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Urinary Tract Infections in Infants and Children

Overview

Urinary tract infection (UTI) is one of the most common serious bacterial infections among the pediatric population.1Tsai J, Lin C, Yang SS, et al. Diagnosis of pediatric urinary tract infections. Urol Sci. 2016; 27(3): 131-134.   Indeed, pediatric UTI is a common cause of presentation to healthcare providers that makes it an important area of concern for parents and clinicians alike. 2Copp HL, Schmidt B. Work up of Pediatric Urinary Tract Infection. The Urologic clinics of North America. 2015;42(4):519-526.    Of late, the importance of UTI has been increasingly acknowledged, particularly the role of UTI as an occult cause of febrile illness in young children. UTIs are a frequent cause of morbidity in children and exhibit high rates of recurrence.3 Zorc JJ, Kiddoo DA, Shaw KN. Diagnosis and Management of Pediatric Urinary Tract Infections. Clinical Microbiology Reviews. 2005;18(2):417-422.   4Zaffanello M, Malerba G, Cataldi L, et al. Genetic Risk for Recurrent Urinary Tract Infections in Humans: A Systematic Review. J Biomed Biotechnol. 2010; 2010:321082.   Although the outcomes of a UTI are usually benign, it can progress to renal scarring, particularly in early infancy. Renal scarring, in the long-term, may lead to various sequelae including hypertension, proteinuria, renal damage and even chronic renal failure.5Guidelines on Urological Infections. Available at: https://uroweb.org/wp-content/uploads/18_Urological-infections_LR.pdf. Accessed on 02/11/2017.   Therefore, a comprehensive understanding of the various aspects of pediatric UTI including etiology, clinical features, and management options seems pertinent for the prevention of long-term morbidity and sequelae.1Tsai J, Lin C, Yang SS, et al. Diagnosis of pediatric urinary tract infections. Urol Sci. 2016; 27(3): 131-134.

Burden of Pediatric Urinary Tract Infection

The prevalence and incidence of pediatric UTI varies dependent on age, sex, race, ethnicity, and circumcision status. UTI is the most common bacterial infection in children less than two years of age.2Copp HL, Schmidt B. Work up of Pediatric Urinary Tract Infection. The Urologic clinics of North America. 2015;42(4):519-526.   3 Zorc JJ, Kiddoo DA, Shaw KN. Diagnosis and Management of Pediatric Urinary Tract Infections. Clinical Microbiology Reviews. 2005;18(2):417-422.    6Shaikh N, Morone NE, Lopez J, et al. Does this child have a urinary tract infection? JAMA. 2007;298(24):2895-904.    Among the pediatric population, the cumulative incidence is estimated to be 2% in boys and 7% in girls, in the first 6 years of life, with 2.2% of boys and 2.1% of girls having had a UTI before reaching 2 years of age. 2Copp HL, Schmidt B. Work up of Pediatric Urinary Tract Infection. The Urologic clinics of North America. 2015;42(4):519-526.    The global pattern of UTI epidemiology resonates in developing countries as well, with studies reporting UTI in up to 9% of febrile children aged 1-60 months, with a significantly higher prevalence in girls. Of note, a higher UTI prevalence (8-35%) is reported in malnourished children with the risk of bacteriuria increasing significantly with the severity of malnutrition.7 Urinary Tract Infections in Infants and Children in Developing Countries in the Context of IMCI. Available at: http://apps.who.int/iris/bitstream/10665/69160/1/WHO_FCH_CAH_05.11.pdf. Accessed on 02/11/2017.    UTI exhibits a higher rate of recurrence among children; the estimated recurrence rate of pediatric UTI is around 30-40%, with the majority of recurrences occurring in the first 12 months after the initial infection.4Zaffanello M, Malerba G, Cataldi L, et al. Genetic Risk for Recurrent Urinary Tract Infections in Humans: A Systematic Review. J Biomed Biotechnol. 2010; 2010:321082.   Risk of recurrent UTI is greater in infants <6 months of age, severe vesico-ureteric reflux and abnormal nuclear renal scans at time of first infection.7 Urinary Tract Infections in Infants and Children in Developing Countries in the Context of IMCI. Available at: http://apps.who.int/iris/bitstream/10665/69160/1/WHO_FCH_CAH_05.11.pdf. Accessed on 02/11/2017.

