Urinary Tract Infections in Renal Patients

Chronic Renal Failure and Urinary tract infection: How are these Linked?

Urinary tract infection (UTI) is a common occurrence in patients with renal failure.¹Chemlal A, Ismaili FA Karimi I, et al. Urinary tract infections in chronic renal failure patients hospitalized in Nephrology: bacteriological profile and risk factors. The Pan African Medical Journal . 2015; 20: 100.  Chronic renal failure is a significant risk factor for the development of UTIs due to metabolic disorders leading to secondary immunodeficiency with a disorder of all components of immunity.²Sobotova D. [Urinary tract infections and chronic renal failure]. Vnitr Lek.2011 Jul-Aug;57(7-8):626-30.  UTI is a frequent reason for increased consultation in nephrology clinics and is usually seen in a large number of hospitalized patients.¹Chemlal A, Ismaili FA Karimi I, et al. Urinary tract infections in chronic renal failure patients hospitalized in Nephrology: bacteriological profile and risk factors. The Pan African Medical Journal . 2015; 20: 100.  It occur most frequently after kidney transplantation in chronic renal failure patients when graft pyelonephritis is a life-threatening complication. The commonly affected population includes women of childbearing age and seniors of both the sexes with multiple risk factors.²Sobotova D. [Urinary tract infections and chronic renal failure]. Vnitr Lek.2011 Jul-Aug;57(7-8):626-30.  A retrospective cohort study³Hsiao CY, Lin HL, Lin YK, Chen CW, Cheng YC, Lee WC, Wu TC. Urinary tract infection in patients with chronic kidney disease. Turk J Med Sci. 2014;44(1):145-9.  was conducted in favor of this notion. The aim of the study was to review the data on epidemiology, clinical features, and outcomes of UTI in patients with chronic kidney disease. The study included a total of 276 chronic kidney disease patients requiring hospitalization due to UTI. Results revealed that majority of patients with CKD and UTIs were elderly and females were more prone to have bacteriuria and upper UTI. Moreover, patients with renal stone were more likely to have UTI than other bacteriuria patients.

All the above mentioned data evince that chronic kidney disease is a common risk factor for the development of UTI in adults and elderly patients. However, it occurs in children also. UTI is among the most common bacterial infections in childhood and 2% to 5% of children experience at least 1 infection prior to puberty.⁴Salo J, Ikaheimo R, Tapiainen T, Uhari M. Childhood urinary tract infections as a cause of chronic kidney disease. Pediatrics. 2011 Nov;128(5):840-7.  Children with chronic renal failure more commonly experience lower UTI symptoms. This was validated in a study⁵Oborn H, Herthelius M. Lower urinary tract symptoms in children and adolescents with chronic renal failure. J Urol. 2010 Jan;183(1):312-6.  conducted to evaluate the bladder function before renal transplant in children with chronic renal failure. Outcomes of the study divulged that 100% of (13 of 13) the patients developed UTI and showed the signs of bladder dysfunction (incontinence, abnormal bladder capacity, discontinuous urinary flow and/or residual urine).

UTI in chronic kidney disease is very serious due to its grafted heavy morbidity and mortality. In such patients UTI is immediately complicated infection imposing taking into particular diagnosis and treatment.¹Chemlal A, Ismaili FA Karimi I, et al. Urinary tract infections in chronic renal failure patients hospitalized in Nephrology: bacteriological profile and risk factors. The Pan African Medical Journal . 2015; 20: 100.  

