U r i n a r y Tr a c t I n f e c t i o n

Lindsay E. Nicolle, MD

KEYWORDS
 Urosepsis  Pyelonephritis  Complicated urinary infection  Bacteremia

KEY POINTS
 The urinary tract is one of the most common sources for life-threatening infections.
 Severe infections usually occur in individuals with complicated urinary tract infection,
including after urologic procedures in which appropriate perioperative prophylaxis is
not given.
 A broad range of organisms may be isolated, depending on whether it is community-
acquired or health care–acquired and prior exposure of the patient to antimicrobials.
 Effective antimicrobial therapy requires an agent that is excreted by the kidneys.
 The prognosis is generally better for urosepsis than for other common infection sources of
septic shock.

INTRODUCTION

Urinary tract infection presents as the clinical syndromes of acute, uncomplicated, uri-
nary infection, including acute nonobstructive pyelonephritis; complicated urinary
tract infection; asymptomatic bacteriuria; and, in men, bacterial prostatitis. Severe
or life-threatening infection usually occurs with complicated urinary infection. Compli-
cated urinary infection occurs in men and women with functional or structural abnor-
malities of the urinary tract. Obstruction or mucosal trauma are the most common
precipitating events for urosepsis. Although 20% to 30% of women with acute nonob-
structive pyelonephritis or men with acute bacterial prostatitis have bacteremia, these
syndromes seldom progress to severe sepsis or shock.

EPIDEMIOLOGY
Frequency
The urinary tract is a common source of infection for patients who present with severe
sepsis or septic shock. In a US tertiary care medical facility, the urinary tract was the
source for 40% of patients who presented to the emergency department with septic
shock and 25% of inpatients who developed septic shock.1 In two cohorts of adult

Department of Internal Medicine, Health Sciences Centre, University of Manitoba, Room

GG443, 820 Sherbrook Street, Winnipeg, Manitoba R3A 1R9, Canada
E-mail address: lnicolle@hsc.mb.ca

Crit Care Clin 29 (2013) 699–715

http://dx.doi.org/10.1016/j.ccc.2013.03.014 criticalcare.theclinics.com
0749-0704/13/$ – see front matter Ó 2013 Elsevier Inc. All rights reserved.
700 Nicolle

patients with septic shock admitted to critical care units from 1996 to 2007, in 28 fa-
cilities in Canada, the United States, and Saudi Arabia, the urinary tract was the source
of sepsis for 14.7% and 18.3%.2 The urinary tract was the source for 30.2% of Austra-
lian and New Zealand patients presenting to emergency departments with sepsis and
septic shock.3 Some series report a lower proportion of patients with a urinary source.
In 12 intensive care units in France, 8.4% of patients with septic shock had a urinary
source4 and a 1-year prospective study of patients admitted with sepsis to intensive
care units in Iceland reported a urinary source for only 8%.5
The proportion of subjects presenting with different types of urinary infection who
develop severe sepsis or shock are summarized in Table 1. Bacteremic complicated
urinary infection and urologic procedures without appropriate perioperative antimicro-
bial prophylaxis carry a high risk of life threatening infection. In women with acute
nonobstructive pyelonephritis, on the other hand, progression to septic shock is
exceptional and, should it occur, suggests an underlying complicating factor. Urinary
tract infection is also acquired by patients in the critical care unit, attributable to the
high prevalence of indwelling catheter use in this setting. However, few of these infec-
tions are severe. Laupland and colleagues16 reported an incidence density of urinary
infection acquired in the critical care unit of 9.6/1000 ICU days during a 3-year period
in a regional critical care system, but the bacteremia or fungemia rate with infection
was only 0.1/1000 ICU days.

Risk Factors
Several risk factors are associated with the most severe presentations of urinary tract
infection (Table 2). In a Korean study of bacteremic urinary infection, urinary tract

Table 1
Proportion of subjects developing severe sepsis or septic shock

Country, Reference Population Severe Sepsis or Shock

UK6 Percutaneous nephrolithotomy Antibiotic: 13.5%
No antibiotic: 33%
India7 Percutaneous nephrolithotomy Antibiotic: 19%
No antibiotic: 49%
Taiwan8 Community-onset bacteremic UTI ESBL: 41.7%
Not ESBL: 4.4%
Israel9 Proteus mirabilis UTI 28.3%
Taiwan10 P mirabilis UTI Bacteremia: 31.3%
No bacteremia: 22.6%
Taiwan11 ESBL urosepsis Community-acquired: 0
Health care–associated: 19.5%
Hospital-acquired: 14.4%
Korea12 Complicated pyelonephritis, Community-acquired: 19.2%
bacteremia Health care–acquired: 46%
Israel13 Women, complicated pyelonephritis 13.3%
US14 Women admitted for parenteral 0
therapy, acute uncomplicated
pyelonephritis
Korea15 UTI bacteremia, nosocomial 25%
acquisition

Abbreviations: ESBL, extended spectrum beta-lactamase; UTI, urinary tract infection.

