Key points

Introduction

Normal micturition requires proper function of the bladder and urethral sphincter complex. This process requires coordination between the central and the peripheral nervous systems. Disruption of this pathway caused by damage or disease interferes with this coordinated effort and can lead to neurogenic bladder (NGB) with abnormal bladder storage and emptying. Management of NGB is a challenging long-term issue for both patients and providers. Improper management of NGB and pyelonephritis can result in renal injury and eventually renal failure. Recurrent pyelonephritis results in renal scarring and contributes to deterioration of the kidney. Although advances in medical care have significantly reduced the morbidity and mortality of urinary tract infection (UTI) in NGB, currently 10% to 15% of patients with NGB die from sepsis of urinary origin.

Because of the causal and functional heterogeneity of NGB, each patient must be approached individually, because risk factors vary significantly between patients. This article addresses UTI in the general NGB population and evaluates the epidemiology, pathogenesis, risk factors, evaluation, diagnosis, treatment, and prevention in these patients.

Introduction

Normal micturition requires proper function of the bladder and urethral sphincter complex. This process requires coordination between the central and the peripheral nervous systems. Disruption of this pathway caused by damage or disease interferes with this coordinated effort and can lead to neurogenic bladder (NGB) with abnormal bladder storage and emptying. Management of NGB is a challenging long-term issue for both patients and providers. Improper management of NGB and pyelonephritis can result in renal injury and eventually renal failure. Recurrent pyelonephritis results in renal scarring and contributes to deterioration of the kidney. Although advances in medical care have significantly reduced the morbidity and mortality of urinary tract infection (UTI) in NGB, currently 10% to 15% of patients with NGB die from sepsis of urinary origin.

Because of the causal and functional heterogeneity of NGB, each patient must be approached individually, because risk factors vary significantly between patients. This article addresses UTI in the general NGB population and evaluates the epidemiology, pathogenesis, risk factors, evaluation, diagnosis, treatment, and prevention in these patients.

Epidemiology

Estimates of NGB in the United States include approximately 400,000 people with diagnoses of spina bifida (SB), spinal cord injury (SCI), cerebral palsy, multiple sclerosis (MS), and Parkinson disease. UTIs are the most common infection in this population; 31% of patients with a new diagnosis of SCI were diagnosed with a UTI within the first year, and 21% required hospitalization. In patients with SB, UTI is the most common complaint in the emergency room setting. Patients with SCI average 2.5 symptomatic UTIs per year, with similar findings in other NGB populations. With the increased frequency and severity of infection, there is higher risk of morbidity and mortality secondary to urosepsis and end-stage renal disease relative to the general population.

Pathogenesis

In the past, mechanical factors such as increased postvoid residuals (PVR), urinary stasis, and bladder stones were thought to be the primary causal factors in development of recurrent UTI in patients with NGB. However, emerging data suggest that the propensity to develop infections is much more complex ( Fig. 1 ), and dysfunctional immune response in the bladder may be a strong contributor as well.

Multifactorial causes of UTI in NGB.

( From Vasudeva P, Madersbacher H. Factors implicated in pathogenesis of urinary tract infections in neurogenic bladders: Some revered, few forgotten, others ignored. Neurourol Urodyn 2014;33(1):95–100; with permission.)

Bladder dysfunction

Abnormal urodynamic parameters in patients with NGB may correlate with increased risk of UTI. Prior studies showed that detrusor overactivity, decreased bladder compliance, and vesicoureteral reflux are significant risk factors for febrile UTI among patients with spinal dysraphism. The mechanism by which these abnormalities lead to increased rate of UTI is not clear, but there are several theories. Evidence suggests that increased intravesical pressure results in bladder ischemia, which in turn may result in delayed or deficient immune response to pathogens. Animal and human studies have found that increased intravesical pressure significantly reduces blood flow, in both the distended and empty bladder, suggesting global dysfunction. Although most patients with NGB have abnormal urodynamic studies, many of these parameters can be mitigated successfully with medications or surgery.

Urinary stasis/increased postvoid residual

Normal voiding is protective against development of UTI, because emptying greatly decreases overall bacterial count in the urine, which is then diluted by bladder filling. Animal studies have shown that 99.9% of bacteria injected into the bladder are removed by voiding. Based on these studies, inefficient voiding with residual urine in theory predisposes to development of UTI. Multiple studies have investigated the association between PVR urine volume and rate of developing UTI. Among patients with spinal cord injury and NGB, PVR of greater than 300 mL was associated with a 4 to 5 times greater rate of development of UTI. Two studies of patients after stroke showed that PVR greater than 150 mL was an independent risk factor for development of UTI, and PVR greater than 100 mL resulted in 4.9-fold increase in UTI development compared with those with PVR less than 100 mL. In a rat model of SCI and UTI, PVR did not correlate with UTI, suggesting other contributing factors. Although the exact PVR necessary to predispose a patient with NGB to UTI is not clear, urinary stasis and increased PVR are risk factors associated with UTI.