Complicated UTI

Complicated UTI is defined as the infection which occurs in a patient with an anatomically abnormal urinary tract or the presence of significant medical or surgical comorbidities.⁶Neal DE Jr. Complicated urinary tract infections. Urol Clin North Am. 2008 Feb;35(1):13-22; v.  Complicated UTIs include those involving the parenchyma (pyelonephritis or prostatitis) and frequently occur in the setting of obstructive uropathy or after instrumentation. Moreover, it also includes the presence of obstruction, stones or high-pressure vesico-ureteric reflux, perinephric abscess, life-threatening septicemia or a combination of these predispose to kidney damage (Figure 1).⁷Najar MS, Saldanha CL, Banday KA. Approach to urinary tract infections.Indian Journal of Nephrology. 2009;19(4):129-139.  Complicated UTIs are the major cause of hospital admissions and are associated with significant morbidity and healthcare cost.⁸Bader MS, Hawboldt J, Brooks A. Management of complicated urinary tract infections in the era of antimicrobial resistance. Postgrad Med. 2010 Nov;122(6):7-15.  These are also common and potentially life threatening conditions.⁹Mnif MF, Kamoun M, Kacem FH, et al. Complicated urinary tract infections associated with diabetes mellitus: Pathogenesis, diagnosis and management. Indian Journal of Endocrinology and Metabolism.2013;17(3):442-445.  Hence, the need for early detection is of utmost importance.

Signs and Symptoms of UTI

Signs and symptoms of UTI vary by age and gender of the patient and whether a catheter is present. In young women the symptoms typically include a frequent and intense urge to urinate and a painful, burning feeling in the bladder or urethra during urination. However, the quantity of urine may be very small. Besides, in older women and men the symptoms include tiredness, lethargy and weakness and have muscle aches and abdominal pain. Color of the urine may vary from cloudy, dark, to bloody or have a foul smell. In patients with catheter, fever may be the only symptom that cannot be attributed to any other cause. Usually, with the involvement of bladder only, UTIs do not cause fever. A fever may be the primary sign indicative of the infection that has reached the kidneys or has penetrated the prostate. Other symptoms of a kidney infection may include pain in the back or side below the ribs, nausea, and vomiting (Box 1).¹⁰Urinary tract infection in adults. Available at: https://www.niddk.nih.gov/health-information/health-topics/urologic-disease/urinary-tractinfections-in-adults/Pages/facts.aspx. Accessed on: 30/7/16.  

Diagnosis of UTI

The detection of pathogen in the presence of clinical symptoms is a benchmark for diagnosis of a UTI. The clinical diagnosis of UTI is essentially based on the medical history of the patient. Specific data may either amplify the probability of an infection of the urinary tract or reduce it. The factors that have been established from clinical studies are mentioned in table 1. After medical history urine testing is the second important element in the diagnosis of UTI. The best method for a urine test is to perform a bacteriological urine culture, with identification of the pathogen, quantification and sensitivity testing. Additionally, orientating indirect methods are often used in practice to detect the bacteria or inflammation (dip sticks). Moreover, the bacterial count may be assessed by urine microscopy and immersion culture media.¹¹Schmiemann G, Kniehl E, Gebhardt K, Matejczyk MM, Hummers-Pradier E.The Diagnosis of Urinary Tract Infection: A Systematic Review. Deutsches Arzteblatt International. 2010;107(21):361-367.   Sensitivity testing may also be ordered by the physician to test the bacteria for sensitivity to different antibiotics.

Some, additional tests may also be performed to detect any abnormality in the urinary tract of patient. These include kidney and bladder ultrasound, voiding cystourethrogram, computerized tomography (CT) scan, magnetic resonance imaging (MRI), radionuclide scan, urodynamics and cystoscopy.

Kidney and bladder ultrasound: The images in an ultrasound can show abnormalities in the kidneys and bladder. However, this test cannot reveal all important urinary abnormalities or measure working capacity of kidneys.

Voiding cystourethrogram: This is an x-ray image of the bladder and urethra taken while the bladder is full and during urination, also called voiding. It is used to show the abnormalities of inside of the urethra and bladder. It can also determine whether the flow of urine is normal when the bladder empties.

CT scan: It is a combination of x-rays and computer technology to create three-dimensional (3-D) images. It provides a more clear and detailed images to help the clinicians understand the problem.

MRI: It uses radio waves and magnets to produce detailed pictures of the body’s internal organs and soft tissues without using x rays. Like CT scans, it can also provide more clear and detailed images.

