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Acute complicated urinary tract infection (including pyelonephritis) in adults

Acute complicated urinary tract infection (including pyelonephritis) in adults
Authors:
Thomas M Hooton, MD
Kalpana Gupta, MD, MPH
Section Editor:
Stephen B Calderwood, MD
Deputy Editor:
Allyson Bloom, MD
Literature review current through: Aug 2021. | This topic last updated: Mar 19, 2021.

INTRODUCTION — Urinary tract infections (UTIs) include cystitis (infection of the bladder/lower urinary tract) and pyelonephritis (infection of the kidney/upper urinary tract). The pathogenesis of UTI begins with colonization of the vaginal introitus or urethral meatus by uropathogens from the fecal flora, followed by ascension via the urethra into the bladder. Pyelonephritis develops when pathogens ascend to the kidneys via the ureters. Pyelonephritis can also be caused by seeding of the kidneys from bacteremia. It is possible that some cases of pyelonephritis are associated with seeding of the kidneys from bacteria in the lymphatics.

This topic will review the approach to adults with acute complicated UTI, which we define as a UTI that has possibly extended beyond the bladder (ie, UTI with fever or other systemic symptoms, suspected or documented pyelonephritis, and UTI with sepsis or bacteremia). (Related Pathway(s): Urinary tract infection (UTI): Empiric antibiotic selection for acute complicated UTI in adults.)

In contrast, when there are symptoms of cystitis in the absence of fever, flank pain, costovertebral angle tenderness, and other signs of systemic illness, we consider this acute simple cystitis. This approach to categorizing UTI (table 1) differs from other conventions, as discussed in detail below.

Our approaches to the diagnosis and management of acute simple cystitis (ie, cystitis symptoms in the absence of fever, flank pain, costovertebral angle tenderness, and other signs of systemic illness) and UTIs in special populations are discussed elsewhere:

(See "Acute simple cystitis in women".)

(See "Acute simple cystitis in men".)

(See "Urinary tract infections and asymptomatic bacteriuria in pregnancy".)

(See "Catheter-associated urinary tract infection in adults".)

(See "Kidney transplantation in adults: Urinary tract infection in kidney transplant recipients".)

(See "Recurrent simple cystitis in women".)

Asymptomatic bacteriuria is also discussed in detail elsewhere. (See "Asymptomatic bacteriuria in adults".)

UTI in children is also discussed separately. (See "Urinary tract infections in children: Epidemiology and risk factors" and "Urinary tract infections in children: Long-term management and prevention" and "Urinary tract infections in infants and children older than one month: Clinical features and diagnosis" and "Urinary tract infections in infants older than one month and young children: Acute management, imaging, and prognosis".)

TERMINOLOGY — We use the term acute complicated urinary tract infection (UTI) to refer to an acute UTI with any of the following features, which suggest that the infection extends beyond the bladder (table 1):

Fever (>99.9°F/37.7°C) – This temperature threshold is not well defined and should be individualized, taking into account baseline temperature, other potential contributors to an elevated temperature, and the risk of poor outcomes should empiric antimicrobial therapy be inappropriate.

Other signs or symptoms of systemic illness (including chills or rigors, significant fatigue or malaise beyond baseline).

Flank pain.

Costovertebral angle tenderness.

Pelvic or perineal pain in men, which can suggest accompanying prostatitis. (See "Acute bacterial prostatitis" and "Chronic bacterial prostatitis".)

By this definition, pyelonephritis is a complicated UTI, regardless of patient characteristics. In the absence of any of these symptoms, we consider patients with UTI to have acute simple cystitis and manage the patient differently. (See "Acute simple cystitis in women" and "Acute simple cystitis in men".)

We do not automatically consider patients with underlying urologic abnormalities (such as nephrolithiasis, strictures, stents, or urinary diversions), immunocompromising conditions (such as neutropenia or advanced HIV infection), or poorly controlled diabetes mellitus to have a complicated UTI if they have no concerning symptoms for upper tract or systemic infection. However, such patients can be at higher risk for more serious infection and have not traditionally been included in studies evaluating the antibiotic regimens we typically use for acute simple cystitis. Thus, we follow such patients more closely and/or have a low threshold to manage them as complicated UTI (eg, if they have subtle signs or symptoms that could be suggestive of more extensive infection). Many patients with significant urologic abnormalities come to clinical attention for UTI because of signs or symptoms consistent with complicated UTI as defined here (rather than features of simple cystitis alone).

We also do not automatically consider men to have acute complicated UTI in the absence of concerning symptoms for upper tract or systemic infection. However, the possibility of prostatic involvement should always be considered in men, and this is incorporated into our approach to men with apparent simple cystitis. (See "Acute simple cystitis in men".)

Certain populations, such as pregnant women and renal transplant recipients, have unique management considerations and thus are not included in the above categorization. These populations are discussed elsewhere. (See "Urinary tract infections and asymptomatic bacteriuria in pregnancy" and "Kidney transplantation in adults: Urinary tract infection in kidney transplant recipients".)

These definitions of acute simple cystitis and complicated UTI are different from other categorizations, which themselves are somewhat variable. Specifically, cystitis or pyelonephritis in a nonpregnant premenopausal woman without underlying urologic abnormalities has traditionally been termed acute uncomplicated UTI [1], and complicated UTI has been defined, for the purposes of treatment trials, as cystitis or pyelonephritis in a patient with underlying urologic abnormalities. Individuals who do not fit into either category have often been treated as having a complicated UTI by default. We favor an approach to treatment based on the extent of infection and severity of illness. Since complicated UTI, as defined here, is a more serious infection than simple cystitis, the efficacy of an antimicrobial agent is of greater importance, and certain agents used for simple cystitis should not be used for complicated UTI because they do not achieve adequate levels in tissue, which may be important for cure. Risk for infection with drug-resistant organisms is a consideration in antibiotic selection for both simple cystitis and acute complicated UTI.

