Acute uncomplicated pyelonephritis

Authors

Kiyohito Ishikawa (Department of Urology, Fujita Health University, School of Medicine, JAPAN) Katsumi Shigemura (Department of Urology, Kobe University, School of Medicine, JAPAN)

Abstract

Patients with acute uncomplicated pyelonephritis often show impaired immune function that aggravates infectious diseases. Urinary tract infection (UTI) is also one of the major complications for diabetic patients. Some of the therapeutic recommendations for UTIs have been revised recently, partly because of the emergence of antibiotic resistant bacteria such as quinolone-resistant Escherichia coli and Extended spectrum beta-lactamase (ESBL) producing bacteria, mainly E. coli and Klebsiella pneumonia, which vary from country to country or between regions in frequency of emergence and spread. An era of antimicrobial resistance (AMR) has arrived, where the use of antibiotics should be reconsidered. Several newly established antimicrobial agents are commercially available for the treatment of resistant bacteria, such as penicillins or cephalosporins with beta-lactamase inhibitors. This revised guideline includes new recommendations for antibiotic use based on changing trends in antibiotic resistance.

Epidemiology and pathogenesis

1. Classification and characteristics of the disease: Pyelonephritis is the inflammation of the renal parenchyma and renal pelvis by ascending infection from the urinary tract. Renal tissue destruction spreads to the parenchyma and easily induces sepsis or bloodstream infection (LE:3). It is classified as either acute uncomplicated UTI or complicated UTI with an underlying disease.

2. Spectrum and frequency of causative organisms: The spectrum of etiological bacteria is similar in uncomplicated upper and lower UTIs, with Escherichia coli the causative pathogen in about 80% of cases (LE: 2a).

Treatment

1. Principles of antimicrobial therapy: Renal excretion typed antibiotics such as β- lactams and quinolones are recommended (LE:1a, GR:A).

2. De-escalation: The effect of empirical therapy must be determined three days after the start of treatment. Then, in accordance with bacterial culture results, it is necessary to switch to definitive therapy (LE:2a, GR:A).

3. Switch therapy: We recommend switching from parenteral antimicrobial agents to oral medications such as antipyretics by around 24 hours after symptom remission (LE:1a, GR:A).

4. Add on therapy: An oral agent is selected asthe first line chemotherapy for outpatients with mild or moderate acute uncomplicated pyelonephritis. However, combination with a single injection drug during the first visit is also recommended (LE:1a, GR:A).

5. Severe conditions: When we find special conditions such as hydronephrosis, abscess formation and gas production, we must diagnose accurately and quickly and perform urological procedures to preserve renal function (LE:2a, GR:A).

6. Combination therapy: We recommend combination therapy in more severe pyelonephritis cases with urosepsis, severe sepsis, or septic shock (LE:2a, GR:A).

Figure 1. Algorithm of the diagnosis and treatment for acute pyelonephritis

Introduction

The present state of antimicrobial resistance development is alarming[1]. Antibiotic resistance in Asian countries mirrors the global increase in resistant strains,[2][3] especially the steadily increasing occurrence of ESBL producing bacteria showing resistance to most antibiotics [4].

It is essential to consider the local microbial environment and resistance pattern as well as risk factors for harboring resistant microbes in individual patients. There is a direct correlation between the use of antibiotics and resistance development. There is an urgent need to combat resistance development by a prudent use of available antibiotics.

The current guidelines aim to provide both urologists and physicians from other medical specialties with evidence-based guidance regarding the treatment of UTI. High-quality clinical research using strict internationally recognized definitions and classifications as presented in this section is encouraged.

Definition of the disease

Overview

Acute uncomplicated pyelonephritis remains one of the most common indications for prescribing of antimicrobials to otherwise healthy community-dwelling women. Despite published guidelines for the optimal selection of an antimicrobial agent and duration of therapy, studies demonstrate wide variations in prescribing practices[5][6][7][8][9].

