Continuing Education Activity

Acute pyelonephritis is a bacterial infection causing inflammation of the kidneys. Pyelonephritis is generally a complication of an ascending urinary tract infection that spreads from the bladder to the kidneys. Certain populations, such as pediatric patients, renal transplant patients, and pregnant patients, warrant special attention. Symptoms usually include fever, flank pain, nausea, vomiting, burning with urination, increased urinary frequency, and urgency. It is important to differentiate acute pyelonephritis, a medical condition treated primarily with antibiotics, from pyonephrosis (obstructive pyelonephritis), a clinically similar condition that requires urgent surgical drainage of an obstructed, infected renal pelvis. The microbiology of pyelonephritis can be complex, and antibiotic resistance is common. The role of imaging is discussed, and suggested empiric antibiotics are identified. This activity outlines the clinical presentation, diagnosis, and management of acute pyelonephritis and highlights the role of the interprofessional team in caring for patients with the condition.

Objectives:

• Identify the clinical features and risk factors associated with acute pyelonephritis.

• Describe expected signs and symptoms in a patient with pyelonephritis.

• Select appropriate imaging modalities for diagnosing acute pyelonephritis and monitoring treatment response.

• Collaborate with interprofessional teams, including urologists, radiologists, and infectious disease specialists, to optimize patient care.

Introduction

Acute pyelonephritis is a bacterial infection causing renal inflammation and is one of the most common kidney diseases. Pyelonephritis generally occurs as a complication of an ascending urinary tract infection (UTI), which spreads from the bladder superiorly to the kidney, although the infection may also be spread hematogenously.[1]

Symptoms usually include fever, flank pain, chills, nausea, vomiting, anorexia, burning on urination, increased frequency, and urgency.[1] The most common acute pyelonephritis symptoms are usually fever and flank pain.

Acute pyelonephritis can be divided into complicated and uncomplicated types. Complicated pyelonephritis includes pregnant patients, patients with uncontrolled diabetes, kidney transplants, urinary anatomical abnormalities, acute or chronic kidney failure, as well as immunocompromised patients, and those with hospital-acquired bacterial infections. It is essential to distinguish between complicated and uncomplicated pyelonephritis, as patient management and disposition depend on it.

Chronic pyelonephritis refers to the disease process of pyogenic scarring and long-term inflammatory changes from persistent or recurrent renal infections, usually associated with vesicoureteral reflux or other significant urological anatomic abnormalities in children. In adults, it may describe the condition of an ongoing or intractable kidney infection associated with a major anatomical anomaly of the urinary tract, calculi, or an abnormal inflammatory response, such as in xanthogranulomatous pyelonephritis.[2][3][4]

Etiology

Bacteria can reach the kidneys in two ways: hematogenous spread or through an ascending infection from the lower urinary tract. Hematogenous spread is uncommon and usually occurs in patients who are debilitated, immunocompromised, or have ureteral obstructions. Bacterial access to the kidneys would be through the bloodstream via bacteremia.[5] 

Most patients will get acute pyelonephritis through an ascending infection. Following contamination of the periurethral area with a pathogen from the rectum, the bacteria will first attach to urethral mucosal epithelial cells and eventually travel to the bladder.[5]  From there, the bacteria must overcome the natural host defenses and multiply fast enough to allow progression up the ureter to the kidneys.[5][6] Urinary tract infections occur more frequently in females due to their shorter urethras, hormonal changes, and proximity of the urethra to the anus.[7]

Any urinary outflow obstruction can lead to incomplete bladder emptying and urinary stasis, which allows bacteria multiplication without being flushed out. Urinary tract obstruction caused by a kidney stone can also lead to a potentially lethal and dangerous form of acute pyelonephritis known as obstructive pyelonephritis or pyonephrosis.[8]

A less common cause of acute pyelonephritis is vesicoureteral reflux (VUR), which is a congenital condition where urine flows backward from the bladder into the kidneys during voiding.[9] Up to 40% of children diagnosed with a UTI will also be diagnosed with vesicoureteral reflux. In addition, 10% of children with VUR will show renal scarring, which can lead to long-term renal impairment.[10]

Renal transplant patients are especially at risk of pyelonephritis due to a combination of immunosuppression and abnormal transplant kidney anatomy, especially in the first 6 months post-transplant. One study showed a single episode of pyelonephritis was associated with a 45% higher risk of transplant loss and death.[11]

The Microbiology of Pyelonephritis 

Escherichia coli is by far the most common cause of acute pyelonephritis and most other urinary tract infections.[7][12] Klebsiella pneumoniae is the second most common causative organism, followed by Proteus, Pseudomonas, Enterococci, Staphylococci, and other enterobacteria.[1][13]

Candida spp is another possible causative agent, usually found in patients with diabetes, older individuals, patients who have previously been treated extensively with antibiotics, hospitalized patients (especially in the ICU), and those with indwelling catheters.[14][15][16][17] Candida spp may cause fungus balls and radiolucent urinary tract filling defects, further complicating treatment.[18][19]

The growing prevalence of extended-spectrum beta-lactamase (ESBL) producing bacteria and fluoroquinolone resistance greatly complicates antibiotic selection for these serious infections.[20][21][22][23] This is a common and growing problem as over 90% of UTI-causing bacteria are resistant to at least one antibiotic, and close to 80% have become resistant to at least two.

