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JAID/JSC Guidelines for Clinical Management of Infectious Disease 2015 − Urinary tract infection/male genital infection

Open AccessPublished:September 08, 2017DOI:https://doi.org/10.1016/j.jiac.2017.02.002
      Tabled 1
      Contents
      • 1.
        Introduction734
      • 2.
        Urinary tract infections734
        • 2.1.
          Cystitis734
        • 2.2.
          Pyelonephritis737
        • 2.3.
          Urosepsis740
        • 2.4.
          Cystitis in dialysis patients741
        • 2.5.
          Asymptomatic bacteriuria742
        • 2.6.
          Catheter-related urinary tract infection743
        • 2.7.
          Urinary tract infection in children744
      • 3.
        Male genital infection746
        • 3.1.
          Acute bacterial prostatitis746
        • 3.2.
          Acute epididymitis747
      References748

      1. Introduction

      The general medical environment is subject to constant changes due to the advent of various drug-resistant microorganisms, with the field of urinary tract/genital infection not an exception. Although antimicrobial agents effective against enterobacteriaceae, primarily gram-negative rods, are typically selected for conventional therapeutic strategies, a number of studies of fluoroquinolone-resistant Escherichia coli, ESBL-producing bacteria, and multi-drug resistant Pseudomonas aeruginosa have recently been presented, as well as reports regarding carbapenem-resistant enterobacteriaceae. Therefore, measures to control nosocomial infections must be intensified. It is also of concern that these resistant bacteria have been observed in community-acquired as well as nosocomial infections. The cause of such spread of resistant bacteria is none other than the result of inappropriate use of conventional measures against infections and inappropriate use of antimicrobials, thus medical workers are strongly advised to use antimicrobials properly with the possibility of “collateral damage” in mind.
      In 2012, the Japanese Association for Infectious Disease/Japanese Society of Chemotherapy published “JAID/JSC Guide to Clinical Management of Infectious Diseases 2011” to provide practical guidelines for appropriate use of antimicrobials. In 2014, a revised edition titled “JAID/JSC Guide to Clinical Management of Infectious Diseases 2014” was published. These guides are presented in Japanese as pocket editions that concisely describe important points and are convenient to use. The contents have been reconstituted as the present guidelines by supplementing with commentaries so as to make the intent of the recommendations more understandable. We trust that the present edition will help medical practitioners sufficiently understand both the meaning and limitations of the background and evidence supporting these recommendations, and learn to properly utilize antimicrobials in a flexible manner. We also intend to serially revise these Guidelines every few years, as they are likely to become obsolete in view of constant reports of the advent and spread of novel antimicrobial resistant bacteria.
      Supplementary notes:
      • 1.
        The recommendation grades and evidence level of cited literature were determined according to the Outline for Preparation of Guidelines to Clinical Management of Infectious Disease (see below) established by the Japanese Association for Infectious Disease/Japanese Society of Chemotherapy.
      • Recommendation grade
      A: Strongly recommended
      B: Generally recommended
      C: Comprehensive evaluation by attending physician
      Evidence level
      I: Randomized comparative study
      II: Non-randomized comparative study
      III: Case report
      IV: Specialist's opinion
      • 2.
        Lists of antimicrobial abbreviations and doses for neonates are presented at the end of this volume.
      • 3.
        Treatment not covered by Japanese national health insurance system (including disease name, antimicrobial dose, and bacterial species).

      2. Urinary tract infections

      2.1 Cystitis

      Executive summary
      • Most urinary tract infections are ascending infections caused by enterobacteriaceae. They are classified into uncomplicated infections associated with no obvious underlying disease and complicated infections with an underlying disease.
      • In premenopausal women with acute cystitis, gram-positive cocci, such as Staphylococcus saprophyticus, are isolated relatively frequently, while Gram-negative E. coli organisms show a 90% or higher susceptibility to penicillins when given in combination with a β-lactamase inhibitor (BLI), cephalosporins, or fluoroquinolones. Therefore, fluoroquinolones may be the first choice when the causative bacterium is unknown or confirmed to be gram-positive cocci, while penicillins with a BLI or cephalosporins are recommended when the urine examination results reveal a gram-negative rod infection (BII).
      • As compared with premenopausal women with acute cystitis, the frequency of isolation of gram-positive cocci is low and isolated E. coli organisms show a high rate of fluoroquinolone resistance in postmenopausal women. Therefore, penicillins with a BLI or cephalosporins are recommended as the first choice (BII), while fluoroquinolones should be selected when the presence of gram-positive cocci has been confirmed.
      • Oral antimicrobials, such as FRPM and FOM, are effective against ESBL-producing bacteria (BII).
      • In cases complicated with cystitis, a urine culture examination should be performed before administration of antimicrobials in order to identify the causative bacterium and examine antimicrobial susceptibility (AII).
      • In cases of recurrent or refractory urinary tract infection, a urine culture examination should be performed after an antimicrobial-free interval of 3 days following termination of any preceding administration of antimicrobials in order to identify the causative bacteria (CIV).
      Commentary
      Urinary tract infections including cystitis are ascending infections caused by enterobacteriaceae [
      • Yamamoto S.
      • Tsukamoto T.
      • Terai A.
      • Kurazono H.
      • Takeda Y.
      • Yoshida O.
      Genetic evidence supporting the fecal-perineal-urethral hypothesis in cystitis caused by Escherichia coli.
      ]. They are classified into uncomplicated infections with no obvious underlying disease and complicated infections with an underlying disease, a distinction that is necessary not only for understanding the etiology and pathology but also for providing effective treatment. Most patients suffering from acute uncomplicated cystitis are sexually active women [
      • Stamatiou C.
      • Bovis C.
      • Panagopoulos P.
      • Petrakos G.
      • Economou A.
      • Lycoudt A.
      Sex-induced cystitis-patient burden and other epidemiological features.
      ], and acute uncomplicated cystitis in premenopausal and postmenopausal women should be separately discussed.
      Diseases that commonly underlie complicated cystitis are malignant tumors of the urinary tract and neurogenic bladder in elderly patients and congenital abnormalities of the urinary tract in children.
      Clinical symptoms of cystitis include pollakisuria, urination pain, cloudy urine, incomplete emptying sensation, and discomfort in the bladder region, and are not usually accompanied by fever. A urine examination, which may demonstrate purulent urine or bacteriuria, is essential for diagnosis.
      In patients with acute uncomplicated cystitis, a urine culture test prior to the initial antimicrobial administration is not considered essential. However, if the infection is recurrent or refractory, a urine culture examination should be performed after an interval of at least 3 days following termination of a preceding antimicrobial administration (BIV). Particularly, in refractory cystitis cases, microbial substitution and vulvovaginitis may be induced by excessive antibacterial administration (CVI). For complicated cystitis, it is recommended that a urine culture be performed as well as examination for antimicrobial susceptibility of the causative bacteria before starting the initial antibacterial administration [
      • Shigehara K.
      • Uchibayashi T.
      • Maeda E.
      • Namiki M.
      Detection of drug-resistant Escherichia coli in patients with complicated cystitis; analysis of risk factors.
      ,
      • Ishikawa K.
      • Matsumoto T.
      • Yasuda M.
      • Uehara S.
      • Muratani T.
      • Yagisawa M.
      • et al.
      The nationwide study of bacterial pathogens associated with urinary tract infections conducted by the Japanese Society of Chemotherapy.
      ] (AII).
      Gram-negative rods, including E. coli, Proteus mirabilis, and Klebsiella species, account for 80–85% of the microorganisms isolated from acute uncomplicated cystitis patients, while Gram-positive cocci, including Staphylococcus, Streptococcus, and Enterococcus species, account for about 15–20% of those [
      • Matsumoto T.
      • Hamasuna R.
      • Ishikawa K.
      • Takahashi S.
      • Yasuda M.
      • Hayami H.
      • et al.
      Nationwide survey of antibacterial activity against clinical isolates from urinary tract infections in Japan (2008).
      ,
      • Hayami H.
      • Takahashi S.
      • Ishikawa K.
      • Yasuda M.
      • Yamamoto S.
      • Uehara S.
      • et al.
      Nationwide surveillance of bacterial pathogens from patients with acute uncomplicated cystitis conducted by the Japanese surveillance committee during 2009 and 2010: antimicrobial susceptibility of Escherichia coli and Staphylococcus saprophyticus.
      ]. E. coli, the microorganism most frequently isolated from patients with acute uncomplicated cystitis (accounting for approximately 70% of affected cases), generally shows good antimicrobial susceptibility, though approximately 10% of the isolates are resistant to treatment with penicillins with a BLI, sulfamethoxazole-trimethoprim (SMZ-TMP), cephalosporins, and fluoroquinolones [
      • Matsumoto T.
      • Hamasuna R.
      • Ishikawa K.
      • Takahashi S.
      • Yasuda M.
      • Hayami H.
      • et al.
      Nationwide survey of antibacterial activity against clinical isolates from urinary tract infections in Japan (2008).
      ,
      • Hayami H.
      • Takahashi S.
      • Ishikawa K.
      • Yasuda M.
      • Yamamoto S.
      • Uehara S.
      • et al.
      Nationwide surveillance of bacterial pathogens from patients with acute uncomplicated cystitis conducted by the Japanese surveillance committee during 2009 and 2010: antimicrobial susceptibility of Escherichia coli and Staphylococcus saprophyticus.
      ]. Of note, ESBL-producing strains, which account for approximately 5% of isolated E. coli, are resistant to penicillins and cephalosporins, while about 70% of ESBL-producing strains are also resistant to fluoroquinolones, though a high percentage is susceptible to FOM, FRPM, or aminoglycosides [
      • Hayami H.
      • Takahashi S.
      • Ishikawa K.
      • Yasuda M.
      • Yamamoto S.
      • Uehara S.
      • et al.
      Nationwide surveillance of bacterial pathogens from patients with acute uncomplicated cystitis conducted by the Japanese surveillance committee during 2009 and 2010: antimicrobial susceptibility of Escherichia coli and Staphylococcus saprophyticus.
      ,
      • Matsumoto T.
      • Muratani T.
      • Nakahama C.
      • Tomono K.
      Clinical effects of 2 days of treatment by fosfomycin calcium for acute uncomplicated cystitis in women.
      ,
      • Hamasuna R.
      • Tanaka K.
      • Hayami H.
      • Yasuda M.
      • Takahashi S.
      • Kobayashi K.
      • et al.
      the Japanese Research Group for UTI (JRGU)
      Treatment of acute uncomplicated cystitis with faropenem for 3 days versus 7 days: multicentre, randomized, open-label, controlled trial.
      ].
      Fluoroquinolones are highly effective against both gram-negative rods and gram-positive cocci, and recommended as the first choice for both premenopausal and postmenopausal cystitis patients in “JAID/JSC Guide to Clinical Management of Infections 2011”. However, the percentages of fluoroquinolone-resistant and ESBL-producing gram-negative rods, including primarily E. coli strains, have recently shown progressive increases, thus restrictions regarding use of fluoroquinolones are considered necessary in the future [
      • Gupta K.
      • Hooton T.M.
      • Naber K.G.
      • Wullt B.
      • Colgan R.
      • Miller L.G.
      • 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.
      ]. For example, according to results of a nationwide surveillance conducted in Japan, the isolation rate of gram-positive cocci (such as S. saprophyticus) was as high as 17% in premenopausal women with acute uncomplicated cystitis, while the susceptibility rates of E. coli strains to penicillins with a BLI, cephalosporins, and fluoroquinolones were 90% or higher [
      • Hayami H.
      • Takahashi S.
      • Ishikawa K.
      • Yasuda M.
      • Yamamoto S.
      • Uehara S.
      • et al.
      Nationwide surveillance of bacterial pathogens from patients with acute uncomplicated cystitis conducted by the Japanese surveillance committee during 2009 and 2010: antimicrobial susceptibility of Escherichia coli and Staphylococcus saprophyticus.
      ]. Therefore, fluoroquinolones may be used as the first choice when a urine test shows gram-positive cocci, while cephalosporins or penicillins with BLI are recommended instead of fluoroquinolones when gram-negative rods have been confirmed (BII). On the other hand, the isolation rate of gram-positive cocci from postmenopausal women with acute uncomplicated cystitis was found to be as low as 9% and E. coli strains showed a high rate of resistance to fluoroquinolone of 18%, thus cephalosporins or penicillins with a BLI are recommended as the first choice (BII).
      As for the duration of antimicrobial administration, 3 days is generally considered necessary for fluoroquinolones and SMZ-TMP, while 7 days are needed for β-lactams such as penicillins with BLI and cephalosporins [
      • Gupta K.
      • Hooton T.M.
      • Naber K.G.
      • Wullt B.
      • Colgan R.
      • Miller L.G.
      • 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.
      ], though some third-generation cephalosporins have been shown to be effective with a 3-day administration (I) [
      • Hooton T.M.
      • Roberts P.L.
      • Stapleton A.E.
      Cefpodoxime vs ciprofloxacin for short-course treatment of acute uncomplicated cystitis: a randomized trial.
      ,
      • Kavatha D.
      • Giamarellou H.
      • Alexiou Z.
      • Vlachogiannis N.
      • Pentea S.
      • Gozadinos T.
      • et al.
      Cefpodoxime-proxetil versus trimethoprim-sulfamethoxazole for short-term therapy of uncomplicated acute cystitis in women.
      ].