MICROBIOLOGY — Escherichia coli is the most frequent cause of acute complicated urinary tract infections (UTIs). Other uropathogens include other Enterobacteriaceae (such as Klebsiella spp and Proteus spp), Pseudomonas, enterococci, and staphylococci (methicillin-sensitive Staphylococcus aureus [MSSA] and methicillin-resistant S. aureus [MRSA]) [2,3]. The prevalence of particular pathogens depends partially on the host. As examples, Pseudomonas is more common in patients with health care exposures or instrumentation. Staphylococcus saprophyticus is an occasional cause of pyelonephritis in young, otherwise healthy women. UTI due to Candida spp is discussed in detail elsewhere. (See "Candida infections of the bladder and kidneys".)

Risk factors for UTI with resistant organisms include recent broad-spectrum antimicrobial use, health care exposures, and travel to parts of the world where multidrug-resistant organisms are prevalent [4-8] (table 2).

Increasing rates of resistance in uropathogens have been reported globally. As an example, in the United States, one study documented a threefold increase in the prevalence of extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae among hospitalized patients with UTIs from 2000 to 2009 [9]. In another study of patients with pyelonephritis presenting to emergency departments across the United States, approximately 6 percent of the 453 E. coli isolates produced ESBL, although rates varied by region and complicating features [10]. In particular, a specific strain of E. coli, sequence type 131 (ST131), has emerged globally as a major cause of fluoroquinolone-resistant and ESBL-producing E. coli urinary tract infections [11]. In one study of E. coli clinical isolates from extraintestinal sites, predominantly urine, collected at Veterans Affairs (VA) laboratories across the United States, the ST131 clone accounted for the majority of fluoroquinolone-resistant and ESBL isolates and was calculated to account for 28 percent of all VA E. coli isolates nationwide [12]. Carbapenem resistance among Enterobacteriaceae has also increased. (See "Extended-spectrum beta-lactamases", section on 'Epidemiology' and "Overview of carbapenemase-producing gram-negative bacilli", section on 'Epidemiology'.)

CLINICAL MANIFESTATIONS

Typical presentation — The clinical spectrum of acute complicated urinary tract infection (UTI) encompasses both cystitis with complicating features and pyelonephritis:

Symptoms and signs of cystitis include dysuria, urinary frequency and urgency, suprapubic pain, and hematuria. Patients with acute complicated UTI also have fever or other features of systemic illness (including chills, rigors, or marked fatigue or malaise beyond baseline), which suggest that infection has extended beyond the bladder.

Symptoms and signs of pyelonephritis classically include fever, chills, flank pain, costovertebral angle tenderness, and nausea/vomiting [13]. Symptoms of cystitis are often but not universally present. Atypical symptoms have also been described, with some patients complaining of pain in the epigastrium or lower abdomen.

For men, the clinical spectrum of UTI includes prostatitis, which should be considered in men presenting with cystitis symptoms that are recurrent or are accompanied by pelvic or perineal pain. (See "Acute bacterial prostatitis" and "Chronic bacterial prostatitis".)

Not all patients with acute complicated UTI present with clear symptoms localizing to the urinary tract. As an example, patients with spinal cord injury and neurogenic bladder can present with autonomic dysreflexia and increased spasticity. Elderly or debilitated patients may present with more generalized signs or symptoms of infection (eg, fever and chills) without clear symptoms localizing to the urinary tract.

Pyuria is present in almost all patients with UTI.

Complications — Patients with acute complicated UTI can also present with bacteremia, sepsis, multiple organ system dysfunction, shock, and/or acute renal failure. This is more likely to occur in patients with urinary tract obstruction, recent urinary tract instrumentation, or other urinary tract abnormalities, and in patients who are elderly or have diabetes mellitus.

Acute pyelonephritis can also be complicated by progression of the upper urinary tract infection to renal corticomedullary abscess, perinephric abscess, emphysematous pyelonephritis, or papillary necrosis. Risk factors for such complications include urinary tract obstruction and diabetes mellitus (particularly for emphysematous pyelonephritis and papillary necrosis). (See "Renal and perinephric abscess" and "Emphysematous urinary tract infections".)

Xanthogranulomatous pyelonephritis is a rare variant of pyelonephritis in which there is massive destruction of the kidney by granulomatous tissue. Most cases occur in the setting of obstruction due to infected renal stones. Affected patients can present with weeks to months of insidious and nonspecific signs and symptoms, such as malaise, fatigue, nausea, or abdominal pain. This condition is discussed in detail elsewhere. (See "Xanthogranulomatous pyelonephritis".)

DIAGNOSTIC APPROACH

Evaluation — Acute complicated urinary tract infection (UTI) should be suspected in patients with dysuria, urinary frequency or urgency, or suprapubic pain who also have fever, chills, flank pain, pelvic or perineal pain (in men), or who otherwise appear clinically ill. Acute pyelonephritis, specifically, should be suspected in patients presenting with fever and flank pain, even in the absence of typical symptoms of cystitis. Acute complicated UTI is also often suspected in patients with nonlocalizing fever or sepsis. Evaluation includes examination to assess for other causes of illness and urine studies.

Physical exam should assess for costovertebral angle, abdominal, and suprapubic tenderness. Among sexually active young women, a pelvic examination may be warranted, particularly if symptoms are not convincing for a UTI, to evaluate for cervical motion or uterine tenderness, which would be suggestive of pelvic inflammatory disease (see "Pelvic inflammatory disease: Clinical manifestations and diagnosis", section on 'Evaluation'). Among men with symptoms of pelvic or perineal pain, cautious digital rectal examination may be warranted to evaluate for a tender or edematous prostate that would suggest acute prostatitis. (See "Acute bacterial prostatitis".)

UTI is often suspected in elderly or debilitated patients who have nonspecific signs or symptoms, such as falls, change in functional status, and change in mental status. However, growing evidence indicates these are not reliable predictors of bacteriuria or UTI [14,15] and suggests that treatment for UTI in this setting is not associated with improved outcomes [16-18]. When these nonspecific signs or symptoms are accompanied by signs or symptoms of systemic infection or pyelonephritis, evaluation for acute complicated UTI with urine studies, in addition to a general infectious workup, is appropriate. (See "Diagnosis of delirium and confusional states", section on 'Diagnostic tests'.)

