Johns Hopkins ABX Guide
Pyelonephritis, Acute, Uncomplicated
PATHOGENS
- Like uncomplicated cystitis, most acute uncomplicated pyelonephritis (AUP) is caused by E. coli (75-95%).
- Other Enterobacterales (e.g., Klebsiella spp.) and S. saprophyticus are additional pathogens.
- 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 for acute pyelonephritis.
- S. aureus: an uncommon pathogen for urinary tract infection in those who are not instrumented. Consider evaluation for systemic infection, e.g., endocarditis, bacteremia.
CLINICAL
- Epidemiology: Most AUPs occur in women between 18 and 40 years, so this module has recommendations for adults, not children.
- Risk factors: uncomplicated cystitis, sexual intercourse, use of spermicide-impregnated condoms.
- 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 (see uncomplicated acute bacterial cystitis).
- Abdominal and/or pelvic pain may be present.
- Costovertebral angle tenderness to percussion is 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 the patient is stable. If the below factors are present, consider inpatient treatment.
- Pregnancy
- Emesis (inability to reliably keep down oral medications)
- Sepsis parameters, systemic inflammatory response syndrome (SIRS)
- Complicated pyelonephritis (including men)
- Complications: renal or perinephric abscess, emphysematous pyelonephritis, nephronia (focal bacterial nephritis), renal papillary necrosis.
DIAGNOSIS
- When the diagnosis is suspected, urine must always be obtained (via clean-catch, mid-stream sample OR catheterized specimen) for urinalysis and culture (with antibiotic susceptibility testing).
- Urine specimens should be received in the laboratory within 30 minutes of collection (or stored at 4°C and tested within 18h) to reduce the risk of bacteria overgrowth.
- Bacterial colony counts typically >100,000 CFU/mL.
- The absence of pyuria and bacteriuria suggests an alternative diagnosis (unless obstruction is 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 childbearing age.
- Imaging is warranted for patients with sepsis, concern for urolithiasis (especially if urine pH ≥7.0 given concern for struvite stones), new AKI (given concern for obstruction), or lack of improvement with 48h appropriate therapy.
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 d
- Consider an initial dose of a parenteral agent, particularly if fluoroquinolone resistance is >10%. Then, complete treatment is guided by the results of antimicrobial sensitivity.
- Ceftriaxone 1 gm IM or IV x 1
- Ertapenem 1 gm IV x1 (if a history of an ESBL-producing organism)
- Gentamicin 7 mg/kg IM or IV x 1 (if severe penicillin allergy)
- Ciprofloxacin 400 mg IV x 1
- Modify initial treatment based on 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 7-14 days is an appropriate treatment of uncomplicated cystitis for pathogens known to be sensitive.
- Oral beta-lactams have historically been viewed as second-line agents due to high rates of relapse (even when the pathogen is susceptible); whether this is a result of under-dosing is a subject of investigation.
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)
- Ertapenem 1 g IV once daily
- Gentamicin 7 mg/kg IV once daily (with or without ampicillin 2 grams IV q4h)
- Tobramycin 7 mg/kg IV once daily (with or without ampicillin 2 grams IV q4h)
- Duration: typically 48h parenteral therapy or until afebrile, then switch to oral treatment based upon susceptibility data to complete 7d (fluoroquinolone) or 7-14d (TMP-SMX) course.
- If beta-lactam is used to complete therapy, a 10-14 days duration is appropriate.
