Clinical manifestations diagnosis and treatment of acute pyelonephritis

INTRODUCTION —

ACUTE PYELONEPHRITIS IS A URINARY TRACT INFECTION THAT HAS PROGRESSED FROM THE LOWER URINARY TRACT TO THE UPPER URINARY TRACT. Most episodes of acute pyelonephritis are uncomplicated but hospitalization may be required [1] .

Acute uncomplicated pyelonephritis typically occurs in healthy, young women and must be distinguished from :

o acute complicated pyelonephritis and from o chronic pyelonephritis

Acute complicated pyelonephritis is progression of upper urinary tract infection to :

o emphysematous pyelonephritis, o renal corticomedullary abscess, o perinephric abscess, or o papillary necrosis

Chronic pyelonephritis is an uncommon cause of chronic tubulointerstitial disease due to recurrent infection, such as infection in association with a chronically obstructing kidney stone (possibly producing xanthogranulomatous pyelonephritis) or vesicoureteral reflux [= ουρητηροκυστική παλινδρόμηση].

Affected patients can present with weeks to months of insidious symptoms.

ACUTE UNCOMPLICATED PYELONEPHRITIS

Clinical manifestations —

The clinical manifestations of acute uncomplicated pyelonephritis include ¨

o flank pain, o abdominal or pelvic pain, o nausea, vomiting, o fever (≥ 37.8ºC), and/or costovertebral angle tenderness

FEVER HAS BEEN STRONGLY CORRELATED WITH THE DIAGNOSIS OF ACUTE PYELONEPHRITIS; THUS, PATIENTS WITH CLINICAL MANIFESTATIONS OF ACUTE PYELONEPHRITIS IN THE ABSENCE OF FEVER SHOULD BE EVALUATED FOR ALTERNATIVE DIAGNOSES [2] .

Symptoms of cystitis may or may not be present [3] .

In some cases, the presentation may mimic pelvic inflammatory disease. Rarely, patients with acute pyelonephritis present with :

o sepsis,o multiple organ system dysfunction, o shock, and/or acute renal failure

Diagnosis —

The diagnosis of acute uncomplicated pyelonephritis can usually be made from the history, physical examination, and laboratory evaluation.

The physical examination should focus on vital signs and evaluation of the abdomen, pelvis, and the costovertebral angles.

In the setting of vaginal symptoms or poorly localized tenderness, a pelvic examination should be performed to distinguish pelvic inflammatory disease from acute uncomplicated pyelonephritis.

Pregnancy testing is also appropriate.

A urinalysis should be performed to evaluate for pyuria, which is present in virtually all patients with acute pyelonephritis.

THE ABSENCE OF PYURIA STRONGLY SUGGESTS AN ALTERNATIVE DIAGNOSIS OR THE PRESENCE OF AN OBSTRUCTING LESION [4] .

White cell casts indicate a renal origin for the pyuria. Other urinalysis parameters lack adequate sensitivity for evaluation of pyelonephritis.

Nitrite testing, for example, has a sensitivity of 35 to 80 percent; it is not useful for detecting presence of organisms unable to reduce nitrate to nitrite, such as enterococci and staphylococci.

Urine culture and antimicrobial susceptibility testing of uropathogens should be performed in the setting of acute pyelonephritis.

Up to 95 percent of episodes of pyelonephritis are associated with >10(5) CFU per mL of organisms, although some patients with pyelonephritis have colony counts of 10(3) to 10(4) CFU per mL [5] .

If the urine sample for culture is obtained through a newly-inserted catheter, some clinicians consider a colony count of ≥ 10(2) CFU

per mL sufficient for diagnosis of pyelonephritis.

The lower colony counts are extrapolated from studies of cystitis but have not been systematically evaluated in the setting of pyelonephritis.

Urine gram stain may be helpful for rapid preliminary diagnostic purposes and for guiding the choice of empiric therapy pending culture results.