Patient risk factors for antibiotic resistance include recent broad-spectrum use of antimicrobials (especially quinolones and beta-lactams), obstructive uropathy, increased healthcare interactions, recurrent UTIs, hospital admissions, indwelling catheters, older patient age, and inappropriate antibiotic use (eg, inadequate or overlong duration of treatment, incorrect dosage, poor antimicrobial selection).[13][24][25][26][27][28][29][30]

Other factors include the general overuse of antibiotics in healthcare, increased agricultural use of antibiotics, availability of many antibiotics without prescriptions in many parts of the world, migration and travel patterns, non-adherence to best practice guidelines on antimicrobial use, and failure to limit the use of last-resort antibiotics appropriately.[13][31]

Generally, a specific antibiotic is considered clinically useful if bacterial resistance in the community is 10% or less.[32][13][33][34] Antibiotics with minimal tissue penetration or urinary excretion (such as nitrofurantoin) are not generally recommended for treating pyelonephritis.[12]

In developing countries, there are some unique factors such as delays in seeking proper medical care due to poverty, use of alternative therapies from non-traditional healers, inadequate healthcare delivery systems and sanitation, poor patient health education, governmental regulatory issues such as failure to join the Global Antibiotic Resistance Partnership (GARP) as recommended by the WHO, and lack of resources to identify counterfeit drugs or verify the quality of dispensed medications.[35]

Epidemiology

Acute pyelonephritis in the United States is found at a rate of 15 to 17 cases per 10,000 females and 3 to 4 cases per 10,000 males annually, with an annual total of 250,000 cases annually reported in the US.[36] One large study of over 750,000 patients in Sweden found that uncomplicated UTI/cystitis developed into pyelonephritis 0.47% of the time with antibiotic treatment. This risk rose to 1.43% if an antibiotic prescription was not filled within 5 days of cystitis diagnosis.[37]

Young, sexually active women are most often affected by acute pyelonephritis due to their higher incidence of UTIs, but men have a higher mortality rate.[7][12][38] Men are more likely to have diabetes, nephrolithiasis, or kidney disease than women.[39] Groups with extremes of age, such as older adults and infants, are also at higher risk. Acute pyelonephritis has no racial predisposition.[40]

Pregnant women are also considered a high-risk group due to physiologic changes predisposing them to an increased risk of UTI. Acute pyelonephritis leads to maternal complications and, in some studies, also preterm delivery and low birth weight. Asymptomatic bacteriuria occurs in 2% to 7% of pregnant women.[41]  While clinical guidelines in North America and Europe have recommended screening for and treating asymptomatic bacteriuria in pregnant patients to avoid pyelonephritis, these guidelines are based on studies now considered low-quality from the 1960s and 1980s. More recent data found no significant difference in cases of pyelonephritis with treatment of asymptomatic bacteriuria, and overall events of pyelonephritis were low (0 vs 1 event in the treated and untreated groups, respectively). Therefore, more recent data supports not treating asymptomatic bacteriuria in pregnant women, especially given that antibiotics can have potential adverse effects. More high-quality randomized controlled trials are needed in this area.[41][42][43]

Pathophysiology

E coli is the most common bacteria causing acute pyelonephritis due to its unique ability to adhere to and colonize the urinary tract and kidneys. E coli have adhesive appendages called P-fimbriae, which interact with receptors on the surface of uroepithelial cells. Animal models show neutrophils are crucial to controlling bacterial ascent, while macrophages are responsible for much of the inflammatory and scarring response.[44]

Kidneys infected with E coli will develop an acute response by releasing chemokines and other inflammatory factors. Besides the local inflammatory response, this can ultimately result in scarring of the renal parenchyma. Animal models show collagen deposition in areas near renal abscesses, suggesting that connective tissue replaces functional renal tissue to contain bacterial dissemination.[44] Likely, a combination of disrupted renal cell barriers and localized inflammation, cytokine release, clotting, and hypoxia contribute to renal scarring. Inflammatory cytokines, bacterial toxins, and other reactive processes lead to complete renal involvement (pyelonephritis) and may progress to sepsis and septic shock.

Histopathology

Mucosal injury is a prominent feature of acute pyelonephritis, leading to submucosal nests of inflammatory cells and engorged peritubular capillaries. The mucosal injury ranges from superficial erosions to frank ulceration. Submucosal collagen and engorged peritubular capillaries are also demonstrated acutely.[45] The renal tissues become markedly infiltrated with neutrophils, macrophages, and plasma cells.[46] Plugs may form within the renal tubules, sometimes extending into the interstitium. This may result in focal degeneration or destruction of the renal tubules and present as localized areas of necrosis and microabscess formation in the renal parenchyma.[46]

History and Physical

Acute pyelonephritis will classically present as a triad of fever, flank pain, and nausea or vomiting, but not all symptoms need to be present.[1] In patients without nausea or vomiting, anorexia is common.

