Urinary Tract Infection: Clinical Perspectives on Urinary Tract Infection

2. Diagnosis and Management of Infections of the Urinary Tract

Magnus Grabe 

(1)

Department of Urology, Skåne University Hospital, Malmö, SE-205 02, Sweden

Magnus Grabe

Email: magnus.grabe@skane.se

Abstract

Urinary tract infections are among the most frequent infections encountered in both the community and the hospital environment. They range from harmless asymptomatic bacteriuria and self-curing cystitis to severe pyelonephritis with life-threatening sepsis. Escherichia coli is the most common gram-negative urinary tract pathogen followed by Proteus sp., Klebsiella sp., and other Enterobacteriaceae. Gram-positive species such as Enterococci and Staphylococcus spp. are often found in urine culture.

Early diagnoses and determination of the severity of the infection are necessary for an effective medical treatment. Urological patients are particularly prone to urinary tract infections, and the identification of a possible risk factor requiring a surgical intervention or drainage can be vital to the patient.

In view of the worsening resistance pattern of common urinary pathogens against available antibiotics, it is important to comply with evidence-based, recommended treatment regimens.

Keywords

Asymptomatic bacteriuriaCystitisPyelonephritisRisk factors for urinary tract infectionsSepsisUrine cultureUrinary tract infection

What Is an Infection of the Urinary Tract?

The normal urinary tract is sterile. Urinary tract infection (UTI) is defined as an inflammatory response of the urothelium to the invasion of microorganisms, usually bacteria, also called uropathogens. The invasion of bacteria, as shown by bacterial growth on the culture of urine, is defined as bacteriuria. Symptomatic UTI is the presence of both bacteriuria and typical symptoms, while asymptomatic bacteriuria (ABU) is the presence of bacteriuria in the absence of symptoms. ABU in conjunction with an indwelling catheter is often referred to as colonization of the urinary tract.

Is UTI a Major Health Problem?

Urinary tract infections are among the most frequent infections encountered in the community. Catheter-associated infections account for approximately 30–40 % of the healthcare-associated infections (HAI) and are an important source of severe urinary tract infections and septicemia. Prevalence studies have shown that up to 10 % of patients in urological wards have healthcare-associated complicated infections.

What Is the Classification of UTI?

For practical reasons, it is reasonable to classify UTI as:

·               Bacteriuria or colonization (presence of microorganisms in urine)

·               Uncomplicated UTI (uUTI)

·                      Cystitis

·                      Uncomplicated pyelonephritis

·               Complicated UTI (cUTI)

·                      Febrile, upper UTI

·                      Complicated pyelonephritis

·               Sepsis

It is understood that there is no known or detected underlying abnormality or dysfunction of the urinary tract in uUTI, while in cUTI there is one or several such complicating factors (Tables 2.1 and 2.2).

UTI can be sporadic, recurrent, or reinfection. Usually there should go more than 6 months between episodes of UTI to speak about sporadic or isolated infections, while recurrent UTI are defined as three or more infections per year. Reinfections mean the acquisition of a new infection, while relapse is the reappearance of the same bacterial strain originating from a focus in the urinary tract, i.e., the prostate, a bladder diverticulum, and a kidney stone.

How Frequent Is Bacteriuria in the Population?

The overall prevalence of bacteriuria in the population is estimated to 3.5 %. Bacteriuria is present in schoolgirls in 1–2 % and young women in 1–5 %. The rate is increasing with age, and it is estimated that some 25 % of all women over the age of 65 years living at their home have bacteriuria, while this figure range from 25 to 50 % in women cared for in institutions for elderly persons. All patients with indwelling catheters or other long-term urinary tract stents have bacteriuria.

How Frequent Is Symptomatic UTI in the Population?

The cumulative incidence of UTI through the age of 6 years is approximately 1 % in girls and 0.1–0.2 % in boys. One third of all women will have reported a UTI before the age of 24 years, and the cumulative probability of UTI in women is about 50 % at 50 years of age. There is a 40–50 % risk of a new infection within a few months.

Do Men Have UTI?

UTI in men are uncommon until the age of 50 years, when increasing bladder outlet obstruction is developing and markedly changes the odds of having a UTI. On the other hand, adult men are prone to bacterial prostatitis, a urogenital infection involving both the prostatic gland and the lower urinary tract (NIH prostatitis type I and II).