      2.1.1 Acute uncomplicated cystitis (premenopausal)

      • Disease characteristics
      Cystitis that occurs acutely without obvious underlying disease is frequently observed in sexually active women. Cure must be assessed within 5–7 days after termination of antimicrobial administration (BIV) [
      • Matsumoto T.
      • Takahashi S.
      • Kiyota H.
      • Yasuda M.
      • Ishikawa K.
      • Takahashi A.
      • et al.
      Japanese guideline for clinical research of antimicrobial agents on urogenital infections: the first edition.
      ].
      • Causative microorganisms
      Approximately 80% of acute uncomplicated cystitis is caused by gram-negative rods, of which E. coli is most frequently isolated, followed by P. mirabilis and Klebsiella species. Approximately 20% of the cases are caused by gram-positive cocci, of which S. saprophyticus is most frequently isolated, followed by other Staphylococcus, Streptococcus, and Enterococcus species [
      • Matsumoto T.
      • Hamasuna R.
      • Ishikawa K.
      • Takahashi S.
      • Yasuda M.
      • Hayami H.
      • et al.
      Nationwide survey of antibacterial activity against clinical isolates from urinary tract infections in Japan (2008).
      ,
      • Hayami H.
      • Takahashi S.
      • Ishikawa K.
      • Yasuda M.
      • Yamamoto S.
      • Uehara S.
      • et al.
      Nationwide surveillance of bacterial pathogens from patients with acute uncomplicated cystitis conducted by the Japanese surveillance committee during 2009 and 2010: antimicrobial susceptibility of Escherichia coli and Staphylococcus saprophyticus.
      ].
      • Recommended antimicrobials
      E. coli organisms isolated from patients with acute uncomplicated cystitis are relatively susceptible to a variety of antimicrobials, while the rate of susceptibility to penicillins administered with BLI, cephalosporins, and fluoroquinolones is at least 90% though penicillins alone without BLI are not effective (BII) [
      • Matsumoto T.
      • Hamasuna R.
      • Ishikawa K.
      • Takahashi S.
      • Yasuda M.
      • Hayami H.
      • et al.
      Nationwide survey of antibacterial activity against clinical isolates from urinary tract infections in Japan (2008).
      ,
      • Hayami H.
      • Takahashi S.
      • Ishikawa K.
      • Yasuda M.
      • Yamamoto S.
      • Uehara S.
      • et al.
      Nationwide surveillance of bacterial pathogens from patients with acute uncomplicated cystitis conducted by the Japanese surveillance committee during 2009 and 2010: antimicrobial susceptibility of Escherichia coli and Staphylococcus saprophyticus.
      ]. Since β-lactams are often ineffective against gram-positive cocci, fluoroquinolones should be prescribed when gram-positive cocci are suspected based on urine test findings (BII) [
      • Shigehara K.
      • Uchibayashi T.
      • Maeda E.
      • Namiki M.
      Detection of drug-resistant Escherichia coli in patients with complicated cystitis; analysis of risk factors.
      ,
      • Ishikawa K.
      • Matsumoto T.
      • Yasuda M.
      • Uehara S.
      • Muratani T.
      • Yagisawa M.
      • et al.
      The nationwide study of bacterial pathogens associated with urinary tract infections conducted by the Japanese Society of Chemotherapy.
      ]. When gram-negative rods have been confirmed by a urine test, the use of fluoroquinolones should be refrained, and cephalosporins or penicillins with BLI are recommended (BII).
      • Key points
      Approximately 70% of ESBL-producing E. coli strains are resistant to fluoroquinolones. Oral antimicrobials such as FOM and FRPM, or parenteral antimicrobials such as carbapenems, aminoglycosides, and TAZ/PIPC are effective against ESBL-producing bacteria [
      • Hayami H.
      • Takahashi S.
      • Ishikawa K.
      • Yasuda M.
      • Yamamoto S.
      • Uehara S.
      • et al.
      Nationwide surveillance of bacterial pathogens from patients with acute uncomplicated cystitis conducted by the Japanese surveillance committee during 2009 and 2010: antimicrobial susceptibility of Escherichia coli and Staphylococcus saprophyticus.
      ,
      • Matsumoto T.
      • Muratani T.
      • Nakahama C.
      • Tomono K.
      Clinical effects of 2 days of treatment by fosfomycin calcium for acute uncomplicated cystitis in women.
      ,
      • Hamasuna R.
      • Tanaka K.
      • Hayami H.
      • Yasuda M.
      • Takahashi S.
      • Kobayashi K.
      • et al.
      the Japanese Research Group for UTI (JRGU)
      Treatment of acute uncomplicated cystitis with faropenem for 3 days versus 7 days: multicentre, randomized, open-label, controlled trial.
      ].
      First choices
      • LVFX, oral, 500 mg, once a day for 3 days
      • CPFX, oral 200 mg, 2 to 3 times a day for 3 days
      • TFLX, oral, 150 mg, twice a day for 3 days
      Alternatives
      • CCL, oral, 250 mg, 3 times a day for 7 days
      • CVA/AMPC, oral, 250 mg, 3 times a day for 7 days
      • CFDN, oral, 100 mg, 3 times a day for 5–7 days
      • CFPN-PI, oral, 100 mg, 3 times a day for 5–7 days
      • CPDX-PR, oral, 100 mg, twice a day for 5–7 days
      • FOM, oral, 1 g, 3 times a day for 2 days∗∗
      • FRPM, oral, 200 mg, 3 times a day for 7 days∗∗
      *Not used when gram-positive cocci have been detected or are suspected.
      **Used when ESBL-producing bacteria have been detected or are suspected.

      2.1.2 Cystitis in elderly women (postmenopausal)

      • Disease characteristics
      Cystitis in postmenopausal women shows a lower cure rate and higher recurrence as compared to premenopausal women (I) [
      • Nicolle L.E.
      • Madsen K.S.
      • Debeeck G.O.
      • Blochlinger E.
      • Borrild N.
      • Bru J.P.
      • et al.
      Three days of pivmecillinam or norfloxacin for treatment of acute uncomplicated urinary infection in women.
      ]. Although, 3 days may be considered to be an insufficient period of administration for fluoroquinolones in elderly women, a study found no significant difference for efficacy or recurrence rate between the 3-day and 1-week administrations of CPFX (AI) [
      • Vogel T.
      • Verreault R.
      • Gourdeau M.
      • Morin M.
      • Grenier-Gosselin L.
      • Rochette L.
      Optimal duration of antibiotic therapy for uncomplicated urinary tract infection in older women; a double-blind randomized controlled trial.
      ].
      • Causative microorganisms
      In postmenopausal women with acute uncomplicated cystitis, gram-positive cocci are isolated less frequently and the fluoroquinolone-resistance rate of E. coli is higher as compared to premenopausal women.
      • Recommended antimicrobials
      Since, in postmenopausal women, the fluoroquinolone-resistance rate of E. coli is higher as compared to that in premenopausal women, fluoroquinolones are not recommended, while cephalosporins or penicillins with BLI are recommended as the first choice for postmenopausal women (BII). However, when gram-positive cocci have been detected in a urine test, fluoroquinolones are recommended. If there is a history of previous use of antimicrobials, and ESBL-producing bacteria are suspected or have been detected, FRPM or FOM should be selected [
      • Hayami H.
      • Takahashi S.
      • Ishikawa K.
      • Yasuda M.
      • Yamamoto S.
      • Uehara S.
      • et al.
      Nationwide surveillance of bacterial pathogens from patients with acute uncomplicated cystitis conducted by the Japanese surveillance committee during 2009 and 2010: antimicrobial susceptibility of Escherichia coli and Staphylococcus saprophyticus.
      ,
      • Matsumoto T.
      • Muratani T.
      • Nakahama C.
      • Tomono K.
      Clinical effects of 2 days of treatment by fosfomycin calcium for acute uncomplicated cystitis in women.
      ,
      • Hamasuna R.
      • Tanaka K.
      • Hayami H.
      • Yasuda M.
      • Takahashi S.
      • Kobayashi K.
      • et al.
      the Japanese Research Group for UTI (JRGU)
      Treatment of acute uncomplicated cystitis with faropenem for 3 days versus 7 days: multicentre, randomized, open-label, controlled trial.
      ].
      • Key points
      Treatment for a urinary tract infection is the similar to that in premenopausal women, though examinations for the presence of underlying disease should be performed in recurrence or refractory cases (BIV). Cranberry juice has been reported to be effective for prevention of recurrence in women aged 50 years and older with a significant prevention rate shown by drinking a beverage containing 65% cranberry juice once a day (BII) [
      • Takahashi S.
      • Hamasuna R.
      • Yasuda M.
      • Arakawa S.
      • Tanaka K.
      • Ishikawa K.
      • et al.
      A randomized clinical trial to evaluate the preventive effect of cranberry juice (UR65) for patients with recurrent urinary tract infection.
      ]. Transvaginal estriol (0.5 mg/day) has also been reported to be effective for prevention of recurrence, though that treatment is not prevalent in Japan.
      First choices
      • CCL, oral, 250 mg, 3 times a day for 7 days
      • CVA/AMPC, oral, 250 mg, 3 times a day for 7 days
      • CFDN, oral, 100 mg, 3 times a day for 5–7 days
      • CFPN-PI, oral, 100 mg, 3 times a day for 5–7 days
      • CPDX-PR, oral, 100 mg, twice a day for 5–7 days
      Alternatives
      • LVFX, oral, 500 mg, once a day for 3 days*
      • CPFX, oral, 200 mg, 2 to 3 times a day for 3 days*
      • TFLX, oral, 150 mg, twice a day for 3 days*
      • FOM, oral, 1 g, 3 times a day for 2 days**
      • FRPM, oral, 200 mg, 3 times a day for 7 days**
      *Selected when Gram-positive cocci are suspected or have been detected
      **Selected when ESBL-producing bacteria are suspected or have been detected

      2.1.3 Cystitis in pregnant women

      • Disease characteristics
      Antimicrobial agents must be carefully selected in consideration of their adverse effects on the fetus. Therefore, the duration of antimicrobial administration should be minimized as much as possible (CIV).
      • Causative microorganisms
      The same as in acute uncomplicated cystitis (see Section 2.1.1 above).
      • Recommended antimicrobials
      The usual course of administration is cephalosporins for 5–7 days, while it is recommended to avoid the use of fluoroquinolones, tetracyclines, and SMZ-TMP in the early stage of pregnancy, and sulfonamides in the late stage (BII) [
      • Takahashi S.
      • Hamasuna R.
      • Yasuda M.
      • Arakawa S.
      • Tanaka K.
      • Ishikawa K.
      • et al.
      A randomized clinical trial to evaluate the preventive effect of cranberry juice (UR65) for patients with recurrent urinary tract infection.
      ]. When the causative bacterium shows resistance to cephalosporins, administration of antimicrobials such as CVA/AMPC and FOM may be considered (BIV).
      • Key point
      In pregnant women, asymptomatic bacteriuria should also be aggressively treated (BII) [
      • Macejko A.M.
      • Schaeffer A.J.
      Asymptomatic bacteriuria and symptomatic urinary tract infections during pregnancy.
      ]. (See “Asymptomatic bacteriuria”.)
      First choices
      • CFDN, oral, 100 mg, 3 times a day for 5–7 days
      • CFPN-PI, oral, 100 mg, 3 times a day for 5–7 days
      • CPDX-PR, oral, 100 mg, twice a day for 5–7 days
      • CCL, oral, 250 mg, 3 times a day for 7 days
      Alternatives
      • CVA/AMPC, oral, 250 mg, 3 times a day for 7 days*
      • FOM, oral, 1 g, 3 times a day for 2–3 days*
      *Since the safety of administration during pregnancy has not been established, these antimicrobials should be given only when the therapeutic benefit is judged to surpass the risk.

      2.1.4 Complicated cystitis (non-catheterized)

      • Disease characteristics
      Patients with an underlying disease of the urinary tract or systemic disease are likely to develop a urinary tract infection, which can be recurrent and refractory. Commonly underlying diseases include benign prostate hypertrophy, prostate cancer, bladder cancer, neurogenic bladder, urethral stenosis, and bladder stones. Congenital anomalies of the urinary tract are often found in children, while malignant tumors and a neurogenic bladder are frequently observed in elderly individuals. Underlying diseases include not only anatomical or functional abnormalities of the urinary tract, but also immunosuppressive status due to diabetes, or administration of steroids or anticancer agents.
      • Causative microorganisms
      Microorganisms causative of complicated cystitis vary widely and include gram-negative rods such as E. coli, Klebsiella, Citrobacter, Enterobacter, Serratia, Proteus species, and P. aeruginosa, as well as gram-positive cocci such as Enterococcus and Staphylococcus species. Bacteria that show resistance to various antibacterial agents are often isolated from patients with a history of frequent antimicrobial treatment, therefore, attention to the presence of fluoroquinolone-resistant, ESBL-producing, and metallo-β-lactamase-producing strains, as well as MRSA is necessary (BIV) [
      • Hooton T.M.
      • Roberts P.L.
      • Stapleton A.E.
      Cefpodoxime vs ciprofloxacin for short-course treatment of acute uncomplicated cystitis: a randomized trial.
      ,
      • Kavatha D.
      • Giamarellou H.
      • Alexiou Z.
      • Vlachogiannis N.
      • Pentea S.
      • Gozadinos T.
      • et al.
      Cefpodoxime-proxetil versus trimethoprim-sulfamethoxazole for short-term therapy of uncomplicated acute cystitis in women.
      ].
      • Recommended antimicrobials
      Antimicrobials with a broad-spectrum and strong activity, such as new oral cephalosporins and fluoroquinolones, should be selected first, while they should be re-selected or de-escalated to those with a narrower spectrum based on the results of antimicrobial susceptibility testing when available (BIV). For patients with a refractory infection, treatment by hospitalization may be indicated, while parental administration may also be considered (BIV).
      • Key points
      In complicated cystitis, accurate recognition of urinary or systemic underlying disease along with appropriate management is required simultaneously with administration of antimicrobials (BIV).
      First choices
      • LVFX, oral, 500 mg, once a day for 7–14 days
      • CPFX, oral, 200 mg, 2 to 3 times a day for 7–14 days
      • TFLX, oral, 150 mg, twice a day for 7–14 days
      • STFX, oral, 100 mg, once a day for 7–14 days
      • CVA/AMPC, oral, 250 mg, 3 times a day for 7–14 days
      • SBTPC, oral, 375 mg, 3 times a day for 7–14 days
      Alternatives
      • CFDN, oral, 100 mg, 3 times a day for 7–14 days
      • CPDX-PR, oral, 200 mg, twice a day for 7–14 days
      • CFPN-PI, oral, 100–150 mg, 3 times a day for 7–14 days
      Refractory cases
      • MEPM, intravenous, 0.5 g, twice a day for 3–14 days
      • DRPM, intravenous, 0.25 g, twice a day for 3–14 days
      • IPM/CS, intravenous, 0.5 g, twice a day for 3–14 days
      • CFPM, intravenous, 1 g, twice a day for 3–14 days
      • CZOP, intravenous, 1 g, twice a day for 3–14 days
      • TAZ/PIPC, intravenous, 4.5 g, 2 to 3 times a day for 3–14 days

