Acute Pyelonephritis

Acute pyelonephritis is a potentially organ- and/or life-threatening infection that characteristically causes scarring of the kidney.[4] An episode of acute pyelonephritis may lead to significant renal damage; acute kidney injury; abscess formation (eg, nephric, perinephric); sepsis; or sepsis syndrome, septic shock, and multiorgan system failure.

A population-based study of acute pyelonephritis in the United States found overall annual rates of 15–17 cases per 10,000 females and 3–4 cases per 10,000 males.[5]

Diagnosing and managing acute pyelonephritis is not always straightforward. Wide variation exists in the clinical presentation, severity, options, and disposition of the disease.

Patients in the age range of 5-65 years typically present with lower urinary tract infection (UTI) symptoms (eg, dysuria, frequency, urgency, gross hematuria, suprapubic pain) and classic upper UTI symptoms (eg, flank pain, back pain), with or without systemic signs and symptoms (eg, fever, chills, abdominal pain, nausea, vomiting, costovertebral angle tenderness) and with or without leukocytosis. However, acute pyelonephritis can present as nonspecific symptoms.

A number of studies using immunochemical markers have shown that many women who initially present with lower urinary tract symptoms actually have pyelonephritis. Their pyelonephritis is often identified when short-course therapy for uncomplicated cystitis fails.

With patients at the extremes of age, the presentation may be so atypical that pyelonephritis is not in the differential diagnosis. Infants may present with feeding difficulty or fever, and the elderly may have mental status change or fever.

Acute pyelonephritis is complex, and there is no consistent set of signs and symptoms that is both sensitive and specific for the diagnosis. Therefore, clinicians must maintain a high index of suspicion.

In contrast to the plethora of data available for the treatment of cystitis, less substantial data are available regarding the appropriate antibiotic choice or duration of therapy for acute pyelonephritis. An additional cause for concern is the growing resistance of uropathogens to standard agents. Nevertheless, useful recommendations can be made.

The current emphasis on cost-effectiveness and the advent of newer antibiotics have led clinicians to reevaluate the benefit of hospitalization in patients with acute pyelonephritis. Most cases of uncomplicated pyelonephritis in young women can be managed successfully on an outpatient basis. However, outpatient management of acute pyelonephritis requires close follow-up care. The first follow-up visit should occur in 1-2 days, depending on the clinician's estimation of the severity of the infection. Any deterioration or unsatisfactory improvement warrants admission for intravenous antibiotics and evaluation for any complications. (See Treatment.)

Complicated pyelonephritis results from structural and functional abnormalities, urologic manipulations, or underlying disease; it includes pyelonephritis in men and in the elderly. Any patient with complicated pyelonephritis should be referred, if possible, to a physician trained in the management of these cases (eg, a nephrologist, urologist, or infectious disease specialist). The patient will require ongoing management, including repeat cultures, metabolic studies, and appropriate imaging studies.

Acute pyelonephritis results from bacterial invasion of the renal parenchyma. Bacteria usually reach the kidney by ascending from the lower urinary tract.[6] In all age groups, episodes of bacteriuria occur commonly, but most are asymptomatic and do not lead to infection. The development of infection is influenced by bacterial factors and host factors.[7]

Bacteria may also reach the kidney via the bloodstream. Hematogenous sources of gram-positive organisms, such as Staphylococcus, are intravenous drug abuse and endocarditis. Experimental evidence suggests that hematogenous spread of gram-negative organisms to the kidney is less likely unless an underlying problem exists, such as an obstruction. Little or no evidence supports lymphatic spread of uropathogens to the kidney.

Most bacterial data are derived from research with Escherichia coli, which accounts for 70-90% of uncomplicated UTIs and 21-54% of complicated UTIs (ie, UTIs that are secondary to anatomic or functional abnormalities that impair urinary tract drainage; are associated with metabolic disorders; or involve unusual pathogens). A subset of E coli, the uropathogenic E coli (UPEC), also termed extraintestinal pathogenic E coli (ExPEC), accounts for most clinical isolates from UTIs.

UPEC derives commonly from the phylogenetic groups B2 and D, which express distinctive O, K, and H antigens. UPEC genes encode several postulated virulence factors (VFs), including adhesins, siderophores, protectins, and toxins, as well as having the metabolic advantage of synthesizing essential substances.

Virulence factors

Adhesins have specific regions that attach to cell receptor epitopes in a lock-and-key fashion. Mannose-sensitive adhesins (usually type 1 fimbriae) are present on essentially all E coli. They contribute to colonization (eg, bladder, gut, mouth, vagina) and possibly pathogenesis of infection; however, they also attach to polymorphonuclear neutrophils (PMNs), leading to bacterial clearance.

Mannose-resistant adhesins permit the bacteria to attach to epithelial cells, thereby resisting the cleansing action of urine flow and bladder emptying. They also allow the bacteria to remain in close proximity to the epithelial cell, enhancing the activity of other VFs.

The P fimbriae family of adhesins is epidemiologically associated with prostatitis, pyelonephritis (70-90% of strains), and sepsis. This family of adhesins is associated with less than 20% of asymptomatic bacteriuria (ABU) strains. The AFA/Dr family is associated with diarrhea, UTI, and particularly pyelonephritis in pregnancy. The S/F1C family is associated with neonatal meningitis and UTI.

Siderophores are involved in iron uptake, an essential element for bacteria, and possibly adhesion. Protectins and their contributions to virulence include the following:

• Lipopolysaccharide (LPS) coatings: resist phagocytosis
• Tra T and Iss: resist action of complement
• Omp T: cleave host defense proteins (eg, immunoglobulins)

Toxins, which affect various host cell functions, include the following:

• Alpha-hemolysin
• Cytotoxic necrotizing factor–1
• Cytolethal distending toxin
• Secreted autotransporter toxin

No single VF is sufficient or necessary to promote pathogenesis. Apparently, multiple VFs are necessary to ensure pathogenesis, although adhesins play an important role.

Asymptomatic bacteriuria strains

Bacterial strains that produce ABU may in some instances provide a measure of protection against symptomatic infections from UPEC and other organisms. On the other hand, ABU may also cause increased morbidity and mortality. Once bacteriuria is established, these strains appear to stop producing adhesins, allowing them to survive and persist without producing an inflammatory reaction.

Pathogens

As noted above, UPEC account for most uncomplicated pyelonephritis cases and a significant portion of complicated pyelonephritis cases. The following microorganisms are also commonly isolated:

• Staphylococcus saprophyticus
• Klebsiella pneumoniae
• Proteus mirabilis
• Enterococci
• S aureus
• Pseudomonas aeruginosa
• Enterobacter species

This is the same spectrum of organisms cultured in cystitis. In 10-15% of symptomatic cystitis cases, cultures using routine methods remain negative, although the symptoms typically respond to antibiotic therapy. In some cases, cultures using selective media have grown Gardnerella vaginalis, Mycoplasma hominis, and Ureaplasma urealyticum. These data cannot be extended to acute pyelonephritis, but they do illustrate the difficulties in isolating the causative organism.

Epithelial attachment and inflammatory response

Evidence suggests that the pathogenesis of pyelonephritis takes a 2-step path. First, UPEC attaches to the epithelium and triggers an inflammatory response involving at least 2 receptors, glycosphingolipid (GSL) and Toll-like receptor 4 (TLR4). In the mouse model, GSL is the primary receptor and TLR4 is recruited and is an important receptor for the release of chemokines. When TLR4 is genetically absent, an asymptomatic carrier state develops in the infected mice.

Second, as a result of the inflammatory response, chemokines (eg, interleukin-8 [IL-8], which is chemotactic for PMNs) are released and attach to the neutrophil-activating chemokine receptor 1 (CXCR1), allowing PMNs to cross the epithelial barrier into the urine. In children prone to pyelonephritis, for example, CXCR1 expression has been shown to be significantly lower than in control subjects.

Several other host factors militate against symptomatic UTI. Phagocytosis of bacteria in urine is maximized at pH 6.5-7.5 and osmolality of 485 mOsm; values deviating from these ranges lead to significantly reduced or absent phagocytosis. Other important factors are the flushing action of urine flow in the ureter and bladder, the inhibition of attachment of type 1 fimbriae E coli to uroepithelial cells by tubular cell–secreted Tamm-Horsfall protein, and the inhibition of attachment by some surface mucopolysaccharides on the uroepithelial cells.

Complicated infection

Complicated UTI is an infection of the urinary tract in which the efficacy of antibiotics is reduced because of the presence of one or more of the following:

• Structural abnormalities of the urinary tract
• Functional abnormalities of the urinary tract
• Metabolic abnormalities predisposing to UTIs
• Unusual pathogens
• Recent antibiotic use
• Recent urinary tract instrumentation

For more information on this topic, see Pathophysiology of Complicated Urinary Tract Infections.

Obstruction

Obstruction is the most important factor. It negates the flushing effect of urine flow; allows urine to pool (urinary stasis), providing bacteria a medium in which to multiply; and changes intrarenal blood flow, affecting neutrophil delivery. Obstruction may be extrinsic or intrinsic. Extrinsic obstruction occurs with chronic constipation (particularly in children), prostatic swelling/mass (eg, hypertrophy, infection, cancer), and retroperitoneal mass.

Intrinsic obstruction occurs with bladder outlet obstruction, cystocele, fungus ball, papillary necrosis, stricture, and urinary stones. With increasing size of stone, the probability of stone passage decreases while the probability of obstruction increases. Nonetheless, stones as small as 2 mm have resulted in obstruction, while 8-mm stones have occasionally passed spontaneously.

Infectious stones, urease stones, or triple-phosphate stones composed of magnesium ammonium phosphate or struvite and apatite account for 10-15% of all urinary stones. They develop secondary to the action of urea-splitting organisms and can grow rapidly and branch out (ie, staghorn calculi).

If left untreated, staghorn calculi will destroy the kidney and may cause the death of the patient. Complications include azotemia, hydropyonephrosis, perinephric abscess, pyelonephritis (severe or end-stage), sepsis, and xanthogranulomatous pyelonephritis.

Incomplete bladder emptying may be related to medication (eg, anticholinergics). The spermicide nonoxynol-9 inhibits the growth of lactobacilli. Lactobacilli produce hydrogen peroxide, which protects the vaginal ecosystem against pathogens. Frequent sexual intercourse causes local mechanical trauma to the urethra in both partners.

Atrophic vaginal mucosa in postmenopausal women predisposes to the colonization of urinary tract pathogens and UTIs because of the higher pH (5.5 vs 3.8) and the absence of lactobacilli. Bacterial prostatitis (acute or chronic) produces bacteriuria, whereas nonbacterial prostatitis and pelviperineal pain syndrome (prostadynia) do not.