The focus of this guideline is the treatment of women with acute uncomplicated pyelonephritis, with diagnoses limited in these guidelines to premenopausal, non-pregnant women with no known urological abnormalities or comorbidities. It should be noted that women who are postmenopausal or have well-controlled diabetes without urological sequelae may be considered by some experts to have uncomplicated UTI, but a discussion of specific management of these groups is outside the scope of this guideline.

The issues of in vitro resistance prevalence and the potential for collateral damage were considered as important factors in making optimal treatment choices and thus are reflected in the rankings of recommendations.

Epidemiology

Sexually active women are at risk for acute uncomplicated pyelonephritis. All male patients are treated as complicated pyelonephritis.

The spectrum of etiological agents is similar in uncomplicated upper and lower UTIs, with Escherichia coli the causative pathogen in 70-95% of cases[10] and Staphylococcus saprophyticus in 5-10%. Occasionally, other Enterobacteriaceae, such as Proteus mirabilis and Klebsiella spp., are isolated[11](LE: 2a).

Since suitable surveillance studies are lacking, the spectrum and susceptibility patterns of uropathogens that cause uncomplicated cystitis can be used as a guide for empirical therapy[12](LE: 4, GR: B). However, S. saprophyticus is less frequent in acute pyelonephritis as compared to acute cystitis (LE: 4, GR: B).

Classifications

Traditionally, UTI is classified based on clinical symptoms, laboratory data and microbiological findings. In practice UTI is divided into uncomplicated and complicated cases, with complicated cases defined as those involving an underlying disease. The grade or severity of infection is vitally important for deciding on an appropriate therapy. EAU guidelines[5] include a scale of 1-6 that is related to the risk of fatal outcome. Grade 2 indicates a mild or moderate case and grade 3 indicates severe cases. In mild and moderate cases, patients do not require hospitalization, while severe cases such as women with pyelonephritis require hospitalization[13].

Diagnostic criteria

Clinical symptoms

Acute pyelonephritis is suggested by flank pain, nausea and vomiting, fever > 38°C and general malaise, and it can occur in the absence of symptoms of cystitis[14].

Physical examination

Costovertebral angle tenderness of the affected side is often seen.

Laboratory investigation

Urinalysis, including the assessment of white and red blood cells and nitrites, is recommended for routine diagnosis[15](LE: 4, GR: C). Uropathogen colony counts > 104cfu/mL are considered to indicate clinically relevant bacteriuria[16](LE: 2b, GR: C). A urine culture test is essential for proof of the causative bacteria and to determine drug susceptibility. In blood examination, inflammatory findings such as leukocytosis, left-shifted nuclear, CRP[17][18][19] , elevated procalcitonin[19] and an elevated sedimentation rate can be seen.

If bacteremia is suspected, blood culture tests are necessary, especially in situations of suspected sepsis.[20] This may be accompanied by a state of shock, and attention should be paid to hemodynamics[13].

Radiological investigation

Evaluation of the upper urinary tract with ultrasound should be performed to rule out urinary tract obstruction or renal stone disease (LE: 4, GR: C).

Additional investigations, such as non-enhanced helical CT, excretory urography or DMSA scanning, should be considered if the patient remains febrile after 72 h of treatment (LE: 4, GR: C).

Abdominal CT is also useful in the differential diagnosis of emphysematous pyelonephritis, pyonephrosis, renal abscess, and acute uncomplicated pyelonephritis^[21].

Treatment

Medication

In patients suspected of having pyelonephritis, a urine culture and antimicrobial susceptibility test should always be performed, and initial empirical therapy should be tailored appropriately on the basis of the infecting uropathogen (LE:3, GR:A).

Mild and moderate cases are indicated as patients not requiring hospitalization and severe cases are indicated as women with pyelonephritis requiring hospitalization[13].

For the treatment of acute pyelonephritis, renal excretion typed antibiotics such as β- lactams[22] or quinolones[23][24] are recommended (LE;1, GR:A). The safety margin of aminoglycosides is so narrow that patients with renal dysfunction require close attention (LE:4, GR:B). If necessary, TDM is recommended.

