Current Recommendations on the Management of Urinary Tract Infections

Introduction

Classification of Urinary Tract Infections: An Overview

Urinary tract infections can be categorized on the basis of different parameters, as depicted in figure 1. According to the anatomic location, they can be broadly classified into upper and lower (box 1).²Definition and classification of urinary tract infection. Available at: http://www.guiasalud.es/egpc/traduccion/ingles/ITU/completa/documentos/apartado04/definicion_clasificacion.pdf. Accessed on: 5.11.2015. ⁷Jancel T, Dudas V. Management of uncomplicated urinary tract infections. West J Med. 2002 Jan;176(1):51-55. The infections of kidney and ureter are known as infections of upper urinary tract whereas the infections of bladder and urethra are suggestive of lower tract infections. These infections are named according to the involvement of site. The infections of urethra and ureter are referred to as urethritis and ureteritis, respectively while that of bladder and kidney are known as cystitis and pyelonephritis. Moreover, they can also be classified as primary or recurrent, depending on the nature of occurrence. In addition, another approach to classify these infections is related to the factor that triggers the infection. On the basis of this, they are categorized into uncomplicated and complicated.³Najar MS, Saldanha CL, Banday KA. Approach to urinary tract infections.Indian J Nephrol. 2009 Oct;19(4):129-139. ⁹Vasudevan R. Urinary Tract Infection: An Overview of the Infection and the Associated Risk Factors. J Microbiol Exp. 2014 May 15;1(2):00008. ¹⁰Nicolle LE; AMMI Canada Guidelines Committee*. Complicated urinary tract infection in adults. Can J Infect Dis Med Microbiol. 2005 Nov;16(6):349-60. ¹¹Powers RD. New directions in the diagnosis and therapy of urinary tract infections. Am J Obstet Gynecol. 1991 May;164(5 Pt 2):1387-9. An uncomplicated infection is an episode of cysto-urethritis following bacterial colonization of the ureteral and bladder mucosae. It is regarded as uncomplicated because sequelae are less likely to occur.³Najar MS, Saldanha CL, Banday KA. Approach to urinary tract infections.Indian J Nephrol. 2009 Oct;19(4):129-139. These infections usually develop in otherwise healthy patients who have a history of lower tract symptoms of short duration.¹¹Powers RD. New directions in the diagnosis and therapy of urinary tract infections. Am J Obstet Gynecol. 1991 May;164(5 Pt 2):1387-9. On the contrary, a complicated urinary tract infection occurs in a patient with a structural or functional abnormality of the genitourinary tract.¹⁰Nicolle LE; AMMI Canada Guidelines Committee*. Complicated urinary tract infection in adults. Can J Infect Dis Med Microbiol. 2005 Nov;16(6):349-60. Complicated infections include those involving the parenchyma (pyelonephritis or prostatitis) and often occur in cases of obstructive uropathy or post-instrumentation. The presence of obstruction, stones or high-pressure vesico-ureteric reflux, perinephric abscess, septicemia or a combination of these predispose to renal damage. Episodes may be refractory to therapy, and may often result in relapses and significant consequences such as sepsis, metastatic abscess and rarely acute renal failure.³Najar MS, Saldanha CL, Banday KA. Approach to urinary tract infections.Indian J Nephrol. 2009 Oct;19(4):129-139. ⁹Vasudevan R. Urinary Tract Infection: An Overview of the Infection and the Associated Risk Factors. J Microbiol Exp. 2014 May 15;1(2):00008. ¹⁰Nicolle LE; AMMI Canada Guidelines Committee*. Complicated urinary tract infection in adults. Can J Infect Dis Med Microbiol. 2005 Nov;16(6):349-60. ¹¹Powers RD. New directions in the diagnosis and therapy of urinary tract infections. Am J Obstet Gynecol. 1991 May;164(5 Pt 2):1387-9.