Which Are the Most Frequent Factors Associated with a cUTI?

Table 2.1

Main factors associated with complicated UTI

Factors associated with complicated UTI

Examples

Congenital anatomic and functional abnormality

Pelvio-ureteral junction (PUJ) obstruction

Vesicoureteral reflux

Congenital neurological disorder (i.e., myelomeningocele)

Obstruction of the urinary tract

Kidney stone disease

Bladder outlet obstruction

Residual urine

Ureteral tumor

Extrinsic compression of the ureter

Ureteral stricture

Neurological dysfunction

Spinal cord injury

Multiple sclerosis

Stroke

Concomitant medical disorders

Diabetes mellitus

Disorder of the immune system

Which Pathogens Cause UTI?

It is essential to know the likely causative pathogens for an appropriate antimicrobial treatment. Most UTI are caused by the microorganisms listed in Table 2.3Escherichia coli is the most frequently encountered microbe, present in as many as 75–80 % of the community-acquired uUTI and approximately 35–50 % of the UTI. Other main gram-negative bacterial species are Klebsiella and Proteus spp., Pseudomonas sp. and gram-positive strains such as Enterococcus faecalis, and some Staphylococci species, i.e., Staphylococcus epidermidisStaphylococcus aureusand Staphylococcus saprophyticus, the latter usually only in female UTI.

Are There Other Specific Infections of the Urinary Tract?

Bacillus tuberculosis is causing progressive destruction and scares of the urinary tract with retained calcifications. Tuberculosis is still a worldwide infectious disease of major importance and hits the urinary tract in at least some 5–10 % of the cases. Also the blood fluke Schistosoma haematobium (bilharzias, snail fever) is endemic in defined geographic areas, producing fibrotic lesions, strictures, and scares of the ureter and bladder as well as being a possible underlying cause of bladder cancer.

What Is the Pathogenesis of UTI?

The bowel constitutes the reservoir of the microorganisms colonizing the urogenital tracts. Ecoli infections have been extensively studied and are caused by a disturbance in the host-parasite balance. The vagina, periurethral zone, and even the urethra are naturally colonized by microorganisms originating from the fecal flora and the perineal skin. Ecoli adheres to the uro-epithelium through adhesines (P fimbriae and type 1 fimbriae). The bacteria can also express toxins such as α-hemolysin and cytotoxic necrotic factor 1.

The hosts’ defense is relying on specific local and systemic antibodies and the inflammatory response. The bacterial adhesion to the epithelium produces a signal and activation of the cellular defense functions. Chemokines are released, stimulating a neutrophil recruitment. In UTI, the more severe the infection, the higher is the expression of virulence factors. In ABU, there is an attenuation of virulence factors, whereas in uncomplicated pyelonephritis, the expression is usually high. The more compromised the natural defense mechanisms of the host, the fewer the expression of virulence. There are indications that some individuals are genetically more susceptible to UTI.

Are There Any Risk Factors?

A wide range of factors have been identified that can increase susceptibility to UTI (Table 2.2). An intrinsic factor is a factor harbored within the patient such as a genetic, biological, or functional abnormality. An extrinsic factor is related to external features such as hygiene and behavior, the introduction of a catheter, and urological instrumentation.

Table 2.2

Factors that might increase the susceptibility to UTI

Factors

Examples

Genetic and familiar factors

Host response capacity

Nonsecretor status

ABO blood-group antigens

Biological factors

Congenital abnormalities

Urinary tract obstruction

Prior history of UTI

Medical concomitant diseases (Table 2.1)

Dysfunction of the urinary tract

Renal transplant

Immunologic abnormalities (i.e., HIV)

Behavioral

Sexual intercourse

Some contraceptive devices (i.e., diaphragms, condoms, spermicides)

Urological surgery and instrumentation

Catheters/stents/foreign materials

Infections associated with an instrument or operation

Others

Estrogen deficiency in aging women

Previous use of antibiotics

Long hospital stay

Reduced mental status

What Are the Most Common Symptoms?