Etiology of Urinary Tract Infection

Knowledge about the microbial etiology is valuable in all cases of UTIs, particularly in the treatment phase, for selecting the most appropriate antibiotics.8Epp A, Larochelle A. Recurrent Urinary Tract Infection. J Obstet Gynaecol Can. 2010; 32(11):1082-1090.  The most predominant pathogen implicated in UTIs in all age groups is the Gram-negative bacillus Escherichia coli, which is supposed to be the cause in about 80–90% of uncomplicated UTIs among children.7 Urinary Tract Infections in Infants and Children in Developing Countries in the Context of IMCI. Available at: http://apps.who.int/iris/bitstream/10665/69160/1/WHO_FCH_CAH_05.11.pdf. Accessed on 02/11/2017.   9 Ejrnæs K. Bacterial characteristics of importance for recurrent urinary tract infections caused by Escherichia coli. Dan Med Bull. 2011;58(4):B4187.   An India based study10 Sharma I, Paul D. Prevalence of community acquired urinary tract infections in Silchar Medical College, Assam, India and its antimicrobial susceptibility profile. Indian J Med Sci. 2012;66(11-12):273-9.    evaluated the microbial spectrum involved in UTIs and revealed that the most commonly isolated bacterium was E. coli with a frequency rate of 33.3% followed by Staphylococcus aureus (22.2%), Klebsiella pneumoniae (11.1%), coagulase negative Staphylococcus (7.4%), Pseudomonas spp. (7.4%),Proteus myxofaciens(3.7%), Proteus mirabilis (3.7%), Edwardsiella tarda (3.7%), Morganella morganii(3.7%), and Citrobacter fruendii (3.7%); Figure 1.

Specifically referring to uncomplicated infections, E. coli has been established as the predominant pathogen accounting for as many as 80% cases, followed by S. saprophyticus (5-15%), Enterococci, Klebsiella species and P. mirabilis, all being responsible for a small percentage of infections. On the other hand, the bacterial spectrum of complicated infections is much broader, including both Gram-negative and -positive, and often multi-resistant organisms.11 Jancel T, Dudas V. Management of uncomplicated urinary tract infections. West J Med. 2002 Jan;176(1):51–55.    12 Wagenlehner FM, Naber KG. Antibiotic treatment for urinary tract infections: pharmacokinetic/pharmacodynamic principles. Expert Rev Anti Infect Ther. 2004 Dec;2(6):923-31.    13 Blondeau JM. Current issues in the management of urinary tract infections: extended-release ciprofloxacin as a novel treatment option. Drugs. 2004;64(6):611-28.

The urinary tract may become infected through different mechanisms, such as retrograde ascent of fecal-perineal bacteria, nosocomial or bacterial introduction in a medical setting through instrumentation, and urinary tract involvement as part of a systemic infection (Figure 2). Retrogarde ascent is considered the most common mechanism of UTI, wherein the bacteria usually come from the host’s bowel and gets into the urinary tract through vaginal or periurethral colonization.6Shaikh N, Morone NE, Lopez J, et al. Does this child have a urinary tract infection? JAMA. 2007;298(24):2895-904.    14 Ma JF, Shortliffe LM. Urinary tract infection in children: etiology and epidemiology. Urol Clin North Am. 2004 Aug;31(3):517-26.

Clinical Features of Urinary Tract Infections in Children

Clinical features of UTI vary greatly by age of the patient, with clinical presentation becoming more specific as the child grows older.15 Habib S. Highlights for Management of a Child with a Urinary Tract Infection. Int J Pediatr. 2012;2012:943653.    The sign and symptoms of pediatric UTIs are very broad and range from asymptomatic infection to mild lower urinary tract symptoms, to febrile and systemic illness.2Copp HL, Schmidt B. Work up of Pediatric Urinary Tract Infection. The Urologic clinics of North America. 2015;42(4):519-526.  Young infants with UTI may present diverse and non-specific symptoms including unexplained fever, sepsis, lethargy, prolonged jaundice, hematuria, poor feeding, vomiting, diarrhea, and irritability.1Tsai J, Lin C, Yang SS, et al. Diagnosis of pediatric urinary tract infections. Urol Sci.2016; 27(3): 131-134.   15 Habib S. Highlights for Management of a Child with a Urinary Tract Infection. Int J Pediatr. 2012;2012:943653.    Indeed, combinations of findings is more useful than individual symptoms.6Shaikh N, Morone NE, Lopez J, et al. Does this child have a urinary tract infection? JAMA. 2007;298(24):2895-904.