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Burden of Urinary Tract Infections

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Etiopathogenesis of Urinary Tract Infections: At a Glance

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Although the pathogenesis of urinary tract infections is not well established, several studies have suggested specific interactions between the host and microbes that are causally related to bacteriuria. As discussed previously, the microbes play a vital role in the development of urinary tract infections. In addition, host factors including age, diabetes, long term hospitalization and the kind of medical devices used among the patients like the catheters must also be taken into consideration, as they also contribute significantly. Bacteria in the enteric flora periodically gain access to the genitourinary tract. In women, close proximity of anus to peri-urethra enhances the risk of development. Bacterial colonization of periurethra often precedes the onset of bladder bacteriuria. After periurethral colonization, uropathogens enter the bladder via the urethra, kidney via ureters and prostate via the ejaculatory ducts. The urethra and uretero-vesicle junction serve as the mechanical barriers that prevent ascension. In the bladder, the organisms multiply, colonize the bladder mucosa and invade mucosal surface. Bladder infection sets the stage for subsequent migration to the kidneys.³Najar MS, Saldanha CL, Banday KA. Approach to urinary tract infections.Indian J Nephrol. 2009 Oct;19(4):129-139. ⁹Vasudevan R. Urinary Tract Infection: An Overview of the Infection and the Associated Risk Factors. J Microbiol Exp. 2014 May 15;1(2):00008. ²¹Moore KN, Day RA, Albers M. Pathogenesis of urinary tract infections: a review. J Clin Nurs. 2002 Sep;11(5):568-74. Thus, early identification of the disease is of utmost importance for timely and effective intervention. The following section sheds light on the approach to diagnosis of these infections.

Diagnostic Approach to Urinary Tract Infections

As these infections are widely prevalent, a high level of diagnostic accuracy is essential. Recording the history carefully is imperative to formulate an appropriate diagnosis. The clinical diagnosis of an infection of the urinary tract is partly based on the medical history. Various potential factors that may increase or decrease the likeliness of an infection are mentioned in table 1. In addition, specific laboratory investigations and imaging techniques (if required) also help in diagnosing the condition. Detection of the underlying pathogen is vital for the diagnosis of a urinary tract infection. In context to this, urine culture remains the gold standard. It also enables the estimation of the level of bacteriuria. Although the precise values of bacteriuria, suggestive of a urinary tract infection are not well established, many laboratories define 10⁵Kalra OP, Raizada A. Approach to a Patient with Urosepsis. J Glob Infect Dis.2009 Jan-Jun;1(1):57-63. colony forming units (cfu)/mL urine as the threshold.²²Schmiemann G, Kniehl E, Gebhardt K, Matejczyk MM, Hummers-Pradier E.The diagnosis of urinary tract infection: a systematic review. Dtsch Arztebl Int.2010 May;107(21):361-7.

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It helps in diagnosing an infection from simple cystitis to complicated pyelonephritis with sepsis with absolute certainty. The major indications for urine cultures include patients displaying signs and symptoms of urinary tract infections, follow-up of recently treated infections of urinary tract, removal of indwelling urinary catheter, screening for asymptomatic bacteriuria during pregnancy; and patients with obstructive uropathy and stasis before instrumentation.³Najar MS, Saldanha CL, Banday KA. Approach to urinary tract infections.Indian J Nephrol. 2009 Oct;19(4):129-139. Moreover, urine microscopy and immersion culture media may be used to assess the bacterial count. Urine dip sticks are one of the most frequently used diagnostic tools if the clinical evidence is suggestive of an infection. Multistix are often used and help in identifying nitrite (a metabolic product of typical pathogens of the urinary tract), leukocyte esterase, protein and blood (as a marker of inflammation). The detection of nitrite increases the probability of a urinary tract infection, with a likelihood ratio [LR] of 2.6 to 10.6. However, the sensitivity is relatively low. On the contrary, the detection of leukocyte esterase increases the probability to a lesser degree (LR 1.0 to 2.6). The detection of blood is highly sensitive, but the specificity is low. As far as the value of protein is concerned in confirming the infection, inconsistent results have been obtained.²²Schmiemann G, Kniehl E, Gebhardt K, Matejczyk MM, Hummers-Pradier E.The diagnosis of urinary tract infection: a systematic review. Dtsch Arztebl Int.2010 May;107(21):361-7. In addition, a simple Gram-stained smear can enhance the specificity of the test as morphology and stain characteristics help in identifying the pathogen that is likely to be involved.³Najar MS, Saldanha CL, Banday KA. Approach to urinary tract infections.Indian J Nephrol. 2009 Oct;19(4):129-139.

