Complicated Urinary Tract Infections - StatPearls - NCBI Bookshelf
Complicated Urinary Tract Infections - StatPearls - NCBI Bookshelf
Complicated Urinary Tract Infections - StatPearls - NCBI Bookshelf
Affiliations
1 Waikato DHB
2 Creighton University School of Medicine
Urinary tract infections (UTIs) are among hospitals' most common presenting causes of sepsis.
Some simple UTIs can be managed with outpatient antibiotics, leading to almost universally good
outcomes. However, complicated UTIs may lead to florid urosepsis, which can be fatal. Several risk
factors can complicate UTIs, leading to treatment failure, repeat infections, or significant morbidity
and mortality. It is essential to determine if the patient's infection may have resulted from one of
these risk factors and whether the episode will likely resolve with first-line antibiotics. Complicated
UTIs present with more significant morbidity, carry a higher risk of treatment failure, and typically
require longer antibiotic courses, frequently requiring additional workup. This activity reviews the
evaluation and management of complicated UTIs and highlights the role of interprofessional team
members in collaborating to provide well-coordinated care and enhance outcomes for affected
patients.
Objectives:
Differentiate between simple and complicated urinary tract infections based on risk factors,
clinical presentation, and potential complications.
Assess patients with complicated urinary tract infections to identify underlying anatomical
abnormalities, immune status, and potential sources of infection.
Implement evidence-based management protocols for the appropriate use of antibiotics and
treatment strategies tailored to specific risk profiles.
Collaborate amongst the interprofessional team to enhance and ensure continuity of care for
patients affected by complicated urinary tract infections.
Introduction
Urinary tract infections (UTIs) are among the most common causes of sepsis presenting in
hospitals. UTIs have a wide variety of presentations. Some are simple UTIs that can be managed
with outpatient antibiotics and carry a reassuring clinical course with an almost universally good
outcome. On the other end of the spectrum, florid urosepsis in a comorbid patient can be fatal. UTIs
can also be complicated by several risk factors leading to treatment failure, repeat infections, or
significant morbidity and mortality with a poor outcome. It is vitally important to determine if the
presenting episode results from these risk factors and whether the episode is likely to resolve with
first-line antibiotics.[1][2][3][4]
It is important to properly define a complicated UTI as an infection that carries a higher risk of
treatment failure. These infections typically require longer courses of treatment, different
antibiotics, and sometimes additional workups.
In a clinical context not associated with treatment failure or poor outcomes, a simple UTI (or
simple cystitis) is an infection of the urinary tract due to appropriate susceptible bacteria. Typically
this is an infection in an afebrile non-pregnant immune-competent female patient. Pyuria and/or
bacteriuria without any symptoms is not a UTI and may not require treatment. An example would
be an incidental positive urine culture in an asymptomatic, afebrile non-pregnant immune-
competent female. A complicated UTI is any UTI other than a simple UTI, as defined above.
Therefore, all UTIs in immunocompromised patients, males, pregnant patients, and those
associated with fevers, stones, sepsis, urinary obstruction, catheters, or involving the kidneys are
considered complicated infections.
The normal female urinary tract has a comparatively short urethra and, therefore, carries an
inherent predisposition to proximal seeding of bacteria. This anatomy increases the frequency of
infections. Simple cystitis, a one-off episode of ascending pyelonephritis, and occasionally even
recurrent cystitis in the proper context can be considered a simple UTI, provided there is a prompt
response to first-line antibiotics without any long-term sequela.
Any UTI that does not conform to the above description or clinical trajectory is considered a
complicated UTI. In these scenarios, one can almost always find protective factors that failed to
prevent infection or risk factors that lead to poor resolution of sepsis, higher morbidity, treatment
failures, and reinfection.[5][6][7] The reason for the distinction is that complicated UTIs have a
broader spectrum of bacteria as an etiology and have a significantly higher risk of clinical
complications.[8] The presence of urinary tract stones and catheters is likely to increase the
incidence of recurrences compared to patients without these foci of bacterial colonization.[9]
Infections occurring despite the presence of anatomical protective measures (UTIs in males
are, by definition, considered complicated UTIs)
Etiology
Most UTIs are due to the colonization of the urogenital tract with rectal and perineal flora. The
most common organisms include Escherichia coli, Enterococcus, Klebsiella, Pseudomonas, and other
Enterococcus or Staphylococcus species. Of these, Escherichia coli is the most common, followed by
Klebsiella. Residential care patients, diabetics, and those with indwelling catheters or
immunocompromise can also colonize with Candida.[10] E. coli and possibly Klebsiella
overwhelmingly cause simple UTIs. Complicated UTIs tend to be caused by a much wider range of
organisms which is significant because multidrug resistance is increasing, and therefore specific
antibiotic regimens will vary.
Epidemiology
In the United States, there are over 626,000 hospital admissions a year for complicated UTIs,
comprising about 1.8% of all annual hospitalizations, with 80% of these being non-catheter related.
[11] Cohorts with more risk factors show an increased incidence of UTIs. Risk factors include
female gender, increasing age, diabetes, obesity, long-term catheters, and frequent intercourse
(although UTI is not defined as a sexually transmitted infection).
Simple UTIs in nonpregnant immune-competent females have been estimated to occur with as
high as 0.7 infections per person per year. Fifty percent of females will have at least 1 UTI at
some stage in life.
Complicated UTI incidence is associated with specific risk factors. For example, there is a 10%
daily risk of developing bacteriuria with indwelling bladder catheters and up to a 25% risk of
bacteriuria progressing to a UTI.
