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Bush Beats 2018 › Bush Beats Vol-4, No-1, 2018

Recurrent Urinary Tract Infections: Management Strategies

Overview

Urinary tract infection (UTI) is known as an inflammatory response to colonization of urinary tract by microbial pathogens; most commonly bacteria.1Parida S, Mishra SK. Urinary tract infections in the critical care unit: A brief review. Indian J Crit Care Med. 2013;17(6):370-374.   These bacterial intruders or uropathogens intend to cause adhesions, and release toxins within the urinary tract giving rise to plenty of urinary and systemic signs and symptoms. The infection is found to be prevalent among men and women but it shows a predilection for women owing to their distinct anatomy and reproductive physiology. A variety of parameters tends to intensify the risk of UTI such as age, parity, gravidity, pregnancy and association of diseases contributing to the increased virulence and bacterial overload. It’s widespread prevalence also accounts for utilization of large amount of healthcare resources, imposing a huge financial constraint. 2Ronald A. The etiology of urinary tract infection: traditional and emerging pathogens. Dis Mon. 2003;49(2):71-82.   3Foxman B. Epidemiology of urinary tract infections: incidence, morbidity, and economic costs. Dis Mon. 2003;49(2):53-70.

UTIs are caused by both Gram-negative and Gram-positive bacteria, as well as by certain group of fungi.4Flores-Mireles AL, Walker JN, Caparon M, et al. Urinary tract infections: epidemiology, mechanisms of infection and treatment options. Nat Rev Microbiol. 2015;13(5):269-284.   Escherichia coli remains the predominant uropathogen (80%) isolated, followed by Staphylococcus saprophyticus (10-15%). Klebsiella, Enterobacter, Streptococcus, Serratia, Enterococci, and Proteus species account for the remaining 5-10% of UTIs.2Ronald A. The etiology of urinary tract infection: traditional and emerging pathogens. Dis Mon.2003;49(2):71-82.    3Foxman B. Epidemiology of urinary tract infections:incidence, morbidity, and economic costs. Dis Mon. 2003;49(2):53-70.    5Lentz, G. Urinary Tract Infections in Obstetrics and Gynecology. Glob libr women’s med. 2009; DOI 10.3843/GLOWM.10118.   It should be noted that colonization of uropathogens may involve lower as well as upper urinary tract. The infections of the lower urinary tract include cystitis, urethritis, prostatitis, and epididymitis, and those of the upper urinary tract include pyelonephritis.6Jancel T, Dudas V. Management of uncomplicated urinary tract infections. West J Med. 2002; 176(1):51-55    The clinical features of UTIs most commonly include urinary frequency, urgency, dysuria, suprapubic pain, and possible hematuria (Table 1).7Bergamin PA, Kiosoglous AJ. Non-surgical management of recurrent urinary tract infections in women. Transl Androl Urol.2017;6(Suppl 2): S142-S152.     8Al-Badr A, Al-Shaikh G. Recurrent Urinary Tract Infections Management in Women: A review. Sultan Qaboos Univ Med J.2013;13(3):359-367.

Adult women of all ages have increased susceptibility to UTIs, with an incidence ratio of 8:1 as compared to men.8Al-Badr A, Al-Shaikh G. Recurrent Urinary Tract Infections Management in Women: A review. Sultan Qaboos Univ Med J.2013;13(3):359-367.   In older adults (> 65 years), UTIs are the second most common cause of infectious disease hospitalization, after lower respiratory tract infections.9Rowe TA, Juthani-Mehta M. Urinary tract infection in older adults. Aging health. 2013;9(5):10.   UTI is also common in children, with 1.7% of boys and 8.4% of girls being affected by the age of seven years.10Tewary K, Narchi H. Recurrent urinary tract infections in children: Preventive interventions other than prophylactic antibiotics. World J Methodol. 2015 Jun 26;5(2):13-9.   One-third to one-half of the affected children will suffer from at least one recurrence of UTI.11Paintsil E. Update on recent guidelines for the management of urinary tract infections in children: the shifting paradigm. Curr Opin Pediatr. 2013; 25(1):88-94.