Imaging studies are not routinely required for diagnosis of acute uncomplicated pyelonephritis but can be helpful in certain circumstances.

Microbiology —

Escherichia coli is the most common cause of acute pyelonephritis.

In a report of over 2700 uropathogens isolated from patients with acute pyelonephritis, Escherichia coli accounted for about 82 percent of isolates in women and about 73 percent in men [6] .

Klebsiella pneumoniae was next in frequency, accounting for 2.7 percent of isolates in women and 6.2 percent in men.

Staphylococcus saprophyticus accounted for less than 3 percent of isolates

Treatment —

Initial treatment includes supportive care and initiation of empiric antibiotic therapy.

Inpatient management is appropriate in the following circumstances:

o Severe illness with high fevers, pain, ando marked debility Inability to maintain oral hydration oro take oral medicationso Pregnancy o Concerns about patient compliance

Outpatient management is safe and effective for patients with mild to moderate illness who can be stabilized with rehydration and antibiotics in an outpatient facility and discharged on oral antibiotics under close supervision.

In an emergency department report of 44 patients with pyelonephritis, for example, a 12 hour observation period with parenteral antibiotic therapy, followed by completion of outpatient oral antibiotics was effective management for 97 percent of patients [7] .

Empiric antibiotics —

Empiric antibiotic selection should be guided by knowledge of the epidemiology of antimicrobial susceptibility when available, since rates of antibiotic resistance fluctuate with patterns of antibiotic use in the community.

In a report of 4342 urine isolates from patients with cystitis in the mid 1990s, the prevalence of resistance to trimethoprim-sulfamethoxazole rose from 9 to 18 percent over a five year period [8] .

In comparison, resistance to ciprofloxacin and aminoglycosides was very low.

However, a subsequent study in this region demonstrated that antibiotic resistance trends had reversed [6] .

Among E. coli isolates from over 3200 patients in the late 1990s, there was a decrease in trimethoprim-sulfamethoxazole resistance together with an increase in the rate of ciprofloxacin resistance (24 to 13 percent and 1.7 to 3.4 percent, respectively) [6] .

These changes paralleled a reduction in the use of trimethoprim-sulfamethoxazole and an increase in the use of a fluoroquinolone for management of outpatient urinary tract infections (53 to 32 percent and 35 to 61 percent, respectively).

Risk for pyelonephritis due to an organism resistance to trimethoprim-sulfamethoxazole or fluoroquinolones appears to vary substantially by region, and risk stratification cannot reliably predict patients at for infection with resistant organisms [9,10] .

Recent antibiotic use should be considered in the selection of an empiric regimen pending culture and susceptibliity data.

Oral antibiotics —

We favor an oral fluoroquinolone such as Q

o levofloxacin (500 to 750 mg orally once daily) or o ciprofloxacin (500 mg orally twice daily)

for initial empiric treatment of acute pyelonephritis (show table 2) [11,12] .

The newer fluoroquinolone moxifloxacin should be avoided because of uncertainty regarding effective concentrations in urine.

o Trimethoprim-sulfamethoxazole (1 double strength tablet orally twice daily), or

o trimethoprim (200 mg orally once daily) can be used if the infecting strain is known to be susceptible.

If gram-positive cocci are observed on Gram stain, enterococcus or S. saprophyticus should be suspected and amoxicillin (500 mg orally three times daily or 875 mg orally twice daily) should be added to the treatment regimen until the causative organism isidentified.

AMPICILLIN AND SULFONAMIDES SHOULD NOT BE USED FOR EMPIRIC THERAPY BECAUSE OF THE HIGH RATE OF RESISTANCE AMONG CAUSATIVE PATHOGENS.

o Cefpodoxime (200 mg orally twice daily) oro cefixime (400 mg orally once daily)

may also be effective for the treatment of acute uncomplicated pyelonephritis, although published data are limited.

Cefixime likely has limited activity against S. saprophyticus.

