Urinary Tract Infections (UTI)

Urinary tract infections

Urinary tract infection is defined as bacterial invasion of the urinary tract and can occur anywhere between the urethra and kidney. The classification of UTI is usually based according to the area of infection — bladder infection is known as cystitis, kidney infection as pyelonephritis, and urine as bacteriuria.

The direct and indirect costs of urinary tract infections

It is the second most common cause of infection of patients attending outpatient clinics of primary care units overall, and the most common cause of microbial infection of outpatient patients. It has been estimated that UTIs are responsible for 7 million outpatient visits annually, along with 1 million emergency department visits in the US. The economic impact of UTIs is correspondingly large, totaling about $1.6 billion in direct costs annually and includes GP visits, prescriptions, hospital admission costs as well as travel costs, days off work and morbidity. Indirect costs are the lost productivity associated with a disease. Studies of female college students found that UTIs led to 6.1 days of symptomatology, 2.4 days of limited activity, and 0.4 days of bedtime.

Epidemiology, pathogenesis, and risk factors

The actual incidence of UTI is somewhat unclear. According to one estimate, 1 in 2 women will experience an episode of UTI in her lifetime. About 7 million cases of acute cystitis are diagnosed annually in young women in the U.S., but the true number is likely much higher because about 50% of all women with UTIs do not go to their doctor.

The risk factors of urinary tract infections can be either modifiable or related to the genetic predisposition of the individual, and differ according to the age of the patient. UTIs in young premenopausal women are usually related to sexual activity, while postmenopausal women have different risk factors associated with comorbidities, including vaginal atrophy due to estrogen deficiency and increased urine stasis. Hopkins et al. observed an increased incidence of urinary tract infections in women in their immediate family who had a member suffering from recurrent urinary tract infections. Another genetic factor is the nonsecretor status for ABO blood group antigens. Studies show that uropathogenic coliforms attach more easily to the urothelium of these women. Postmenopausal women often have additional risk factors such as a history of genitourinary surgery, urinary incontinence, presence of cystocele, or even a large urine residue. Diabetes mellitus is associated with the occurrence of non-common uropathogens and an increased likelihood of developing complications such as emphysematous pyelonephritis or cystitis. Female patients with diabetes and recurrent urinary tract infections have symptomatic episodes 2–3 times more often than women without diabetes and recurrent UTIs.

Modifiable risk factors include methods of contraception, especially the use of vaginal septums and spermicidal agents. One large double-blind controlled trial identified 2 other sexually correlated risk factors: frequency of sexual intercourse and change of sexual partner within the previous year. Estrogen deficiency in postmenopausal women is another known risk factor for UTI that can be reversed with topical (vaginal) replacement therapy. The recent (within the previous 2–4 weeks) use of antibiotics systematically, (disrupts the vaginal flora), is another factor that increases a woman's susceptibility to urinary tract infections. The most common pathogenetic mechanism through which bacteria enter the urinary tract is the periurethral areas. It has been hypothesized that women are more prone to urinary tract infections than men because their urethra is shorter as well as its close proximity to the anus. About 80% of urinary tract infections in the community are due to coliform O, followed by other less common pathogens including Staphylococcus saprophyticus, Klebsiella, Proteus, Enterobacter spp., and enterococci.

Asymptomatic bacteriuria

It is the presence of bacteria in the urine, it is a clinical feature of all types of urinary tract infections. When it is not accompanied by any other symptom, it is referred to as asymptomatic bacteriuria or microbiuria. A diagnosis of asymptomatic bacteriuria requires the presence of 100,000 colonies (CFU)/ml from a medium current pure urine collection sample or at least 100 CFU/mL for a catheterization sample. The urine test strip for leukocyte esterase and nitrite is of little use in an asymptomatic patient.

Asymptomatic bacteriuria should only be treated in pregnant women who should routinely undergo urine culture at the end of the first trimester. Patients without lower urinary tract symptoms should not undergo the urine stick test or urine culture for the following reasons: Most premenopausal women with asymptomatic microbiuria will eliminate microbes spontaneously and no significant benefit has been demonstrated from the treatment of asymptomatic microbiuria in diabetics, the elderly, patients with spinal cord injury.

Pregnant women with asymptomatic bacteriuria should be covered with 3–7 days of antibiotic therapy and periodically investigated for asymptomatic microbiuria for the remainder of pregnancy. According to the American Society of Infectious Diseases, untreated bacteriuria in pregnant women has been linked to premature birth, and underweight children.