Catheter use

Urinary catheters are a mainstay management strategy for patients with NGB. Significant research has examined indwelling catheterization and clean intermittent catheterization (CIC), as well as catheter material, with the primary outcome in most studies being frequency of UTI.

CIC is the preferred method of drainage in patients with NGB as long as their dexterity or caretaker support and body habitus allow access. However, CIC increases the risk for UTI caused by catheter contamination and the introduction of external microorganisms into the bladder environment. A study comparing quadriplegic patients with NGB managed with either CIC or suprapubic catheter (SP) found an annual rate of symptomatic UTI of 26% for the CIC group, and 12% for the SP group, although SP was more often complicated by bladder stones (65% vs 30%). In addition, patients with indwelling catheters have higher rates of bladder cancer and renal scarring. In both groups the overall rate of infection remains high.

Catheters are generally made from silicon or other soft rubbers. Because of concerns for catheterization trauma as a contributing causal factor for development of UTI, hydrophilic coated catheters are under investigation. These catheters have a slippery, prelubricated surface and may cause less urethral trauma and irritation. In a randomized study of patients with recent SCI with initiation CIC, there was a 21% reduction in incidence of symptomatic UTI among the hydrophilic catheter group compared with the polyvinyl chloride catheter group at 3 months after initiation. However, this difference did not persist at 6 months. A more recent meta-analysis of 5 studies (n = 462) comparing patients using hydrophilic or nonhydrophilic catheters in CIC found a significantly decreased rate of symptomatic UTI among the hydrophilic group (odds ratio [OR] = 0.36; P <.0001), as well as less gross hematuria (OR = 0.57; P = .001). Although no clear consensus has been reached regarding the efficacy of hydrophilic catheters in prevention of UTI, they are favored by some patients because of comfort and convenience.

Silver alloy–impregnated and antibiotic-coated catheters have been shown to decrease asymptomatic bacteriuria, but only for 1 week after initiation of use and are therefore not recommended in the NGB population at this time.

External condom catheters have approximately the same rate of symptomatic UTI as CIC and are a reasonable management strategy in male patients with a low-resistance bladder outlet. However, many patients with NGB do not drain optimally with a condom catheter with increased PVR, potentially leading to both bladder and upper tract damage.

Immune dysfunction

A recent hypothesis under investigation is immune dysfunction incited by SCI. In a rat model of induced SCI-UTI, animals had decreased proinflammatory and antiinflammatory responses to uropathogenic Escherichia coli , and inflammation was not appropriately suppressed after the infection was eliminated. This dysfunctional immunologic response may redispose to infection and hinder bacterial eradication.

Although the urine and urinary tract luminal space commonly contain bacteria during acute UTI, uropathogenic bacteria such as uropathogenic E coli (UPEC) and Klebsiella pneumoniae also invade urothelial cells. Studies from murine UTI models show that UPEC can proliferate within the urothelium, which may not be easily eradicated with antibiotic treatment, providing a nidus of reinfection. Using the rat model of SCI-UTI, intracellular replication of E coli in the bladder urothelium of the NGB has been observed and may underlie the challenge of effective treatment of UTI with NGB and be a risk factor for recurrent disease.

In addition to the immune dysfunction that seems to be inherent to NGB, pharmacologic immunosuppression in patients with MS and NGB may provide a further risk for recurrent UTI. Some centers test patients with MS for bacteriuria before initiation of steroid induction therapy and treat even asymptomatic bacteriuria to avoid potential development of invasive disease once steroid treatment is underway, although the degree of infection reduction is not clear.

Diagnosis

A key factor complicating the study and treatment of UTI in NGB is the lack of consensus definition of infection, both in study populations and in clinical practice. Impaired sensation with nonspecific infectious symptoms, as well as ubiquitous bacterial colonization of the bladder in patients with NGB, often leads to an unclear clinical picture.

Monitoring for infection

There is universal agreement that renal and bladder function in patients with NGB should be monitored, but no consensus regarding monitoring frequency, studies that should be performed, or definition of UTI. A meta-analysis of studies evaluating follow-up among patients with SCI showed no clear definition of UTI and no demonstrable utility in routine screening with urinalysis or urine culture. A systematic review of UTI in the pediatric SB literature found that only a third of studies provided a definition of UTI, and, of those, the definitions were heterogeneous. After analysis of these studies, the investigators suggested the following definition for UTI in pediatric patients with SB: greater than or equal to 2 symptoms (fever>38°C, abdominal pain, new back pain, new or worse incontinence, pain with catheterization or urination, or malodorous/cloudy urine), and greater than 100,000 colony-forming units (CFU)/mL of a single organism, and greater than 10 white blood cells (WBC) per high-power field (HPF) on microscopy. The National Institute on Disability and Rehabilitation Research provides guidelines for diagnosis of UTI in patients with SCI: greater than 10 ² CFU/mL from intermittent catheterized specimen, greater than 10 ⁴ CFU/mL from condom catheter, and any value from indwelling and suprapubic catheters, along with pyuria and signs and symptoms of UTI.