For all patients with suspected acute complicated UTI, we send urine for both urinalysis (either by microscopy or by dipstick) and culture with susceptibility testing. Urinalysis results inform the diagnosis. Since pyuria is present in almost all patients with UTI; its absence suggests an alternative diagnosis, particularly in patients who present with nonspecific symptoms. White cell casts, in particular, suggest a renal origin for pyuria. However, pyuria and bacteriuria may occasionally be absent if the infection does not communicate with the collecting system or if the collecting system is obstructed. Growth of bacteria on urine culture also supports the diagnosis of UTI, and susceptibility testing is essential to ensuring appropriate antimicrobial treatment. If available, urine Gram stain can also be helpful to narrow down the list of potential causative organisms and inform empiric antimicrobial selection. (See 'Management' below.)

Issues related to urine collection and testing as well as interpretation of urine culture colony counts are found elsewhere. (See "Sampling and evaluation of voided urine in the diagnosis of urinary tract infection in adults".)

Pregnancy testing is appropriate in women of childbearing potential when the possibility of pregnancy cannot be reasonably excluded by history alone. Blood tests, such as general chemistry and complete blood counts, are not generally necessary unless the patient is hospitalized. Blood cultures are warranted for those who present with sepsis or severe illness.

Imaging — Most patients with acute complicated UTI do not warrant imaging studies for diagnosis or management. Imaging is generally reserved for those who are severely ill, have persistent clinical symptoms despite 48 to 72 hours of appropriate antimicrobial therapy, or have suspected urinary tract obstruction (eg, if the renal function has declined below baseline or if there is a precipitous decline in the urinary output). Imaging is also appropriate in patients who have recurrent symptoms within a few weeks of treatment [19].

The main objective of imaging is to evaluate for a process that may delay response to therapy or warrant intervention, such as a calculus or obstruction, or to diagnose a complication of infection, such as a renal or perinephric abscess [19]. Imaging should be obtained urgently in patients with sepsis or septic shock to identify any evidence of obstruction or abscess that requires urgent source control.

Computed tomography (CT) scanning of the abdomen and pelvis (with and without contrast) is generally the study of choice to detect anatomic or physiologic factors associated with acute complicated UTI; it is more sensitive than excretory urography or renal ultrasound for detecting renal abnormalities predisposing to or caused by infection and in delineating the extent of the disease [20,21]. CT without contrast has become the standard radiographic study for demonstrating calculi, gas-forming infections, hemorrhage, obstruction, and abscesses [21]. Contrast is needed to demonstrate alterations in renal perfusion. CT findings of pyelonephritis include localized hypodense lesions due to ischemia induced by marked neutrophilic infiltration and edema (image 1A-C) [20,22]. The CT can be normal in patients with mild infection [23].

Renal ultrasound is appropriate in patients for whom exposure to contrast or radiation is undesirable [24]. Magnetic resonance imaging (MRI) is not advantageous over CT except when avoidance of contrast dye or ionizing radiation is warranted [25]. (See "Contrast-associated and contrast-induced acute kidney injury: Clinical features, diagnosis, and management" and "Prevention of contrast-induced acute kidney injury associated with angiography".)

Resolution of radiographic hypodensities may lag behind clinical improvement by up to three months [20,22,26].

Diagnosis — The diagnosis of acute complicated UTI is made in the following clinical scenarios:

Symptoms of cystitis (dysuria, urinary urgency, and/or urinary frequency) along with fever (>99.9ºF/37.7ºC) or other signs or symptoms of systemic illness, such as chills, rigors, or acute mental status changes. In such cases, pyuria and bacteriuria support the diagnosis.

Flank pain and/or costovertebral angle tenderness in the setting of pyuria and bacteriuria. This is suggestive of pyelonephritis. Fever and typical symptoms of cystitis are usually present, but their absence does not rule out the diagnosis. CT findings that support the diagnosis include low attenuation extending to the renal capsule on contrast enhancement with or without swelling and complications such as renal abscesses. However, a normal CT does not rule out the possibility of mild pyelonephritis.

Fever or sepsis without localizing symptoms in the setting of pyuria and bacteriuria may be attributed to UTI if other causes have been ruled out. Careful clinical assessment is necessary. The diagnosis of acute complicated UTI is unlikely if pyuria is absent.

The presence of bacteriuria (≥105 colony-forming units/mL of a uropathogen) with or without pyuria in the absence of any symptom that could be attributable to a UTI is called asymptomatic bacteriuria and generally does not warrant treatment in nonpregnant patients who are not undergoing urologic surgery. (See "Asymptomatic bacteriuria in adults".)

The diagnosis of UTI in a patient with an indwelling urinary catheter is discussed in further detail elsewhere. (See "Catheter-associated urinary tract infection in adults", section on 'Diagnosis'.)

The diagnosis of bacterial prostatitis in men, which can present with similar symptoms as complicated UTI, is discussed separately. (See "Acute bacterial prostatitis", section on 'Diagnosis' and "Chronic bacterial prostatitis", section on 'Diagnosis'.)

MANAGEMENT — Empiric antimicrobial therapy should be initiated promptly, taking into account risk factors for drug resistance, including previous antimicrobial use and results of recent urine cultures, with subsequent adjustment guided by antimicrobial susceptibility data. Urology should be consulted to address anatomic abnormalities if these are suspected or identified on imaging. (Related Pathway(s): Urinary tract infection (UTI): Empiric antibiotic selection for acute complicated UTI in adults.)

Approach to management of patients diagnosed with Candida urinary tract infections (UTIs) is discussed elsewhere. (See "Candida infections of the bladder and kidneys", section on 'Treatment'.)