The most frequent symptoms and clinical signs of UTI are:

·               Dysuria, urgency, frequency, and suprapubic tenderness for the lower urinary tract

·               Fever and abdominal or flank pain, usually accompanied by flank tenderness, and nausea as signs of a febrile upper UTI or pyelonephritis

·               Chills and shivering as signs of bacteremia

·               Circulatory instability and eventually organ failure as signs of sepsis

How to Diagnose a UTI?

The diagnosis of a UTI is based on the combination of symptoms and laboratory findings.

Urine dipstick test for leukocytes esterase and nitrate is basic, easy, and reliable in most infections. The first demonstrate the presence of leukocytes in the urine or pyuria (≥10 WBC/mm3). The second displays the presence of bacteria. Consistent pyuria with a series of negative urine culture leads to the suspicion of a specific infection.

Bacterial count in terms of colony-forming units (cfu) is important. For sporadic cystitis in women, a bacterial count of ≥103 cfu/mL is accepted, while ≥104 cfu/mL is necessary to define an uncomplicated pyelonephritis. A cUTI requires the same symptoms and ≥104 cfu/mL in females and ≥105 cfu/mL in males. ABU is defined as the presence of ≥105 cfu/mL in at least two consecutive cultures in an otherwise symptom-free individual.

A midstream urine culture (MSU culture) is followed by a susceptibility testing that will guide in the choice of antibiotics.

Basic blood samples are collected for hemoglobin, white blood cells (WBC) and differential count, C-reactive protein (CRP), and S-creatinine. Sampling is unnecessary in sporadic uUTI but highly recommended in uncomplicated pyelonephritis and UTI as part of the diagnostic process.

In case of high fever, chills, and clinical suspicion of severe upper UTI and/or septicemia, it is essential to collect at least two samples of blood for blood culture. Imaging of the urinary tract is required in recurrent infections, in case of febrile infection or when a complicating factor is suspected. Radiological evaluation is also done in case of treatment failure. This can be done with an ultrasound examination, an intravenous pyelogram, or a computerized tomography, depending on the clinical situation and available methods.

What Are the Principles of Management of UTI?

There are three main aims in the management of UTI:

·               Effective therapeutic response

·               Prevention of recurrence

·               Reduce the development of resistance of bacterial strains

How Do You Treat an Uncomplicated UTI?

Cystitis is the most common UTI, involving only the lower urinary tract, and is seen in both pre- and postmenopausal women. There is no fundamental difference in the principle of treatment. However, with increased age, the recurrence rate may increase and, thus, the regimens length.

In sporadic UTI, empiric treatment can be initiated on the basis of symptoms without any further workup. A short treatment of 3–5 days is sufficient (Table 2.3). No clinical or microbiological follow-up is usually required. However, if therapy fails, laboratory testing should be undertaken.

A more thorough diagnostic evaluation is indicated for women with evidence of uncomplicated pyelonephritis. This workup includes a urine analysis, urine culture and susceptibility testing, blood samples, and, when considered as necessary, radiological evaluation. Involving the renal parenchyma, this infection is more serious and requires a 7–14-day treatment. Clinical and microbiological follow-up is recommended.

How Do You Treat a Recurrent UTI?

Recurrent UTI is defined as three or more infections within a year. Recurrent UTI are seen in women with a family history of UTI and limited intake of fluids and few voiding occasions. Sexual intercourse and some contraceptive measures may increase the frequency of UTI. In elderly women, prolapse, intestinal troubles, and concomitant diseases such as diabetes are underlying causes for recurrent UTI. Patients with recurrent UTI should be investigated for any anatomical or functional abnormality by imaging of the urinary tract, cystoscopy, and urodynamic studies as required.

In men, recurrent bacteriuria and urogenital infections can be caused by a chronic bacterial prostatitis (NIH type II). Clinical and microbiological follow-up is recommended.