 Urinary Tract Infection 701

Table 2
Risk factors for more severe presentations of urinary infection

Variable Reference
12,17
Urinary obstruction
6
Hydronephrosis
6,17
Mucosal trauma in patients with bacteriuria, including urologic surgery
and indwelling catheters
6
Prolonged urologic surgery
8,17
Infection with selected organisms, including resistance
11,12
Health care–acquired infection
12
Liver cirrhosis
6
Female gender

obstruction (odds ratio [OR] 4.39; 95% CI 1.78–10.82), health care–associated infec-
tion (OR 3.49; 1.59–7.69), and liver cirrhosis (OR 4.6; 1.40–15.22) were independent
predictors of septic shock.12 A case-control study of patients with Escherichia coli uri-
nary infection reported clinical presentations of hesitancy and/or retention (OR 7.8;
1.6–37), a history of urogenital procedure (OR 5.4; 2–14.7), and presence of the kps
MT virulence gene in the E coli strain isolated were independent predictors of bacter-
emia.17 Other potential risk factors for life-threatening urinary infection include poorly
controlled diabetes, neutropenia, and elderly patients.

Microbiology
A wide spectrum of organisms are isolated from patients with complicated urinary
infection (Table 3) and may be the causative organism for patients with septic shock.
The relative proportions of different species varies with patient characteristics and
the likelihood of health care–acquisition. E coli is the most common organism iso-
lated for community-acquired infections but is less common in health care–acquired
infections. E coli isolated from women with acute nonobstructive pyelonephritis are
characterized by specific virulence features, including the Pap pilus. However, for
patients with complicated urinary tract infection expression of E coli, virulence fac-
tors does not predict more severe presentations.23,24 Enterococcus spp and
Candida spp are more frequent in patients with indwelling devices.19–21 Other Enter-
obacteriaceae, gram-positive organisms, and nonfermenters such Pseudomonas
aeruginosa, Acinetobacter spp, and Stenotrophomonas spp, are also occasionally
isolated.
A retrospective review of patients at one US hospital reported that 14.2% of patients
with septic shock and blood cultures positive for Candida spp had a urinary source for
infection.25 Risk factors for isolation of yeast species include presence of diabetes,
chronic indwelling catheters, and broad-spectrum antimicrobial therapy.26 Organisms
isolated from complicated urinary tract infection tend to be more resistant to antimi-
crobials, particularly for patients with health care–acquired infections. Extended spec-
trum beta lactamase (ESBL) and carbapenemase-producing E coli and Klebsiella
pneumoniae are increasingly isolated from community-acquired and health care–ac-
quired infections. The urinary tract was reported to be the source for 72% of patients
with ESBL-producing E coli and K pneumoniae bacteremia presenting to a Taiwanese
emergency department.27
 702
Nicolle
Table 3
Organisms isolated from selected patients with severe presentations of complicated urinary tract infection
18 19 20 21 22
Reference
Population Bacteremia, HCA, Quebec Bacteremia, CA-UTI, Elderly, Bacteremia, Korea Elderly, Bacteremia, Israel Nephrectomy for
United States Urosepsis, Austria
E coli 47% 12.8% 81% 46.1% 56.6%
Klebsiella pneumoniae 12% 5.6% 7.0% 13.5% 9.4%
P mirabilis — 1.6% — 7.8% 9.4%
Enterobacteriaceae 10% 6.8% 3.5% 3.6 3.8%
Pseudomonas spp 6% 8.1% — 15.5% 5.8%
Acinetobacter spp — 1.2 — 1.0 —
Enterococcus spp 8% 28.4% — 3.6 3.8%
Staphylococcus aureus 8% 8.8% 3.5% 8.3 —
Coagulase-negative 4% 5.9% — — —
staphylococcus
Streptococcus spp — 0.9% — 0.5 —
Other gram positive — — 4.7% — —
Other 3% — — — —
Candida spp 2% 19.7% — — 11.3%

Abbreviations: CA-UTI, catheter-acquired urinary tract infection; HCA, health care–acquired.