Parenteral antibiotics —

We favor ceftriaxone or fluoroquinolones (in areas where fluoroquinolone resistance is relatively low) for initial empiric treatment of hospitalized patients with acute uncomplicated pyelonephritis

Some clinicians favor fluoroquinolones over ceftriaxone given their excellent genitourinary penetration.

Patients with beta-lactam or fluoroquinolone resistance or hypersensitivity may be treated with aztreonam (1 g IV every 8 to 12 hours).

Routine follow-up management —

Patients initially treated with parenteral therapy who improve clinically and can tolerate oral fluids may transition to oral antibiotic therapy.

Fluoroquinolone serum levels achieved with oral and intravenous dosing are equivalent, and the modes of delivery are equally effective clinically [13] .

We favor a 7-day course of antibiotics for mild to moderately ill patients with a prompt response to treatment and with infecting strains that are susceptible to the chosen antibiotic [11] :

In a study of 255 women with uncomplicated pyelonephritis comparing a 7-day course of ciprofloxacin to a 14-day course of trimethoprim-sulfamethoxazole, patients treated with ciprofloxacin had a more favorable clinical cure rate than those treated with trimethoprim-sulfamethoxazole (96 versus 83 percent ) [14] .

A five-day course of oral levofloxacin 750 mg once daily was as effective as a ten-day course of ciprofloxacin [15] .

This levofloxacin regimen has FDA approval for uncomplicated pyelonephritis only and is not appropriate for complicated pyelonephritis.

However, beta lactam regimens should be administered for a full 14-day course given failure rates with a shorter duration of therapy [16] .

The duration of antibiotic therapy need not be extended in the setting of bacteremia in the absence of other complicating factors; there is no evidence that bacteremia portends a worse prognosis [13] .

Surveillance blood cultures to demonstrate clearance of bacteremia are appropriate, although follow-up urine cultures are not needed in patients with acute pyelonephritis whose symptoms resolve on antibiotics.

Persistent symptoms —

Patients with persistent clinical symptoms on antibiotic therapy should be evaluated for complicated pyelonephritis with radiographic imaging and additional laboratory investigation

PATIENTS WITH DELAYED RESPONSE TO THERAPY SHOULD RECEIVE A LONGER COURSE OF ANTIBIOTICS (14 TO 21 DAYS), EVEN IN THE ABSENCE OF EVIDENCE FOR COMPLICATED DISEASE.

Patients with recurrent symptoms within a few weeks of treatment for pyelonephritis should have repeat urine culture and antimicrobial susceptibility testing.

If the pathogen isolated is the same isolate as in the initial episode with the same susceptibility profile, a repeat course of treatment with another antibiotic agent should be instituted.

In addition, radiographic studies should be performed to evaluate for complicated pyelonephritis.

Imaging —

Patients with persistent fever or clinical symptoms after 48 to 72 hours of appropriate antimicrobial therapy for uncomplicated pyelonephritis should undergo radiologic evaluation of the upper urinary tract with ultrasound or computed tomography (CT) scan.

These modalities are useful for evaluating obstruction, abscess, or other complications of pyelonephritis [17-19] .

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

ACUTE COMPLICATED PYELONEPHRITIS —

Complicated pyelonephritis is progression of upper urinary tract infection to :

o renal corticomedullary abscess, o perinephric abscess, o emphysematous pyelonephritis, or o papillary necrosis

Risk factors for progression to complicated pyelonephritis include :

o urinary tract obstruction, o urologic dysfunction, o antibiotic resistant pathogen(s), and o diabetes (particularly for emphysematous pyelonephritis and

papillary necrosis)

Clinical manifestations —

In addition to the clinical manifestations of uncomplicated

pyelonephritis discussed above, complicated pyelonephritis MAY BE ASSOCIATED WITH WEEKS TO MONTHS OF INSIDIOUS, NONSPECIFIC SIGNS AND SYMPTOMS SUCH AS MALAISE, FATIGUE, NAUSEA, OR ABDOMINAL PAIN.