Abdominal pain, back pain, dysuria, frequency, urgency, new onset urinary incontinence, suprapubic discomfort, and vomiting increase the likelihood of a UTI in children who can tell their symptoms verbally (Table 1). In older children, the presence of specific urinary symptoms can be used as a criterion for further evaluation. Neonates and young infants with febrile UTI are more vulnerable to bacteremia or sepsis than older children and require careful evaluation and management.1Tsai J, Lin C, Yang SS, et al. Diagnosis of pediatric urinary tract infections. Urol Sci.2016; 27(3): 131-134.   6Shaikh N, Morone NE, Lopez J, et al. Does this child have a urinary tract infection? JAMA. 2007;298(24):2895-904.   16 Ahmed SM, Swedlund Sk. Evaluation and Treatment of Urinary Tract Infections in Children. Am Fam Physician. 1998;57(7):1573-1580.

Management of Pediatric Urinary Tract Infections

Antibiotic Treatment for Acute Urinary Tract Infections

The aim of UTI management in children is to eradicate the infection and prevent severe systemic illness, relieve symptoms, and prevent and/or minimize possible long-term complications.1Tsai J, Lin C, Yang SS, et al. Diagnosis of pediatric urinary tract infections. Urol Sci.2016; 27(3): 131-134.   2Copp HL, Schmidt B. Work up of Pediatric Urinary Tract Infection. The Urologic linics of North America. 2015;42(4):519-526.   17Urinary tract infection in children diagnosis, treatment and long-term management. Available at: https://www.nice.org.uk/guidance/cg54/evidence/full-guideline-pdf-196566877. Accessed on 02/11/2017.    Given the outlook that diagnostic sensitivity based on a typical history ranges between 50-80%, empirical antibiotic therapy, without additional testing, is an attractive option to clear the infectious process from urinary tract, and is quite conventional in many countries, while being appropriate as well.8>Epp A, Larochelle A. Recurrent Urinary Tract Infection. J Obstet Gynaecol Can. 2010; 32(11):1082-1090.   18 Schmiemann G, Kniehl E, Gebhardt K, et al. The diagnosis of urinary tract infection: a systematic review. Dtsch Arztebl Int. 2010 May;107(21):361-7.   19 Mohsin R, Siddiqui KM. Recurrent urinary tract infections in females. J Pak Med Assoc 2010;60(1):55-59.   20 Schauberger CW, Merkitch KW, Prell AM. Acute cystitis in women: experience with a telephone-based algorithm. Wisconsin Medical Journal 2007;106(6):326-329.   21 Hummers-Pradier E, Kochen MM. Urinary tract infections in adult general practice patients. Br J Gen Pract. 2002;52(482):752–761.

A wide range of antibiotics are used to treat acute UTI in infants and children. 17Urinary tract infection in children diagnosis, treatment and long-term management.Availableat:https://www.nice.org.uk/guidance/cg54/evidence/full-guideline-pdf-196566877. Accessed on 02/11/2017.    In general, nitrofurantoin, trimethoprim/sulfamethoxazole (TMP/SMZ), fluoroquinolones and cephalosporins are first-line therapies for acute uncomplicated UTI.17Urinary tract infection in children diagnosis, treatment and long-term management. Available at: https://www.nice.org.uk/guidance/cg54/evidence/full-guideline-pdf-196566877. Accessed on 02/11/2017.    22Wang A, Nizran P, Malone MA, et al. Urinary tract infections. Prim Care. 2013;40(3): 687-706.   Use of these antibiotics is indicated clinically in favor of a more rapid resolution of symptoms and clearance of bacteriuria, since administration of appropriate antibiotic therapy is the key to achieving good therapeutic outcomes in UTIs.23 Mazzulli T. Diagnosis and management of simple and complicated urinary tract infections (UTIs). The Can J Urol 2012;19 Suppl 1:42-48.   24 Chen YH, Ko WC, Hsueh PR. Emerging resistance problems and future perspectives in pharmacotherapy for complicated urinary tract infections. Expert Opin Pharmacother. 2013 Apr;14(5):587-96.

