UTI in Patients with Chronic Renal Insufficiency & Diabetes

Overview

Urinary tract infections (UTIs) are a common condition seen both in hospital and the community setting. They are predominantly caused by Gram-negative bacilli (70%), and Escherichia coli is the most common pathogen. Certain conditions associated with a higher risk of UTIs are shown in Table 1.¹Tandogdu Z, et al. Urinary Tract Infections in Immunocompromised Patients with Diabetes, Chronic Kidney Disease, and Kidney Transplant. European Urology Focus. 2016;2:394-399.

These conditions may deteriorate the host defensive mechanism or allow a bypass route for pathogens in the urinary tract.¹Tandogdu Z, et al. Urinary Tract Infections in Immunocompromised Patients with Diabetes, Chronic Kidney Disease, and Kidney Transplant. European Urology Focus. 2016;2:394-399.

The most common acquired conditions causing deterioration in host defence mechanisms are:¹Tandogdu Z, et al. Urinary Tract Infections in Immunocompromised Patients with Diabetes, Chronic Kidney Disease, and Kidney Transplant. European Urology Focus. 2016;2:394-399.

• Diabetes mellitus (DM)
• Chronic kidney diseases (CKDs)
• End stage renal disease
• Solid organ transplantation (specifically kidney transplantation).

Urine conditions that increase susceptibility to urinary pathogens are as mentioned below:¹Tandogdu Z, et al. Urinary Tract Infections in Immunocompromised Patients with Diabetes, Chronic Kidney Disease, and Kidney Transplant. European Urology Focus. 2016;2:394-399.

• Urinary pH between 6 and 7
• Glucosuria
• Idiopathic hypercalciuria
• Elevated urinary iron

Females are prone to UTIs due to the shortness of the urethra, which is close to the vagina and anus; the lack of prostatic fluid, which has antibacterial activity; or the use of spermicides and/or diaphragms.²Hsiao CY, et al. Urinary tract infection in patients with chronic kidney disease. Turk J Med Sci. 2014; 44:145-149. doi:10.3906/sag-1303-51

CKD may result from recurrent UTIs and retrospective infection to the kidneys. CKD has already become a burden of global health. With advances in haemodialysis and medical care, patients sustaining CKD have had prolonged survival.

Even so, these patients may have some medical problems that cause CKD, such as DM, uncontrolled high blood pressure, primary kidney diseases, or drug toxicities, which may result in chronic medical problems. They may have complications of reduced kidney function, such as hypertension, malnutrition, anaemia, bone disease, and decreased quality of life. In addition, due to prolonged haemodialysis that may compromise their immune system, they are vulnerable to infection, including UTIs.²Hsiao CY, et al. Urinary tract infection in patients with chronic kidney disease. Turk J Med Sci. 2014; 44:145-149. doi:10.3906/sag-1303-51

The underlying reasons for the higher risk of UTI in patients with CKD are thought to be an altered host reaction and anatomic and functional disorders of the urinary tract. The alteration in host protective functions is thought to be due to:¹Tandogdu Z, et al. Urinary Tract Infections in Immunocompromised Patients with Diabetes, Chronic Kidney Disease, and Kidney Transplant. European Urology Focus. 2016;2:394-399.

• Loss of antibacterial properties of the urine
• Mild immunosuppression in uraemia
• Inhibition of protective mucosa production in the urothelium

Evidence of a correlation between CKD and higher UTI risk is most solid for autosomal dominant polycystic kidney disease (ADPKD) and CKD associated with stone disease.¹Tandogdu Z, et al. Urinary Tract Infections in Immunocompromised Patients with Diabetes, Chronic Kidney Disease, and Kidney Transplant. European Urology Focus. 2016;2:394-399.

Patients with type 2 diabetes mellitus are at increased risk of infections, with the urinary tract being the most frequent infection site. Various impairments in the immune system, in addition to poor metabolic control of diabetes, and incomplete bladder emptying due to autonomic neuropathy may all contribute in the pathogenesis of UTIs in diabetic patients. Factors that were found to enhance the risk for UTI in diabetics include age, metabolic control, and long-term complications, primarily diabetic nephropathy and cystopathy.³Nitzan O, Elias M, Chazan B, Saliba W. Urinary tract infections in patients with type 2 diabetes mellitus: review of prevalence, diagnosis, and management. Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy. 2015;8:129-136.   Diabetes is also associated with worse outcomes of UTI, including longer hospitalisations and increased mortality.³Nitzan O, Elias M, Chazan B, Saliba W. Urinary tract infections in patients with type 2 diabetes mellitus: review of prevalence, diagnosis, and management. Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy. 2015;8:129-136.

