered mental status, malaise, or lethargy with no other identified cause; flank pain; costovertebral angle tenderness; acute hematuria; pelvic discomfort; and in those whose catheters have been removed, dysuria, urgent or frequent urination, or suprapubic pain or tenderness.⁹Hooton TM, Bradley SF, Cardenas DD, et al. Urinary Catheter Guidelines CID 2010:50;625-663.  

Limiting unnecessary catheterization is the first step in the prevention of CAUTI. In men for whom a urinary catheter is indicated and who have minimal postvoid residual urine, condom catheterization should be considered as an alternative to short-term and long-term indwelling catheterization to reduce CA-bacteriuria in those who are not cognitively impaired. A closed catheter drainage system, with ports in the distal catheter for needle aspiration of urine, should be used to reduce CAUTI.⁹Hooton TM, Bradley SF, Cardenas DD, et al. Urinary Catheter Guidelines CID 2010:50;625-663.  

Antibiotic use may play a role in UTI prevention. Antibiotic prophylaxis is unnecessary for catheterization lasting fewer than 3 days. For catheterization limited to 2 weeks, either TMP-SMX or nitrofurantoin is effective. The cost:benefit ratio of prophylactic antibiotic treatment is maximized at about 2 weeks of catheterization; after that point, the emergence of resistant organisms is a virtual certainty. When prescribing antimicrobials for UTI, it is important to change the catheter because of the bacterial biofilm lining the old catheter.¹⁰Available on http://www.medscape.com/viewarticle/412692_3 Accessed on 19/4/13.  

In pregnant women

Urinary tract infections (UTIs) occur commonly during pregnancy. Many factors may contribute to the development of UTIs during pregnancy. One important factor is ureteral dilatation, thought to occur due to hormonal effects and mechanical compression from the growing uterus. Ureteral dilation can cause bacteria to spread from the bladder to the kidneys, increasing the risk of pyelonephritis.¹¹Hooton TM. UpToDate 2010.  

Asymptomatic bacteriuria during pregnancy has been associated with an increased risk of pre-term delivery and low birth weight. Pyelonephritis in pregnancy can have serious consequences such as maternal sepsis, pre-term labour and premature delivery and requires prompt and aggressive treatment.¹²Delzell JE, Lefevre ML. Am Fam Physician 2000;61:713-21.  

Antibiotic choice should cover common pathogens and can be changed if required after the organism is identified and sensitivities are determined. Nitrofurantoin 50 mg four times a day is a drug of choice in treating UTI I pregnant women but it should be avoided during 36+ weeks.

Nitrofurantoin in the treatment of UTI in pregnant women

Nitrofurantoin has been used extensively and is considered safe to use during pregnancy,¹³Australian Medicines Handbook. Adelaide: Australian Medicines Handbook Pty Ltd, 2004.   but not during delivery or when nearing term (i.e > 36 weeks). This is because of the possibility of haemolytic anaemia in the newborn, due to immature erythrocyte enzyme systems (glutathione instability).¹⁴Available at http://bpac.org.nz/magazine/2011/april/pregnant_uti. asp. Accessed on 18/4/13.  

Nitrofurantoin has been shown to be effective in treating asymptomatic bacteriuria, with one study finding a cure rate of 86% achieved with a seven day course.¹⁵Smaill FM, Vazquez JC. Cochrane Database Syst Rev 2007;2:CD000490.  ^,16Lumbiganon P, Villar J, et al. Obstet Gynecol 2009;113:339-45.   Nitrofurantoin attains therapeutic concentrations in the urine and is suitable for treating asymptomatic bacteriuria

and acute cystitis, however, it is not appropriate for treating pyelonephritis because it does not achieve adequate tissue penetration.¹⁷Macejko AM, Schaeffer AJ. Urol Clin North Am 2007;34(1):35-42.  

European guidelines are now moving towards nitrofurantoin or fosfomycin trometamol as first- and second-line agents with trimethoprim or cotrimoxazole advised only in areas where resistance rates for E. coli are less than 20%.¹⁸  

Prospects for new therapeutic strategies

As with other infection in the body, urinary tract infection is also managed by antibiotics. Until recently, broad spectrum antibiotics were the preferred drugs for treatment of UTI. But the trend until recently of increasing cases of Clostridium difficile diarrhea has led to a shift from broad to narrow spectrum antibiotics.¹⁸Beveridge LA, Davey PG, Phillips G. Clin Interv Aging. 2011; 6: 173-180.  

Also the increasing antimicrobial resistance among strains of extra intestinal pathogenic E. Coli challenges successful treatment of UTIs.