Furthermore, clinical algorithms serve as valuable tools in enhancing the diagnostic precision. A urinary tract infection with a low bacterial count is most reliably detected with the algorithm used by McIsaac that takes into account burning sensation or discomfort while passing urine, detection of leukocytes, any detection of nitrite. The diagnosis is established if at least two test criteria are present (sensitivity 80%, specificity 54%). However, the specificity of this algorithm is low, thus it may be associated with a high rate of false positives. Therefore, the following point system may be employed as an alternative:²²Schmiemann G, Kniehl E, Gebhardt K, Matejczyk MM, Hummers-Pradier E.The diagnosis of urinary tract infection: a systematic review. Dtsch Arztebl Int.2010 May;107(21):361-7. ²³McIsaac WJ, Moineddin R, Ross S. Validation of a decision aid to assist physicians in reducing unnecessary antibiotic drug use for acute cystitis. Arch Intern Med. 2007 Nov 12;167(20):2201-6. ²⁴Little P, Turner S, Rumsby K, Warner G, Moore M, Lowes JA, Smith H, Hawke C,Turner D, Leydon GM, Arscott A, Mullee M. Dipsticks and diagnostic algorithms in urinary tract infection: development and validation, randomised trial, economic analysis, observational cohort and qualitative study. Health Technol Assess. 2009 Mar;13(19):iii-iv,ix-xi,1-73. It has been observed that it gives sensitivity of 76% and specificity of 74%.²²Schmiemann G, Kniehl E, Gebhardt K, Matejczyk MM, Hummers-Pradier E.The diagnosis of urinary tract infection: a systematic review. Dtsch Arztebl Int.2010 May;107(21):361-7. ²³McIsaac WJ, Moineddin R, Ross S. Validation of a decision aid to assist physicians in reducing unnecessary antibiotic drug use for acute cystitis. Arch Intern Med. 2007 Nov 12;167(20):2201-6. ²⁴Little P, Turner S, Rumsby K, Warner G, Moore M, Lowes JA, Smith H, Hawke C,Turner D, Leydon GM, Arscott A, Mullee M. Dipsticks and diagnostic algorithms in urinary tract infection: development and validation, randomised trial, economic analysis, observational cohort and qualitative study. Health Technol Assess. 2009 Mar;13(19):iii-iv,ix-xi,1-73.

Nitrite positive = 2
Leukocytes positive = 1.5
Hematuria = 1
Moderately severe dysuria = 1
Moderately severe nocturia = 0.5

Imaging Techniques

Imaging should usually be done 3-6 weeks after cure of acute infection in order to determine the underlying cause of infection or renal damage or that may influence management. It is rarely performed in the acute phase, especially where there is severe loin pain, to identify possible sepsis (pyonephrosis or abscess) or to differentiate acute pyelonephritis from ureteric colic. In patients with acute infection such as severe loin pain or whose infection does not settle on treatment, ultrasound and plain X-ray are advised to exclude pyonephrosis, intrarenal or perinephric sepsis or calculi. However, if no abnormality could be seen on ultrasound, computed tomography should be performed. If ureteric colic is suspected, intravenous urography or spiral computed tomography must be done. In patients with unexplained impairment of bladder emptying, urodynamic studies may be required. Table 2 gives an overview of the most common imaging modalities that may be employed in the diagnosis of urinary tract infections. In women, there is no specific indication for imaging following a single or infrequent infection. However, recurrent attacks more often than 2 per 6 months should be investigated by ultrasound and plain kidney-ureter-bladder (KUB). On the other hand, as urinary tract infections are less likely to occur in men than in women, imaging is indicated after the first reported bacteriuria to exclude predisposing factors, particularly impaired bladder emptying. With regard to this, ultrasound and plain film appear to be relevant options.³Najar MS, Saldanha CL, Banday KA. Approach to urinary tract infections.Indian J Nephrol. 2009 Oct;19(4):129-139. These diagnostic aids may help in diagnosing the condition accurately and in turn facilitate selection of an optimal treatment option.