Symptoms will usually develop within several hours or over a day. Cystitis symptoms, such as dysuria and hematuria, are more likely to be found in women.[1]

In children, common symptoms of acute pyelonephritis may be absent. Symptoms such as failure to thrive, fever, and feeding difficulty are most common in neonates and children under two years old. Elderly patients may present with sudden dementia or altered mental status, fever, loss of appetite, renal failure, and damage to other organ systems.

When a patient with pyelonephritis is febrile, the fever may be high, often higher than 103 °F (39.4 °C).[1] Despite this, patients with acute pyelonephritis generally do not appear severely ill or toxic, and many will appear reasonably well.

Vital signs are usually otherwise normal, but a systolic blood pressure lower than 90 mm Hg suggests a more serious disease process and possible sepsis.[1]

On physical examination, the patient's general appearance will be variable.[1]

• Costovertebral angle tenderness is commonly unilateral over the affected kidney, but bilateral costovertebral angle tenderness may be present in some cases.

• Suprapubic tenderness during the abdominal examination will vary from minimal to moderate.

• Rebound, guarding, and rigidity are generally absent, and abdominal tenderness other than in the suprapubic area is typically absent.

• Bowel sounds are usually present and active. The skin will also appear normal except in cases of possible Herpes zoster.

• Clinical findings of pyelonephritis in men, older adults, and young children may be more variable.

Evaluation

A good history and physical are the mainstays of evaluating acute pyelonephritis, but laboratory and imaging studies can be helpful.

A urine specimen should always be obtained for a urinalysis and culture in patients suspected of pyelonephritis. Consider a urethral catheterization if a patient is unable to void even with adequate hydration, morbid obesity in females, patients too ill to perform the collection themselves reliably, and in younger children (where a suprapubic aspiration is a reasonable alternative). Obtaining a urine specimen prior to administering antibiotics greatly improves the yield. Even then, urine culture may be negative in up to 30% of pyelonephritis cases, possibly due to the administration of outpatient antibiotics.[47] Blood cultures are frequently obtained but rarely affect treatment as the urine culture primarily provides culture results.[48][49]

On urinalysis, pyuria is the most common finding in patients with acute pyelonephritis.

• Nitrite production will indicate that the causative bacteria is a urease-producing organism, possibly not E coli. While useful when positive, only about 25% of patients with a urinary tract infection will demonstrate nitrites on urinalysis.[50] Therefore, negative nitrites on a dipstick urinalysis do not rule out a UTI or acute pyelonephritis.[50]

• Proteinuria, bacteriuria, and microscopic hematuria may be present on urinalysis. Other causes, such as kidney stones, should also be considered if hematuria is present. In young women with acute pyelonephritis, up to about 40% are likely to demonstrate gross hematuria, which is much less common in men with the infection. The finding of a single bacteria on a microscopic oil-immersion examination of unspun urine should indicate at least 100,000 colony-forming units (cfu)/mL for diagnosis.

Blood work such as a complete blood cell count (CBC) is sent to look for leukocytosis and laboratory signs of sepsis. The complete metabolic panel can be used to search for aberrations in creatinine and BUN to assess kidney function. There are no serum biomarkers available specific for pyelonephritis, although urinary neutrophil gelatinase-associated lipocalin may be a useful and sensitive indicator of acute pyelonephritis in children and possibly in adults.[51][52][53][54] A threshold value of 29.4 ng/mL has been suggested as it gives greater than 90% sensitivity and specificity in pediatric acute pyelonephritis.[51][52]

In addition to urine cultures, a laboratory evaluation for suspected urinary sepsis should be performed when appropriate. This may include C-reactive protein, lactic acid, procalcitonin, and the neutrophil-to-lymphocyte ratio (where >5 suggests sepsis).[55][56][57][58][59] For more details, see StatPearls' companion reference on "Laboratory Evaluation of Sepsis."[55]

Imaging studies are not usually required for the diagnosis of uncomplicated acute pyelonephritis but should be considered for patients considered high-risk.

High-risk patients where imaging should be considered would include patients with diabetes (especially if poorly controlled), recurrent pyelonephritis, anatomical or surgically corrected urinary tract anomalies, hospital-acquired infections, sepsis, urolithiasis, transplant recipients, immunosuppressed individuals, solitary kidneys, worsening renal function, AIDS, fever for longer than 48 hours, toxicity lasting more than 72 hours, and those unresponsive to treatment, as recommended by the American College of Radiology.[12][60]

The imaging study of choice for acute pyelonephritis is abdominal/pelvic CT without and with contrast.[12] Noncontrast studies can highlight urolithiasis, which can greatly complicate treatment and cannot be excluded clinically.