For Gram-positive bacteria susceptibility to the first and second-line drugs is often poor, so close attention to the selection of antibiotics for treatment is essential (LE:3, GR:B).

Mild and moderate cases of acute uncomplicated pyelonephritisedit

In mild and moderate cases of acute uncomplicated pyelonephritis, oral therapy for 7-14 days is usually sufficient (LE: 1b, GR: B). A fluoroquinolone for 7-14 days can be recommended as first-line therapy if the resistance rate of E. coli is still < 10% [25] (LE: 1b, GR: A). If the fluoroquinolone dose is increased, the treatment can probably be reduced to 5-7 days[26][27](LE: 1b, GR: B). Fluoroquinolones such as sitafloxacin and moxifloxacin also can be expected to have clinical effects against strains with low susceptibility to fluoroquinolones[28](LE: 4, GR: C). However, increasing numbers of fluoroquinolone-resistant E. coli have already been found in some Asian countries, and this restricts the empirical use of fluoroquinolones[3].

Oral ciprofloxacin (500 mg twice daily) for 7-10 days, with or without an initial 400 mg dose of intravenous ciprofloxacin, is an appropriate choice for therapy in patients not requiring hospitalization where the prevalence of resistance of community uropathogens to fluoroquinolones is not known to exceed 10% (LE: 1, GR: A). If an initial one-time intravenous agent is used, long-acting antimicrobials, such as 1 g of ceftriaxone or a consolidated 24 hours dose of an aminoglycoside could be used in lieu of an intravenous fluoroquinolone (LE: 3, GR: B). If the prevalence of fluoroquinolone resistance is thought to exceed 10%, 1 g of ceftriaxone or aminoglycoside is recommended as an initial one-time intravenous agent (LE:3, GR:B). (i. Data are insufficient to make a recommendation about what fluoroquinolone resistance level requires an alternative　agent in conjunction with or to replace a fluoroquinolone for treatment of pyelonephritis.)

A third-generation oral cephalosporin, such as cefpodoxime proxetil, ceftibuten, cefditoren pivoxil, or cefcapene pivoxil could be an alternative [29] [30](LE: 1b, GR: B). However, available studies have demonstrated only equivalent clinical, but not microbiological, efficacy compared with ciprofloxacin.

Oral β-lactam agents are often less effective than other available agents for treatment of pyelonephritis (LE: 3, GR: B). If an oral β-lactam agent is used, an initial intravenous long-acting antimicrobial agent (LE: 2, GR: B) or a consolidated aminoglycoside is recommended (LE: 3, GR: B). (i. Data are insufficient to modify the previous guideline recommendation for a duration of therapy of 10–14 days for treatment of pyelonephritis with a β-lactam agent.)

Oral trimethoprim-sulfamethoxazole (160/800 mg [1 double-strength tablet] twice-daily for 14 days) is an appropriate choice for therapy if the uropathogen is known to be susceptible (LE: 1, GR: A). If trimethoprim-sulfamethoxazole is used when the susceptibility is not known, an initial intravenous long-acting antimicrobial agent (LE: 2, GR: B) or a consolidated aminoglycoside is recommended (LE: 3, GR: B).

In communities with high rates of fluoroquinolone-resistant and ESBL-producing E. coli (> 10%), initial empirical therapy with carbapenem[31] has to be considered until susceptibility testing demonstrates that oral drugs can also be used (LE: 4, GR: B).

Table 1. Oral therapy in mild and moderate cases

1) lower dose studied, but higher dose recommended by experts.

2) not studied as monotherapy for acute uncomplicated pyelonephritis.

3) mainly for Gram-positive pathogens

Severe cases of acute uncomplicated pyelonephritis

Patients with severe pyelonephritis, who cannot take oral medication because of systemic symptoms such as nausea and vomiting, have to be treated initially with one of the following parenteral antibiotics:

Table 2. Initial parenteral therapy in severe cases

1) Lower dose studied, but higher dose recommended by experts.