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Managing Urinary Tract Infections in the Era of Antimicrobial Resistance: Focus on Nitrofurantoin and Potassium Citrate

Contribution of Nitrofurantoin in Combating Urinary Tract Infections

This nitrofuran derivative has a unique mechanism of action.³⁷Stock I. Nitrofurantoin–clinical relevance in uncomplicated urinary tract infections. Med Monatsschr Pharm. 2014 Jul;37(7):242-8. ³⁸Cunha BA, Schoch PE, Hage JR. Nitrofurantoin: Preferred Empiric Therapy for Community-Acquired Lower Urinary Tract Infections. Mayo Clin Proc. 2011 Dec;86(12):1243-1244. It mainly acts by inhibiting various bacterial enzymes that participate in bacterial carbohydrate metabolism at three different locations in the Krebs cycle. In addition, it also interferes with cell wall synthesis. The nitrogroup coupled onto the heterocyclic furan ring represents the specific active site of the drug that has to be activated by microbial nitroreductases to form bactericidal end-products which bind to deoxyribonucleic acid (DNA) and protein with consequent inhibition of nucleic acid synthesis. To summarize, it acts by undergoing reduction by bacterial nitroreductases to produce toxic derivatives that attach to ribosomal proteins and cause defective transcription and translation in bacteria (figure 5).³⁹Xavier BB, Vervoort J, Stewardson A, Adriaenssens N, Coenen S, Harbarth S, Goossens H, Malhotra-Kumar S. Complete Genome Sequences of Nitrofurantoin-Sensitive and -Resistant Escherichia coli ST540 and ST2747 Strains. Genome Announc. 2014 Apr 10;2(2).pii:e00239-14. ⁴⁰Breeze AS, Obaseiki-Ebor EE. Mutations to Nitrofurantoin and Nitrofurazone Resistance in Escherichia coli K12. Journal of General Microbiology.1983;129:99-103. Furthermore, the pharmacokinetic properties such as pH dependent resorption at normal urinary pH (approximately 5.5 pH); excretion primarily into the lower urinary tract, i.e., bladder urine, renders it a beneficial agent in the treatment of urinary tract infections.³⁸Cunha BA, Schoch PE, Hage JR. Nitrofurantoin: Preferred Empiric Therapy for Community-Acquired Lower Urinary Tract Infections. Mayo Clin Proc. 2011 Dec;86(12):1243-1244. In addition, this drug displays advantages in terms of site specificity and attainment of high urinary levels. It is rarely associated with any adverse events, thus presenting an excellent safety profile.41 Another property of this drug that makes it a suitable agent in the management of urinary tract infections is minimal resistance to pathogens.³⁷Stock I. Nitrofurantoin–clinical relevance in uncomplicated urinary tract infections. Med Monatsschr Pharm. 2014 Jul;37(7):242-8. ⁴¹Cunha BA. Nitrofurantoin–current concepts. Urology. 1988 Jul;32(1):67-71. ⁴²McOsker CC, Fitzpatrick PM. Nitrofurantoin: mechanism of action and implications for resistance development in common uropathogens. J Antimicrob Chemother. 1994 May;33Suppl A:23-30. ⁴³Sahm DF, Thornsberry C, Mayeld DC, Jones ME, Karlowsky JA. Multidrugresistant urinary tract isolates of Escherichia coli: prevalence and patient demographics in the United States in 2000. Antimicrob Agents Chemother.2001May;45(5):1402-6.

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Evidence-Based Efficacy of Nitrofurantoin in Patients with Urinary Tract Infections