The typical symptoms of UTI in the general population, such as dysuria, urgency, and frequency, are rarely present in the NGB population. More common symptoms, especially in the SCI population, include autonomic dysreflexia, increased spasticity, new or worsening urinary incontinence, vague back or abdominal pain, or foul-smelling urine. Patients with SCI are able to predict the presence of a UTI based on symptoms with an accuracy of only 61% to 66.2%, although they are much better at predicting when they did not have a UTI (negative predictive value 82.8%) than when they did (positive predictive value 32.6%). In the same study, cloudy urine had the highest accuracy (83.1%), whereas presence of pyuria had the highest sensitivity (82.8%) in predicting the presence of UTI. The absence of pyuria strongly suggests another cause for the symptoms. In contrast, foul smell of the urine has a low sensitivity as a predictor for UTI (48.3%), with multiple noninfectious causes.

Heterogeneous definitions of UTI in the NGB population have long hampered clinical and research efforts. Universally accepted diagnosis criteria will lead to less ambiguity in diagnosis and treatment, reduce overtreatment of asymptomatic bacteriuria, and allow researchers to design more robust studies with outcomes that can be generalized to better care for this population and develop preventive measures ( Fig. 2 ).

Management algorithm for patients with NGB and suspected UTI. ^a Positive urinalysis: greater than 10 WBC/HPF on microscopy (not validated end point). ^b Positive urine culture: greater than 10 ² CFU/mL from intermittent catheterized specimen, greater than 10 ⁴ CFU/mL from condom catheter, and any value from indwelling and suprapubic catheters (not validated). ^c Symptoms include 2 or more of: fever greater than 38°C, abdominal pain, new back pain, new or worse incontinence, pain with catheterization or urination, and malodorous/cloudy urine. ^d Urine culture should not be performed in the absence of symptoms, but often is, thus is included in this algorithm. ^e Treatment duration may vary based on other considerations.

( Data from Madden-Fuentes RJ, Ross SS. Urinary tract infections in the spina bifida population. Novel Insights into Urinary Tract Infections and Their Management 2014:61; and Everaert K, Lumen N, Kerckhaert W, et al. Urinary tract infections in spinal cord injury: prevention and treatment guidelines. Acta Clin Belg 2009;64(4):335–40.)

Treatment

Treatment of UTI in NGB mirrors that in the general population, with some exceptions. Most importantly, urine cultures must be obtained before antibiotic administration. Antibiotic choice should be tailored to the specific pathogen and sensitivities of the culture data, because pathogen and sensitivity trends in the NGB population differ from the general population. A study of patients with SCI found E coli to be the primary cause in 18% of symptomatic UTI, compared with 75% to 95% in the general population. In addition, bacterial isolates may vary in the community versus hospital settings and have higher rates of resistance to commonly prescribed antibiotics, making broad-spectrum antibiotics necessary in severe cases.

Commonly, patients with NGB have a urinalysis or urine culture performed by providers who are not accustomed to caring for patients with NGB, and the identification of asymptomatic colonization prompts inappropriate antibiotic treatment. Avoiding treatment of asymptomatic bacteriuria in NGB is important, except in select populations such as those on immunosuppression, pregnant women, or patients undergoing a urologic procedure. Recurrent courses of antibiotics result in higher rates of antibiotic-resistant isolates and antibiotic prophylaxis has limited efficacy and is associated with increased antibiotic resistance. Education of both patients with NGB and providers who care for these patients is necessary to promote antibiotic stewardship and prevent inappropriate treatment of asymptomatic bacteriuria.

Choice of treatment duration is largely based on provider experience, because there are few data supporting specific treatment durations. A 60-patient study of those with SCI and symptomatic UTI randomized to either a 3-day or 14-day course of antibiotics found an increased rate of bacteriuria and symptomatic relapse in the 3-day group (37% and 23%, respectively), compared with the 14-day group (7% and 0%, respectively). In patients with indwelling Foley catheters and catheter-associated UTIs, the Infectious Disease Society of America recommends early catheter exchange and a 7-day to 14-day treatment course with culture-specific antibiotics. A recent study of patients with SCI with indwelling catheters evaluated a 5-day treatment course with early catheter exchange versus a 10-day course with catheter retention and found that the 5-day course was associated with more relapses, reinforcing the belief that long treatment durations are necessary in patients with NGB.

A review of UTI in patients with SCI sought to determine optimal antibiotic choices and treatment durations. They recommend 5 days of antibiotic treatment of chronic SCI with no fever, 7 days for acute SCI with no fever, and 14 days for UTI with fever. The investigators suggest nitrofurantoin or trimethoprim for UTI in chronic SCI, fluoroquinolones or cefuroxime in UTI in acute SCI, and broad-spectrum intravenous coverage with fever. However, this may vary depending on the local antibiogram.