      2.2 Pyelonephritis

      Executive summary
      • Acute uncomplicated pyelonephritis without underlying disease frequently occurs in sexually active women.
      • The causative bacteria are similar to those in cystitis.
      • For treatment:, renally excreted antimicrobials, such as β-lactams and quinolones, are recommended (AI).
      • The effectiveness of empiric therapy is evaluated at 3 days after beginning treatment and switched to definitive therapy when the results of culture testing become available (BII).
      • Parenteral antimicrobial administration is switched to oral administration at 24 h after remission and the total administration period is 14 days (AI).
      • For patients treated as outpatients, when oral antimicrobials are selected for the treatment, a concomitant one-time parenteral administration is also recommended at the initial visit (AI).
      • Abdominal CT scanning is most useful for differential diagnosis of diseases that require urological emergency drainage, such as hydronephrosis, emphysematous pyelonephritis, pyonephrosis, and renal abscess (AII).
      • A urine culture test is essential for demonstration of causative bacteria and evaluation of antimicrobial susceptibility. In patients with sepsis, 2 sets of blood culture samples should be obtained (AII).
      Commentary
      Pyelonephritis is a type of febrile urinary tract infection caused by a retrograde infection of the urinary tract and characteristically tends to be complicated by a bloodstream infection due to extension of tissue destruction from the collecting ducts to renal parenchyma. The disease can be classified as acute uncomplicated pyelonephritis or complicated pyelonephritis with an underlying disease (e.g., prostate hypertrophy, neurogenic bladder, urinary stones, urinary catheterization, malignant tumors, or immunosuppressive status due to diabetes or oral steroid administration). Acute uncomplicated pyelonephritis frequently occurs in sexually active women. Pyelonephritis occurring in males is invariably assumed to be complicated [
      • Ishikawa K.
      • Matsumoto T.
      • Yasuda M.
      • Uehara S.
      • Muratani T.
      • Yagisawa M.
      • et al.
      The nationwide study of bacterial pathogens associated with urinary tract infections conducted by the Japanese Society of Chemotherapy.
      ,
      • Matsumoto T.
      • Hamasuna R.
      • Ishikawa K.
      • Takahashi S.
      • Yasuda M.
      • Hayami H.
      • et al.
      Nationwide survey of antibacterial activity against clinical isolates from urinary tract infections in Japan (2008).
      ].
      In addition to preceding symptoms of cystitis (unperceived in some patients), systemic symptoms, such as fever and malaise, and local symptoms, such as costovertebral angle (CVA) pain or tenderness appear. Furthermore, gastrointestinal symptoms, such as nausea and vomiting, are often simultaneously observed.
      Similar to the causative microorganisms of cystitis, E. coli accounts for about 70% of uncomplicated pyelonephritis, whereas the causative microorganisms of complicated pyelonephritis vary widely and are difficult to predict.
      Purulent urine and bacteriuria are observed in a urine test. A urine culture test is essential for demonstration of the causative bacterium and examination of antimicrobial susceptibility. With blood tests, findings suggestive of inflammation such as leukocytosis, shift to the left, increased CRP [
      • Yasufuku T.
      • Shigemura K.
      • Yamashita M.
      Selection of first-line i.v.antibiotics for acute pyelonephritis in patient required emergency hospital admission.
      ,
      • Claessens Y.E.
      • Schmidt J.
      • Batard E.
      • Grabar S.
      • Jegou D.
      • Hausfater P.
      • 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) multicentre study.
      ], or procalcitonin (PCT) [
      • Matsumoto T.
      • Takahashi S.
      • Kiyota H.
      • Yasuda M.
      • Ishikawa K.
      • Takahashi A.
      • et al.
      Japanese guideline for clinical research of antimicrobial agents on urogenital infections: the first edition.
      ], as well as increased erythrocyte sedimentation rate are often observed. Notably, if bacteremia should be suspected, 2 sets of blood culture samples obtained [
      • Yasufuku T.
      • Shigemura K.
      • Yamashita M.
      Selection of first-line i.v.antibiotics for acute pyelonephritis in patient required emergency hospital admission.
      ]. The condition may be accompanied by shock and attention should also be paid to patient hemodynamics [
      • Kim K.S.
      • Kim K.
      • Jo Y.H.
      A simple model to predict bacteremia in women with acute pyelonephritis.
      ].
      For treatment, renally excreted antimicrobials, such as β-lactams and fluoroquinolones, are recommended (AI). The effectiveness of empiric therapy should be evaluated at 3 days after beginning antimicrobial administration, then the treatment is switched to definitive therapy when results of susceptibility from urine and blood culture testing become available (BII). Parenteral administration of antimicrobials should be switched to oral administration upon remission of symptoms, such as fever. The total duration of oral and parenteral antimicrobial administration is 14 days (AI).
      Some mild cases may be treated on an outpatient basis with oral antimicrobials, though a concomitant one-time parenteral administration is also recommended at the initial visit (AI). For patients with severe pyelonephritis, such as calculi-related pyelonephritis, urosepsis, or septic shock, combination antibacterial therapy is recommended (AII).
      Generally, asymptomatic bacteriuria is not regarded as an indication for antibacterial treatment, which should be performed only for acute exacerbation with symptoms including fever and urination pain (BII). However, since 20–40% of febrile urinary tract infections in pregnant women are reportedly prevented by treating asymptomatic bacteriuria, aggressive treatment is recommended in case of pregnant women with asymptomatic bacteriuria (AI).
      In cases with severe conditions, such as emphysematous pyelonephritis, pyonephrosis, and renal abscess, prompt and accurate diagnosis is required to perform urological interventions in order to protect renal function as well as save the lives (AII). Imaging modalities including abdominal CT scanning and ultrasound imaging are useful for diagnosis of such severe conditions (AII) [
      • Ishikawa K.
      Emphysematous pyelonephritis and renal abscess.
      ].

      2.2.1 Acute uncomplicated pyelonephritis (premenopausal)

      • Disease characteristics
      Acute uncomplicated pyelonephritis frequently occurs in sexually active women and primary symptoms include fever, nausea, vomiting, and hip and back pain (percussion tenderness). The condition is defined as “mild/moderate” when outpatient treatment is possible, and “severe” when treatment by hospitalization is necessary [
      • Kim K.S.
      • Kim K.
      • Jo Y.H.
      A simple model to predict bacteremia in women with acute pyelonephritis.
      ]. Indications for outpatient treatment are; (1) vital signs do not indicate shock, (2) diagnostic criteria for systematic inflammatory response syndrome (SIRS) are not fulfilled, (3) there is no nausea or vomiting, (4) no signs of dehydration are observed, (5) there is no concurrent disease that impairs immune function (i.e., cancer, diabetes, AIDS), and (6) no signs of severe infection (i.e., hypotension, confusion) are noted. Urinalysis and urine culture test are essential to evaluate efficacy of empiric therapy and consider the timing of switching to definitive therapy.
      • Causative microorganisms
      Similar to microorganisms causative of acute uncomplicated cystitis [
      • Schit G.C.
      • Naber K.G.
      • Botto H.
      • Palou J.
      • Mazzei T.
      • Gualco L.
      • Palou J.
      • et al.
      An international survey on the antimicrobial resistance of pathogen involved in uncomplicated urinary tract infection.
      ] (see Section 2.1.1 above).
      • Recommended antimicrobials
      Renally excreted antimicrobials, such as β-lactams [
      • Takahashi S.
      • Kurimura Y.
      • Takeyama K.
      • Hashimoto K.
      • Miyamoto S.
      • Ichihara K.
      • et al.
      Efficacy of treatment with carbapenems and third-generation cephalosporins for patients with febrile complicated pyelonephritis.
      ] and fluoroquinolones [
      • Sandberg T.
      • Skoog G.
      • Hermansson A.B.
      Ciprofloxacin for 7 days versus 14 days in women with acute pyelonephritis; a randomized, open-babel and double-blind, placebo-controlled, non-inferiority trial.
      ], are recommended (AI). The effectiveness of empiric therapy should be evaluated at 3 days after beginning antibacterial treatment and then switched to definitive therapy when results of culture testing become available (BII) [
      • Lee S.S.
      • Kim Y.
      • Chung D.R.
      Impact of discordant empirical therapy on outcome of community-acquired bacteremic acute pyelonephritis.
      ].Parenteral administration are switched to oral administration following remission of symptoms, such as fever, and CVA pain, and antimicrobials are administered for a total of 14 days (AI). Administration of aminoglycosides, which have a narrow safety range, requires caution in patients with insufficient renal function (BIV). Therapeutic antimicrobial monitoring (TDM) is performed as necessary. For patients with mild/moderate pyelonephritis who can be treated as outpatients, a concomitant one-time parenteral administration is also recommended at the initial visit (AI).
      • Key points
      Generally, E. coli and Klebsiella pneumoniae show a high antimicrobial susceptibility, particularly to β-lactams, fluoroquinolones, and aminoglycosides. However, ESBL-producing and fluoroquinolone-resistant E. coli have been recently reported to be increasing. In addition, the susceptibility of gram-positive cocci to empiric antimicrobials might be insufficient, and caution is needed when selecting antimicrobials (BIII).
      • Mild/moderate acute uncomplicated pyelonephritis
      CTRX, AMK, PZFX, and LVFX are recommended as one-time parenteral administration in a concomitant manner at the beginning of treatment (I).
      First choices
      • LVFX, oral, 500 mg, once a day for 7–14 days*
      • CPFX, oral, 200 mg, 3 times a day for 7–14 days*
      • TFLX, oral, 150 mg, 3 times a day for 7–14 days*
      • STFX, oral, 100 mg, twice a day for 7–14 days*
      Alternatives
      • CDTR-PI, oral, 200 mg, 3 times a day for 14 days
      • CFPN-PI, oral, 150 mg, 3 times a day for 14 days
      • CPDX-PR, oral, 200 mg, twice a day, for 14 days
      • Severe acute uncomplicated pyelonephritis
      First choices
      • CTM, intravenous, 1–2 g, 3 to 4 times a day Note 1
      • CTRX, intravenous, 1–2 g, 1 to 2 times a day
      • CAZ, intravenous, 1–2 g, 3 times a day Note 1
      Alternatives
      • AMK, intramuscular or intravenous, 200–400 mg, once a day∗∗
      • PZFX, intravenous, 1000 mg, twice a day Note 2
      • LVFX, intravenous, 500 mg, once a day
      • TAZ/PIPC, intravenous, 4.5 g, 3 times a day
      • MEPM, intravenous, 1 g, 3 times a day
      Note 1. A dose of 2 g, 3 to 4 times a day is not covered by Japanese national health insurance.
      Note 2. Covered by Japanese national health insurance only when given to patients with complicating sepsis.
      *The alternatives are recommended if the fluoroquinolone-resistance rate of E. coli isolated from patients in the community with a uncomplicated urinary tract infection is 20% or higher and if the present patient has a history of treatment with a fluoroquinolone within the previous 6 months (BII) [
      • Lee S.S.
      • Kim Y.
      • Chung D.R.
      Impact of discordant empirical therapy on outcome of community-acquired bacteremic acute pyelonephritis.
      ].
      **Aminoglycosides may be co-administered with penicillins (CIV).

      2.2.2 Acute uncomplicated pyelonephritis (postmenopausal)

      • Disease characteristics
      In postmenopausal women, the prevalence of urinary tract infection is increased and the incidence of recurrence is high compared to premenopausal women. Even in patients with no history of disease, it is important to examine for the presence of age-associated underlying conditions, such as benign/malignant diseases of the urinary tract and immunosuppressive status. Clinical symptoms, physical findings, and examinations are the same as for acute uncomplicated pyelonephritis in premenopausal women (see Section 2.2.1).
      • Causative microorganisms
      Same as for acute uncomplicated pyelonephritis in premenopausal women (see Section 2.2.1).
      • Recommended antimicrobials
      Same as for acute uncomplicated pyelonephritis in premenopausal women (see Section 2.2.1).
      • Key points
      The duration of administration tends to be prolonged in these cases. Although transvaginal estriol (0.5 mg/day) has been reported to be effective, that treatment is not widely accepted in Japan.

      2.2.3 Pyelonephritis in pregnant women

      • Disease characteristics
      Clinical symptoms, physical findings, and test results are the same as for acute uncomplicated pyelonephritis in premenopausal women (see Section 2.2.1). A study found that about 20–40% of febrile urinary tract infections during pregnancy can be prevented by treating asymptomatic bacteriuria, thus aggressive treatment of asymptomatic bacteriuria is recommended only for pregnant women (AI).
      • Recommended antimicrobials
      The same as for acute uncomplicated pyelonephritis (see Section 2.2.1), cephalosporins are recommended (AII). Fluoroquinolones are contraindicated because of teratogenicity.
      Use of fluoroquinolones, tetracyclines, and SMZ-TMPs in the early stage of pregnancy, and sulfonamides in the late stage of pregnancy should be avoided.
      • Mild/moderate acute uncomplicated pyelonephritis
      CTRX is also recommended as a one-time intravenous agent and used concomitantly at the beginning of treatment (AI).
      • CDTR-PI, oral, 200 mg, 3 times a day for 14 days
      • CFPN-PI, oral, 100–150 mg, 3 times a day for 14 days
      • CPDX-PR, oral, 100–200 mg, twice a day for 14 days
      • Severe acute uncomplicated pyelonephritis
      • CTM, intravenous, 1–2 g, 3 to 4 times a day Note
      • CAZ, intravenous, 1–2 g, 3 times a day Note
      • CTRX, intravenous, 1–2 g, 1 to 2 times a day
      Note: A dose of 2 g, 3 to 4 times a day is not covered by Japanese national health insurance.

      2.2.4 Complicated pyelonephritis (non-catheterized)

      • Disease characteristics
      Urinary or systemic underlying diseases are seen in affected patients. However, the symptoms are sometimes milder than those in acute uncomplicated pyelonephritis cases and antibacterial treatment is indicated only for exacerbation with clinical symptoms (BI). Recurrence/refractory cases are not rare as long as the underlying disease persists. Although the symptoms and test results are the same as those seen for acute uncomplicated pyelonephritis (see Section 2.2.1), it is necessary to make a prompt and accurate diagnosis, and perform urological interventions (such as drainage) as necessary in patients with severe conditions, such as hydronephrosis, abscess formation, and gas accumulation (AII).
      • Causative microorganisms
      Microorganisms causing complicated pyelonephritis vary widely, thus a urine culture test is essential [
      • Ishikawa K.
      • Matsumoto T.
      • Yasuda M.
      • Uehara S.
      • Muratani T.
      • Yagisawa M.
      • et al.
      The nationwide study of bacterial pathogens associated with urinary tract infections conducted by the Japanese Society of Chemotherapy.
      ,
      • Matsumoto T.
      • Hamasuna R.
      • Ishikawa K.
      • Takahashi S.
      • Yasuda M.
      • Hayami H.
      • et al.
      Nationwide survey of antibacterial activity against clinical isolates from urinary tract infections in Japan (2008).
      ]. Bacteria resistant to various antimicrobials are often isolated from patients with a history of antibacterial treatment. Among gram-positive cocci, Enterococcus species is the most frequently isolated, while Staphylococcus is also often detected. As for Gram-negative rods, enterobacteriaceae, such as E. coli, Klebsiella, Citrobacter, Enterobacter, Serratia, and Proteus, and non-fermenting species such as P. aeruginosa have also been isolated from affected patients.
      • Recommended antimicrobials
      Appropriate antimicrobial for treatment must be selected with an understanding of the antimicrobial susceptibility pattern in each facility or region. Determination of the causative bacterium is difficult and the possibility of detection of multi-drug resistant strains is high, thus broad spectrum antimicrobials should be selected for empiric therapy. The effectiveness of empiric therapy is evaluated at 3 days after beginning treatment, and the switch to definitive therapy occurs after obtaining results of urine and blood culture testing (BII) [
      • Lee S.S.
      • Kim Y.
      • Chung D.R.
      Impact of discordant empirical therapy on outcome of community-acquired bacteremic acute pyelonephritis.
      ]. Even when a favorable response is observed, it is desirable to de-escalate to a antibacterial agent with a narrower spectrum based on the results of antimicrobial susceptibility testing (B II) [
      • Lee S.S.
      • Kim Y.
      • Chung D.R.
      Impact of discordant empirical therapy on outcome of community-acquired bacteremic acute pyelonephritis.
      ]. At 24 h after remission of symptoms such as fever, treatment should be switched to oral therapy and continued for 14 days in total (AI) [
      • Naber K.G.
      • Wullt B.
      • Wagenlehner F.M.E.
      Antibiotic treatment of uncomplicated urinary tract infection in premenopausal women.
      ].
      • Key points
      Multi-drug resistant microorganisms, such as fluoroquinolone-resistant, ESBL-producing, and metallo-β-lactamase-producing bacteria, are increasing being found to be the cause of complicated urinary tract infections, thus caution is necessary. In patients with a complicated urinary tract infection, accurate identification and appropriate management of the underlying are essential, because antimicrobial treatment alone is insufficient to overcome the infection. Combination therapy with 2 or more antibacterial agents is recommended for patients with more severe pyelonephritis, such as those with obstructive pyelonephritis with urolithiasis, urosepsis, or septic shock (AII) [
      • Yasufuku T.
      • Shigemura K.
      • Yamashita M.
      Selection of first-line i.v.antibiotics for acute pyelonephritis in patient required emergency hospital admission.
      ,
      • Ha Y.E.
      • Kang C.I.
      • Joo Ej
      Clinical implications of healthcare-associated infection in patients with community-onset acute pyelonephritis.
      ].
      • Mild/moderate conditions
      CTRX, AMK, PZFX, and LVFX are recommended as one-time intravenous agents to be given concomitantly at the beginning of treatment (AI).
      First choices
      • LVFX, oral, 500 mg, once a day for 7–14 days
      • CPFX, oral, 200 mg, 3 times a day for 7–14 days [
        • Schit G.C.
        • Naber K.G.
        • Botto H.
        • Palou J.
        • Mazzei T.
        • Gualco L.
        • Palou J.
        • et al.
        An international survey on the antimicrobial resistance of pathogen involved in uncomplicated urinary tract infection.
        ]
      • TFLX, oral, 150 mg, 3 times a day for 7–14 days
      • STFX, oral, 100 mg, twice a day for 7–14 days
      Alternatives
      • CDTR-PI, oral, 200 mg, 3 times a day for 14 days
      • CFPN-PI, oral, 150 mg, 3 times a day for 14 days
      • CPDX-PR, oral, 200 mg, twice a day for 14 days
      • Severe conditions
      First choices
      • CAZ, intravenous, 1–2 g, 3 times a day Note 1
      • CTRX, intravenous, 1–2 g, 1 to 2 times a day
      • TAZ/PIPC, intravenous, 4.5 g, 3 times a day
      Alternatives
      • AMK, intramuscular or intravenous, 200 mg, once a day∗∗
      • PZFX, intravenous, 1000 mg, twice a day Note 2
      • LVFX, intravenous, 500 mg, once a day
      • CFPM, intravenous, 1–2 g, 3 times a day Note 1
      • IPM/CS, intravenous, 0.5–1 g, 2 to 3 times a day
      • MEPM, intravenous, 0.5–1 g, 3 times a day
      • DRPM, intravenous, 0.5 g, 2 to 3 times a day
      Note 1: A dose of 2 g, 3 times a day is not covered by Japanese national insurance.
      Note 2. Covered by Japanese national insurance only when given to patients with complicating sepsis
      *The alternatives are recommended if the fluoroquinolone-resistance rate of E. coli isolated from patients with complicated urinary tract infection in the community is 20% or higher or if the patient has a history of administration of a fluoroquinolone antimicrobial within the previous 6 months (BII) [
      • Lee S.S.
      • Kim Y.
      • Chung D.R.
      Impact of discordant empirical therapy on outcome of community-acquired bacteremic acute pyelonephritis.
      ].
      **Aminoglycosides may be co-administered with penicillin (CIV).

