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Utis In Special Populations

UTIs - so common in the population

Urinary tract infections (UTIs) are widely prevalent in the population as one of the most common bacterial infections acquired in community and in hospitals, which makes them an important topic for the consulting physicians.1,4    The clinical spectrum of UTIs is extensive and encompasses wide ranging severity patterns, ranging from asymptomatic bacteriuria, to symptomatic and recurrent UTIs, to sepsis associated with UTI requiring hospitalization5  ; the infection being initially identified as upper and lower UTIs based on clinical presentation, and further differentiated as uncomplicated and complicated for ease of management.6,7    While a vast majority of UTI cases in outpatients are uncomplicated; UTIs are assumed to be complicated when there is an underlying condition or risk factors for a severe clinical course or for secondary harms.4   This latter subgroup of complicated UTIs hence requires greater diagnostic accuracy and diverse treatment strategies.

Of note, the clinical implications of urinary infections may be more significant in certain populations, such as women, children, diabetics, the hospitalized, and those with anatomic abnormalities, advanced age, and catheterization and instrumentation, that are at increased risk of infection because of unique considerations relevant to their characteristic phenotype accompanied by underlying/associated morbid state.8,9   Approaches to management, including diagnosis and treatment, in such patients are generally similar to other patients with UTIs; but would require considering distinctiveness unique to their clinical condition, often complicated by the underlying abnormality.

In this review, we discuss UTIs in some of such diverse patient populations since such a categorization of infection by clinical syndrome and by host, as based on above facts, (e.g., acute cystitis in young women, acute pyelonephritis, catheter-related infection, asymptomatic bacteriuria in pregnancy) would help the clinician determine appropriate strategies in individual patients. Conventionally, the presence of defined signs and symptoms, derived from history and physical examination, supported with positive laboratory results [urinalysis or culture (the gold standard)], confirms a diagnosis of UTI, which should follow clearance of bacteriuria as the universal therapeutic need.10

Etiology of UTIs

Knowledge about the microbial etiology is beneficial in all cases of UTIs in not only the treatment phase, for selecting the most appropriate antibiotics, but also in pre-treatment phase given that infection with organisms not usually implicated in causing UTIs might be an indicator of an underlying structural abnormality or renal calculi, which per se makes the UTI complicated.11   The most predominant pathogen implicated in UTIs in all age groups is the gram-negative bacillus Escherichia coli (E. coli), which is supposed to be the cause in about 80-90% of community-acquired UTIs and 30-50% of hospital-acquired UTIs.12   In rest of the cases, enterococci, Staphylococcus saprophyticus, Klebsiella spp., Proteus mirabilis, etc. may be isolated.13   Etiology is generally less predictable and more diverse in complicated UTIs, than in uncomplicated, encompassing a broad range of bacteria. Besides, there exists possibility of mixed infections with more than one organism.

Symptoms in different subgroups

Patients with UTIs can present with diverse signs and symptoms that might primarily be dependent on part of the urinary tract affected (Table 1).14,15      Most patients with uncomplicated UTIs (cystitis or lower UTI) usually present with dysuria, urinary frequency, urinary urgency, and/or suprapubic pain.16   Fever and/or costovertebral angle tenderness is generally not present in UTIs originating from the bladder, and its presence would indicate involvement of the upper urinary tract (pyelonephritis). Some other symptoms indicative of the renal involvement include pain in the back or side below the ribs, nausea, and vomiting.17

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Furthermore, similar to the prevalence rates of UTIs that are highly dependent on the age and gender4  ; symptoms may also vary dependent on the age of the patient (Table 2), and the presence or absence of a catheter.18,19      While young women typically have a frequent and intense urge to urinate, and a painful, burning feeling in the bladder or urethra during urination; older patients are more likely to be tired and weak, and have muscle aches and abdominal pain.

UTIs in different populations

UTIs in women

Women are at greater risk of developing a UTI than men, probably due to a shorter urethra20  ; wherein it may occur in up to 50% of them at least once in their lifetimes. UTIs in women is mostly uncomplicated across the entire age spectrum - commonly manifested as acute uncomplicated cystitis -, which occurs in those without underlying diseases and with no functional or structural anomalies of the urinary tract.21,22     The mean annual incidence of uncomplicated UTIs in women is 15% in those aged 15-39, and 10% in that aged 40-79 years.23   This age and gender predisposition may also have diagnostic implications in practice. For instance, if a young female patient presents to physician with the typical symptoms of frequent and intense urge to urinate and a painful, burning feeling in the bladder or urethra during urination, there is high probability that she has an infection of the urinary tract.4   Accuracy of this symptom based diagnosis increases with number of symptoms; as women with one symptom of UTI have an infection probability of about 50%, while probability rises to more than 90% with a combination of symptoms (i.e, dysuria, frequency, and absence of vaginal irritation or discharge).24,26      The amount of urine may be very small however.