Indications for hospitalization — The decision to admit patients with acute complicated UTI should be individualized. The decision to admit is usually clear when patients are septic or otherwise critically ill. Otherwise, general indications for inpatient management include persistently high fever (eg, >38.4°C/>101°F) or pain, marked debility, or inability to maintain oral hydration or take oral medications. Additionally, inpatient management is warranted when urinary tract obstruction is suspected or there are concerns regarding patient adherence.

Outpatient management is acceptable for patients with acute complicated UTI of mild to moderate severity who can be stabilized, if necessary, with rehydration and antimicrobials in an outpatient facility or the emergency department and discharged on oral antimicrobials with close follow-up.

Many patients can be managed in the outpatient setting. As an example, in a study of 44 patients with pyelonephritis but no major comorbidities, a 12-hour observation period with parenteral antimicrobial therapy in the emergency department followed by completion of outpatient oral antimicrobials was effective management for 97 percent of patients [27].

Empiric antimicrobial therapy — The approach to empiric therapy of acute complicated UTI depends on the severity of illness, the risk factors for resistant pathogens, and specific host factors [1]. The choice among the options presented for each population depends on susceptibility of prior urinary isolates, patient circumstances (such as allergy or expected tolerability, history of prior antimicrobial use), local community resistance prevalence of Enterobacteriaceae (if known), and drug toxicity, interactions, availability, and cost (table 3 and algorithm 1 and algorithm 2). (Related Pathway(s): Urinary tract infection (UTI): Empiric antibiotic selection for acute complicated UTI in adults.)

Urine culture and susceptibility testing should be performed in all patients, and the initial empiric regimen should be tailored appropriately to the susceptibility profile of the infecting pathogen, once known [1]. (See 'Directed antimicrobial therapy and duration' below.)

Data evaluating the efficacy of various regimens for acute complicated UTI are limited, and only a small number of different regimens have been formally evaluated [28,29]. The recommendations in this section are based instead on the expected microbial spectrum of antimicrobial agents that achieve adequate urinary tract and systemic levels.

Critical illness and/or urinary tract obstruction — We use a broad-spectrum antimicrobial regimen for empiric therapy of patients with acute complicated UTI who are critically ill (ie, with severe sepsis or otherwise warranting intensive care unit admission), getting worse on current therapy, or who have suspected urinary tract obstruction (eg, if the renal function has declined below baseline or if there is a decline in urine output) (table 3 and algorithm 1).

In such patients, we suggest an antipseudomonal carbapenem (imipenem 500 mg intravenously [IV] every six hours, meropenem 1 g IV every eight hours, or doripenem 500 mg IV every eight hours) to cover extended-spectrum beta-lactamase (ESBL)-producing organisms and Pseudomonas aeruginosa, as well as vancomycin to cover methicillin-resistant Staphylococcus aureus (MRSA). Daptomycin and linezolid are alternatives to vancomycin.

The rationale for such broad coverage in these patients is the high risk of adverse outcomes should empiric antimicrobial therapy be insufficient and the increasing prevalence of multidrug-resistant organisms, even in the general population (see 'Microbiology' above). Patients who have a UTI in the setting of urinary tract obstruction are at a particularly high risk of clinical decompensation.

Ultimately, however, the selection of antimicrobial therapy should be individualized. In locations where the community prevalence of multidrug-resistant organisms is low, regimens with a narrower spectrum may be appropriate. Such regimens are presented elsewhere. (See 'Other hospitalized patients' below.)

Advanced cephalosporin or carbapenem combinations with beta-lactamase inhibitors, the novel cephalosporin cefiderocol, the advanced aminoglycoside plazomicin, and parenteral fosfomycin also have activity against some ESBL-producing Enterobacteriaceae and, in some cases, multidrug-resistant P. aeruginosa isolates and are effective for acute complicated UTI [30-34]; however, because of cost and antimicrobial stewardship concerns, they should only be used in select cases of highly resistant infections. If carbapenem resistance is suspected based on prior susceptibility testing results, an infectious diseases consult should be obtained. (See "Overview of carbapenemase-producing gram-negative bacilli", section on 'Treatment'.)

Patients with critical illness or obstruction also warrant imaging to evaluate for obstruction or other complications that may warrant intervention. (See 'Imaging' above.)

Results of urine culture and susceptibility testing should be followed to ensure that the chosen empiric antimicrobial regimen is appropriate and to guide selection of definitive therapy. If feasible, antibiotics with a narrow spectrum of activity should be chosen to complete the antibiotic course. (See 'Directed antimicrobial therapy and duration' below.)

Other hospitalized patients — For patients who are hospitalized for acute complicated UTI (see 'Indications for hospitalization' above) but are not critically ill and do not have suspected urinary tract obstruction, our approach to empiric antimicrobial regimen selection depends on the risk for infection with multidrug-resistant gram-negative organisms (table 3 and algorithm 1).

No risk factors for infection with a multidrug-resistant gram-negative organism (table 2) – For these patients, we favor ceftriaxone (1 g IV once daily) or piperacillin-tazobactam (3.375 g IV every six hours) for parenteral treatment because of their safety profile and narrow spectrum compared with other parenteral agents. Oral or parenteral fluoroquinolones (ciprofloxacin or levofloxacin) are also reasonable alternatives if the patient has not had a urinary isolate resistant to fluoroquinolones in the prior three months and the community prevalence of E. coli fluoroquinolone resistance is not known to be higher than 10 percent.

Concern for particular pathogens should further inform the choice between these options. If Enterococcus or Staphylococcus species are suspected (eg, because of prior urinary isolates or gram-positive cocci on a current urine Gram stain), piperacillin-tazobactam is preferred because it has activity against these organisms (if the patient cannot use piperacillin-tazobactam because of allergies or otherwise, vancomycin plus one of the other gram-negative agents can be used). If drug-resistant gram-positive organisms are suspected because of previous urinary isolates or other risk factors, vancomycin (for MRSA) or linezolid or daptomycin (for vancomycin-resistant Enterococcus [VRE]) should be added. If there is a risk of P. aeruginosa (eg, because of prior urinary isolates or febrile neutropenia), piperacillin-tazobactam or a fluoroquinolone should be chosen. Other antipseudomonal agents that can be used include cefepime (2 g IV every 12 hours) and ceftazidime (2 g IV every eight hours).