The incidence of UTI is maximum in women, with mean annual incidence ranging from 10-15%, with a higher incidence seen in younger females.12Guay DR. Contemporary management of uncomplicated urinary tract infections. Drugs. 2008;68(9):1169-205.   It is estimated that one in three women will experience at least one clinically significant UTI by age 24 and almost 50-60% of women will have at least one UTI in their lifetime.8Al-Badr A, Al-Shaikh G. Recurrent Urinary Tract Infections Management in Women: A review. Sultan Qaboos Univ Med J. 2013;13(3):359-367.   with its varied clinical syndromes and affected host groups, remains one of the most common but widely misunderstood and challenging infectious diseases encountered in clinical practice.13Drekonja DM, Johnson JR. Urinary tract infections. Prim Care. 2008; 35(2):345-67.

Classification of Urinary Tract Infections

Traditionally, UTIs are classified into 6 categories; uncomplicated, complicated, isolated, unresolved, reinfection, and relapse. Uncomplicated UTIs usually affect individuals who are otherwise healthy and have no structural or physiological urinary tract abnormalities, and there is no associated disorder that impairs the host defense mechanisms.4Flores-Mireles AL, Walker JN, Caparon M, et al. Urinary tract infections: epidemiology, mechanisms of infection and treatment options. Nat Rev Microbiol. 2015;13(5):269-284.    8Al-Badr A, Al-Shaikh G. Recurrent Urinary Tract Infections Management in Women: A review. Sultan Qaboos Univ Med J. 2013;13(3):359-367.    14Mohsin R, Siddiqui KM. Recurrent urinary tract infections in females. J Pak Med Assoc. 2010;60(1):55-9.   Cystitis and pyelonephritis are the two subcategories of uncomplicated UTIs. Complicated UTIs are associated with factors that compromise the urinary tract or host defense, including ureteric obstruction, urinary retention caused by neurological disease, renal failure, pregnancy and the presence of foreign bodies such as calculi, indwelling catheters or other drainage devices. 4Flores-Mireles AL, Walker JN, Caparon M, et al. Urinary tract infections: epidemiology, mechanisms of infection and treatment options. Nat Rev Microbiol. 2015;13(5):269-284.    6Jancel T, Dudas V. Management of uncomplicated urinary tract infections.West J Med. 2002; 176(1):51-55     Reinfection is considered when there has been no growth after a treated infection, but the same organism regrows two weeks after therapy, or when a different microorganism grows during any period of time (Table 2)8Al-Badr A, Al-Shaikh G. Recurrent Urinary Tract Infections Management in Women: A review. Sultan Qaboos Univ Med J.2013;13(3):359-367.    14Mohsin R, Siddiqui KM. Recurrent urinary tract infections in females. J Pak Med Assoc. 2010;60(1):55-9.    15Najar MS, Saldanha CL, Banday KA. Approach to urinary tract infections. Indian J Nephrol. 2009;19(4):129-139.

Recurrent Urinary Tract Infections

Recurrent UTIs are defined as having more than two infections in a 6-month period, or 3 infections within the preceding 12 months, with complete resolution for at least two weeks.7Bergamin PA, Kiosoglous AJ. Non-surgical management of recurrent urinary tract infections in women. Transl Androl Urol. 2017;6(Suppl 2): S142-S152.    16Epp A, Larochelle A, Lovatsis D, et al. Recurrent urinary tract infection. J Obstet Gynaecol Can. 2010;32(11):1082-101.    Recurrent UTIs may occur due to relapse (symptomatic recurrent UTIs with the same organism after adequate therapy) or reinfection (recurrent UTIs with previously isolated bacteria after treatment and with a negative intervening urine culture, or a recurrent UTI caused by a different pathogen). In conditions where the same pathogen is isolated, distinction between relapse and reinfection becomes challenging. It is supposed that most recurrent UTIs represent reinfection with the same organism.7Bergamin PA, Kiosoglous AJ. Non-surgical management of recurrent urinary tract infections in women. Transl Androl Urol.2017;6(Suppl 2): S142-S152.    17Kodner CM, Gupton EKT. Recurrent Urinary Tract Infections in Women: Diagnosis and Management. Am Fam Physician. 2010;82(6):638-643.   Herein, it should be noted that reinfection accounts for 80-95% of recurrent UTIs in women. 14Mohsin R, Siddiqui KM. Recurrent urinary tract infections in females. J Pak Med Assoc. 2010;60(1):55-9.    15Najar MS, Saldanha CL, Banday KA. Approach to urinary tract infections. Indian J Nephrol. 2009;19(4):129-139.

