Urinary Tract Infections (UTIs)

DefinitionTop

The term urinary tract infection (UTI) is defined as the presence of microorganisms in the urinary tract above the bladder sphincter in symptomatic patients.

Significant bacteriuria is defined as bacteriuria with proposed thresholds ranging from ≥103 to 105 bacterial colony forming units (CFU)/mL in a clean-catch voided urine or ≥102 CFU/mL in a single catheterized specimen.

Asymptomatic bacteriuria (ABU) (historically “asymptomatic UTI”) is defined as ≥105 bacterial CFU/mL in a culture of urine in patients without signs or symptoms of UTI. The presence of white blood cells (WBCs) or nitrites has no implications for the differentiation between ABU and symptomatic UTI.

Uncomplicated UTI may be diagnosed in a nonpregnant female patient without genitourinary abnormalities and without impairment of the local and systemic immune responses (ie, without UTI risk factors; see below). It is caused by microorganisms typical for UTI.

Complicated UTI: The rationale for separating complicated UTI from uncomplicated UTI is that these cases are more likely not to respond to first-line treatment or are more prone to relapse. Complicated UTI refers to the following:

1) UTI in a female patient with anatomical abnormalities, functional abnormalities, or both that affect urine flow (including pregnancy).

2) Individuals with impaired systemic or local immune response.

3) All UTIs in male patients (according to most guidelines).

4) UTI caused by uncommon or multiresistant microorganisms.

Recurrent UTI may be caused by relapse or reinfection.

Relapse of UTI is a recurrent UTI that develops after prior antimicrobial treatment and is caused by the microorganism(s) responsible for the previous UTI episode, which persist in the urinary tract. In clinical practice, a recurrent UTI is regarded as a relapse if the onset of signs and symptoms occurs within ≤2 weeks of completing the treatment of the previous UTI and the same etiologic agent is isolated in both instances.

Reinfection is a recurrent UTI caused by a microorganism that originates from outside of the urinary tract and is an entirely new etiologic agent. In clinical practice, a recurrent UTI is regarded as a reinfection if the onset of signs and symptoms occurs after >2 weeks of completing the treatment of a previous UTI, even if the etiologic agent remains the same.

Etiology and PathogenesisTop

Physiologically, the urinary tract remains sterile, with the exception of the distal part of the urethra, which is colonized by saprophytic coagulase-negative staphylococci (eg, Staphylococcus epidermidis), vaginal coccobacilli (Gardnerella [previously known as Haemophilus] vaginalis), nonhemolytic streptococci, corynebacteria, and lactobacilli. Pathogenic colonization of the urinary tract is predominantly ascending. The first stage of an ascending UTI involves colonization of the urethral opening by uropathogenic bacteria; women are more susceptible to this process due to the constant presence of uropathogenic microorganisms in the vaginal vestibule, as well as due to the closer proximity of the urethral opening to the anus and the short urethra. Sexual intercourse can facilitate ascending colonization in female patients. Subsequently, the microorganisms enter the bladder. In immunocompetent individuals, microbial colonization typically does not extend beyond the bladder. The risk of kidney involvement increases as the bacteria continue to persist in the bladder or in the presence of risk factors (see below). Hematogenous and lymphatic spread of infection is responsible for only ~2% of all cases of UTI, but these have the most severe course and usually affect patients who are seriously ill, immunodeficient, or both.

Risk factors for developing a complicated course of UTI: Urinary retention, nephrolithiasis, vesicoureteral reflux, catheterization, diabetes mellitus (particularly poorly controlled), advanced age, pregnancy, postpartum period, hospitalization for unrelated reasons.

Etiologic agents:

1) Bacteria:

a) Uncomplicated and recurrent cystitis: Escherichia coli (70%-95% of patients), Staphylococcus saprophyticus (5%-10% of patients, predominantly sexually active women), Proteus mirabilis, Klebsiella spp, Enterococcus spp, and other pathogens (≤5% of patients).

b) Uncomplicated acute pyelonephritis: As above, but the proportion of E coli infections is higher and no S saprophyticus infections are observed.

c) Complicated UTI: E coli (≤50% of patients); compared to uncomplicated UTI, more cases are due to infection with Enterococcus spp (≤20%), Klebsiella spp (10%-15%), Pseudomonas spp (~10%), P mirabilis, and mixed bacterial flora.

d) ABU: In women most frequently E coli; in patients with a long-term indwelling urinary catheter, usually mixed bacterial flora, in particular Pseudomonas spp, Candida spp, and urease-positive bacteria (eg, Proteus spp).

