Version May 2024
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 adult and adolescent females".)
●(See "Acute simple cystitis in adult and adolescent males".)
●(See "Urinary tract infections and asymptomatic bacteriuria in pregnancy".)
●(See "Catheter-associated urinary tract infection in adults".)
●(See "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 children less than two years: 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 adult and adolescent females" and "Acute simple cystitis in adult and adolescent males".)
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 adult and adolescent males".)
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 "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 Enterobacterales (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 Enterobacterales 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 Enterobacterales has also increased. (See "Extended-spectrum beta-lactamases", section on 'Epidemiology' and "Carbapenem-resistant E. coli, K. pneumoniae, and other Enterobacterales (CRE)", section on 'Overall prevalence of CRE'.)
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. Older 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 older adults 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. Costovertebral angle tenderness is highly suggestive of pyelonephritis although can be seen less frequently with other kidney pathology. In a retrospective study of over 3000 individuals who presented to an emergency department and had imaging findings diagnostic of pyelonephritis, 89 percent had costovertebral angle tenderness compared with 27 percent of the 62 patients who were ultimately diagnosed with renal infarct [14].
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 older 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 [15,16] and suggests that treatment for UTI in this setting is not associated with improved outcomes [17-19]. 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. (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 or who have S. aureus isolated from the urine. (See 'Regimen selection' below.)
Imaging — Most patients with acute complicated UTI do not warrant imaging studies for diagnosis or management [20]. 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.
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. 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 [20-22]. CT without contrast has become the standard radiographic study for demonstrating calculi, gas-forming infections, hemorrhage, obstruction, and abscesses [22]. 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) [21,23]. The CT can be normal in patients with mild infection [24].
Renal ultrasound is appropriate in patients for whom exposure to contrast or radiation is undesirable [25]. Magnetic resonance imaging (MRI) is not advantageous over CT except when avoidance of contrast dye or ionizing radiation is warranted [26]. (See "Contrast-associated and contrast-induced acute kidney injury: Clinical features, diagnosis, and management" and "Prevention of contrast-associated acute kidney injury related to angiography".)
Resolution of radiographic hypodensities may lag behind clinical improvement by up to three months [21,23,27].
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 [28].
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 Enterobacterales (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' 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 [29,30]. 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 or meropenem 1 g 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. However, the selection of antimicrobial therapy should be individualized. In locations where the community prevalence of multidrug-resistant organisms (in particular, ESBL-producing organisms) is low, regimens with a narrower spectrum may be appropriate. In such cases, regimen selection can be based on individual risk of resistance, as discussed elsewhere. (See 'Other hospitalized patients' below.)
The rationale for broad coverage in the setting of critical illness or obstruction 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. When broad-spectrum regimens are used empirically, it is important to tailor the regimen if culture and susceptibility testing indicate that a narrower agent would be active. (See 'Directed antimicrobial therapy' 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 Enterobacterales and, in some cases, multidrug-resistant P. aeruginosa isolates and are effective for acute complicated UTI [31-35]; however, because of cost and antimicrobial stewardship concerns, as well as limited data for some of the agents, 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 "Carbapenem-resistant E. coli, K. pneumoniae, and other Enterobacterales (CRE)", section on 'Approach to 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' 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) for parenteral treatment because of its safety profile and narrow spectrum compared with other parenteral agents (table 3). 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 antibiotic selection. If Enterococcus species are suspected (eg, because of prior urinary isolates), piperacillin-tazobactam can be used because it has activity against these organisms in addition to typical gram-negative pathogens. 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 to the gram-negative agent (eg, ceftriaxone). If there is a risk of P. aeruginosa (eg, because of prior urinary isolates or febrile neutropenia), piperacillin-tazobactam, cefepime, or a fluoroquinolone are appropriate options.
●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 g IV every six hours, cefepime 2 g IV every 12 hours, or an antipseudomonal carbapenem (imipenem 500 mg IV every six hours or meropenem 1 g IV every eight hours) (table 3).
Concern for particular pathogens should further inform regimen selection. If patients have risk factors for an ESBL-producing organism, we avoid cefepime, and for those with recent (eg, within the prior three months) history of infection with ESBL-producing organisms, we specifically choose a carbapenem. If resistant Enterococcus species or MRSA are suspected (eg, because of prior urinary isolates), we add vancomycin (for MRSA) or daptomycin or linezolid (for vancomycin-resistant Enterococcus [VRE]). All the listed options have activity against P. aeruginosa; ceftazidime (2 g IV every eight hours) is another antipseudomonal agent.