2) Not studied as monotherapy in acute uncomplicated pyelonephritis.

3) Mainly for Gram-positive pathogens.

4) Same protocol for acute uncomplicated pyelonephritis and complicated UTI (stratification not always possible)

Women with pyelonephritis requiring hospitalization should be initially treated with an intravenous antimicrobial regimen, such as a fluoroquinolone; an extended-spectrum cephalosporin or extended-spectrum penicillin, with or without an aminoglycoside; or a carbapenem. The choice between these agents should be based on local resistance data, and the regimen should be tailored on the basis of susceptibility results (LE: 3, GR: B).

Hospital admission should be considered if complicating factors cannot be ruled out by available diagnostic procedures and/or the patient has clinical signs and symptoms of sepsis (LE: 4, GR: B).

After improvement, the patient can be switched to an oral regimen using one of the above-mentioned antibacterials, if active against the infecting organism, to complete the 1-2 week course of therapy (LE: 1b, GR: B).

Follow up

Routine post-treatment urinalysis and urine cultures in an asymptomatic patient might not be indicated (LE: 4, GR: C). In women whose pyelonephritis symptoms do not improve within 3 days, or resolve and then recur within 2 weeks, repeated urine culture and antimicrobial susceptibility tests and an appropriate investigation, such as renal ultrasound, CT or renal scintigraphy, should be performed (LE: 4, GR: B).

In patients with no urological abnormality, it should be assumed that the infecting organism is not susceptible to the agent originally used, and an alternative tailored treatment should be considered based on culture results (LE: 4, GR: B). For patients who relapse with the same pathogen, the diagnosis of uncomplicated pyelonephritis should be reconsidered. Appropriate diagnostic steps are necessary to rule out any complicating factors (LE: 4, GR: C).

Further Research

There are no prospective studies with larger cohort or randomized-control studies to evaluate appropriate management strategies for uncomplicated pyelonephritis. However, as mentioned above, oral 3rd generation cephalosporines have not been recommended for this infectious disease category owing to their low bioavailability. Further evidence is needed for definitive evaluation.

Conclusions

Uncomplicated pyelonephritis is mainly considered as a non-life-threating infection; however, European guidelines have introduced newly-established broad-spectrum antibiotics including beta-lactamase inhibitors. This implies that uncomplicated pyelonephritis is no longer considered a “safe” disease since it can lead to sepsis. Further prospective research in Asian populations is necessary for definitive conclusions.

Abbreviations

ESBL: extended-spectrum β-lactamase, UTI: urinary tract infection, CRP: C-reactive protein, TDM: therapeutic drug monitoring, CT: computed tomography, DMSA: dimercaptosuccinic acid

References

1. Carlet J, Collignon P, Goldmann D, et al. Society’s failure to protect a precious resource: antibiotics. Lancet. 2011;378(9788):369-371.

2. Gyssens IC. Antibiotic policy. Int J Antimicrob Agents. 2011; 38 Suppl:11-20.

3. Shin J, Kim J, Wie SH, Cho YK, Lim SK, Shin SY, Yeom JS, et al.: Fluoroquinolone resistance in uncomplicated acute pyelonephritis:epidemiology and clinical impact. Microb Drug Resist. 2012; 18: 169-175.

4. Oteo J, Pérez-Vázquez M, Campos J. Extended-spectrum [beta]-lactamas producing Escherichia coli:changing epidemiology and clinical impact. CurrOpin Infect Dis. 2010; 23: 320-326.

5. Grabe M, Bartoletti R, Bjerklund-Johansen TE, Cek HM, Pickard RS, Tenke P, Wagenlehner F, Wullt B: Guidelines on Urological Infections, European Association of Urology UPDATE 2014 :8-19.

6. Naber KG, Wullt B and WagenlehnerFME : Antibiotic treatment of uncomplicated urinary tract infection in premenopausal women. Urogenital Infections. International Consultation on Urogenital Infections, Stockholm, Sweden, 2009, EAU Edition 2010 : 171-199.