This increased antibiotic resistance poses a challenge in successful treatment of UTI for attending healthcare

specialist as well as patients. The increasing challenge of antimicrobial resistance is epitomized by the global increase in E. coli that possess extended-spectrum beta-lactamases (ESBLs), a suite of enzymes that confer resistance to cephalosporins and monobactams. This poses a problem in selection of suitable antibiotic. Some studies have analyzed the efficacy of different drugs in UTI management and prevention and some of them have analyzed antibacterial resistance for different drugs.

Given the increased problems with resistance and health care associated infection, the use of narrow spectrum agents where possible is now strongly encouraged. The use of narrow spectrum agents highlights the necessity for accurate diagnosis and the importance of obtaining cultures in the elderly prior to commencing antibiotics.¹⁸Beveridge LA, Davey PG, Phillips G. Clin Interv Aging. 2011; 6: 173-180.  

Renuart et al conducted a study to evaluate the antimicrobial susceptibility in UTI patients and demonstrated that increased resistance to amoxicillin, co-trimaxozole, amoxicillin- clavulanate and ciprofloxacin when compared to nitrofurantoin (Figure 2).¹Renuart AJ, Goldfarb DM, et al. PLoS ONE 2013;8(3): e57776.   This study supports the use of Nitrofurantoin for simple cystitis.

Conclusion

Urinary tract infections (UTIs) remain the most common bacterial infection in childhood and in women. E. Coli is responsible for more than 80% of UTIs. Typical symptoms of a lower UTI include frequency and dysuria without fever, chills or back pain whereas upper UTI usually presents with symptoms of pyelonephritis such as loin pain, flank tenderness, fever or other signs of a systemic inflammatory response. There are several approaches to the treatment and management of UTIs. Various natural therapies have been tried in UTI prevention, among which cranberry juice has shown some good results. Among the antibiotics used in UTI management, nitrofurantoin has shown efficacy and more importantly reduced bacterial resistance.

References

1. Renuart AJ, Goldfarb DM, et al. PLoS ONE 2013;8(3): e57776.
2. Rijal A, Ghimire G, Gautam K, Barakoti A. J Nepal Health Res Counc. 2012 Jan;10(1):24-7.
3. Nicolle LE, Friesen D, Harding GK, Roos LL. Clin Infect Dis 1996; 22(6):1051-6.
4. Habib S. International Journal of Pediatrics. Volume 2012, Article ID 943653, 6 pages doi:10.1155/2012/943653.
5. Edlin RS, Shapiro DJ, Hersh AL, Copp HL. J Urol. 2013 Jan 28.
6. Jonhnson JR. Flouroquinolones in urinary tract infections. In:Ronald AR, Low DE(eds) Fluoroquinolone antibiotics. Germany. Springer 2003 : 107-119.
7. Kliegman RM, Behrman RE, Jenson HB, Stanton BF. Nelson Textbook of Pediatrics, 19th edition.
8. Kodner CM, Gupton EKT. Am Fam Physician. 2010 Sep 15;82(6):638-643.
9. Hooton TM, Bradley SF, Cardenas DD, et al. Urinary Catheter Guidelines CID 2010:50;625-663.
10. Available on http://www.medscape.com/viewarticle/412692_3 Accessed on 19/4/13.
11. Hooton TM. UpToDate 2010.
12. Delzell JE, Lefevre ML. Am Fam Physician 2000;61:713-21.
13. Australian Medicines Handbook. Adelaide: Australian Medicines Handbook Pty Ltd, 2004.
14. Available at http://bpac.org.nz/magazine/2011/april/pregnant_uti. asp. Accessed on 18/4/13.
15. Smaill FM, Vazquez JC. Cochrane Database Syst Rev 2007;2:CD000490.
16. Lumbiganon P, Villar J, et al. Obstet Gynecol 2009;113:339-45.
17. Macejko AM, Schaeffer AJ. Urol Clin North Am 2007;34(1):35-42.
18. Beveridge LA, Davey PG, Phillips G. Clin Interv Aging. 2011; 6: 173-180.
19. Assefa A, Asrat D, Woldeamanuel Y, et al. Ethiop Med J. 2008 Jul;46(3):227-35.
20. Mwaka AD, Mayanja-Kizza H, Kigonya E, et al. Afr Health Sci. 2011 Jun;11(2):182-9.
21. Mendoza-Valdes A, Rosete A, Rios Bueno E, Med Klin (Munich). 2010 Oct;105(10):698-704.
22. Ruxer J, Możż M, Siejka A, et al. Diabetologia Doświadczalna i Kliniczna 2006;6(5): 277-282.
23. Tasbakan MI, Pullukcu H, Sipahi OR, et al. International Journal of Antimicrobial Agents 40 (2012) 554-556.
24. McKinnell JA, Stollenwerk NS, Jung CW, et al. Mayo Clin Proc. 2011 Jun;86(6):480-8.