      2.3 Urosepsis

      Executive summary
      • Urosepsis is defined as sepsis caused by a severe infection of the urinary tract or male genitalia.
      • While E. coli is the most frequent causative bacteria, gram-negative rods, such as Klebsiella, Proteus, and Serratia, and gram-positive cocci, such as Enterococcus and Staphylococcus, are also observed. Determination of the causative microorganism is difficult without culture test findings (II), thus urine/blood culture and antimicrobial susceptibility testing are essential routine examinations (AIII).
      • SIRS is observed and septic shock may occur, thus monitoring of hemodynamics is necessary (BIV).
      • Renal-excreted β-lactams and fluoroquinolones with a broad spectrum and strong antibacterial activity should be selected (AII). Generally, antimicrobials are given at high doses except in patients with renal dysfunction (AII).
      • In patients with septic shock, intravenous administration of antimicrobials must be initiated as early as possible within 1 h (AII).
      • Urosepsis must be treated by a combination of drainage to relieve stagnation of urine flow, appropriate systemic management, and appropriate antibacterial therapy (AIV).
      Commentary
      Urosepsis is defined as sepsis caused by infection of the urinary tract or male genitalia [
      • Wagenlehner F.M.
      • Pilatz A.
      • Naber K.G.
      • Weidner W.
      Therapeutic challenges of urosepsis.
      ], and is reported to account for about 25% of all cases of sepsis [
      • Book M.
      • Lehmann L.E.
      • Schewe J.C.
      • Weber S.
      • Stuber F.
      Urosepsis. Current therapy and diagnosis.
      ], and 9–31% of those of severe sepsis or septic shock [
      • Kumar A.
      • Ellis P.
      • Arabi Y.
      • Roberts D.
      • Light B.
      • Parrillo J.E.
      • et al.
      Initiation of inappropriate antimicrobial therapy results in a fivefold reduction of survival in human septic shock.
      ,
      • Levy M.M.
      • Artigas A.
      • Phillips G.S.
      • Rhodes A.
      • Beale R.
      • Osborn T.
      • et al.
      Outcomes of the Surviving Sepsis Campaign in intensive care units in the USA and Europe: a prospective cohort study.
      ]. In patients with a urinary tract infection, if urine flow is disturbed by stones impacted in the ureter or catheter occlusion, urinary tract pressure rapidly increases, after which bacteria mechanically invade the renal parenchyma and blood, causing urosepsis, a severe infection (IV) [
      • Kumon H.
      Pathogenesis and management of bacterioalbiofilms in urinary tract.
      ]. In many patients treated in the ICU, urosepsis is a nosocomial infection derived from a urinary tract infection. It is related to urinary tract catheter placement in 90% or more of affected patients, who are mostly asymptomatic in the early period after infection (II) [
      • Tambyah P.A.
      • Maki D.G.
      Catheter associated urinary tract infection is rarely symptomatic; a prospective study of 1,497 catheterized patients.
      ].
      Monitoring of hemodynamics is necessary in these patients, as they show SIRS, and may also develop severe sepsis or septic shock [
      • Moreno R.P.
      • Metnitz B.
      • Adler L.
      • Hoechtl A.
      • Bauer P.
      • Metnitz P.G.
      SAPS 3 Investigators. Sepsis mortality prediction based on predisposition, infection and response.
      ], in addition to symptoms of an antecedent urinary tract or male genital infection, with local symptoms accompanied by fever, such as CVA pain, urination pain, or scrotal pain, though those are not perceived in some patients (BIV) [
      • Kim K.S.
      • Kim K.
      • Jo Y.H.
      A simple model to predict bacteremia in women with acute pyelonephritis.
      ].
      Purulent urine and bacteriuria are observed in urine test findings, and blood test results show inflammation, such as leukocytosis wit left shift, and elevation of serum CRP [
      • Yasufuku T.
      • Shigemura K.
      • Yamashita M.
      Selection of first-line i.v.antibiotics for acute pyelonephritis in patient required emergency hospital admission.
      ,
      • Claessens Y.E.
      • Schmidt J.
      • Batard E.
      • Grabar S.
      • Jegou D.
      • Hausfater P.
      • 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) multicentre study.
      ], procalcitonin (PCT) [
      • Claessens Y.E.
      • Schmidt J.
      • Batard E.
      • Grabar S.
      • Jegou D.
      • Hausfater P.
      • 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) multicentre study.
      ], and ESR. The causative bacterium must be identified with antimicrobial susceptibility examination prior to administration of antimicrobials, thus urine and blood culture tests are essential routine procedures (AIII) [
      • Dellinger R.P.
      • Levy M.M.
      • Rhodes A.
      • Annane D.
      • Gerlach H.
      • Opal S.M.
      • et al.
      Surviving Sepsis Campaign; international guidelines for management of severe sepsis and septic shock; 2012.
      ].
      Intravenous administration of antimicrobials must be initiated as early as possible within 1 h if the patient develops septic shock (AII) [
      • Dellinger R.P.
      • Levy M.M.
      • Rhodes A.
      • Annane D.
      • Gerlach H.
      • Opal S.M.
      • et al.
      Surviving Sepsis Campaign; international guidelines for management of severe sepsis and septic shock; 2012.
      ,
      • Kumar A.
      • Roberts D.
      • Wood K.E.
      • Light B.
      • Parrillo J.E.
      • Sharma S.
      • et al.
      Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock.
      ]. Renal-excreted β-lactams and fluoroquinolones with a broad antibacterial spectrum and high antibacterial activity are recommended (AII) [
      • Wagenlehner F.M.
      • Weidner W.
      • Naber K.G.
      Pharmacokinetic characteristics of antimicrobials and optimal treatment of urosepsis.
      ,
      • Naber K.G.
      Which fluoroquinolones are suitable for the treatment of urinary tract infections?.
      ,
      • Arakawa S.
      • Kawai S.
      • Hori S.
      • Watanabe S.
      • Totsuka K.
      A clinical phase III study of pazufloxacin in patients with sepsis.
      ].
      The empiric antimicrobial treatment is selected from third generation cephalosporins, carbapenems, and penicillins with BLI. Particularly, in a region with a high prevalence of ESBL-producing bacteria, a carbapenem should be selected for the empiric therapy (AII) [
      • Takahashi S.
      • Kurimura Y.
      • Takeyama K.
      • Hashimoto K.
      • Miyamoto S.
      • Ichihara K.
      • et al.
      Efficacy of treatment with carbapenems and third-generation cephalosporins for patients with febrile complicated pyelonephritis.
      ,
      • Alhambra A.
      • Cuadros J.A.
      • Cacho J.
      • Gomez-Garces J.L.
      • Alos J.I.
      In vitro susceptibility of recent antibiotic-resistant urinary pathogens to ertapenem and 12 other antibiotics.
      ]. Although a combination of antimicrobial therapy including fluoroquinolones and aminoglycosides has been reported to be useful for control of multi-drug resistant strains, no evidence has been presented showing that combination antibacterial therapy to be effective for treatment of sepsis (IV) [
      • Wagenlehner F.M.
      • Lichtenstern C.
      • Rolfes C.
      • Mayer K.
      • Uhle F.
      • Weidner W.
      • et al.
      Diagnosis and management for urosepsis.
      ].
      In urosepsis patients, abdominal ultrasonography and abdominal CT scanning are useful for detecting the source of infection [
      • Dellinger R.P.
      • Levy M.M.
      • Rhodes A.
      • Annane D.
      • Gerlach H.
      • Opal S.M.
      • et al.
      Surviving Sepsis Campaign; international guidelines for management of severe sepsis and septic shock; 2012.
      ,
      • Kumar A.
      • Roberts D.
      • Wood K.E.
      • Light B.
      • Parrillo J.E.
      • Sharma S.
      • et al.
      Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock.
      ]. When those imaging modalities demonstrate hydronephrosis, abscess formation, or gas accumulation, urinary drainage by such procedures as ureteral stenting or percutaneous nephrostomy should be promptly performed (B). Urosepsis may not be cured without a combination of relief of urinary stagnation, appropriate systemic management, and appropriate antibacterial treatment (AIV) [
      • Hotchkiss R.S.
      • Karl I.E.
      The pathophysiology and treatment of sepsis.
      ].
      • Disease characteristics
      Urosepsis is a type of sepsis caused by infection of the urinary tract or male genitalia. Affected patients show SIRS, and may develop severe sepsis or septic shock [
      • Moreno R.P.
      • Metnitz B.
      • Adler L.
      • Hoechtl A.
      • Bauer P.
      • Metnitz P.G.
      SAPS 3 Investigators. Sepsis mortality prediction based on predisposition, infection and response.
      ], thus monitoring of hemodynamics is necessary. To provide appropriate systemic management and relevant antimicrobial therapy, it is recommended to treat patients in cooperation with urologists, ICU staff, and specialists in treatment of infections (C).
      • Causative microorganisms
      Microorganisms causing urosepsis are primarily enterobacteriaceae [
      • Wagenlehner F.M.
      • Pilatz A.
      • Weidner W.
      Urosepsis—from the view of the urologist.
      ]. While gram-negative rods, such as E. coli, Klebsiella, Proteus, and Serratia, species account for about 80%, and gram-positive cocci, such as Enterococcus and Staphylococcus species, account for about 20% [
      • Ishihara s
      • Deguchi T.
      Urosepsis.
      ].
      When a complicated urinary tract infection underlies urosepsis, the causative bacteria can vary widely [
      • Ishikawa K.
      • Matsumoto T.
      • Yasuda M.
      • Uehara S.
      • Muratani T.
      • Yagisawa M.
      • et al.
      The nationwide study of bacterial pathogens associated with urinary tract infections conducted by the Japanese Society of Chemotherapy.
      ,
      • Matsumoto T.
      • Hamasuna R.
      • Ishikawa K.
      • Takahashi S.
      • Yasuda M.
      • Hayami H.
      • et al.
      Nationwide survey of antibacterial activity against clinical isolates from urinary tract infections in Japan (2008).
      ] and are difficult to determine without culture tests. In compromised patients, urosepsis may be caused by Candida or P. aeruginosa [
      • Johansen T.E.
      • Cek M.
      • Naber K.G.
      • Stratchounski L.
      • Svendsen M.V.
      • Tenke P.
      Hospital acquired urinary tract infections in urology departments; pathogens, susceptibility and use of antibiotics. Data from the PEP and PEAP-studies.
      ].
      • Recommended antimicrobials
      Renal-excreted β-lactams or fluoroquinolones with a broad antibacterial spectrum and high antibacterial activity are recommended (AII) [
      • Wagenlehner F.M.
      • Weidner W.
      • Naber K.G.
      Pharmacokinetic characteristics of antimicrobials and optimal treatment of urosepsis.
      ,
      • Naber K.G.
      Which fluoroquinolones are suitable for the treatment of urinary tract infections?.
      ,
      • Arakawa S.
      • Kawai S.
      • Hori S.
      • Watanabe S.
      • Totsuka K.
      A clinical phase III study of pazufloxacin in patients with sepsis.
      ].
      Generally, septic patients should be treated with high doses of antibacterial agents, except for those with renal dysfunction (AII) [
      • Arakawa S.
      • Kawai S.
      • Hori S.
      • Watanabe S.
      • Totsuka K.
      A clinical phase III study of pazufloxacin in patients with sepsis.
      ,

      Grabe M, Bjerklund-Johansen TE, Botto H, Cek M, Naber KG, Pickard RS, et al. Guidelines on Urological Infections 2013. European Association of Urology Guidelines. http://www.uroweb.org/guidelines/eau-clinical-guidelines/.

      ]. Since the causative bacteria are often resistant to antimicrobials, empiric therapy should be initiated with a antimicrobial of broad spectrum, followed by de-escalation therapy by selecting the antimicrobial after the results of antimicrobial susceptibility of causative microorganisms are demonstrated (BIV) [
      • Dellinger R.P.
      • Levy M.M.
      • Rhodes A.
      • Annane D.
      • Gerlach H.
      • Opal S.M.
      • et al.
      Surviving Sepsis Campaign; international guidelines for management of severe sepsis and septic shock; 2012.
      ]. The prolonged duration of parenteral antibacterial administration is generally 3–5 days after resolution of fever or control of complications (e.g., pyonephrosis or renal abscess) (BIV) [
      • Kumar A.
      • Roberts D.
      • Wood K.E.
      • Light B.
      • Parrillo J.E.
      • Sharma S.
      • et al.
      Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock.
      ], though a longer administration may be necessary in some cases depending on disease state.
      • Key points
      For treatment of urosepsis patients, refer to sections regarding treatments for pyelonephritis, prostatitis, and epididymitis, as well as catheter-related urinary tract infections. For refractory urosepsis, the appropriate antimicrobial should be selected based on the results of urine culture, blood culture, and antimicrobial susceptibility tests.
      First choices/alternatives
      • CAZ, intravenous, 1–2 g, 3 times a day Note 1
      • MEPM, intravenous, 1 g, 3 times a day
      • DRPM, intravenous, 0.5–1 g, 2 to 3 times a day
      • IPM/CS, intravenous, 0.5 g, 4 times a day
      • TAZ/PIPC, intravenous, 4.5 g, 3 times a day
      • PZFX, intravenous, 1000 mg, twice a day
      • LVFX, intravenous, 500 mg, once a day Note 2
      • CPFX, intravenous, 300 mg, twice a day
      Note 1: A dose of 2 g, 3 times a day is not covered by Japanese national health insurance.
      Note 2: Not covered by Japanese national health insurance.
      *A frequency of 3 times rather than 2 is recommended depending on severity.