Approximately 30-44% of women who have an episode of UTI are supposed to have a recurrence, often within three months. Observational cohort studies have revealed a recurrence rate of 0.3-7.6 infections per patient per year, with an average rate of 2.6 infections per year.18Gupta K, Trautner BW. Diagnosis and management of recurrent urinary tract infections in nonpregnant women. The BMJ. 2013;346:f3140.   Besides, available data from primary care setting suggest that 53% of women older than 55 years and 36% of younger women experience a recurrence within one year. Recurrent UTIs, frequently observed in otherwise healthy young women with anatomically and physiologically normal urinary tracts, are a major healthcare concern.16Epp A, Larochelle A, Lovatsis D, et al. Recurrent urinary tract infection. J Obstet Gynaecol Can. 2010;32(11):1082-101.    17Kodner CM, Gupton EKT. Recurrent Urinary Tract Infections in Women: Diagnosis and Management. Am Fam Physician. 2010;82(6):638-643.

Risk Factors for Recurrent Urinary Tract Infections

Several risk factors are associated with recurrent UTIs including an impairment of the body’s immune system and virulence factors. 7Bergamin PA, Kiosoglous AJ. Non-surgical management of recurrent urinary tract infections in women. Transl Androl Urol. 2017;6(Suppl 2): S142-S152.    The strongest risk factor for recurrent UTIs in sexually-active premenopausal women is frequency of sexual intercourse. Besides, the use of spermicides for contraception, the age of the first UTI, and a maternal history of UTI are some of the other important risk factors (Table 3). An increased postvoid residual urinary volume (> 50 mL) is an independent risk factor for recurrent UTIs in postmenopausal women.8Al-Badr A, Al-Shaikh G. Recurrent Urinary Tract Infections Management in Women: A review. Sultan Qaboos Univ Med J.2013;13(3):359-367.    14Mohsin R, Siddiqui KM. Recurrent urinary tract infections in females. J Pak Med Assoc. 2010;60(1):55-9.    15Najar MS, Saldanha CL, Banday KA. Approach to urinary tract infections. Indian J Nephrol. 2009;19(4):129-139.

Management Strategies for Recurrent Urinary Tract Infections

UTI encompasses a spectrum of clinical conditions that demand prompt management to curb its rising morbidity and mortality.19Hay AD. Managing UTI in Considering that patients with recurrent UTIs are often complex and difficult to manage, the long-term management options in this cohort of patients need to be multimodal and should focus on prevention of relapse and recurrence.    7Bergamin PA, Kiosoglous AJ. Non-surgical

The approach to management of recurrent UTIs encompasses breaking the recurrence cycle and treating any reversible causes. Although there are several non-antimicrobial options for recurrent UTIs, they lack substantial studies and data to authenticate their benefits. Cranberry products may decrease recurrent UTIs in premenopausal women, but they are less effective than antibiotic prophylaxis, and data are inconsistent.7Bergamin PA, Kiosoglous AJ. Non-surgical management of recurrent urinary tract infections in women. Transl Androl Urol. 2017;6(Suppl 2): S142-S152.    20Dason S, Dason JT, Kapoor A. Guidelines for the diagnosis and management of recurrent urinary tract infection in women. Canadian Urological Association Journal. 2011;5(5):316-322.   Vaccines, which are made from combinations of heat killed uropathogenic strains, are also being explored as a prevention strategy; nonetheless, limited clinical success has constrained their widespread availability. In this context, it seems prudent to adopt a management plan including a combination of a non-antimicrobial and selective antimicrobial regime. Herein, it should be noted that patients suffering from recurrent UTIs can be treated safely and effectively with continuous antibiotic prophylaxis, post-coital therapy, and self-initiated treatment (Box 1).7Bergamin PA, Kiosoglous AJ. Non-surgical management of recurrent urinary tract infections in women. Transl Androl Urol. 2017;6(Suppl 2): S142-S152.    14Mohsin R, Siddiqui KM. Recurrent urinary tract infections in females. J Pak Med Assoc. 2010;60(1):55-9.