The most common pathogens isolated from urine of diabetic patients with UTI are Escherichia coli , other Enterobacteriaceae such as Klebsiella spp., Proteus spp., Enterobacter spp., and Enterococci. Patients with diabetes are more prone to have resistant pathogens as the cause of their UTI, including extended-spectrum β -lactamase-positive Enterobacteriaceae, fluoroquinolone-resistant uropathogens, carbapenem-resistant Entero-bacteriaceae, and vancomycin-resistant Enterococci.This might be due to several factors, including multiple courses of antibiotic therapy that are administered to these patients, frequently for asymptomatic or only mildly symptomatic UTI, and increased incidence of hospital-acquired and catheter-associated UTI, which are both associated with resistant pathogens. Type 2 diabetes is also a risk factor for fungal UTI.³Nitzan O, Elias M, Chazan B, Saliba W. Urinary tract infections in patients with type 2 diabetes mellitus: review of prevalence, diagnosis, and management. Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy. 2015;8:129-136.

Epidemiology

The frequency of UTI in patients with chronic renal insufficiency is not known to be different from that in the general population. On the one hand, the chronic disease that causes the renal insufficiency could reduce the risk for UTI as a result of reduction of risk factors such as sexual activity. Alternatively, the risk might be increased by disease factors (e.g., papillary necrosis, nephrolithiasis, neurogenic bladder) and the management of comorbidities with Foley catheters and intravenous lines.⁴Gilbert DN. Urinary tract infections in patients with chronic renal insufficiency. Clin J Am Soc Nephrol. 2006;1:327–331. doi: 10.2215/CJN.01931105

DM has been identified as an independent risk factor for UTI.¹Tandogdu Z, et al. Urinary Tract Infections in Immunocompromised Patients with Diabetes, Chronic Kidney Disease, and Kidney Transplant. European Urology Focus. 2016;2:394-399.  Type 2 diabetes is not only a risk factor for community acquired UTI but also for health care associated UTI, catheter associated UTI, and post renal transplant recurrent UTI.³Nitzan O, Elias M, Chazan B, Saliba W. Urinary tract infections in patients with type 2 diabetes mellitus: review of prevalence, diagnosis, and management. Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy. 2015;8:129-136.

Not only are UTIs more prevalent in patients with DM, but the clinical manifestations and impact of infections are also more intense. The factors that further increase the risk of more severe UTI in patients with type 2 diabetes aged >45 yr are: Chronic antibiotic consumption, renal disease, urinary incontinence, and age >60 yr.¹Tandogdu Z, et al. Urinary Tract Infections in Immunocompromised Patients with Diabetes, Chronic Kidney Disease, and Kidney Transplant. European Urology Focus. 2016;2:394-399.

Clinical Presentation

The characteristic symptoms of UTI in the adult are primarily dysuria with irritating voiding symptoms like urinary urgency, frequency, nocturia, painful voiding, bladder discomfort or stranguria which greatly distress the patient. A sensation of bladder fullness or lower abdominal discomfort is usually present.⁵.Hotchandani R, Aggarwal KK. Urinary tract infections in women. Indian Journal of Clinical Practice. 2012; 23(4):187-192.

The spectrum of UTI in diabetes patients ranges from asymptomatic bacteriuria (ASB) to lower UTI (cystitis), pyelonephritis, and severe urosepsis. Serious complications of UTI, such as emphysematous cystitis and pyelonephritis, renal abscesses and renal papillary necrosis, are all encountered more frequently in type 2 diabetes than in the general population.³Nitzan O, Elias M, Chazan B, Saliba W. Urinary tract infections in patients with type 2 diabetes mellitus: review of prevalence, diagnosis, and management. Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy. 2015;8:129-136.   The clinical presentation and severity grading of UTIs are shown in Table 2.¹Tandogdu Z, et al. Urinary Tract Infections in Immunocompromised Patients with Diabetes, Chronic Kidney Disease, and Kidney Transplant. European Urology Focus. 2016;2:394-399.

Diagnosis

The diagnosis of UTI should be suspected in any patient with symptoms consistent with UTI. These symptoms are: Frequency, urgency, dysuria, and suprapubic pain for lower UTI; and costovertebral angle pain/tenderness, fever, and chills, with or without lower urinary tract symptoms for upper UTI.³Nitzan O, Elias M, Chazan B, Saliba W. Urinary tract infections in patients with type 2 diabetes mellitus: review of prevalence, diagnosis, and management. Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy. 2015;8:129-136.