Radionuclide scan: It is an imaging technique that relies on the detection of small amounts of radiation after injection of radioactive chemicals. These chemicals when injected into the blood can provide information about kidney function. It can also be put into the fluids used to fill the bladder and urethra for X-ray, MRI, and CT imaging.

Urodynamics: Any procedure that looks at how well the bladder, sphincters, and urethra are storing and releasing urine is referred to as urodynamics. These tests focus on the ability of bladder to hold the urine and empty the bladder steadily and completely. These tests can also depict whether the bladder is having abnormal contractions that cause leakage.

Cystoscopy: It is a procedure that uses a tube-like instrument to look inside the urethra and bladder. It may be used to detect swelling, redness, and other signs of infection in these organs.¹⁰Urinary tract infection in adults. Available at: https://www.niddk.nih.gov/health-information/health-topics/urologic-disease/urinary-tractinfections-in-adults/Pages/facts.aspx. Accessed on: 30/7/16.  

Clinical options for the Treatment of Complicated UTI

UTI diagnosis is established by the recognition of a significant leukocyturia and bacteriuria of the mid-stream urine analysis in men and catheter urine in women. Accurate diagnosis is made possible by the case history as well as clinical, sonographical and laboratory tests (leucocytes, CRP) to classify into a cystitis and infection of the parenchyma, respectively an uncomplicated or complicated UTI. Untreated complicated UTIs have a bad prognosis.¹²Peters HJ. Antibiotic treatment of complicated urinary tract infections. Z Arztl Fortbild (Jena). 1995 Jun;89(3):279-86.   There is an increase in the number of complicated UTI due to rise in the resistant gram-negative bacteria. The situation arises mainly due to spread of extended spectrum β-lactamase (ESBL) bacteria that imposes a significant therapeutic challenge. Even though a broad range of pathogens can cause complicated UTI, Escherichia coli remain the most common amid them.¹³Ranjan KP, Ranjan N. Complicated urinary tract infection caused by extended spectrum β-lactamase-producing Escherichia coli. Urology Annals. 2014;6(2):112-113.  There is an increase in resistance to first-line antimicrobial agents, including fluoroquinolones in Escherichia coli. The WHO report has suggested that there is a high level of E. coli resistance to third generation cephalosporins and fluoroquinolones (two important and commonly used types of antibacterial medicine) in the south-east Asia region.¹⁴WHO’s first global report on antibiotic resistance reveals serious,worldwide threat to public health. Available at: http://www.who.int/ mediacentre/news/releases/2014/amr-report/en/. Accessed on: 30/7/16.   This rising antimicrobial resistance necessitates the need for an optimal therapeutic agent.

Effective anti-microbial therapy is the foundation of management of serious UTIs. Appropriate selection of optimal antimicrobial agent must take into account the patient-specific factors including history of allergy, renal function, concomitant medications; infection characteristics such as severity, community- vs. institutional- or hospitalacquired, need for IV agent; local resistance patterns; pharmacokinetic and pharmacodynamic characteristics; and cost of therapy. In severe complicated UTI empirical therapy should based on the local resistance pattern, but the treatment should be adapted according to susceptibility testing. However, in mild to moderate complicated UTI the antimicrobial therapy may not be initiated until testing results is available.¹⁵Wagenlehner FM, Naber KG. Current challenges in the treatment of complicated urinary tract infections and prostatitis. Clin Microbiol Infect. 2006 May;12 Suppl 3:67-80.   In this context nitrofurantoin is the most commonly used antibiotic agent.¹⁶Jancel T, Dudas V. Management of uncomplicated urinary tract infections.Western Journal of Medicine. 2002;176(1):51-55.  