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Further to this systematic assessment of the patient symptoms, addition of a urine dipstick test to the diagnostic protocol would help in achieving a more definite diagnosis.23,27      The dipstick test is a widely used reasonable alternative to urinalysis as a diagnostic tool in women who present with acute dysuria or urgency, that if positive for leukocyte esterase and/or nitrites in a midstream-void specimen would reinforce a clinical diagnosis of UTI. This important marker, leukocyte esterase, is specific (94-98%) and reliably sensitive (75-96%) for detecting uropathogens equivalent to 100,000 colony forming units (CFUs) per mL of urine. Microscopic hematuria may be present in 40-60% of patients with UTI.28

Often, the predictable nature of uropathogens for uncomplicated UTIs makes routine urine cultures not necessary. But, urinalysis may be appropriate for patients who fail initial treatment, have upper UTI (pyelonephritis), and present with atypical symptoms. Herein, a colony count of 1,000 cfu per mL (80% sensitivity and 90% specificity) shall be advocated for those with symptomatic UTI. A cut-off of 100,000 cfu per mL defines asymptomatic bacteriuria.28

Recurrent UTIs in women

Recurrent UTI is a common finding among young, healthy women, albeit they generally have normal urinary tracts; that require urine culture for diagnosis.25   As well, recurrent UTIs are also common among women with dysfunctional voiding. Predictors of recurrent UTIs among symptomatic women include: symptoms following intercourse, signs or symptoms of pyelonephritis, and prompt resolution of symptoms with antibiotics; whilst presence of nocturia and persistence of symptoms between UTI episodes are strong negative predictors for recurrent infection.

As an estimate, about 25% of women experience a second episode within six months of their first UTI.2   This recurrence can either be in form of a relapse or reinfection. The latter is however more common, and occurs more than two weeks after a patient has completed antimicrobial therapy; generally attributable to infection with a different organism (or even a different strain of E. coli  ). In contrast, relapse occurs in about 5-10% of women within two weeks of completing antimicrobial therapy, and is attributable to persistence of the same pathogen in the urinary tract system, perhaps suggesting infEction with an antimicrobial-resistant pathogen.

UTIs in pregnant women

UTIs are the most common bacterial infections during pregnancy, characterized by presence of significant bacteria anywhere along the urinary tract.29,30      The clinical diagnosis may therefore range from acute cystitis, pyelonephritis to asymptomatic bacteriuria. Many factors may contribute to the development and progression of UTIs during pregnancy; for instance, ureteral dilatation - thought to occur because of hormonal effects and mechanical compression from the growing uterus - can cause bacteria to spread from bladder to the kidneys, increasing the risk of pyelonephritis.31

Asymptomatic bacteriuria in pregnant women

Often, UTIs during pregnancy may be asymptomatic, making it imperative to screen a woman for bacteriuria during the first trimester. While bacteriuria in those with symptoms compatible with UTI is considered significant if a voided urine specimen grows > 103   cfu/mL of the uropathogen; bacteriuria in an asymptomatic pregnant woman would be considered significant if two consecutive voided urine specimens grow > 105   cfu/mL of the same bacterial species on quantitative culture.16   Thus, asymptomatic bacteriuria is present if a patient does not exhibit clinical signs of UTI despite upper limit of ≥105   cfu/mL exceeding in two consecutive properly collected samples of midstream urine (from women).

Treatment is not indicated in most cases of asymptomatic bacteriuria, but asymptomatic bacteriuria in pregnancy is a specific subgroup for whom screening for asymptomatic bacteriuria and its treatment has been shown to be beneficial; the other subgroup being those undergoing selected manipulation of their genitourinary tract systems. This therapeutic need is important in pregnancy in order to decrease the occurrence of pyelonephritis and possibly also damage to the child.