Owing to its clinical efficacy, minimal resistance to uropathogens, and minimal propensity for collateral damage, it has been recommended by several international guidelines (Infectious Diseases Society of America, European Society for Microbiology and Infectious Diseases, European Association of Urology, and Scottish Intercollegiate Guidelines) as a first line drug for the treatment of uncomplicated urinary tract infections.³⁷Stock I. Nitrofurantoin–clinical relevance in uncomplicated urinary tract infections. Med Monatsschr Pharm. 2014 Jul;37(7):242-8. ⁴³Sahm DF, Thornsberry C, Mayeld DC, Jones ME, Karlowsky JA. Multidrugresistant urinary tract isolates of Escherichia coli: prevalence and patient demographics in the United States in 2000. Antimicrob Agents Chemother.2001May;45(5):1402-6. ⁴⁴Grabe M, Bartoletti R, Johansen TEB, et al. Guidelines on Urological Infections.Available at: http://uroweb.org/wp-content/uploads/19-Urologicalinfections_LR2.pdf [Accessed on 15/2/2016]. ⁴⁵Scottish Intercollegiate Guidelines Network (SIGN). Management of suspected bacterial urinary tract infection in adults. Edinburgh: SIGN; 2012.(SIGN publication no. 88). [July 2012]. Available at: http://www.sign.ac.uk/pdf/sign88.pdf [Accessed on 15/2/2016] ⁴⁶International 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 for Microbiology and Infectious Diseases. Clinical Infectious Diseases 2011;52(5):e103-e120. The duration of this therapy as mentioned in the book, Clinical Companion in Nephrology is 3 days for women and 7 days for men.⁴⁷Clinical Companion in Nephrology. Mark Findlay, Christopher Isles. Springer,May 2015. Available at: https://books.google.com.sg/books?id=0K0lCQAAQBAJ&pg=PA248&dq=duration+of+nitrofurantoin+treatment&hl=en& sa=X&redir_esc=y#v=onepage&q=duration%20of%20nitrofurantoin%20treatment&f=false. Accessed on: 23.3.2016.

Data available from several studies provides evidence in favor of its efficacy in the management of urinary tract infections. In a study by Kumar and coworkers,²⁹Kumar Y, Sood S, Sharma A, Mani KR. Antibiogram and characterization of resistance markers among Escherichia coli Isolates from urinary tract infections. J Infect Dev Ctries. 2013 Jul 15;7(7):5130-9. nitrofurantoin displayed sensitivity to about 90.9% of the E. coli isolates from patients with urinary tract infections (figure 6).²⁹Kumar Y, Sood S, Sharma A, Mani KR. Antibiogram and characterization of resistance markers among Escherichia coli Isolates from urinary tract infections. J Infect Dev Ctries. 2013 Jul 15;7(7):5130-9. A comparative study assessed the susceptibility of antimicrobial resistant urinary E. coli isolates to fluoroquinolones and nitrofurantoin for a duration of 3 years. The results showed that 9.5% were resistant to ciprofloxacin while only 1.9% were resistant to nitrofurantoin.⁴⁷Clinical Companion in Nephrology. Mark Findlay, Christopher Isles. Springer,May 2015. Available at: https://books.google.com.sg/books?id=0K0lCQAAQBAJ&pg=PA248&dq=duration+of+nitrofurantoin+treatment&hl=en& sa=X&redir_esc=y#v=onepage&q=duration%20of%20nitrofurantoin%20treatment&f=false. Accessed on: 23.3.2016. The researchers also analyzed the antimicrobial and clinical efficacy of nitrofurantoin in the treatment of acute lower urinary tract infections in certain parts of the world where resistance rates of uropathogens to trimethoprim/sulfamethoxazole are high.48 In this openlabel, single-arm study, adult patients with positive urine culture were enrolled. The primary endpoint analysis revealed a microbial eradication rate of 92.3% on administration of nitrofurantoin (figure 7). At 35 to 42 days, the eradication rate was 83.3%. Moreover, urinary nitrofurantoin concentrations were mostly above minimum inhibitory concentrations of the isolated uropathogens. The drug was generally well tolerated. These findings indicate good antimicrobial and clinical efficacy of nitrofurantoin in the treatment of urinary tract infections as well as acceptable tolerability in adults.⁴⁸Karlowsky JA, Thornsberry C, Jones ME, Sahm DF. Susceptibility of Antimicrobial-Resistant Urinary Escherichia coli Isolates to Fluoroquinolones and Nitrofurantoin. Clin Infect Dis. 2003;36(2):183-187. Another study by Olorunmola and coworkers⁴⁹Mendoza-Valdes A, Rosete A, Bueno ER, Frentzel A, Trapp S, Kirch W, Mueller EA. Antimicrobial and clinical efficacy of nitrofurantoin in the treatment of acute lower urinary tract infections in adults. Med Klin (Munich). 2010 Oct;105(10):698-704. also showed high sensitivity of nitrofurantoin in comparison with other antibiotics to E. coli isolates from cases of

