Complicated Urinary Tract Infections


Article Author:
Ayan Sabih


Article Editor:
Stephen Leslie


Editors In Chief:
Stephen Leslie
Karim Hamawy


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Trevor Nezwek
Radia Jamil
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Steve Bhimji
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beata Beatty
Nazia Sadiq
Hajira Basit
Phillip Hynes
Tehmina Warsi


Updated:
3/5/2019 5:08:00 PM

Introduction

Urinary tract infections (UTIs) are among the most common causes of sepsis presenting to 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 almost universal good progress, and 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 that can lead to treatment failure, repeat infections, or significant morbidity and mortality with a poor outcome. It is vitally important to determine if the presenting episode is the result of 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 infections which carry a higher risl of treatment failure as these typically require longer antibiotic courses and sometimes additional workup.

In a clinical context that is not associated with treatment failure or poor outcomes, a simple UTI, or simple cystitis, is an infection of the urinary tract that occurs due to appropriate susceptible bacteria. Typically this is an infection in a nonpregnant immune competent female patient.  Pyuria and/or bacteriuria without any symptoms is not a UTI and may not require treatment. An example would be a patient with a Foley catheter or an incidental positive urine culture in an asymptomatic non pregnant immune competent female.

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 right context can be considered as simple UTI, provided there is a prompt response to first-line antibiotics without any long-term sequela.

Any urinary tract infection that does not conform to the above description or clinical trajectory is considered a complicated UTI. In these scenarios, one can 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]

Examples of a complicated UTI include:

  • Infections occurring despite the presence of anatomical protective measures (UTI in males are by definition considered complicated UTI)
  • Infections occurring due to anatomical abnormalities, for example, an obstruction, hydronephrosis, renal tract calculi, or colovesical fistula
  • Infections occurring due to an immune compromised state, for example, steroid use, post chemotherapy, diabetes, elderly population, HIV)
  • Atypical organisms causing UTI
  • Recurrent infections despite adequate treatment (multi-drug resistant organisms)
  • Infections are occurring in pregnancy (including asymptomatic bacteriuria)
  • Infections are occurring after instrumentation, nephrostomy tubes, ureteric stents or bladder catheters
  • Infections in renal transplant patients
  • Infections are occurring in patients with impaired renal function
  • Infections following prostatectomies or radiotherapy

Etiology

Most cases of urinary tract infections 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. Residential care patients, diabetics and those with indwelling catheters or any form of immunocompromise can also colonize with Candida.

Epidemiology

Cohorts with more risk factors show an increased incidence of urinary tract infections. Risk factors include female anatomy, increasing age, diabetes, obesity, and frequent intercourse (although UTI is not defined as a sexually transmitted infection).

Simple UTI (nonpregnant immune competent female) have been estimated to occur with as high a frequency as 0.7 infections per person per year. Fifty percent of females will have at least one 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 that bacteriuria will progress to a UTI.

Bacteriuria occurs in up to 14% of diabetic females but does not tend to occur with a higher frequency in diabetic males.

The incidence of asymptomatic bacteriuria in pregnant females is similar to that in nonpregnant females (2% to 7%) but tends to progress to symptomatic UTI in as many as 40% of pregnant women. 

Asymptomatic bacteriuria also tends to increase with age in females and is present in up to 80% of the elderly female population. It is rare among younger healthy males but can be present in up to 15% of older males.

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.

Increased incidence of UTI has been described in patients using Dapagliflozin (SGLT2i). [8]

History and Physical

Despite the frequency of which urinary tract infections present to a hospital, UTI (especially complicated UTI) remain a clinical entity causing considerable confusion, diagnostic uncertainty, and a source of significant inappropriate antibiotic prescriptions.

Symptoms (increased urinary frequency, urgency, hematuria, dysuria, suprapubic or flank pain) are the most important clinical criteria for initially diagnosing a UTI. There must also be an appropriate clinical scenario in which infection of the urogenital tract is the most likely explanation for these symptoms. In this situation, it is appropriate to start empiric treatment with first-line antibiotics. A urine sample should also be sent for microscopy and culture before starting treatment, although that is not always possible. The urine sample would almost always show an abnormal red cell or white cell count and bacteria.