Urinalysis is mandatory in all patients who present with dysuria. The gold standard is evaluation of a spun midstream clean catch urine specimen. Bacteria or pyuria (or both) are usually found in patients with UTI.⁵.Hotchandani R, Aggarwal KK. Urinary tract infections in women. Indian Journal of Clinical Practice. 2012; 23(4):187-192.   Pyuria can be detected either by microscopic examination (defined as ≥10 leucocytes/mm³Nitzan O, Elias M, Chazan B, Saliba W. Urinary tract infections in patients with type 2 diabetes mellitus: review of prevalence, diagnosis, and management. Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy. 2015;8:129-136. ), or by dipstick leucocyte esterase test (sensitivity of 75–96% and specificity of 94–98%, as compared with microscopic examination). A dipstick also tests for the presence of urinary nitrite. A positive test indicates the presence of bacteria in urine, while a negative test can be the product of low count bacteriuria or bacterial species that lack the ability to reduce nitrate to nitrite (mostly Gram-positive bacteria). Microscopic or macroscopic haematuria is sometimes present, and proteinuria is also a common finding.³Nitzan O, Elias M, Chazan B, Saliba W. Urinary tract infections in patients with type 2 diabetes mellitus: review of prevalence, diagnosis, and management. Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy. 2015;8:129-136.

A urine culture should be obtained in all cases of suspected UTI in diabetic patients, prior to initiation of treatment. The only exceptions are cases of suspected acute cystitis in diabetic women who do not have long-term complications of diabetes, including diabetic nephropathy, or any other complicating urologic abnormality.³Nitzan O, Elias M, Chazan B, Saliba W. Urinary tract infections in patients with type 2 diabetes mellitus: review of prevalence, diagnosis, and management. Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy. 2015;8:129-136.

Treatment Options

Management of UTI in diabetes patients

As a general rule, treatment of UTI in diabetic patients is similar to that of UTI in non-diabetic patients. Treatment of UTI in patients with type 2 diabetes depends on several factors, including: Presence of symptoms, if infection is localised in the bladder (lower UTI) or also involves the kidney (upper UTI), presence of urologic abnormalities, severity of systemic symptoms, accompanying metabolic alterations, and renal function. Treatment should also involve correction of metabolic complications caused by the infectious process. First- line treatment options for various types of UTI are detailed in Table 3.³Nitzan O, Elias M, Chazan B, Saliba W. Urinary tract infections in patients with type 2 diabetes mellitus: review of prevalence, diagnosis, and management. Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy. 2015;8:129-136.

There is no indication to treat ASB in diabetic patients.³Nitzan O, Elias M, Chazan B, Saliba W. Urinary tract infections in patients with type 2 diabetes mellitus: review of prevalence, diagnosis, and management. Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy. 2015;8:129-136.    A placebo-controlled, randomised prospective study of 105 women with diabetes mellitus found that during a mean follow up period of 27 months, antibiotic treatment did not affect the rate of symptomatic UTI, pyelonephritis, or hospitalisations for UTI.⁶Nicolle LE, Zhanel GG, Harding GK. Microbiological outcomes in women with diabetes and untreated asymptomatic bacteriuria. World J Urol. 2006;24(1):61–65.

The choice of antibiotics in patients with diabetes mellitus should also take into consideration possible drug interactions between antimicrobials and anti-diabetics or antihypertensive agents, and impaired glucose homeostasis that may be caused by certain antibiotics.⁷Chan JC, Cockram CS, Critchley JA. Drug-induced disorders of glucose metabolism. Mechanisms and management. Drug Saf. 1996;15(2):135–157.   Dosage adjustment is required in diabetic patients with renal impairment for some antimicrobials agents.⁸Munar MY, Singh H. Drug dosing adjustments in patients with chronic kidney disease. Am Fam Physician. 2007;75(10):1487–1496. 2000 Mar-Apr;13(2):120-5

Management of recurrent episodes of UTI is similar to non-diabetic patients. In young women without diabetic complications, post coital or daily low dose antibiotic prophylaxis may be offered. In patients with renal failure, complex urologic abnormalities, or highly resistant bacteria, long-term antibiotic prophylaxis is less effective.

In patients requiring catheterisation due to incomplete bladder voiding, intermittent catheterisation is preferred over a chronic indwelling catheter.³Nitzan O, Elias M, Chazan B, Saliba W. Urinary tract infections in patients with type 2 diabetes mellitus: review of prevalence, diagnosis, and management. Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy. 2015;8:129-136.