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UTI. The findings revealed widespread resistance of the isolates to all the antibiotics (51.1% – 94.3%), except nitrofurantoin which showed a low resistance rate of 7.3% (figure 8).⁵⁰Olorunmola FO, Kolawole DO, Lamikanra A. Antibiotic Resistance and Virulence Properties in Escherichia Coli Strains from Cases of Urinary Tract Infections. Afr J Infect Dis. 2013;7(1):1-7. Similar outcomes have also been reported from studies conducted in Indian patients with urinary tract infections.¹⁷Sood S, Gupta R. Antibiotic resistance pattern of community acquired uropathogens at a tertiary care hospital in Jaipur, Rajasthan. Indian J Community Med. 2012;37(1):39-44. The investigators of one such study demonstrated that E. coli was the most frequently isolated microbe accounting for 61.84% of the total isolates. Moreover, majority of E. coli strains were resistant to various antibiotics such as ampicillin (>80%), amoxiclav (>80%), co-trimoxazole (>67%), nalidixic acid (>95%), norfloxacin (>77%), and ciprofloxacin (>74%). However, nitrofurantoin was reported as the drug with least resistance (>5-6%) to E. coli throughout the study duration of 30 months.¹⁷Sood S, Gupta R. Antibiotic resistance pattern of community acquired uropathogens at a tertiary care hospital in Jaipur, Rajasthan. Indian J Community Med. 2012;37(1):39-44. Another study by Dash and colleagues¹⁹Dash M, Padhi S, Mohanty I, Panda P, Parida B. Antimicrobial resistance in pathogens causing urinary tract infections in a rural community of Odisha, India. J Family Community Med. 2013 Jan;20(1):20-6. reported nitrofurantoin to be one of the most active antimicrobial drugs with low resistance to uropathogens in Indian patients with urinary tract infections.¹⁹Dash M, Padhi S, Mohanty I, Panda P, Parida B. Antimicrobial resistance in pathogens causing urinary tract infections in a rural community of Odisha, India. J Family Community Med. 2013 Jan;20(1):20-6. Thus, it can be stated that while E. coli remains the most common causative pathogen in infections of urinary tract, nitrofurantoin continues to be the most effective drug for the management of the same.⁵¹Khatri B, Basnyat S, Karki A, et al. Etiology and antimicrobial susceptibility pattern of bacterial pathogens from urinary tract infection. Nepal Med Coll J.2012 Jun;14(2):129-32. Besides, the holistic management of UTI may also comprise drugs for relieving disturbing symptoms.

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Alleviating the Symptom of Burning Micturition: Role of Potassium Citrate

Individuals, especially women, who seek medical care for their acute symptoms of dysuria, such as burning micturition, stinging, or itching are usually diagnosed with an acute uncomplicated lower UTI.⁵²S Peltz, S Hashmi. Home remedy for dysuria. Br J Gen Pract. 1991 Feb;41(343):82. ⁵³Zalmanovici Trestioreanu A, Green H, Paul M, Yaphe J, Leibovici L. Cochrane Database of Systematic Reviews 2010, Issue 10. Art. No.: CD007182. Available at: https://grupoinfeccsomamfyc.files.wordpress.com/2010/10/itucochrane_2010.pdf. Accessed on: 9.12.15. Amongst these manifestations, burning micturition may be the most common distressing feature. This can be attested by a study conducted by Shaifali and coworkers, which enrolled 139 females, aged ≥15 years, who were clinically examined for symptoms of UTI. The outcomes of the study revealed that burning micturition (73.4%) was the most prevalent trait reported by the participants, followed by frequency (43.9%), urgency (20.9%), painful voiding (20.1%), difficulty (5.0%), and nocturnal incontinence (1.4%).⁵⁴Shaifali I, Gupta U, Mahmood SE, Ahmed J. Antibiotic Susceptibility Patterns of Urinary Pathogens in Female Outpatients. N Am J Med Sci. 2012;4(4):163-169. These bothersome experiences may draw attention towards the goal of subsidence of these symptoms first. Therefore, such affected patients can be offered a choice of urinary alkalinizers prior to or concomitantly with an appropriate antibiotic therapy so as to provide symptomatic relief.³⁵Scottish Intercollegiate Guidelines Network (SIGN) Management of suspected bacterial urinary tract infection in adults. Edinburgh: SIGN; 2012. (SIGN publication no. 88). [July 2012]. Available at: http://www.sign.ac.uk.Accessed on: 5.11.2015. ⁵⁵Mifsud I. Treatment of lower urinary tract infections in an era of increased antimicrobial resistance. Journal of the Malta College of Pharmacy Practice.2013;19:8-11.