Severe complicated urinary tract infections can present as severe undifferentiated sepsis or even septic shock.

Furthermore, urinary tract infections may present with nonspecific grumbling symptoms, atypical presenting features (delirium in the elderly), signs mimicking an acute abdomen, be a trigger for precipitating diabetic emergencies such as diabetic ketoacidosis (DKA), and even present without any symptoms (asymptomatic bacteriuria in pregnancy).

Evaluation

A good quality urine specimen is vital in making the diagnosis. However, treatment must not be delayed if the clinical scenario is strongly suggestive of urinary tract infection.[9][10][11]

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.  In general, obtaining a urine specimen for culture is recommended whenever possible and feasible.

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 been partially treated. A pre-prostate and post-prostate massage or exam urine sample (also known as the four-glass test or even the shortened 2-glass test) can improve the diagnostic yield.

Blood cultures are also useful in more severe septic presentations. A positive blood culture can sometimes also help corroborate a urine sample result and reduce the suspicion of contamination.

Other microbiology and culture specimens can be directed if there is multifocal sepsis.

Radiological investigations are not helpful in the initial diagnosis of most infections limited to the genitourinary tract, as there should be sufficient clues from the history, physical examination, and laboratory results. Ultrasound and CT scans may sometimes be useful or even critical for diagnosing perinephric abscess, urinary retention, hydronephrosis and obstructive pyelonephritis from stones in septic patients. All patients who fail to respond to appropriate broad-spectrum antibiotics should undergo imaging to exclude complications such as abscesses, urinary retention, calculi, gas, and hydronephrosis. 

All patients who present with a complicated UTI, even the first presentation of ascending pyelonephritis in nonpregnant immune competent females, should undergo a renal tract ultrasound at a minimum to evaluate for anatomical abnormalities, hydronephrosis or lesions.  Since there is no reliable clinical method to rule out urinary obstructions in complicated UTIs (such as a stone), it is the responsibility of the treating physician to do so with ultrasound or CT.

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 as well as broad-spectrum antibiotics administered in the emergency department. Antibiotic choice should always be according to local guidelines.[12][13][14][15]

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.

On the other hand, nonseptic stable patients may be treated as outpatients.

Broad-spectrum, empiric antibiotics should always be switched to a targeted narrow-spectrum antibiotic, if possible, once culture results are available. Initial broad-spectrum choices tend to be penicillins or beta-lactams, cephalosporins, fluoroquinolones, and carbapenems (especially if dealing with an extended-spectrum beta-lactamases (ESBL) organism). The specific choice will depend on the individual hospital's microbiological spectrum and antibiogram.

Patients who present with repeat infections may also be initially treated as per their previous urine culture results. Imaging to look for a source of infection such as an abscess or stone should be done with relapsing infections that involve the same organisms.

In most cases, treatment response should be evident in 24 to 48 hours. A poor response may indicate 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, or fistulas). A Foley catheter, to guarantee good bladder drainage, is often recommended for these patients if they are septic and have increased post-void residual volumes.

Failure to respond to appropriate antibiotics should suggest a possible obstructive component such as obstructive pyelonephritis. In such cases, a renal ultrasound or non-contrast CT scan should be done for diagnosis and immediate surgical drainage performed if an obstructed, infected kidney is found (either double J stenting or a percutaneous nephrostomy).

Prophylactic antibiotics are seldom recommended due to rapid bacterial resistance patterns developing.

Patients with permanent catheters such as suprapubic tubes should avoid prophylactic antibiotics. They should be treated only when symptomatic.

Mandelamine is a twice-daily medication that, in acid urine, is converted to formaldehyde which is a potent urinary antiseptic. This can be useful in patients with persistently elevated post-void residuals instead of prophylactic antibiotics.

Pearls and Other Issues

Diagnostic Pitfalls

Urinary tract infections are primarily a clinical diagnosis, and expert opinion should be sought before initiating treatment of an isolated positive result in an otherwise asymptomatic patient, the only exception being asymptomatic bacteria.

Quite often, clinicians end up treating the positive culture report rather than a genuine urinary tract infection.  Most often, positive culture in an asymptomatic patient can be traced to a poor sampling technique.