At least one risk factor for infection with a multidrug-resistant gram-negative organism (table 2) – For these patients, we favor empiric treatment with piperacillin-tazobactam 3.375 mg IV every six hours or an antipseudomonal carbapenem (imipenem 500 mg IV every six hours, meropenem 1 g IV every eight hours, or doripenem 500 mg IV every eight hours).

Concern for particular pathogens should further inform regimen selection. For patients who have a recent (eg, within the prior three months) history of infection with ESBL-producing organisms, we typically choose a carbapenem. If Enterococcus species or MRSA are suspected (eg, because of prior urinary isolates or gram-positive cocci on a current urine Gram stain), we add vancomycin (for MRSA) or daptomycin or linezolid (for vancomycin-resistant Enterococcus [VRE]).

If available (not in the United States), parenteral fosfomycin is also effective for complicated UTI and has activity against certain MDR organisms, such as ESBL-producing organisms [34]; we would reserve this agent as an alternative to carbapenems as more widespread use could promote resistance, decreasing the utility of oral fosfomycin. Advanced cephalosporin or carbapenem combinations with beta-lactamase inhibitors, the novel cephalosporin cefiderocol, and the advanced aminoglycoside plazomicin also have activity against some ESBL-producing Enterobacteriaceae and, in some cases, multidrug-resistant P. aeruginosa isolates and are effective for acute complicated UTI [30-33]; however, because of cost and antimicrobial stewardship concerns, they should only be used in select cases of highly resistant infections. If carbapenem resistance is suspected based on prior susceptibility testing results, an infectious diseases consult should be obtained. (See "Overview of carbapenemase-producing gram-negative bacilli", section on 'Treatment'.)

Results of urine culture and susceptibility testing should be followed to ensure that the chosen empiric antimicrobial regimen is appropriate and to guide selection of definitive therapy. If feasible, antibiotics with a narrow spectrum of activity should be chosen to complete the antibiotic course. (See 'Directed antimicrobial therapy and duration' below.)

Outpatients — Patients with acute complicated UTI of mild to moderate severity who can take oral medications reliably can be treated in the outpatient setting. The approach to selection of an empiric outpatient antimicrobial regimen depends on the risk factors for infection with a multidrug-resistant organism (in particular ESBL-producing isolates) (table 3 and algorithm 2). Recommended regimens are outlined below. (See 'Low risk of MDR infection' below and 'High risk of MDR infection' below.)

Whether fluoroquinolones can be used (accounting for contraindications or concerns for fluoroquinolone resistance specifically) is also an important consideration in regimen selection. In the absence of resistance, fluoroquinolones provide a broad spectrum of antimicrobial activity against most uropathogens (including P. aeruginosa), and achieve high levels in the urinary tract. Studies of acute complicated UTI have shown that the fluoroquinolones are generally comparable or superior to other broad-spectrum antimicrobials, including parenteral regimens [28,35]. However, increasing rates of resistance to fluoroquinolones among uropathogens, even among outpatients, are diminishing their value for this purpose [36]. (See "Acute simple cystitis in women", section on 'Resistance trends in E. coli'.)

When a fluoroquinolone can be used, ciprofloxacin or levofloxacin are the most common agents. Other less commonly used fluoroquinolones that are effective for UTIs include ofloxacin and norfloxacin. Moxifloxacin attains lower urinary levels than other fluoroquinolones and should not be used.

Although there are concerns about the potential adverse effects, including Clostridioides difficile infection and ecological effects (ie, selection of resistant organisms) caused by the fluoroquinolones, their benefits are thought to outweigh their risks for acute complicated UTI.

Low risk of MDR infection — For outpatients with acute complicated UTI and no risk factors for infection with a multidrug-resistant (MDR) gram-negative organism (table 2), empiric antimicrobial regimen selection depends on contraindications to or other concerns with fluoroquinolones (table 3 and algorithm 2). These include allergy or intolerance to the fluoroquinolone class (including prolonged QT interval or other risk factors for torsades de pointes) or an unmodifiable drug interaction.

Fluoroquinolone-based regimens – For patients who have no contraindications to fluoroquinolone and are at low personal risk for a fluoroquinolone-resistant isolate (table 2), we suggest an oral fluoroquinolone for empiric therapy. Appropriate regimens include ciprofloxacin 500 mg twice daily, ciprofloxacin 1000 mg extended release once daily, or levofloxacin 750 mg once daily [37-41]. Fluoroquinolones are given for five to seven days.

In the case that community prevalence of E. coli fluoroquinolone resistance is known to be higher than 10 percent, we suggest a single dose of a long-acting parenteral agent prior to administering the fluoroquinolone [42]. We prefer ceftriaxone (1 g IV or intramuscular [IM] once) because of its safety, efficacy, and microbial spectrum. Ertapenem (1 g IV or IM once) is an alternative for patients with an allergy that precludes ceftriaxone use or expected resistance to ceftriaxone, and aminoglycosides (gentamicin or tobramycin 5 mg per kg IV or IM once) are reserved for patients who cannot use the other two. Since timely use of an agent with in vitro activity is essential to treat acute complicated UTI and minimize progression of infection, the threshold for selecting an antimicrobial for empiric broad-spectrum therapy should be set at a relatively low resistance prevalence. For fluoroquinolones, a resistance prevalence of 10 percent has been suggested based on expert opinion [1].

The benefits of fluoroquinolones are thought to outweigh their risks for acute complicated UTI, but patients should be advised about the uncommon but potentially serious musculoskeletal and neurologic adverse effects associated with fluoroquinolones. (See "Fluoroquinolones", section on 'Adverse effects'.)