Antibiotic Therapy: Role of Nitrofurantoin

As UTI is one of the most common bacterial infections encountered among masses, the use of anti-infective agents to counteract the rising infection has been a frontline strategy.19Hay AD. Managing UTI in Antimicrobial therapy aims at eliminating the bacterial growth in the urinary tract through the use of antibiotics, which are well-tolerated, effective, and economic.14Mohsin R, Siddiqui KM. Recurrent urinary tract infections in females. J Pak Med Assoc. 2010;60(1):55-9.   It is well known that appropriate antibiotic therapy leads to higher rates of symptomatic relief and bacterial eradication in women with uncomplicated UTI. Several options are available for antimicrobial use, which have been shown to be highly effective in reducing the risk of recurrent UTI in women.7Bergamin PA, Kiosoglous AJ. Non-surgical management of recurrent urinary tract infections in women. Transl Androl Urol. 2017;6(Suppl 2): S142-S152.   The dosing regimen should be patient-friendly to ensure compliance and the therapy should be prescribed only for the least possible time to decrease the risk of antibiotic-resistance.14Mohsin R, Siddiqui KM. Recurrent urinary tract infections in females. J Pak Med Assoc. 2010;60(1):55-9.

Alarmingly, the frequent misuse of antibiotics has significantly contributed to the rising problem of antimicrobial resistance, which has made the treatment complicated and challenging. 21Dash M, Padhi S, Mohanty I, et al. Antimicrobial resistance in pathogens causing urinary tract 15 infections in a rural community of Odisha, India. J Family Community Med. 2013;20(1):20-6.   22Guidelines on Urological Infections. Available at: http://uroweb.org/wp-content/uploads/19-Urological-infections_LR2.pdf. Accessed on: 27.10.2017.   23Olafsson M, Kristinsson KG, Sigurdsson JA. Urinary tract infections, antibiotic resistance and sales of antimicrobial drugs—an observational study of uncomplicated urinary tract infections in Icelandic women. Scand J Prim Health Care. 2000;18(1):35-8.    24Cagnacci S, Gualco L, Debbia E, et al. European emergence of cipro oxacin-resistant Escherichia coli clonal groups O25:H4-ST 131 and O15:K52:H1causing community-acquired uncomplicated cystitis. J Clin Microbiol. 2008;46(8):2605-12.    It has been reported that E. coli, the most commonly implicated pathogen in urinary tract infections has become resistant to several antibiotics including fluoroquinolones, trimethoprim/ sulfamethoxazole, penicillins, and cephalosporins.25Bader MS, Hawboldt J, Brooks A. Management of complicated urinary tract infections in the era of antimicrobial resistance. Postgrad Med. 2010;122(6):7 15.    26Kumar Y, Sood S, Sharma A, et al. Antibiogram and characterization of resistance markers among Escherichia coli Isolates from urinary tract infections. J Infect Dev Ctries. 2013;7(7):513-9.    Thus, the rising antimicrobial resistance mandates the need for an optimal therapeutic agent. Selection of such an agent must take into account local resistance patterns, patient-specific factors, including anatomic site of infection and severity of disease, pharmacokinetic and pharmacodynamic principles.25Bader MS, Hawboldt J, Brooks A. Management of complicated urinary tract infections in the era of antimicrobial resistance. Postgrad Med. 2010;122(6):7 15.    27Wagenlehner FM, Weidner W, Naber KG. Emergence of antibiotic resistance amongst hospital-acquired urinary tract infections and pharmacokinetic/ pharmacodynamic considerations. J Hosp Infect. 2005; 60(3):191-200.    28Scottish 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/assets/sign88.pdf. Accessed on: 27.10.2017.   

Multidrug resistance is one of the major barriers to the medical management of UTIs. Antibiotics such as trimethoprim and fluoroquinolones are prone to resistance and cross-resistance. In particular, growing resistance among pathogens and other microorganisms towards fluoroquinolones is a matter of concern, and hence these drugs should be kept as optional therapies for acute cystitis. 29Agarwal M, Rattan A. Nitrofurantoin sensitivity pattern pan India. WJPR. 2017;6(2):464-494.    In context to this, nitrofurantoin has emerged as a drug of choice, with good efficacy and favorable tolerability profile.30Mc Kinnell JA, Stollenwerk NS, Jung CW, et al. Nitrofurantoin Compares Favorably to Recommended Agents as Empirical Treatment of Uncomplicated Urinary Tract Infections in a Decision and Cost Analysis. Mayo Clin Proc. 2011;86(6):480-8.    31Gupta K, Hooton TM, Roberts PL, et al. Short course nitrofurantoin for the treatment of acute uncomplicated cystitis in women. Arch Intern Med. 2007;167(20):2207-12.   Nitrofurantoin, unlike many other antimicrobials, has the advantage of withstanding the growing antimicrobial resistance and has started becoming the empirical treatment of choice. 29Agarwal M, Rattan A. Nitrofurantoin sensitivity pattern pan India. WJPR. 2017;6(2):464-494.   