Role of Nitrofurantoin in the Management of UTIs

Nitrofurantoin is a synthetic derivative of imidazolidinedione. It inhibits bacterial DNA, RNA, and cell wall protein synthesis. Nitrofurantoin has been used in clinical practice since more than 50 years. Despite it’s long history of usage, resistance is least with nitrofurantoin. Nitrofurantoin is uro-specific antibiotic with highest efficacy and least resistance.¹⁷Nitrofurantoin. Available at: https://pubchem.ncbi.nlm.nih.gov/compound/nitrofurantoin#section=Top. Accessed on: 1/8/16.   It is widely used for the treatment of UTIs caused by susceptible strains of Escherichia coli, enterococci, Staphylococcus aureus, Staphylococcus saprophyticus, Klebsiella species, Enterobacter species, and Proteus species.¹⁸Nitrofurantoin. Available at: https://pubchem.ncbi.nlm.nih.gov/compound/nitrofurantoin#section=Therapeutic-Uses. Accessed on: 1/8/16.   The mechanism of action of nitrofurantoin involves reduction by bacterial nitroreductases to generate toxic derivatives that attach to ribosomal proteins, causing defective transcription and translation in bacteria.¹⁹Xavier BB, Vervoort J, Stewardson A, et al. Complete Genome Sequences of Nitrofurantoin-Sensitive and -Resistant Escherichia coli ST540 and ST2747 Strains. Genome Announcements. 2014;2(2):e00239-14.  Nitrofurantoin is well absorbed from the gastrointestinal tract with the majority of absorption taking place in the proximal small bowel.

Nitrofurantoin has negligible effect on intestinal flora.²⁰Munoz-Davila MJ. Role of Old Antibiotics in the Era of Antibiotic Resistance. Highlighted Nitrofurantoin for the Treatment of Lower Urinary Tract Infections. Antibiotics. 2014;3(1):39-48.  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.

Efficacy of Nitrofurantoin in UTI Management

Nitrofurantoin has established efficacy in the treatment of UTIs as suggested by various reports. According to the European Association of Urology, nitrofurantoin is recommended as the first line agent for the management of UTIs.²¹Grabe M, Bartoletti R, Johansen TEB, et al. Guidelines on Urological Infections. Available at: http://uroweb.org/wp-content/uploads/19- Urological-infections_LR2.pdf. Accessed on: 1/8/16.   Past reports have also suggested that nitrofurantoin has remained effective even after more than 50 years of extensive use worldwide with essentially no resistance. Additionally, it is an ideal antibiotic therapy for a variety of UTIs.²²Cunha BA, Schoch PE, Hage JR. Nitrofurantoin: Preferred Empiric Therapy for Community-Acquired Lower Urinary Tract Infections. Mayo Clinic Proceedings. 2011;86(12):1243-1244.   Also there is good evidence concerning its efficacy in the management if UTIs. An open-label study²³Mendoza-Valdes A, Rosete A, Rios Bueno E, 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.   was conducted to demonstrate the clinical efficacy of nitrofurantoin in the treatment of UTI. A total of 20 adult patients with positive urine culture were treated with nitrofurantoin sustained release 100 mg twice daily for 7 days. The results of the study divulged that after 12 to 16 days of therapy the microbial eradication rate was 92.3% and after 35 to 42 days the eradication rate was 83.3%, respectively (Figure 2).