 Urinary Tract Infection 703

DIAGNOSIS
Definitions
The International Sepsis Forum Consensus Conference Definitions of Infection in the
Intensive Care Unit for urosepsis are summarized in Box 1 for noncatheterized pa-
tients and Box 2 for catheterized patients.28 These definitions were developed to stan-
dardize the diagnostic criteria for patient enrollment into clinical trials. They have not
yet, however, been validated for use, and the utility in clinical care is not yet known.

History
Relevant history suggesting a urinary source of infection includes:
 Recent urologic intervention: sepsis following a urologic procedure in patients
with preexisting bacteriuria usually presents within 24 hours of the procedure
 Indwelling urethral catheter or presence of other devices such as ureteric stents
or nephrostomy tubes: recent catheter trauma or catheter obstruction increases
the likelihood of a urinary source for fever
 Symptoms consistent with renal colic: severe flank pain radiating to the
groin suggests ureteric calculus and obstruction rather than nonobstructive
pyelonephritis
 Presence of gross hematuria
 Lower tract irritative symptoms (dysuria, hesitancy, urgency)
 Recent antimicrobial treatment of urinary tract infection.

Physical Examination
Costovertebral angle tenderness, hematuria, or presence of an indwelling device are
localizing findings suggesting a genitourinary site of infection. However, patients with
urinary infection may have no localizing signs, or may not be able to communicate
symptoms. The most common presentation of urinary infection in the patient with
an indwelling urethral catheter is fever alone. In the absence of localizing genitourinary
findings, the diagnosis of urinary infection is a diagnosis of exclusion (ie, no other sites
for infection are apparent). The nonspecific presentation of some patients means

Box 1
Criteria for definition of urosepsis in noncatheterized patients
Upper urinary tract infection (kidney, ureter, or tissue surrounding the retroperitoneal or peri-
nephric space)
One of:
 Organism isolated from culture of fluid (other than urine) or tissue from the affected site
 An abscess or other evidence of infection seen on direct examination during surgery or by
histopathology examination
Or two of:
 Fever (>38 C)
 Urgency
 Localized pain or tenderness at involved site
 Any one of: microscopic examination (urinalysis or Gram stain) with pyuria or 105 colony
forming unit (cfu)/ml; purulent drainage from the affected site; pyuria; hematuria;
organism isolated from urine culture; positive Gram stain; radiographic evidence of infection
(eg, ultrasound, computed tomography, magnetic resonance imaging, radiolabeled scan).
704 Nicolle

Box 2
Criteria for definition of urosepsis in the catheterized patient

1. Lower urinary tract infection

a. Presence of suggestive signs and symptoms, including fever (>38 C), urgency, frequency,
dysuria, pyuria, hematuria, positive Gram stain, pus, suggestive imaging
and
b. Positive dipstick for leukocyte esterase and/or nitrate or pyuria (10 white blood cells/mL
or 3 white blood cells or high-power field of unspun urine) or organisms seen on Gram
stain of unspun urine or frank pus expressed around the urinary catheter or >103 CFU/mL
or if the patient can report symptoms, modified Centers for Disease Control and
Prevention (CDC) criteria must be met
2. Upper urinary tract infection (kidney, ureter, bladder, urethra, or tissue surrounding the
retroperitoneal or perinephric space)
a. One of the following criteria: Organism isolated from culture of fluid (other than urine)
or tissue from the affected site, an abscess or other evidence of infection seen on direct
examination during surgery, or by histopathologic examination
b. Or two of the following: Fever (>38 C), urgency, localized pain or tenderness at involved
site, and any of: purulent drainage from the affected site, pyuria, hematuria, organism
isolated from culture, positive Gram stain, radiographic evidence of infection (eg,
ultrasound, CT, MRI, radiolabeled scan)
3. Modified CDC criteria
a. One of: fever (>38 C), urgency, frequency, dysuria or suprapubic tenderness, and a urine
culture 105 CFU/mL, with no more than two species of organism
or
b. Two of: fever (>38 C), urgency, frequency, dysuria, or suprapubic tenderness, and any
one of:
i. Positive dipstick for leukocyte esterase and/or nitrate
ii. Pyuria (10 white blood cells/mL or 3 white blood cells or high-power field of
unspun urine)
iii. Organisms seen on Gram stain of unspun urine
iv. Two urine cultures with repeated isolation of the same uropathogen with
102 CFU/mL, in a nonvoided specimen
v. Two urine cultures with 105 CFU/mL of single uropathogens in a patient being
treated with appropriate antimicrobial therapy

From Calandra T, Cohen J, International Sepsis Forum Definition of Infection in the ICU
Consensus Conference. The international sepsis forum consensus conference on definitions
of infection in the intensive care unit. Crit Care Med 2005;33:1538–48; with permission.

