Pyelonephritis, Acute, Uncomplicated

PATHOGENS

Like uncomplicated cystitis, the vast majority of acute uncomplicated pyelonephritis (AUP) is caused by E. coli (75-95%).
Additional pathogens include other Enterobacteriaceae (e.g., Klebsiellaspp.) and S. saprophyticus.
- Proteus spp. can cause pyelonephritis; repeated episodes with this pathogen should raise concern for struvite stones.
- S. agalactiae and Enterococcus spp. are possible but uncommon pathogens.
- S. aureus is an uncommon pathogen and should raise concern for other infectious process (e.g., blood stream infection, endocarditis).

CLINICAL

Epidemiology: essentially all AUP cases occur in women 18-40 years.
- Risk factors: uncomplicated cystitis, sexual intercourse, use of spermicide-impregnated condoms.
- Presence of functional or anatomic urologic abnormalities define the infection as complicated pyelonephritis; consider management in consultation with a specialist.
  - Acute pyelonephritis is uncommon in men absent a urinary tract abnormality.
Clinical: signs and symptoms include fever, chills, flank pain, nausea, and vomiting.
- Patients may or may not have symptoms of a lower tract UTI (uncomplicated acute bacterial cystitis).
- Abdominal and/or pelvic pain may be present.
- Costovertebral angle tenderness to percussion typical.
- Differential diagnosis: Pelvic inflammatory disease (PID), appendicitis, urolithiasis, biliary tract disease, acute pancreatitis, basal pneumonia.
Criteria for hospitalization: can be treated as an outpatient if patient stable. If below factors present, consider inpatient treatment.
- Pregnancy
- Emesis (inability to reliably keep down oral medications)
- Sepsis parameters, systemic inflammatory response syndrome (SIRS)
- Complicated pyelonephritis infection (including men)
Complications: renal or perinephric abscess, emphysematous pyelonephritis, nephronia (focal bacterial nephritis), renal papillary necrosis.

DIAGNOSIS

When diagnosis suspected, always obtain urine (via clean-catch, mid-stream sample OR catheterized specimen) for urinalysis and culture (with antibiotic susceptibility testing).
- Urine specimen: should be received in the laboratory within 1 h of collection (or stored at 4°C and tested within 18h) to reduce risk of overgrowth of bacteria.
- Bacterial colony counts typically >100,000 CFU/mL.
- Absence of pyuria and bacteriuria suggest an alternative diagnosis (unless obstruction present).
Although blood cultures are positive in 20–30% of cases, there is little evidence that results influence management or outcome.
Physical examination should include costovertebral angle percussion, abdominal examination, and possibly pelvic examination.
Pregnancy testing should be performed for all women of child-bearing age.

TREATMENT

Empiric Outpatient

Empiric, initial, oral, outpatient treatment: if local rates of E. coli fluoroquinolone resistance are low (< 10%):
- Ciprofloxacin 500 mg PO twice daily x 7 d
- Ciprofloxacin extended release 1000 mg PO x 7 d
- Levofloxacin 750 mg orally x 5-7 d

Consider an initial dose of a parenteral agent, particularly if fluoroquinolone resistance is >10%. Then complete treatment as guided by antimicrobial sensitivity results.
- Ceftriaxone 1 gm IM or IV x 1
- Gentamicin 5 mg/kg IM or IV x 1
- Ciprofloxacin 400 mg IV x 1
Modify initial treatment based upon results of urine culture and sensitivity.
- While trimethoprim/sulfamethoxazole should not be used for initial empiric therapy because of high rates of resistance, TMP/SMX 160/800 mg (one DS tablet) PO twice daily x 14 days is appropriate treatment of uncomplicated cystitis for pathogens known to be sensitive.
- Oral beta-lactams are second-line agents due to high rates of relapse (even when pathogen is susceptible).