Table 2.3

Classification of UTI, most frequent causative pathogens, and treatment recommendation

Type of UTI

Bacteria

Antibiotics

Length of treatment

Remarks

uUTI (sporadic)

Ecoli (75–80 %)

TMP (+/− SMZ)

3–5 days

Avoid F-quinolones

Cystitis

Proteus spp. (≤5 %)

Pivmecillinam

Klebsiella spp. (≤5%)

Nitrofurantoin

Ssaprophyticus (5–10 %)

Fosfomycin

Enterococcus spp. (<5 %)

2G cephalosporins

uUTI (recurrent)

Ditto

Ditto+

7–10 days

 

F-quinolones

uUTI (pyelonephritis)

Ecoli (75–80 %)

3G cephalosporins

7–14 days

Parenchymal infection

Proteus spp. (≤5%)

F-quinolones

Klebsiella spp. (≤5%)

TMP + SMZ

Others

UTI in pregnancy

Ditto

Ref. to national recommendations

7 days

Long-term prophylaxis

cUTI

Ecoli (35–50 %)

3G cephalosporins

10–14 days

Empirical treatment. adjustment according to culture result

ProteusKlebsiellaother Enterobacteriacae spp. (15–25 %)

F-quinolones

Pseudomonas (5–15 %)

TMP + SMZ

Enterococcus (5–20 %)

Aminoglycosides

Others (<10 %)

Acute bacterial prostatitis (NIH type I)

Ecoli

3G cephalosporins

≥14 days

Consider Chlamydia infection in young men

Other uropathogens

F-quinolones

TMP + SMZ

Aminoglycosides

Septicemia

Ecoli (35–50 %)

3G cephalosporins

10–14 days

2 AB

ProteusKlebsiellaother Enterobacteriacae spp. (15–25 %)

F-quinolones

General supportive treatment

Pseudomonas (5–15 %)

TMP + SMZ

Enterococcus (5–20 %)

Aminoglycosides

Others (<10 %)

Catheter-associated UTI

Ecoli

According to culture

5–10 days

No AB in ABU

ProteusKlebsiellaEnterococcus faecalis spp.

Only symptomatic UTI

Pseudomonas spp.

Others

uUTI uncomplicated urinary tract infection, cUTI complicated urinary tract infection, TMP trimethoprim, SMZ sulfamethoxazole, Spp species, 2G and 3G second and third generation, AB antibiotic, ABUasymptomatic bacteriuria

Are There Any Preventive Measures Against Recurrence?

There is little evidence for each of the different measures that are usually given as recommendation to women with recurrent UTI. It is essential to inform and promote an understanding of the reasons for recurrence and to detect any underlying cause.

General advice includes:

·               A high intake of fluids

·               Regular urination in order to avoid distension of the bladder and residual urine with bacterial growth opportunities

·               Good hygiene and postcoital voiding

·               Avoidance of spermicides

Antibiotic prophylaxis reduces the number of episodes but is controversial in view of the development of antibiotic resistance. Short courses à la demand is an alternative. Both cranberry extracts (Vaccinium macrocarpon) and vaccination with bacterial extracts are under investigation.

What Is Acute Bacterial Prostatitis?

Acute bacterial prostatitis is a serious, usually febrile infection creating an inflammation of the glandular tissue. The condition is accompanied by dysuria, perineal pain, bladder outlet voiding symptoms, and fever. Inflammatory parameters such as CRP and white blood count are increased. In adult men, the causative microorganisms are the usually uropathogens, although sexually transmitted infections also have to be considered. In younger men, Chlamydiainfection must be taken into account.

As for UTI, the treatment is empirical and initiated with an antibiotic covering the usual uropathogens until culture is available. It should last for at least 14 days. Clinical and microbiological follow-up is recommended.

What Is Different About a UTI During Pregnancy?

The consequences of UTI or untreated ABU during pregnancy can be significant, including an elevated risk of pyelonephritis, premature delivery, fetal mortality, and pregnancy-induced hypertension. Therefore, screening for bacteriuria is highly recommended. Owing to the seriousness of inadequate management during pregnancy, all infections should be adequately treated, usually for a period of 7–10 days, depending on the severity. Additionally, it is generally recommended to give long-term prophylaxis in case of ABU.

Should Asymptomatic Bacteriuria Be Treated?

It is recommended not to treat ABU except during pregnancy. Only episodes of symptomatic bacteriuria should be given antibiotics. The same recommendations as for UTI are valid. ABU must be controlled prior to urological surgery.

Should Catheter-Associated Infections Be Treated?