urinary tract infection is frequently overdiagnosed as a source for fever, including

among critical care unit patients.29
Urine Culture
A definitive diagnosis of urinary tract infection usually requires a positive urine culture.
Exceptions to this occur when there is an abscess of the renal cortex or perinephric
space that does not communicate with the renal tubules, an infected renal cyst, or
when the infection is proximal to a complete obstruction within the urinary tract. Sys-
temic antimicrobial therapy will usually sterilize the urine within minutes. Thus, a urine
 Urinary Tract Infection 705

specimen for culture should be collected before initiation of antimicrobial therapy. A

single organism is usually isolated; however, polymicrobial bacteriuria is common in
subjects with chronic indwelling catheters, elderly functionally impaired patients,
and some patients with complex genitourinary abnormalities.
The urine specimen must be collected using a method that minimizes contamination.
The specimen may be collected when an indwelling catheter is inserted for output moni-
toring or other indications. When an indwelling catheter is in situ, the urine specimen
should be collected from the catheter port or through catheter puncture using a sterile
needle and syringe. A chronic indwelling catheter in situ for 2 weeks or longer will have
substantial biofilm formation along the catheter surface. Urine collected through the
tubing of these catheters is contaminated by organisms growing in the biofilm that
may not be present in the bladder. The catheter should be replaced by a sterile catheter
and a urine specimen collected immediately through the new catheter to obtain a spec-
imen of bladder urine.30 When there is obstruction of the urinary tract, an abscess, or
infected renal cyst, the specimen for culture should be collected by percutaneous aspi-
ration, if possible. The method of specimen collection should be noted on the specimen
requisition, so the laboratory has relevant information for processing.
Correct interpretation of the quantitative urine culture is essential for appropriate
management of urinary infection. Urine is an excellent culture media for most aerobic
organisms. When small numbers of organisms are inoculated into the bladder, quan-
titative counts of 105 colony-forming units (CFU)/mL are achieved within a few hours
of incubation. Patients with indwelling urethral catheters have a pool of urine retained
in the bladder because of the catheter bulb. Thus, 105 CFU/mL of the infecting or-
ganisms should be isolated from the urine for most patients with urinary infection.
Some exceptions to this include:
 When patients are undergoing diuresis, organisms may not remain in the bladder
long enough to achieve the higher quantitative counts.
 Lower quantitative counts are occasionally isolated from urine specimens of pa-
tients receiving antimicrobial therapy at the time of specimen collection.
 For Candida spp, 104 CFU/mL is considered the appropriate quantitative
count.28
 A quantitative count of 102 CFU/mL of a uropathogen is appropriate for diag-
nosis of bacteriuria when a specimen is collected by in and out catheter or imme-
diately following the insertion of an initial indwelling catheter.
 Lower quantitative counts isolated from patients with chronic indwelling cathe-
ters are often attributable to catheter biofilm contamination rather than bladder
bacteriuria.
Asymptomatic bacteriuria is common in many populations with complicated urinary
infection, including virtually all patients with chronic indwelling catheters. In the
absence of localizing genitourinary signs and symptoms, a positive blood culture or
diagnostic imaging to support a urinary source for infection, a positive urine culture,
by itself, does not confirm urinary tract infection. Golob and colleagues29 described
60 specimens with bacteriuria in 407 urine cultures obtained from subjects in 42 crit-
ical care units. Bacteriuria was not associated with fever, leukocytosis, or the combi-
nation of fever and leukocytosis in these patients. Symptomatic urinary infection is
overdiagnosed and overtreated in patients with asymptomatic bacteriuria.

Blood Cultures
A positive blood culture confirms the identification and susceptibilities of the infecting
organism and supports a diagnosis of urinary infection when similar organisms are
706 Nicolle