About 20% of all bacteremias associated with health care originate from the urinary tract. The
mortality associated with these urinary tract-based bacteremias can be up to 10%.
[12] Bacteriuria occurs in up to 14% of diabetic females but does not tend to occur with a
higher frequency in diabetic males.
Asymptomatic bacteriuria tends to increase with age in females and is present in up to 80% of
the older female population. It is rare among younger healthy males but can be present in up
to 15% of older males.
About 9.4% of all urological inpatients developed a complicated UTI during their hospital stay.
[13][14]
An increased incidence of UTI has been described in patients using dapagliflozin (SGLT2i)
which treats diabetes by producing glycosuria.[15]
UTIs are the most common infections in renal transplant patients. Up to 25% of these patients
will develop a UTI within the first year after a transplant.
UTIs are the seventh most common reason for a patient to be seen in an emergency
department in the US, constituting over 1 million visits annually. Of these, about 22% (220 000)
are considered complicated UTIs, and about 100 000 are admitted to the hospital yearly.[16]
[17]
Pathophysiology
A biofilm is an encapsulated, structured microorganism colony that has created its polymeric
matrix to protect and adhere to bodily structures, stones, or foreign bodies.[18] Biofilms
also involve various pathogens of relatively low virulence and can cause severe, potentially life-
threatening infections.[9][10] Urinary stasis due to dysfunctional voiding or obstruction facilitates
bacterial invasion of tissues and provokes a host response.[19] Foreign bodies such as stones
and catheters are commonly associated with biofilms. Catheters, in particular, offer access to the
urinary tract by bacteria, and the biofilm then protects the organisms from elimination. Multiple
organisms are often involved in biofilms.[20]
Most antibiotics cannot effectively penetrate biofilms and cannot treat bacteria located there.[21]
[22] Biofilm bacteria also tend to grow slowly, reducing the effectiveness of antibiotics that are
more effective in rapidly dividing organisms.[23][24] While irrigation and free urinary flow can
help minimize biofilm development, they cannot prevent it. The only effective therapy is to remove
and replace the affected foreign body. Catheters that have been in place for 1 to 2 weeks or longer
should be replaced before obtaining a urinalysis or urine culture to avoid contamination from the
biofilm that has developed on the catheter. A complete biofilm will form on a urinary catheter in
about 2 weeks. Patients with frequent catheter-associated UTIs may therefore benefit from more
frequent catheter changes.
Given their frequency in hospitals, UTIs (especially complicated UTIs) remain a clinical entity,
causing considerable confusion and diagnostic uncertainty and a source of significant
inappropriate antibiotic prescriptions.
The most important clinical criteria for initially diagnosing a simple UTI are symptoms (increased
urinary frequency, urgency, hematuria, dysuria, or suprapubic pain). There must also be an
appropriate clinical scenario in which infection of the urogenital tract is the most likely
explanation for these symptoms. It is appropriate to start empiric treatment with first-line
antibiotics in this situation. A urine sample should also be sent for microscopy and culture before
beginning treatment, although that is not always possible. The urine sample almost always shows
an abnormal red or white cell count, positive nitrites, and bacteria.
Any UTI that fails to resolve with first-line therapy or occurs in a high-risk patient population
should be considered a complicated UTI. Complicated UTI symptoms include all of those listed
above, as well as fever, chills, flank pain, sepsis from a urological source, cystitis symptoms lasting
>7 days, known multiple antibiotic resistance, permanent Foley or suprapubic catheters, acute
mental status changes (especially in older individuals) and high-risk patient populations
(pregnancy, immunocompromised state, renal transplantation, abnormal urinary function as in
patients with neurogenic or dysfunctional bladders, immediate post-urological surgery, renal
failure, pediatrics, etc).[8]
Complicated UTIs may also present with nonspecific symptoms, atypical presenting features
(delirium in older individuals), signs mimicking an acute abdomen, triggers for precipitating
diabetic emergencies (diabetic ketoacidosis), and even an absence of symptoms (asymptomatic
bacteriuria in pregnancy). Severe complicated UTIs can present as undifferentiated sepsis or even
septic shock.
Evaluation
A good quality urine specimen is vital in making the diagnosis. However, treatment must not be
delayed if the clinical scenario strongly suggests a UTI.[25][26][27]
Most patients can provide a high-quality midstream urine sample with appropriate instructions. If
that is not possible, a catheterized urine sample (indwelling catheter or a straight in-out catheter)
may be used. Catheter insertion is not without some risk, and this must be weighed against the
diagnostic advantage of having a urine specimen for analysis and culture. Obtaining a urine
specimen for culture before initial antibiotic administration is recommended whenever possible
and feasible. Most patients with complicated UTIs will demonstrate pyuria. The presence of white
blood cell casts strongly suggests renal involvement. Different normal white cell ranges depend on
the urine sample, and the results should be interpreted accordingly.
Often, urine samples in prostatitis may not be diagnostic, especially if the patients have already
been partially treated. A pre-and post-prostate massage urine sample (also known as the 4-glass test
or even the shortened 2-glass test) can improve the diagnostic yield in patients with prostatitis. In
general, pelvic or perineal pain, difficulty in urination, failure of initial therapy, and rapid
recurrence of symptoms suggest prostatitis.
Some patients with clinical signs of a UTI may not demonstrate any urinary bacteria on culture.
Patients with asymptomatic bacteriuria have no urinary symptoms but grow large numbers of
bacteria on culture.[8] Urine with a cloudy appearance or foul odor may suggest infection, but
these findings have not been clearly demonstrated to correlate with either bacteriuria or a UTI.[28]
Older patients, especially those with dementia, are at increased risk for complicated UTIs.