• Ultrasonography can be used to evaluate a patient with possible pyelonephritis, but a negative study does not exclude the diagnosis.[61] Ultrasound can still be a useful study because it can be done quickly at the bedside, has no radiation exposure, and may reveal renal abnormalities such as renal calculi, hydronephrosis, abscess formation, or an elevated renal resistive index, which can prompt further testing or definitive treatment.[61] In particular, a negative ultrasound study does not exclude obstructive pyelonephritis, and a CT scan should be considered in high-risk patients.[12]

• MRI with diffusion-weighted imaging can be useful for patients with contraindications to intravenous contrast and in pregnancy when ultrasound is insufficient.[12][62][63][64] The apparent diffusion coefficient (ADC) results can help diagnose pyelonephritis and differentiate it from a renal abscess.[62][63][64]

• A CT scan of the abdomen and pelvis with IV contrast is the imaging study of choice for acute pyelonephritis, especially when complicating factors such as stones are present.[12] However, a noncontrast study may be necessary to rule out urolithiasis. If the serum creatinine level precludes using IV contrast, a noncontrast study is usually sufficient, or an MRI can be performed.[65] CT scans can also identify emphysematous and xanthogranulomatous pyelonephritis, which require more aggressive treatment.[3][63][66][67] Please see our companion StatPearls article, "Xanthogranulomatous Pyelonephritis," for further information on this condition.[3]
  • Typical findings of acute pyelonephritis would include focal, wedge-shaped defects on contrast-enhanced CT scans.[63][68][69]
  • Other findings would include fat stranding, diminished urinary contrast excretion, decreased enhancement of the renal parenchyma, and global enlargement.[68]

CT scans are indicated and recommended for patients at high risk.[60] While renal ultrasound can be performed, the preferred imaging in such critical situations is a CT scan, as ultrasonography is unreliable.[61] An MRI would be a suitable alternative.[63]

The vast majority of patients with pyelonephritis will have unilateral renal involvement, but bilateral disease may also occur with similar symptoms.[70] Patients with bilateral pyelonephritis tend to appear sicker, have more rapid disease progression, are more likely to develop acute kidney injury, and generally have poorer outcomes compared to those with just unilateral involvement.[70][71][72] The early use of imaging can help distinguish unilateral from bilateral disease.[70][71][72]

Pregnant patients with acute pyelonephritis require hospital admission given the associated with preterm labor and should be evaluated initially with ultrasound. If the diagnosis is still equivocal and since CT scans are not recommended during pregnancy, consideration should given to an MRI scan or cystoscopy with retrograde pyelography, especially for possible obstructive pyelonephritis.[12]

Acute lobar nephronia or acute focal bacterial nephritis is a rare radiological diagnosis made in patients who clinically appear to have acute pyelonephritis but who fail to improve on appropriate therapy without any clear explanation. It is more commonly found in children than in adults.[73]

The diagnosis is made by CT scanning that describes a mass-like, wedge-shaped, or roundish hypodense renal defect with indistinct borders after IV contrast administration that is only poorly seen on images without contrast.[74][75] There are no distinctive or definitive ultrasound features.[76][77] The diagnosis requires a contrast-enhanced CT (preferred) or an intravenous pyelogram, but it can also be made with an MRI in patients who cannot be given contrast.[74][76][77][78][79]

The defect represents vascular ischemia, usually affecting a wedge-shaped portion of the renal parenchyma due to a locally intense kidney infection without gas, liquefaction, or abscess formation. This can quickly progress (in 3 days or less) to the typical walled-off cavity with central tissue necrosis consistent with a frank renal abscess.[80] The condition is more often seen in diabetics and is sometimes associated with papillary necrosis.

Acute lobar nephronia is generally considered an intermediate step between acute pyelonephritis and a renal abscess.[73][77] It should be suspected in patients with pyelonephritis who have persistent fever (4 or more days in adults, 2 or more days in children) despite appropriate antibiotic therapy without urinary obstruction or any other obvious cause.[73][81]

Contrast-enhanced CT remains the best diagnostic imaging modality. Ultrasound is not considered an adequate imaging modality to diagnose acute lobar nephronia, although a focal loss of corticomedullary differentiation, nephromegaly, or a localized, hypoechoic renal mass might be ultrasonographic findings that could suggest the diagnosis.[73][76][77][82][83][84]

Treatment is prolonged antibiotic therapy, usually four weeks in adults and at least three weeks in children.[73][85][86] After successful antibiotic therapy, the affected area leaves a renal cortical scar.

Obstructive pyelonephritis (pyonephrosis), an acute surgical emergency requiring urgent surgical drainage of an infected renal pelvis complicated by obstructing urinary calculi, cannot always be clinically distinguished from acute pyelonephritis. Therefore, renal imaging (noncontrast CT scanning) should be considered in at-risk patients.[12][87] This would include patients who appear particularly ill, who have signs or symptoms of sepsis, who fail to improve on standard therapy after 48 to 72 hours, who have a history of urolithiasis, or where obstructive pyelonephritis is otherwise suspected.[12][87]

The diagnosis of obstructive pyelonephritis can sometimes be made with ultrasound, which would demonstrate fluid levels, echogenic debris, and air or gas in the collecting system.[88] However, ultrasound may not demonstrate the obstructing calculus, and a CT may be needed to identify the cause and location of the urinary obstruction, determine the size of any ureteral or ureteropelvic junction stones, confirm the diagnosis, and identify any extrarenal pathology or complications.[88]

Treatment / Management

Healthy, young, non-pregnant women who present with uncomplicated pyelonephritis can be treated as outpatients. The mainstays of treatment of acute pyelonephritis are antibiotics, analgesics, and antipyretics. Nonsteroidal anti-inflammatory drugs (NSAIDs) work well to treat both pain and fever associated with acute pyelonephritis. The initial selection of antibiotics will be empiric and should be based on the local antibiotic resistance patterns, which should be available at each hospital or institution (antibiograms). Antibiotic therapy should then be adjusted based on the urine culture results.