Nitrofurantoin was approved by the FDA in 1953 for the treatment of lower UTI.32Huttner A, Verhaegh EM, Harbarth S, et al. Nitrofurantoin revisited: a systematic review and meta-analysis of controlled trials. J Antimicrob Chemother. 2015;70(9):2456-64.  The updated guidelines of Infectious Disease Society of America (IDSA) and the European Society for Microbiology and Infectious Diseases have now elevated this drug, in use for more than 50 years, to first-line therapeutic option for uncomplicated UTI.33Shultz HJ. Cystitis Treatment in Women, Circa 2011: New Role for an Old Drug. Mayo Clin Proc. 2011; 86(6):477-479.   The recommended dosage of nitrofurantoin by the IDSA and the European Society for Microbiology (2010) is 100 mg twice-daily for 5 days for treating acute uncomplicated cystitis in women. The American College of Obstetricians and Gynecologists recommends a 7-day, four times a day regimen of nitrofurantoin 50 to 100 mg or a 7-day, twice-daily regimen of nitrofurantoin 100 mg for treating non-pregnant women with uncomplicated acute bacterial cystitis. 29Agarwal M, Rattan A. Nitrofurantoin sensitivity pattern pan India. WJPR. 2017;6(2):464-494.

Nitrofurantoin is also recommended as the first choice prophylactic treatment for children with recurrent UTI and urinary tract abnormalities.34Brendstrup L, Hjelt K, Petersen KE, et al. Nitrofurantoin versus trimethoprim prophylaxis in recurrent urinary tract infection in children. A randomized, double-blind study. Acta Paediatr Scand. 1990;79(12):1225-34.   The factors favoring nitrofurantoin as a first-line drug of choice are its efficacy, minimal resistance, and low incidence of drug resistance.33Shultz HJ. Cystitis Treatment in Women, Circa 2011: New Role for an Old Drug. Mayo Clin Proc. 2011; 86(6):477-479.   Indeed, nitrofurantoin is shown to exert antibacterial activity in the urine, but exhibits little systemic antibacterial effect, thus safeguarding against collateral damage.35Treatment of Urinary Tract Infection (UTI). Available at: http://tmedweb.tulane.edu/pharmwiki/doku.php/treatment_of_utis. Accessed on: 27.10.2017.    36Gupta K, Hooton TM, Naber KG. International Clinical Practice Guidelines for the Treatment of Acute Uncomplicated Cystitis and Pyelonephritis in Women: A 2010 Update by the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases. Clinical Infectious Diseases.2011; 52(5): e103-e120.

Nitrofurantoin is mainly metabolized by the kidneys and excreted through both glomerular filtration and tubular secretion. It is ideal for the management of lower UTIs as it achieves a high concentration in urine.37Shakti L, Veeraraghavan B. Advantage and limitations of nitrofurantoin in multi-drug resistant Indian scenario. Indian J Med Microbiol. 2015;33(4):477-81.   The mechanism of antimicrobial action of nitrofurantoin is not fully understood. The active form of the drug is produced by bacterial nitroreductases after reduction of the nitro group. The resultant intermediate metabolites bind to bacterial ribosomes and inhibit several bacterial enzymes involved in the synthesis of DNA and RNA.32Huttner A, Verhaegh EM, Harbarth S, et al. Nitrofurantoin revisited: a systematic review and meta-analysis of controlled trials. J Antimicrob Chemother. 2015;70(9):2456-64.   Nitrofurantoin also interferes with cell wall synthesis and in addition, affects the metabolism of carbohydrates in the bacteria by inhibiting a number of enzymes at three different points in the Krebs cycle.38Munoz-Davila MJ. Role of Old Antibiotics in the Era of Antibiotic Resistance. Highlighted Nitrofurantoin for the Treatment of Lower Urinary Tract Infections. Antibiotics (Basel). 2014;3(1):39-48.   Nitrofurantoin also acts by providing intermittent urinary antibacterial activity and probably by inhibiting bacterial attachment.15Najar MS, Saldanha CL, Banday KA. Approach to urinary tract infections. Indian J Nephrol. 2009;19(4):129-139.     16Epp A, Larochelle A, Lovatsis D, et al. Recurrent urinary tract infection. J Obstet Gynaecol Can. 2010;32(11):1082-101.   The multiple antibacterial mechanisms and action sites is probably responsible for the lack of development of clinically significant bacterial resistance to nitrofurantoin.39McOsker CC, Fitzpatrick PM. Nitrofurantoin: mechanism of action and implications for resistance development in common uropathogens. J Antimicrob Chemother 1994;33 Suppl A:23-30.