While asymptomatic bacteriuria during pregnancy has been associated with intrauterine growth retardation, increased risk of pre-term delivery and low-birth-weight; pyelonephritis in pregnancy can have serious consequences, such as maternal sepsis, pre-term labour and premature delivery, warranting prompt and aggressive treatment.30

UTIs in elderly patients

UTIs in elderly are frequent and polymorphic clinical symptoms, particularly in the frail elderly, the spectrum of which varies from a relatively benign cystitis to potentially life-threatening pyelonephritis.32,34     It is a significant factor in their morbidity and mortality, for which females are much more concerned than males, even if the female to male ratio decreases with increasing age and UTI becomes almost half as frequent in men compared to women.35   Both symptomatic UTIs and asymptomatic bacteriuria are commonly encountered in older women. However, it is important to differentiate the two clinically, with regards to management, since asymptomatic bacteriuria is generally transient in older women, often resolves without any treatment, and is not associated with morbidity or mortality, even though its prevalence might markedly increase in this group.4   Establishing a diagnosis of symptomatic UTI in older women is therefore important, and requires careful clinical evaluation, with possible laboratory assessment using urinalysis and urine culture.5   A positive diagnosis of symptomatic UTI is made when the patient has both clinical features and laboratory evidence of a urinary infection. If other causes are absent; patients presenting with any two of the signs and symptoms given in box 1 meet the clinical diagnostic criteria for symptomatic UTI.5   A positive urine culture (≥105   cfu/mL) with no more than two uropathogens and pyuria would confirm the diagnosis of UTI. Alternatively, testing for UTI can be easily performed in the clinic using dipstick tests, which if negative for leukocyte esterase and nitrites would exclude infection if done following a low pretest probability of UTI. The older women are also prone to develop recurrent symptomatic UTI, the risk of which is accentuated by an array of factors (Box 2).5   Chronic suppressive antibiotics for a period of 6 to 12 months and/or vaginal estrogen therapy effectively reduces symptomatic UTI episodes, and should be considered in those with recurrent UTIs.

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UTIs in patients with diabetes mellitus

Type 2 diabetes is a reported risk factor for more frequent and severe UTIs that may impose a substantial direct medical cost burden.36   These patients might even run a distinctly greater risk of a complicated course and complications than non-diabetics.37,38     Several underlying factors, such as glucosuria, adherence of bacteria to the uroepithelium and immune dysfunction, may account for this increased predilection to UTIs in diabetic patients.39   Interestingly, an induction of interleukin-6 (IL-6) in human bladder smooth muscle cells by fatty acids represent a novel pathogenetic factor underlying the higher frequency and persistence of UTIs in patients with metabolic diseases.40   It is seen that female patients with medically treated diabetes frequently exhibit asymptomatic bacteriuria or UTI, with the former being several-fold more common.4,41     However, the urinary infection might also manifest in its more severe form as acute pyelonephritis, given that population-based data also identify diabetes as a major comorbidity in hospitalized patients with pyelonephritis.42   In contrast, while asymptomatic bacteriuria also occurs more frequently in diabetic women, its impact on true incidence of symptomatic urinary infection in diabetic women may be more subtle. Substantially higher rates of hospitalization for pyelonephritis are observed in diabetics possibly due to several reasons, encompassing increased frequency and severity of acute pyelonephritis; severe complications of acute pyelonephritis, such as emphysematous pyelonephritis, renal and perinephritic abscess, and bacteremia. These complications indeed do occur more frequently in diabetics.42

UTIs in children

UTIs are a frequent cause of morbidity in children, affecting up to 10% of them, with high rates of recurrence.43   The incidence however varies dependent on age and sex; it being the most common bacterial infection in children less than two years of age, with retrograde ascent as the predominant mechanism of infection. Majority of pediatric UTIs are caused by E. coli  ; but, similar to incidence, signs and symptoms vary greatly by age of the patient and severity of the disease, with clinical presentation becoming more specific as the child grows older. In infants, the most useful features for identifying a UTI include presence of fever, history of a previous UTI, and suprapubic tenderness; indeed, combinations of findings is more useful than individual symptoms. Abdominal pain, back pain, dysuria, frequency, or both, and new-onset urinary incontinence increase the likelihood of a UTI in children who can tell their symptoms verbally.44   This, as such, indicates the significant impact of dysfunctional voiding and urge syndrome in increasing the risk of UTIs in children. Furthermore, UTIs in children may be complicated by presence of unusual obstruction and vesicoureteric reflux (VUR) as well, warranting additional investigations after two episodes of UTI in girls and one in boys in order to avoid the complications, such as pyelonephritis and renal scarring.16,45,46        The clinical diagnosis of UTIs per se may be found on presence of pyuria (> 5 leukocytes per field) and bacteriuria in a fresh urine sample; though a definitive diagnosis would require positive urine culture.