      2.4 Cystitis in dialysis patients

      Executive summary
      • Urinary tract infection accounts for 11–25% of the various infections seen in dialysis patients (II). Furthermore, 28–45% of those patients show purulent urine and 25% bacteriuria, though urine sampling is often difficult (II).
      • Bacteria detected in dialysis patients with an infection vary widely from gram-positive cocci to gram-negative rods, irrespective of which organ they are obtained from (II).
      • Asymptomatic bacteriuria without lower urinary tract symptoms (irritable bladder) is not an indication for antibacterial treatment. Antimicrobials should only be administered for symptomatic exacerbations (BIV).
      • When treating a urinary tract infection in a dialysis patient, the dose (initial loading and maintenance), timing of administration, and administration period must be designed in consideration of excretion dynamics, protein-binding rate, and dialyzability of the antimicrobial (AII).
      Commentary
      In Japan, chronic dialysis therapy is performed in about 300,000 patients annually and an increase in cases with diabetic nephropathy is a recent characteristic of diseases requiring chronic dialysis therapy (II) [
      Committee of Renal Data RegistryJapanese Society for Dialysis Therapy
      Overview of regular dialysis treatment in Japan (as of 31 December 2011).
      ]. Following heart failure, infection is the second most frequent cause of death among dialysis patients [
      • Johansen T.E.
      • Cek M.
      • Naber K.G.
      • Stratchounski L.
      • Svendsen M.V.
      • Tenke P.
      Hospital acquired urinary tract infections in urology departments; pathogens, susceptibility and use of antibiotics. Data from the PEP and PEAP-studies.
      ]. Of the various infections observed in those patients, urinary tract infection has been reported to account for 11–23% in Japan and other countries (II) [
      • Kessler M.
      • Hoen B.
      • Mayeux D.
      • Hestin D.
      • Fontenaille C.
      Bacteremia in patients on chronic hemodialysis. A multicenter prospective survey.
      ,
      • Murayama Y.
      • Oozono Y.
      • Kadota J.
      • Miyazaki M.
      • Hashimoto A.
      • lida K.
      • et al.
      Clinical and immunological evaluation of infection in patients on hemodialysis.
      ], though diagnosis is often difficult in dialysis patients because of reduced urine volume (II) [
      • Murayama Y.
      • Oozono Y.
      • Kadota J.
      • Miyazaki M.
      • Hashimoto A.
      • lida K.
      • et al.
      Clinical and immunological evaluation of infection in patients on hemodialysis.
      ].
      A urinary tract infection in dialysis patients is generally diagnosed by demonstration of purulent urine/bacteriuria, and related signs and symptoms. Bacteriuria is observed in 25% of these patients [
      • Chaudhry A.
      • Stone W.J.
      • Breyer J.A.
      Occurrence of pyuria and bacteriuria in asymptomatic hemodialysis patients.
      ], though asymptomatic bacteriuria without lower urinary tract symptoms (irritable bladder) is not an indication for antibacterial therapy. Antimicrobials should only be administered for symptomatic exacerbation (see Section 2.5. Asymptomatic bacteriuria). No evidence has been presented in regard to effective treatment for asymptomatic bacteriuria in dialysis patients. Although purulent urine is observed in 28–45% of these patients [
      • Chaudhry A.
      • Stone W.J.
      • Breyer J.A.
      Occurrence of pyuria and bacteriuria in asymptomatic hemodialysis patients.
      ,
      • Eissinger R.P.
      • Asghar F.
      • Kolasa C.
      • Weinstein M.P.
      Does pyuria indicate infection in asymptomatic dialysis patients?.
      ], and urinary white blood cell count increases significantly with a decrease in urine volume (II), no study has yet provided criteria concerning purulent urine in dialysis patients with a symptomatic urinary tract infection [
      • Fasolo L.R.
      • Rocha L.M.
      • Campbell S.
      • Peixoto A.J.
      Diagnostic relevance of pyuria in dialysis patients.
      ].
      As for the decline in defense against infection in dialysis patients, factors including functional abnormalities of immunocompetent cells, anemia, malnutrition, metabolic acidosis, and impairment of the cutaneous/mucosal barrier have been investigated (III) [
      • Kessler M.
      • Hoen B.
      • Mayeux D.
      • Hestin D.
      • Fontenaille C.
      Bacteremia in patients on chronic hemodialysis. A multicenter prospective survey.
      ,
      • Khan I.H.
      • Catto G.R.
      Long-term complications of dialysis; infection.
      ,
      • Saitoh H.
      • Nakamura K.
      • Hida M.
      • Satoh T.
      Urinary tract infection in oliguric patients with chronic renal failure.
      ], though the mechanism remains to be elucidated in detail.
      The therapeutic strategy for urinary tract infection in patients with renal failure is similar to that in individuals with normal renal function, and antimicrobials administered for treatment of cystitis need not be changed for dialysis patients (BIII) [
      • Nicolle L.
      Best pharmacological practice; urinary tract infections.
      ,
      • Wagenlehner F.M.
      • Naber K.G.
      Treatment of bacterial urinary tract infections; presence and future.
      ]. However, since adverse reactions readily occur in patients with renal failure if the dose or administration method of antimicrobials is inappropriate (III) [
      • Scheen A.J.
      Medications in the kidney.
      ,
      • Bouvier d'Yvoire M.J.Y.
      • Maire P.H.
      Dosage regimens of antibacterials.
      ], the dose (loading and maintenance) and administration period must be designed in consideration of excretion dynamics, protein-binding rate, and dialyzability of the antibacterial agents (B). In dialysis patients, transfer to the organs and the urine of antimicrobials may decrease with low renal blood flow while oral antimicrobials are expected to be effective when urine volume is still maintained. The optimal dose and dosing interval of each antimicrobial should be determined according to the glomerular filtration rate (AII) [
      • Munar M.Y.
      • Singh H.
      Drug dosing adjustments in patients with chronic kidney disease.
      ], though no study has yet clarified the administration period of antimicrobials for urinary tract infection in dialysis patients.
      • Disease characteristics
      Sampling of urine is often difficult in dialysis patients and a finding of purulent urine is not relevant for assessment of the therapeutic effect. Therefore, improvements in irritable bladder symptoms, such as urination pain and pollakisuria, are used as major indices for evaluation of the therapeutic effect toward cystitis in dialysis patients (C). Also, a decline in the defense function against infection is an exacerbating factor in these patients, and not only administration of antimicrobials but also management of systemic conditions may be necessary for treatment of infection.
      • Causative microorganisms
      Bacteria isolated from dialysis patients with urinary tract infection vary widely from gram-positive cocci to gram-negative rods irrespective of which the sources they are obtained from (II) [
      • Hara K.
      • Harada K.
      • Ozono Y.
      Infectious disease science in dialytic therapy - bacterial infection.
      ]. Thus, since terminal renal failure is an underlying systemic disease, cystitis in dialysis patients should be classified as a complicated urinary tract infection and it is recommended that the distribution of the causative bacterium, antimicrobial selection, and administration period are similar to those in cases of complicated cystitis (see Section 2.1.4. Complicated cystitis) (C). Demonstration of the causative bacterium and antimicrobial susceptibility by urine culture testing when possible is important (C).
      • Recommended antimicrobials
      Selection of antimicrobials as empiric therapy is difficult for dialysis patients with cystitis, thus antimicrobials with a broad antibacterial spectrum and high antibacterial activity, such as oral cephalosporins and fluoroquinolones, should be selected (CIV) [
      • Williams D.H.
      • Schaeffer A.J.
      Current concepts in urinary tract infections.
      ,
      • Naber K.G.
      Experience with the new guidelines on evaluation of new anti-infective drugs for the treatment of urinary tract infections.
      ]. The regimen of an initial administration of LVFX at 500 mg and then a maintenance dose of 250 mg after dialysis is promising in regard to efficacy and safety (AII) [
      • Urata M.
      • Ota M.
      • Kitamura Y.
      • Sai Y.
      • Okamura M.
      • Inariba H.
      • et al.
      Pharmacokinetics of high dose levofloxacin in Japanese patients undergoing maintenance hemodialysis.
      ]. Furthermore, in consideration of the increased susceptibility to infection of dialysis patients, treatment over a longer period is necessary as compared to patients with normal renal function, and a treatment period of 7–14 days is required. It will be necessary to administer antimicrobials over an even longer period in some patients (CIII) [
      • Nicolle L.
      Best pharmacological practice; urinary tract infections.
      ].
      • Key points
      No randomized controlled trial (RCT) has been conducted to evaluate the optimal treatment for urinary tract infection in patients with renal failure. Antimicrobials is recommended to be selected according to the severity of clinical symptoms. Since the blood concentration of an antimicrobial is directly related to its antibacterial activity or toxicity, monitoring of its serum concentration is important in dialysis patients. Particularly, trough level, which reflects antimicrobial accumulation, is the most accurate index of antimicrobial excretion, and an effective and safe dosing plan should be devised on the basis of serum antimicrobial concentration especially when administering aminoglycosides and glycopeptides.
      First choices
      • LVFX, oral, once at 500 mg on first day (loading dose); thereafter once every other day at 250 mg for 7–14 days
      • CPFX, oral, 200 mg, once a day for 7–14 days
      Alternatives
      • CFDN, oral, 100 mg, once a day on days of dialysis after dialysis has finished, for 7–14 days
      • CPDX-PR, oral, 100 mg, every 48 h on days of dialysis after dialysis has finished, for 7–14 days
      For refractory cystitis
      • MEPM, intravenous, 1 g, once a day on first day (loading dose); thereafter 0.5 g, once a day on days of dialysis after dialysis has finished, for 7–14 days
      • CPR, intravenous, 1 g, once a day on first day (loading dose); thereafter 0.5 g, once a day on days of dialysis after dialysis has finished, for 7–14 days
      • SBT/ABPC, intravenous, 1.5 g, once a day, on days of dialysis after dialysis has finished, for 7–14 days
      • CPFX, intravenous, 300 mg, once a day on first day (loading dose); thereafter 200 mg, once a day on days of dialysis after dialysis has finished, for 7–14 days

      2.5 Asymptomatic bacteriuria

      Executive summary
      • The effectiveness of antibacterial therapy for asymptomatic bacteriuria has not been established, except for pregnant women and prior to urological treatments. Screening and treatment of asymptomatic bacteriuria is not recommended in premenopausal non-pregnant women (AI), diabetic patients (AI), community-dwelling elderly (AI), institutionalized elderly (AI), spinal cord injury patients (AIII), and patients with urinary catheterization (AI).
      • Pregnant women should be screened at least once during the early stage of pregnancy and treated if the results are positive (AI).
      • Patients undergoing transurethral prostatectomy are screened and treated for bacteriuria (AI). Both screening and treatment should be performed before other urological treatments expected to involve urinary mucosal bleeding (AIII).
      • In women, antimicrobial therapy may be considered for asymptomatic bacteriuria that persists after removal of a urethral catheter for 48 h or longer (CI).
      Commentary
      Results of clinical studies have established that a urinary tract infection cannot be prevented by antimicrobials administered for asymptomatic bacteriuria in premenopausal non-pregnant women [
      • Asscher A.W.
      • Sussman M.
      • Waters W.E.
      • Evans J.A.
      • Campbell H.
      • Evans K.T.
      • et al.
      Asymptomatic significant bacteriuria in the non-pregnant woman. Ⅱ. Response to treatment and follow-up.
      ], diabetic patients [
      • Harding G.K.M.
      • Zhanel G.G.
      • Nicolle L.E.
      • Cheang M.
      Antimicrobial treatment in diabetic women with asymptomatic bacteriuria. Manitoba diabetes urinary tract infection study group.
      ], institutionalized elderly [
      • Boscia J.A.
      • Kobasa W.D.
      • Knight R.A.
      • Abrutyn E.
      • Levison M.E.
      • Kaye D.
      Therapy vs. no therapy for bacteriuria in elderly, ambulatory, nonhospitalized women.
      ,
      • Nordenstam G.R.
      • Brandberg C.A.
      • Oden A.S.
      • Svanborg-Eden C.M.
      • Svanborg A.
      Bacteriuria and mortality in an elderly population.
      ,
      • Heinamaki P.
      • Haavesto M.
      • Hakulinen T.
      • Mattila K.
      • Rajola S.
      Mortality in relation to urinary characteristics in the very aged.
      ,
      • Nicolle L.E.
      • Mayhew W.J.
      • Bryan L.
      Prospective, randomized comparison of therapy and no therapy for asymptomatic bacteriuria in institutionalized elderly women.
      ,
      • Nicolle L.E.
      • Bjornson J.
      • Harding G.K.
      • MacDonell J.A.
      Bacteriuria in elderly institutionalized men.
      ,
      • Abrutyn E.
      • Mossey J.
      • Berlin J.A.
      • Boscia J.
      • Levison M.
      • Pitsakis P.
      • et al.
      Does asymptomatic bacteriuria predict mortality and does antimicrobial treatment reduce mortality in elderly ambulatory women?.
      ,
      • Ouslander J.G.
      • Schapira M.
      • Schnelle J.F.
      • Uman G.
      • Fingold S.
      • Tuico E.
      • et al.
      Does eradicating bacteriuria affect the severity of chronic urinary incontinence in nursing home residents?.
      ], spinal cord injury patients [
      • Mohler J.L.
      • Cowen D.L.
      • Flanigan R.C.
      Suppression and treatment of urinary tract infection in patients with an intermittently catheterized neurogenic bladder.
      ,
      • Maynard F.M.
      • Diokno A.C.
      Urinary infection and complications during clean intermittent catheterization following spinal cord injury.
      ], and patients with a chronic indwelling urethral catheter [
      • Maynard F.M.
      • Diokno A.C.
      Urinary infection and complications during clean intermittent catheterization following spinal cord injury.
      ,
      • Platt R.
      • Polk B.I.
      • Murdock B.
      • Rosner B.
      Mortality associated with nosocomial urinary-tract infection.
      ,
      • Sobel J.D.
      • Kauffman C.A.
      • McKinsey D.
      • Zervos M.
      • Vazquez J.A.
      • Karchmer A.W.
      • et al.
      Candiduria; a randomized, double-blind study of treatment with fluconazole and placebo. The national institute of allergy and infectious diseases mycoses study group.
      ,
      • Warren J.W.
      • Anthony W.C.
      • Hoopes J.M.
      • Muncie Jr., H.L.
      Cephalexin for susceptible bacteriuria in afebrile, long-term catheterized patients.
      ,
      • Alling B.
      • Brandberg A.
      • Secberg S.
      • Svanborg A.
      Effect of consecutive antibacterial therapy on bacteriuria in hospitalized geriatric patients.
      ]. Therefore, in general, asymptomatic bacteriuria should not be regarded as an indication for antimicrobial treatment.
      However, the risk of pyelonephritis developing from asymptomatic bacteriuria is 20–30 times higher in pregnant as compared with non-pregnant women. The risk of pyelonephritis occurrence, ranging from 20 to 35%, can be reduced to 1–4% by administration of antimicrobials [
      • Smaill F.
      Antibiotics for asymptomatic bacteriuria in pregnancy.
      ]. Thus, pregnant women should be screened at least once during the early stage of pregnancy and treated if the results are positive (AI).
      Urological procedures that involve mucosal bleeding are closely related to bacteremia and sepsis, and 60% of the patients who undergo a transurethral prostatectomy without antibacterial treatment develop bacteremia [
      • Grabe M.
      Antimicrobial agents in transurethral prostatic resection.
      ]. Thus, prior to that procedure, patients must be screened and treated for bacteriuria (AI). Such screening and treatment are also necessary prior to urological procedures expected to involve mucosal bleeding (AIII).
      In patients with bacteriuria persisting following removal of a urethral catheter for 48 h or longer, antibacterial therapy is reported to be effective. One study found that a urinary tract infection occurred in 7 (17%) of 42 untreated patients but in none of treated patients [
      • Harding G.K.
      • Nicolle L.E.
      • Ronald A.R.
      • Preiksaitis J.K.
      • Forward K.R.
      • Low D.E.
      • et al.
      How long should catheter-acquired urinary tract infection in women be treated.
      ]. Although administration of antimicrobials may be considered, further evaluations are necessary, because long-term efficacy has not been established (CI).
      • Disease characteristics
      Asymptomatic bacteriuria is not accompanied by symptoms suggestive of a urinary tract infection, such as fever and irritable bladder. Bacteriuria is defined as detection of 105/ml or more bacteria in 2 consecutive urine tests in women or in 1 test in men, or detection of 102/ml or more bacteria in urine sampled by catheterization once in both genders [
      • Nicolle L.E.
      • Bradley S.
      • Colgan R.
      • Rice J.C.
      • Schaeffer A.
      • Hooton T.M.
      Infectious Diseases Society of AmericaAmerican Society of NephrologyAmerican Geriatric Society
      Infectious diseases society of America guidelines for the diagnosis and treatment of asymptomatic bacteriuria in adults.
      ].
      • Estimated causative microorganisms
      The most frequent causative agent is E. coli, while other enterobacteriaceae (e.g., Proteus, Klebsiella species) can also be detected [
      • Nicolle L.E.
      Asymptomatic bacteriuria.
      ].
      • Recommended antimicrobials
      When antimicrobial therapy is necessary, the antimicrobial is selected according to urine culture test results. Narrow-spectrum and safe antimicrobials should be selected as much as possible.
      • Key points
      Since asymptomatic bacteriuria is not an indication for treatment except for pregnant women and prior to urological treatment, there is little significance in monitoring urine culture testing in asymptomatic patients. In principle, a urine culture is unnecessary unless a symptomatic urinary tract infection is suspected (AI).
      • 1)
        Pregnant women
      For pregnant women, β-lactams should be selected in consideration of effects on the fetus. From the viewpoint of safety, SMZ-TMPs (late stage of pregnancy), fluoroquinolones, and aminoglycosides should be avoided (A). The treatment period is 3–7 days.
      • AMPC, oral, 500 mg, 3 times a day for 3–7 days
      • CFDN, oral, 100 mg, 3 times a day for 3–7 days
      • CFPN-PI, oral, 100 mg, 3 times a day for 3–7 days
      • CPDX-PR, oral, 100 mg, twice a day for 3–7 days
      • 2)
        Prior to urological procedures
      Treatment of asymptomatic bacteriuria should be guided by urine culture results prior to urological procedures. No clinical studies concerning the appropriate timing to initiate treatment or the treatment period have been conducted, and further research is necessary.