Unusual organisms include Mycoplasma, Pseudomonas, and urea-splitting organisms. Pseudomonas aeruginosa has several mechanisms that promote adherence, including alginate, other membrane proteins, pili, and surface-associated exoenzyme S.

Urea-splitting organisms produce urease, which hydrolyzes urea, yielding ammonia, bicarbonate, and carbonate; this leads to a more alkaline urine and allows crystal formation (staghorn calculus) from the supersaturation of carbonate apatite and struvite. Staghorn calculi continue to grow in size, leading to infection, obstruction, or both.

Complications of obstruction with superimposed infection include hydronephrosis, pyonephrosis, urosepsis, and xanthogranulomatous pyelonephritis. Additionally, the pathogens can sequester in the struvite stones, protected from the host’s immune system. Proteus species are the most common urea-splitting organisms. E coli, Klebsiella, Pseudomonas, and Staphylococcus can also produce urease, however, and are sometimes involved in staghorn calculus formation.

Pregnancy

Pregnancy produces hormonal and mechanical changes that predispose the woman to upper urinary traction infections. Hydroureter of pregnancy, secondary to both hormonal and mechanical factors, manifests as dilatation of the renal pelvis and ureters (greater on the left than on the right), with the ureters containing up to 200 mL of urine. Progesterone decreases ureteral peristalsis and increases bladder capacity. The enlarging uterus displaces the bladder, contributing to urinary stasis. 

Diabetes

Diabetes mellitus produces autonomic bladder neuropathy, glucosuria, leukocyte dysfunction, microangiopathy, and nephrosclerosis; additionally, it leads to recurrent bladder instrumentation secondary to the neuropathy. Complicated UTIs in patients who have diabetes mellitus include the following:

• Renal and perirenal abscess
• Emphysematous pyelonephritis
• Emphysematous cystitis
• Fungal infections
• Xanthogranulomatous pyelonephritis
• Papillary necrosis

Uropathogens that cause the majority of acute pyelonephritis cases and the frequency with which they are cultured in uncomplicated versus complicated cases, are listed in Table 1. Unusual pathogens include mycobacteria, yeasts and fungi, and opportunistic pathogens such as Corynebacterium urealyticum.

Table 1. Bacterial Etiology of Urinary Tract Infections (Open Table in a new window)

Epidemiologic data on the incidence of pyelonephritis are limited. A population-based study of acute pyelonephritis in the United States found overall annual rates of 15-17 cases per 10,000 females and 3-4 cases per 10,000 males.[5] In women aged 18−49 years, the estimated incidence is 28 cases per 10,000.[8]  At least 250,000 cases of pyelonephritis are diagnosed annually in the United States. The cost of treating acute pyelonephritis has been estimated to be $2.14 billion per year.[5]

Acute pyelonephritis develops in 20-30% of pregnant women with untreated asymptomatic bacteriuria (ABU) (2-9.5%), most often during the late second and early third trimesters. The incidence of pyelonephritis in infants and children is difficult to ascertain because of the infrequency of typical symptoms. Up to 25% of children with UTI and no signs or symptoms of pyelonephritis do have bacteria demonstrable in the upper urinary tract.

No racial predilection of pyelonephritis has been demonstrated. Pyelonephritis is significantly more common in females than in males, although this difference narrows considerably with increasing age, especially in patients aged 65 years and older. In females, pyelonephritis shows a trimodal distribution, with an elevated incidence in girls aged 0-4 years, a peak in women 15-35 years of age, and a gradual increase after age 50 years to another peak at 80 years of age.[5]

In males, the age distribution of pyelonephritis is bimodal. Males also demonstrate a peak incidence of pyelonephritis at 0-4 years of age. Rates gradually increase after 35 years of age and peak at 85 years of age.[5]

Acute pyelonephritis shows a seasonal variation. In Washington state, cases occurred most frequently during the months of July and August among females and during August and September in the male population.[5]

Timely diagnosis and management of acute pyelonephritis has a significant impact on the outcome. Any patient with acute pyelonephritis who deteriorates suddenly or does not respond to conventional therapy may have a complication, resistant organism, or unrecognized comorbidity.

Pyelonephritis causes considerable morbidity. Data can be extrapolated from the morbidity data for acute lower urinary tract infections: specifically, acute cystitis in women produces approximately 6.1 days with symptoms, 2.4 days of restricted activity, 1.2 days that the patient is unable to work or attend class, and 0.4 days bedridden.  In women aged 18−49 years, 7% of pyelonephritis cases require hospital admission.[8]

For patients with pyelonephritis who have an organ-threatening infection, the follow-up examination is important to be sure that the patient is progressing satisfactorily and that recovery is complete. Failure to diagnose these complications in a timely fashion could predispose the patient to a poor outcome. Pregnant patients with pyelonephritis are at significant risk for premature labor.

Kofteridis et al found that acute pyelonephritis is linked to bacteremia, longer hospital stays, and higher mortality in patients with diabetes mellitus.[9] In a retrospective study of 206 elderly patients, 88 of whom had diabetes, bacteremia occurred in 30.7% of patients with diabetes but in only 11% of the control patients. Moreover, compared with the control patients, patients with diabetes had longer-lasting fevers (median, 4.5 vs 2.5 days), longer hospital stays (median, 10 vs 7 days), and higher mortality (12.5% vs 2.5%).

Mortality is higher in patients older than 65 years; it is also higher with septic shock, bedridden status, and immunosuppression. In men, mortality is also increased with use of antibiotics during the previous month. Morbidity (prolonged hospital stay) in both men and women is increased with a change in initial treatment, diabetes mellitus, and long-term indwelling catheter.

Uncomplicated pyelonephritis

In healthy, nonpregnant women with uncomplicated disease, the prognosis is excellent for full recovery and minimal damage to the kidney. In healthy men without any known complicating conditions, the prognosis is good for full recovery; however, urologic evaluation is recommended to rule out an underlying complicating condition. In infants and children, the prognosis is good. Importantly, children should undergo a urologic evaluation after the first episode to rule out structural abnormalities.

Uncomplicated pyelonephritis is not a fatal disease in the antibiotic era. Pyelonephritis becomes a potentially fatal disease when secondary conditions develop, such as emphysematous pyelonephritis (20-80% mortality rate), perinephric abscess (20-50% mortality rate), or one of the sepsis syndromes (>25% overall mortality rate).

Emphysematous pyelonephritis

In emphysematous pyelonephritis, the mortality rate is 60% in cases in which the gas is localized to the renal parenchyma, regardless of treatment. The mortality is 80% if the gas has spread in the perinephric space and the patient is treated with antibiotics alone. In emphysematous pyelitis, the mortality rate is 20%.

Sepsis

The genitourinary system is the source of severe sepsis in 9.1% of all cases annually. The mortality for these GU-related cases is 16.1%. Overall mortality from severe sepsis significantly increases with chronic kidney disease (36.7%), acute renal dysfunction (38.2%), and age older than 64 years (25-42% with progressively increasing age to older than 85 years). In the age range of 0-4 years, the mortality is 5%; for ages 5-50 years, it is less than 3%.

Acute kidney injury

Rarely, acute pyelonephritis can cause acute kidney injury (AKI) in children, healthy adults, and pregnant women. When this occurs, characteristically, recovery proceeds more slowly than with AKI from other causes. In most instances, other factors are thought to contribute to the AKI (eg, medications, hypovolemia, obstruction, sepsis). In a retrospective review of 403 adult patients hospitalized for acute pyelonephritis, multivariate analysis showed that age over 65, complicated or bilateral pyelonephritis, and initial shock were independent risk factors for the occurrence of AKI.[10]

A Danish population-based cohort study of 8760 patients found that preadmission impaired kidney function is a strong risk factor for development of AKI in patients with pyelonephritis. The 30-day risk of AKI rose steadily from 16% in patients with a preadmission estimated glomerular filtration ration (eGFR) ≥90 mL/min/1.73 m2 to 47% for patients with preadmission eGFR of < 30.[11]

Kidney scarring

In children, kidney scarring can be detected in 6-15% after a febrile UTI. Of these patients, almost all males and some females have demonstrable kidney scarring and a globally small kidney with smooth renal outlines in infancy, usually associated with vesicoureteral reflux (VUR) and thought to be congenital. Most female infants do not have demonstrable scarring on initial imaging, but they subsequently develop it. Delay in treatment of cystitis or pyelonephritis, recurrent UTIs, urinary obstruction, and VUR increase the risk of scarring. In children, normal ultrasonogram findings alone cannot reliably rule out the presence of either reflux or kidney scarring.[12]

Acute pyelonephritis (single episode; first UTI ever in one half of cases) in an adult woman leads to kidney scarring in 46%, as demonstrated by scintigraphic scanning 10 years later. Subsequent UTIs do not appear to affect the risk of future scarring.

Kidney scarring has been demonstrated to be 4 times more likely after pyelonephritis in pregnant women than in nonpregnant women. In addition, acute pyelonephritis during pregnancy is associated with the following complications:

• Acute kidney dysfunction (elevated creatinine) in 2% of cases (20-25% in the past)
• Acute kidney injury in 0.03% of cases
• Acute respiratory distress syndrome (bilateral chest radiograph infiltrates and hypoxemia without pulmonary hypertension) in 1-8% of cases
• Low birth weight (< 2500 g) in 7% of cases
• Preterm delivery (< 37 wk gestation) in 5% of cases (6-50% in the past)
• Recurrence prior to delivery in 18-20% of cases
• Sepsis (positive blood cultures) in 17% of cases

Kidney transplant pyelonephritis

Acute kidney transplant pyelonephritis occurring in the first 3 months after transplant has a significant association with graft loss (>40%) by 96 months, as compared with all kidney transplant cases with or without the occurrence of pyelonephritis at any time after the transplant up to 96 months (25-30%).

Patients must take antibiotics as directed and complete the course as prescribed. This minimizes the risk of recurrence and the development of resistant organisms.

Patients should be advised to drink plenty of fluids, as avoidance of dehydration is important for both patient well-being and kidney function. When under stress, men typically drink only enough liquid to replace two thirds of the loss. When ill, individuals drink less and predispose themselves to dehydration. Unavoidable daily water loss is 1.5 L, of which approximately 500 mL is replaced by the oxidation of carbohydrates. Because patients cannot measure urine specific gravity at home, they should drink enough water or other liquid to produce light-colored urine, almost like water.

For patient education information, see Kidney Infection.

The classic presentation in acute pyelonephritis is the triad of fever, costovertebral angle pain, and nausea and/or vomiting. These may not all be present, however, or they may not occur together temporally. Symptoms may be minimal to severe and usually develop over hours or over the course of a day. Infrequently, symptoms develop over several days and may even be present for a few weeks before the patient seeks medical care. Symptoms of cystitis may or may not be present to varying degrees. These may include urinary frequency, hesitancy, lower abdominal pain, and urgency.