In light of the above requirement, potassium citrate demonstrates superior efficacy in alkalizing urine.⁵⁶Sakhaee K, Nicar M, Hill K, Pak CY. Contrasting effects of potassium citrate and sodium citrate therapies on urinary chemistries and crystallization of stoneforming salts. Kidney International. 1983;24:348-352. This citrate preparation provides an alkali load and increases the urinary citrate, thereby maintaining a urinary pH of 6.0-6.5.⁵⁷Zuckerman JM, Assimos DG. Hypocitraturia: Pathophysiology and Medical Management. Rev Urol. 2009;11(3):134-144. ⁵⁸Whitmore KE. Complementary and Alternative Therapies as Treatment Approaches for Interstitial Cystitis. Rev Urol. 2002;4(Suppl 1):S28-S35. This process makes the urine less acidic, which may serve to improve the condition of painful and burning micturition in patients with UTIs.⁵⁵Mifsud I. Treatment of lower urinary tract infections in an era of increased antimicrobial resistance. Journal of the Malta College of Pharmacy Practice.2013;19:8-11. ⁵⁹McNally MA, Pyzik PL, Rubenstein JE, Hamdy RF, Kossoff EH. Empiric use of potassium citrate reduces kidney-stone incidence with the ketogenic diet.Pediatrics. 2009;124(2):e300-4. Besides alleviating symptoms, achievement of alkaline pH may also augment the natural defense mechanisms, including enhancement of phagocytosis, thereby destroying the infecting organisms, such as E. coli and S. saprophyticus.⁶⁰Gargan RA, Hamilton-miller JMT, Brumfitt W. Effect of pH and osmolality on in vitro phagocytosis and killing by neutrophils in urine. Infection and Immunity.1993;61(1):p.8-12. Moreover, it may also assist in preventing later onset of UTI. Corroborating to this fact was a study performed by Lopez and colleagues, which illustrated that children experiencing ≥ 2 episodes of UTI with a normal urinary tract and hypercalciuria, showed significant improvement with absence of further episodes of UTI on treatment with potassium citrate.⁶¹Lopez MM, Castillo LA, Chavez JB, Ramones C. Hypercalciuria and recurrent urinary tract infection in Venezuelan children. Pediatr Nephrol.1999;13(5):433-7. The absorbed citrate ions possess another beneficial property. These induce negative charge, which may increase the susceptibility of bacterial strains to certain antibiotics.⁶²Dong PV, Ha CH, Binh LT, Kasbohm J. Chemical synthesis and antibacterial activity of novel-shaped silver nanoparticles. International Nano Letters.2012;2:1-9. ⁶³Guha A, Choudhury A, Unni BG, Roy MK. Effect of outer-membrane permeabilizers on the activity of antibiotics and plant extracts against Pseudomonas aeruginosa. Folia Microbiol (Praha). 2002;47(4):379-84.