- 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 |
Use for mild-to-moderate acute uncomplicated pyelonephritis caused by Enterococcus or to complete a 14d course, which began with parenteral ampicillin. Employ only after susceptibility data returns. | |
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 14-day course of treatment. | |
An alternative agent for susceptible pathogens. One observational, non-randomized study showed it to be non-inferior to ceftriaxone for acute pyelonephritis in terms of clinical response, length of hospital stay, and 30-day readmission rates for cystitis or pyelonephritis. | |
Active against many community-acquired Enterobacteriaceae and can be used to commence outpatient therapy followed by oral therapy. However, as noted with aminoglycosides, no long-term post-antibiotic effect has been demonstrated. | |
Active against most Gram-negative organisms, including P. aeruginosa. Attains good levels in urine. | |
Compared with levofloxacin for treating patients with pyelonephritis or complicated lower UTI, this agent was more likely to be associated with microbiological cures and was non-inferior in achieving clinical cures. | |
Moxifloxacin | This fluoroquinolone is not a good choice for UTIs as it attains poor urine levels with mostly hepatic excretion. |
It is not recommended for acute pyelonephritis as it does not attain therapeutic levels in renal parenchyma. | |
Fluoroquinolones (FQ) are the first line of empiric treatment for acute pyelonephritis. | |
Fluoroquinolones (FQ) are the first line of empiric treatment for acute pyelonephritis. | |
An effective modality when given IV or IM or as a first dose in outpatient treatment. Given the 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 impacts on the kidneys. All aminoglycosides are associated with the risk of ototoxicity beginning with the first dose. | |
An effective modality when given IV or IM or as a first dose in outpatient treatment. In light of the 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 impacts on the kidneys. All aminoglycosides are associated with the risk of ototoxicity beginning with the first dose. | |
Amikacin should be limited to those patients with organisms resistant to other aminoglycosides. | |
Do not use oral preparation for severe pyelonephritis because of limited systemic absorption. The drug has been used for AUP at higher dosings by IV preparation [12-16 g IV per day in 3 or 4 divided doses], but it is unavailable in the United States. | |
FDA-approved for uUTI in 2024, this beta-lactam is effective against many Gram-negative organisms and could be an appropriate oral step-down choice. This prodrug of mecillinam has been used for AUP in Scandinavian countries for many years and is incorporated in Danish and Norwegian guidelines. | |
Bactrim or Septra should not be empiric therapy, given resistance rates in E. coli; however, it would be appropriate to step down oral treatment if organisms are susceptible. |
OTHER INFORMATION
- Recommendations based on International clinical practice guidelines by the IDSA and the European Society for Microbiology and Infectious Diseases.
- The route of infection is ascending: organisms enter the urethra, colonize the bladder, ascend to the renal pelvis and ultimately invade the 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: | Outpatient Regimens: |
Enterobacteriaceae, including Escherichia coli | Inpatient regimen (until afebrile x 48h, then outpatient regimen) | |
Staphylococcus saprophyticus | Outpatient regimens: Inpatient regimens (Give IV until afebrile X 48h, then PO for total 14d): | Outpatient regimens: |
Basis for recommendation
- Lee RA, Centor RM, Humphrey LL, et al. Appropriate Use of Short-Course Antibiotics in Common Infections: Best Practice Advice From the American College of Physicians. Ann Intern Med. 2021;174(6):822-827. [PMID:33819054]
Comment: ACP Guidance puts as best practice in men and women with AUP that short-course therapy should be used, either with fluoroquinolones (5 to 7 days) or TMP-SMZ (14 days) based on antibiotic susceptibility.
- Johnson JR, Russo TA. Acute Pyelonephritis in Adults. N Engl J Med. 2018;378(1):48-59. [PMID:29298155]
Comment: A concise review of diagnosis and treatment, with the latter including the need for supportive care and source control as factors contributing to decision-making regarding patient disposition (home, observation unit, or inpatient admission).
- 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, the American Urological Association, the Association of Medical Microbiology 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 women with no known urological abnormalities or co-morbidities.
References
- Hansen BÅ, Grude N, Lindbæk M, et al. The efficacy of pivmecillinam in oral step-down treatment in hospitalised patients with E. coli bacteremic urinary tract infection; a single-arm, uncontrolled treatment study. BMC Infect Dis. 2022;22(1):478. [PMID:35590284]
Comment: Though not an acute pyelonephritis study, this single-arm study looked at GU-tract-related E coli bacteremia, primarily in older adults who were hospitalized and found that PIV 400 mg QID given for 1 week following 3 days of parenteral antibiotics.
- Jansåker F, Frimodt-Møller N, Benfield TL, et al. Mecillinam for the treatment of acute pyelonephritis and bacteremia caused by Enterobacteriaceae: a literature review. Infect Drug Resist. 2018;11:761-771. [PMID:29872326]
Comment: The drug is recommended for AUP in Danish and Norwegian treatment guidelines when used at a dose of at least 400 mg TID of pivmecillinam (the prodrug of medicinal).
- 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: A non-randomized, observational study suggests 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 cures and was superior in attaining microbiological cures. Composite (clinical + microbiological) cure rates were superior for ceftolazane-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: A contemporary study confirmed that 7 days of ciprofloxacin provide adequate therapy for acute uncomplicated pyelonephritis; unlike earlier studies, this one included middle-aged women and women with more severe illnesses. The work also suggests that 14 days of therapy should not be used, partly to minimize needless antibiotic therapy and the increased risk for antibiotic-resistant organisms with prolonged treatment.
- 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 include 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, research questions, and outstanding issues. This novobiocin-resistant organism is resistant to nitrofurantoin but sensitive to 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 outcomes did not differ among patients with concordant and non-concordant isolates from the two sites (blood and urine).
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 authors’ conclusions are effective, decrease nephrotoxicity, and are 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 - 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