Most cases of acute pyelonephritis will be caused by E. coli, for which patients can be treated with oral cephalosporins or sulfamethoxazole-trimethoprim for 14 days or a fluoroquinolone for a week.

For cases of uncomplicated pyelonephritis, the American College of Physicians recommends sulfamethoxazole-trimethoprim for 14 days or fluoroquinolone for 5 to 7 days, based on local bacterial resistance patterns and antibiotic sensitivity results from urine cultures.[89] Most compliant patients with uncomplicated pyelonephritis without significant comorbidities (>95%) can be treated as outpatients on oral antibiotics after initial evaluation and management in the Emergency Department and possibly a single parenteral dose of an appropriate antibiotic, usually ceftriaxone.[90]

Overall, resistance to sulfamethoxazole-trimethoprim and fluoroquinolones in the US has been reported to be at least 33% and 10%, respectively.[20] It is, therefore, important to know the local bacterial resistance when deciding on initial empiric therapy. Fluoroquinolones and sulfamethoxazole/trimethoprim will not alter vaginal flora, which is one of the reasons they are preferred over other agents assuming bacterial susceptibility.

Where local bacterial sensitivity patterns indicate a prevalence of 10% or more community resistance to any particular antibiotic, the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases recommend administering an initial long-acting parenteral antibiotic (such as an aminoglycoside, ertapenem, or ceftriaxone) in the emergency department before discharge.[32] Ertapenem is often reserved exclusively for the most resistant cases, and aminoglycosides can be nephrotoxic, although a single dose is deemed safe.[91][92][93][94][95] For these reasons, ceftriaxone is often the preferred parenteral agent selected.

It is critically important for a physician to be designated and responsible for reviewing the culture results when available and communicating these findings with the patient, particularly regarding any changes in their therapy. Always change therapy to a narrower agent whenever safe and possible based on available culture and sensitivity results.

In general, fluoroquinolones are the preferred oral antibiotic agent if the organism is sensitive and may be used empirically where the prevailing community resistance is 10% or less. Sulfamethoxazole-trimethoprim for 14 days or cephalexin for 7 to 10 days can be appropriate in some situations, but growing bacterial resistance makes these antimicrobials less useful for empiric use.

Ceftriaxone is generally a good choice for initial empiric parenteral therapy of pyelonephritis. Carbapenems should generally be reserved for the most critically ill patients or when no other agents are appropriate.

A single dose of gentamicin can be considered in addition to whatever other treatment is selected, as gentamicin achieves high renal tissue levels, has minimal effect on kidney function, and improves outcomes.[91][92][93][94][95][96]

Appropriate empiric antibiotics for outpatients with acute pyelonephritis include:

• If quinolone resistance in community-acquired infections is 10% or less: 
  • Fluoroquinolone for 7 days (14 days in male patients)

• If quinolone resistance in community-acquired infections is greater than 10%, choose one of the following (assuming bacterial sensitivity): 
  • 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
  • Sulfamethoxazole-trimethoprim for 14 days

Follow-up should be 24 to 48 hours after discharge to evaluate symptoms and adjust therapy, if necessary. Simple, uncomplicated cases with complete resolution of symptoms do not require imaging or follow-up urine cultures.[97] If there is difficulty in finding an appropriate oral antimicrobial agent once the bacterial cultures are available due to resistance, patient allergies, or other factors, consider an infectious disease consultation.

Indications for inpatient care include obvious signs of sepsis, high fever, significant or difficult-to-control pain, persistent nausea (which would limit hydration and not allow oral drug therapy), marked debility, failure of outpatient treatment, significant comorbidities, likelihood of non-compliance with therapy, and inadequacy of home care. Patients who are immunocompromised, renal transplant recipients, have poorly controlled diabetes, are pregnant, or are suspected of a urinary tract obstruction should also be admitted. About 20% of all patients with acute pyelonephritis will require inpatient treatment.[39]

Intolerance of oral medications or lack of suitable oral antibiotics will require parenteral treatment, but not necessarily inpatient hospitalization, depending on the availability and appropriateness of home IV therapy. 

Acute pyelonephritis complicated by ureteral obstruction, typically ureterolithiasis, constitutes obstructive pyelonephritis or pyonephrosis, which is a surgical emergency and requires immediate surgical drainage by a double J stent or percutaneous nephrostomy together with targeted antibiotic therapy. It is not recommended to delay emergency drainage procedures until the patient is more "stable" for surgery.[8][12] Postponing surgery by 48 hours or more increases the mortality by 29%.[98] These patients are often septic and should be admitted.[12]

Appropriate empiric antibiotics for inpatients with acute pyelonephritis include:

• An antipseudomonal carbapenem (imipenem or meropenem) plus vancomycin (for the most critically ill)
• Ceftriaxone (usually preferred for most cases)
• Fluoroquinolone (depending on local resistance)
• Piperacillin-tazobactam (preferred for suspected Enterococcus or Pseudomonas)
• Cefepime (not for ESBL)
• Cefotaxime
• Cefuroxime
• Ceftazidime 
• Aztreonam
• Aminoglycosides (gentamicin, tobramycin, or amikacin)
• An antipseudomonal carbapenem (if a recent ESBL bacterial isolate is found)

          PLUS

• Add vancomycin or linezolid if a Gram-positive organism is suspected.