Fluoroquinolone-sparing regimens – For patients who have contraindications to fluoroquinolones or other concerns about fluoroquinolone use, our approach depends on the relative severity of illness. For those with mild infection, we use a single dose of a long-acting parenteral agent followed by a non-fluoroquinolone oral agent [42].

As above, we prefer ceftriaxone (1 g IV or IM once) as a long-acting parenteral agent because of its safety, efficacy, and microbial spectrum. Ertapenem (1 g IV or IM once) is an alternative for patients with an allergy that precludes ceftriaxone use or expected resistance to ceftriaxone, and aminoglycosides (gentamicin or tobramycin 5 mg per kg IV or IM once) are reserved for patients who cannot use the other two.

Following the dose of the parenteral agent, options include the following:

Trimethoprim-sulfamethoxazole – one double-strength (160 mg/800 mg) tablet orally twice daily for 7 to 10 days

Amoxicillin-clavulanate – 875 mg orally twice daily for 10 to 14 days

Cefpodoxime – 200 mg orally twice daily for 10 to 14 days

Cefdinir – 300 mg orally twice daily for 10 to 14 days

Cefadroxil – 1 g orally twice daily for 10 to 14 days

For outpatients who are systemically ill or are at risk for more severe illness, we favor continuing the parenteral therapy until culture and susceptibility testing results can guide selection of an appropriate oral agent.

Results of urine culture and susceptibility testing should be followed to ensure that the chosen empiric antimicrobial regimen is appropriate and to guide modification of the regimen, if necessary. (See 'Directed antimicrobial therapy and duration' below.)

High risk of MDR infection — For outpatients with acute complicated UTI and risk factors for infection with a multidrug-resistant (MDR) gram-negative organism (table 2), we suggest giving an initial dose of ertapenem 1 g IV or IM (table 3 and algorithm 2). Plazomicin is a potential alternative in this setting; clinical experience with this agent is limited.

For patients who have no contraindications to fluoroquinolones (ie, allergy or expected intolerability, including risk factors for torsades de pointes, or unmodifiable drug interaction) and have not had fluoroquinolone use or a fluoroquinolone-resistant urinary isolate in the prior three months, we follow this dose of ertapenem with a fluoroquinolone. Appropriate regimens include ciprofloxacin 500 mg twice daily, ciprofloxacin 1000 mg extended release once daily, and levofloxacin 750 mg once daily [37-41]. Fluoroquinolones are given for five to seven days. The benefits of fluoroquinolones for acute complicated UTI are thought to outweigh their risks, but patients should be advised about the uncommon but potentially serious musculoskeletal and neurologic adverse effects associated with fluoroquinolones. (See "Fluoroquinolones", section on 'Adverse effects'.)

For patients who have either contraindications or concern for fluoroquinolone resistance, we instead continue to administer ertapenem 1 g IV or IM daily in the outpatient setting until culture and susceptibility testing results return. As above, once-daily plazomicin is a potential alternative; dosing and toxicity monitoring are discussed elsewhere. (See "Dosing and administration of parenteral aminoglycosides", section on 'Plazomicin'.)

Once available, culture and susceptibility testing results should guide selection of definitive therapy. (See 'Directed antimicrobial therapy and duration' below.)

Directed antimicrobial therapy and duration — Results of urine culture and susceptibility testing should be used to confirm that the chosen empiric regimen is active and to tailor the regimen, if appropriate. In many cases, broad-spectrum empiric regimens can be replaced by a more narrow-spectrum agent.

Patients who were initially treated with a parenteral regimen can be switched to an oral agent once symptoms have improved, as long as culture and susceptibility testing allow. Appropriate oral agents to treat acute complicated UTI include levofloxacin (750 mg once daily), ciprofloxacin (500 mg twice daily or 1000 extended release once daily), and trimethoprim-sulfamethoxazole (one double-strength [160 mg/800 mg] tablet orally twice daily) [37-39]. Oral beta-lactams are less effective for acute complicated UTI but are appropriate alternatives if susceptibility is documented and the other agents are not feasible. If Enterococcus is isolated, amoxicillin (500 mg orally every eight hours or 875 mg twice daily) is the agent of choice if the organism is susceptible [43,44]. Use of nitrofurantoin, fosfomycin, and pivmecillinam should generally be avoided in the setting of acute complicated UTI because they do not achieve adequate tissue levels outside the bladder [1].

Occasionally, susceptibility results preclude the use of an oral regimen and a parenteral agent is needed to complete the course of treatment. Options for outpatient administration of parenteral antimicrobials include use of a peripherally inserted central catheter, a preexisting central catheter, or IM injection.

Total duration of antimicrobial therapy generally ranges from 5 to 14 days, depending on the rapidity of clinical response and the antimicrobial chosen to complete the course. Fluoroquinolones are given for 5 to 7 days, trimethoprim-sulfamethoxazole for 7 to 10 days [45], and beta-lactams for 10 to 14 days. Longer durations may be warranted in patients who have a nidus of infection (such as a nonobstructing stone) that cannot be removed. The duration of antimicrobial therapy need not be extended in the setting of bacteremia in the absence of other complicating factors; there is no evidence that bacteremia portends a worse prognosis [46].

Several trials have indicated that five- or seven-day regimens of fluoroquinolones are comparable to longer durations [38,47]. There are limited data evaluating the use of other oral agents for acute complicated UTI [45,48,49].

Addressing underlying urinary tract abnormalities — In addition to antimicrobial therapy, the possibility of urinary obstruction should be considered and managed, if identified. Patients who have underlying anatomical or functional urinary tract abnormalities (including neurogenic bladder, indwelling bladder catheters, nephrostomy tubes, urethral stents) may warrant additional management, such as more frequent catheterization to improve urinary flow, exchange or removal of a catheter, and/or urologic or gynecologic consultation. Antimicrobials alone may not be successful unless such underlying conditions are corrected [50]. (See "Catheter-associated urinary tract infection in adults", section on 'Catheter management'.)