Antimicrobial Spectrum of Nitrofurantoin

The antibacterial spectrum of nitrofurantoin is broad and the drug is particularly effective against the main uropathogens. Nitrofurantoin is active against E. coli, Enterococci, S. aureus, Klebsiella pneumonia, Enterobacter species, Citrobacter species, group B Streptococci and most strains of multidrug-resistant Gram-negative bacilli.33Shultz HJ. Cystitis Treatment in Women, Circa 2011: New Role for an Old Drug. Mayo Clin Proc. 2011; 86(6):477-479.    37Shakti L, Veeraraghavan B. Advantage and limitations of nitrofurantoin in multi-drug resistant Indian scenario. Indian J Med Microbiol.2015;33(4):477-81.   40Cunha BA, Schoch PE, Hage JR. Nitrofurantoin: Preferred Empiric Therapy for Community-Acquired Lower Urinary Tract Infections. Mayo Clin Proc. 2011;86(12):1243-1244.   Nitrofurantoin is gaining prominence in the management of UTIs due to increasing incidence of resistance against other commonly used antibiotics, such as trimethoprim/sulfamethoxazole (TMP/SMX), resulting in treatment failures.33Shultz HJ. Cystitis Treatment in Women, Circa 2011: New Role for an Old Drug. Mayo Clin Proc. 2011; 86(6):477-479.   Interestingly, a study by Olorunmola and coworkers 41Olorunmola FO, Kolawole DO, Lamikanra A. Antibiotic Resistance and Virulence Properties in Escherichia Coli Strains from Cases of Urinary Tract Infections. African Journal of Infectious Diseases. 2013;7(1):1-7.   revealed high sensitivity of nitrofurantoin in comparison with other antibiotics to E. coli isolates from cases of UTI. The findings revealed widespread resistance of the isolates to all the antibiotics (51.1-96.4%), except nitrofurantoin that showed a low resistance rate of 7.3% (Figure 1). Likewise, a study by Olson et al, in 2009 revealed that no E. coli isolate was resistant to nitrofurantoin compared to almost 30% isolates resistant to TMP-SMX. 29Agarwal M, Rattan A. Nitrofurantoin sensitivity pattern pan India. WJPR. 2017;6(2):464-494.

Modified Release Nitrofurantoin

Modified release formulation should be preferred over conventional and sustained release formulations, as modified release nitrofurantoin provides release of initial loading dose in beginning to achieve desired MIC levels. This is followed by release of maintenance dose, which releases constantly over period of time to maintain adequate urinary concentration. Loading dose ensures no risk of treatment failure. It has been seen that modified release nitrofurantoin formulation provides better GI tolerance when compared to conventional and plain nitrofurantoin tablets. Advantages of modified release nitrofurantoin are discussed in Box 2. 29Agarwal M, Rattan A. Nitrofurantoin sensitivity pattern pan India. WJPR. 2017;6(2):464-494.

Evidence Based Efficacy of Nitrofurantoin

Strategies to prevent recurrent UTIs include low-dose antimicrobial prophylaxis over long term or postcoital antibiotic treatment in premenopausal women.42Nickel JC. Practical Management of Recurrent Urinary Tract Infections in Premenopausal Women. Reviews in Urology. 2005;7(1):11-17.   Nitrofurantoin is a good option for long term prophylaxis of lower UTIs as it is effective, and well-tolerated with few adverse effects. It has been recommended at a dose of 50 mg at night for a period of 12 months to prevent recurrence of UTI. 43Brumfitt W, Hamilton-Miller JM. Efficacy and safety profile of long-term nitrofurantoin in urinary infections: 18 years’ experience. J Antimicrob Chemother. 1998;42(3):363-71.   Alternatively, post-coital prophylaxis involving early bladder voiding and nitrofurantoin (50 or 100 mg single tablet), has also been found effective in preventing recurrence of UTI. 44Pfau A, Sacks T, Engelstein D. Recurrent urinary tract infections in premenopausal women: prophylaxis based on an understanding of the pathogenesis. J Urol. 1983;129(6):1153-7.