isolated from the blood and urine. Rarely, the same species is isolated from urine and
blood but with different susceptibilities. If there are multiple organisms isolated from
the urine culture, a positive blood culture assists in identifying the clinically important
strains for selection of antimicrobial therapy. Documentation of a positive blood cul-
ture may also be relevant for patients who subsequently develop metastatic infection,
which may present weeks or months after the initial infection.
Urinalysis
Pyuria accompanies symptomatic urinary infection but is a nonspecific finding. It is
present for most patients with asymptomatic bacteriuria and is common with any in-
flammatory condition of the genitourinary tract including following urologic surgery,
interstitial nephritis, or presence of indwelling urinary devices. The absence of pyuria
may be useful to exclude urinary infection, but the presence of pyuria will not confirm
bacteriuria or differentiate symptomatic urinary tract infection from asymptomatic
bacteriuria.
Inflammatory Markers
The procalcitonin level predicts bacteremia in patients with febrile urinary tract infec-
tion.31 Further evaluation of the utility of initial or serial procalcitonin levels is necessary
to determine the utility of this parameter in predicting outcomes or assisting in the
management of life-threatening urinary infections.
Diagnostic Imaging
When a patient presents with a suspected urinary source for severe sepsis or septic
shock, diagnostic imaging should be performed urgently to identify and characterize
abnormalities that may require source control, unless the contributing factor is already
apparent. Imaging studies may identify severe unilateral or bilateral pyelonephritis,
intrarenal or perinephric abscesses, emphysematous pyelonephritis, and obstruction
at any level. An infused CT scan is the optimal diagnostic imaging modality.32 Renal
and pelvic ultrasound is not as sensitive as CT, but will identify many abnormalities
and be more accessible in some settings. MRI is not as reliable for identifying stones
or gas in tissues, and is not recommended for initial imaging for identification of a po-
tential source for urosepsis.

ANTIMICROBIAL MANAGEMENT
Pharmacokinetic Considerations
Optimal therapy of urinary tract infection requires treatment with antimicrobial agents
that are excreted by the kidneys and achieve high levels in renal tissue and urine.33
Treatment with antimicrobials without renal excretion may be effective to resolve
bacteremia and improve symptoms, but often will not eradicate organisms from the
urinary tract. Relapse of the infection can occur once the antimicrobials are discontin-
ued. There is decreased blood flow to the affected kidney in patients who have severe
obstruction to urine flow, a unilateral nonfunctioning kidney, or renal failure. The
impaired excretion of antimicrobials by the affected kidney means adequate tissue
and urine antimicrobial levels may not be achieved. Patients with renal impairment
may require more prolonged antimicrobial therapy and, in some cases, it may not
be possible to achieve microbiologic cure.
Guidelines
The European Association of Urology has published guidelines for antimicrobial ther-
apy for management of urosepsis.34 The recommended agents include an extended
 Urinary Tract Infection 707

spectrum cephalosporin (cefotaxime, ceftriaxone, ceftazidime), fluoroquinolone with

mainly renal excretion (ciprofloxacin, ofloxacin, levofloxacin), anti-pseudomonas active
acylaminopenicillin/beta lactamase inhibitor (piperacillin/tazobactam), or a carbape-
nem (imipenem, meropenem, ertapenem, doripenem)—all with or without an aminogly-
coside. The recommended duration for therapy is 3 to 5 days after defervescence or
control of the complicating factor.

Clinical Trials
The clinical trial evidence to support selection of a specific antimicrobial regimen for
empiric treatment of life-threatening urinary infection is limited. In a recent evidence-
based review, 79 articles relevant to empiric antimicrobial therapy for patients with se-
vere sepsis and septic shock were identified, but none of these specifically addressed
urinary tract infection.35 A few comparative clinical trials have enrolled patients with
complicated urinary infection but have excluded subjects with life-threatening infec-
tion. In trials of parenteral antimicrobial therapy for complicated urinary infection, levo-
floxacin was as effective as doripenem,36 ertapenem was similar to ceftriaxone,37
cefepime to ceftazidime,38 and aztreonam to cefotaxime.39

Empiric Antimicrobial Therapy

Patients with life-threatening urinary tract infection require prompt institution of
empiric broad spectrum antimicrobial therapy selected to provide coverage for poten-
tial pathogens. The observation that earlier initiation of antimicrobial therapy improves
survival with septic shock is consistent for patients with a urinary source.2,4 Many an-
timicrobials are effective (Table 4). During selection of the specific regimen, consider-
ation should be paid to the likely infecting organism and susceptibilities, current or
recent antimicrobial therapy received by the patient, local antimicrobial resistance
prevalence, and patient renal function and tolerance. Patients with health care–ac-
quired infections or recent antimicrobial therapy for any indication have a higher likeli-
hood of infection with a resistant organism.
Aminoglycosides are concentrated within renal tubular cells and are very effective
for the treatment of pyelonephritis. However, this class of antimicrobials has limited
perfusion into the kidney when there is renal impairment and are less effective for treat-
ment of these patients. In addition, the side effects of eighth nerve toxicity and renal
impairment are of concern. Empiric therapy with an aminoglycoside is appropriate if
resistant organisms or patient intolerance limit the use of other effective agents. The
appropriateness of continuation of aminoglycoside therapy should be reassessed
once urine culture results are known. If the aminoglycoside must be continued, moni-
toring of antimicrobial levels and renal function are necessary.
Ciprofloxacin and levofloxacin are the recommended fluoroquinolones; moxifloxa-
cin has limited urine excretion and is not indicated for the treatment of urinary tract
infection. Cefotaxime is preferred to ceftriaxone for patients with renal failure. Ceftri-
axone has increased biliary excretion when there is renal failure, so effective antimi-
crobial levels may not be achieved in the kidney. There is no evidence that dual
therapy improves outcomes with urinary infection. A second agent is recommended
only to provide broader coverage for potentially resistant organisms, where
necessary.
Linezolid is the preferred therapy for ampicillin-resistant, vancomycin-resistant
Enterococcus (VRE) strains. Empiric therapy with a carbapenem is recommended for
ESBL-producing E coli and K pneumoniae. The optimal treatment of urinary tract infec-
tion for carbapenemase-producing organisms, including KPC or NDM-1 producers, is
not known. These strains are often susceptible only to tigecycline or colistimethate,
708 Nicolle