Herein, it should be noted that recent guidelines of the National Institute for Health and Care Excellence (NICE) suggests short-duration (2-4 days) antibiotic therapy for the treatment of cystitis/lower UTI. Arguably, oral antibiotics and shorter courses are more convenient for patients, and have lesser risks and adverse effects. Moreover, appropriate use of antibiotics may help control the development of antibiotic resistance in the community. 17Urinary tract infection in children diagnosis, treatment and long-term management. Available at:https://www.nice.org.uk/guidance/cg54/evidence/full-guideline-pdf-196566877. Accessed on 02/11/2017.

Role of Nitrofurantoin in Pediatric Urinary Tract Infections

The finding that high resistance to broad-spectrum antibiotics, especially to extended-spectrum β-lactams, carbapenems, and fluoroquinolones among uropathogens is emerging as a critical problem in many countries, makes the need of judicious use of antimicrobials even more important.24 Chen YH, Ko WC, Hsueh PR. Emerging resistance problems and future perspectives in pharmacotherapy for complicated urinary tract infections. Expert Opin Pharmacother. 2013 Apr;14(5):587-96.   In this context, international recommendations clearly warn against the broad and uncritical use of fluoroquinolones for uncomplicated infections;18 Schmiemann G, Kniehl E, Gebhardt K, et al. The diagnosis of urinary tract infection: a systematic review. Dtsch Arztebl Int. 2010 May;107(21):361-7.   while similar concerns exist for the use of amoxicillin and (to some extent) of trimethoprim on account of a marked increase in the number of resistant pathogens.25Urinary tract infection. Available at: http://www.umm.edu/patiented/articles/how_antibiotics_used_treating_urinary_tract_infections_000036_8.htm. Accessed on 03/11/2017.   26 Fluoroquinolones in children. Available at:http://www.who.int/selection_medicines/committees/subcommittee/2/fluoroquinolones_rev.pdf. Accessed on 03/11/2017.

In such instances, nitrofurantoin is a possible alternative for patients with uncomplicated and complicated UTIs, recommended as the first-line agent for acute uncomplicated UTI.24 Chen YH, Ko WC, Hsueh PR. Emerging resistance problems and future perspectives in pharmacotherapy for complicated urinary tract infections. Expert Opin Pharmacother. 2013 Apr;14(5):587-96.   27 Colgan R, Williams M. Diagnosis and Treatment of Acute Uncomplicated Cystitis. Am Fam Physician 2011;84(7):771-76.   The recommendation appears consistent with guidelines from various international organizations, such as NICE and the Infectious Diseases Society of America (IDSA), and by some textbooks, such as Nelson Textbook of Pediatrics, which show nitrofurantoin as an appropriate choice in UTIs owing to the minimal overall resistance and favorable side-effect profile seen with this drug (Box 1).17Urinary tract infection in children diagnosis, treatment and long-term management. Available at: https://www.nice.org.uk/guidance/cg54/evidence/full-guideline-pdf-196566877. Accessed on 02/11/2017.    28Gupta K, Hooton TM, Naber KG, et al. Executive Summary: 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. Clin Infect Dis. 2011;52(5):561-564.    29 Nelson 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+2015&hl=en&sa=X&redir_esc=y#v=snippet&q=nitrofurantoin&f=false. Accessed on: 04/11/2017.    It achieves good antibacterial activity in the urine, and is bactericidal against a mean of 95.6% of E. coli UTIs.30Rijal A, Ghimire G, Gautam K, et al. Antibiotic susceptibility of organisms causing urinary tract infection in patients presenting to a teaching hospital. J Nepal Health Res Counc. 2012;10(1):24-7.    31 Kashanian J, Hakimian P, Blute M Jr, et al. Nitrofurantoin: the return of an old friend in the wake of growing resistance. BJU Int. 2008;102(11):1634-7.

Long-Term Prophylaxis in Children with Recurrent Urinary Tract Infections: Role of Nitrofurantoin