Uncomplicated urinary tract infections

Acute cystitis or uncomplicated UTI is defined as a symptomatic bladder infection in a healthy, non-pregnant person with a normal genitourinary system. 95% of cases of acute cystitis occur in women. Uncomplicated UTI is generally considered a benign disease and there is no evidence of long-term secondary complications including chronic kidney failure, kidney scarring, or hypertension. Symptoms of cystitis are frequent urination, burning and stinging during urination, dysuria, urge to urinate, and stranguria. Frequent urination is the most common symptom and hematuria, suprapubic pain or tension as well as a change in urine odor may also occur. Many women can accurately diagnose their acute cystitis based on one or more previous UTI experiences. The differential diagnosis of acute cystitis includes pyelonephritis, vaginitis, sexually transmitted diseases, urethral syndrome, interstitial cystitis, and dysmenorrhea.

The clinician should always investigate for fever, low back pain, vaginal discomfort, presence of discharge, changes in sexual activity or partner. Any of these symptoms can indicate a condition other than acute cystitis. A group of experts argues that no further diagnostic procedure is required if the history is typical of UTI and the patient does not report vaginal discharge or discomfort. The researchers demonstrated that this method is effective without a significant increase in adverse outcomes. This same group also demonstrated that telephone cystitis management is safe and cost-effective in a small randomized, controlled trial.

The urine test strip (stick) is a standard method of diagnosis for acute cystitis, but there is great disagreement about its usefulness and role. But there is no question that this test is fast, affordable, and easy to apply even in the doctor's office. But neither nitrite nor leukocyte esterase alone have sufficient sensitivity and specificity to diagnose or exclude cystitis. When used together, and either one or both results are positive, then sensitivity ranges from 68% to 88% and specificity varies greatly from study to study. However, according to the same meta-analysis, when results from both tests are negative, the negative predictive value is sufficient to rule out infection. Researchers have shown that some patients with UTI symptoms but negative urine sticks may experience improvement in symptomatology when treated with antibiotics. However, the use of antibiotics in the absence of evidence of bacterial infection raises concerns about promoting antibiotic resistance. Urine culture is required during the treatment of patients with a negative urine stick.

Microscopic urinalysis

Microscopic examination of a centrifuged urine sample can be used to detect bacterial concentrations greater than 100,000 CFU/mL, but it is laborious, often poorly interpreted and poorly executed, and thus does not improve the diagnostic process. Three or more white blood cells (WBCs) per field of vision indicate the possibility of infection. The presence of more than 20 epithelial cells/field of vision indicates infection.

Urine cultivation

When one or two results of the urine stick test strip are positive in a symptomatic patient, then urine cultivation is not necessary. Patient populations in which urine culture is indicated are those with predisposing factors for the development of upper urinary tract infections or complicated urinary tract infections (such as patients with hydronephrosis or atonic bladder).

Urinary cultivation should also be taken in patients whose symptoms do not subside after treatment or recur within 2–4 weeks of treatment, to detect resistant or unusual microorganisms.

First-line urinary tract infection treatment

There is much debate about which antibiotics should be used as a first-line treatment for UTIs. The ideal empirical treatment for UTIs should be able to neutralize the most likely pathogens, be well tolerated, short-lived, and affordable. Most experts in the United States agree that trimethoprim-sulfamethoxazole (TMP-SMX) is the drug of choice as a first-line treatment for uncomplicated urinary tract infections. It has an efficacy ranging from 90% to 95%, and can be given as a three-day regimen. For patients who are allergic to sulfamethoxazole, trimethoprim as 3-day monotherapy is equally effective.

Nitrofurantoin is also a very good choice as a first-line treatment. It is indicated only as a treatment of uncomplicated urinary tract infections. Nitrofurantoin has low resistance (1.1%), and is well tolerated with an excellent safety profile (a record since it exceeds 50 years). The disadvantage of nitrofurantoin is that its maximum efficacy — 85% to 90% — is achieved with a seven-day regimen. If given as a three-day regimen, the cure rate is reduced to 70%–80%.

Treatment of second line urinary tract infection

Fluoroquinolones are generally used as second-line therapy for the empirical treatment of uncomplicated UTIs, due to the cost of treatment and the continuous increase in coliform resistance to antibiotics. Quinolones can also be given as a three-day regimen with efficacy rates identical to TMP-SMX (90%–95%). The three most used quinolones in the USA are ciprofloxacin, levofloxacin and gatifloxacin. All 3 drugs tolerate well and can be given daily once a day for a total duration of 3 days. Many studies have been conducted to determine whether or not quinolones can be administered as a one-time, single-dose therapy. The results show that single dose administration has cure rates of only 70% with limited ability to eradicate S saprophyticus.