Management of UTI in patients with chronic renal insufficiency

The selection of the drug for empiric therapy is based on efficacy versus the likely infecting organism plus the patient’s allergy history, drug toxicity profile, drug excretory pathway, drug cost, and other factors.⁴Gilbert DN. Urinary tract infections in patients with chronic renal insufficiency. Clin J Am Soc Nephrol. 2006;1:327–331. doi: 10.2215/CJN.01931105

The recommended empiric therapy is a fluoroquinolone that achieves both adequate serum and urine concentrations. Hence, moxifloxacin or gemifloxacin should not be used because of their low urine concentrations. The dose of drug is adjusted for the degree of renal insufficiency as suggested by the drug package insert or standard reference sources. The primary goal is to achieve predictably effective serum and urine concentrations. Ciprofloxacin urine concentrations, 24 h after an adjusted dose, are reported as above the minimum inhibitory concentration (MIC) of urinary pathogens in patients with a creatinine clearance of <50 mL/min.⁴Gilbert DN. Urinary tract infections in patients with chronic renal insufficiency. Clin J Am Soc Nephrol. 2006;1:327–331. doi: 10.2215/CJN.01931105    If enterococcal infection is suspected on the basis of the urine Gram stain, positive blood culture, or other factors, then empiric therapy with piperacillin-tazobactam, ticarcillin-clavulanate, or ampicillin-sulbactam is suggested. For severely penicillin allergic patients, vancomycin is reasonable.⁴Gilbert DN. Urinary tract infections in patients with chronic renal insufficiency. Clin J Am Soc Nephrol. 2006;1:327–331. doi: 10.2215/CJN.01931105

In the bacteraemic patient with septic shock, an empiric carbapenem (imipenem or meropenem) is reasonable because of the high level of predictive efficacy versus Escherichia coli , other Enterobacteriaceae, many enterococci, and Pseudomonas aeruginosa .⁴Gilbert DN. Urinary tract infections in patients with chronic renal insufficiency. Clin J Am Soc Nephrol. 2006;1:327–331. doi: 10.2215/CJN.01931105

The management of pyelonephritis in patients with glomerular filtration rate (GFR) in the 10 to 50 mL/min range requires only reduction of dosage to avoid high serum concentrations and the concomitant increased risk for concentration dependent adverse drug events. Ciprofloxacin or levofloxacin are suggested as first choices for empiric therapy.⁴Gilbert DN. Urinary tract infections in patients with chronic renal insufficiency. Clin J Am Soc Nephrol. 2006;1:327–331. doi: 10.2215/CJN.01931105    Trimethoprim alone, in reduced dosage can be prescribed for the treatment of uncomplicated cystitis in patients with a low creatinine clearance.⁴Gilbert DN. Urinary tract infections in patients with chronic renal insufficiency. Clin J Am Soc Nephrol. 2006;1:327–331. doi: 10.2215/CJN.01931105

Determining the identity and antibiotic susceptibilities of the causative organism before commencing treatment, is strongly recommended. Selection of an oral antibiotic based upon the susceptibility pattern of the micro-organism. Commonly used regimens for patients with normal renal function are ciprofloxacin 250 mg orally twice-daily, amoxicillin 500 mg orally three times daily, and nitrofurantoin 100 mg orally twice-daily (provided estimated GFR >60 mL/min/1.73 m²Hsiao CY, et al. Urinary tract infection in patients with chronic kidney disease. Turk J Med Sci. 2014; 44:145-149. doi:10.3906/sag-1303-51). The dosing of ciprofloxacin and amoxicillin must be adjusted in patients with reduced renal function. The American Geriatrics Society 2015 Beers Criteria Update Expert Panel has revised its recommendation to avoid use of nitrofurantoin in renal impairment from patients with a creatinine clearance (CrCl) of less than 60 mL/min to those with a CrCl of less than 30 mL/min, based on two retrospective studies that identified the safety and efficacy of nitrofurantoin in this population.⁹Hoang P, Salbu RL. Updated nitrofurantoin recommendations in the elderly: A closer look at the evidence. Consult Pharm. 2016 Jul; 31(7):381-4. doi: 10.4140/ TCP.n.2016.381.