Another confusing scenario is that of septic, delirious, elderly patient who is unable to provide a history or demonstrate adequate examination signs to help localize a septic source. Quite frequently, these patients are treated as having a presumed UTI in the absence of a clear alternative septic source.

UTI associated radiological changes can sometimes take several months to resolve and must be interpreted with care in cases of recurrent or persistent infections.

UTI must be considered as a differential diagnosis when evaluating a patient with a pelvic inflammatory disease or an acute abdomen.

Male patients with a urinary tract infection must also be screened for sexually transmitted infections.

Interstitial cystitis is frequently misdiagnosed and treated as a UTI, and must be considered as an alternative diagnosis in patients who keep presenting with cystitis symptoms without positive 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 urinary tract infections, and antibiotics may sometimes prove ineffective.

Management Pitfalls

Multidrug-resistant infections are becoming a major source of in-hospital mortality and morbidity. Suppressive antibiotic regimens are sometimes used in poorly responding or resistant cases. These presentations should always be guided by a dedicated infectious disease team, as long-term suppressive antibiotics come with a unique set of complications.

Long-term antibiotic prophylaxis must also be used with caution, as it would increase the risk of resistance and change susceptibilities of colonized organisms. On occasion, residual urinary symptoms may take several months to resolve or might never resolve (especially in the case of indwelling catheters, post-prostatectomy cases, post bladder surgery, or radiotherapy), and do not always indicate a genuine urinary tract infection.

Long-term prophylaxis with nitrofurantoin is associated with hypersensitivity pneumonitis. Patients should be counseled accordingly.

It helps to identify predisposing factors for the infection and correct them if possible. For example, the diabetic patient would benefit from improving glycemic control. Renal tract anatomic abnormalities may be assessed by urology to see if an intervention is appropriate (renal calculi, BPH, ureteric strictures). Immunocompromising factors may be addressed if possible (steroids, HIV). Finally, nephrotoxic medications may be rationalized in patients with suboptimal renal functions.

 

Enhancing Healthcare Team Outcomes

The management of complex UTI is multidisciplinary that includes a urologist, nephrologist, infectious disease expert, internist, pharmacist and the primary care provider.

Complicated UTIs need to treated more carefully to serve patients with these infections and to avoid overuse and misuse of antibiotics that will ultimately result in more resistant infections in the future. Using the right antibiotic for the right duration is key. Practitioners should not hesitate to take advantage of 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 some other medical problem such as diabetes, sepsis, an abscess, urinary retention or an obstructing stone with a possible pyonephrosis. Bladder drainage with a Foley and appropriate imaging tests can identify these problems.

These patients need close monitoring because of potential complications. The outlook for patients with severe UTI is guarded and even those who do recover tend to have a prolonged recovery period.[16][17][18] (Level V)


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Complicated Urinary Tract Infections - Questions

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A 65-year-old female presents with fever and chills. Her heart rate is 126 beats/min and blood pressure is 90/60 mmHg. A urinalysis reveals dark colored urine and is positive for leukocyte esterase and nitrites. Which of the following is the best empirical treatment?



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Which of the following patient descriptions will be considered a simple urinary tract infection?



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A 60-year-old patient presents with left flank pain, dysuria, elevated WBC of 22,000/microliter and 103 F fever. The patient voids 200 mL and urinalysis is consistent with a urinary tract infection. The patient weighs over 400 pounds. He has no history of kidney stones but has diabetes mellitus. Initial renal ultrasound was negative for hydronephrosis. He was started on antibiotics pending urine culture results. After 24 hours, the patient is no better and remains febrile. What is the most appropriate next step in management?



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A 17-year-old female presents to the emergency department (ED) with diabetic ketoacidosis (DKA). Her Glasgow coma scale is 13, and she is unable to give a reliable history. She has diabetes mellitus type 1 and has had four previous presentations with DKA due to poor medication compliance. On examination, she is profoundly dehydrated, febrile at 38 C, and hypotensive with a systolic blood pressure of 90 mmHg. Her chest was clear on auscultation. Her abdomen is soft and does not have any signs suggesting of peritonitis. There were no obvious soft tissue or joint inflammations. She had been brought into the ED by her partner, who stated that she was fully compliant with her insulin regimen. She had been in good health recently other than a bladder infection that was treated with a few days of antibiotics last week. Her bedside urine dip stick was positive for glucose and ketones, but negative for leukocytes and nitrites. Her blood gas showed a metabolic acidosis picture (pH 7.25). Her blood panel is still pending. Other than fluids and insulin, which of the following is the next best step in management?