Recurrent urinary tract infections

A patient is considered to have recurrent UTIs if they have 3 or more symptomatic episodes within a period of twelve months. This may be a result of microbes remaining in the bladder that are not eradicated despite treatment or from a continuous infection by another microorganism. These 2 causes of recurrent urinary tract infections are clinically similar, with the latter being more common. The risk factors for recurrent UTIs are almost identical to those listed above for uncomplicated gingival infections. Recurrent urinary tract infections are mainly caused by coliforms (70%–95% of cases) followed by S saprophyticus (5%–20%), and opportunistically by other uropathogens. Imaging should be performed if the clinician suspects any anatomical or functional abnormality of the genitourinary system. However, such abnormalities are present in less than 5% of all patients with recurrent urinary tract infections. Clinical indications for imaging use are the occurrence of haematuria, acute pyelonephritis, or persistent signs and symptoms of cystitis despite adequate and appropriate treatment.

Pharmacotherapy

The occurrence of an episode of acute cystitis should be treated with routine treatment for uncomplicated urinary tract infections. Once the symptomatic episode subsides, there are several options for the patient suffering from recurrent urinary tract infections. Continuous sedation therapy (chemoprophylaxis) requires the patient to take low-dose antibiotics daily (usually at bedtime) for 6 months to 1 year. Options include TMP-SMX, trimethoprim, nitrofurantoin, and quinolones. Daily sedation therapy effectively prevents infection during the treatment period, and allows the inflamed bladder mucosa to regain its inherent ability to cope with the infection. Unfortunately, 50% of women will relapse within 3 months after chemoprophylaxis ends.

Prophylactic treatment after sexual intercourse is a more cost-effective method for treating recurrent UTI in women where a clear documented link between intercourse and infection has been found (in the last 48 hours). Trimethoprim and ciprofloxacin are commonly prescribed medications and are an effective method of prophylaxis. Prophylactic treatment after sexual intercourse and chemoprophylaxis are equally effective, but patients in the first method take fewer drugs and experience fewer side effects from them.

Pyelonephritis

Upper urinary tract infections are usually caused by bacteria that invade the ureter through the bladder, but can also be the result of a blood-borne infection. The initial clinical picture of upper and lower urinary tract infections may be the same and difficult to separate. In general, lower urinary tract infections are characterized by symptoms associated with urination and absence of systemic symptomatology. Symptoms indicative of an upper urinary tract infection include fever, chills, and low back tenderness. A detailed examination should include palpation for renal masses.

Laboratory testing

Urine and blood cultures should be taken in the febrile patient suspected of upper urinary tract infection, always before starting antibiotics. Blood tests in patients with pyelonephritis are likely to reveal leukocytosis, increased erythrocyte sedimentation rate, as well as increased C-reactive protein. Biochemical testing should also be performed for possible diabetes mellitus.

Imaging test

In patients with back pain, hematuria, or those presenting systemic symptoms, one should suspect the diagnosis of pyelonephritis and therefore should undergo imaging examination, i.e., ultrasonography as well as simple radiography of kidneys, ureters, and bladder (NOK). Intravenous urography or preferably computed tomography with intravenous contrast medium is given in cases where we want to further investigate any findings of routine imaging tests. Pyelonephritis in CT is most demonstrated as a delineation deficit in the affected areas of the kidney parenchyma.

Treatment of urinary tract infection

Treatment of pyelonephritis depends on the severity of the symptomatology. Toxic patients should be hospitalized and empirical treatment with intravenous ampicillin and aminoglycoside (gentamicin). It is necessary to adjust the dose of aminoglycoside according to creatinine clearance and ideal body weight. The combination of these two antibiotics is effective against the full range of uropathogens. Alternatives include amoxicillin with clavulanic acid or a third-generation cephalosporin. Intravenous antibiotics are continued until fever and bacteremia subside, usually after about 3 days, and continued with antibiotics according to antibiogram sensitivities for another 10–14 days. Treatment with 10–14 days with fluoroquinolones or TMP-SMX has been shown to be safe and effective in patients who do not present with noisy symptoms. Both drugs are well tolerated. Cure rates after 7–14 days with empirical treatment range from 85% to 95%. When urine is sterilized in repeat cultures, patients may continue empirical treatment or administer an antibiotic according to the susceptibility test.

Herbal and natural remedies

The herbs and natural juice of cranberry remedies have long been thought to have properties that prevent or relieve the symptoms of UTI. Recently, Western medicine has begun to scientifically investigate blueberries for their action in the prevention and treatment of urinary tract infections. Blueberries have a higher acid content than other fruits, and in the past it was thought that the clinical benefit of cranberry juice was due to its bacteriostatic effect on uropathogens. However, there is still no concrete scientific evidence that taking cranberry juice significantly changes the pH of urine. In vitro studies have shown that a very large part of the proanthocyanides found in blueberries can prevent the adhesion of P fimbriated coliforms to the epithelium of the cystic mucosa. Two recent, well-designed, randomized trials demonstrated that cranberry juice can reduce the number of symptomatic UTIs over twelve months. However, both studies had high rates of treatment dropout, which raises tolerance issues. Nor is it clear whether the same benefit can be obtained from a concentrated substance in tablet form on the market. Cranberry juice can be an effective preventive measure, but further evidence is needed for its widespread use.