[29] Dementia can cause a decline in personal hygiene and an increase in various voiding issues.
There is also an increased risk for urinary catheterization. Diagnosis can be more difficult as
patients with dementia may present with altered mental status, increased confusion, or agitation
instead of the usual lower urinary tract symptoms.[30]
Blood cultures are useful in more severe septic presentations. A positive blood culture can
sometimes help corroborate a urine sample result and reduce any suspicion of contamination.
Radiological investigations are not helpful in initially diagnosing most infections limited to the
genitourinary tract. There should be sufficient clues from the history, physical examination, and
laboratory results. Ultrasound and CT scans may be helpful or even critical for diagnosing a
perinephric abscess, urinary retention, hydronephrosis, and obstructive pyelonephritis from
stones in septic patients. All septic patients and febrile patients who fail to respond to appropriate
broad-spectrum antibiotics within 48 to 72 hours should undergo imaging to exclude complications
such as abscesses, urinary retention, calculi, gas, and obstructive uropathy, pyonephrosis, and
hydronephrosis. Renal ultrasonography is quicker, less expensive, and avoids radiation exposure to
the patient, but the CT scan is the definitive standard. It should be strongly considered in complex
or intractable cases, even if the ultrasound is negative, as the results can sometimes be life-saving.
[31]
All patients who present with a complicated UTI, even the first presentation of ascending
pyelonephritis in non-pregnant immune-competent females, should undergo a renal tract
ultrasound at a minimum to evaluate for anatomical abnormalities hydronephrosis, stones, or
other lesions. Since there is no reliable clinical method to rule out urinary obstructions in
complicated UTIs (such as a stone), the treating physician must do so with an ultrasound or CT
scan.[32]
Treatment / Management
As UTI can present with severe, life-threatening sepsis and multiorgan involvement. Resuscitation
often precedes definitive treatment. The severely septic patient might need aggressive fluid
resuscitation and broad-spectrum antibiotics administered in the emergency department.
Antibiotic choices should always be made according to local bacterial resistance patterns and
guidelines.[33][34][35][36]
Patients presenting with septic shock may not respond to fluid resuscitation alone, and there
should be a low threshold to consider vasopressor support in light of a poor initial response to
fluids.[8][37][38] Alternatively, nonseptic-stable patients may be treated as outpatients.
Patients who present with repeat infections may also be initially treated as per their previous urine
culture results until new cultures are available. Imaging to identify a source of infection, such as an
abscess or stone, should be done with relapsing infections that involve the same organisms.
[40] Patients who presented initially with hematuria should be rechecked for urinary blood after
the infection has been successfully treated.
Treatment response should be evident in 24 to 48 hours in most cases. A poor response may
indicate an inappropriate antibiotic selection, polymicrobial infections, atypical infections,
hydronephrosis, obstructing stone causing pyonephrosis, complications such as a perinephric
abscess or emphysematous UTI, fluid collections such as urinary retention or anatomical lesions
leading to poor response (nephrocalcinosis acting like an infective nidus, obstructive urinary tract
lesions, urinary calculi, or fistulas). To guarantee good bladder drainage, a temporary Foley
catheter is often recommended for these patients if they are septic, particularly if they have
increased post-void residual volumes.
Antibiotic therapy in complicated UTIs is typically 10 to 14 days. While technically, any UTI in a
male is considered a "complicated UTI," many experts will treat what appears to be an
unambiguous lower urinary tract infection in an otherwise healthy man with no known bladder
dysfunction, stones, or other high-risk factors the same as a simple UTI with first-line antibiotic
agents such as fosfomycin, trimethoprim-sulfamethoxazole, or nitrofurantoin. In recurrent
infections, prostatitis should be suspected and treated accordingly, especially if the same organism
is encountered.
Most (97%) of patients with mild or moderate pyelonephritis without major comorbidities can be
managed as outpatients after initial parenteral antimicrobial therapy and a short observation
period.[41]
Men presenting with recurrent UTIs or bacterial prostatitis may require 4 to 6 weeks or longer to
eradicate their infecting bacteria completely. Men with benign prostatic hyperplasia (BPH) and
recurrent or intractable UTIs should be considered for surgical therapy.[42] Nitrofurantoin is not
generally recommended in complicated UTIs in men due to poor tissue penetration, particularly in
the kidneys, testicles, and prostate.
Failure to respond to appropriate antibiotics should suggest a possible urinary blockage, such as
obstructive pyelonephritis. In such cases, a renal ultrasound or non-contrast CT scan should
be performed for diagnosis, and immediate surgical drainage performed if an obstructed, infected
kidney is found (either by double J stenting or a percutaneous nephrostomy).
Treatment success involves proper antibiotic selection, appropriate dosage adjustment, and correct
duration of therapy. Eradicating high-risk factors whenever possible, such as removing infected
stones or indwelling catheters, is also warranted.
Prophylactic antibiotics are seldom recommended routinely due to the rapid development of
bacterial resistance. When the clinical situation requires prophylaxis, nitrofurantoin is usually the
preferred agent at 50 mg/d, generally taken before bed.[43][44]
Patients with permanent Foley catheters or suprapubic tubes should avoid prophylactic antibiotics
and only be treated when symptomatic. More frequent changes of urinary catheters are
recommended in chronically catheterized patients with recurrent or frequent infections. Patients
with long-term Foley catheters tend to have fewer infections if converted to a suprapubic tube.