Gross hematuria (hemorrhagic cystitis) is present in 30-40% of pyelonephritis cases in females, most often young women. Gross hematuria is unusual in males and should prompt consideration of a more serious cause.

Pain may be mild, moderate, or severe. Flank pain may be unilateral or sometimes bilateral. Discomfort or pain may be present in the back (lower or middle) and/or the suprapubic area. Patients may describe suprapubic symptoms as discomfort, heaviness, pain, or pressure. Upper abdominal pain is unusual, and radiation of pain to the groin is suggestive of a ureteral stone.

Fever is not always present. When present, it is not unusual for the temperature to exceed 103°F (39.4°C). The patient may demonstrate rigor, and chills may be present in the absence of demonstrated fever. Malaise and weakness may also be present.

Gastrointestinal symptoms vary. Anorexia is common. Nausea and vomiting vary in frequency and intensity from absent to severe. Diarrhea occurs infrequently.

The classic signs and symptoms observed in adults are often absent in children, particularly neonates and infants. In children 2 years of age and younger, the most common symptoms of urinary tract infection (UTI) are failure to thrive, feeding difficulty, fever, and vomiting. When fever is present, pyelonephritis should be in the differential diagnosis.

Elderly patients may present with typical manifestations of pyelonephritis, or they may experience fever, mental status change, decompensation in another organ system, or generalized deterioration.

Complicated pyelonephritis

A history of the following indicates an increased risk of complicated pyelonephritis:

• Structural abnormalities of the urinary tract
• Functional abnormalities of the urinary tract
• Metabolic abnormalities predisposing to UTIs
• Recent antibiotic use
• Recent urinary tract instrumentation

The presence of any one of the above complicating factors should raise the clinician’s index of suspicion. In many instances, more than one complicating factor is involved. In addition, if the patient is male, elderly, or a child or has had symptoms for more than 7 days, the infection should be considered complicated until proven otherwise.

The patient may or may not have a fever. If fever is present, the temperature may be greater than 103°F (39.4°C). In contrast, the temperature may be subnormal in patients with associated sepsis. Tachycardia may or may not be present, depending on associated fever, dehydration, and sepsis.

Blood pressure is usually within the reference range, unless the patient has underlying hypertension, in which case the pressure may be elevated above the patient's baseline. A systolic blood pressure below 90 mm Hg suggests shock secondary to sepsis or perinephric abscess.

The patient's appearance is variable. Most commonly, the patient is uncomfortable or appears ill. Patients usually do not have a toxic appearance, unless there is an underlying problem, such as sepsis, perinephric abscess, or significant dehydration.

On abdominal examination, suprapubic tenderness usually ranges from mild to moderate without rebound. Abdominal tenderness other than in the suprapubic area suggests another diagnosis. Patients usually do not have rigidity or guarding, and bowel sounds are often normally active.

Flank or costovertebral angle (CVA) tenderness is most commonly unilateral over the involved kidney, although bilateral discomfort may be present. Discomfort varies from absent to severe. This finding is usually not subtle and may be elicited with mild or moderately firm palpation.

In women, a pelvic examination should be performed. Tenderness of the cervix, uterus, and adnexa should be absent. Any positive finding suggests an additional or alternative diagnosis. A gynecologic cause of the symptoms should be pursued if any of the following are present:

• Doubt as to the diagnosis
• Signs or symptoms of urethritis or vaginitis
• A history of dyspareunia

Complications occur more often in patients with diabetes mellitus, chronic kidney disease, sickle cell disease, kidney transplant (particularly during the first 3 months), AIDS, and other immunocompromised states. It can sometimes be difficult to determine whether the entities listed below are occurring as a complication of pyelonephritis or are occurring in the absence of pyelonephritis but with signs and symptoms suggestive of pyelonephritis. The important point is to have a high index of suspicion for these complications.

Complications may involve any of the following:

• Acute kidney injury
• Chronic kidney damage leading to hypertension and kidney failure
• Sepsis syndromes
• Renal papillary necrosis
• Xanthogranulomatous pyelonephritis

Abscesses

Abscesses may include renal cortical abscess, renal corticomedullary abscess, or perinephric abscess. Older adults have a higher incidence of renal corticomedullary abscesses, which affect men and women equally.

Corticomedullary abscess

Patients with renal corticomedullary abscesses often present with chills, fever, and flank or abdominal pain, and patients may have dysuria and/or nausea and vomiting. Leukocytosis may be present. Bacteriuria, pyuria, hematuria, or proteinuria may be present, as the intrarenal abscesses drain in the collecting system, but the urinalysis results may be normal in as many as 30% of patients. Bacteremia may be observed in acute focal or multifocal bacterial nephritis.

Corticomedullary abscess is usually associated with a urinary tract abnormality, such as vesicoureteral reflux or obstruction. It is commonly caused by Enterobacteriaceae.

The pathology represents a spectrum of disease, as follows:

• Acute focal bacterial nephritis (eg, acute lobar nephroma, focal pyelonephritis) that affects a single renal lobe, with interstitial inflammation represented by marked polymorphonuclear leukocytes
• Acute multifocal bacterial nephritis, with a similar process throughout the kidney that produces liquefaction and abscess formation
• Xanthogranulomatous pyelonephritis, with chronic parenchymal infection, granulomatous tissue, and perirenal fibrosis
• Emphysematous pyelonephritis, with severe, necrotizing infection

Perinephric abscess

The suppurative material of the abscess is located between the renal capsule and the surrounding renal fascia. The material is secondary to chronic or recurrent pyelonephritis; rupture or extension of a suppurative process from within the kidney; or dissemination (blood, lymph) or direct extension from other sites of infection. Although it is usually confined to the perinephric space, it may extend to the colon, flank, groin, lung (empyema, nephrobronchial fistula), paracervical area, peritoneal cavity, psoas muscle, skin surface, or subphrenic space.

Development is insidious. Presentation may include the following:

• Fever
• Chills
• Unilateral flank pain (70%)
• Dysuria (40%)
• Nausea
• Vomiting
• Weight loss (25%)
• Flank tenderness
• Costovertebral angle tenderness
• Abdominal tenderness (60%)
• Referred pain (ie, hip, thigh, or knee)
• Flank or abdominal mass (< 50%)
• Pyuria (70%)
• Sterile urine (40%)
• Bacteremia (40%)
• Curvature of the spine away from the involved kidney

One third of patients are diagnosed upon admission; another third are diagnosed at autopsy. Perinephric abscess is not usually readily apparent; a high index of clinical awareness is necessary.

Renal cortical abscess

Renal cortical abscess (renal carbuncle) is an uncommon condition that is usually caused by the hematogenous spread of S aureus. It occurs 3 times more commonly in men than in women. Microabscesses develop in the cortex and coalesce to form a circumscribed abscess that may or may not communicate with the collecting system. This process takes days to months.

Patients with renal cortical abscess may present with chills, fever, and flank or abdominal pain. A flank mass or a bulge in the lumbar region may be evident. Some patients have abnormal results on lung examination of the affected side (dullness to percussion, rales). Blood and urine culture results usually are negative, but the white blood cell (WBC) count is often elevated.

Emphysematous pyelonephritis, pyelitis, and cystitis

Emphysematous pyelonephritis, which most commonly occurs in persons with diabetes, is a severe, necrotizing form of acute multifocal bacterial nephritis with extension of the infection through the renal capsule. This leads to the presence of gas within the kidney substance and in the perinephric space. Persons with diabetes (with or without obstruction) account for 85-100% of cases, although some cases have occurred in patients without diabetes who had obstruction. Females outnumber males (2-6:1).

Emphysematous pyelonephritis occurs in the left kidney in approximately two thirds of cases. The etiology is usually Enterobacteriaceae (E coli, 60%), with some reported cases of Streptococcus species and Candida species. A triad of diabetes, obstruction, and remote or recent pyelonephritis should raise clinical suspicion. Patient presentation includes fever, chills, abdominal pain, nausea, vomiting, flank pain, flank mass (50%), crepitation (over thigh or flank), urinary symptoms, and pyuria.

Emphysematous pyelitis (pneumopyonephrosis) involves gas that is localized to the collecting system. Diabetes mellitus is present in 85-100% of patients. The left kidney is more frequently affected than the right. Presentation is similar to that of pyelonephritis. On plain radiographs, the gas pattern is noted in the renal pelvis and may be seen in the ureter. The patient should be admitted and treated with intravenous antibiotics. The mortality rate is 20%.

Emphysematous cystitis (cystitis emphysematosa) involves gas that is localized to the bladder secondary to a bladder infection. Gas in the bladder is more frequently related to a fistula between the bladder and the colon or vagina than to a gas-producing infection. As many as 80% of patients are diabetic.

Patient presentation is similar to that for pyelonephritis. Plain radiographs may demonstrate gas in the bladder wall or lumen, an air-fluid level in the bladder, or a cobblestone appearance to the bladder wall. CT scan is the study of choice to help localize the gas to the proper organ. Treatment involves intravenous antibiotics and relief of any outlet obstruction. This condition is not as serious as the other two previously described emphysematous conditions.

Xanthogranulomatous pyelonephritis

Xanthogranulomatous pyelonephritis is a rare form of pyelonephritis that is almost always associated with chronic obstruction (eg, from staghorn calculus [75% of cases], other calculus, stricture, or tumor).  This disease is usually unilateral and most frequently affects the right kidney.[13]

In adults, the female-to-male ratio is 3:1; in children, it is 1.1:1. It is a chronic infection that finally manifests acutely with fever and flank pain or tenderness, and it may be complicated by a flank mass, cutaneous fistula, septic arthritis, or hematochezia if extension has occurred beyond the renal capsule. Kidney function is absent (71%) or poor (25%) in almost all cases.  A biopsy should be performed to confirm the diagnosis and exclude renal carcinoma.[13]

Tuberculosis

Tuberculosis (TB) of the kidney results from hematogenous spread but is relatively rare in developing countries. Unlike most other extrapulmonary manifestations of the disease, TB of the kidney does not become manifest until 5-15 years after the primary infection. Constitutional symptoms are uncommon, and most patients present with symptoms of bladder irritation.

Initially, pyuria is observed, and with progression of the disease, proteinuria and blood may be observed as well. Repeated urine samples should be sent for mycobacterial culture. A loss of calyceal architecture and ureteric obstruction may be observed on imaging studies.

Concurrent pulmonary disease is present in 5% of patients, and the tuberculin test rarely is helpful. Antituberculous medicines should be administered for 6 months. If the ureter is obstructed, corticosteroids have been advocated; if obstruction persists, surgical intervention is necessary.

In the outpatient setting, pyelonephritis is usually suggested by the history and physical examination and supported by urinalysis results, which should include microscopic analysis. Other laboratory studies are used to identify complicating conditions and to assist in determining whether the patient should be admitted.