2) Microorganisms undetectable using standard methods typically result in urethritis and include Chlamydia trachomatis, Neisseria gonorrhoeae, and viruses (predominantly herpes simplex virus).

3) Fungi: Most frequently Candida albicans and other Candida spp, Cryptococcus neoformans, and Aspergillus spp; these cause ~5% of complicated UTI. Fungal UTI most frequently affects patients receiving immunosuppressive treatment, as well as patients with diabetes mellitus, those treated with antibiotics, with indwelling urinary catheters, and after instrumental procedures in the urinary tract. However, in most instances yeasts are colonizers not causing symptomatic UTI (see Candiduria).

Clinical Features And Natural HistoryTop

The clinical picture is very diverse: from asymptomatic bacteriuria to severe sepsis (urosepsis). Manifestations include urination-related symptoms (dysuria, urinary frequency), involuntary urination (in cystitis, usually in older women, it may be of an exertional or effort-independent nature), pain in the suprapubic region (in cystitis) or lumbar spine, leakage from the urethra (a typical symptom of urethritis). General symptoms such as fever, chills, headache, nausea, and vomiting are usually indicative of an upper UTI (pyelonephritis). On the basis of natural history and necessary diagnostic and therapeutic procedures, the following types of UTI are distinguished:

1) Acute cystitis in women.

2) Recurrent cystitis in women.

3) Uncomplicated acute pyelonephritis in women.

4) Complicated UTI.

5) ABU.

DiagnosisTop

Diagnostic Tests

1. Urinalysis:

1) Leukocyturia, WBC casts (suggestive of pyelonephritis), microscopic hematuria (frequent in women with cystitis).

2) Urinalysis has limited value in patients with clear symptoms of UTI. Neither leukocyturia nor detection of nitrites produced from nitrates by Enterobacteriaceae are sufficiently sensitive or specific to diagnose UTIs. The findings need to be correlated with the patient’s symptoms.

2. Urine culture:

1) The most common cause of uncomplicated cystitis in female outpatients are Escherichia coli or Staphylococcus saprophyticus; thus, treatment can be started without performing urine cultures.

2) Perform urine cultures in all other patients with UTI, as well as in women with signs and symptoms of cystitis not responding to a standard empiric treatment, hospitalized patients, patients with suspected complicated UTI, and patients in whom the current episode of UTI occurred within <1 month of the previous episode.

3) The results of a standard urine culture are negative in patients with nonbacterial cystitis or urethritis.

3. Other diagnostic tests not to be routinely used:

1) Blood tests: Elevated WBC counts, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) or procalcitonin levels.

2) Blood cultures may be positive in patients with severe UTI.

3) Imaging studies are indicated in complicated UTI as well as in uncomplicated acute pyelonephritis in women if the signs and symptoms of infection persist or worsen in spite of standard treatment. Abdominal ultrasonography can detect abnormalities of the urinary tract (eg, nephrolithiasis, urinary retention, cysts, malformations) and complications of UTI (renal or perinephric abscess). Urography is indicated predominantly in patients with suspected abnormalities of the pyelocalyceal system or the ureters, especially if computed tomography (CT) is not available. Contrast-enhanced CT allows for visualization of anatomic abnormalities and has the highest sensitivity for detecting perinephric abscesses; it may also visualize focal bacterial nephritis.

Diagnostic Criteria

UTI is diagnosed on the basis of clinical features. Always attempt to confirm the diagnosis with urine cultures (except for uncomplicated cystitis in women, which may be diagnosed solely on the basis of the clinical features). Significant bacteriuria is only indicative of UTI if the patient is symptomatic (versus ABU).

Differential Diagnosis

Differential diagnosis should include other conditions causing voiding problems, dysuria, pelvic pain (diseases of the reproductive tract in women, diseases of the prostate in men), renal colic, and inflammation of other abdominal organs.