Empiric Inpatient

Use local antibiotic susceptibility data to guide initial empiric therapy.
- Ciprofloxacin 400 mg IV q12h (if local fluoroquinolone resistance rates < 10%)
- Levofloxacin 500 mg IV once daily (if local fluoroquinolone resistance rates < 10%)
- Ceftriaxone 1 g IV once daily (with or without an aminoglycoside, e.g., gentamicin 5 mg/kg IV daily)
- Gentamicin 5 mg/kg IV once daily (with or without ampicillin 2 grams IV q4h)
- Tobramycin 5 mg/kg IV once daily (with or without ampicillin 2 grams IV q4h)
- Piperacillin/tazobactam 3.375 g IV q6h (with or without an aminoglycoside, e.g., gentamicin 5 mg/kg IV daily)
- Meropenem 2 grams IV q8h
Duration: typically 48h parenteral therapy or until afebrile, then switch to oral therapy based upon susceptibility data to complete 7d (fluoroquinolone) or 14d (TMP-SMX) course.
- If beta-lactam is used to complete therapy, 10-14 days duration needed.
Suspected or proven Enterococcus spp. infection: ampicillin 2 g IV q4h plus aminoglycoside (e.g., gentamicin 5 mg/kg IV daily) for initial therapy, then complete 10-14 d therapy with amoxicillin if susceptible.

Selected Drug Comments

Drug	Recommendation
Amoxicillin	Use for mild-to-moderate acute uncomplicated pyelonephritis caused by Enterococcus or to complete a 14d course of therapy for same which began with parenteral ampicillin. Employ only after susceptibility data returns.
Ampicillin	For infections caused by Enterococcus spp., this parenteral agent (with or without an aminoglycoside) can be used initially for severe cases of acute uncomplicated pyelonephritis. Use PO amoxicillin to complete a 14d course of treatment.
Cefazolin	May be considered as an alternative agent for susceptible pathogens. One observational, non-randomized study showed it to be non-inferior to ceftriaxone for acute pyelonephritis vis-a-vis clinical response, length of hospital stay, and 30-day readmission rates for cystitis or pyelonephritis.
Ceftriaxone	Active against most Enterobacteriaceae and can be used to commence outpatient therapy followed by oral therapy. However, there is no demonstrated long term post-antibiotic effect as noted with aminoglycosides.
Ceftazidime	Active against most Gram-negative organisms including P. aeruginosa. Attains good levels in urine.
Ceftolozane/tazobactam	When compared with levofloxacin for the treatment of patients with pyelonephritis or complicated lower UTI, this agent was more likely to be associated with microbiological cure and was non-inferior in achieving clinical cure.
Moxifloxacin	This fluoroquinolone is not a good choice for UTIs as it attains poor urine levels with mostly hepatic excretion.
Nitrofurantoin	Not recommended for acute pyelonephritis as it does not attain therapeutic levels in renal parenchyma.
Ciprofloxacin	Fluoroquinolones (FQ) are the first line empiric treatment for acute pyelonephritis.
Levofloxacin	Fluoroquinolones (FQ) are the first line empiric treatment for acute pyelonephritis.
Gentamicin	An effective modality along when given IV or IM or given as a first dose in outpatient treatment. In light of the proven post antibiotic effect of aminoglycosides, this regimen may be preferable when combined parenteral and oral outpatient treatment is used. Single dose therapy has not been associated with adverse impact on the kidneys. All aminoglycosides are associated with the risk of ototoxicity beginning with the first dose.
Tobramycin	An effective modality along when given IV or IM or given as a first dose in outpatient treatment. In light of the proven post antibiotic effect of aminoglycosides, this regimen may be preferable when combined parenteral and oral outpatient treatment is used. Single dose therapy has not been associated with adverse impact on the kidneys. All aminoglycosides are associated with the risk of ototoxicity beginning with the first dose.
Amikacin	Use of amikacin should be limited to those patients with organisms found to be resistant to other aminoglycosides.
Fosfomycin	Do not use oral preparation for severe pyelonephritis because of limited systemic absorption. Drug has been used for AUP at higher dosings by IV preparation [12-16 g IV per day in 3 or 4 divided doses].