Easily diagnosed cases typically occur in women, both pregnant and nonpregnant.[14] Insidious onset may occur in the following:

• Men
• Patients at the extremes of age
• Patients harboring subclinical pyelonephritis
• Hospitalized patients

Imaging studies may be required to make the diagnosis in infants and children in whom pyelonephritis presents insidiously. Imaging studies are rarely indicated for the diagnosis of acute pyelonephritis in an adult who presents with typical signs and symptoms, but they may be warranted if the presentation is atypical or confusing. Imaging is also warranted if the patient deteriorates or does not respond to therapy, in which case the important considerations are nephrolithiasis, obstructive uropathy, and perinephric abscess.

Urine specimens obtained for urinalysis and culture should approximate the urine contained in the bladder as closely as possible. The procedures for collecting such a urine specimen are as follows:

• Clean catch
• Urethral catheterization
• Suprapubic needle aspiration

Clean catch

When properly collected, a clean-catch specimen adequately reflects the microbiology of the urine in the bladder. This technique can be performed by ambulatory females aged 6 years and older who do not have any limiting physical handicap.

Importantly, female patients should wash only the area where urine is passed, wash front to back, hold the cup by the outside, and keep the labia spread while collecting the urine. This is to ensure that the urine goes into the cup without touching the labia. The presence of a large number of epithelial cells on microscopic examination suggests that the specimen is not a true clean catch and is unreliable for culture because of contamination with vaginal contents.

Clean-catch technique can also be performed by ambulatory males aged 6 years and older who do not have any limiting physical handicap. Specimens are usually reliable. Importantly, the patient should clean the head of the penis, retract the foreskin (if uncircumcised), maintain a good stream, and hold the cup by the outside. In the presence of epispadias or hypospadias, care must be taken to maintain a good stream while collecting the specimen.

Urethral catheterization

Catheterization poses a small risk of introducing bacteria into the normally sterile bladder environment. Circumstances that justify this risk when a urine culture is necessary include the following:

• Inability to void, or difficulty voiding urine even with hydration
• Marked obesity or redundant labia in females
• Ill patients who cannot reliably perform the procedure
• Performance of a urologic procedure during which a specimen can be collected
• Children 2-6 years of age (if a clinician-assisted clean-catch specimen cannot be collected)

For details on performing this procedure, see Urethral Catheterization in Women and Urethral Catheterization in Men.

Suprapubic needle aspiration

Suprapubic needle aspiration is rarely necessary. Indications are as follows:

• An alternative is lacking
• To exclude contamination from other methods of collection
• To verify the presence of an infecting organism that is otherwise considered a contaminant
• To verify infection in an infant who has a positive culture result from a specimen obtained from a strap-on device

For details on performing this procedure, see Suprapubic Aspiration.

Pyuria is defined as more than 5-10 white blood cells (WBCs) per high-power field (hpf) on a specimen spun at 2000 rpm for 5 minutes. Almost all patients with pyelonephritis have significant pyuria (> 20 WBCs/hpf), although the numbers may be smaller, particularly in those with subacute pyelonephritis.

The dipstick leukocyte esterase test (LET) helps screen for pyuria. LET results have a sensitivity of 75-96% and a specificity of 94-98% for detecting more than 10 WBC/hpf.

The nitrite production test (NPT) for bacteriuria has 92-100% sensitivity and 35-85% specificity. It may be falsely negative in the presence of diuretic use, low dietary nitrate, or organisms that do not produce nitrate reductase (eg, Enterococcus, Pseudomonas, Staphylococcus). Combined, the LET-NPT has a sensitivity of 79.2% and a specificity of 81%, which is too low for it to be used as the only screening study for bacteriuria.

Gross hematuria occurs infrequently with pyelonephritis and is more common with cystitis (hemorrhagic cystitis). When gross hematuria is present, the differential should include calculi, cancer, glomerulonephritis, tuberculosis, trauma, and vasculitis.

Microscopic hematuria may be present in patients with uncomplicated acute pyelonephritis, but other causes should be considered, particularly calculi. This is especially true if the patient does not respond to therapy. White cell casts are suggestive of pyelonephritis; however, centrifuge speeds (> 2000 rpm) used for urinalysis sediment preparation often fracture them and lead to their absence in the sediment.

Proteinuria is expected (up to 2 g/day). When it exceeds 3 g/day, glomerulonephritis should be considered.

The presence of a single bacterium in an unspun urine specimen by oil-immersion microscopic examination is equivalent to at least 105 colony-forming units (cfu)/mL. Bacteria are identified much more easily on a stained versus an unstained specimen.

Urinary neutrophil gelatinase-associated lipocalin

Urinary neutrophil gelatinase-associated lipocalin (NGAL) is a sensitive biomarker for the diagnosis of acute pyelonephritis in children. In a case-control study of 134 children with acute pyelonephritis or febrile states of other etiology, NGAL values were significantly higher in children with acute pyelonephritis. At a cut-off value of 29.4 ng/mL, urinary NGAL had 92.5% sensitivity and 90.7% specificity for diagnosing acute pyelonephritis. NGAL was also useful for differentiating acute pyelonephritis from cystitis and differentiating cystitis from febrile states with etiology other than urinary tract infection.[15]

Urinary concentrations of NGAL may also help identify children with acute pyelonephritis who are at increased risk of developing kidney scarring. In a study of 54 children, urinary NGAL levels were significantly higher in patients with acute pyelonephritis with scarring than in those without scarring. At a cut-off value of 7.32 ng/ml, the sensitivity and specificity of this marker for diagnosing scar formation were 81.3% and 66%, respectively.[16]

Urine culture is indicated in any patient with pyelonephritis, whether treated in an inpatient or an outpatient setting, because of the possibility of antibiotic resistance. Reliable results require proper specimen collection.

Blood cultures are indicated in any patient who is being admitted or who has already been admitted. Approximately 12-20% of patients have cultures that are positive for infection. Bacteremia has not been associated with a poor outcome unless sepsis or another significant comorbidity is present.

Imaging may be required to make the diagnosis in infants and children in whom pyelonephritis presents insidiously. Imaging is warranted at the time of admission in patients with the following conditions:

• AIDS
• Poorly controlled diabetes
• Organ transplant (particularly kidney)
• Other immunocompromised state
• Sepsis syndrome
• Septic shock

Imaging early in the presentation of acute pyelonephritis may be more useful than previously thought. In one study, 16% of patients admitted for acute pyelonephritis were found to have new and clinically significant abnormalities on kidney imaging at the time of admission. Later in the hospital course, imaging studies are used for the prompt evaluation of a potentially organ- or life-threatening complication.

Indications for imaging studies are as follows:

• Fever or positive blood culture results that persist for longer than 48 hours
• Sudden worsening of the patient’s condition
• Toxicity persisting for longer than 72 hours
• Complicated urinary tract infection

After acute pyelonephritis has resolved, imaging studies may be used during a follow-up examination to identify urinary tract abnormalities that can predispose the patient to infection. In addition, studies may be used in conjunction with urologic procedures, including cystoscopy.

Contrast-enhanced helical/spiral computed tomography (CECT) is the imaging study of choice, both in adults and in children with acute pyelonephritis[17] . CECT is more sensitive than ultrasonography and intravenous pyelography (which has only 25% sensitivity), and it can more readily identify alterations in kidney parenchymal perfusion, alterations in contrast excretion, perinephric fluid, and nonrenal disease.

Noncontrast helical/spiral CT findings may be normal in acute pyelonephritis with mild parenchymal involvement, but the findings are usually positive when the involvement is moderate or severe. It is the standard study for demonstrating gas-forming infections, hemorrhage, inflammatory masses, and obstruction.

If findings are suggestive of nephrolithiasis complicating the presentation, a noncontrast CT scan of the kidneys, ureters, and bladder (KUB) or a CT urogram should be obtained to exclude the possibility of obstruction or hydronephrosis.[18] CT has 97% accuracy in identifying kidney stones. (See the images below.)

Nonobstructing distal left ureteral calculus 2 X 1 X 2 cm.

Bilateral hydronephrosis.

Abscesses typically appear on CT scans as low-density masses with contrast enhancement of the wall from inflamed/dilated blood vessels (see the image below). Acute focal bacterial nephritis has a lobar distribution of inflammation, wedge-shaped hypodense lesions (postcontrast), and masslike hypodense lesions in severe infections. Xanthogranulomatous pyelonephritis (see the images below, as well as Xanthogranulomatous Pyelonephritis Imaging) may have the following CT features:

• Large kidney calculi
• Nonfunctioning kidneys
• Contrast enhancement around low-attenuation areas
• Thickening of the Gerota fascia
• Spherical areas of low attenuation

Multiple abscesses, upper pole of left kidney.

Magnetic resonance imaging (MRI) can detect kidney infection or masses and urinary obstruction, and it can evaluate the kidney vasculature. Although American College of Radiology Appropriateness Criteria finds CT most appropriate for imaging, MRI and ultrasound are the primary imaging modalities used in pregnant patients with acute pyelonephritis.[17]

A study of diffusion-weighted MRI found that MRI had higher sensitivity than CT (with or without contrast) for the diagnosis of acute pyelonephritis, and could differentiate areas of nephritis and kidney abscesses. However, MRI was less useful than CT for the diagnosis of renal calculi and emphysematous pyelonephritis.[19]

As there is no radiation exposure, MRI can be used in pregnancy.[20] The cost and availability of MRI remain concerns, however.[20]

Ultrasonography (US) can sometimes detect acute pyelonephritis, but a negative study does not exclude the possibility. Power Doppler US is superior to color Doppler US in the detection of pyelonephritis but remains inferior to contrast-enhanced helical/spiral computed tomography (CECT).

Kidney US is nevertheless a useful imaging modality in patients with complicated UTIs, and it may be performed at the bedside in a patient who is hemodynamically unstable. It is relatively inexpensive and does not involve radiation or iodinated contrast. It is an alternative to CT to identify hydronephrosis if there is concern regarding nephrolithiasis.[18] US is useful in screening for urinary obstruction in children admitted for febrile illnesses.

In a study of 207 patients with acute pyelonephritis, Enikeev et al reported that the main findings on US were the following[21] :

• Decreased mobility of the kidney
• Enlargement of the kidney
• Thickened parenchyma
• Hydrophilic parenchyma
• Impairment of corticomedullary differentiation

 On US, a kidney abscess may appear as a fluid-filled mass with a thick wall. Acute focal bacterial nephritis appears as a poorly defined mass with low-amplitude echoes and disruption of the corticomedullary junction. In xanthogranulomatous pyelonephritis, imaging reveals stones in approximately 70% of patients.

US findings may be falsely negative in 36% of cases of perinephric abscesses. Other drawbacks to US are the difficulty in differentiating kidney abscess from tumor and the difficulty in interpreting results in obese patients. Angiography may help differentiate kidney abscess from kidney tumor because an abscess often has increased peripheral vascularization, while the remainder of the mass is avascular.