Several species of lactobacillus also appear to exhibit protective effects against coliform colonization, including adhesion to the epithelium of the vagina, inhibition of adhesion and growth of uropathogens, H2O2 production, and biosurfactant secretion. Currently, the only effective method of administration is through a vaginal suppository, which is not yet commercially available. Commercially available oral solution containing lactobacillus CG has not been shown to reduce the risk of urinary tract infection.

Recent advances in urinary tract infection research | vaccine

There are 2 vaccines for use in recurrent urinary tract infections in clinical trials in the United States: SolcoUrovac (Solco Basel, Germany) and Uro-Vaxom (OM PHARMA, Switzerland) already marketed in Greece. SolcoUrovac is a combination of 10 heat-inactivated bacteria including 6 E. coli subtypes, plus 1 subtype of proteus mirabilis, proteus morganii, enterococcus faecalis, and klebsiella pneumoniae. The vaccine is given as a vaginal suppositorie, and is currently being evaluated for intramuscular and submucosal. Early Phase II data of the study showed a significant reduction in infections versus placebo, with 80% of patients being infection-free for one year.

UroVaxom is a p.os preparation of immuno-active ingredients from 18 subtypes of E.Coli. A meta-analysis of 5 clinical studies showed that this vaccine is significantly more effective than placebo in preventing recurrent urinary tract infections and that it has similar efficacy to many of the antibiotics recommended daily as chemoprophylaxis treatment without the burden of taking and developing antibiotic resistance. There have been few and minor adverse reactions such as mild skin rash and gastrointestinal upset.

A third method investigated in the prevention of recurrent urinary tract infections is intravesical injection of hyaluronic acid (Cystistat). All patients received 4 weekly infusions, then one monthly booster for 4 months. Patients were disease-free during the five-month treatment phase and 70% of them were relapse-free at the end of one year of follow-up.

New chemotherapeutic agents

New chemotherapeutic agents are under development in almost every current class of antibiotics. The new mechanisms being investigated are bacterial flow pump inhibitors that would be used in combination with a currently available agent to increase its effectiveness. Many resistant bacteria, such as pseudomonas aeruginosa, show overexpression of bacterial flow pumps. MurA inhibitors are another new class, targeting the bacterial enzyme MurA to inhibit cell wall synthesis in both gram-negative and gram-positive organisms. The development of agents with alternating mechanisms of action and innovative treatment strategies, such as vaccines, are key weapons in the fight against the development of antibiotic resistance. New research has shown that forskolin herbal extract may have an auxiliary role along with antibiotics in eradicating microbes nesting inside the intracellular bladders of the bladder epithelium. However, these results are preliminary and human trials are needed before we can verify the action of this substance in the treatment of urinary tract infections.

The future of research in urinary tract infections

Antimicrobial resistance

According to experts, the most important drawback and concern in treating urinary tract infections with antibiotics is the development of antimicrobial resistance. The following strategies have been proposed to prevent resistance: reduced antibiotic uptake and a combination of two classes of antibiotics. The administration of antibiotics can certainly be reduced by not using them to treat asymptomatic microbiuria in the non-pregnant population and to provide short-term regimen therapy for uncomplicated urinary tract infections. The combination of two types of antibiotics to prevent the development of resistance is based on our experience with the treatment of tuberculosis. The chances of a pathogen mutating to develop resistance to 2 or more drugs simultaneously are very rare. Unfortunately, a large study confirming this theory of urinary tract infections is missing, but one study demonstrated a benefit in combining ciprofloxacin and macrolide from using ciprofloxacin alone.

The sensitivity of coliform bacteria to TMP-SMX is increasing, approaching the rise and approaching the 20% threshold, where it would no longer be appropriate as an empirical treatment. Antimicrobial resistance to fluoroquinolones, although relatively low, is also increasing especially in areas where overprescription is common, mainly by primary care physicians. Resistance to ampicillin and amoxicillin is now approaching 50%, and therefore these drugs should no longer be used as first-line therapy in the non-pregnant patient with UTI. Nitrofurantoin resistance remains low despite widespread use and is therefore preferred by many urologists as chemoprevention.

Although UTIs are always present on an outpatient basis, much of the information about diagnosis and treatment changes frequently. The doctor must be able to respond to new developments, counseling, and treatment of patients with urinary tract infection. The public is becoming more aware of, and aware, of newer and alternative forms of treatment, and we as physicians owe it to our patients to join the science behind these changes.