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A 90-year-old rest home resident is brought to the emergency department. She has a permanent indwelling urinary catheter. She is not oriented. She is dehydrated but maintaining her blood pressure. Her clinical examination is otherwise unremarkable. The rest home staff state that she was fully oriented till the night before, and was in good health. In addition to fluids, what is the next best step in management?



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Which of the following is not defined as a complicated urinary tract infection (UTI)?



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Complicated Urinary Tract Infections - References

References

Girgenti V,Pelizzo G,Amoroso S,Rosone G,Di Mitri M,Milazzo M,Giordano S,Genuardi R,Calcaterra V, Emphysematous Pyelonephritis Following Ureterovesical Reimplantation for Congenital Obstructive Megaureter. Pediatric Case Report and Review of the Literature. Frontiers in pediatrics. 2019;     [PubMed]
Habak PJ,Griggs, Jr RP, Urinary Tract Infection In Pregnancy 2018 Jan;     [PubMed]
Shortridge D,Duncan LR,Pfaller MA,Flamm RK, Activity of ceftolozane-tazobactam and comparators when tested against Gram-negative isolates collected from paediatric patients in the United States and Europe during 2012-2016 as part of a global surveillance programme. International journal of antimicrobial agents. 2019 Feb 1;     [PubMed]
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Lemoine L,Dupont C,Capron A,Cerf E,Yilmaz M,Verloop D,Blanckaert K,Senneville E,Alfandari S, Prospective evaluation of the management of urinary tract infections in 134 French nursing homes. Medecine et maladies infectieuses. 2018 Aug;     [PubMed]
Karmazyn BK,Alazraki AL,Anupindi SA,Dempsey ME,Dillman JR,Dorfman SR,Garber MD,Moore SG,Peters CA,Rice HE,Rigsby CK,Safdar NM,Simoneaux SF,Trout AT,Westra SJ,Wootton-Gorges SL,Coley BD, ACR Appropriateness Criteria{sup}®{/sup} Urinary Tract Infection-Child. Journal of the American College of Radiology : JACR. 2017 May;     [PubMed]
Yasuda M, Urogenital infections. Nihon rinsho. Japanese journal of clinical medicine. 2017 Apr;     [PubMed]
Bonine NG,Berger A,Altincatal A,Wang R,Bhagnani T,Gillard P,Lodise T, Impact of Delayed Appropriate Antibiotic Therapy on Patient Outcomes by Antibiotic Resistance Status From Serious Gram-negative Bacterial Infections. The American journal of the medical sciences. 2019 Feb;     [PubMed]
Kaye KS,Bhowmick T,Metallidis S,Bleasdale SC,Sagan OS,Stus V,Vazquez J,Zaitsev V,Bidair M,Chorvat E,Dragoescu PO,Fedosiuk E,Horcajada JP,Murta C,Sarychev Y,Stoev V,Morgan E,Fusaro K,Griffith D,Lomovskaya O,Alexander EL,Loutit J,Dudley MN,Giamarellos-Bourboulis EJ, Effect of Meropenem-Vaborbactam vs Piperacillin-Tazobactam on Clinical Cure or Improvement and Microbial Eradication in Complicated Urinary Tract Infection: The TANGO I Randomized Clinical Trial. JAMA. 2018 Feb 27;     [PubMed]
Karve S,Ryan K,Peeters P,Baelen E,Rojas-Farreras S,Potter D,Rodríguez-Baño J, The impact of initial antibiotic treatment failure: Real-world insights in patients with complicated urinary tract infection. The Journal of infection. 2018 Feb;     [PubMed]
Donnan JR,Grandy CA,Chibrikov E,Marra CA,Aubrey-Bassler K,Johnston K,Swab M,Hache J,Curnew D,Nguyen H,Gamble JM, Comparative safety of the sodium glucose co-transporter 2 (SGLT2) inhibitors: a systematic review and meta-analysis. BMJ open. 2019 Feb 1;     [PubMed]

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