Scintigraphy with technetium-99m dimercaptosuccinic acid (99mTc-DMSA) is almost as sensitive clinically as contrast-enhanced helical/spiral computed tomography (CECT) in detecting focal kidney abnormalities during acute pyelonephritis in adults. DMSA is a radiotracer that localizes to the kidney cortex. This modality is not used much in adults, however, because the findings are not specific; focal abnormalities may indicate abscess, cyst, infarct, pyelonephritis, or tumor. Additionally,99mTc-DMSA scintigraphy is much less available in the acute setting than CECT.

In children, however,99mTc-DMSA scintigraphy is the preferred study, because it involves less radiation exposure than CT scans. It is excellent for helping detect inflammation, scarring, and the distribution of function between kidneys.

In pediatric studies, diffusion-weighted magnetic resonance imaging (DW-MRI) compares favorably with 99mTc-DMSA scintigraphy. A study in seven children with acute pyelonephritis diagnosed on scintigraphy within 7 days of fever onset found that whole-body non-enhanced DW-MRI had 80% sensitivity and 100% specificity for detecting acute pyelonepritis lesions.[22]

Bosakova et al reported that non-contrast DW-MRI has higher sensitivity than 99mTc-DMSA scintigraphy for detecting acute inflammatory kidney lesions and multifocal lesions in pediatric patients with acute pyelonephritis. Their prospective study included 31 children aged 3-18 years with a first episode of febrile urinary tract infection and without a previously detected congenital urinary tract malformation, who were evaluated within 5 days of diagnosis. DW-MRI confirmed acute inflammatory changes of the kidney parenchyma, mostly unilateral, in all 31 patients, whereas scintigraphy detected inflammatory lesions in 22 (100% versus 71%; P = 0.002). [23]

CT urography and MR urography are evolving modalities that surpass intravenous urography, which was the prior mainstay of urinary tract imaging.[24] CT urography provides a detailed anatomic depiction of the urinary tract. MR urography has the advantage of not using ionizing radiation and has the potential to provide more functional information than CT. However, MR urography is less established than CT urography and is less reliable in providing diagnostic image quality.[24]

CT urography and MR urography are currently used in the evaluation of hematuria and will become more applicable to the study of other urologic problems.

Histology and/or imaging studies may help make the diagnosis of papillary necrosis. The sloughed papillae may be obtained by straining the urine and sending for histology. Retrograde pyelography is the radiologic procedure of choice, but ultrasonography or CT scan also reveals the diagnosis.

Findings of early renal papillary necrosis include a dilated calyceal fornix, retracted or irregular papillary tip, and extension of contrast into the parenchyma. A club-shaped cavity in the medulla or papilla may be formed in later disease. When a separated papilla is surrounded by contrast, a ring may be visualized, which is characteristic of papillary necrosis.

For more information on this topic, see Papillary Necrosis.

Features of acute pyelonephritis include suppurative necrosis or abscess formation within the kidney substance. In contrast, features of chronic pyelonephritis (chronic interstitial nephritis) include the following:

• Papillary atrophy and blunting
• Interstitial fibrosis with inflammatory infiltrate (ie, lymphocytes, plasma cells, neutrophils [occasional]), tubule changes (ie, dilated with possible colloid casts, contracted with atrophy of epithelium), and concentric fibrosis around the parietal layer of the Bowman capsule

Ambulatory younger women who present with signs and symptoms of uncomplicated acute pyelonephritis may be candidates for outpatient therapy. They must be otherwise healthy and must not be pregnant. In addition, they must be treated initially in the emergency department (ED) with vigorous oral or intravenous (IV) fluids, antipyretic pain medication, and a dose of parenteral antibiotics. Studies have shown that outpatient therapy for selected patients is as safe as inpatient therapy for a comparable group of patients and is much less expensive.

Use analgesics as needed. Early in the course of the illness, parenteral analgesics are often necessary to reduce morbidity from symptoms. Nonsteroidal anti-inflammatory drugs and narcotics are complementary; do not assume that one class is better than the other.

Admission is usually appropriate for patients who are severely ill, pregnant, or elderly or who have comorbid disorders that increase the complexity of management or the complication rate (eg, diabetes mellitus, chronic lung disease, congenital or acquired immunodeficiency). Admission may also be advisable for patients whose social situation is unstable, because of the possibility of poor compliance or poor follow-up.

Emergency surgery may be indicated in a patient with fever or positive blood culture results persisting longer than 48 hours; in a patient whose condition deteriorates; or in a patient who appears toxic for longer than 72 hours. These patients may have an abscess, emphysematous pyelonephritis, or an obstructing calculus. The etiology may not be immediately evident, but an unexpected change in the clinical picture warrants immediate evaluation for potential surgical intervention.

After recovery from the acute infection, patients may be candidates for elective surgery to reverse conditions that predispose to recurrent kidney infections and damage, such as the following:

• Congenital anomalies
• Fistulae involving the urogenital tract
• Prostatic hyperplasia
• Kidney calculi
• Vesicoureteral reflux

Antibiotic selection is typically empirical, because the results of blood or urine cultures are rarely available by the time a decision must be made. Initial selection should be guided by local antibiotic resistance patterns. Culture results from specimens collected before the initiation of therapy should be checked in 48 hours to determine antibiotic efficacy.

The pathogen in community-acquired infections is usually Escherichia coli or other Enterobacteriaceae. Acceptable regimens may include fluoroquinolones, cephalosporins, penicillins, extended-spectrum penicillins, carbapenems, and aminoglycosides.[25, 3] If enterococci are suggested on the basis of Gram stain results, ampicillin or vancomycin can replace the fluoroquinolone. If any doubt exists as to the diagnosis, coverage of both Enterobacteriaceae and enterococci is acceptable.

There is a higher incidence of enterococcal infections in hospitalized and other institutionalized patients. Ampicillin or amoxicillin should be included in the regimen. If the patient is allergic to penicillin, vancomycin should be substituted.

In choosing an empirical antibiotic regimen, consideration should include the local antibiogram and drug-resistance rates. For example, in a community with growing fluoroquinolone resistance, agents in that class may not be an ideal first-line choice. In light of increasing resistance, short courses of treatment are preferred. In one clinical trial, a 7-day course of oral ciprofloxacin was shown to be a safe and successful treatment for acute pyelonephritis in women, including older women and those with more severe infection.[26]

For uncomplicated pyelonephritis, the American College of Physicians (ACP) recommends administering a short course of fluoroquinolones (5 to 7 days) or trimethoprim-sulfamethoxazole (TMP-SMX; 14 days), based on antibiotic susceptibility.[27]

Patient characteristics should also be considered. For example, patients who have been frequently exposed to antibiotics (eg, solid-organ transplant and hematopoietic transplant patients) or are from institutional facilities are at a greater risk for infection with drug-resistant pathogens, such as extended-spectrum beta-lactamase–producing or carbapenemase-producing organisms.

For more information, see Pyelonephritis Empiric Therapy and Pyelonephritis Organism-Specific Therapy

Oral versus parenteral administration

Growing data suggest that oral antibiotic therapy, parenteral antibiotic therapy, and initial parenteral antibiotic therapy followed by oral antibiotic therapy are equally effective regimens, although most of the studies have been small.[28, 29] Some clinicians believe that initiating therapy with an intravenous or intramuscular dose of medication reduces the risk of therapeutic failure; other clinicians believe that a completely oral course is sufficient. Data exist to support both assertions.

One conventional regimen comprises levofloxacin, 500 mg/day, given intravenously and then orally for 7-14 days. A short-course regimen of intravenous levofloxacin at 750 mg/day for 5 days proved non-inferior to that conventional regimen in a prospective, open-label, randomized, controlled clinical trial in 317 Chinese patients with complicated urinary tract infections and acute pyelonephritis.[30]

To be considered for oral therapy, patients must meet several prerequisites. They must, of course, be able to tolerate oral medication. In addition, they must have no indication for admission, and close monitoring to ensure good compliance must be possible.

One prospective study supports using oral therapy alone in patients who can tolerate oral intake, lack signs of sepsis, and do not show signs of obstruction or kidney suppuration on urinary tract ultrasonography. Another study (prospective, randomized, unblinded) in a controlled hospital setting found no difference in efficacy between oral and intravenous ciprofloxacin for the initial management of severe pyelonephritis.

The 2010 guidelines from the Infectious Diseases Society of America (IDSA) recommend that women with pyelonephritis who require hospitalization be treated initially with an intravenous antimicrobial regimen. The choice of antimicrobial agents should be based on local resistance data, with the regimen tailored on the basis of susceptibility results.[3]

Although the guidelines recommend either 14 days of TMP-SMX or 7 days of ciprofloxacin for the treatment of pyelonephritis, a study in 272 women with susceptible E coli pyelonephritis reported similar clinical outcomes with 7 days of TMP-SMX therapy compared with 7 days of ciprofloxacin.[31]

Because of the high rate of resistance of E coli, the empirical use of TMP-SMX should be avoided in patients who require hospitalization. If beta-lactam drugs and fluoroquinolones are contraindicated, administer aztreonam parenterally. As such, the patient will need to be admitted.

Regimens for complicated cases

With complicated acute pyelonephritis, treat patients parenterally until defervescence and improvement in the clinical condition warrants changing to oral antibiotics. Complete the course of therapy with an oral agent selected on the basis of culture results.[29] Acceptable regimens include the following:

• Ampicillin and an aminoglycoside
• Cefepime
• Imipenem
• Meropenem
• Piperacillin-tazobactam
• Ticarcillin-clavulanate
• Ceftazidime-avibactam ^{[32, 33]}
• Meropenem-vaborbactam

If the patient is allergic to penicillin, vancomycin should be substituted. Vancomycin or linezolid are options if enterococci are a consideration.