UTIs in hospitalized and immunocompromised patients

UTIs in hospitalized patients are frequently complicated due to abnormalities of the genitourinary tract, such as presence of urinary calculi, cystic renal disease, obstruction, anatomic abnormalities, neurologic bladder dysfunction, or a foreign body. Similarly, UTIs in patients with transplanted kidneys and immunologic illnesses, such as systemic lupus erythematosus (SLE), are also considered complicated, and carry a high mortality rate.47,48       Perse, it represents the most common complication after kidney transplantation that can be potentially life-threatening for the immunocompromised host.49

Catheter-associated UTIs (CAUTIs)

Conditions such as incomplete voiding, elevated intravesical pressure and catheter use consistently contribute to an increased risk of symptomatic UTIs in patients.50   This predisposition is important seeing the 3-10% daily risk of bacteriuria in patients with urethral catheters, which account for almost 80% of nosocomial UTIs in hospitals; associated with indwelling urinary catheters.51,52     In essence, a UTI would be universal if the device remains in place for 30 days or longer.

CAUTIs in patients with indwelling urethral or suprapubic or intermittent catheterization is defined by presence of signs and symptoms compatible with UTI, with no other identified source of infection, together with ≥103   cfus/mL of ≥1 bacterial species in a single catheter urine specimen, or in a midstream voided urine specimen from a patient whose catheter has been removed within the preceding 48 hours. Signs and symptoms suggestive of CAUTIs include new onset or worsening of fever, rigors, altered mental status, malaise, or lethargy attributable to no other identifiable cause; flank pain; costovertebral angle tenderness; pelvic discomfort; acute hematuria; and in those whose catheters have been removed, dysuria, urgent or frequent urination, or suprapubic pain or tenderness. Often, fever - not attributable to any other cause - might be the only symptom in a patient with a urinary catheter.

The first and foremost step in prevention of CAUTIs shall be to limit unnecessary catheterization, while antibiotic use may also play a role in preventing CAUTIs. Antibiotic prophylaxis is unnecessary for catheterization lasting less than three days, but shall be considered for catheterization limited to two weeks, for which nitrofurantoin can be an effective choice. The cost:benefit ratio of prophylactic antibiotic treatment is maximized at about two weeks of catheterization; after which, the emergence of resistant organisms may be a virtual certainty. Finally, when prescribing antimicrobials for CAUTIs, it is important to change the catheter because of the bacterial biofilm lining the old catheter.53

Urinary alkalinization for alleviating burning micturition

Burning micturition is one of the most characteristic symptoms of UTIs that may warrant consideration even before definite antimicrobial therapy.54,55     Symptomatic relief may be provided to such patients through use of urine alkalinizing agents prior to initiating definite antibiotic treatment, or concurrently.56,57     In this context, potassium citrate has documented superior efficacy in urine alkalinization, and is preferred over sodium-containing salts, such as sodium bicarbonate or sodium citrate, as a first line urine alkalinizing agent. Distinct clinical advantages of potassium citrate include: high palatability, pleasant taste, and tolerability even with long-term use. Oral potassium citrate effectively increases urinary pH, resulting in less acidic urine and achieving its goal of urine alkalinization.58   Like this, it may cater to the troublesome condition of painful and burning micturition in patients with UTIs.59   Furthermore, raising the urinary pH may also increase the ability of natural defense mechanisms to eliminate the infecting organisms. It is seen that potassium citrate normalizes pH of urine to 6-6.5 throughout the day; which possibly improves the ability of phagocytosis and killing of pathogens, such as E. coli and S. saprophyticus, by neutrophils.60