TreatmentTop

The goal of treatment of a clinically overt UTI is eradication of pathogens from the urinary tract using antimicrobial agents. Initially the choice of drugs is empiric, and subsequent adjustments are based on the results of urine cultures (if indicated). Always attempt to eliminate modifiable risk factors for UTI (if any).

General Measures

1. Administration of oral or IV fluids to maintain appropriate volume status.

2. Treatment of fever, pain, or both, for instance, with acetaminophen (INN paracetamol) or nonsteroidal anti-inflammatory agents.

Antimicrobial Treatment

Antimicrobial treatment depends on the type of UTI (see treatment descriptions in relevant chapters).

PrognosisTop

1. Uncomplicated UTI: The prognosis is good.

2. Chronic or recurrent UTI in patients with persistent anatomic urinary tract abnormalities (eg, nephrolithiasis, vesicoureteral reflux) may result in chronic kidney disease.

3. Complications of UTI: Some complications, such as urosepsis (particularly in older patients), are associated with high mortality rates.

PreventionTop

Recurrent UTI typically manifests as uncomplicated cystitis, much less frequently as uncomplicated acute pyelonephritis. Methods of preventing uncomplicated UTI are listed below. Recurrences of complicated UTI are a distinct clinical issue and have usually been associated with urinary tract abnormalities, impaired immunity, or drug-resistant pathogens.

Nonpharmacologic Prevention

An increase in fluid intake by 1.5 L per day may prevent recurrent UTIs.Evidence 1Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to lack of blinding and a relatively low sample size.Hooton TM, Vecchio M, Iroz A, et al. Effect of Increased Daily Water Intake in Premenopausal Women With Recurrent Urinary Tract Infections: A Randomized Clinical Trial. JAMA Intern Med. 2018 Nov 1;178(11):1509-1515. doi: 10.1001/jamainternmed.2018.4204. PMID: 30285042; PMCID: PMC6584323.

Other measures that are supported by limited evidence and may also be considered for women with recurrent UTIs:

1) Voiding immediately after feeling the urge or at regular intervals every 2 to 3 hours as well as shortly before bedtime and immediately after sexual intercourse.

2) Avoiding the use of feminine hygiene deodorants, diaphragms, and vaginal spermicides.

3) Avoiding bubble baths and bath cosmetics.

4) Daily intake of cranberry juice (non–older age women).

5) Daily intake of supplements such as D-mannose or probiotics.

Pharmacologic Prevention

Pharmacologic prevention may be considered if nonpharmacologic measures are not successful:

1. Vaginal suppositories containing lactobacilli.Evidence 2Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to imprecision and relying on subgroup analysis. Grin PM, Kowalewska PM, Alhazzan W, Fox-Robichaud AE. Lactobacillus for preventing recurrent urinary tract infections in women: meta-analysis. Can J Urol. 2013 Feb;20(1):6607-14. Review. PMID: 23433130.

2. Vaginal estrogen cream (in postmenopausal women).

3. Methenamine hippurate in women without urinary tract abnormalities.

4. Antimicrobial prophylaxis (options):

1) Self-treatment of female patients at the onset of signs and symptoms as in uncomplicated cystitis. Advise the patient to seek medical attention if the signs and symptoms do not resolve within 48 hours or are atypical.

2) Postcoital prophylaxis: A single antimicrobial dose after sexual intercourse. Agents and dosage as in long-term prophylaxis. This strategy may be recommended for patients with a well-established temporal relationship of UTI episodes with sexual activity.

3) Long-term prophylaxis (last resort): Oral trimethoprim/sulfamethoxazole 40 mg/240 mg, trimethoprim 100 mg, norfloxacin 200 mg or ciprofloxacin 125 to 250 mg, cephalexin 125 to 250 mg, daily at bedtime or 3 times/wk, initially for 6 months. Nitrofurantoin 50 to 100 mg (there is a risk of chronic lung disease with prolonged use). If UTI continues to recur, consider extension of prophylaxis to ≥2 years.

5. Prophylaxis of catheter-associated UTI: The use of hydrophilic catheters can reduce the frequency of infections. Antibiotic prophylaxis in patients using clean intermittent self-catheterization may be beneficial in terms of reducing UTI recurrence rates in the short term; however, emergence of antimicrobial resistance may preclude longer-term management using this approach and is therefore generally not recommended.