Meropenem-vaborbactam (Vabomere) is a combination of the carbapenem antibiotic meropenem with the beta-lactamase inhibitor vaborbactam. Specifically, vaborbactam inhibits bacterial production of the Klebsiella pneumoniae carbapenemase (KPC) enzyme, which confers resistance to carbapenems. The US Food and Drug Administration (FDA) has approved meropenem-vaborbactam for adults aged 18 years and older with pyelonephritis and other complicated urinary tract infections (UTIs) caused by designated susceptible Enterobacteriaceae: Escherichia coli, K pneumoniae, and Enterobacter cloacae species complex.[34]

The safety and efficacy of meropenem-vaborbactam were demonstrated in a study of more than 500 adults with complicated UTI, including pyelonephritis, in which cure or improvement in symptoms and a negative urine culture were seen in about 98% of patients treated with meropenem-vaborbactam, versus about 94% of patients treated with piperacillin–tazobactam. Approximately 7 days after completing treatment, about 77% of patients treated with meropenem-vaborbactam demonstrated resolution of symptoms and a negative urine culture, compared with about 73% of patients treated with piperacillin–tazobactam.[34]

Antibiotic therapy

Patients presenting with acute pyelonephritis can be treated with a single dose of a parenteral antibiotic followed by oral therapy, provided they are monitored within the first 48 hours. In a study of febrile, nonpregnant women presenting with symptoms of acute pyelonephritis, 25% were hospitalized; of nonhospitalized patients, 80% were treated with a single parenteral dose of ceftriaxone or gentamicin, followed by oral therapy (usually TMP-SMX). Twelve percent returned with persistent symptoms, most in the first day; most of those patients were admitted.[5]

Acute pyelonephritis has customarily been treated with 14 days of antibiotics, and the IDSA guidelines maintain this recommendation for TMP-SMX and beta-lactam agents. However, evidence suggests that in young, healthy women who are receiving a fluoroquinolone, including ciprofloxacin, the course of treatment can be shortened to 7 days. Levofloxacin, 750 mg/day, can be given for 5 days.[35, 36] Young, healthy males should complete a 14-day course.[3]

Outpatient treatment is appropriate for patients who have an uncomplicated infection that does not warrant hospitalization. Oral antibiotics are used to treat patients with mild to moderate illness. (See Table 2, below, for a description of outpatient treatments for pyelonephritis.)

Table 2. Outpatient Treatment for Pyelonephritis (Open Table in a new window)

For female patients suspected of having acute pyelonephritis, the IDSA guidelines recommend sending urine for culture and susceptibility testing and then starting empirical antibiotic therapy.[3]

The fluoroquinolones are well tolerated and quite effective. They are probably the outpatient antibiotic treatment of choice for pyelonephritis. They (along with TMP-SMX) do not eradicate the protective lactobacilli from the vagina. An important caveat for the use of fluoroquinolones in the elderly is their potential to cause aortic aneurysm or dissection; hypoglycemia; and a variety of neuropsychiatric symptoms, ranging from seizures to worsening of dementia.[37]

In communities where the prevalence of resistance in uropathogens to fluoroquinolones is not known to be greater than 10%, the IDSA guidelines advise that patients who do not require hospitalization be treated with oral ciprofloxacin, 500 mg twice daily for 7 days, with or without an initial 400-mg dose of intravenous ciprofloxacin. If the uropathogen’s fluoroquinolone resistance is greater than 10%, an initial intravenous dose of a long-acting parenteral antimicrobial (eg, ceftriaxone, 1 g) is recommended.[3]

On an individual basis, for persons with community-onset UTI and fever, a case-control study found that the risk of fluoroquinolone-resistant E coli infection increased if the patient had undergone recent hospitalization or urinary catheterization or if the patient had used a fluoroquinolone within the past 6 months.[28]

Intravenous fluids

If oral intake is not tolerated, intravenous hydration is warranted. Intravenous fluids should include 1 L of 5% dextrose in saline to reverse any existing ketosis, regardless of whether ketones are detected in the urine. Additional intravenous hydration is accomplished with normal saline. Exercise caution regarding conditions that might be adversely affected by improper amounts of fluid, saline, or glucose.

Follow-up

If the patient is not admitted at the time of diagnosis, follow-up reevaluation is important in 1-2 days to be sure the patient is progressing properly. A good rule based on common sense is that if the managing clinician is concerned that the patient may not respond well to outpatient management but still thinks the patient deserves a trial at home, the initial follow-up visit should take place in 24 hours. If the clinician thinks that the patient will do quite well with outpatient management, the initial follow-up visit can take place in 48 hours.

If the patient thinks that he or she is not progressing well or is getting worse, the patient should be evaluated emergently for consideration for admission and intravenous antibiotics.

Continue supportive care by prescribing antiemetics, antipyretics, analgesics, and urinary tract analgesics as needed. Have the patient complete a 14-day course of oral antibiotics. Evidence suggests that when treating a young, healthy female, the course of treatment can be shortened to 7 days from 14 days, if the antibiotic being used is a fluoroquinolone. Healthy young males should complete a 14-day course.

Obtain follow-up urine culture results in any patient with a complicated UTI, a complicated course, or increased risk of infection. Urine cultures are generally not indicated in healthy, nonpregnant women with resolved symptoms.[14] All patients with a complicated UTI should be considered for outpatient follow-up imaging of the urinary tract to identify abnormalities that predispose to further infections.

Rest is essential for recovery. Activity should be minimal. The patient should not return to work for 2 weeks, so as to allow time for the infection to be eliminated and for the patient to recover physical strength. Temper this recommendation depending on the physical condition of the patient and the presence of comorbid conditions.

The decision regarding admission of a patient with acute pyelonephritis depends on age; host factors, such as immunocompromising chemotherapy or chronic diseases, known urinary tract structural abnormalities, renal calculi, recent hospitalization, or urinary tract instrumentation; and the patient's response to ED therapy.

Admit all patients with complicated UTI. Complicating factors include the following:

• Structural urinary tract abnormalities (eg, calculi, tract anomalies, indwelling catheter, obstruction)
• Metabolic disease (eg, diabetes, kidney insufficiency)
• Impaired host defenses (eg, HIV, current chemotherapy, underlying active cancer)
• Pregnancy

Admission is also indicated for patients with apparent clinically uncomplicated pyelonephritis who have any of the following:

• Inability to maintain adequate oral hydration
• Evidence of vasomotor instability
• Unrelenting fever despite antipyretic therapy
• Debilitating pain or dehydration that cannot be corrected promptly in the ED
• Inadequate home care or resources to fill prescriptions or comply with the medical regimen (eg, homeless patients, adolescents, elderly patients in an acute illness setting who are at risk for clouded judgment, patients with substance abuse issues or other issues that will prevent adequate compliance)

Inpatient care includes the following:

• Continue supportive care
• Monitor urine and blood culture results
• Monitor comorbid conditions for deterioration
• Maintain hydration status with IV fluids until hydration can be maintained with oral intake
• Continue IV antibiotics until defervescence and significant symptomatic improvement occur; convert to an oral regimen tailored to urine or blood culture results

In patients with acute pyelonephritis who require hospitalization, treatment begins with IV antibiotics. IV therapy should be given for 24-48 hours or until severe symptoms improve. A systematic review of 8 randomized, controlled trials in hospitalized patients with acute pyelonephritis found that early switching to oral antibiotic treatment appears to be as effective and safe as exclusively IV regimens.[38]

Selection of a regimen should be based on local resistance data, and the regimen should be tailored on the basis of susceptibility results. Recommended regimens are listed in Table 3, below. However, a multinational study in 184 patients found that cefazolin is non-inferior to ceftriaxone for the empirical treatment of acute pyelonephritis in hospitalized patients. At 72 hours, defervescence or normalization of white blood cell count had occurred in 87.0% of the cefazolin group versus 85.9% of the ceftriaxone group; in addition, no difference was observed between the two groups for length of stay or 30-day readmission for cystitis or pyelonephritis.[39]

Table 3. Inpatient Treatment for Acute Pyelonephritis (Open Table in a new window)

However, an Israeli medical center that instituted a program of initial empirical treatment of pyelonephritis with aminoglycosides reported higher rates of in vitro activity and lower overall mortality than with non-aminoglycoside antibiotic therapy, without excess nephrotoxicity. In the study, which included 2026 patients, 715 treated with aminoglycosides and 1311 treated with non-aminoglycoside drugs, aminoglycosides were more likely to have in vitro activity against clinical isolates (odds ratio 2.0; P < 0.001); death at 30 days occurred in 55 (7.6%) versus 145 (11%) patients treated with aminoglycosides and non-aminoglycoside drugs, respectively (adjusted hazard ratio 0.78; P = 0.013). The incidence of acute kidney injury was 2.5% versus 2.9%, respectively; P = 0.6).[40]

Duration of therapy

Duration of therapy should be at least 10-14 days, inclusive of initial IV therapy. Patient circumstances may warrant more prolonged therapy.

The PROGRESS (Procalcitonin-guided Antimicrobial Therapy to Reduce Long-Term Sequelae of Infections) study found that in septic patients, procalcitonin levels can be used to guide discontinuation of antibiotics. This multicenter randomized trial in 266 patients, 95 of whom had acute pyelonephritis, used an ≥80% reduction in procalcitonin level or any procalcitonin level of ≤0.5 μg/L at Day 5 or later as a criterion for discontinuing antibiotics.[41]

In PROGRESS, procalcitonin-guided discontinuation, compared with standard of care, resulted in a shorter median length of antibiotic therapy (5 versus 10 days), a lower rate of infection-associated adverse events such as infections by multidrug-resistant organisms and Clostridioides difficile (7.2% versus 15.3%), and lower 28-day mortality (15.2% versus 28.2%). The cost of hospitalization was also reduced in the procalcitonin arm.[41]

For renal cortical abscesses (renal carbuncles), surgical drainage was once the only treatment. However, modern antibiotics alone often are curative. A semisynthetic penicillin, cephalosporin, fluoroquinolone, or vancomycin is recommended. Generally, parenteral antibiotics should be administered for 10-14 days, followed by oral therapy for 2-4 weeks. Fever should resolve within 5-6 days, and pain should resolve within 24 hours. If parenteral antibiotic therapy is successful, oral therapy is instituted for an additional 2-4 weeks.

If patients do not respond within 48 hours, percutaneous (or open) drainage should be performed. Other surgical options are enucleation of the carbuncle or nephrectomy.

Treatment of renal corticomedullary abscess includes parenteral antibiotics for 48 hours (usually successful), incision and drainage, and nephrectomy. If antibiotic therapy is successful, oral therapy is instituted for an additional 2 weeks.

Mortality associated with perinephric abscesses is 20-50%, but this rate can be decreased with early recognition, surgical drainage, and antimicrobial therapy (not adequate alone). Antibiotics should include an aminoglycoside and an antistaphylococcal agent. If Pseudomonas species are considered or demonstrated, an antipseudomonal beta-lactam antibiotic should be added. For enterococci, an aminoglycoside and ampicillin are recommended. Other organisms that have been reported include tuberculosis and fungi. Nephrectomy may be necessary.

A major challenge with calculi-related UTI is that the organisms can survive within the calculus. In the presence of acute infection, calculi must be removed immediately using cystoscopy or open surgical procedure. In a review of adult patients with obstructive pyelonephritis due to a ureteral stone or kidney stone with hydronephrosis (n=311,100), delayed decompression (2 or more days after admission) increased the odds of in-hospital death by 29% (odds ratio 1.29, 95% confidence interval 1.03-1.63, P=0.032).[42]

The preferred method of treatment is surgical. Options include extracorporeal shockwave lithotripsy (ESWL), endoscopic methods, percutaneous methods, and open surgery. For staghorn calculus, the treatment of choice is to remove the whole stone. Fragments left behind remain infected and will grow again. Antibiotic therapy should be used in conjunction.