[45] Changing the Foley is recommended to eliminate the contaminated biofilm and reduce
recurrences if a catheterized patient develops an infection.[8]
Cranberry supplements have been studied with conflicting evidence of efficacy in treating
complicated or recurrent UTIs.[48][49][50] Probiotics have not shown any significant
benefit compared with placebo in treating complicated UTIs.[51]
Fosfomycin has shown good activity in patients with urinary tract stones.[52][53] It has significant
penetration inside urinary calculi and was more effective than cefuroxime.[53] Fosfomycin is also
being used parenterally as empiric therapy for complicated UTIs in some parts of the world but not
widely yet in the US.[54][55] It is suggested that its use be limited to cases where carbapenems
cannot be used to maintain efficacy.
Neomycin alone showed no efficacy in controlling bacteriuria, but chlorhexidine and povidone-
iodine have been shown to reduce UTIs and bacteriuria.[56] Neosporin can also be used as a short-
term (10-day) continuous bladder irrigation with a 3-way Foley catheter.[59] Bladder antibiotic
installations are particularly useful in dialysis and anuric patients because they are not dependent
on the renal excretion of antibiotics. Interestingly, heparin bladder instillations have also shown
some activity in reducing recurrent UTIs, most likely by providing a mucopolysaccharide coating to
the urothelial bladder surface.[60]
Initial antibiotic selection in septic or systemically ill patients prior to receiving specific culture
results will depend on individual patient characteristics and local bacterial resistance
antibiograms. For example, fluoroquinolones are generally not recommended for empiric use if the
local resistance is ≥ 10%. A discussion with a local infectious disease specialist can help determine
the best initial empiric approach for the specific local community. Generally, parenteral antibiotics
are recommended for patients with systemic or severe illness until urine culture results can guide
the antibiotic selection. If no such antibiotic is apparent, consider an infectious disease
consultation.
Ceftriaxone or piperacillin-tazobactam can be used in patients who are less severely ill. (Due
to its greater activity, piperacillin-tazobactam is preferred if Enterococcus,
Staphylococcus, or Pseudomonas is suspected.)
Parenteral fosfomycin has also been used for complicated UTIs and has good activity against
many highly resistive organisms, such as ESBL-producing bacteria (not available in the US).
Aminoglycosides are usually reserved for patients where other less nephrotoxic drugs cannot
be used due to resistance or allergy.
For maximum coverage in the sickest patients, consider using a carbapenem with anti-
pseudomonal activity, such as imipenem (which will cover ESBL-producing organisms) and
vancomycin (for MRSA). Ertapenem generally has little activity against Pseudomonas and
would not be an appropriate choice.
Newer Antibiotic Agents For Multidrug-Resistant Infections
The development of multiple drug-resistant organisms has prompted the investigation of older
antimicrobials (primarily aminoglycosides and tetracyclines) as well as the development of new
antibiotics and combinations, such as:
Aztreonam/avibactam
Cefepime-enmetazobactam
Cefepime-zidebactam
Cefiderocol
Ceftazidime/avibactam
Ceftolozane/tazobactam
Eravacycline
Glycylcyclines
Imipenem/relebactam
Meropenem/vaborbactam
Omadacycline
Plazomicin
Tebipenem[61][62]
One UTI symptom (dysuria, urgency, or frequency) or sign (fever, chills, suprapubic pain,
costovertebral angle tenderness, or flank pain)
The US Centers for Disease Control and Prevention (CDC): National Health Safety Network (NHSN)
defines CAUTI differently. They include the presence of a fever, suprapubic tenderness, or
costovertebral angle pain, along with a colony count >100 000 with no more than 2 different
organisms.[76] This definition does not consider other potential sources of fever, so many experts
feel this definition is less useful and tends to overestimate the actual CAUTI rate.[77] Therefore, the
IFDSA definition is usually preferred in clinical practice.
Between 15% to 25% of all hospitalized patients will have a urinary catheter at some time during
their hospital stay. It is estimated that 21% to 50% of such catheters are unnecessary and do not
meet guidelines for initial placement.[78] The CDC has estimated that from 17% to 69% of all
CAUTIs are preventable with optimally applied infection control measures. This means up to 9000
deaths and 380 000 infections a year are potentially avoidable.
Twenty percent of hospital-acquired bacteremias in acute care facilities are attributed to urinary
catheterization, and 50% are in long-term care centers.[79][80] According to the NHSN, this
amounts to about 450 000 CAUTI events annually, with 13 000 deaths and a total annual cost of $340
to $450 million.[81]
Catheterized patients are expected to have bacteriuria due to colonization and the development of
biofilms. The rate of bacterial colonization is approximately 3% to 10% per catheterization day. This
translates into 100% bacterial colonization after the first 30 days. Besides the duration of Foley
catheterization, other identified risk factors include female gender, older patient age, diabetes,
bacterial colonization of the drainage bag, urethral catheterization (compared to suprapubic), and
errors in sterile catheter insertion procedures or maintenance care.
Bacterial inoculation of the bladder in catheterized patients may be extraluminal (through the
external biofilm) or intraluminal (from catheter blockage or contamination of the drainage bag).