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 [35]; we would reserve this agent as an alternative to carbapenems as more widespread use could promote resistance, decreasing the utility of oral fosfomycin. Additionally, it may not be tolerated as well as other agents [36].
Advanced cephalosporin or carbapenem combinations with beta-lactamase inhibitors and the novel cephalosporin cefiderocol also have activity against some ESBL-producing Enterobacterales and, in some cases, multidrug-resistant P. aeruginosa isolates and are effective for acute complicated UTI [31-34]; however, because of cost and antimicrobial stewardship concerns, they should only be used in select cases of highly resistant infections [37]. If carbapenem resistance (or otherwise extensive drug resistance) is suspected based on prior susceptibility testing results, an infectious diseases consult should be obtained. Treatment of carbapenem-resistant Enterobacterales and extensively drug-resistant Pseudomonas is discussed in detail elsewhere. (See "Carbapenem-resistant E. coli, K. pneumoniae, and other Enterobacterales (CRE)", section on 'Approach to treatment' and "Principles of antimicrobial therapy of Pseudomonas aeruginosa infections", section on 'Management of multidrug-resistant organisms'.)
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' 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 [29,38]. However, increasing rates of resistance to fluoroquinolones among uropathogens, even among outpatients, are diminishing their value for this purpose [39]. (See "Acute simple cystitis in adult and adolescent females", 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. Because of the prevalence of fluoroquinolone resistance and underlying comorbidities associated with adverse effects, fluoroquinolone-sparing regimens are often an appropriate option.
●Fluoroquinolone-based regimens – For patients who have no contraindications to fluoroquinolones 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 [40-44]. 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 [45]. 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]. However, in an outpatient who is not severely ill and has low personal risk of MDR, avoiding a fluoroquinolone altogether because of resistance concerns is not necessary.
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 [45].
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 7 to 10 days
•Cefpodoxime – 200 mg orally twice daily for 7 to 10 days
•Cefadroxil – 1 g orally twice daily for 7 to 10 days
The choice among those should be guided by the susceptibility of prior urinary isolates and resistance rates in the community. We do not typically use cefdinir for patients with complicated UTI because it has low bioavailability, achieves only 10 to 20 percent urinary concentration, and does not offer an advantage over cefpodoxime. However, if no other options are available, some data suggest that it achieves high clinical response rates as a step down option following parenteral ceftriaxone [46].
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. The durations of therapy listed above assume that the patient is appropriately responding to antibiotic therapy; longer durations or re-evaluation may be warranted in those who are slow to respond. These issues are discussed in detail elsewhere. (See 'Directed antimicrobial therapy' below.)
In some cases, results of urine culture and susceptibility testing may be known at the time of treatment initiation. For those with mild illness caused by a susceptible pathogen, oral therapy selected based on susceptibility testing without initial parenteral therapy is reasonable. Potential regimens are discussed elsewhere. (See 'Regimen selection' 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 [40-44]. 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' below.)
Directed antimicrobial therapy
Regimen selection — Results of urine culture and susceptibility testing should be used 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. Options depend on the pathogen identified:
●Enterobacterales (eg, E. coli, K. pneumoniae, P. mirabilis):
•Susceptible isolates – For susceptible Enterobacterales, 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) [40-42]. Oral beta-lactams (eg, amoxicillin-clavulanate 875 mg orally twice daily, cefpodoxime 200 mg orally twice daily, cefadroxil 1 g orally twice daily) may be less effective for acute complicated UTI (based on cystitis studies) but are appropriate alternatives if susceptibility is documented and the other agents are not feasible.
•Resistant isolates – Some isolates that are resistant to beta-lactams (eg, ESBL-producing Enterobacterales) may still be susceptible to fluoroquinolones and trimethoprim-sulfamethoxazole, in which case those agents can be used orally as above. However, for Enterobacterales that are resistant to fluoroquinolones, trimethoprim-sulfamethoxazole, and oral beta-lactams, a parenteral agent is generally needed to complete the course of treatment. We use the most narrow-spectrum agent that has expected activity. For ESBL-producing bacteria, this is usually a carbapenem (meropenem, imipenem, or ertapenem). The drawbacks to using piperacillin-tazobactam or cefepime for ESBL-producing bacteria are discussed elsewhere. Treatment of carbapenem-resistant gram-negative bacteria is also discussed elsewhere. (See "Extended-spectrum beta-lactamases", section on 'Treatment options' and "Carbapenem-resistant E. coli, K. pneumoniae, and other Enterobacterales (CRE)", section on 'Approach to treatment'.)
