Acute Pyelonephritis

Clinical Description, Epidemiology, and Etiology

Pyelonephritis connotes infection of the renal pelvis and/or parenchyma, and is defined clinically by the presence of flank pain and/or tenderness, usually accompanied by fever, in a patient with bacteriuria and pyuria (7). Pyelonephritis exhibits many of the same epidemiological associations as cystitis, but is approx 20-fold less common. Patients with pyelonephritis usually feel systemically ill and may have nausea and vomiting, abdominal pain, headache, and myalgias (1). Some develop bacteremia, which can precipitate septic shock and its characteristic sequelae.

Table 1

Treatment Regimens for UTI in Adults

Condition Characteristic Pathogens

Acute cystitis Escherichia coli, Staphylo coccus saprophyticus, Proteus mirabilis, Klebsiella pneumoniae

Acute pyelonephritis E. coli, P. mirabilis, K.

pneumoniae (S. saprophyticus)

Mitigating Circumstances

Recommended Empirical Treatment3

None

Male, diabetes, symptoms for > 7 d, recent UTI or antimicrobial use, childhood UTI, age > 65 yr

Pregnancy

Mild-to-moderate illness; no nausea or vomiting; no comorbid conditions outpatient therapy acceptable

Severe illness or possible urosepsis, and/or comorbid conditions: hospitalization required

3-d oral regimenb: TMP-SMZ or trimethoprim (if < 10-20% of E. coli resistant), or a fluoroquinolone

Consider 7-10 d oral regimenb: an oral fluoroquinolone, trimethoprim-sulfmethoxazole or trimethoprim (if < 10-20% of E. coli resistant), amoxicillin-clavulanate, Cefixime, or Cefpodoxime proxetil

Consider 7-d oral regimenb: amoxicillin, macrocrystall line nitrofurantoin, Cefixime, Cefpodoxime proxetil, or TMP-SMZ (only if <10-20% of £ coli are resistant

Oralb fluoroquinolone for 7 d, oral TMP-SMZ for 10-14 d (only if < 5% of E. coli resistant), or oral amoxicillin-clavulanate for 14 d (if Enterococcus suspected or documented); all with or without an initial parenteral0 dose of a fluoroquinolone, gentamicin, or ceftriaxone

A parenteral0 fluoroquinolone, i.v. gentamicin, i.v. ampicillin (or mezlocillin or piperacillin) plus i.v. gentamicin (preferred if Enterococcus suspected or documented), i.v. piperacillin-tazobactam, i.v. imipenem, or iv meropenem (if Enterococcus suspected or documented and renal function a unstable), or iv ceftriaxone +/- gentamicin, until patient is better; then an oralb regimen as for cystitis (or amoxicillin, if only susceptible Enterococcus), to complete 14 d therapy

Complicated UTI (including E. coli, Proteus, Klebsiella, catheter-associated UTI)

Pseudomonas, and Serratia species; enterococci; staphylococci

Pregnancy: hospitalization recommended

Mild-to-moderate illness, no nausea or vomiting: outpatient therapy acceptable

Severe illness or possible urosepsis: hospitalization required

Parenteralc ceftriaxone, aztreonam, or gentamicin (with or without ampicillin), ampicillin-sulbactam, or piperacillin-tazobactam until patient is better; then oralb amoxicillin, amoxicillin-clavulanate, a cephalosporin, or TMP-SMZ (as for cystitis), to complete 14 d of therapy

An oralb fluoroquinolone (or TMP-SMZ, if organism known to be susceptible) for 10-14 d

Parenteral therapyc as for severe uncomplicated pyelonephritis, with inclusion of activity against Pseudomonas (and Enterococcus, if Gram stain suggestive or not done), until patient is better; then an oralb regimen as for cystitis (or amoxicillin, if if only susceptible Enterococcus), to complete 14 d therapy a Treatments listed are those to be prescribed before the etiologic agent is known (Gram staining can be helpful); they can be modified once the agent has been identified. The recommendations are the author's and are limited to drugs currently approved by the Food and Drug Administration, although not all the regimens listed are approved for these indications. Fluoroquinolones (enoxacin, ciprofloxacin, grepafloxacin, levofloxacin, lomefloxacin, norfloxacin, ofloxacin, sparfloxacin, or trovafloxacin) should not be used in pregnancy. Trimethoprim-sulfamethoxazole, although not approved for use in pregnancy, has been widely used. It should be avoided during the first trimester (possible teratogenicity) and near term (kernicterus). Gentamicin should be used with caution in pregnancy because of its possible effects on fetal eighth nerve development. Trimethoprim-sulfamethoxazole should not be used as empiric monotherapy for pyelonephritis in locales where the prevalence of resistance among E. coli exceeds 5%.