Extraluminal is the more common method (66% vs 34%).[84]
The most common organisms causing CAUTIs include E. coli (24%), Candida or yeast
(24%), Enterococcus (14%), Pseudomonas (10%), and Klebsiella (10%). Many organisms are
becoming increasingly resistant to antibiotics, including fluoroquinolones, third- and fourth-
generation cephalosporins, aminoglycosides, and carbapenems.[85]
Routine instillation of various antiseptics into the urinary drainage bags can help reduce calcium
phosphate precipitates and decrease bacterial counts. Hydrogen peroxide 3% and chlorhexidine
have minimal to no effect in reducing urinary bag bacteriuria.[86] The most effective agents are
1/4% acetic acid, diluted household white vinegar (1:3 dilution), and household bleach (1:10
dilution).[87][88] Diluted vinegar is the most effective in dissolving calcium phosphate grit,
precipitate, and debris, which clogs catheters and bags and lowers the bacteria count. The diluted
bleach solution is the most effective in controlling bacterial growth, but none of these measures has
been proven to reduce CAUTIs. Therefore, the IFDSA guidelines advise against the routine addition
of antiseptics to the drainage bag of catheterized patients because of a lack of proven efficacy.[74]
Surprisingly, many of the recommended, obvious, or suggested catheter-related interventions have
failed to demonstrate clear evidence of reductions in CAUTIs, including:
Antiseptic filters and antireflux mechanisms built into the urinary drainage bags
The most effective strategy in reducing CAUTIs is to avoid indwelling catheters whenever possible,
discontinue them as soon as clinically feasible, and use optimal sterile placement techniques and
maintenance procedures.[80]
Requiring mandatory educational programs for all health care workers involved in urinary
catheter insertion or care
Using alternative urinary control measures (pads, condom catheters, mechanical suction
devices, suprapubic tubes, Cunningham clamps, intermittent catheterization, etc) whenever
possible
Implementing automatic catheter removal orders at the time of initial Foley insertion unless
specifically instructed otherwise and justification is provided
Strictly adhering to guidelines for diagnosing and treating CAUTIs to avoid overtreating
asymptomatic bacteriuria
Minimizing unnecessary urine cultures, which often produce positive cultures even in
uninfected patients, is a strong temptation for inappropriate antibiotic use
Obtaining urine cultures when treating patients for a UTI so culture results are available if the
initial treatment fails
Following guidelines for correct specimen collection procedures for urinalyses and cultures
Carefully investigating all alternative sources of infections and fevers before diagnosing a
CAUTI
Spinal cord injury patients with catheters offer unique challenges in diagnosing, preventing, and
treating CAUTIs. Many of these patients require permanent or intermittent catheterization, which
leads to a high incidence of asymptomatic bacteriuria that does not require treatment.
[94] Impaired patient sensation may delay the appearance of pertinent, relevant symptoms. The
development of non-specific symptoms such as fever, bacteriuria, and positive urine cultures will
often lead to a diagnosis of CAUTI, even when the actual infection may be elsewhere. This leads to
the frequent overdiagnosis and overtreatment of CAUTI in this patient population.[95]
At least 35% of spinal cord injured patients diagnosed and treated for CAUTI are estimated to have
only asymptomatic bacteriuria.[96] To facilitate diagnosis, it has been suggested that increased
spasticity and autonomic dysreflexia be included as potential symptoms of a CAUTI in this
population, but it is unclear how clinically useful this will be.[74]
The general principle of early catheter removal does not necessarily apply to spinal cord injured
patients who may not have a suitable alternative for safe bladder drainage. Inappropriate Foley
catheter removal puts them at risk for urinary retention, vesicoureteral reflux, renal failure,
autonomic dysreflexia, and sepsis. Clean intermittent self-catheterization is safe, effective, and
associated with a lower incidence of bacteriuria and CAUTIs, but there are still increased risks of
infection, false passages, urethral strictures, bladder overdistention or retention, and a heavy
reliance on caregivers for logistical support and supplies.[97][98]
There is some evidence that long-term use of nitrofurantoin and D-mannose prophylaxis can
effectively reduce CAUTI in spinal cord-injured patients.[99][100] Silver and hydrophilic-coated
catheters also appeared to help reduce CAUTIs, but the studies were small and not considered
definitive.[101][102] Cranberry supplements and other nutraceuticals have demonstrated either no
activity or conflicting results in reducing CAUTIs in this population.[103][104]
A guidelines-based model for ordering urine cultures and antibiotics has significantly reduced
overdiagnosis and overtreatment of asymptomatic bacteriuria in long-term catheterized patients
by over 70%.[105][106]
UTIs in Pregnancy
Between 2% and 7% of pregnant women will develop asymptomatic bacteriuria, usually early in
their pregnancy.[94] Patients with a history of prior UTIs, diabetes, a larger number of prior
deliveries, and lower socioeconomic status are at higher risk.[107] Without treatment, up to 35%
will progress to a symptomatic UTI and/or pyelonephritis during the pregnancy.[108] Most studies
suggest untreated bacteriuria during pregnancy is associated with an increased risk of low birth
weight babies, prematurity, preeclampsia, and perinatal mortality.[107][109][110] Pyelonephritis
has also been associated with poor pregnancy outcomes, particularly prematurity.[111] Treatment
of asymptomatic bacteriuria and cystitis generally includes 3 to 7 days of amoxicillin-clavulanate,
cephalexin, cefpodoxime, or a single dose of fosfomycin.[112] Nitrofurantoin and
sulfamethoxazole/trimethoprim may also be used but not during the first trimester or close to term.
[108][113][114]
It is well known that chronic renal disease will decrease urinary excretion of antibiotics, but other
factors also play a role.[116] There is reduced urinary antibacterial function, uremic
immunosuppression, lower antibacterial levels within the bladder and renal tissues, inhibition of
urothelial antimicrobial functions, and possibly reduced urinary volume.[8][117][118][119] People
with diabetes who have glucosuria will demonstrate increased bacterial adherence to the detrusor
urothelium as well as decreased neutrophil efficacy.[120]
Diagnosing a UTI in dialysis patients can be challenging, as 30% to 40% of patients will typically
demonstrate pyuria without infection.[121] The diagnosis, therefore, also requires symptoms and a
positive urine culture. Infections are often related to catheterization, and Candida is the most
common organism in this population.[122]
Antibiotics must be used cautiously in patients with severe or end-stage renal failure.