Options for outpatient administration of parenteral antimicrobials include use of a peripherally inserted central catheter, a pre-existing central catheter, or IM injection.
Nitrofurantoin, oral 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].
Novel options for outpatient management of resistant gram-negative bacteria are needed. In a randomized trial that included 868 adults hospitalized for complicated UTI, an experimental oral carbapenem, tebipenem, resulted in similar clinical cure rates as intravenous ertapenem, each given for 7 to 10 days (93 versus 94 percent at day 19) [47]. Microbiologic cure rates were lower with tebipenem for ESBL-producing organisms, but clinical response with these pathogens remained high. While a promising agent, the risk of selecting for carbapenem resistance is a concern and judicious use, if available in the future, will be important.
●Enterococcus – 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; other UpToDate contributors favor a higher dose of amoxicillin in this setting [48,49]. (See "Treatment of enterococcal infections", section on 'Urinary tract infection'.)
●Pseudomonas – Directed therapy of Pseudomonas UTI is discussed in detail elsewhere. (See "Pseudomonas aeruginosa infections of the eye, ear, urinary tract, gastrointestinal tract, and central nervous system", section on 'Treatment'.)
●Staphylococcus – Oral options include trimethoprim-sulfamethoxazole (one double-strength [160 mg/800 mg] tablet orally twice daily) or, for methicillin-susceptible Staphylococcus species, cefadroxil (500 mg twice daily). S. aureus is a relatively uncommon urinary isolate. When S. aureus is isolated from the urine in a patient with complicated UTI, blood cultures are warranted to rule out bacteremia; we typically obtain two sets of cultures. The urinary tract can be the original source of S. aureus bacteremia or a secondary site seeded from hematogenous spread. The reported rate of concurrent or subsequent bacteremia in patients with S. aureus bacteriuria varies between approximately 5 and 20 percent [50-52]. (See "Clinical manifestations of Staphylococcus aureus infection in adults", section on 'Bacteriuria'.)
Duration — Total duration of antimicrobial therapy generally ranges from 5 to 10 days, depending on the rapidity of clinical response and the antimicrobial chosen to complete the course. For individuals who have an appropriate clinical response (symptomatic improvement within the first 48 to 72 hours of therapy), we give fluoroquinolones for 5 to 7 days, trimethoprim-sulfamethoxazole for 7 to 10 days [53], and beta-lactams for 7 to 10 days. For those who have slow response to appropriate antibiotic therapy (eg, no symptomatic improvement within the first 48 to 72 hours of therapy), evaluation should assess for infectious complications or for underlying anatomic abnormalities that could delay response (see 'Imaging' above). Longer antibiotic 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 when other complicating factors are absent; there is no evidence that bacteremia portends a worse prognosis [54,55]. A potential exception is S. aureus bacteremia, which is discussed in detail elsewhere. (See "Clinical approach to Staphylococcus aureus bacteremia in adults", section on 'Clinical approach'.)
Several systematic reviews and meta-analyses of randomized trials have suggested that shorter antibiotic courses (seven days or fewer) for complicated UTI result in similar clinical cure rates compared with longer courses [56-58]. Most of these data come from randomized trials of fluoroquinolones, in which five- or seven-day regimens of fluoroquinolones were comparable to longer durations [41,43,59]. Although one randomized trial among males with complicated UTI suggested lower rates of microbiologic response with 7 versus 14 days of fluoroquinolone therapy, clinical response rates were similar [60]. Data are more limited for other antibiotic classes, and studies evaluating beta-lactams included older agents that are not commonly used for UTI. Nevertheless, those studies failed to identify a clear clinical benefit to treating longer than 10 days [55,57].
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 [61]. (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".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Beyond the Basics topics (see "Patient education: Urinary tract infections in adolescents and adults (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Terminology – 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. (See 'Terminology' above.)
We do not consider patients with underlying urologic abnormalities (eg, nephrolithiasis, strictures, stents, or urinary diversions), immunocompromising conditions (eg, neutropenia or advanced HIV), or poorly controlled diabetes mellitus to have complicated UTI if they have no concerning symptoms for upper tract or systemic infection.
●Microbiology – Relevant uropathogens include primarily Escherichia coli, but also other Enterobacterales, 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.)
●Clinical features – Patients with complicated UTI can have symptoms of cystitis (eg, dysuria, urinary frequency, urinary urgency, suprapubic pain) plus fever or other features of systemic illness (eg, chills, rigors, or new marked fatigue or malaise). Alternatively, they may have more prominent features of pyelonephritis, which classically include fever, chills, flank pain, costovertebral angle tenderness, and nausea/vomiting, with or without symptoms of cystitis. In males, pelvic or perineal pain accompanying urinary symptoms suggests prostatitis.