Follow-up — Symptoms should improve promptly if antimicrobial therapy is effective. Among patients treated as outpatients, those who had pyelonephritis should have close follow-up either face-to-face or by telephone within 48 to 72 hours.

Any patients who have worsening symptoms following initiation of antimicrobials, persistent symptoms after 48 to 72 hours of appropriate antimicrobial therapy, or recurrent symptoms within a few weeks of treatment should have additional evaluation, including abdominal/pelvic imaging (generally with computed tomography if not already performed) for factors that might be compromising clinical response. Urine culture and susceptibility testing should be repeated, and treatment should be tailored to the susceptibility profile of other causative organisms isolated.

For patients who had hematuria on initial presentation, a urinalysis should be repeated several weeks following antimicrobial therapy to evaluate for persistent hematuria. (See "Etiology and evaluation of hematuria in adults", section on 'Overall approach to the evaluation'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Urinary tract infections in adults".)

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Beyond the Basics topics (see "Patient education: Urinary tract infections in adolescents and adults (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

We use the term acute complicated urinary tract infection (UTI) to refer to an acute UTI with any features that suggest that the infection extends beyond the bladder (table 1). These include fever (eg, >99.9°F/37.7°C), other signs or symptoms of systemic illness (including chills, rigors, or altered mental status), flank pain, and costovertebral angle tenderness. By this definition, pyelonephritis is a complicated UTI, regardless of patient characteristics. This definition is distinct from traditional categorizations of UTI and is more focused on the clinical presentation and severity of illness. (See 'Terminology' above.)

Relevant uropathogens include primarily Escherichia coli, but also other Enterobacteriaceae, other gram-negative bacilli (including Pseudomonas aeruginosa), staphylococci, enterococci, and Candida species. Risk factors for resistant organisms include recent broad-spectrum antimicrobial use, health care exposures, and travel to parts of the world where multidrug-resistant organisms are prevalent (table 2). (See 'Microbiology' above.)

Acute complicated UTI should be suspected in patients with dysuria, urinary frequency or urgency, or suprapubic pain who also have fever, chills, flank pain, or otherwise appear clinically ill. Acute pyelonephritis, specifically, should be suspected in patients presenting with fever and flank pain, even in the absence of typical symptoms of cystitis. In men, pelvic or perineal pain accompanying urinary symptoms suggests prostatitis. UTI is also often suspected in patients with pyuria and bacteriuria who have nonspecific signs of systemic illness, such as lethargy or delirium, or in patients with nonlocalizing fever or sepsis. (See 'Clinical manifestations' above and 'Evaluation' above.)

For patients with suspected acute complicated UTI, we send urine for both urinalysis (either by microscopy or by dipstick) and culture with susceptibility testing. Imaging is generally reserved for those who are severely ill, have suspected urinary tract obstruction, have persistent symptoms despite 48 to 72 hours of appropriate antimicrobial therapy, or have recurrent symptoms. (See 'Evaluation' above and 'Imaging' above.)

The diagnosis of acute complicated UTI is made in patients who have consistent clinical findings as well as pyuria and bacteriuria. UTI is unlikely if pyuria is absent. (See 'Diagnosis' above.)

Outpatient management is acceptable for patients with acute complicated UTI of mild to moderate severity who can be stabilized, if necessary, with rehydration and antimicrobials in an outpatient facility or the emergency department and discharged on oral antimicrobials with close follow-up. (See 'Indications for hospitalization' above.)

The approach to empiric therapy of acute complicated UTI depends on the severity of illness, the risk factors for resistant pathogens, and specific host factors (table 3 and algorithm 1 and algorithm 2). (See 'Empiric antimicrobial therapy' above.)

For patients who are critically ill or have urinary tract obstruction, we suggest an antipseudomonal carbapenem plus vancomycin (Grade 2C). (See 'Critical illness and/or urinary tract obstruction' above.)

For other hospitalized patients, we suggest ceftriaxone or piperacillin-tazobactam if there are no risk factors for a multidrug-resistant (MDR) gram-negative infection (table 2) (Grade 2C). Oral or parenteral fluoroquinolones are also reasonable options. For patients who have risk factors for an MDR gram-negative infection, we suggest piperacillin-tazobactam or an antipseudomonal carbapenem (Grade 2C). (See 'Other hospitalized patients' above.)

For outpatients without risk factors for an MDR gram-negative infection (table 2), we suggest an oral fluoroquinolone, such as levofloxacin or ciprofloxacin (Grade 2B). If the community prevalence of E. coli fluoroquinolone resistance is known to be higher than 10 percent, we also suggest a single dose of a long-acting parenteral agent prior to administering the fluoroquinolone (Grade 2C). (See 'Low risk of MDR infection' above.)

For outpatients with risk factors for an MDR gram-negative infection (table 2), we suggest an initial dose of ertapenem (Grade 2C). Subsequently, an oral fluoroquinolone or daily ertapenem can be used. (See 'High risk of MDR infection' above.)

Results of urine culture and susceptibility testing should be used to confirm that the chosen empiric regimen is active and to tailor the regimen, including switching a parenteral regimen to an oral agent once symptoms have improved. Appropriate oral agents to treat acute complicated UTI include fluoroquinolones (eg, levofloxacin or ciprofloxacin, given for 5 to 7 days) or trimethoprim-sulfamethoxazole (given for 7 to 10 days). Oral beta-lactams (given for 10 to 14 days) are less effective for acute complicated UTI but are appropriate alternatives if susceptibility is documented and the other agents are not feasible. (See 'Directed antimicrobial therapy and duration' above.)

Patients who have underlying anatomical or functional urinary tract abnormalities (including neurogenic bladder, indwelling bladder catheters, nephrostomy tubes, urethral stents) may warrant additional management, such as more frequent catheterization to improve urinary flow, exchange or removal of a catheter, and/or urologic or gynecologic consultation. (See 'Addressing underlying urinary tract abnormalities' above.)

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Topic 16109 Version 56.0

References

1 : International clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women: A 2010 update by the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases.