Recurrent infections may be particularly bothersome regardless of age and gender, and are potential indication for prophylaxis. 32Finer G, Landau D. Pathogenesis of urinary tract infections with normal female anatomy. Lancet Infect Dis. 2004; 4: 631–35.   Nitrofurantoin is beneficial not only in the treatment of UTIs but also as a prophylactic agent. Falakaflaki et al33 Falakaflaki B, Fallah R, Jamshidi MR, et al. Comparison of Nitrofurantoin and Trimethoprim-Sulphamethoxazole for Long-Term Prophylaxis in Children with Recurrent Urinary Tract Infections. International Journal of Pharmacology. 2007; 3(2):179-182.   compared prophylactic effect of nitrofurantoin and TMP/SMX in recurrent UTI in children, and aimed to determine antibiotic resistance pattern while receiving prophylaxis. A total of 132 patients were randomized to receive either TMP/SMX (n = 66) or nitrofurantoin (n = 66) as single night dose for six months. Patients were categorized into three groups according to age: 3-12 months, 1-5 years, and 6-12 years. The results revealed that nitrofurantoin was more effective than TMP-SMX in preventing recurrent UTIs over a 6-month period; rate of recurrence was 36.2% in nitrofurantoin group compared with 63.8% in the TMP/SMX group (P = 0.029). Of note, this protective effect was more significant in children aged 1-5 years compared to other age groups (nitrofurantoin vs. TMP/SMX, 30.4% vs. 69.5%, P = 0.046); Figure 3. In the nitrofurantoin group, 37.5% of the organisms causing the UTIs were resistant to the prophylactic agent, whereas the number was comparatively higher in the TMP/SMX group; 56% of the organisms were resistant to TMP/SMX. Findings of the study substantiated that nitrofurantoin has a lower rate of recurrence and causes less emergence of resistance bacteria than TMP/SMX, and is therefore, more suitable for prevention of recurrent UTIs in the pediatric population.

Conclusion

Urinary tract infection is one of the most common serious bacterial infections among the pediatric population and a common cause of presentation to healthcare providers. Escherichia coli is considered the predominant pathogen implicated in about 80–90% of uncomplicated UTIs among children. The aim of UTI management in children is to eradicate the infection and prevent severe systemic illness, relieve symptoms, and prevent and/or minimize possible long-term complications. A wide range of antibiotics are used to treat acute UTI in infants and children including nitrofurantoin, trimethoprim/sulfamethoxazole, fluoroquinolones and cephalosporins. Of late, high resistance to broad-spectrum antibiotics, especially to extended-spectrum β-lactams, carbapenems, and fluoroquinolones among uropathogens is emerging as a critical problem in many countries. In such instances, nitrofurantoin is a promising alternative for patients with uncomplicated and complicated UTIs, recommended as the first-line agent for acute uncomplicated UTI. Nitrofurantoin achieves good antibacterial activity in the urine, and it is beneficial not only in the treatment of UTIs but also as a prophylactic agent. Available data substantiate that nitrofurantoin is more effective than TMP-SMX in preventing recurrent UTIs over a 6-month period. Besides, it has a lower rate of recurrence and causes less emergence of resistance bacteria than TMP/SMX, and is, therefore, more suitable for prevention of recurrent UTIs in the pediatric population.