The findings in this study mirrored other report²⁴Olorunmola 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.   whereby E. coli isolates from cases of UTI were tested for their sensitivity to commonly used antibiotics and control of virulence factors using standard methods. Results of report suggested that there was a high and widespread resistance (51.1 % to 94.3 %) to all the antibiotics used except nitrofurantoin (7.3 %) (Figure 3). In addition to its efficacy it is also considered to be a cost effective drug in comparison to other antibiotic agents. In order to compare the cost of nitrofurantoin with other recommended antibiotics for the treatment of UTIs, a cost-minimization and sensitivity analyses²⁵McKinnell JA, Stollenwerk NS, Jung CW, Miller LG. Nitrofurantoin Compares Favorably to Recommended Agents as Empirical Treatment of Uncomplicated Urinary Tract Infections in a Decision and Cost Analysis.Mayo Clinic Proceedings. 2011;86(6):480-488.  was performed. The analyses used nitrofurantoin and trimethoprim-sulfamethoxazole (TMP-SMX) to evaluate the costs. Results divulged that nitrofurantoin was found to be cost-minimizing when the prevalence of fluoroquinolone resistance exceeded 12% among uropathogens or the prevalence of TMP-SMX resistance exceeded 17%. From the perspective of a payer, nitrofurantoin appears to be a reasonable substitute to TMP-SMX and fluoroquinolones for empirical treatment of uncomplicated UTIs, particularly in the current era of high prevalence of antibiotic resistance among community uropathogens. Thus, taking into account the superior efficacy, low cost, and low impact on promoting antimicrobial resistance, nitrofurantoin should be considered as a reasonable alternative to TMP-SMX and fluoroquinolones for first-line therapy for uncomplicated UTIs. Physicians should use fluoroquinolone cautiously. Regulatory bodies like US Food and Drug Administration (FDA) has updated labeling for fluoroquinolone antibiotics and has warned against their use in patients with uncomplicated urinary tract infections and other infections, unless the patients have no other treatment options. The new labeling of fluoroquinolone strengthens warnings about the risks for disabling and potentially permanent adverse effects including tendonitis and tendon rupture, central nervous system effects, myasthenia gravis exacerbation, peripheral neuropathy, prolongation of the QT interval, torsades de pointes, and phototoxicity. These effects can occur hours to weeks after exposure and can occur together. Fluoroquinolones have risks and benefits that should be considered very carefully.

Use of Nitrofurantoin in Renal Impairment Patients

Recent studies have provided exciting novel insight into the use of nitrofurantoin in renal impairment patients. Current data favors its use in patients with chronic renal diseases. The data suggests that nitrofurantoin can be safely administered to patients with creatinine clearance of at least 40 mL/min/1.73 m2. According to the pharmacological reports, nitrofurantoin achieves very low plasma concentrations, and abut 40% of it is excreted in the urine.²⁶Mody L, Juthani-Mehta M. Urinary Tract Infections in Older Women: A Clinical Review. JAMA. 2014;311(8):844-854.  

In a recently conducted study²⁷Singh N, Gandhi S, McArthur E, et al. Kidney function and the use of nitrofurantoin to treat urinary tract infections in older women. CMAJ : Canadian Medical Association Journal. 2015;187(9):648-656.   the use of nitrofurantoin was studied in patients with reduced kidney function. It was a population based study which included older women with mean age 79 years and estimated glomerular filtration rate was relatively low (median 38 mL/min per 1.73 m²). All the patients were randomized to receive 1 of 4 antibiotics including nitrofurantoin, ciprofloxacin, norfloxacin or trimethoprim-sulfamethoxazole. After 14 days the analyses was repeated for older women with relatively high estimated glomerular filtration rate (median 69 mL/min per 1.73 m2). Results divulged that the baseline characteristics of the 4 antibiotic groups were similar. Also, treatment failure with nitrofurantoin was comparable to that of other antibiotics. As an inference of the study results the authors suggest that the presence of mild or moderate reductions in estimated glomerular filtration rate did not justify the avoidance of nitrofurantoin in patients with UTI and reduced renal function.

Similar results were demonstrated in another study²⁷Bains A, Buna D, Hoag NA. A retrospective review assessing the efficacy and safety of nitrofurantoin in renal impairment. Can Pharm J 2009;142:248-52.  which compared the efficacy of nitrofurantoin in renal function impairment group and control group. The cure rate in the impaired renal function and control group was reported to be 71% (95% CI 63-79) and 78% (95% CI 73-84) respectively (figure 4). Likewise, in a more recent study²⁹Geerts AF, Eppenga WL, Heerdink R, et al. Ineffectiveness and adverse events of nitrofurantoin in women with urinary tract infection and renal impairment in primary care. Eur J Clin Pharmacol 2013;69:1701-7.  nitrofurantoin treatment was not associated with a higher risk of ineffectiveness in women with UTI and moderate renal impairment (30-50 ml/min/1.73 m²).