OTHER INFORMATION

Recommendations based on International clinical practice guidelines by the IDSA and the European Society for Microbiology and Infectious Diseases.
Route of infection is ascending: organisms enter urethra, colonize bladder, ascend to the renal pelvis and ultimately invade renal parenchyma.
More virulent forms of E. coli are more likely to cause uncomplicated acute pyelonephritis than cystitis but are more susceptible to antimicrobial therapy.

Pathogen Specific Therapy

Pathogen	1st Line Agent	2nd Line Agent
Enterobacteriaceae including Escherichia coli	Outpatient Regimens: Ciprofloxacin Levofloxacin	Outpatient Regimens: TMP/SMX Cephalexin Cefpodoxime Cefixime Ceftriaxone Gentamicin
Enterobacteriaceae including Escherichia coli	Inpatient regimen (until afebrile x 48h, then outpatient regimen) Ciprofloxacin Levofloxacin Gentamicin ± ampicillin Tobramycin ± ampicillin Ceftriaxone ± gentamicin
Staphylococcus saprophyticus	Outpatient regimens: Ciprofloxacin Levofloxacin Inpatient regimens (Give IV until afebrile X 48h, then PO for total 14d): Ciprofloxacin Levofloxacin Ceftriaxone ± gentamicin	Outpatient regimens: Amoxicillin/clavulanate

Basis for recommendation

Gupta K, Hooton TM, Naber KG, et al. International clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women: A 2010 update by the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases. Clin Infect Dis. 2011;52(5):e103-20. [PMID:21292654]
Comment: Provides the clinical practice guideline formulated by a panel of international experts convened by the IDSA and ESCMID to update the previous guideline from 1999. Co-sponsors include the American Congress of Ob/GYN, American Urological Association, Associatrion of Medical Microbiologty and Infectious Diseases-Canada, and the Society for Academic Emergency Medicine. This guideline focuses on uncomplicated acute bacterial cystitis and acute pyelonephritis in pre-menopausal, non-pregnant jwomen with no known urological abnormalities or co-morbidities.