b Multiday oral regimens for adults with normal renal and hepatic function are: TMP-SMZ, 160-800 mg every 12 h; trimethoprim, 100 mg every 12 h; ciprofloxacin, 500 mg every 12 h; grepafloxacin, 400 mg daily; levofloxacin, 500 mg daily; lomafloxacin, 400 mg daily; norfloxacin, 400 mg every 12 h; ofloxacin, 200-300 mg every 12 h; sparfloxacin, 400 mg x1, then 200 mg daily; amoxicillin-clavulanate, 875 mg every 12 h; amoxicillin, 500 mg every 8 h; cefpodoxime proxetil, 100 mg every 12 h; cefixime, 400 mg daily; and macrocrystalline nitrofurantoin, 100 mg 4x a day.

c Parenteral regimens for adults with normal renal and hepatic function are: ciprofloxacin, 200-400 mg every 12 h; levofloxacin, 500 mg daily; ofloxacin, 200-400 mg every 12 h; gentamicin, 5 mg/kg daily; ceftriaxone, 1-2 g daily; aztreonam, 1 g every 8-12 h; ampicillin, mezlocillin, and piperacillin, 1-2 g every 6 h; piperacillin-tazobactam, 3.75 g every 6-8 h; imipenem cilastatin, 250-500 mg every 8 h; and meropenem 500 mg every 8 h.

Adapted, by permission, from Stamm WE, Hooten TM. Management of urinary tract infections in adults. N Engl J Med 1993; 329;1328-1334.

The distribution of pathogens in pyelonephritis is similar to that of cystitis, although the particular strains of E. coli that cause pyelonephritis are more likely than cystitis (and particularly than fecal) isolates to express digalactoside-binding adhesins (P fimbriae), hemolysin, and other virulence factors that assist the organism in colonizing the upper urinary tract, foiling host defense mechanisms, and injuring or invading the host (24).

Inpatient vs Outpatient, and Intravenous vs Oral Therapy

One of the major recent developments in the management of acute pyelonephritis is the growing acceptance of outpatient therapy with oral agents for stable patients who have mild to moderate severity of illness (25-29). Such patients can be observed in the emergency department for a period of time and given intravenous fluid replacement, with or without an initial intravenous dose of antibiotic [A]. If they are clinically stable and able to retain oral fluids, and if they seem likely to comply with an oral regimen and to return for reevaluation in case their condition should worsen or they should develop a complication of therapy, they can then be discharged home to complete a course of oral therapy, with a defined plan in place for follow-up by telephone and/or in person. Those who are more severely ill, clinically unstable, unable to tolerate oral medications, or who have an unstable psychosocial situation should be admitted to the hospital for traditional inpatient therapy (27,30). Although outpatient oral management of acute pyelonephritis has been most extensively studied in otherwise healthy young women, it also may be appropriate for certain carefully selected women with underlying medical or urolog-ical conditions, children, and men [C].

Empiric Therapy (Table 1)

Although pretherapy urine cultures should be obtained for all patients with acute pyelonephritis [C], culture results are rarely available before therapy must be initiated. Hence, for both inpatients and outpatients the initial therapeutic regimen usually must be selected empirically, with or without the benefit of a urine Gram stain (8,11,30). For community-acquired infections in otherwise healthy hosts, E. coli is the main pathogen of concern, whereas in nosocomially acquired infections or those occurring in compromised hosts, other more resistant organisms (including Pseudomonas aeruginosa and occasionally Enterococcus) must be anticipated. Fluoroquinolones, whether given orally or intravenously, are usually suitable for empiric therapy [A] (11). Trimethoprim-sulfamethoxazole alone is now inadvisable for empiric therapy even of mild uncomplicated pyelonephritis in many locales because of the risk of therapeutic failure if antimicrobial resistance is present [A] (11,31).

