Acute uncomplicated pyelonephritis

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Authors

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

Executive summary

Epidemiology and pathogenesis

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

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

Treatment

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

2. De-escalation: We must determine the effect of empirical therapy to guide the 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 to oral medications from parenteral antimicrobial agents by around 24 hours after symptom remission, such as antipyretic. The total duration of administration is for 14 days (LE:1a, GR:A).

4. Add on therapy: Oral agent is selected for the first line chemotherapy to the outpatients, who are mild or moderate cases of acute uncomplicated pyelonephritis.However, the combination of a single injection of the drug during the first visit is also recommended (LE:1a, GR:A).

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

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

Figure 1. Algorithm of the diagnosis and treatment for acute pyelonephritis
Ishikawa slide 2.png

Introduction

Recently the present state of microbial resistance development is alarming[1]. The use of antibiotics in different Asian countries mirrors the global increase in resistant strains[2][3]. Especially the presence of ESBL producing bacteria showing resistance to most antibiotics is steadily increasing in the population[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 for combating 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 are 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 a wide variation in prescribing practices[5][6][7][8][9].

The focus of this guideline is treatment of women with acute uncomplicated pyelonephritis, 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

Acute uncomplicated pyelonephritis is with a predilection for sexually active women. 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 saprophyticusin 5-10%. Occasionally, other Enterobacteriaceae, such as Proteus mirabilis and Klebsiella spp., are isolated[11](LE: 2a).

As a result of the lack of suitable surveillance studies, 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. Practically, UTI has been divided in uncomplicated and complicated case, which is with the underlying diseases. When we decide the policy of therapy, grade of severity of infection is so important. EAU guideline[5] set on a scale of 1-6 that is related to the risk of fatal outcome. Grade 2 indicates mild or moderate case and grade 3 means severe cases. Mild and moderate cases are indicated as the patients not requiring hospitalization and severe cases are indicated as women with pyelonephritis requiring 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 angletenderness of the affected side is often appeared.

Laboratory investigation

Urinalysis, including the assessment of white and red blood cells and nitrites, is recommended for routine diagnosis[15](LE: 4, GR: C). Colony counts > 104cfu/mL of uropathogens are considered to be indicative of clinically relevant bacteriuria[16](LE: 2b, GR: C).Urine culture test is essential in order to examine the drug susceptibility and the proof of the causative bacteria. In blood examination, inflammatory findings which are leukocytosis, left-shifted nuclear, CRP[17][18][19]and procalcitonin[19] rise, and elevated sedimentation rate can be seen.

Suspecting the presence of bacteremia, it is necessary to blood culture test in situations of sepsis with systemic inflammatory response syndrome[18][20]. There may be accompanied by a state of shock, it should distribute attention to hemodynamics[13].

Radiological investigation

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

Additional investigations, such as an non-enhanced helical CT, excretory urography, or DMSA scanning, should be considered if the patients remain 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 urineculture and susceptibility test should always be performed, andinitial empirical therapy should be tailored appropriately onthe basis of the infecting uropathogen (LE:3, GR:A).

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

For the treatment of acute pyelonephritis, the renal excretion typed antibiotics, such as β- lactams[22] or quinolones[23][24] , is recommended (LE;1, GR:A). Safety margin of aminoglycosidesis so narrow that patients on renal dysfunctionmust require attentions (LE:4, GR:B). If necessary, it is recommended TDM.

In the Gram-positive bacteria, susceptibility to the first and second-line drugs is often seemed to be poor. So we need to require attention to the selection of antibiotics in the treatment (LE:3, GR:B).

Mild and moderate cases of acute uncomplicated pyelonephritis

In mild and moderate cases of acute uncomplicated pyelonephritis, oral therapy of 10-14 days is usually sufficient (LE: 1b, GR: B). A fluoroquinolone for 7-10 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 days[26][27](LE: 1b, GR: B). New typed fluroquinolone, such as sitafloxacin and moxifloxacin can be also expected clinical effect against fluoroquinolone-low susceptible strains[28](LE: 4, GR: C). However, increasing numbers of fluoroquinolone-resistant E. coli in the community have already been found in some parts of the Asian countries, thus restricting 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, a long acting antimicrobial, 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%, 1g of ceftriaxone or aminoglycoside is recommended 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 alternativeagent in conjunction with or to replace a fluoroquinolonefor 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 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 an aminoglycoside[31] or carbapenem has to be considered until susceptibility testing demonstrates that oral drugs can also be used (LE: 4, GR: B).

Pyelonephritis Table 1.png

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:

Pyelonephritis Table 2.png

Women with pyelonephritis requiring hospitalization should be initially treated with an intravenous antimicrobial regimen, such as a fluoroquinolone; an aminoglycoside[31], with or without ampicillin; an extended-spectrum cephalosporinor extended-spectrum penicillin, with or without anaminoglycoside; or a carbapenem. The choice between these agents should be based on local resistance data, and theregimen 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).

Abbreviations

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

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