2 : Population-based epidemiologic analysis of acute pyelonephritis.

3 : A practical guide to antimicrobial management of complicated urinary tract infection.

4 : Urinary Tract Infections due to Multidrug-Resistant Enterobacteriaceae: Prevalence and Risk Factors in a Chicago Emergency Department.

5 : Risk factors for community-acquired ciprofloxacin-resistant Escherichia coli urinary tract infection.

6 : Clinical Management of an Increasing Threat: Outpatient Urinary Tract Infections Due to Multidrug-Resistant Uropathogens.

7 : Prevalence and risk factors for quinolone resistance among Escherichia coli strains isolated from males with community febrile urinary tract infection.

8 : Two Simple Rules for Improving the Accuracy of Empiric Treatment of Multidrug-Resistant Urinary Tract Infections.

9 : Secular trends in gram-negative resistance among urinary tract infection hospitalizations in the United States, 2000-2009.

10 : Fluoroquinolone-Resistant and Extended-Spectrumβ-Lactamase-Producing Escherichia coli Infections in Patients with Pyelonephritis, United States(1).

11 : Editorial commentary: flying under the radar: the stealth pandemic of Escherichia coli sequence type 131.

12 : Escherichia coli sequence type 131 (ST131) subclone H30 as an emergent multidrug-resistant pathogen among US veterans.

13 : Site of infection in acute urinary-tract infection in general practice.

14 : A double-blind comparative study of norfloxacin versus placebo in hospitalised elderly patients with asymptomatic bacteriuria.

15 : Treatment of asymptomatic UTI in older delirious medical in-patients: A prospective cohort study.

16 : Interleukin-6 concentrations in the urine and dipstick analyses were related to bacteriuria but not symptoms in the elderly: a cross sectional study of 421 nursing home residents.

17 : Urine culture doubtful in determining etiology of diffuse symptoms among elderly individuals: a cross-sectional study of 32 nursing homes.

18 : Risk Factors and Outcomes Associated With Treatment of Asymptomatic Bacteriuria in Hospitalized Patients.

19 : Risk Factors and Outcomes Associated With Treatment of Asymptomatic Bacteriuria in Hospitalized Patients.

20 : Frequency of development of early cortical scarring in acute primary pyelonephritis.

21 : Radiologic evaluation of patients with renal infections.

22 : Computerized tomography in acute pyelonephritis: the clinical correlations.

23 : Computerized tomography in acute pyelonephritis: the clinical correlations.

24 : Computerized tomography in acute pyelonephritis: the clinical correlations.

25 : State of the art: imaging of renal infections.

26 : Sequelae of acute renal infections: CT evaluation.

27 : Treatment of pyelonephritis in an observation unit.

28 : Systematic review and meta-analysis of antimicrobial treatment effect estimation in complicated urinary tract infection.

29 : Empiric therapy for hospital-acquired, Gram-negative complicated intra-abdominal infection and complicated urinary tract infections: a systematic literature review of current and emerging treatment options.

30 : Efficacy of ceftolozane/tazobactam against urinary tract and intra-abdominal infections caused by ESBL-producing Escherichia coli and Klebsiella pneumoniae: a pooled analysis of Phase 3 clinical trials.

31 : Ceftazidime-avibactam or best available therapy in patients with ceftazidime-resistant Enterobacteriaceae and Pseudomonas aeruginosa complicated urinary tract infections or complicated intra-abdominal infections (REPRISE): a randomised, pathogen-directed, phase 3 study.

32 : 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.

33 : Once-Daily Plazomicin for Complicated Urinary Tract Infections.

34 : Fosfomycin for Injection (ZTI-01) Versus Piperacillin-tazobactam for the Treatment of Complicated Urinary Tract Infection Including Acute Pyelonephritis: ZEUS, A Phase 2/3 Randomized Trial.

35 : Fluoroquinolone antimicrobial agents.

36 : In vitro antimicrobial resistance of urinary Escherichia coli isolates among U.S. outpatients from 2000 to 2010.

37 : Comparison of ciprofloxacin (7 days) and trimethoprim-sulfamethoxazole (14 days) for acute uncomplicated pyelonephritis pyelonephritis in women: a randomized trial.

38 : A double-blind, randomized comparison of levofloxacin 750 mg once-daily for five days with ciprofloxacin 400/500 mg twice-daily for 10 days for the treatment of complicated urinary tract infections and acute pyelonephritis.

39 : Once daily, extended release ciprofloxacin for complicated urinary tract infections and acute uncomplicated pyelonephritis.

40 : Ciprofloxacin for 7 days versus 14 days in women with acute pyelonephritis: a randomised, open-label and double-blind, placebo-controlled, non-inferiority trial.

41 : Trimethoprim and ciprofloxacin resistance and prescribing in urinary tract infection associated with Escherichia coli: a multilevel model.

42 : Short-term effectiveness of ceftriaxone single dose in the initial treatment of acute uncomplicated pyelonephritis in women. A randomised controlled trial.

43 : Ampicillin for the treatment of complicated urinary tract infections caused by vancomycin-resistant Enterococcus spp (VRE): a single-center university hospital experience.

44 : Outcomes of Aminopenicillin Therapy for Vancomycin-Resistant Enterococcal Urinary Tract Infections.

45 : Clinical practice. Uncomplicated urinary tract infection.

46 : Oral vs intravenous ciprofloxacin in the initial empirical management of severe pyelonephritis or complicated urinary tract infections: a prospective randomized clinical trial.

47 : Treatment duration of febrile urinary tract infection: a pragmatic randomized, double-blind, placebo-controlled non-inferiority trial in men and women.

48 : Guidelines for antimicrobial treatment of uncomplicated acute bacterial cystitis and acute pyelonephritis in women. Infectious Diseases Society of America (IDSA).

49 : Fewer bacterial relapses after oral treatment with norfloxacin than with ceftibuten in acute pyelonephritis initially treated with intravenous cefuroxime.

50 : A practical guide to the management of complicated urinary tract infection.