Intravenous antibiotics are typically given for at least 48 hours, at which point, culture results are available, and patients should have noted a positive clinical response.[99] 

• For patients who have responded well, consider switching to appropriate oral antibiotic treatment, as this has been shown to provide equivalent results to continued parenteral therapy.

• If not, consider changing antibiotics, maintaining parenteral therapy, and obtaining appropriate imaging if not already done. Consider consulting urology if imaging indicates obstruction or infectious disease if imaging is negative.

Septic patients should be admitted for parenteral therapy and have appropriate imaging. Antibiotic therapy should generally be continued for 10 to 14 days. It is reasonable to ask local infectious disease specialists for advice about empiric therapy for pyelonephritis.

Preferred antibiotics for treating pyelonephritis in pregnant patients, according to the American College of Obstetricians and Gynecologists Clinical Consensus Statement, include ampicillin-sulbactam or ampicillin plus optional gentamicin, cefepime, ceftriaxone, or aztreonam (in penicillin-allergic patients).[48] There is insufficient data on the use of carbapenems in pregnancy, so they are not recommended in the US, but their use is allowed in Europe.[41]

Cefotaxime, ceftazidime, and piperacillin-tazobactam may also be considered based on local resistance patterns and individual patient factors. Treatment should begin immediately without waiting for culture results and continue for 14 days. Antibiotics should be adjusted based on the patient's culture results and clinical improvement.[48] Fluoroquinolones, nitrofurantoin, and fosfomycin should be avoided when treating pyelonephritis during pregnancy.[48][100][101][102]

Post-pyelonephritis prophylaxis with nitrofurantoin 100 mg or cephalexin 250 mg to 500 mg daily may be considered, as recurrent pyelonephritis will otherwise occur in up to 25% of pregnant patients. Once started, such prophylaxis should continue through the pregnancy and an additional 4 to 6 weeks after delivery.[48][103][48]

Procalcitonin levels can help optimize when antibiotic therapy can be safely discontinued. A multicenter randomized study found that a procalcitonin reduction of at least 80% or any level less than 0.5 μg/L by 5 or more days after admission was medically and clinically sufficient, more cost-effective, required fewer hospital inpatient days, and reduced antibiotic-related complications like pseudomembranous colitis when compared to standard therapy.[104]

Complicated cases, those with an increased risk of infection, and all patients who were hospitalized or received parenteral antibiotics should have follow-up urine cultures 1 to 2 weeks after completion of therapy, and imaging should be considered if not previously performed. Monthly urine cultures have been suggested for selected higher-risk patients.

Depending on local resistance patterns and individual culture sensitivity results, treatment for highly resistant infections may include the following:[32][13][33][34][105][106][107][108]

• Aminoglycosides (amikacin, gentamicin, tobramycin)
• Aztreonam
• Aztreonam-avibactam
• Carbapenems
• Cefepime
• Cefiderocol
• Cefotaxime
• Cefpodoxime
• Ceftazidime-avibactam
• Ceftriaxone
• Chloramphenicol
• Daptomycin
• Fluoroquinolones
• Linezolid
• Meropenem-vaborbactam
• Piperacillin-tazobactam
• Tigecycline

Fosfomycin is preferred for UTIs as it remains effective in multidrug-resistant infections, but its use in pyelonephritis is controversial. It is not officially recommended or approved for pyelonephritis in the United States due to inadequate renal tissue and serum levels, although urine drug levels are quite high.[32] It has been used successfully in many patients with pyelonephritis and may be reasonable in selected cases off-label.[107][108][109][110][111]

Due to its high urine levels and relative immunity from bacterial resistance, fosfomycin may be very suitable as an oral step-down therapy for outpatient use after parenteral antibiotics such as ertapenem.[112][113] Fosfomycin is not routinely tested or listed in bacterial culture or sensitivity reports but may be specifically requested.[112] While safe to use, fosfomycin is not recommended for the treatment of pyelonephritis during pregnancy.[48][114]

Aminoglycosides are relatively underutilized in treating pyelonephritis. A single aminoglycoside dose can improve outcomes and increase survival and should be considered in sicker or higher-risk patients.[91][96][92][93][94][95] Aminoglycosides achieve high renal tissue levels, can be used in addition to other antimicrobials, act synergistically with many antibiotics (including beta-lactams and carbapenems), lower mortality, and improve outcomes of serious kidney infections without causing significant nephrotoxicity.[92][115][116][117] Aminoglycoside-based treatment can also help avoid the overuse of carbapenems.[118] Using proper dosing guidelines and following recommended protocols for ongoing treatment is important.[115][116]

Reducing antibiotic resistance patterns is something every prescribing physician can do. Urinary tract infections account for up to 40% of all antibiotics prescribed and used worldwide. Initial treatment can generally focus on symptomatic therapy until culture-specific results and sensitivities are available, generally within 48 hours.[119] The risk of an uncomplicated UTI progressing to pyelonephritis is relatively low at only 1% to 2%.[119]