Nitrofurantoin and tetracyclines (other than doxycycline) should be avoided. Aminoglycosides can
be used cautiously, as they are potentially nephrotoxic. Other antibiotics, such as trimethoprim-
sulfamethoxazole, trimethoprim alone, cephalexin, second- and third-generation cephalosporins,
and fluoroquinolones can generally be used at a reduced (usually 50%) dose.[123][124]
[125] Ertapenem has a renal failure- and dialysis-suggested dosing schedule, but neurotoxicity has
been reported even when using the recommended dosages.[126] Moxifloxacin can be used in
patients with renal failure but will not achieve adequate urinary concentrations and, therefore,
cannot be recommended for UTIs.
A number of antibiotics generally do not require any adjustment, even in severe renal failure.
These include:
Azithromycin
Ceftriaxone
Clindamycin
Doxycycline
Fosfomycin
Linezolid
Nafcillin
Rifampin
Trimethoprim
For patients with severe renal failure (<30 mL/min.), nitrofurantoin, aminoglycosides, and
methenamine should not be used. Preferred agents for a UTI in such patients would be
trimethoprim or fosfomycin. Other agents that can be used include carbapenems, cephalosporins,
doxycycline, penicillins, and quinolones.
For patients with end-stage renal failure, quinolones (ciprofloxacin, levofloxacin) are considered
first-line agents for UTIs. Cefdinir and cefpodoxime as considered second-line backup therapy.[127]
[128]
Diagnosing a complicated UTI can be difficult in renal transplant patients. Symptoms may be subtle
and non-specific such as nausea or unusual fatigue. Fever and palpable tenderness over the graft
site are more likely to be associated with a UTI than acute rejection. Therefore, renal transplant UTI
patients with systemic signs of infection, such as fever or graft tenderness on palpation, should
have blood cultures and standard urine cultures taken. About 9% of blood cultures will
ultimately return positive for bacteremia.[132] A diagnostic renal biopsy should be considered in
questionable cases of pyelonephritis in renal transplant recipients or when a UTI is associated with
graft dysfunction, especially during the first 6 months after the transplant.[133] (Patients with acute
rejection are more likely to have azotemia, worsening proteinuria, and hypertension.)
All symptomatic UTIs in renal transplant patients are considered complicated UTIs. Morbidity and
mortality from UTIs increase in kidney transplant patients as the required immunosuppression
increases infection risk and interferes with therapy.[134][135] The current 1-year mortality from
infectious complications in renal transplant recipients is <5%, having dropped from almost 50%
historically, mostly due to advances in surgical techniques and postoperative care.[136]
UTIs are most common during the first year after transplantation and will occur in approximately
25% of transplant recipients during that time.[132][137] About 7% of renal transplant recipients
will develop recurrent UTIs associated with an increased risk of multiple antibiotic resistance,
transplant failure, and death.[138] Ascending UTIs with the early progression to frank
pyelonephritis are more common in renal transplant recipients as they have very short ureters and
will often lack an effective antireflux mechanism. The incidence of acute pyelonephritis also
appears to be related to the frequency of rejection episodes and recurrent UTIs. Renal transplant
patients who develop pyelonephritis are more likely to develop increases in serum creatinine along
with a decrease in creatinine clearance which is often persistent.[139]
Screening for asymptomatic bacteriuria immediately posttransplantation for the first 90 days is
controversial, as many experts recommend it while others do not.[140][141] There is no good data
suggesting that screening or treating asymptomatic bacteriuria during the first 3 months after
transplantation is helpful, so this remains a judgment call by the transplant team. If screening is
done, microscopic urinalyses with urine cultures are recommended at 2, 4, 8, and 12 weeks after
surgical transplantation.[142]
Screening for asymptomatic bacteriuria after the first 3 months is not recommended as treatment
beyond this point has not been effective in UTI prevention or graft preservation and may lead to
unnecessary antibiotic use and increased bacterial resistance.[143][144] Historically it was thought
that graft and patient survival were not affected by adequately treated complicated UTIs, but more
recent data suggests that acute and recurrent graft pyelonephritis are significant risk factors for
decreased long-term graft and patient survival.[145][146]
Posttransplantation risk factors for UTIs include female gender, advanced patient age, longer time
on dialysis prior to transplantation, recurrent UTIs in the recipient prior to transplantation,
polycystic kidney disease, Foley catheterization, ureteral stent placement, use of a deceased-donor
transplant, and urinary tract obstruction or dysfunction.[147][148][149]
Antibiotic UTI prophylaxis is commonly used for the first 6 to 12 months posttransplantation.[150]
Some experts continue the prophylaxis indefinitely.[151] Trimethoprim-sulfamethoxazole is the
most commonly used prophylactic agent, but there are concerns about increasing bacterial
resistance. Cephalexin and norfloxacin prophylaxis has been used successfully in patients unable
to take trimethoprim-sulfamethoxazole.[152] Methenamine hippurate (1000 mg twice daily) with or
without vitamin C (1000 mg twice daily) has also been used successfully for UTI prophylaxis in
renal transplant patients.[153][154] Further, it can be safely used in patients with a creatinine
clearance of >10 mL/min but should not be used with sulfa drugs due to the potential formation of
bladder precipitates. Fosfomycin has been used effectively in addition to standard trimethoprim-
sulfamethoxazole therapy before urologic procedures and for this population's UTI/asymptomatic
bacteriuria treatment.[144][155]