7. Gupta K, Hooton TH, NaberKG : International clinical guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women: A 2010 update by the infectious disease society of America and the European society for microbiology and infectious diseases. Clin Infect Dis. 2011; 52: 103-120.

8. Gilbert DN, Moellering RC, Eliopoulos GM , et al. : Kidney Bladder and Prostate. The Sanford Guide to Antimicrobial Therapy 2014 (44TH Edition) 2014: p34-35.

9. Aoki N, Arakawa S, Ouchi K, Kiyota H, Tateda K, Mikasa K, Mikamo H, Watanabe S: The JAID/JSC Guide to Clinical Management of Infectious Disease 2011. Life science shuppan KK. Japan 2012 March.

10. Schit GC, Naber KG, Botto H, et al.: An international survey on the antimicrobial resistance of pathogen involved in uncomplicated urinary tract infection. Int J Antimicr Agents 2009; 34: 407-413.

11. Naber KG, Schito G, Botto H, et al. Surveillance study in Europe and Brazil on clinical aspects and Antimicrobial Resistance Epidemiology in Females with Cystitis (ARESC): implications for empiric therapy. Eur Urol. 2008; 54:1164-1175.

12. Kim KS, Kim K, Jo YH.: A simple model to predict bacteremia in women with acute pyelonephritis. J Infect. 2011; 63: 124-130.

13. Scholes D, Hooton TM, Roberts PL, et al. Risk factors associated with acute pyelonephritis in healthy women. Ann Intern Med. 2005; 142:20-27.

14. Fulop T.: Acute Pyelonephritis Workup. Aug 22, 2012. [Access date February 2014 ] http://emedicine.medscape.com/article/245559-workup#aw2aab6b5b3

15. Rubin US, Andriole VT, Davis RJ, et al.: Evaluation of new anti-infective drugs for the treatment of UTI. Clin Infect Dis. 1992;15:216.

16. Yang WJ, Cho IR, Seong do H, Song YS, Lee DH, Song KH, Cho KS, Sung Hong W, Kim HS.: Clinical implication of serum C-reactive protein in patients with uncomplicated acute pyelonephritis as marker of prolonged hospitalization and recurrence. Urology. 2009; 73: 19-22.

17. Yasufuku T, Shigemura K, Yamashita M.: Selection of first-line i.v.antibiotics for acute pyelonephritis in patient required emergency hospital admission. J Infect Chemother. 2011; 14(2): 231-237.

18. Claessens YE, Schmidt J, Batard E, et al.: Can C-reactive protein, procalcitonin and mid-regional pro-atrial natriuretic peptide measurements guide choice of in-patients or out-patients care in acute pyelonephritis? Biomarkers In Sepsis (BIS) multicentrestudy. ClinMicrobiol Infect. 2010; 16(6): 753-760.

19. Etienne M, Van Elslande H, Choplin-Renard J, Pestel-Caron M, Caron F.: Antibiotic resistance in adult female patients hospitalized for acute pyelonephritis: rates and predicting factors. Med Mal Infect. 2014; 44: 217-222.

20. Singer M, Deutschman CS2, Seymour CW, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016 Feb 23;315(8):801-10.

21. Takahashi S, Kurimura Y, Takeyama K : Efficacy of treatment with carbapenemes and third-generation cephalosporins for patients with febrile complicated pyelonephritis. J Infect Chemother. 2009; 15(6): 390-395.

22. Jeon JH, Kim K, Han WD, Song SH, Park KU, Rhee JE, Song KH, Park WB, Kim ES, Park SW, Kim NJ, Oh MD, Kim HB.: Empirical use of ciprofloxacin for acute uncomplicated pyelonephritis caused by Escherichia coli in communities where the prevalence of fluoroquinolone resistance is high. Antimicrob Agents Chemother. 2012; 56: 2043-3046.