Although food and vitamin supplements that are rich in phosphorus and magnesium are advisable, remember that magnesium (and other divalent cations) can chelate fluoroquinolones, preventing their absorption from the gut.

Acidifying agents have been used. Ascorbic acid does not significantly decrease urinary pH, and ammonium chloride provides only temporary acidification. This approach is of little clinical usefulness. Urease inhibitors are effective in reducing stone formation, but long-term use is fraught with neurosensory, hematologic, and dermatologic adverse effects.

Treatment for renal papillary necrosis is admission for intravenous antibiotic therapy. The agents chosen should cover E coli and Enterobacter, Proteus, and Klebsiella species. Treatment for more serious infections also should cover Pseudomonas and Enterococcus species.

Parenteral agents that may be used empirically pending the result of a urine culture include the following:

• Gentamicin
• Cefotaxime
• Ceftriaxone
• Ceftazidime
• Cefepime
• Piperacillin-tazobactam
• Imipenem-cilastatin
• Meropenem
• Ciprofloxacin

Parenteral therapy should be continued until the fever and other symptoms resolve. Duration of therapy generally is 14 days. If the response is not good, CT-guided drainage or surgical drainage with debridement is indicated.

The treatment of choice for xanthogranulomatous pyelonephritis is nephrectomy after the patient is stabilized. See Xanthogranulomatous Pyelonephritis for more information.

Physiologic changes in the urinary tract predispose pregnant women to an increased risk of cystitis and pyelonephritis, which may lead to preterm labor and kidney damage. Hydroureter of pregnancy develops around the seventh week and progresses throughout the remainder of pregnancy; it resolves by 8 weeks post partum. The ureters may dilate sufficiently to contain 200 mL or more of urine. In addition, the kidneys enlarge and bladder capacity may double. The left kidney is more affected than the right.

The prevalence of bacteriuria in pregnancy is 2-25%, depending on the study criteria. Symptomatic UTI occurs in 1-3% of all pregnancies and leads to premature labor in 20-50% of cases.

The recommendation is that all pregnant women have a screening urine culture at 16 weeks' gestation. If the results are negative for a UTI, no additional cultures are indicated. If the patient has a history of recurrent UTIs, further cultures and other screening techniques (eg, nitrite dipstick or urine Gram stain) may be needed to detect the development of asymptomatic bacteriuria.

Successful treatment of bacteriuria prevents pyelonephritis. Fluoroquinolones and aminoglycosides should be avoided in pregnancy. Accepted regimens for treating asymptomatic bacteriuria include the following:

• Amoxicillin 250 mg orally 3 times a day for 3 or 7 days; or 3 g in a single dose
• Cephalexin 2 or 3 g in a single dose
• Nitrofurantoin 200 mg in a single dose; or 100 mg 4 times a day for 3 or 7 days

Inpatient admission is warranted for any pregnant patient with pyelonephritis. The treatment of choice during pregnancy includes the use of beta-lactam antibiotics. Intravenous antibiotics should be administered until the patient is afebrile for 24 hours and symptomatically improved. It is recommended to avoid fluoroquinolones in pregnant patients. Aminoglycosides should also be avoided due to potential risk of ototoxicity following prolonged fetal exposure. See Table 4, below, for regimens for pyelonephritis in pregnant patients.

Table 4. Treatment of Pyelonephritis During Pregnancy (Open Table in a new window)

Once patients are afebrile for at least 48 hours, they can be switched to oral antibiotics, with the regimen choice guided by results from susceptibility studies, and discharged to complete 10-14 days of treatment. Obtain an additional urine culture 1-2 weeks after the completion of therapy to verify eradication of the infection. Obtain monthly urine cultures until delivery to monitor the urine for recurrent infection.

Postcoital therapy with cephalexin or nitrofurantoin is recommended for prophylaxis against recurrent infection. If the initial infection requires a second agent for clearing the infection or a recurrent infection occurs, suppressive therapy until delivery is indicated with nitrofurantoin (50 mg or 100 mg at bedtime). Recurrent infection or persistent bacteriuria is an indication for urological evaluation 3-6 months after delivery.

Caution should be used when prescribing nitrofurantoin for prophylaxis, as adverse effects of this medication include peripheral neuropathy, pulmonary toxicity, and hepatotoxicity. Nitrofurantoin-induced liver injury and death have been reported. Hepatotoxicity is reversible if recognized early and nitrofurantoin is stopped, so hepatic enzymes should be monitored in women at higher doses or with prolonged use.[43]

In pediatric patients with acute pyelonephritis, indications for immediate urologic referral include the following:

• Abnormal electrolyte values associated with acidosis
• Elevated blood urea nitrogen level
• Hypertension
• A palpable bladder
• Voiding difficulty (dribbling, poor stream, straining)

Aside from the effects of acute infection, the overriding concern is progressive deterioration in function of an already compromised kidney (hypoplastic or dysplastic) secondary to scarring from recurrent pyelonephritis with or without associated obstruction. Infants and preschool-aged children are at greatest risk. Initial management varies with patient age and presentation.

Close follow-up, regardless of whether the patient is initially admitted, is essential to ensure recovery. Immediate reevaluation is encouraged for any recurrence of symptoms. Neither treatment of asymptomatic bacteriuria nor long-term suppressive therapy has been found to be effective.

Urologic evaluation is necessary to establish the presence of any urologic abnormality. The preferred imaging study for the diagnosis of acute pyelonephritis is technetium-99m dimercaptosuccinic acid (99m Tc-DMSA) scintigraphy. Ultrasonography is the imaging study of choice for the diagnosis of urinary tract structural abnormalities. (See Workup/Scintigraphy).

Age-related data adapted from Harwood-Nuss and colleagues and Hansson and colleagues are presented below in Table 5.[44, 45]

Table 5. Pediatric Urinary Tract Infections (Open Table in a new window)

Consultation is indicated if the infection is complicated. Most cases of acute pyelonephritis occur in adult women and are readily managed without consultation. The following are reasons for consulting various subspecialists:

• A urologist may be consulted regarding patients with ureteral or urethral obstruction, urinary stones, urogenital abnormality, or recurrent pyelonephritis, or for the first episode of pyelonephritis in an infant or child.
• A nephrologist may be consulted regarding patients with acute kidney injury or advanced chronic kidney disease or for neonates or infants.
• An infectious disease specialist may be consulted regarding patients with an unusual or resistant pathogen, those who are immunocompromised, patients with persisting fever (> 48 hours) or toxicity (> 72 hours), or patients whose blood culture results are positive for more than 48 hours.
• An obstetrician may be consulted for patients who are pregnant.

A regular diet is permitted as tolerated. Special diets, such as those for patients with diabetes mellitus, should be honored. Maintaining hydration is very important. If admission is not indicated and the patient will be monitored in an outpatient setting, hydration status should be normalized with intravenous fluids; the physician should not assume that the patient can or will accomplish this with oral hydration alone.

Rest is essential for recovery. Activity should be minimized. Patients who are treated in an outpatient setting should not return to work for 2 weeks in order to allow time for the infection to be eliminated. This time also allows the patient to recover physical strength. This recommendation can be tempered in special circumstances as warranted by the clinician.

Prevention of pyelonephritis involves identifying clinical situations that could lead to pyelonephritis and developing a strategy to decrease that likelihood. These strategies may include a change in contraceptive behavior, administration of prophylactic antibiotics, or early identification and treatment of cystitis.

If these strategies do not eliminate infection, recurrence of infection, or relapse (reinfection less than 14 days after completing an appropriate regimen), the patient needs to undergo systematic evaluation for predispositional anatomic, functional, or structural abnormalities.

For more information, see Prevention of Urinary Tract Infection (UTI).

The United Kingdom's National Institute for Health and Care Excellence (NICE) has issued guidelines on acute pyelonephritis in children, young people, and adults who do not have a urinary catheter in place. The recommendations cover management, self care, and choice of first-line antibiotic; for second-line therapy, NICE advises consulting with a local microbiologist.[46]

For non-pregnant women and males aged 16 years and over, first-choice oral antibiotics are as follows:

• Cephalexin
• Amoxicillin/clavulanate (if culture confirms susceptibility)
• Trimethoprim (if culture confirms susceptibility)
• Ciprofloxacin (but consider safety issues; discontinue at the first signs of a serious adverse reaction, including tendon pain or inflammation)

First-choice intravenous (IV) antibiotics (eg, for patients who are vomiting, unable to take oral antibiotics, or severely unwell) are as follows (antibiotics may be combined if susceptibility or sepsis is a concern):

• Amoxicillin/clavulanate (only in combination, and if culture confirms susceptibility)
• Cefuroxime
• Ceftriaxone
• Ciprofloxacin (but consider safety issues)
• Gentamicin
• Amikacin

First-choice antibiotics for pregnant women aged 12 years and over are as follows:

• Oral: Cephalexin
• IV: Cefuroxime

For children < 3 months, the NICE guidelines recommend referral to a pediatric specialist for treatment with IV antibiotics. For children > 3 months and adolescents under 16 years of age, first-choice oral antibiotics are as follows:

• Cephalexin
• Amoxicillin/clavulanate (if culture confirms susceptibility)

First-choice IV antibiotics for children > 3 months and adolescents under 16 years of age are as follows:

• Amoxicillin/clavulanate (only in combination, and if culture confirms susceptibility)
• Cefuroxime
• Ceftriaxone
• Gentamicin
• Amikacin

Antibiotic therapy is essential in the treatment of acute pyelonephritis and prevents progression of the infection. Urine culture and sensitivity testing should always be performed, and when results become available, empirical therapy should be tailored to the infecting uropathogen.[3]

Patients presenting with complicated pyelonephritis should be managed as inpatients and treated empirically with broad-spectrum parenteral antibiotics. Depending on patient presentation, antibiotic therapy can be completed with oral therapy. Antibiotics are administered for at least 10-14 days. On the basis of patient presentation, longer duration of therapy may be needed.

Class Summary

Sulfonamides such as trimethoprim-sulfamethoxazole(TMP-SMX) have bacteriocidal activity and are used in the treatment of pyelonephritis.

Trimethoprim-sulfamethoxazole (Bactrim, Bactrim DS, Septra, Septra DS)

This drug combination is designed to take advantage of the synergy between trimethoprim and sulfonamides. TMP-SMX activity covers common urinary tract pathogens, both aerobic gram-positive and gram-negative bacteria, except Pseudomonas aeruginosa.

Oral trimethoprim-sulfamethoxazole (160 mg/800 mg [1 double-strength tablet] twice-daily for 14 days) is an appropriate choice for therapy if the uropathogen is known to be susceptible. This agent has been given an A-I rating in the 2010 IDSA guidelines for treating pyelonephritis.