There is an increased incidence of Klebsiella pneumoniae being the infecting organism in renal
transplant patients.[135] Besides Escherichia coli and Klebsiella pneumoniae, other common
pathogenic bacteria include Enterobacter cloaca. Pseudomonas aeruginosa, and Enterococcus. Due
to reduced host resistance factors, treatment is typically 14 to 21 days. Patients suspected of having
a UTI but demonstrating a negative urine culture should be tested for Corynebacterium
urealyticum, which requires special culture media for identification.[156]
Simple cystitis is typically treated for 10 to 14 days. (Nitrofurantoin may be used if the GFR is ≥30
mL/min.)[157][158][159] The optimal duration of antibiotic therapy for complicated UTIs is unclear,
but the standard treatment period is 14 to 21 days, although this can be extended. Infected cysts,
for example, may need 4 to 6 weeks of treatment. Trimethoprim-sulfamethoxazole would be less
ideal if the local resistance prevalence is reported as ≥20%.[160][161][162]
Selective imaging can be helpful in some renal transplant patients with UTIs. The initial test is
usually ultrasonography. Patients with polycystic kidney disease may have an infected cyst which
can be challenging to identify. Such patients often have flank pain related to the infected renal cyst
rather than graft discomfort. In such cases, a CT-PET scan can be beneficial.[163][164][165] A non-
contrast CT scan is a reasonable next step if the ultrasound is negative, especially in patients with a
history of nephrolithiasis. (While contrast is useful, it also is potentially nephrotoxic and cannot be
used safely in patients with elevated serum creatinine levels.) Voiding cystourethrograms can
identify reflux, and urodynamics will diagnose bladder dysfunction and outflow obstruction.
Specific Infections
Emphysematous cystitis is a lower UTI of the bladder where there is gas within the bladder wall
caused by gas-producing bacteria. Such gas-forming bacteria are usually Escherichia
coli or Klebsiella pneumonia. (Other organisms that can produce gas
include Proteus, Enterococcus, Pseudomonas, Clostridium, and rarely Aspergillus and Candida.)
Infrequently, infectious colitis has caused emphysematous cystitis without clinical signs or
evidence of a UTI.[166] It typically develops in people with diabetes, females more than males,
older individuals, and those with some urinary obstruction. High glucose levels in the bladder wall
tissue certainly play a part, but the precise etiology of emphysematous cystitis is not well
understood.[167] The mean age of presentation is about 68 years, and approximately 50% of
patients will have 2 or more significant comorbidities. One-third of patients will present with
sepsis, 25% with abdominal pain, 17% with UTI symptoms, 6% with hematuria, and 8%
asymptomatic with incidental findings on an imaging examination.[168] While the diagnosis can
sometimes be made by ultrasound or plain KUB x-ray, most are identified by CT scans. Treatment
primarily involves culture-specific antibiotics, bladder drainage, supportive care, and elimination
of risk factors. Ninety percent of cases can be managed conservatively, and only 5% to 10% will
require some type of surgery.[168]
Definitive treatment of the obstruction is usually delayed until the immediate infectious process
has been controlled. Percutaneous nephrostomy is usually preferred for the most severe cases as
there is minimal manipulation of the infected stone and no risk of possible failure to bypass the
obstruction cystoscopically from a retrograde approach.[175] A particularly large collection of
stones should also be initially drained and managed percutaneously.[173][176] It has been
suggested that definitive stone surgery be conducted within 3 weeks of ureteral stent
placement. Complications, specifically reduced postoperative UTIs, are minimized if the stone
removal operative time is <75 minutes.[177]
Other specific infections involving the urinary tract are best found in our companion articles on
those specific topics. These include tuberculosis, candidiasis, schistosomiasis, filariasis, prostatitis,
orchitis, epididymitis, necrotizing fasciitis, renal and scrotal abscesses, etc.
New diagnostic methods and guideline implementation guides are being developed to hasten
proper diagnosis, minimize inappropriate antibiotic use, and improve antimicrobial selection
accuracy. These new aides include computer programs with artificial intelligence algorithms, new
classes of biomarkers, and cell-free DNA analysis, among others. New catheter materials, coatings,
innovative bacterial growth interference agents, and anti-infective vaccinations for high-risk
populations are being studied. Entirely new classes of antibiotics are being designed and created.
[181] Bacteriophages (viruses that attack only specific bacteria) have been used anecdotally but
successfully on a very limited basis for highly resistant infections.[95][182][183] Bacteriophages
can not only prevent the formation of biofilms but can produce polysaccharide depolymerase,
which allows for phage penetration deep into existing biofilms where antibiotics cannot reach
them. They are also unaffected by bacterial antibiotic resistance mechanisms.[95][184]
Differential Diagnosis
The differential diagnosis of a complicated UTI includes:
Abscess
Acute pyelonephritis
Bladder cancer
Cystitis
Focal nephronia
Herpes simplex
Interstitial cystitis
Obstructive pyelonephritis
Prostatitis
Urethritis
Urolithiasis
Vaginitis
Prognosis
The FDA recommends the use of dual primary endpoints to determine the eradication of
complicated UTIs: both a clinical response (symptom resolution with no new UTI symptoms) AND a
microbiological response (urine culture demonstrating <1000 CFU/mL).[8]
Complications
Inadequate treatment of complicated UTIs will increase the likelihood of an early recurrence or
even an outright failure of therapy. The infection can spread to other organs, result in an abscess,
or progress to sepsis and sometimes death.