Nitrofurantoin is to be taken along with food or milk to suppress the GI irritation which is usually known to occur with its consumption. Modified release (MR) nitrofurantoin formulations are preferred over the conventional formulations because the former maintain urinary concentration over duration of 12 hours, decrease dosage frequency to twice a day, better gastrointestinal tolerability and enhance patient compliance. When nitrofurantoin MR formulation is given, a part of the drug is released immediately and gets rapidly accumulated in urine for immediate action within first hour while the remaining drug is released steadily and continuously for the whole day to maintain adequate urinary concentration. Nitrofurantoin MR formulation for uncomplicated UTIs consist of 100 mg PO two times per day for 7 days. Long-term suppressive therapy consists of 50 to 100 mg PO at bedtime.¹⁰Spencer RC, Moseley DJ, Greensmith MJ. Nitrofurantoin modified release versus trimethoprim or co-trimoxazole in the treatment of uncomplicated urinary tract infection in general practice. J Antimicrob Chemother. 1994 May; 33 Suppl A: 121-9.    ¹¹Antimicrobial prescribing guidelines in general practice; National Health Service; 2012; v1.0:14-19.    ¹²Agarwal M, Rattan A. Nitrofurantoin sensitivity pattern pan India. WJPR. 2017;6(2):464-494.

Conclusion

UTIs are common among patients with type 2 diabetes mellitus. In these patients, UTIs are more severe, caused by more resistant pathogens, and are associated with worse outcomes than in patients without diabetes. Treatment should be offered only to symptomatic cases, as ASB is a common finding, and antibiotic treatment in such cases serves mostly to increase bacterial resistance. Treatment should be tailored according to severity of infection and culture results.

There is an increasing population of UTI in patients with chronic renal insufficiency. At present, a prudent approach is to treat the patient who has pyelonephritis with an active fluoroquinolone alone after appropriate dose reduction. Fluoroquinolones should also be effe-ctive in patients with urethritis/cystitis. Trimethoprim alone is an alternative for cystitis treatment, with the caveat that 15 to 20% of the isolates may be resistant.Multidrug resistance is one of the major barriers to the medical management of UTIs. Antibiotics like trimethoprim and fluoroquinolones are prone to resistance and cross-resistance. In case of fluoroquinolones, the resistance among pathogens and other microorganisms and hence these drugs should be kept as optional therapies for acute cystitis. Nitrofurantoin, unlike many other antimicrobials, has the advantage of withstanding the growing antimicrobial resistance and has started becoming the empirical treatment of choice.

References

1. Tandogdu Z, et al . Urinary Tract Infections in Immunocompromised Patients with Diabetes, Chronic Kidney Disease, and Kidney Transplant. European Urology Focus. 2016;2:394-399.
2. Hsiao CY, et al. Urinary tract infection in patients with chronic kidney disease. Turk J Med Sci. 2014; 44:145-149. doi:10.3906/sag-1303-51
3. Nitzan O, Elias M, Chazan B, Saliba W. Urinary tract infections in patients with type 2 diabetes mellitus: review of prevalence, diagnosis, and management. Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy. 2015;8:129-136.
4. Gilbert DN. Urinary tract infections in patients with chronic renal insufficiency. Clin J Am Soc Nephrol . 2006;1:327–331. doi: 10.2215/CJN.01931105
5. Hotchandani R, Aggarwal KK. Urinary tract infections in women. Indian Journal of Clinical Practice . 2012; 23(4):187-192.
6. Nicolle LE, Zhanel GG, Harding GK. Microbiological outcomes in women with diabetes and untreated asymptomatic bacteriuria. World J Urol . 2006;24(1):61–65.
7. Chan JC, Cockram CS, Critchley JA. Drug-induced disorders of glucose metabolism. Mechanisms and management. Drug Saf. 1996;15(2):135–157.
8. Munar MY, Singh H. Drug dosing adjustments in patients with chronic kidney disease. Am Fam Physician . 2007;75(10):1487–1496.
9. Hoang P, Salbu RL. Updated nitrofurantoin recommendations in the elderly: A closer look at the evidence. Consult Pharm. 2016 Jul; 31(7):381-4. doi: 10.4140/TCP.n.2016.381.
10. Spencer RC, Moseley DJ, Greensmith MJ. Nitrofurantoin modified release versus trimethoprim or co-trimoxazole in the treatment of uncomplicated urinary tract infection in general practice. J Antimicrob Chemother. 1994 May; 33 Suppl A: 121-9.
11. Antimicrobial prescribing guidelines in general practice; National Health Service; 2012; v1.0:14-19.
12. Agarwal M, Rattan A. Nitrofurantoin sensitivity pattern pan India. WJPR. 2017;6(2):464-494.