Asymptomatic infections associated with an indwelling catheter, a ureteral catheter or stent, or a nephrostomy tube should not be treated unless there are obvious signs of clinical infection. Only clinical significant infections are given antimicrobial agents.

How Do You Treat a Complicated UTI?

In case of high fever and/or shivering, a urine culture and two blood cultures are highly recommended. When a UTI is suspected, imaging investigation of the urinary tract for underlying cause and risk factor assessment is required. The treatment is combined:

·               Medical with one or two antimicrobial agents

·               Surgical, i.e., when drainage or other surgical measures are required

The medical treatment is empirical and initiated with at least one intravenous antibiotic for 1–3 days until the fever is controlled and the laboratory findings show a stabilization or decrease of the inflammatory process (Table 2.3). At the same time, the result of the urine culture and susceptibility of the microorganisms will be available, guiding in the choice of subsequent agents. It is important to note that former urine cultures can guide in the choice of the first antibiotics. Monitoring and full life-supportive measures have to be taken as requested. A clinical and microbiological follow-up is recommended.

What Is the Best Way to Treat a Sepsis?

Sepsis is a serious life-threatening condition requiring rigorous antibiotic treatment similar to that of UTI. Urine and blood cultures are imperative. Monitoring and full life-support treatment in cooperation with intensive care specialists is mandatory. Initial treatment with two antibiotics is recommended (Table 2.3). As for UTI, the treatment is both medical and surgical. Necessary imaging and potential causative factors, i.e., obstructive kidney stone, residual urine, and tumor disease, have to be detected early and managed properly. The same follow-up as for UTI is recommended.

Which Antibiotic(s) Should Be Used to Treat UTI?

The most useful antibiotics for the different types of infections are listed in Table 2.4. Uncomplicated UTI are treated with short 3- to 5-day courses with trimethoprim, trimethoprim-sulfamethoxazole, nitrofurantoin, pivmecillinam, or fosfomycin, when available. It is essential to avoid fluoroquinolones for lower UTI.

Uncomplicated pyelonephritis can usually be treated for 7–14 days with trimethoprim-sulfamethoxazole or a fluoroquinolone. β-lactam penicillins with a β-lactamase inhibitor, cephalosporins, fluoroquinolones, and aminoglycosides are useful for UTI and sepsis.

In pregnancy, β-lactam antibiotics and nitrofurantoin can be given, while fluoroquinolones, tetracyclines, and even trimethoprim are to be avoided due to the risk of adverse effects on fetal development.

Table 2.4

List of the most common antimicrobial agents used for the treatment of uUTI and cUTI. The list below is indicative and mentions the most common side effects, interactions, and contraindication

Name

Mode of action

Dose (adults)

Main adverse effects (*see comments)

Important interactions and contraindications

Trimethoprim

Acid folic metabolism

160 mg × 2

GI disturbances

Known hypersensitivity to trimethoprim

Allergic reactions (skin rash)

Renal insufficiency

Might interact with some contraceptive drugs, cyclosporine, and glibenclamide

Avoid during first term of pregnancy

Trimethoprim + sulfamethoxazole

Acid folic metabolism

160/800 mg × 2

GI disturbances

Known hypersensitivity to trimethoprim and/or sulfamethoxazole

Reduce dose according to renal function

Allergic reactions (skin rash)

Renal insufficiency

Renal function reduction

Might interact with some contraceptive drugs, cyclosporine, and glibenclamide

Avoid during pregnancy

Mecillinam

Bacterial cell wall synthesis

200 mg × 3 or 400 mg × 2

GI disturbances

Known hypersensitivity to beta-lactam antibiotics

Pivmecillinam

Allergic reaction (immediate or delayed)

Interaction with probenecid

Avoid during last month of pregnancy

Ampicillin + BLI

Bacterial cell wall synthesis

500–750 mg × 2

Dito mecillinam

Dito mecillinam

Cephalosporins

Bacterial cell wall synthesis

Depend on compound

GI disturbances

Risk for cross allergic reaction in known hypersensitivity to other beta-lactam antibiotics

Examples

Dose adapted to clinical severity

Allergic reactions (immediate and delayed)

Interaction with probenecid

Cefotaxime (IV)

1 g × 3 (IV)

Cefadroxil (oral)