Avoiding the overuse of broad-spectrum antibiotics in such situations can help reduce bacterial antibiotic resistance.[119] The overwhelming majority of uncomplicated urinary tract infections can be managed using nitrofurantoin, fosfomycin, or pivmecillinam, and 3 to 5 days of therapy is generally sufficient.[119] 

The FDA is currently reviewing Pivmecillinam for use in the US for UTIs; it has been available in Europe, Scandinavia, and Canada for over 40 years and boasts a 95% cure rate for cystitis with very little resistance noted.[120][121][122] Bacterial resistance is reported as 5% or less, even in countries where it has been frequently used.[122][123] It has a unique bacteriocidal mechanism of action: inhibition of penicillin-binding protein 2.[123] As it delivers high renal tissue concentrations, it may also be suitable for treating pyelonephritis, and an intravenous version is available.[123][124]

Changing the treatment of uncomplicated urinary tract infections (by symptomatic measures only when possible until culture and sensitivity results are available) and then using preferred first-line agents (nitrofurantoin, fosfomycin, or pivmecillinam) whenever possible for no more than seven days can help reduce bacterial antibiotic resistance and improve outcomes.[119] Improved point-of-care rapid diagnostic testing can also help improve antibiotic stewardship.[34]

Differential Diagnosis

When diagnosing acute pyelonephritis, it is initially wise to keep the differential broad. Physicians should consider other disorders as well when patients present with fever, flank pain, and costovertebral angle tenderness. Because symptoms can be variable (unilateral, bilateral, radiating, sharp, dull) and because pyelonephritis can progress to sepsis and shock, the differential diagnoses associated with pyelonephritis can be extensive.

Common mimics of acute pyelonephritis can include but are not limited to the following:

• Appendicitis
• Cholecystitis
• Costochondritis
• Diverticulitis
• Ectopic pregnancy 
• Endometritis
• Focal nephronia
• Herpes zoster
• Lobar pneumonia
• Nephrolithiasis
• Ovarian cyst pathology
• Pancreatitis
• Pelvic inflammatory disease
• Perinephric abscess
• Pyonephrosis (obstructive pyelonephritis)
• Renal abscess
• Rib fracture
• Ureterolithiasis
• Ureteropelvic junction obstruction
• Urolithiasis
• Xanthogranulomatous pyelonephritis[12][125]

Prognosis

Most cases of pyelonephritis (80%) are managed in an outpatient setting, with most patients improving with oral antibiotics, antinflammatories, and antipyretics. Usually, young, healthy women with uncomplicated pyelonephritis are most likely to be treated as outpatients.[40] 

Uncomplicated pyelonephritis is not considered a dangerous or lethal disease unless associated with secondary conditions such as emphysematous pyelonephritis, perinephric abscess, pyonephrosis, or sepsis. In such cases, mortality rates of 25% or more have been reported, but much depends on disease severity, patient comorbidities, early diagnosis, bacterial resistance patterns, and the prompt implementation of appropriate antibiotic therapy.[126]

Despite pyelonephritis improving in most cases, there is still significant morbidity and mortality associated with severe or complicated cases of this disease.

Pregnant females with acute pyelonephritis are at very high risk for premature delivery, as well as other complications such as acute respiratory distress syndrome, acute renal injury, sepsis, restricted intrauterine growth, and even fetal death.[127]

Overall mortality for acute pyelonephritis has been reported at around 10% to 20% in some studies, with a recent study from Hong Kong finding a mortality rate closer to 7.4%.[128]

Increased mortality is associated with older age (more than 65 years), diabetes, renal failure, disseminated intravascular coagulation, sepsis (septic shock), long-term indwelling catheters, limited mobility (bedridden), and male gender.

With early recognition of the underlying etiology and prompt intervention with appropriate treatment, even patients with severe pyelonephritis generally have a good outcome.[128]

Early use of appropriate antibiotics improves outcomes and can be life-saving.[126]

Complications

Acute pyelonephritis can have several complications, with one of the more serious complications being emphysematous pyelonephritis.[67][129]

Emphysematous pyelonephritis is a necrotizing kidney infection usually caused by E. coli or Klebsiella pneumoniae and is a severe complication of acute pyelonephritis. Emphysematous pyelonephritis is usually seen in the setting of diabetes and occurs more frequently in women. The diagnosis can be made with ultrasound, but CT is typically necessary for confirmation. The overall mortality rate of emphysematous pyelonephritis is estimated to be approximately 38%, with better outcomes associated with patients who receive both medical and surgical management versus medical management alone.[67][129][130]

Other complications include:

• Acute focal nephronia (Acute focal bacterial nephritis)
• Acute renal failure
• Chronic pyelonephritis
• Obstructive pyelonephritis
• Papillary necrosis
• Perinephric abscess
• Renal abscess
• Renal scarring and atrophy
• Renal vein thrombosis
• Sepsis and urosepsis
• Xanthogranulomatous pyelonephritis

Consultations

Most cases of acute pyelonephritis are uncomplicated and do not require consultations. Complicated cases may require consults with urology, obstetrics and gynecology, pediatrics, and infectious diseases.