In a study45Alexiou Z,Mouktaroudi M, Koratzanis G, et al. The significance of compliance for the success of antimicrobial prophylaxis in recurrent lower urinary tract infections:the Greek experience. Int J Antimicrob Agents. 2007 Jul;30(1):40-3.   involving 181 women with recurrent UTI undergoing treatment for (≥6) months, the most effective regimen for antibiotic prophylaxis was nitrofurantoin, with a success rate of 96.8% compared with 82.8% for TMP/SMX and 72.3% for norfloxacin, thus substantiating nitrofurantoin as the most potent among the administered therapeutic agents (Figure 2). Importantly, nitrofurantoin is also shown to be useful in patients with diabetes as they are at increased risk of severe, recurrent UTIs.46Nitzan O, Elias M, Chazan B, et al. Urinary tract infections in patients with type 2 diabetes mellitus: review of prevalence, diagnosis, and management. Diabetes Metab Synd Obes. 2015;8:129-136.   A study47Mozdzan M, Ruxer J, Siejka A. Efficacy of nitrofurantoin in the treatment of chronic urinary tract infections in patients with type 2 diabetes mellitus. Pol Merkur Lekarski. 2006;21(125):434-8.   on 105 women, aged 50-70 years, with diabetes and recurrent UTIs, demonstrated that nitrofurantoin is effective in both prophylaxis and treatment of recurrent UTIs in women with diabetes.

Recurrent Urinary Tract Infections in Pregnancy

UTI is considered the most frequent medical complication of pregnancy. As recurrent UTIs are common in pregnancy, they require prophylactic treatment if they occur.8Al-Badr A, Al-Shaikh G. Recurrent Urinary Tract Infections Management in Women: A review. Sultan Qaboos Univ Med J. 2013;13(3):359-367.  For pregnant women with symptomatic or asymptomatic UTI, the risk of a preterm delivery and low birth weight infant is markedly increased.16Epp A, Larochelle A, Lovatsis D, et al. Recurrent urinary tract infection. J Obstet Gynaecol Can. 2010;32(11):1082-101.   Screening for UTI is recommended in all pregnant women at their first prenatal visit and then in the third trimester.8Al-Badr A, Al-Shaikh G. Recurrent Urinary Tract Infections Management in Women: A review. Sultan Qaboos Univ Med J. 2013;13(3):359-367.  Indications for prophylaxis are; all women with a pre-pregnancy history of recurrent UTIs, unrelenting symptomatic or asymptomatic bacteriuria after two antibiotic treatments, and after only one UTI for a woman who has other conditions, such as diabetes, that may increase the risk of urinary complications during the episode of UTI. Both continuous and post-coital prophylaxis regimens have been shown to be effective, and nitrofurantoin is among the therapeutic agents of choice for pregnant women with recurrent UTI.8Al-Badr A, Al-Shaikh G. Recurrent Urinary Tract Infections Management in Women: A review. Sultan Qaboos Univ Med J.2013;13(3):359-367.    16Epp A, Larochelle A, Lovatsis D, et al. Recurrent urinary tract infection. J Obstet Gynaecol Can. 2010;32(11):1082-101.

Adjuvant Measures

Managing Painful/Burning Micturition

It has been found that burning micturition constitutes the most common distressing feature reported in patients with UTI. A study 48Shaifali I, Gupta U, Mahmood SE, et al. Antibiotic Susceptibility Patterns of Urinary Pathogens in Female Outpatients. N Am J Med Sci. 2012;4(4):163 169.   conducted among 139 females aged ≥15 years revealed the same, wherein burning micturition (73.4%) was the most prevalent symptom reported by the participants, followed by frequency (43.9%), urgency (20.9%), painful voiding (20.1%), difficulty (5.0%), and nocturnal incontinence (1.4%). Therefore, it seems prudent to offer such affected patients a choice of urinary alkalinizers prior to or concomitantly with an appropriate antibiotic therapy so as to provide symptomatic relief.28Scottish 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/assets/sign88.pdf. Accessed on: 27.10.2017.    49Mifsud 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.