23. Sandberg T, Skoog G, HermanssonAB : Ciprofloxacin for 7 days versus 14 days in women with acute pyelonephritis: a randomized, openbabel and double-blind, placebo-controlled, non-inferiority trial. Lancet. 2012; 380(9840): 484-490.

24. Talan DA, Stamm WE, Hooton TM, et al.: Comparison of ciprofloxacin (7 days) and trimethoprimsulfamethoxazole (14 days) for acute uncomplicated pyelonephritis pyelonephritis in women: a randomized trial. JAMA. 2000; 283:1583-1590.

25. Klausner HA, Brown P, Peterson J, et al.: A trial of levofloxacin 750 mg once daily for 5 days versus ciprofloxacin 400 mg and/or 500 mg twice daily for 10 days in the treatment of acute pyelonephritis. Curr Med Res Opin. 2007; 23:2637-2645.

26. Peterson J, Kaul S, Khashab M, et al.: A double-blind, randomized comparison of levofloxacin 750 mg once-daily for five days with ciprofloxacin 400/500 mg twice-daily for 10 days for the treatment of complicated urinary tract infections and acute pyelonephritis. Urology 2008; 71:17-22.

27. Matsumoto T, Yamaguchi H, Uchino K, Takahashi M, Kodama H, Hamajima S, Yonemochi R, Fujita S, Takita A, Yamanouchi N, Shiozawa T, Okutani Y.: Efficacy and safety of sitafloxacin in patients with urinary tract infections. Jpn J Antibiot. 2012; 65: 365-380.

28. Cronberg S, Banke S, Bergman B, et al.: Fewer bacterial relapses after oral treatment with norfloxacinthan with ceftibuten in acute pyelonephritis initially treated with intravenous cefuroxime. Scand J InfectDis. 2001; 33:339-343.

29. Naber KG, Schoenwald S, Hauke W.: Cefpodoximeproxetil in patients with acute uncomplicatedpyelonephritis. International, prospective, randomized comparative study versus ciprofloxacin ingeneral practice. Chemotherapie Journal 2001; 10:29-34.

30. Bader MS, Loeb M, Leto D, Brooks AA. Treatment of urinary tract infections in the era of antimicrobial resistance and new antimicrobial agents. Postgrad Med. 2019 Oct 24:1-17.

31. Lee SS, Kim Y, Chung DR.: Impact of discordant empirical therapy on outcome of community-acquired bacteremic acute pyelonephritis. J Infect. 2011; 62: 159-164.

32. Richard GA, Klimberg IN, Fowler CL, et al.: Levofloxacin versus ciprofloxacin versus lomefloxacin in acute pyelonephritis. Urology 1998; 52: 51-55.

33. Wells WG, Woods GL, Jiang Q, et al.: Treatment of complicated urinary tract infection in adults: combined analysis of two randomized, double-blind, multicentre trials comparing ertapenem and ceftriaxone followed by an appropriate oral therapy. J Antimicrob Chemother. 2004; 53 Suppl 2: ii67-74.

34. Mouton YJ, Beuscart C.: Empirical monotherapy with meropenem in serious bacterial infections. Meropenem Study Group. J Antimicrob Chemother. 1995; 36 Suppl A:145-156.

35. Giamarellou H.: Low-dosage cefepime as treatment for serious bacterial infections. J Antimicrob Chemother. 1993; 32 Suppl B:123-132.

36. Naber KG, Savov O, Salmen HC.: Piperacillin 2 g/tazobactam 0.5 g is as effective as imipenem 0.5 g/ cilastatin 0.5 g for the treatment of acute uncomplicated pyelonephritis and complicated urinary tract infections. Int J Antimicrob Agents. 2002; 19:95-103.

37. Naber KG, Llorens L, Kaniga K, et al.: Intravenous doripenem at 500 milligrams versus levofloxacin at 250 milligrams, with an option to switch to oral therapy, for the treatment of complicated lower urinary tract infection and pyelonephritis. Antimicrob Agents Chemother. 2009; 53: 3782-3792.