Table 4
Antimicrobial regimens for empiric treatment of life-threatening urinary tract infections

Antimicrobial Dosea Comment

Gentamicin  ampicillin 2 g q4 h  3–5 mg/kg/d Ampicillin provides enterococcal
coverage
Tobramycin  ampicillin 7 mg/kg q24 h
Amikacin  ampicillin 15 mg/kg q24 h
Ceftriaxone 2 g q12 h No enterococcal coverage
Cefotaxime 2 g q6–8 h
Ceftazidime 1–2 g q8 h No enterococcal coverage;
P aeruginosa coverage
Piperacillin/tazobactam 3.35 g q6 h Enterococcal and P aeruginosa
coverage
Levofloxacin 750 mg q24 h Increasing resistance observed
Ciprofloxacin 400 mg bid q24 h
Imipenem 500 mg q6 h ESBL and P aeruginosa coverage
Meropenem 500 mg q6 h or 1 g q8 h
Doripenem 500 mg q6 h
Ertapenem 1 g q24 h ESBL coverage, no P aeruginosa
coverage
Aztreonam 1 g q12 h Enterobacteriaceae and P aeruginosa
coverage
Vancomycin 1 g q12 h Susceptible gram-positive organisms

Abbreviation: ESBL, extended spectrum beta-lactamase.

a
Assumes normal renal function.
From Calandra T, Cohen J, International Sepsis Forum Definition of Infection in the ICU
Consensus Conference. The international sepsis forum consensus conference on definitions of
infection in the intensive care unit. Crit Care Med 2005;33:1538–48; with permission.

neither of which is excreted into the urine. Case reports describe cure of patients with
urinary infection with both of these agents, but these are uncommon cases such as
prostatitis40 or patients receiving concomitant antimicrobials.41 If the strain remains
susceptible to an aminoglycoside, this would be appropriate therapy. Combinations
of antibiotics, such as a carbapenem with fosfomycin or an aminoglycoside, have
been suggested for therapy of carbapenemase producers; however, there is limited
experience in treatment of urinary infection.

Fungal Infection
Fluconazole and amphotericin B deoxycholate are recommended for treatment of
fungal urinary infection because both these antifungals have good renal excretion.42
Other azoles (itraconazole, voriconazole, posaconazole), echinocandins (caspofungin,
micafungin, anidulafungin), and amphotericin B lipid formulations are not excreted into
the urine and are not recommended. Fluconazole is the treatment of choice. When
Candida spp resistant to fluconazole are isolated, amphotericin B-deoxycholate is
recommended. For some strains, 5-flucytosine is also effective but requires moni-
toring to prevent potential hematologic toxicity, and is problematic to dose effectively
and safely in individuals with renal impairment.

Specific Therapy
A bacteriologic diagnosis for urinary infection is usually available 48 to 72 hours
following the collection of microbiology specimens. The empiric antimicrobial regimen
 Urinary Tract Infection 709

should be reassessed when culture results are available. When appropriate, the anti-
microbial should be altered to specifically target the infecting organisms isolated.
Modification will usually be to a more narrow spectrum agent. If a resistant organism
is isolated, alternate antimicrobial therapy effective for the known susceptibilities is
required. When patients have a prompt clinical response, step-down to effective
oral antimicrobial therapy may be initiated at any time.