For patients treated initially intravenously, many suitable options for empiric therapy exist, including an aminoglycoside with or without added ampicillin; a third-generation cephalosporin or a P-lactam-P-lactamase inhibitor combination agent, either alone or with an aminoglycoside; or a carbapenem or fluroquinolone alone

[B] (8,11,29,30). Gram-positive cocci in the pretherapy urine Gram stain or a history of urinary tract instrumentation or prior enterococcal UTIs should prompt inclusion of a penicillin with antienterococcal activity or a carbapenem in the initial regimen

Conversion to Oral Therapy and Hospital Discharge

Another opportunity for cost savings without sacrifice of therapeutic efficacy is early conversion from intravenous to oral therapy and prompt discharge from the hospital for patients who initially were admitted to the hospital and treated intravenously. Such patients can be switched to oral therapy once their level of symptomatology has improved to below the threshold for hospital admission, even if there is some degree of persisting fever or flank pain [C]. Similarly, inpatients who have converted to oral therapy can be discharged to home once they have demonstrated the ability to take the first dose of the intended oral medication, providing the home situation is suitable. Observation in the hospital for the traditional "extra day" on oral therapy is not cost effective

The oral regimen to which hospitalized patients are converted can be selected based on susceptibility test results if these are available by the time the patient is ready for oral therapy. Otherwise, an empiric choice can be made based on the preliminary urine culture results, with a fluoroquinolone used for Gram-negative bacilli and amoxicillin for Enterococcus [B] (11). The cost savings achievable by converting to oral therapy and possibly shortening the duration of hospitalization far outweigh the greater drug cost of an oral fluoroquinolone as compared with oral TMP-SMZ, which otherwise would be the drug of choice for known susceptible pathogens (11). Opportunities for empiric conversion to an oral fluoroquinolone in patients with acute pyelonephritis are sufficiently infrequent that the negative impact of this maneuver on antimicrobial susceptibilities due to increased fluoroquinolone use should be negligible [C].

Diagnostic Evaluations

Patients with acute pyelonephritis often are sufficiently ill that it is reasonable to check serum chemistries and blood counts before and possibly again during therapy

[C]. Pretherapy blood cultures, although commonly done, rarely contribute meaningfully to patient management (33). Urinary tract imaging studies and urological consultation can be reserved for patients with pyelonephritis who on the basis of the history or physical examination are suspected at the outset of having an underlying urological abnormality or an anatomical complication of infection in need of instrumentation, and for patients who fail to respond appropriately to medical therapy [C] (7,18,34). Lingering symptoms or fever despite several days of therapy are not indications for imaging studies providing the overall clinical trend is favorable (34), whereas absence of clear improvement after 48 h of appropriate medical therapy is worrisome and should prompt further evaluation [C] (35-37).

Because of its greater sensitivity, computed tomography (CT) is the most cost-effective imaging modality for suspected intrarenal and perinephric abscesses and emphysematous pyelonephritis [C] (37-39). For optimal performance renal CT should be done with intravenous contrast enhancement (39) and, for maximal economy, without an initial sonogram. Ultrasonography is useful mainly if the goal is to evaluate for hydronephrosis or for following abnormalities detected on an initial CT (if visible sonographically) [C] (29,37,40). Spiral CT, if available, is a superior imaging modality specifically for upper urinary tract stones [C] (39).

Duration of Therapy

The duration of therapy for acute pyelonephritis must be individualized for each patient (8,11,41-43). For women with moderate to severe illness who are initially hospitalized and given an aminoglycoside-containing intravenous regimen followed by oral therapy with ampicillin or TMP-SMZ, 14 d of total therapy is highly effective [A] (44). For otherwise healthy women treated as outpatients for mild to moderately severe pyelonephritis, 1 wk of oral ciprofloxacin is as effective as 2 wk of oral TMP-SMZ, and is less likely to encounter antimicrobial resistance [A] (31). For women with underlying complicating conditions and for men, 14 d of total therapy for pyelonephritis is a reasonable target, which can be adjusted up or down based on initial severity of illness and rapidity of response to therapy [C] (7,30).

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