      2.6 Catheter-related urinary tract infection

      Executive summary
      • In asymptomatic patients (asymptomatic bacteriuria), routine urine cultures and treatment for bacteriuria are not recommended (AI).
      • Since the causative microorganisms are often gram-negative rods, broad-spectrum antimicrobials with anti-pseudomonal activity should be selected for empiric therapy according to the susceptibility pattern of each institution (BIV).
      • Gram staining testing of urine samples is useful for determination of the causative bacterium (BIV).
      • Urine should be collected and subjected to culture testing prior to antimicrobial administration, and treatment should be de-escalated based on those results (AIII).
      • Catheters should be removed, if possible. If removal is difficult, the catheter should be exchanged before beginning treatment when it has been in place more than for 2 weeks (AI).
      • The treatment period varies according to the therapeutic course and complications. The period is 7 days when a rapid response to antibacterial therapy is observed, 10–14 days if the response is weak, and 14–21 days when the condition is severe and complicated (BIII).
      • While the occurrence of urinary tract infection can be reduced by prophylactic administration of an antimicrobial at the time of removal of the urethral catheter, this is not recommended as routine, because there are also demerits such as adverse effect, possible induction of resistance, and cost (CI).
      Commentary
      Among patients with asymptomatic bacteriuria, 75–90% do not develop a symptomatic infection (III) [
      • Hooton T.M.
      • Bradley S.F.
      • Cardenas D.D.
      • Colgan R.
      • Geerlings S.E.
      • Rice J.C.
      • et al.
      Infectious Diseases Society of America
      Diagnosis, prevention, and treatment of catheter-associated urinary tract infection in adults; 2009 international clinical practice guidelines from the infectious diseases society of America.
      ]. In a prospective study of patients with asymptomatic bacteriuria with a catheter in place for at least 48 h, there was no difference regarding the incidence of urinary tract infection between those administered an antimicrobial for 3 days after catheter exchange and those with the catheter left in place and not administered an antimicrobial [
      • Leone M.
      • Perrin A.S.
      • Granier I.
      • Visintini P.
      • Blasco V.
      • Antonini F.
      • et al.
      A randomized trial of catheter change and short course of antibiotics for asymptomatic bacteriuria in catheterized ICU patients.
      ]. Occurrence of a urinary tract infection cannot be prevented by antimicrobial administration in patients with asymptomatic bacteriuria, thus eradication of bacteria and routine urine cultures are unnecessary (AI).
      Bacteria causative of a catheter-related urinary tract infection are primarily enterobacteriaceae, such as E. coli and Klebsiella species, and gram-negative rods such as P. aeruginosa. Among gram-positive cocci, Enterococcus species can cause a catheter-related urinary tract infection, while involvement of Staphylococcus species is rare [
      • Sievert D.M.
      • Ricks P.
      • Edwards J.R.
      • Schneider A.
      • Patel J.
      • Srinivasan A.
      • et al.
      Antimicrobial-resistant pathogens associated with healthcare-associated infections; summary of data reported to the national healthcare safety network at the centers for disease control and prevention, 2009-2010.
      ]. Candida is often detected in cultures, though it is discovered in most cases and rarely causes a urinary tract infection (III) [
      • Richards M.J.
      • Edwards J.R.
      • Culver D.H.
      • Gaynes R.P.
      Nosocomial infections in medical intensive care units in the United States. National Nosocomial Infections Surveillance System.
      ].
      In patients with symptoms, empiric therapy should be initiated with administration of an antibacterial agent with a broad spectrum and covering P. aeruginosa. In particular, the susceptibility pattern of gram-negative rods varies among institutions, thus it is recommended to refer to the institutional pattern when selecting antimicrobials (BIV) [
      • Hooton T.M.
      • Bradley S.F.
      • Cardenas D.D.
      • Colgan R.
      • Geerlings S.E.
      • Rice J.C.
      • et al.
      Infectious Diseases Society of America
      Diagnosis, prevention, and treatment of catheter-associated urinary tract infection in adults; 2009 international clinical practice guidelines from the infectious diseases society of America.
      ,
      • Nicolle L.E.
      A practical guide to antimicrobial management of complicated urinary tract infection.
      ].
      Gram staining is useful for determining the causative bacterium (BIV). When cocci are detected by gram staining, penicillins should be selected in consideration of Enterococcus species. There is the possibility of penicillin-resistant enterococci such as Enterococcus faecium depending on the background of the patient, thus concomitant use of anti-MRSA antimicrobials such as VCM should be considered (CIV).
      For patients with a catheter placed for at least 2 weeks, that should be replaced prior to treatment (BI). According to findings of an RCT, the frequency of bacteriuria at 28 days after beginning antibacterial administration (P = 0.02), clinical improvement rate at 72 h after initiation of treatment (P < 0.004), and recurrence rate of urinary tract infection within 28 days (P < 0.015) were lower in cases with catheter replacement [
      • Raz R.
      • Schiller D.
      • Nicolle L.E.
      Chronic indwelling catheter replacementbefore antimicrobial therapy for symptomatic urinary tract infection.
      ]. Furthermore, bacteria that have colonized on the catheter may be detected in cultures from specimens obtained from chronic indwelling catheters and, since the results may not accurately reflect the true causative bacterium, testing of samples collected after catheter replacement is preferred (BIV).
      The treatment period for a catheter-related urinary tract infection has not been sufficiently evaluated, and past reviews in regard to complicated urinary tract infection have presented differing results based on the severity of the condition and presence of complications (BII). The recommended treatment period is 7 days when a rapid response to antibacterial treatment is observed [
      • Warren J.W.
      Catheter-associated bacteriuria in long-term care facilities.
      ], 10–14 days when the response is weak [
      • Nicolle L.E.
      Catheter-related urinary tract infection.
      ], and 14–20 days when the condition is severe and complicated (BII) [
      • Stamm W.E.
      • Hooton T.M.
      Management of urinary tract infections in adults.
      ].
      Meta-analysis findings have indicated that occurrence of urinary tract infections was reduced from 10.5% to 4.7% following prophylactic administration of antibiotics at the time of removal of the urethral catheter (I) [
      • Marschal J.
      • Carpenter C.R.
      • Fowler S.
      • Trautner B.W.
      CDC Prevention Epicenters Program
      Antibiotic prophylaxis for urinary tract infections after removal of urinary catheter; meta-analysis.
      ]. However, that treatment is not recommended as routine because of demerits that include adverse effect, possible induction of resistant strains, and cost (C).
      • Disease characteristics
      A catheter-related urinary tract infection is defined as a symptomatic condition in which 103/mL or more bacterial organisms are detected in a cultured urine sample after collection through the catheter or within 48 h after catheter removal [
      • Hooton T.M.
      • Bradley S.F.
      • Cardenas D.D.
      • Colgan R.
      • Geerlings S.E.
      • Rice J.C.
      • et al.
      Infectious Diseases Society of America
      Diagnosis, prevention, and treatment of catheter-associated urinary tract infection in adults; 2009 international clinical practice guidelines from the infectious diseases society of America.
      ]. Symptoms suggestive of catheter-related urinary tract infection include CVA tenderness, acute hematuria, and pelvic discomfort, as well as systemic symptoms such as fever, chill, and altered level of consciousness, with those after catheter removal including urination pain, pollakiuria, and suprapubic tenderness.
      • Causative microorganisms
      Enterobacteriaceae, such as E. coli, and Klebsiella, Serratia, Citrobacter, and Enterobacter species, and non-fermenting bacteria, such as P. aeruginosa, Acinetobacter, and Enterococcus species, can be causative microorganisms [
      • Sievert D.M.
      • Ricks P.
      • Edwards J.R.
      • Schneider A.
      • Patel J.
      • Srinivasan A.
      • et al.
      Antimicrobial-resistant pathogens associated with healthcare-associated infections; summary of data reported to the national healthcare safety network at the centers for disease control and prevention, 2009-2010.
      ].
      • Recommended antimicrobials
      Antimicrobials should be selected in consideration of the susceptibility pattern of gram-negative rods at each institution (BIV). If Enterococcus species are suspected, penicillin with BLI or anti-MRSA antimicrobials should be selected, as cephalosporins are ineffective (CIV).
      • Key points
      The susceptibility patterns of gram-negative rods vary widely among institutions, thus there is no recommendation for effective empiric therapy. Since results of clinical trials performed at other institutions is not useful in all institutions, it is important to know the antimicrobial susceptibility pattern of microorganisms at each institution (BIV). Particularly, at those where β-lactam-resistant bacteria are highly prevalent, concomitant use of an aminoglycoside is safer in severely ill patients until results of culture tests become available (CIV).
      First choices
      • TAZ/PIPC, intravenous, 4.5 g, 3 times a day for 7–21 days
      • CAZ, intravenous, 1–2 g, 3 times a day Note for 7–21 days
      • CFPM, intravenous, 1–2 g, 3 times a day Note for 7–21 days
      • MEPM, intravenous, 0.5–1 g, 3 times a day for 7–21 days
      Alternatives
      • CPFX, intravenous, 300 mg, twice a day for 7–21 days
      • GM, intramuscular or intravenous, 5 mg/kg, once a day for 7–21 days
      • AMK, intramuscular or intravenous, 15 mg/kg, once a day for 7–21 days
      • PZFX, intravenous, 500 mg, twice a day for 7–21 days
      • LVFX, intravenous, 500 mg, once a day for 7–21 days
      Note: A dose of 2 g, 3 times a day is not covered by Japanese national health insurance.