Duration of Therapy
The duration of treatment for complicated urinary infection is 10–14 days. Clinical trials
have reported that levofloxacin given for 5 days is effective for complicated urinary tract
infection43 and ciprofloxacin for 7 days and 14 days are equally effective for acute non-
obstructive pyelonephritis.44 Thus, shorter courses of antimicrobial therapy are appro-
priate for some patients. The European Urology Guidelines recommend continuing
antimicrobials for only 3 to 5 days following resolution of symptoms.34 Patients who
are immunocompromised or have renal failure may require more prolonged therapy,
but the optimal duration is unknown. Patients with infected renal cysts require pro-
longed therapy of 4 to 6 weeks, and 4 weeks is recommended for men who present
with acute bacterial prostatitis. Treatment of a renal abscess requires continuation of
antimicrobial therapy until the abscess has resolved. This may require several months.

SURGICAL INDICATIONS AND THERAPY

Source control is necessary for relief of obstruction and drainage of infected urine or
abscesses. Urinary catheter placement, ureteric stents, nephrostomy tubes, or other
percutaneous approaches may be sufficient for drainage. Open drainage and, rarely,
nephrectomy is sometimes indicated. A small renal abscess (less than 5 cm) can usu-
ally be managed medically, whereas larger abscesses often require percutaneous or
open drainage.45 Current management of emphysematous pyelonephritis recom-
mends initial percutaneous drainage with antimicrobial therapy, followed by remote
nephrectomy, if necessary, once the patient is stabilized.46 This approach is associ-
ated with improved mortality outcomes compared with universal early nephrectomy.
Fungus balls may also require urologic intervention and removal, particularly when
obstruction is present.42 Berger and colleagues22 described a case series of 65 sub-
jects with nephrectomy for life-threatening urosepsis in Vienna from 1994 to 2007.
Underlying abnormalities were pyelonephritis, usually associated with nephrolithiasis,
in 20% of the patients; obstructed ureteric calculi in 20%; renal abscess in 25%; and
preexisting hydronephrosis in 20%. The mortality from septic shock in these subjects
was 20% and older subjects were significantly more likely to die.

SUPPORTIVE CARE

Supportive care is similar to that recommended for patients presenting with severe
sepsis or septic shock from other sites of infection. This requires immediate hemody-
namic and respiratory resuscitation, with subsequent monitoring and support of organ
function.

PREVENTION

Severe urinary infection can be prevented by consistent use of appropriate prophy-

lactic antimicrobial therapy before urologic interventions and by avoiding indwelling
urethral catheters whenever possible.34 Early recognition and relief of obstruction
in patients at risk may also prevent some episodes. Long-term prophylactic
710 Nicolle

Table 5
Mortality outcomes for patients with life-threatening urinary tract infection and other
infection sources of septic shock

Mortality (Days from Onset)

Population (Reference) Urosepsis Other Sources
Critical care admissions with septic 17.9% (28 d) Pneumonia: 35.8%
shock; Canada, United States, Intraabdominal: 37.3%
Saudi Arabia2 Bloodstream: 39.6%
Severe sepsis critical care units, 23% (in hospital) Pneumonia: 34.7%
France4 Intraabdominal: 31.2%
Bloodstream: 38%
Bacteremic pyelonephritis, 25.9% (7 d) —
Korea12
Elderly, bacteremic UTI, Korea20 11.6% (in hospital) —
Elderly (>75 y), bacteremia UTI, 33% (in hospital) —
Israel21
P mirabilis UTI bacteremia, 28.6% (in hospital) —
Taiwan10
Proteeae bacteremia, Korea47 9.1% (30 d) Primary bacteremia: 34.5%
SST: 45.5%
Biliary: 10.8%
E coli bacteremic UTI, Denmark24 12% (in hospital) —
HA: 24%
CA: 10%
HCA-BSI UTI, Canada18 15% (30 d) All BSI sources: 22%
ESBL bacteremia UTI, Taiwan,11 23.1% (30 d) —
HCA, gram-negative bacteremia 12.1%; OR 0.44 (0.25–0.77) Intraabdominal: 13%
sepsis, Singapore48 vs other site (30 d) Pneumonia: 53.3%
SST: 25%
Community onset bacteremic UTI, ESBL: 8.3% (21 d) —
Taiwan8 Non-ESBL: 4.4%
Community onset bacteremia, 11.2% (30 d) —
UK49 OR 0.26 (0.14, 0.48) vs
other sites
ESBL bacteremia, India50 UTI: 16.4% (14 d); Intraabdominal: 38.4%
OR 0.40 (0.17, 0.96) vs Pneumonia: 71.4%
other sites Undetermined: 20.5%
Nationwide surveillance 10.6% (30 d) —
bacteremic urinary infection, HCA 21%
Korea15 CA 8.3%
Bacteremic, emergency, Taiwan51 4.7% (28 d) reference Pneumonia 40.4%
(OR 13.77; 6.18, 30.71)
vs UTI
Intraabdominal 44.1%
(OR 16.05; 6.59, 39.14)
Primary bacteremia 15.9%
(3.83; 1.67; 8.78)

Abbreviations: BSI, bloodstream infection; CA, community-acquired; HA, hospital–acquired; SST,

skin and soft tissue.
 Urinary Tract Infection 711

antimicrobial therapy is not effective in preventing symptomatic urinary infection in pa-

tients with complicated urinary infection and is not indicated.