Class Summary

Fluoroquinolones are acceptable agents for the treatment of pyelonephritis because they are highly effective against gram-negative and gram-positive bacteria. A major concern with fluoroquinolones is the development of resistance among uropathogens and other organisms. Oral fluoroquinolones are a treatment option for patients not requiring hospitalization where the prevalence of resistance of community uropathogens does not exceed 10%.[3] According to the IDSA 2010 guidelines, if the prevalence of fluoroquinolone resistance exceeds 10%, an initial 1-time intravenous dose of a long-acting parenteral antimicrobial or a consolidated 24-hour dose of an aminoglycoside, is recommended.[3] Fluoroquinolones should be avoided during pregnancy.

Ciprofloxacin (Cipro, Cipro XR)

Oral ciprofloxacin is recommended for patients who do not need hospitalization. Dosing recommendations include 500 mg twice daily for 7 days, with or without an initial 400-mg dose of intravenous ciprofloxacin. Patients can also be given a once-daily regimen of ciprofloxacin extended release at a dosage of 1000 mg for 7 days.

Levofloxacin (Levaquin)

Levofloxacin is also recommended as an oral antibiotic for patients with pyelonephritis not requiring hospitalization. Recommended dose includes the administration of levofloxacin 750 mg for 5 days.

Class Summary

Oral beta-lactams are not as effective for treating pyelonephritis. Based on the IDSA 2010 guidelines, however, if they are used, they should be administered with a single dose of ceftriaxone (Rocephin) 1 g IV ora consolidated 24-hour dose of an aminoglycoside.[3]

Cefaclor

Cefaclor is indicated for the treatment of pyelonephritis, caused by Escherichia coli, Proteus mirabilis, Klebsiella species, and coagulase-negative staphylococci. Cefaclor, 500 mg 3 times a day for 7 days, is recommended for outpatient treatment of pyelonephritis.

Class Summary

Third-generation cephalosporins are broad-spectrum and have bactericidal activity. These drugs are the most active against serious gram-negative pathogens and have some activity against gram-positive pathogens.

Ceftriaxone

Ceftriaxone is a parenteral regimen that can be administered once daily in patients with pyelonephritis requiring hospitalization. For patients with mild to moderate pyelonephritis, a dosage of 1 g every 24 hours is recommended.

Cefotaxime (Claforan)

Cefotaxime has bactericidal activity. It is indicated for the treatment of genitourinary infections caused by Escherichia coli, Enterococcus species, and Klebsiella species, among others. For moderate to severe infections, the usual dose is 1-2 g IV or IM every 8 hours.

Ceftazidime (Fortaz, Tazicef)

Ceftazidime has broad-spectrum activity against gram-negative organisms, including Pseudomonas, and lower efficacy against gram-positive organisms. It is approved for the treatment of complicated and uncomplicated cystitis caused by Pseudomonas aeruginosa; Enterobacter species; Proteus species, including Proteus mirabilis and indole-positive Proteus; Klebsiella species; and E coli.

Class Summary

Cefepime is a fourth-generation drug, which possesses the gram-negative activity of the third-generation agents and the gram-positive activity of the first-generation drugs.

Cefepime (Maxipime)

Cefepime is a fourth-generation cephalosporin. It is indicated for the treatment of uncomplicated and complicated cystitis, including (1) pyelonephritis caused by E coli or Klebsiella pneumoniae when the infection is severe or (2) pyelonephritis caused by E coli, Klebsiella pneumoniae, or Proteus mirabilis when the infection is mild to moderate, including cases associated with concurrent bacteremia with these microorganisms.

Class Summary

Aminopenicillins have a broad spectrum of are bactericidal activity against gram-positive and gram-negative organisms.

Ampicillin

Penicillins such as ampicillin can be administered in combination with aminoglycosides for patients with pyelonephritis who require hospitalization. Ampicillin has bactericidal activity against susceptible organisms.

Amoxicillin-clavulanate (Augmentin, Augmentin XR)

Oral beta-lactams are not as effective for treating pyelonephritis. If they are used, they should be administered with a single dose of ceftriaxone, 1 g IV, or a consolidated 24-hour dose of an aminoglycoside. Amoxicillin-clavulanate possesses the properties of a broad-spectrum antibiotic and a beta-lactamase inhibitor.

Class Summary

Extended-spectrum penicillins have a broad spectrum of bactericidal activity. They are used mainly in the treatment of patients with pyelonephritis requiring hospitalization.[3] The extended-spectrum penicillins are also an option for pregnant patients with pyelonephritis.

Piperacillin-tazobactam (Zosyn)

Piperacillin-tazobactam is useful as empirical therapy before the identification of causative organisms, because of its broad spectrum of bactericidal activity against gram-positive and gram-negative organisms. The dosing recommendation for severe pyelonephritis is 3.375 g IV every 6 hours.

Ampicillin-sulbactam (Unasyn)

Ampicillin has a broad spectrum of bactericidal activity against many gram-positive and gram-negative aerobic and anaerobic bacteria. The presence of sulbactam in the ampicillin-sulbactam formulation effectively extends the spectrum of ampicillin to include many bacteria normally resistant to it and to other beta-lactam antibiotics. Ampicillin-sulbactam, 1.5 g IV every 6 hours, can be used for the treatment of pyelonephritis.

Class Summary

Carbapenem antibiotics are broad-spectrum antibiotics that are structurally related to beta-lactam antibiotics. Carbapenems can be used in the treatment of patients with pyelonephritis requiring hospitalization.[3] The extended-spectrum penicillins are also an option for pregnant patients with pyelonephritis.

Doripenem (Doribax)

Doripenem is approved for the treatment of complicated cystitis, including pyelonephritis that is caused by E coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, and Acinetobacter baumannii. The usual dosage is 500 mg IV every 8 hours. The duration of therapy can range from 10-14 days. Duration includes a possible switch to an appropriate oral therapy after at least 3 days of parenteral therapy, once clinical improvement has been demonstrated. Duration can be extended up to 14 days in patients with concurrent bacteremia.

Ertapenem (Invanz)

Ertapenem is approved for the treatment of complicated cystitis, including pyelonephritis caused by Escherichia coli including cases with concurrent bacteremia or Klebsiella pneumoniae. Usual dosage is 1 g IV every 24 hours for 10-14 days. Duration includes a possible switch to an appropriate oral therapy after at least 3 days of parenteral therapy, once clinical improvement has been demonstrated.

Meropenem (Merrem)

Meropenem is a bactericidal broad-spectrum carbapenem antibiotic that is effective against most gram-positive and gram-negative bacteria. It can be administered at a dose of 500 mg IV every 8 hours.

Imipenem-cilastatin (Primaxin)

Imipenem/cilastatin has bactericidal activity against a wide range of gram-negative and gram-positive organisms. It is an alternative treatment for pyelonephritis because infections resistant to other antibiotics (eg, cephalosporins, penicillin, aminoglycosides) have been shown to respond to treatment with imipenem-cilastatin. The general dosing recommendation is 500 mg IV every 6 hours.

Meropenem/vaborbactam (Vabomere)

Indicated for complicated urinary tract infections (cUTI) caused by carbapenem-resistant Enterobacteriaceae (CRE). Vaborbactam is a non-suicidal beta-lactamase inhibitor that protects meropenem from degradation by certain serine beta-lactamases such as Klebsiella pneumoniae carbapenemase (KPC). Vaborbactam does not have any antibacterial activity and does not decrease the activity of meropenem against meropenem-susceptible organisms.

Class Summary

Aminoglycosides are bactericidal antibiotics used primarily in the treatment of gram-negative infections. They are commonly used in combination with drugs such as ampicillin. For example, gentamicin, an aminoglycoside antibiotic that has gram-negative coverage, is used in combination with both an agent against gram-positive organisms and one that covers anaerobes. Because of their potential nephrotoxicity, aminoglycosides  should be reserved as a last resort, for use in resistant or life-threatening infections. In addition, aminoglycosides should be avoided during pregnancy.

Gentamicin

Gentamicin is not the drug of choice for acute pyelonephritis. Consider using it when penicillins or other less toxic drugs are contraindicated, when clinically indicated, and in mixed infections caused by susceptible staphylococci and gram-negative organisms. Dosing regimens are numerous; adjust the dose based on the creatinine clearance and changes in volume of distribution. Gentamicin may be given intravenously or intramuscularly.

Tobramycin

Tobramycin has bactericidal activity against, and is used to treat infections caused by, E coli, Proteus species, Klebsiella species, Serratia species, Enterobacter species, and Citrobacter species. Tobramycin can be administered intravenously or intramuscularly. Dosage is based on weight and kidney function.

Amikacin

Amikacin has bactericidal activity against gram-negative organisms. Clinical studies have shown that amikacin is clinically effective for serious complicated and recurrent cystitis. Amikacin can be administered intravenously or intramuscularly. Dosage is based on weight and kidney function.

Plazomicin (Zemdri)

Indicated for complicated urinary tract infections, including pyelonephritis caused by the following susceptible microorganism(s): Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, and Enterobacter cloacae. Plazomicin is administered intravenously. Dose is based on weight and kidney function.

Class Summary

Glycopeptide antibiotics such as vancomycin have bactericidal activity and can be used as alternative therapy for patients with pyelonephritis.

Vancomycin (Vancocin)

Vancomycin is a potent antibiotic directed against gram-positive organisms and is active against Enterococcus species. Vancomycin is indicated for patients who cannot receive or did not respond to penicillins and cephalosporins or patients who have infections with resistant staphylococci.

Class Summary

Unlike the penicillins and cephalosporins, aztreonam is a monobactam. Monobactams such as aztreonam are bactericidal; however, they lack activity against gram-positive activity.

Aztreonam (Azactam)

Aztreonam is approved for the treatment of complicated and uncomplicated cystitis. It is approved for the treatment of pyelonephritis caused by Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, Enterobacter cloacae, Klebsiella oxytoca, Citrobacter species, and Serratia marcescens. Aztreonam lacks cross-sensitivity with beta-lactam antibiotics and may be used in patients allergic to penicillins or cephalosporins. General dosing recommendations include administering 1 g IV every 8-12 hours.

Class Summary

Use of a urinary analgesic is indicated when a patient has dysuria to such an extent that it disrupts activities of daily living. These agents relieve pain, discomfort, and spasms of the bladder.

Phenazopyridine (Baridium, Pyridium, UTI Relief)

Phenazopyridine is an azo dye excreted in urine, where it exerts a topical analgesic effect on urinary tract mucosa. Its use is compatible with antibacterial therapy and can help relieve pain and discomfort before antibacterial therapy controls infection.

It is used for symptomatic relief of pain, burning, urgency, frequency, and other discomfort arising from irritation of lower urinary tract mucosa caused by infection, trauma, surgery, endoscopic procedures, or passage of sounds or catheters. Its analgesic action may reduce or eliminate the need for systemic analgesics or narcotics.