Acute complicated UTI can also present with bacteremia, sepsis, multiple organ system dysfunction, shock, and/or acute kidney failure. This is more likely to occur in patients with urinary tract obstruction, recent urinary tract instrumentation, or other urinary tract abnormalities, and in older adults or patients with diabetes mellitus.
On urine studies, pyuria and bacteriuria are almost always present. (See 'Clinical manifestations' above.)
●Evaluation and diagnosis – 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. The diagnosis is made in patients who have consistent clinical findings (eg, signs and symptoms of pyelonephritis or of cystitis with features of systemic infection) as well as pyuria and bacteriuria. Fever or sepsis without localizing symptoms in the setting of pyuria and bacteriuria can also be attributed to complicated UTI if other causes have been ruled out.
The absence of pyuria suggests an alternative diagnosis, particularly if symptoms are nonspecific (table 4). 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.)
●Indications for hospitalization – Indications for inpatient management include sepsis or critical illness, persistently high fever (eg, >38.4°C/>101°F) or pain, marked debility, suspected urinary tract obstruction (eg, due to nephrolithiasis), concern about medication adherence, and inability to maintain oral hydration or take oral medications.
Outpatient management is appropriate for others, including those who can be stabilized with initial treatment (eg, rehydration and antimicrobials) in an outpatient facility or the emergency department. (See 'Indications for hospitalization' above.)
●Empiric 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 (table 3 and algorithm 1 and algorithm 2). (See 'Empiric antimicrobial therapy' above.)
•Critical illness/urinary tract obstruction – For patients who are critically ill or have urinary tract obstruction, we suggest an antipseudomonal carbapenem (meropenem or imipenem) plus vancomycin (table 3 and algorithm 1) (Grade 2C). These patients are at high risk of adverse outcomes if empiric antimicrobial therapy is insufficient, and these regimens cover multidrug-resistant organisms, which are increasing in prevalence. In locations where the community prevalence of multidrug-resistant organisms is known to be low, regimens with a narrower spectrum (as suggested for other hospitalized patients) may be appropriate.
Urinary tract obstruction, if present, requires decompression. (See 'Critical illness and/or urinary tract obstruction' above.)
•Other hospitalized patients – For hospitalized patients without critical illness or urinary tract obstruction who have no risk factors for a multidrug-resistant (MDR) gram-negative infection (table 2), we suggest ceftriaxone (table 3 and algorithm 1)(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, cefepime, or an antipseudomonal carbapenem (Grade 2C). For those with a recent history of an extended-spectrum beta lactamase (ESBL)-producing urinary isolate specifically, we use a carbapenem. (See 'Other hospitalized patients' above.)
•Outpatients without risk for resistance – For outpatients without risk factors for an MDR gram-negative infection (table 2), we suggest an oral fluoroquinolone, such as levofloxacin or ciprofloxacin (table 3 and algorithm 2) (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 such as ceftriaxone or ertapenem prior to administering the fluoroquinolone (Grade 2C). If there are concerns about intolerance or adverse effects with fluoroquinolones, other options include giving a long-acting parenteral agent followed by either trimethoprim-sulfamethoxazole or an oral beta-lactam, or continuing the parenteral agent until susceptibility testing results return. (See 'Low risk of MDR infection' above.)
•Outpatients with risk for resistance – For outpatients with risk factors for an MDR gram-negative infection (table 2), we suggest an initial dose of ertapenem (table 3 and algorithm 2) (Grade 2C). Subsequently, an oral fluoroquinolone or daily ertapenem can be used. (See 'High risk of MDR infection' above.)
●Directed therapy and duration – Urine culture and susceptibility testing results should be used to tailor the regimen to a more narrow-spectrum agent, if appropriate. Parenteral regimens can also be switched to an active oral agent following symptom improvement.
Appropriate oral agents to treat acute complicated UTI include fluoroquinolones (eg, levofloxacin or ciprofloxacin) for 5 to 7 days or trimethoprim-sulfamethoxazole for 7 to 10 days. Oral beta-lactams (eg, amoxicillin-clavulanate, cefpodoxime, or cefadroxil) for 7 to 10 days are less effective for acute complicated UTI but are appropriate alternatives if susceptibility is documented and the other agents are not feasible. Doses are the same as those listed in the table (table 3). (See 'Directed antimicrobial therapy' above.)
●Urologic issues – 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.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Thomas M Hooton, MD, who contributed to earlier versions of this topic review.
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