Herein, it should be noted that potassium citrate demonstrates superior efficacy for urine alkalinization.50Sakhaee K, Nicar M, Hill K, et al. 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 6.0–6.5.51Zuckerman JM,Assimos DG. Hypocitraturia: Pathophysiology and Medical Management. Rev Urol. 2009;11(3):134-144.    52Whitmore 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, achieving its goal of urine alkalinization, which may cater to the troublesome condition of painful and burning micturition in patients with UTIs.50Sakhaee K, Nicar M, Hill K, et al. Contrasting effects of potassium citrate and sodium citrate therapies on urinary chemistries and crystallization of stoneforming salts. Kidney International. 1983;24:348-352.    53McNally 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.

Apart from alleviating symptoms, achievement of alkaline pH may also boost the natural defense mechanisms, including enhancement of phagocytosis, thereby destroying the infecting organisms, such as E. coli and S. saprophyticus.54Gargan 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.   In addition, it may also assist in preventing later onset of urinary tract infection.55Lopez MM, Castillo LA, Chávez JB, Ramones C. Hypercalciuria and recurrent urinary tract infection in Venezuelan children. Pediatr Nephrol. 1999;13(5):433-7.   While being an effective urinary alkalinizer, potassium citrate also displays an acceptable tolerability profile.51Zuckerman JM, Assimos DG. Hypocitraturia: Pathophysiology and Medical Management. Rev Urol. 2009;11(3):134-144.    52Whitmore KE. Complementary and Alternative Therapies as Treatment Approaches for Interstitial Cystitis. Rev Urol. 2002;4(Suppl 1):S28-S35.   Other advantages of potassium citrate include high palatability, pleasant taste, and tolerable even on prolonged use, which make it suitable to be considered a first-line urine alkalinizing agent.50Sakhaee K, Nicar M, Hill K, et al. Contrasting effects of potassium citrate and sodium citrate therapies on urinary chemistries and crystallization of stoneforming salts. Kidney International. 1983;24:348-352.

Besides, a growing body of evidence substantiates the effectiveness of flavoxate therapy in urinary tract disorders. Flavoxate increases bladder capacity and reduces pressure in patients with cystitis with no side effects. Flavoxate is indicated for symptomatic relief of dysuria, urgency, nocturia, suprapubic pain, frequency and incontinence as may occur in cystitis, prostatitis, urethritis, urethrocystitis/urethrotrigonitis.56Gould S. Urinary tract disorders. Clinical comparison of flavoxate and phenazopyridine. Urology. 1975 May;5(5):612–5.    57Servedio C. The use of flavoxate in cystitis and renal colic. Curr Med Res Opin. 1974;2(8):449–54.

Conclusion

Urinary tract infections are some of the most widely encountered clinical bacterial infections in women. A variety of parameters tends to intensify the risk of UTIs such as age, parity, gravidity, pregnancy and association of diseases contributing to the increased virulence and bacterial overload. The clinical features of UTIs most commonly include urinary frequency, urgency, dysuria, suprapubic pain, and possible hematuria. Recurrent UTIs are most commonly caused by reinfection with the original bacterial isolate in young, otherwise healthy women with no anatomic or functional abnormalities of the urinary tract. Although a wide range of bacterial organisms are implicated in their development, E. coli strains are responsible for up to 80% of the infections. The morbidity associated with recurrent UTIs is significant. This necessitates the need for implementation of an appropriate therapeutic strategy. Long term prophylactic measures, including antimicrobial prophylaxis, decrease the continued high incidence of recurrent UTIs. In this context, nitrofurantoin is considered an effective therapeutic option for prophylaxis of recurrent lower UTIs as it is well tolerated, with the added advantage of minimal resistance and low propensity to induce development of drug resistance. The Infectious Diseases Society of America guidelines recommend nitrofurantoin as first-line therapeutic option in the treatment of UTIs. Growing evidence suggests its clinical efficacy as it exhibits minimal resistance to the pathogens, particularly E. coli. It is also important to treat the distressing symptoms of recurrent UTI, such as painful/burning micturition. Herein, potassium citrate therapy seems propitious, since it alkalinizes urine pH and thus relieves the distressing symptoms of UTIs.

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