500 mg–1 g × 2

Nitrofurantoin

30S inhibitor

50 mg × 3

GI disturbances

Known glucose-6-phosphodehydrogenas deficiency

Fever, headache, muscular pain

Directly prior to delivery

Pulmonary lesion

Leucopenia, anemia

Fosfomycin

Bacterial cell wall synthesis

3 g single dose

GI disturbances

Metoclopramide

F-quinolones (ciprofloxacin)

DNA gyrase/topoisomerase

Ciprofloxacin 250–500 mg × 2

GI disturbances

Hypersensitivity to F-quinolones

Ofloxacin 200–400 mg × 2

Allergic reactions

Interaction with tizanidine, antacidum, dairy products, warfarin, etc.

Dose adapted to clinical severity

Headache

History of quinolone-associated tendinitis

Avoid in simple infections

Secondary infections

Dose reduction related to renal function

Only on strict indication during pregnancy

Aminoglycosides

30S inhibitors

3–5 mg/kg/day divided in 3 equal doses.

Nephrotoxicity

Reduced renal function

Gentamicin

Tobramycin can be given in one initial dose in severe infection

Ototoxicity

Therapeutic levels control at 2–3 days or according to kidney function

Tobramycin

Vestibular toxicity

During pregnancy: only in very severe infections

For details on adverse effects and interactions, it is necessary to consult national pharmacological and treatment manuals and pharmacopeia of reference

What Are the Main Risks with Antibiotics?

All antibiotics can induce hypersensitive reactions of immediate or delayed type; gastrointestinal side effects such as diarrhea, nausea, and vomiting; and hematological disorders, i.e., leucopoenia and thrombocytopenia. National pharmacopeia will give detailed adverse reactions, important interactions, and contraindications.

All antibiotics can induce a secondary infection. The most common aregastrointestinal infection with Clostridium difficile, particularly with cephalosporins, F-quinolones, and fungal infection (i.e., Candida albicans infection).

Is There a Threat with the Use of Antibiotics?

There is a growing worldwide threat in the development of multiresistant bacteria. This threat is to be taken seriously as at the end, even simple uncomplicated infection might become difficult to treat. There is a correlation between the use of antimicrobial agents and the development of resistant bacterial strains. The systematic use of some antibiotics produces also a collateral damage, selecting resistant strains in the community and the hospital environment. It is therefore recommended to reduce the prescription to the recommended regimens and to follow local and international guidelines in the management of UTI, as for other infections.

Key Points

·               UTI are among the most frequent uncomplicated infections in the community. Indwelling catheters are the underlying cause of most of the healthcare-associated UTI, usually complicated and often severe.

·               Urine culture is a key diagnostic tool. The result is obtained after that empiric treatment is initiated and leads to relevant adjustment according to the needs.

·               Sporadic cystitis requires only a short 2- to 5-day treatment, while an ascending pyelonephritis needs a 7–14-day antibiotic treatment.

·               Severe complicated UTI and Sepsis can be life-threatening. Treatment has to be initiated without any delay after primary clinical diagnosis.

·               All antibiotics can give both gastrointestinal disturbances and allergic reactions. Knowledge about the renal function is important. Initial treatment can usually be started with normal dosage, but further doses must be adjusted to the renal function and the patient’s general condition.

·               Misuse of antibiotics leads inevitably to bacterial resistance development.

Further Reading

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Bjerklund-Johansen T, Cek M, Naber K, Stratchounski L, et al. Prevalence of hospital-acquired urinary tract infections in Urology Departments. Eur Urol. 2007;51:1100–12.PubMedCrossRef

Cek M, Lenk S, Naber KG, Bishop MC, et al. EAU guidelines for the management of genitourinary tuberculosis. Eur Urol. 2005;48:353–62.PubMedCrossRef

Foxman B. Epidemiology of urinary tract infections: incidence, morbidity and economic costs. Am J Med. 2002;113:5S–13.PubMedCrossRef

Grabe M, Bishop MC, Bjerklund Johansen TE, Botto H, et al. Urological infections. Guidelines of the European Association of Urology. Arnhem: EAU Guidelines Office. ISBN-13:978-90-79754-09-0. www.uroweb.com/professional-resources/guidelines/online/.

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