References

Hobbs AL, Shea KM, Daley MJ, et al. Are first-generation cephalosporins obsolete? A retrospective, non-inferiority, cohort study comparing empirical therapy with cefazolin versus ceftriaxone for acute pyelonephritis in hospitalized patients. J Antimicrob Chemother. 2016;71(6):1665-71. [PMID:26983859]
Comment: Non-randomized, observational study suggesting that cefazolin may be an acceptable choice for susceptible isolates. While over half of patients treated with cefazolin received at least one dose of an additional antibiotic, this study suggests there may be a role for this narrow-spectrum agent in treating acute pyelonephritis.
Wagenlehner FM, Umeh O, Steenbergen J, et al. Ceftolozane-tazobactam compared with levofloxacin in the treatment of complicated urinary-tract infections, including pyelonephritis: a randomised, double-blind, phase 3 trial (ASPECT-cUTI). Lancet. 2015;385(9981):1949-56. [PMID:25931244]
Comment: RCT of patients with complicated lower UTI or pyelonephritis. Ceftolazone-tazobactam was non-inferior to levofloxacin in achieving clinical cure and was superior in achieving microbiological cure. Composite (clinical + microbiological) cure rates were superior for ceftolazone-tazobactam when considering patients whose pathogens were resistant to levofloxacin or were ESBL-positive.
Sandberg T, Skoog G, Hermansson AB, et al. Ciprofloxacin for 7 days versus 14 days in women with acute pyelonephritis: a randomised, open-label and double-blind, placebo-controlled, non-inferiority trial. Lancet. 2012;380(9840):484-90. [PMID:22726802]
Comment: Contemporary study confirming that 7 days of ciprofloxacin provides adequate therapy for acute uncomplicated pyelonephritis; unlike earlier studies, this one included among middle-aged women and women with more severe illness. The work also suggests that 14 days of therapy should not be used, in part to minimize needless antibiotic therapy and the increased risk for antibiotic resistant organisms with prolonged therapy.
Nielubowicz GR, Mobley HL. Host-pathogen interactions in urinary tract infection. Nat Rev Urol. 2010;7(8):430-41. [PMID:20647992]
Comment: The authors provide a concise review of host-pathogen interactions occurring in both uncomplicated and complicated urinary tract infections. Excellent diagrams are provided to accompany the text explaining uropathogenic E. coli virulence factors (fimbriae, toxins, flagella, iron acquisition systems, proteins that function in immune evasion. Host defenses are discussed including the role of urine flow and cell exfoliation, innate and adaptive immune responses, and genetics.
Raz R, Colodner R, Kunin CM. Who are you--Staphylococcus saprophyticus? Clin Infect Dis. 2005;40(6):896-8. [PMID:15736028]
Comment: A concise discussion of S. saprophyticus, its role in UTI , risk factors, pathogenesis and research questions and issues that are outstanding. This novobiocin resistant organism is resistant to nitrofurantoin but sensitive to the fluoroquinolones.
Rating: Important
Velasco M, Martínez JA, Moreno-Martínez A, et al. Blood cultures for women with uncomplicated acute pyelonephritis: are they necessary? Clin Infect Dis. 2003;37(8):1127-30. [PMID:14523779]
Comment: This is a report of a prospective cohort study to determine the utility of blood cultures in combination with urine cultures in the management of new-onset community acquired acute uncomplicated pyelonephritis (APN). Data were collected from 583 cases. In 97.6% of cases the urine and blood isolates matched. Clinical outcome did not differ among patients with concordant and non-concordant isolates from the 2 sites (blood and urine).
Rating: Important
Fihn SD. Clinical practice. Acute uncomplicated urinary tract infection in women. N Engl J Med. 2003;349(3):259-66. [PMID:12867610]
Comment: Excellent, concise review of acute uncomplicated UTIs in women including acute bacterial cystitis (ABC), uncomplicated acute pyelonephritis (AUP), recurrent UTIs (rUTI). The review reiterates that UAP in an otherwise healthy, nonpregnant woman can be treated in the outpatient setting with a 14-day course of TMP-SMX (provided that local rates of E. coliresistance to this drug is <20%). Amoxicillin-clavulanate orally is an alternative for Gram positive organisms. Women with risk factors for complicated disease, including diabetes, should initially be treated in hospital.
Rating: Important
Nicolau DP, Freeman CD, Belliveau PP, et al. Experience with a once-daily aminoglycoside program administered to 2,184 adult patients. Antimicrob Agents Chemother. 1995;39(3):650-5. [PMID:7793867]
Comment: Well-written report on a large case series. The conclusions of the authors -- effective, decreases nephrotoxicity, cost-effective by decreasing ancillary service costs. However, this is a case-series and not a controlled trial. Comparison is general experience with multiple daily dose regimens.
Barclay ML, Begg EJ, Hickling KG. What is the evidence for once-daily aminoglycoside therapy? Clin Pharmacokinet. 1994;27(1):32-48. [PMID:7955770]
Comment: Extensive review of the issue. Notes high serum levels achieve concentration dependent killing; post-antibiotic effect seen yields continued bacterial growth suppression below MIC.
Rating: Important
Rubin RH, Shapiro ED, Andriole VT, et al. Evaluation of new anti-infective drugs for the treatment of urinary tract infection. Infectious Diseases Society of America and the Food and Drug Administration. Clin Infect Dis. 1992;15 Suppl 1:S216-27. [PMID:1477233]
Comment: Although the paper was written as a guideline for evaluating antimicrobials, it provides a very good and concise overview of the clinical and laboratory aspects of UTIs including acute pyelonephritis.
Rating: Important
Talan DA, Stamm WE, Hooton TM, et al. Comparison of ciprofloxacin (7 days) and trimethoprim-sulfamethoxazole (14 days) for acute uncomplicated pyelonephritis pyelonephritis in women: a randomized trial. JAMA. 2000;283(12):1583-90. [PMID:10735395]
Comment: Double-blind randomized study of 214 post-menopausal women with uncomplicated pyelonephritis given ciprofloxacin 500 mg PO twice daily (7 days) vs TMP-SMX 1 DS PO twice daily x 14d. Ciprofloxacin had better clinical response (96% vs 83%) and bacteriologic response (99% vs 89%).
Rating: Important

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