Patients should be informed of the correct use of antibiotics regarding dosing and completing the
full treatment schedule even if they feel better, incorporating reasonable prophylactic lifestyle
measures, and avoiding inappropriate antimicrobial drug use.
Diagnostic Pitfalls
UTIs are primarily a clinical diagnosis, and expert opinion should be sought before initiating
treatment of an isolated positive result in an otherwise asymptomatic patient.
Often, clinicians treat a positive culture report rather than a patient with a genuine UTI.
Usually, a positive culture in an asymptomatic patient can be traced to a poor sampling
technique.
Another confusing scenario is that of a septic, delirious older individual who cannot provide a
history or demonstrate adequate examination signs to help localize a septic source. These
patients are often treated as having a presumed UTI without a clear alternative septic source.
UTI-associated radiological changes can sometimes take several months to resolve and must
be interpreted with care in recurrent or persistent infections.
UTI must be considered in the differential diagnosis of a patient with pelvic inflammatory
disease or an acute abdomen.
Male patients with UTIs should also be screened for sexually transmitted infections.
Interstitial cystitis is frequently misdiagnosed and treated as a UTI and must be considered an
alternative diagnosis in patients who repeatedly present with cystitis symptoms and negative
cultures.
"Sterile pyuria," with persistent urinary WBCs but negative standard urine cultures, could
indicate tuberculosis which requires special cultures.
Bacterial infections only tend to account for 80% of all UTIs, and antibiotics may sometimes
prove ineffective.
Spinal cord injury patients with a UTI may present with increased spasticity or autonomic
dysreflexia.
Management Pitfalls
Frail, older, or debilitated patients with nonspecific signs such as unexplained falls or changes in
mental status are often suspected of having a UTI. While this is correct, such nonspecific changes
are unreliable predictors of a UTI, and antibiotics may not help unless urine studies confirm the
UTI.[185][186]
Multidrug-resistant infections are becoming a major source of in-hospital morbidity and mortality.
Suppressive antibiotic regimens are sometimes used in poorly responding or resistant cases. A
dedicated infectious disease team should optimally guide these care plans, as long-term
suppressive antibiotics have unique complications.
Long-term antibiotic prophylaxis must also be used with caution, as it will increase the risk of
resistance and change the susceptibilities of colonized organisms. Occasionally, residual urinary
symptoms may take several months to resolve or might never resolve (especially in patients with
indwelling catheters, post-prostatectomy cases, post-bladder surgery, or with radiotherapy) and do
not always indicate a genuine UTI. Long-term prophylaxis with nitrofurantoin is associated with
hypersensitivity pneumonitis. Patients should be counseled accordingly.
Identifying predisposing factors for the infection and correcting them, if possible, is helpful. For
example, a diabetic patient would benefit from improving glycemic control. Renal tract anatomic
abnormalities should be assessed to see if an intervention is appropriate (renal calculi, BPH,
ureteric strictures). Immunocompromising factors should be addressed if possible (steroids, HIV).
Finally, nephrotoxic medications should be avoided whenever possible in patients with any degree
of renal compromise. If unavoidable, care should be taken to use the optimal dose and duration of
therapy with regular, routine monitoring of renal function. Finally, do not hesitate to consult your
local infectious disease specialists for assistance. Their primary mission is optimally managing
complicated, challenging, and complex infections.
The management of complex UTIs is best performed by an interprofessional team that may include
a urologist, nephrologist, infectious disease expert, internist, primary care clinicians, pharmacist,
and nurses. Health care professionals need a range of clinical skills. Physicians must be adept at
diagnosing and managing these infections, including interpreting diagnostic tests and selecting
appropriate antibiotics. Nurses require expertise in administering medications, providing wound
care, and monitoring patients for signs of sepsis. Pharmacists play a vital role in optimizing drug
therapy and ensuring appropriate antibiotic stewardship. All team members share the
responsibility of patient education, infection prevention, and monitoring for treatment response.
Complicated UTIs need to be treated more carefully to serve patients with these infections and
avoid overuse and misuse of antibiotics that will ultimately result in more resistant infections.
Using the right antibiotic for the appropriate duration is critical. Practitioners should not hesitate to
use infectious disease specialty services in these situations to help optimize antibiotic use. Failure
of a standard UTI or pyelonephritis to respond to initial treatment should suggest other medical
problems such as diabetes, sepsis, an abscess, urinary retention, or an obstructing stone with a
possible pyonephrosis. Bladder drainage with a Foley catheter and appropriate imaging tests can
identify these problems. These patients need close monitoring because of potential complications.
The outlook for patients with severe complicated UTIs is guarded, and even those who recover tend
to have a prolonged recovery period.[67][187][188]
Effective communication and collaboration among health care professionals are crucial for patient-
centered care. Physicians, advanced care practitioners, nurses, pharmacists, and other team
members must share information about the patient's condition, treatment plan, and complications.
Clear and timely communication enhances coordination, reduces errors, and promotes safer care.
The team should work collaboratively to develop comprehensive care plans that address the
infection, underlying conditions, and any potential complications. This includes clear roles and
responsibilities, regular team meetings, and seamless transitions of care between different settings.
Team performance can be improved through ongoing education and training in infection
management, multidisciplinary collaboration, and communication skills. Regular debriefings, case
discussions, and quality improvement initiatives can help interprofessional teams continually
refine their approach to complicated UTIs, leading to better outcomes and patient safety.
Review Questions
References
Disclosure: Stephen Leslie declares no relevant financial relationships with ineligible companies.