      2.7 Urinary tract infection in children

      Executive summary
      • When administration of an antimicrobial is considered necessary for a child with an unexplained fever, urine culture test prior to administration is recommended for differential diagnosis of urinary tract infection (AI).
      • Urinary tract infection is diagnosed when 104 to 105/mL or more of a single intestinal bacterium species is detected in cultures of catheter or midstream urine samples (AII).
      • Prompt administration of antimicrobials is recommended (AI). The first antimicrobial given should be determined in consideration of the susceptibility of E. coli in the relevant region (AII), then should be de-escalated to a narrow spectrum antimicrobial according to the results of antimicrobial susceptibility testing. Following resolution of fever or improvement in general condition, switching to an oral antimicrobial is also acceptable (AI). Antibacterial therapy for febrile urinary tract infection in children should be continued for 7–14 days (AII).
      • Abdominal ultrasonography of the kidneys and bladder should be performed to investigate potential anatomical abnormalities (AII). Voiding cystourethrography should be performed when abnormalities are noted in ultrasonography findings or when urinary tract infection is recurrent, while indications for voiding cystourethrography following an initial episode of urinary tract infection are controversial even among specialists (BII).
      • Prophylactic administration of antimicrobials is not recommended for the initial episode of urinary tract infection with no anatomical abnormalities. Each case should be evaluated individually when urinary tract infection is recurrent or accompanied by an anatomical abnormality (BI).
      Commentary
      Children with urinary tract infection generally show non-specific symptoms, though often have a severe course leading to sepsis or renal scarring. Therefore, in those with unexplained fever or a poor general condition, antimicrobials should be administered promptly after urinalysis, and urine and blood cultures performed [
      • Hiraoka M.
      • Hashimoto G.
      • Tsuchida S.
      • Tsukahara H.
      • Ohshima Y.
      • Mayumi M.
      Early treatment of urinary infection prevents renal damage on cortical scintigraphy.
      ,
      • Doganis D.
      • Siafas K.
      • Mavrikou M.
      • Issaris G.
      • Martirosova A.
      • Perperidis G.
      • et al.
      Does early treatment of urinary tract infection prevent renal damage?.
      ,
      • Roberts K.B.
      Subcommittee on Urinary Tract InfectionSteering Committee on Quality Improvement and Management
      Urinary tract infection; clinical practice guideline for the diagnosis and management of the initial UTI in febrile infants and children 2 to 24 months.
      ]. Symptoms that suggest urinary tract infection include abdominal pain (likelihood ratio [LR]: 6.3, 95% confidence interval [CI]: 2.5–16.0), back pain (LR: 3.6, 95% CI: 2.1–6.1), pollakisuria or urination pain (LR: 2.2–2.8), and incontinence (LR: 4.6, 95% CI: 2.8–7.6), and urinalysis should be performed when such symptoms are observed [
      • Shaikh N.
      • Morone N.E.
      • Lopez J.
      • Chianese J.
      • Sangvai S.
      • D'Amico F.
      • et al.
      Does this child have a urinary tract infection?.
      ]. Physical findings suggestive of urinary tract infection include suprapubic tenderness (LR: 4.4, 95% CI: 1.6–12.4) and knock pain of the back, which warrant further examinations (AI).
      The prevalence of urinary tract infection in infants with unexplained fever is reported to be about 5% [
      • Shaw K.N.
      • Gorelick M.
      • McGowan K.L.
      • Yakscoe N.M.
      • Schwartz J.S.
      Prevalence of urinary tract infection in febrile young children in the emergency department.
      ]. Although it is unnecessary to perform urinalysis for all patients, a fever of 40 °C or higher (LR: 3.2–3.3) [
      • Hoberman A.
      • Chao H.P.
      • Keller D.M.
      • Hickey R.
      • Davis H.W.
      • Ellis D.
      Prevalence of urinary tract infection in febrile infants.
      ] or an unexplained fever of 39 °C or higher persisting for 2 days or longer (LR: 4.0, 95% CI, 1.2–13.0) [
      • Shaw K.N.
      • Gorelick M.
      • McGowan K.L.
      • Yakscoe N.M.
      • Schwartz J.S.
      Prevalence of urinary tract infection in febrile young children in the emergency department.
      ] are risk factors, and indicate the need for examinations for urinary tract infection (AI). Furthermore, when an unexplained fever is noted in a patient with a history of urinary tract infection, the risk of recurrence is 2–3 times greater than those without a history (II) [
      • Shaw K.N.
      • Gorelick M.
      • McGowan K.L.
      • Yakscoe N.M.
      • Schwartz J.S.
      Prevalence of urinary tract infection in febrile young children in the emergency department.
      ,
      • Hoberman A.
      • Chao H.P.
      • Keller D.M.
      • Hickey R.
      • Davis H.W.
      • Ellis D.
      Prevalence of urinary tract infection in febrile infants.
      ].
      Guidelines in Western countries classify risk separately for males and females, based on findings that the risk of urinary tract infection is relatively low in circumcised boys [
      • Shaikh N.
      • Morone N.E.
      • Lopez J.
      • Chianese J.
      • Sangvai S.
      • D'Amico F.
      • et al.
      Does this child have a urinary tract infection?.
      ,
      • Shaw K.N.
      • Gorelick M.
      • McGowan K.L.
      • Yakscoe N.M.
      • Schwartz J.S.
      Prevalence of urinary tract infection in febrile young children in the emergency department.
      ,
      • Hoberman A.
      • Chao H.P.
      • Keller D.M.
      • Hickey R.
      • Davis H.W.
      • Ellis D.
      Prevalence of urinary tract infection in febrile infants.
      ]. Japanese boys are usually not circumcised, and, indeed, a clinical study performed in Japan found that the incidence of urinary tract infection is higher in boys than girls [
      • Furuichi M.
      • Arakawa A.
      • Hamahata Y.
      • Usui M.
      • Shimoyamada M.
      • Yamada M.
      • et al.
      Characteristics of childhood urinary tract infection in saitama city hospital from 2001 t0 2010.
      ].
      In principle, urinary tract infection must be excluded prior to administration of antimicrobials in patients with unexplained fever (A). With the risks described above in mind, sampling for urinalysis and urine culture testing should be considered in cases at moderate or high risks (A).
      Urine sampling by catheterization is invasive in children. Therefore, it is common to perform urinalysis using a urine collecting bag when urinary tract infection is not highly suspected, while urine culture testing using a catheter should be performed if necessary (B).

      2.7.1 Urinary tract infection in infants and children

      • Sampling methods for urine culture
      • For incontinent patients, urine sampling by catheterization is recommended (AII) [
        • Kramer M.S.
        • Tange S.M.
        • Drummond K.N.
        • Mills E.L.
        Urine testing in young febrile children; a risk-benefit analysis.
        ,
        • Bonadio W.A.
        Urine culturing technique in febrile infants.
        ]. Though there are a few reports of midstream urine sampling in infants (III) [
        • Herreros Fernández M.L.
        • González Merino N.
        • Tagarro García A.
        • Pérez Seoane B.
        • de la Serna Martínez M.
        • Contreras Abad M.T.
        • et al.
        A new technique for fast and safe collection of urine in newborns.
        ], no diagnostic criteria are available for urinary tract infection using a midstream urine specimen. A bladder puncture is not recommended, unless a lesion obstructing the urethra is present (C).
      • For continent patients, midstream urine sampling is recommended (A).
      • When urinalysis is performed for screening, bag sampling after sufficient cleaning of the pubic region is available, while culturing of bag urine is not recommended because it is often contaminated (BII) [
        • Roberts K.B.
        Subcommittee on Urinary Tract InfectionSteering Committee on Quality Improvement and Management
        Urinary tract infection; clinical practice guideline for the diagnosis and management of the initial UTI in febrile infants and children 2 to 24 months.
        ,
        • Etoubleau C.
        • Reveret M.
        • Brouet D.
        • Badier I.
        • Brosset P.
        • Fourcade L.
        • et al.
        Moving from bag to catheter for urine collection in non-toilet-trained children suspected of having urinary tract infection: a paired comparison of urine cultures.
        ].
      • Diagnosis
      • For diagnosis of urinary tract infection, symptoms suggestive of the disease, abnormal urinalysis findings, and significant bacteriuria shown in urine culture test results are necessary (AI) [
        • Roberts K.B.
        Subcommittee on Urinary Tract InfectionSteering Committee on Quality Improvement and Management
        Urinary tract infection; clinical practice guideline for the diagnosis and management of the initial UTI in febrile infants and children 2 to 24 months.
        ,
        • Etoubleau C.
        • Reveret M.
        • Brouet D.
        • Badier I.
        • Brosset P.
        • Fourcade L.
        • et al.
        Moving from bag to catheter for urine collection in non-toilet-trained children suspected of having urinary tract infection: a paired comparison of urine cultures.
        ].
      • The possibility of urinary tract infection is low when both leukocyte and nitrites are negative by urinalysis (LR: 0.20, 95% CI: 0.16–0.26), though the disease should be positively diagnosed when either (LR: 6.1, 95% CI: 4.3–8.6) or both (LR: 28, 95% CI: 17–46) [
        • Whiting P.
        • Westwood M.
        • Watt I.
        • Cooper J.
        • Kleijnen J.
        Rapid tests and urine sampling techniques for the diagnosis of urinary tract infection (UTI) in children under five years; a systematic review.
        ] are positive (AI). According to the AAP Guidelines 2011, pyuria (>5 WBC/hpf), and bacteriuria are essential criteria for diagnosis, while the NICE Guidelines of the UK state that in the presence of bacteria in the urine by microscopy “the infant or child should be regarded as having UTI” even in the absence of pyuria [
        • Baumer J.H.
        • Jones R.W.
        Urinary tract infection in children, national institute for health and clinical excellence.
        ]. A similar opinion that purulent urine is not essential has also been observed in Japanese literature (BII) [
        • Kimata T.
        • Isozaki Y.
        • Kino M.
        • Kaneko K.
        Characteristics of children with upper urinary tract infection having no pyuria.
        ].
      • Bacterial flora are present in the urethra and external genitalia, and thus are likely to contaminate urine samples. A study of pyelonephritis in adult women reported that a bacterial count of 105/mL or greater in a midstream sample is significant [
        • KASS E.H.
        Asymptomatic infections of the urinary tract.
        ]. However, in infants, a bacterial count of 5 × 104/ml in a catheter specimen of urine has been reported to be significant [
        • Hoberman A.
        • Wald E.R.
        • Reynolds E.A.
        • Penchansky L.
        • Charron M.
        Pyuria and bacteriuria in urine specimens obtained by catheter from young children with fever.
        ]. Since this value is rarely used in urine culture testing in Japan, a bacterial count of 104/ml is generally applied as a provisional criterion with regarding other clinical findings.
      • If bacteria are noted in a single microscopic field of gram-stained non-centrifuged urine, the finding corresponds to a bacterial count of 105/ml in culture testing. That finding provides important information for a tentative diagnosis based on urinalysis findings and determination of the causative bacterium (BIV) [
        • Wald E.R.
        Cystitis and pyelonephritis.
        ,
        • Hoberman A.
        • Wald E.R.
        • Reynolds E.A.
        • Penchansky L.
        • Charron M.
        Is urine culture necessary to rule out urinary tract infection in young febrile children?.
        ].
      • Microorganisms
      • E. coli is the causative bacterium in about 80% of the first episodes of urinary tract infection without underlying disease in patients, followed by Enterococcus species accounting for about 10%, and other enterobacteriaceae accounting for the rest (III) [
        • Furuichi M.
        • Arakawa A.
        • Hamahata Y.
        • Usui M.
        • Shimoyamada M.
        • Yamada M.
        • et al.
        Characteristics of childhood urinary tract infection in saitama city hospital from 2001 t0 2010.
        ,
        • Ikemiyagi M.
        • Toyama A.
        • Takasato Y.
        • Kohno M.
        • Tomita M.
        • Shikoro N.
        • et al.
        Differences of the clinical background in the cases of febrile urinary tract infection between Japan and previous study.
        ].
      • As for patients with urinary tract anomaly, with a history of urinary tract infection, or with present underlying disease, enterobacteriaceae other than E. coli, Enterococcus species, and P. aeruginosa are frequently isolated. The percentage of antimicrobial resistant bacteria is known to be increased, and attention to Candida is also necessary.
      • Antimicrobials recommended for initial treatment s
      • Early treatment is important for prevention of renal scarring (AI) [
        • Hiraoka M.
        • Hashimoto G.
        • Tsuchida S.
        • Tsukahara H.
        • Ohshima Y.
        • Mayumi M.
        Early treatment of urinary infection prevents renal damage on cortical scintigraphy.
        ,
        • Doganis D.
        • Siafas K.
        • Mavrikou M.
        • Issaris G.
        • Martirosova A.
        • Perperidis G.
        • et al.
        Does early treatment of urinary tract infection prevent renal damage?.
        ,
        • Roberts K.B.
        Subcommittee on Urinary Tract InfectionSteering Committee on Quality Improvement and Management
        Urinary tract infection; clinical practice guideline for the diagnosis and management of the initial UTI in febrile infants and children 2 to 24 months.
        ].
      • When an initial episode of urinary tract infection is suspected, treatment targeting E. coli should be selected. First-to third-generation cephalosporins should be administered according to the antibiogram of the relevant region (AII).
      • Also, when Enterococcus species cannot be excluded, combination therapy with ampicillin and aminoglycoside should be considered (C) [
        • Roberts K.B.
        Subcommittee on Urinary Tract InfectionSteering Committee on Quality Improvement and Management
        Urinary tract infection; clinical practice guideline for the diagnosis and management of the initial UTI in febrile infants and children 2 to 24 months.
        ].
      • In infants aged less than 3 months, when urinary tract infection is suspected to be complicated by meningitis, note that transfer to spinal fluid of first/second-generation cephalosporins and aminoglycosides may be insufficient (B).
      • In patients with underlying disease, antimicrobials must be selected in consideration of previously isolated microorganisms as well as ESBL-producing bacteria and P. aeruginosa (BII).
      • Treatment period
      • Febrile urinary tract infection in infants should be treated for 7–14 days [
        • Roberts K.B.
        Subcommittee on Urinary Tract InfectionSteering Committee on Quality Improvement and Management
        Urinary tract infection; clinical practice guideline for the diagnosis and management of the initial UTI in febrile infants and children 2 to 24 months.
        ]. No comparative evaluation of the treatment period between 7 and 14 days has been performed, and the duration of treatment is dependent on the discretion of the physician or institution (AII).
      • Acute focal bacterial nephritis (AFBN) should be treated with intravenous antimicrobial therapy for at least 2 weeks and subsequent oral treatment for a total treatment period of 3 weeks (BII) [
        • Cheng C.H.
        • Tsau Y.K.
        • Lin T.Y.
        Effective duration of antimicrobial therapy for the treatment of acute lobar nephronia.
        ].
      • Key points
      Though community-acquired urinary tract infections caused by ESBL-producing gram-negative rods are reported to be increasing, it has been shown that children with pyelonephritis can be successfully treated with no difference in the febrile period or outcome of patients if an effective antimicrobial was subsequently administered even when a third-generation cephalosporin was initially used [
      • Tratselas A.
      • Iosifidis E.
      • Ioannidou M.
      • Saoulidis S.
      • Kollios K.
      • Antachopoulos C.
      • et al.
      Outcome of urinary tract infections caused by extended spectrum β-Lactamase-producing enterobacteriaceae in children.
      ,
      • Katsuta T.
      • Shoji K.
      • Watanabe Y.
      • Saitoh A.
      Treatment of pyelonephritis caused by extended-spectrum β-lactamase–producing enterobacteriaceae in children.
      ]. While careful management of severely ill patients is necessary, it is presently considered unnecessary to use antimicrobials with a broader spectrum than that of third-generation cephalosporins as the empiric treatment of a community-acquired urinary tract infection (CII).
      In Western countries, oral antimicrobials are considered to be effective for use as intravenous antimicrobials when treating febrile urinary tract infections (I) [
      • Hoberman A.
      • Wald E.R.
      • Hickey R.W.
      • Baskin M.
      • Charron M.
      • Majd M.
      • et al.
      Oral versus initial intravenous therapy for urinary tract infections in young febrile children.
      ,
      • Hodson E.M.
      • Willis N.S.
      • Craig J.C.
      Antibiotics for acute pyelonephritis in children.
      ,
      • Bloomfield P.
      • Hodson E.M.
      • Craig J.C.
      Antibiotics for acute pyelonephritis in children.
      ]. However, in Japan, clinical evaluations of oral antimicrobials have thus far been insufficient because medical system and target patient population may be different, and initial treatment by intravenously administration is generally recommended (B). Lower urinary tract infections are usually managed by oral antibacterial therapy (A).
      • 1)
        Neonatal period
      (See “Supplementary Table. Doses for neonates” for doses and administration methods.)
      • Empiric therapy
      First choices
      • ABPC + GM, intravenous
      Second choice
      • CTX, intravenous
      • Definitive therapy
      Based on the results of initial urine culture and antimicrobial susceptibility testing, the antimicrobial should be switched to that with the narrowest spectrum. Antimicrobials indicated for low-birth-weight newborns and neonates include ABPC, CAZ, CZOP, FMOX, AZT, AMK, and VCM, and are generally administered by intravenous infusion for 10–14 days.
      • 2)
        During and after infancy
      • Empiric therapy
      First choices
      • CEZ, intravenous, 30–40 mg/kg, 3 times a day for 7–14 days
      • CTM, intravenous 30–40 mg/kg, 3 times a day for 7–14 days
      • CTX, intravenous, 30–40 mg/kg, 3 times a day for 7–14 days
      • CTRX, intravenous, 50 mg/kg, once a day, or 25 mg/kg twice a day for 7–14 days
      If urosepsis is suspected, and transfer of the antimicrobial to cerebrospinal fluid is necessary, third-generation cephalosporins should be used.
      When Enterococcus is suspected
      • ABPC, intravenous, 30–40 mg/kg, 3 times a day for 7–14 days, with/without VCM, intravenous, 15 mg/kg, 3 times a day for 7–14 days
      • Although rare, when E. faecium is suspected, VCM is used.
      When a complicated urinary tract infection is suspected to be caused by P. aeruginosa
      • PIPC, intravenous, 50 mg/kg, 3 times a day for 7–14 days
      • CAZ, intravenous, 30–40 mg/kg, 3 times a day for 7–14 days
      • CFPM, intravenous, 30–40 mg/kg, 3 times a day for 7–14 days
      • MEPM or DRPM, intravenous, 20 mg/kg, 3 times a day for 7–14 days
      To be considered only when use of carbapenem is inevitable in view of the susceptibility of P. aeruginosa at the treating facility.
      When infection due to ESBL-producing bacteria is suspected
      • MEPM, intravenous, 20 mg/kg, 3 times a day for 7–14 days (If complication by urosepsis is unlikely, carbapenem should not be used.)
      Antimicrobials with limited reports of use
      • DRPM, intravenous, 20 mg/kg, 3 times a day for 7–14 days [
        • Kaniga K.
        • Flamm R.
        • Tong S.Y.
        • Lee M.
        • Friedland I.
        • Redman R.
        Worldwide experience with the use of Doripenem against extended-spectrum-β-lactamase-producing and ciprofloxacin-resistant enterobacteriaceae: analysis of six phase 3 clinical studies.
        ]
      • CMZ, intravenous, 30–40 mg/kg, 3 times a day for 7–14 days (reported for adults only) [
        • Doi A.
        • Shimada T.
        • Harada S.
        • Iwata K.
        • Kamiya T.
        The efficacy of cefmetazole against pyelonephritis caused by extended-spectrum beta-lactamase-producing Enterobacteriaceae.
        ]
      • Definitive therapy
      The antimicrobial should be promptly switched to one noted above that has the narrowest spectrum in culture test results. If fever has been resolved, switching to an oral antimicrobial is considered.
      • AMPC, oral, 15–20 mg/kg, 3 times a day for 7–14 days
      • CCL, oral, 10 mg/kg, 3 times a day for 7–14 days
      • CVA/AMPC, oral, 45 mg/kg, twice a day for 7–14 days (same as AMPC)
      • CDTR-PI, CFPN-PI, CPDX-PR, oral, 3 mg/kg, 3 times a day for 7–14 days (Broad spectrum antimicrobials should only be used when necessary based on the results of antimicrobial susceptibility testing.)
      • SMZ-TMP, oral, 4–6 mg/kg of TMP, twice a day for 7–14 days (Contraindicated for low-birth-weight newborns and neonates.)