The 2015 American Geriatrics Society (AGS) Beers Criteria are presented. Like the 2012 AGS Beers Criteria, they include lists of potentially inappropriate medications to be avoided in older adults. New to the criteria are lists of select drugs that should be avoided or have their dose adjusted based on the individual’s kidney function and select drug-drug interactions documented to be associated with harms in older adults. Based on two retrospective studies, the recommendation to avoid the anti-infective nitrofurantoin in individuals with a creatinine clearance of less than 60 mL/min has been revised, given evidence that it can be used with relative safety and efficacy in individuals with a creatinine clearance of 30 mL/min or greater.³⁰American Geriatrics Society 2015 Updated Beers Criteria for Potentially Inappropriate Medication Use in Older Adults. By the American Geriatrics Society 2015 Beers Criteria Update Expert Panel. Journal of the American Geriatrics Society. J Am Geriatr Soc. 2015;63(11):2227-2246.  

In view of the above-mentioned data it can be suggested that nitrofurantoin can be safely used in UTI patients with mild to moderate renal impairment.

Conclusion

Urinary tract infections are a common occurrence in patients with renal failure. It is a frequent reason for increased consultation in nephrology clinics and is usually seen in a large number of hospitalized patients. Reports have suggested that there is an increased prevalence of urinary tract infections in patients with chronic renal diseases. Urinary tract infection in chronic kidney disease is very serious due to its grafted heavy morbidity and mortality. In such patients it is immediately complicated infection imposing taking into particular diagnosis and treatment. The detection of pathogen in the presence of clinical symptoms is a benchmark for its diagnosis. Diagnostic techniques includes intake of an adequate medical history, urine testing in the laboratory and bladder imaging techniques to detect any abnormality in the bladder. The commonly isolated bacteriological agent in the urine of infected patient is E. coli. Effective anti-microbial therapy is the foundation of management of serious urinary tract infections. In this context nitrofurantoin is the most commonly used antibiotic agent. It is effective against a variety of pathogens including Escherichia coli, enterococci, Staphylococcus aureus, Staphylococcus saprophyticus, Klebsiella species, Enterobacter species, and Proteus species. It is highly efficacious in patients with complicated and uncomplicated urinary tract infections and can be safely used in patients with mild to moderate renal impairment.