Patients with complicated pyelonephritis due to urolithiasis may present with renal colic and gross or microscopic hematuria.

These findings should prompt consideration of xanthogranulomatous pyelonephritis, a variant of chronic pyelonephritis that may be confused with renal cell carcinoma.

Diagnosis —

ACUTE COMPLICATED PYELONEPHRITIS IS ASSOCIATED WITH PYURIA AND BACTERIURIA, although these findings may be absent if the infection does not communicate with the collecting system or if the collecting system is obstructed.

Urine culture with antimicrobial susceptibility testing should be performed.

Parameters for interpretation of urine colony counts are as outlined above for acute uncomplicated pyelonephritis

Microbiology —

o E. coli is the most common cause of complicated pyelonephritis.

o Other pathogens including:o Citrobacter sp, o Enterobacter sp, o Pseudomonas aeruginosa, o enterococci, o Staphylococcus aureus, and o fungi account for a higher proportion in complicated than

uncomplicated pyelonephritis [21]

S. saprophyticus is an uncommon cause of complicated UTI.

Treatment —

Patients with complicated pyelonephritis should be managed initially as inpatients.

Underlying urinary tract anatomic or functional abnormalities (such as obstruction or neurogenic bladder) should be addressed in consultation with an urologist [21] .

Antibiotics alone may not be successful unless such underlying conditions are corrected.

Broad-spectrum parenteral antibiotics should be used for empiric treatment of complicated pyelonephritis

Antimicrobial therapy subsequently must be tailored to individual patient circumstances with consideration of the results of susceptibility testing and prior recent antibiotic therapy.

Transitioning to oral antibiotic therapy is as outlined above for acute uncomplicated pyelonephritis

Antibiotics should be administered for at least 10 to 14 days, although a longer duration of therapy may be warranted for patients with underlying complicating factors.

THE FIVE-DAY REGIMEN OF LEVOFLOXACIN 750 MG ONCE DAILY HAS FDA APPROVAL FOR UNCOMPLICATED PYELONEPHRITIS ONLY AND IS NOT APPROPRIATE FOR COMPLICATED PYELONEPHRITIS.

SUMMARY AND RECOMMENDATIONS

Acute uncomplicated pyelonephritis is a urinary tract infection that has progressed from the lower urinary tract to the upper urinary tract.

Acute complicated pyelonephritis is progression of acute pyelonephritis to emphysematous pyelonephritis, renal corticomedullary abscess, perinephric abscess, or papillary necrosis.

It is frequently associated with an underlying condition such as obstruction, urologic dysfunction, diabetes, or infection with an antibiotic-resistant pathogen.

Clinical manifestations of pyelonephritis include flank pain, nausea, vomiting, fever (≥ 37.8ΊC) and/or costovertebral angle tenderness.

Laboratory evaluation should include urinalysis (to evaluate for pyuria), urine culture and antimicrobial susceptibility testing.

Most episodes of pyelonephritis are associated with >10(5) CFU per mL of organisms, although some patients with pyelonephritis have colony counts of 10(3) to 10(4) CFU per mL.

For patients able to tolerate oral antibiotics, we suggest an oral fluoroquinolone for initial empiric treatment of acute uncomplicated pyelonephritis

For patients unable to tolerate oral antibiotics, we suggest intravenous ceftriaxone or a fluoroquinolone for initial empiric parenteral treatment of acute uncomplicated pyelonephritis

For patients with complicated pyelonephritis, we suggest broad-spectrum parenteral

Subsequent choice and duration of antibiotic therapy must be tailored to antimicrobial susceptibility findings and clinical circumstances.

Imaging (ultrasonography or computed tomography) is warranted in the setting of persistent fever or clinical symptoms after 48 to 72 hours of appropriate antimicrobial therapy to evaluate for obstruction, abscess, or other complications of pyelonephritis.

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