• Urology is usually consulted for patients with ureteral obstruction, hydronephrosis, urolithiasis, urogenital abnormalities, failed initial therapies, or the first episode of pyelonephritis in an infant.

• Obstetrics and gynecology should be consulted for any pregnant patient with acute pyelonephritis.

• Infectious disease should be consulted for immunocompromised patients, multidrug-resistant pathogens, failures of initial appropriate therapy, persistently positive blood cultures for more than 48 hours, sepsis, multiple antimicrobial drug allergies, or other comorbidities making optimal antibiotic selection difficult. Clinicians should not hesitate to consult an infectious disease specialist for any difficult, complex, severe, or intractable pyelonephritis cases.

Deterrence and Patient Education

For healthy, young, premenopausal women, the best way to avoid acute pyelonephritis is to focus on the prevention of UTIs. While many factors may lead to UTIs, a simple way to help prevention is to void before and immediately after intercourse, increase urine volume by drinking more water, and wipe from front to back after urinating and defecating without folding or reusing the toilet paper or wipe.[131] This will help to reduce the introduction of bacteria into the urethra and bladder.[131]

Aside from behavioral interventions, favorable studies have also focused on cranberry juice, probiotics, D-mannose, methenamine, vitamin C, and low-dose prophylactic antibiotics to prevent UTIs.[132][133][134][135][136][137][138][139][140]

To avoid recurrent acute pyelonephritis, patients must finish the entire course of antibiotics and take them as directed. Increasing water intake helps avoid dehydration, reduces the risk of a UTI by flushing the bladder regularly, helps prevent acute pyelonephritis, and improves kidney function.

Pearls and Other Issues

Key facts to keep in mind regarding acute pyelonephritis are as follows: 

• Acute pyelonephritis will classically present as a triad of fever, flank pain, and nausea or vomiting, but not all symptoms have to be present.

• The diagnosis is typically made clinically, and imaging is not required but should be considered for high-risk cases or if urolithiasis is suspected.

• Ultrasonography can detect pyelonephritis, but a negative study does not exclude the diagnosis.

• Most uncomplicated cases of acute pyelonephritis will be caused by E. coli, for which patients can generally be treated with oral cephalosporins, quinolones, or TMP-SMX, depending on community bacterial resistance patterns and specific culture results.

• Always obtain urine cultures before giving any antibiotics.

• Consider a catheterized urine specimen if the clean voided samples are contaminated.

• A specific physician should be responsible for checking the urine cultures, communicating with the patient, and adjusting therapy accordingly.

• Always select the narrowest spectrum antimicrobial agent possible once the culture results are available.

• Switch to an acceptable oral agent as soon as practicable once the culture results are available, and the patient has clinically improved sufficiently.

• Do not use nitrofurantoin or other antimicrobials with inadequate tissue levels as a step-down antibiotic after parenteral therapy, even if culture reports indicate sensitivity.

• Consider using a single aminoglycoside dose empirically for sicker patients in addition to any other selected treatment. A single dose is well tolerated, has minimal transient nephrotoxicity, provides high renal tissue levels, reduces mortality, and provides better overall outcomes.

• Use the neutrophil-to-lymphocyte ratio as an easy, available, early marker of sepsis. Ratios greater than 5 suggest sepsis.

• When appropriate treatment fails, obtain imaging (usually CT scanning) and ask for help from urology and/or infectious disease.

• Older age (>65 years), male gender, impaired renal function, sepsis, or the presence of disseminated intravascular coagulation are associated with increased mortality.

• Do not hesitate to consult with an infectious disease specialist in complicated cases. Optimal antibiotic selection can be extremely difficult due to increasing bacterial resistance, patient allergies and tolerability, drug interactions, renal function, and other factors.

Enhancing Healthcare Team Outcomes

The treatment of acute pyelonephritis is best addressed by a team of healthcare professionals, including primary care providers, emergency room specialists, a nephrologist, an infectious disease consultant, a pain specialist, an internist, a urologist, or an obstetrician if the patient is pregnant. Nurses and pharmacists are critical in monitoring the patient, administering antibiotics, tracking clinical progress, and modifying therapy if indicated. A dietary consult should be considered if the patient has diabetes, but the key is the adequacy of oral hydration.

If reinfection occurs within 14 days of discharge, an investigation should be considered for a predisposing anatomical or functional anomaly. Urology should be consulted if such an anomaly (eg, vesicoureteral reflux, urolithiasis, bladder diverticula, incomplete bladder emptying) is found. A CT scan of the abdomen and pelvis without and with IV contrast, a post-void residual determination, and a careful review of the patient's medical and surgical history will generally accomplish this.

The pharmacist, infectious disease specialist, or the primary treating physician must prescribe based on the culture results and ensure that the patient is on the right drugs to cover the organisms causing the infection. Pharmacists can also help avoid unnecessary nephrotoxic agents that can exacerbate renal damage.

Outcomes

Prompt diagnosis and treatment are the keys to improved outcomes in patients with acute pyelonephritis. Any delay in initiating treatment can lead to very high morbidity. Even short delays in proper management can lead to more prolonged hospital admissions, unnecessary pain, and possible disability. 

After discharge, appropriate follow-up is needed to ensure that full recovery has occurred and any correctable anatomical predisposing factors are adequately treated.