Urinary spasmolytic for alleviating suprapubic pain, urgency, and frequency

Symptoms of UTIs frequently include some combination of dysuria, urinary frequency, urgency, hematuria, and suprapubic pain that needs to be considered for optimal patient outcomes.61,62     An anticholinergic drug might be an option for these bothersome symptoms in absence of significant post-void residual (PVR) urine volumes. However, the concern that anticholinergics may predispose to (acute) urinary retention, particularly in the more prone elderly population, limits their clinical usefulness. In such setting, the anti-spasmodic drug flavoxate that is free from such concerns related to use of anticholinergics can be used to alleviate the symptomatic burden of UTIs. It is a smooth muscle relaxant with extensive indications widely used to treat urgency and urge incontinence. The drug was found to result in statistically significant improvement in frequency and suprapubic pain, together with marked relief in dysuria, hesitancy and burning, in patients suffering from painful conditions of lower urinary tract arising from inflammation and/or infection or from spasm following diagnostic or therapeutic procedures.63   In addition to the potent antispasmodic activity, flavoxate has local anesthetic activity as good as lidocaine.64

Antimicrobial therapy for definite treatment of UTIs

Given the outlook that diagnostic sensitivity based on a typical history ranges between 50% and 80%, immediate antibiotic therapy, without additional testing, is an enticing option to clear the infectious process from urinary tract, and is quite conventional in many countries, while being appropriate as well.4,11,23,65,66             Patients at risk for complicated UTIs, or in whom recurrence continues despite conservative interventions, are candidates for further urologic evaluation.67

In general, nitrofurantoin, fosfomycin, trimethoprim-sulfamethoxazole (TMP/SMZ), fluoroquinolones and cephalosporins are first-line therapies for acute uncomplicated cystitis, in a scenario wherein decisions regarding the choice of agents should be individualized based on multiple factors, like tolerability, community resistance rates and availability.6   Use of these antibiotics is indicated clinically in favour 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.2,68

A rational approach should however be adopted in all cases, considering more judicious use of these antimicrobials because of concerns related to rising antimicrobial resistance. This may be particularly relevant for patients with recurrence or other risk factors for resistance, who will benefit from urine culture for a more definite bacteriological identification prior to antimicrobial therapy.

Role of nitrofurantoin in UTIs

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 countries68  , and guideline recommendations for antibiotic treatment of infections of urinary tract are often not implemented but rather widely ignored in practice, makes the above rational need important even further. In this context, international recommendations clearly warn against the broad and uncritical use of fluoroquinolones for uncomplicated infections  4  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. Moreover, due to more adverse effects with fluoroquinolones, they should not be the first-line option in most situations, as recommended by the World Health Organization (WHO) as well.69,71

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In such instances, nitrofurantoin is a possible alternative for patients with uncomplicated and complicated UTIs, recommended as the first-line agent for acute uncomplicated cystitis.68,72     The recommendation appears consistent with guidelines from various international organizations, such as the Infectious Diseases Society of America (IDSA) and the European Society for Microbiology and Infectious Diseases (ESMI), which show nitrofurantoin as an appropriate choice in UTIs thanks to the minimal overall resistance and favorable side-effect profile seen with this drug.73,76        It achieves good antibacterial activity in the urine, and is bactericidal against a mean of 95.6% of E. coli   UTIs.77

Various studies have demonstrated efficacy of nitrofurantoin in treatment and prophylaxis of UTI in specific population subgroups, with increased susceptibility of the causal pathogenic microorganisms (Table 3).78-87      The clinical advantages of nitrofurantoin may be further increased by using a sustained release formulation in favor of attenuation of adverse effects, fewer fluctuations in plasma drug concentration, and enhanced patient compliance.88

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Conclusion

Urinary tract infections remain a common clinical problem in both the community and hospital settings, with E. coli being responsible for the majority of cases. The clinical picture may vary dependent on age and gender of the patient, presence of an underlying abnormality, or selective manipulation of the urinary tract, but most common presentations include acute uncomplicated cystitis in women. The management in all cases however converges to effective clearance of the bacteria. Drug therapy should therefore be focused on effective use of antimicrobials for eradication of the causal pathogen, for which nitrofurantoin appears a treatment of choice for most patients with UTIs, particularly in an era of rising antibiotic resistance among uropathogens. The drug exhibits rising relevance in this context as it can be used for both treatment and prophylaxis of UTIs, regardless of age and gender, i.e., in both adults and children, and even in pregnant females. These attributes make nitrofurantoin an important agent among the antibiotics used for UTI management, founded on its well-documented efficacy and reduced bacterial resistance in different population subgroups.

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Prof. Dr. Sudhir Khanna

M.S., DNB (Surgery), MCh, DNB (Urology) MNAMS
Chairman Department of Urology
Senior Consultant Urologist
Sir Ganga Ram Hospital, New Delhi

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