References

1. Chemlal A, Ismaili FA Karimi I, et al. Urinary tract infections in chronic renal failure patients hospitalized in Nephrology: bacteriological profile and risk factors. The Pan African Medical Journal . 2015; 20: 100.
2. Sobotova D. [Urinary tract infections and chronic renal failure]. Vnitr Lek.2011 Jul-Aug;57(7-8):626-30.
3. Hsiao CY, Lin HL, Lin YK, Chen CW, Cheng YC, Lee WC, Wu TC. Urinary tract infection in patients with chronic kidney disease. Turk J Med Sci. 2014;44(1):145-9.
4. Salo J, Ikaheimo R, Tapiainen T, Uhari M. Childhood urinary tract infections as a cause of chronic kidney disease. Pediatrics. 2011 Nov;128(5):840-7.
5. Oborn H, Herthelius M. Lower urinary tract symptoms in children and adolescents with chronic renal failure. J Urol. 2010 Jan;183(1):312-6.
6. Neal DE Jr. Complicated urinary tract infections. Urol Clin North Am. 2008 Feb;35(1):13-22; v.
7. Najar MS, Saldanha CL, Banday KA. Approach to urinary tract infections.Indian Journal of Nephrology. 2009;19(4):129-139.
8. Bader MS, Hawboldt J, Brooks A. Management of complicated urinary tract infections in the era of antimicrobial resistance. Postgrad Med. 2010 Nov;122(6):7-15.
9. Mnif MF, Kamoun M, Kacem FH, et al. Complicated urinary tract infections associated with diabetes mellitus: Pathogenesis, diagnosis and management. Indian Journal of Endocrinology and Metabolism.2013;17(3):442-445.
10. Urinary tract infection in adults. Available at: https://www.niddk.nih.gov/health-information/health-topics/urologic-disease/urinary-tractinfections-in-adults/Pages/facts.aspx. Accessed on: 30/7/16.
11. Schmiemann G, Kniehl E, Gebhardt K, Matejczyk MM, Hummers-Pradier E.The Diagnosis of Urinary Tract Infection: A Systematic Review. Deutsches Arzteblatt International. 2010;107(21):361-367.
12. Peters HJ. Antibiotic treatment of complicated urinary tract infections. Z Arztl Fortbild (Jena). 1995 Jun;89(3):279-86.
13. Ranjan KP, Ranjan N. Complicated urinary tract infection caused by extended spectrum β-lactamase-producing Escherichia coli. Urology Annals. 2014;6(2):112-113.
14. WHO’s first global report on antibiotic resistance reveals serious,worldwide threat to public health. Available at: http://www.who.int/ mediacentre/news/releases/2014/amr-report/en/. Accessed on: 30/7/16.
15. Wagenlehner FM, Naber KG. Current challenges in the treatment of complicated urinary tract infections and prostatitis. Clin Microbiol Infect. 2006 May;12 Suppl 3:67-80.
16. Jancel T, Dudas V. Management of uncomplicated urinary tract infections.Western Journal of Medicine. 2002;176(1):51-55.
17. Nitrofurantoin. Available at: https://pubchem.ncbi.nlm.nih.gov/compound/nitrofurantoin#section=Top. Accessed on: 1/8/16.
18. Nitrofurantoin. Available at: https://pubchem.ncbi.nlm.nih.gov/compound/nitrofurantoin#section=Therapeutic-Uses. Accessed on: 1/8/16.
19. Xavier BB, Vervoort J, Stewardson A, et al. Complete Genome Sequences of Nitrofurantoin-Sensitive and -Resistant Escherichia coli ST540 and ST2747 Strains. Genome Announcements. 2014;2(2):e00239-14.
20. Munoz-Davila MJ. Role of Old Antibiotics in the Era of Antibiotic Resistance. Highlighted Nitrofurantoin for the Treatment of Lower Urinary Tract Infections. Antibiotics. 2014;3(1):39-48.
21. Grabe M, Bartoletti R, Johansen TEB, et al. Guidelines on Urological Infections. Available at: http://uroweb.org/wp-content/uploads/19- Urological-infections_LR2.pdf. Accessed on: 1/8/16.
22. Cunha BA, Schoch PE, Hage JR. Nitrofurantoin: Preferred Empiric Therapy for Community-Acquired Lower Urinary Tract Infections. Mayo Clinic Proceedings. 2011;86(12):1243-1244.
23. Mendoza-Valdes A, Rosete A, Rios Bueno E, 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.
24. Olorunmola 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.
25. McKinnell JA, Stollenwerk NS, Jung CW, Miller LG. Nitrofurantoin Compares Favorably to Recommended Agents as Empirical Treatment of Uncomplicated Urinary Tract Infections in a Decision and Cost Analysis.Mayo Clinic Proceedings. 2011;86(6):480-488.
26. Mody L, Juthani-Mehta M. Urinary Tract Infections in Older Women: A Clinical Review. JAMA. 2014;311(8):844-854.
27. Singh N, Gandhi S, McArthur E, et al. Kidney function and the use of nitrofurantoin to treat urinary tract infections in older women. CMAJ : Canadian Medical Association Journal. 2015;187(9):648-656.
28. Bains A, Buna D, Hoag NA. A retrospective review assessing the efficacy and safety of nitrofurantoin in renal impairment. Can Pharm J 2009;142:248-52.
29. Geerts AF, Eppenga WL, Heerdink R, et al. Ineffectiveness and adverse events of nitrofurantoin in women with urinary tract infection and renal impairment in primary care. Eur J Clin Pharmacol 2013;69:1701-7.
30. American Geriatrics Society 2015 Updated Beers Criteria for Potentially Inappropriate Medication Use in Older Adults. By the American Geriatrics Society 2015 Beers Criteria Update Expert Panel. Journal of the American Geriatrics Society. J Am Geriatr Soc. 2015;63(11):2227-2246.