OUTCOMES

The mortality for patients admitted to critical care units with septic shock from a uri-
nary source is reported to be 10% to 20%. This rate is consistently lower than the
30% to 40% mortality reported for other common sources of septic shock
(Table 5). The lower risk of mortality may reflect the relative straightforward approach
to source control for many patients with urinary infection. A urinary source of sepsis is
also less frequently complicated by adult respiratory distress syndrome (ARDS). In a
US facility, 549 (27.8%) of 1973 patients admitted to critical care units with bacter-
emia, pneumonia, or sepsis developed ARDS compared with only 4.7% of those pa-
tients with urosepsis (OR 0.43; 95% CI: 0.27–0.68).52
The mortality of patients with bacteremic urinary infection is significantly lower for
hospital-acquired compared with community-acquired infection, and also varies
with the organism isolated (see Table 5; Table 6). Risk factors for mortality reported
in multivariate analyses are summarized in Table 6. Chin and colleagues20 also re-
ported that, in elderly Koreans with bacteremic urinary infection, in-hospital mortality
was 57.1% for gram-positive organisms but only 7.6% for gram negative organisms.
Chang and colleagues19 reported the case fatality rate for hospital-acquired urinary
tract–related bloodstream infection was 32.8% (95% CI 27.7%–38.2%). E coli had a
lower case fatality rate, 14.6%, than all other gram-negative organisms isolated.
The case fatality rate was 31.9% for Enterococcus (42.3% for VRE and 17.9% for van-
comycin-susceptible), 49.2% for Candida spp, 34.6% for Pseudomonas spp, 42.9%
for coagulase-positive staphylococcus, and 33.3% for Klebsiella spp.
Other potential morbidity includes renal impairment and, for bacteremic patients,
metastatic infection. Urinary tract infection, by itself, seldom causes renal failure.
The prognosis for renal functional impairment usually depends on premorbid renal
function; concomitant illnesses, such as diabetes; and recovery following relief of

Table 6
Risk factors for mortality identified in studies of bacteremic urinary tract infection

Reference Multivariate Risk Factors: HR (95% CI)

United States19 Age/10 y, 1.63 (1.37–2.00)
CA vs HCA, 0.26 (0.14–0.44)
E coli vs other 0.39 (0.17–0.88)
Canada, CA-UTI18 Age, 1.02 (1.00–1.03)
Teaching hospital, 0.62 (0.42–0.94)
Hematology malignancy, 3.00 (1.57–5.75)
Other neoplasia, 1.88 (1.22–2.89)
Foley catheter, 1.85 (1.14–3.00)
S aureus, 2.01 (1.07–3.77)
ESBL urosepsis, Taiwan11 Male, 0.8 (0.01–0.79)
Bacteremia score 4, 20.55 (3.31–127.37)
Shock, 9.86 (1.17–83.01)
Neurologic failure, 11.29 (1.62–78.88)
Elderly, bacteremic UTI, Korea20 Functional dependency, 10.9 (2.2–54.6)
Low serum albumin, 27.0 (2.0–361.2)

Abbreviations: CA, community-acquired; CA-UTI, catheter-acquired urinary tract infection; HCA,

health care–acquired.
712 Nicolle

obstruction or sepsis-related renal impairment. The most common site of metastatic

infection is the vertebral column. Endocarditis, other bone and joint infections, other
endovascular infections with prosthetic devices, and endophthalmitis may also occur.
These infections may not become apparent for weeks after the initial infection.

SUMMARY

The urinary tract is a common source for life-threatening infections. Most patients with
sepsis or septic shock from a urinary source have complicated urinary tract infection.
Obstruction or mucosal trauma are the most common precipitating events. Effective
management requires prompt assessment, appropriate collection of microbiology
specimens, prompt initiation of antimicrobial therapy, source control where appro-
priate, and supportive therapy as required. For empiric antimicrobial therapy, an agent
excreted by the kidneys with broad antimicrobial coverage should be initiated. Pa-
tients with obstruction or abscesses may require source control. Mortality with septic
shock from a urinary source is reported to be 10% to 20%. This is consistently lower
than mortality with septic shock complicating infections from the lungs or intraabdo-
minal abscesses.

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