While being an effective urinary alkalinizer, potassium citrate displays an acceptable tolerability profile as well.⁵⁷Zuckerman JM, Assimos DG. Hypocitraturia: Pathophysiology and Medical Management. Rev Urol. 2009;11(3):134-144. ⁵⁸Whitmore KE. Complementary and Alternative Therapies as Treatment Approaches for Interstitial Cystitis. Rev Urol. 2002;4(Suppl 1):S28-S35. It neither neutralizes the gastric juice nor alters the digestion.⁶⁴Sweetman S. 64. Martindale: The Complete Drug Reference. Edition 37;London:pharmaceutical press; 2011. Other advantages of potassium citrate include high palatability, pleasant taste, and tolerable even on prolonged use, which make it suitable to be considered as a first line urine alkalizing agent.⁵⁶Sakhaee K, Nicar M, Hill K, Pak CY. Contrasting effects of potassium citrate and sodium citrate therapies on urinary chemistries and crystallization of stoneforming salts. Kidney International. 1983;24:348-352. The effect of one tablet of potassium citrate lasts for around 12 hours. It has been suggested that multiple doses of this drug can be administered for up to 3 days.⁶⁵Drugs. Com. Available at: http://www.drugs.com/mmx/potassium-citrateand-sodium-citrate.html. Accessed on: 23.3.2016 Furthermore, it is preferred over sodiumcontaining salts, such as sodium bicarbonate or sodium citrate, as the latter may result in excessive sodium load and thus has to be carefully used in patients with hypertension, heart failure, edema, renal impairment, eclampsia, or hyperaldosteronism.⁵⁶Sakhaee K, Nicar M, Hill K, Pak CY. Contrasting effects of potassium citrate and sodium citrate therapies on urinary chemistries and crystallization of stoneforming salts. Kidney International. 1983;24:348-352. ⁶⁴Sweetman S. 64. Martindale: The Complete Drug Reference. Edition 37;London:pharmaceutical press; 2011. Overall, symptomatic improvement constitutes a significant factor for the affected individuals to cope with UTI,⁶⁶Bleidorn J, Gagyor I, Kochen MM, Wegscheider K, Hummers-Pradier E.Symptomatic treatment (ibuprofen) or antibiotics (ciprofloxacin) for uncomplicated urinary tract infection?–results of a randomized controlled pilot trial. BMC Med. 2010 May 26;8:30. wherein the role of potassium citrate is well-identified. Use of nitrofurantoin and potassium citrate has been recommended by some textbooks like Campbell-Walsh Urology and Nelson Textbook of Pediatrics, as summarized in box 2.⁶⁷Campbell-Walsh Urology Eleventh Edition Review. W. Scott McDougal, Alan J. Wein, Louis R. Kavoussi, Alan W. Partin, Craig A. Peters. Elsevier Health Sciences, Nov 2015. Available at: https://books.google.com.sg/books?id=1B 3mCgAAQBAJ&dq=Campbell+Walsh&source=gbs_navlinks_s. Accessed on: 17.3.2015. ⁶⁸Nelson Textbook of Pediatrics, Volumes 1-2. Robert M. Kliegman, Bonita F.Stanton, Joseph St. Geme, Nina Felice Schor, Richard E. Behrman. Elsevier Health Sciences, Apr 2015. Available at: https://books.google.com.sg/books ?id=mseNCgAAQBAJ&pg=PA12&dq=Nelson+Textbook+of+Paediatrics+201 5&hl=en&sa=X&redir_esc=y#v=onepage&q=potassium%20citrate&f=false.Accessed on: 17.3.2016.

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Conclusion

Urinary tract infections are one of the widely encountered infections and are considered a major reason for which the patients seek medical care. These infections can be categorized into different types based on various parameters. Depending on the anatomic location as upper and lower, according to the nature of occurrence as primary or recurrent, and based on the factor that triggers the infection as uncomplicated and complicated. The etiology of these infections is reported to be polymicrobial in nature. Although a wide range of bacterial organisms are implicated in their development, E. coli strains are responsible for up to 90% of the infections. This necessitates the need for implementation of an appropriate therapeutic strategy. In the light of increasing resistance to antibiotics used for the treatment, nitrofurantoin is considered as a promising drug. It has been recommended as the first line therapy for the management of urinary tract infections by the IDSA guidelines. A wealth of data suggests its clinical efficacy as it displays minimal resistance to the pathogens, especially E. coli. Furthermore, treatment of distressing symptoms, such as burning micturition, stinging, or itching, is also vital in this patient population. In context to this, potassium citrate therapy has garnered considerable attention. It alkalinizes urine pH and thereby relieves symptoms of dysuria.

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