References

  1. Tsai J, Lin C, Yang SS, et al. Diagnosis of pediatric urinary tract infections. Urol Sci. 2016; 27(3): 131-134.
  2. Copp HL, Schmidt B. Work up of Pediatric Urinary Tract Infection. The Urologic clinics of North America. 2015;42(4):519-526.
  3. Zorc JJ, Kiddoo DA, Shaw KN. Diagnosis and Management of Pediatric Urinary Tract Infections. Clinical Microbiology Reviews. 2005;18(2):417-422.
  4. Zaffanello M, Malerba G, Cataldi L, et al. Genetic Risk for Recurrent Urinary Tract Infections in Humans: A Systematic Review. J Biomed Biotechnol. 2010; 2010:321082.
  5. Guidelines on Urological Infections. Available at: https://uroweb.org/wp-content/uploads/18_Urological-infections_LR.pdf. Accessed on 02/11/2017.
  6. Shaikh N, Morone NE, Lopez J, et al. Does this child have a urinary tract infection? JAMA. 2007;298(24):2895-904.
  7. Urinary Tract Infections in Infants and Children in Developing Countries in the Context of IMCI. Available at: http://apps.who.int/iris/bitstream/10665/69160/1/WHO_FCH_CAH_05.11.pdf. Accessed on 02/11/2017.
  8. Epp A, Larochelle A. Recurrent Urinary Tract Infection. J Obstet Gynaecol Can. 2010; 32(11):1082-1090.
  9. Ejrnæs K. Bacterial characteristics of importance for recurrent urinary tract infections caused by Escherichia coli. Dan Med Bull. 2011;58(4):B4187.
  10. Sharma I, Paul D. Prevalence of community acquired urinary tract infections in Silchar Medical College, Assam, India and its antimicrobial susceptibility profile. Indian J Med Sci. 2012;66(11-12):273-9.
  11. Jancel T, Dudas V. Management of uncomplicated urinary tract infections. West J Med. 2002 Jan;176(1):51–55.
  12. Wagenlehner FM, Naber KG. Antibiotic treatment for urinary tract infections: pharmacokinetic/pharmacodynamic principles. Expert Rev Anti Infect Ther. 2004 Dec;2(6):923-31.
  13. Blondeau JM. Current issues in the management of urinary tract infections: extended-release ciprofloxacin as a novel treatment option. Drugs. 2004;64(6):611-28.
  14. Ma JF, Shortliffe LM. Urinary tract infection in children: etiology and epidemiology. Urol Clin North Am. 2004 Aug;31(3):517-26.
  15. Habib S. Highlights for Management of a Child with a Urinary Tract Infection. Int J Pediatr. 2012;2012:943653.
  16. Ahmed SM, Swedlund Sk. Evaluation and Treatment of Urinary Tract Infections in Children. Am Fam Physician. 1998;57(7):1573-1580.
  17. Urinary tract infection in children diagnosis, treatment and long-term management. Available at: https://www.nice.org.uk/guidance/cg54/evidence/full-guideline-pdf-196566877. Accessed on 02/11/2017.
  18. Schmiemann G, Kniehl E, Gebhardt K, et al. The diagnosis of urinary tract infection: a systematic review. Dtsch Arztebl Int. 2010 May;107(21):361-7.
  19. Mohsin R, Siddiqui KM. Recurrent urinary tract infections in females. J Pak Med Assoc 2010;60(1):55-59.
  20. Schauberger CW, Merkitch KW, Prell AM. Acute cystitis in women: experience with a telephone-based algorithm. Wisconsin Medical Journal 2007;106(6):326-329.
  21. Hummers-Pradier E, Kochen MM. Urinary tract infections in adult general practice patients. Br J Gen Pract. 2002;52(482):752–761.
  22. Wang A, Nizran P, Malone MA, et al. Urinary tract infections. Prim Care. 2013;40(3): 687-706.
  23. Mazzulli T. Diagnosis and management of simple and complicated urinary tract infections (UTIs). The Can J Urol 2012;19 Suppl 1:42-48.
  24. Chen YH, Ko WC, Hsueh PR. Emerging resistance problems and future perspectives in pharmacotherapy for complicated urinary tract infections. Expert Opin Pharmacother. 2013 Apr;14(5):587-96.
  25. Urinary tract infection. Available at: http://www.umm.edu/patiented/articles/how_antibiotics_used_treating_urinary_tract_infections_000036_8.htm. Accessed on 03/11/2017.
  26. Fluoroquinolones in children. Available at:http://www.who.int/selection_medicines/committees/subcommittee/2/fluoroquinolones_rev.pdf. Accessed on 03/11/2017.
  27. Colgan R, Williams M. Diagnosis and Treatment of Acute Uncomplicated Cystitis. Am Fam Physician 2011;84(7):771-76.
  28. Gupta K, Hooton TM, Naber KG, et al. Executive Summary: 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. Clin Infect Dis. 2011;52(5):561-564.
  29. Nelson 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+2015&hl=en&sa=X&redir_esc=y#v=snippet&q=nitrofurantoin&f=false. Accessed on: 04/11/2017.
  30. Rijal A, Ghimire G, Gautam K, et al. Antibiotic susceptibility of organisms causing urinary tract infection in patients presenting to a teaching hospital. J Nepal Health Res Counc. 2012;10(1):24-7.
  31. Kashanian J, Hakimian P, Blute M Jr, et al. Nitrofurantoin: the return of an old friend in the wake of growing resistance. BJU Int. 2008;102(11):1634-7.
  32. Finer G, Landau D. Pathogenesis of urinary tract infections with normal female anatomy. Lancet Infect Dis. 2004; 4: 631–35.
  33. Falakaflaki B, Fallah R, Jamshidi MR, et al. Comparison of Nitrofurantoin and Trimethoprim-Sulphamethoxazole for Long-Term Prophylaxis in Children with Recurrent Urinary Tract Infections. International Journal of Pharmacology. 2007; 3(2):179-182.
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