      2.7.2 Screening for complications and prophylactic administration of antimicrobials

      Previously, it has been common practice to perform VCUG for all patients with an initial episode of urinary tract infection and prophylactic administration if abnormalities were found. However, subsequent studies have shown that patients without vesicoureteral reflux (VUR) may also develop upper urinary tract infection and that is not always prevented by prophylactic administration [
      • Craig J.C.
      • Simpson J.M.
      • Williams G.J.
      • Lowe A.
      • Reynolds G.J.
      • McTaggart S.J.
      • et al.
      Prevention of Recurrent Urinary Tract Infection in Children with Vesicoureteric Reflux and Normal Renal Tracts (PRIVENT) Investigators
      Antibiotic prophylaxis and recurrent urinary tract infection in children.
      ,
      • Pennesi M.
      • Travan L.
      • Peratoner L.
      • Bordugo A.
      • Cattaneo A.
      • Ronfani L.
      • et al.
      Is antibiotic prophylaxis in children with vesicoureteral reflux effective in preventing pyelonephritis and renal scars? A randomized, controlled trial.
      ,
      • Garin E.H.
      • Olavarria F.
      • Garcia Nieto V.
      • Valenciano B.
      • Campos A.
      • Young L.
      Clinical significance of primary vesicoureteral reflux and urinary antibiotic prophylaxis after acute pyelonephritis: a multicenter, randomized, controlled study.
      ,
      • Montini G.
      • Rigon L.
      • Zucchetta P.
      • Fregonese F.
      • Toffolo A.
      • Gobber D.
      • et al.
      Prophylaxis after first febrile urinary tract infection in children? A multicenter, randomized, controlled, noninferiority trial.
      ,
      • Roussey-Kesler G.
      • Gadjos V.
      • Idres N.
      • Horen B.
      • Ichay L.
      • Leclair M.D.
      • et al.
      Antibiotic prophylaxis for the prevention of recurrent urinary tract infection in children with low grade vesicoureteral reflux: results from a prospective randomized study.
      ], thus the validity of VCUG and prophylactic administration has been questioned (I).
      Ultrasonography is recommended for all patients with an initial episode of febrile urinary tract infection (AII). The objective of this examination is to detect renal abscess and urinary tract obstructions that require urological intervention, as well as anatomical abnormalities that require additional imaging examinations such as VCUG [
      • Nakamura M.
      • Shinozaki T.
      • Taniguchi N.
      • Koibuchi H.
      • Momoi M.
      • Itoh K.
      Simultaneous voiding cystourethrography and voiding urosonography reveals utility of sonographic diagnosis of vesicoureteral reflux in children.
      ]. It is also important to evaluate kidney size [
      • Hoberman A.
      • Charron M.
      • Hickey R.W.
      • Baskin M.
      • Kearney D.H.
      • Wald E.R.
      Imaging studies after a first febrile urinary tract infection in young children.
      ,
      • Jahnukainen T.
      • Honkinen O.
      • Ruuskanen O.
      • Mertsola J.
      Ultrasonography after the first febrile urinary tract infection in children.
      ]. Abnormalities shown by ultrasonography have been observed in 15% of infants with a febrile urinary tract infection, with intervention necessary in 1–2% [
      • Roberts K.B.
      Subcommittee on Urinary Tract InfectionSteering Committee on Quality Improvement and Management
      Urinary tract infection; clinical practice guideline for the diagnosis and management of the initial UTI in febrile infants and children 2 to 24 months.
      ]. VCUG is unnecessary in all patients with an initial episode of urinary tract infection [
      • Hoberman A.
      • Charron M.
      • Hickey R.W.
      • Baskin M.
      • Kearney D.H.
      • Wald E.R.
      Imaging studies after a first febrile urinary tract infection in young children.
      ], and should only be performed when abnormalities suggestive of VUR are observed or febrile urinary tract infection caused by pathogenic microorganisms other than E. coli has been isolated (BII) [
      • Shaikh N.
      • Craig J.C.
      • Rovers M.M.
      • Da Dalt L.
      • Gardikis S.
      • Hoberman A.
      • et al.
      Identification of children and adolescents at risk for renal scarring after a first urinary tract infection: a meta-analysis with individual patient data.
      ].
      As for prophylactic administration, an RCT found that the effect was unclear [
      • Roberts K.B.
      Subcommittee on Urinary Tract InfectionSteering Committee on Quality Improvement and Management
      Urinary tract infection; clinical practice guideline for the diagnosis and management of the initial UTI in febrile infants and children 2 to 24 months.
      ]. On the other hand, some studies that primarily investigated patients aged 2 years and older found such administration to be effective for prevention of recurrent urinary tract infection [
      • Craig J.C.
      • Simpson J.M.
      • Williams G.J.
      • Lowe A.
      • Reynolds G.J.
      • McTaggart S.J.
      • et al.
      Prevention of Recurrent Urinary Tract Infection in Children with Vesicoureteric Reflux and Normal Renal Tracts (PRIVENT) Investigators
      Antibiotic prophylaxis and recurrent urinary tract infection in children.
      ]. A large-scale RCT (RIVUR study) of 607 children aged 2 months to 6 years with a history of urinary tract infection and grade I-IV VUR was also performed. In this study, those subjects were randomized to two groups of administration of SMZ-TMP an no such administration, then followed for up to 2 years, with setting of the presence or absence of recurrence as the primary endpoint, and kidney disorder, treatment failure, and presence or absence of appearance of resistant strains as the secondary endpoints [
      • Keren R.
      • Carpenter M.A.
      • Hoberman A.
      • Shaikh N.
      • Matoo T.K.
      • Chesney R.W.
      • et al.
      Rationale and design issues of the randomized intervention for children with vesicoureteral reflux (RIVUR) study.
      ,
      • Carpenter M.A.
      • Hoberman A.
      • Mattoo T.K.
      • Mathews R.
      • Keren R.
      • Chesney R.W.
      • et al.
      RIVUR Trial Investigators
      The RIVUR trial: profile and baseline clinical associations of children with vesicoureteral reflux.
      ,
      • Hoberman A.
      • Greenfield S.P.
      • Mattoo T.K.
      • Keren R.
      • Mathews R.
      • Pohl H.G.
      • et al.
      The RIVUR Trial Investigators
      Antimicrobial prophylaxis for children with vesicoureteral reflux.
      ]. Their results showed that recurrent urinary tract infection occurred less frequently in the group that received prophylactic administration of SMZ-TMP (hazard ratio [HR]: 0.50, 95% CI: 0.34–0.74) and the prophylactic effect was particularly high in the group with bladder dysfunction (hazard ratio: 0.21, 95% CI: 0.08–0.58). However, there was no effect on renal scarring (11.9% vs. 10.2%) and E. coli resistant to SMZ-TMP appeared more frequently in the prophylactic administration group (63% vs. 19%).
      Cephalosporins instead of SMZ-TMP are administered in a prophylactic manner in many institutions in Japan, thus the results of the RIVUR study cannot be directly applied to Japanese patients. It has been reported that use of cephalosporins increases the risk of urinary tract infection due to ESBL-producing bacteria and leads to possible loss of useful antimicrobials serving as the mainstay for the treatment of urinary tract infection [
      • Dayan N.
      • Dabbah H.
      • Weissman I.
      • Aga I.
      • Even L.
      • Glikman D.
      Urinary tract infections caused by community-acquired extended-spectrum β-lactamase-producing and nonproducing bacteria: a comparative study.
      ]. Although prophylactic administration of SMZ-TMP is the standard in many countries, it should be noted that it is not covered by the national health insurance system in Japan.
      Overall, prophylactic administration of antimicrobials for an initial episode of urinary tract infection unaccompanied by urinary tract anomalies or grade 1–2 VUR is not recommended as routine treatment (BI). However, patients with a marked urinary tract anomaly or bladder dysfunction should be evaluated on an individual basis (C).
      Representative prescriptions
      • SMZ-TMP, oral, 2 mg/kg of TMP, once a day (before bed) (Contraindicated for low birth-weight newborns or neonates)
      • CCL, oral, 5–10 mg/kg, once a day (before bed) [
        • Kaneko K.
        • Ohtomo Y.
        • Shimizu T.
        • Yamashiro Y.
        • Yamataka A.
        • Miyano T.
        Antibiotic prophylaxis by low-dose cefaclor in children with vesicoureteral reflux.
        ]

      3. Male genital infection

      3.1 Acute bacterial prostatitis

      Executive summary
      • In acute bacterial prostatitis, pyuria and bacteriuria are demonstrated by urinalysis, with general symptoms such as fever and local findings such as urination pain, and the feverish prostate is palpable by rectal examination.
      • E. coli is the most frequent causative microorganism (III) [
        • Lipsky B.A.
        • Byren I.
        • Hoey C.T.
        Treatment of bacterial prostatitis.
        ].
      • Exacerbation such as sepsis is often observed, thus parenteral antimicrobials are generally selected as the initial treatment (BIII).
      Commentary
      Patients with acute prostatitis are presented with general symptoms, such as fever of 38 °C or higher and malaise, and local symptoms, such as urination pain, pollakisuria, urgent desire to urinate, difficulty with urination, and perineal discomfort and pain [
      • Krieger J.N.
      • Nyberg Jr., L.
      • Nickel J.C.
      NIH consensus definition and classification of prostatitis.
      ].
      Laboratory test findings of urinalysis reveal pyuria and bacteriuria, and blood tests show signs of inflammation, such as peripheral leukocytosis, and elevated CRP, PCT and ESR. By a rectal examination, the feverish and enlarged prostate is palpable, and the patient will likely note tenderness. Prostate massage is contraindicated, because that may induce bacteremia (BIII) [
      • Millán-Rodríguez F.
      • Palou J.
      • Bujons-Tur A.
      • Musquera-Felip M.
      • Sevilla-Cecilia C.
      • Serrallach-Orejas M.
      • et al.
      Acute bacterial prostatitis: two different sub-categories according to a previous manipulation of the lower urinary tract.
      ]. Urine culture and antimicrobial susceptibility testing is essential, and blood culture test is also necessary when there is suspected bacteremia or sepsis.
      • Disease characteristics
      Affected patients are classified into those with a previous history of lower urinary tract procedure, such as prostate biopsy or transurethral treatment, and those with no such history. The former group, which accounts for about 10%, is characterized by older age and a high risk of prostate abscess complication [
      • Nickel J.C.
      Prostatitis and related conditions, orchitis, and epididymitis.
      ].
      • Causative microorganisms
      The causative bacterial organisms are reported to be E. coli in 65–87%, P. aeruginosa in 3–13%, Klebsiella species in 2–6%, gram-positive cocci in 3–5%, and others in 9% (III) [
      • Lipsky B.A.
      • Byren I.
      • Hoey C.T.
      Treatment of bacterial prostatitis.
      ,
      • Yoon B.I.
      • Kim S.
      • Han D.S.
      • Ha U.S.
      • Lee S.J.
      • Kim H.W.
      • et al.
      Acute bacterial prostatitis: how to prevent and manage chronic infection?.
      ,
      • Etienne M.
      • Chavanet P.
      • Sibert L.
      • Michel F.
      • Levesque H.
      • Lorcerie B.
      • et al.
      Acute bacterial prostatitis: heterogeneity in diagnostic criteria and management. Retrospective multicentric analysis of 371 patients diagnosed with acute prostatitis.
      ,
      • Lipsky B.A.
      Prostatitis and urinary tract infection in men: what's new; what's true?.
      ].
      • Recommended antimicrobials
      For empiric therapy, antimicrobials are generally administered parenterally, with second/third-generation cephalosporins, penicillins with BLI, and fluoroquinolones primarily used for treatment (BIII) [

      Grabe M, Bjerklund-Johansen TE, Botto H, Cek M, Naber KG, Pickard RS, et al. Guidelines on Urological Infections 2013. European Association of Urology Guidelines. http://www.uroweb.org/guidelines/eau-clinical-guidelines/.

      ,
      • Naber K.G.
      Management of bacterial prostatitis: what's new?.
      ].
      The effectiveness of empiric therapy should be evaluated at 3 days after the beginning of antimicrobial therapy, with the treatment switched to definitive therapy based on the results of culture testing.
      • Key points
      Acute prostatitis is likely severe and is complicated by prostate abscess in 1–2% of affected patients, which requires surgical drainage [
      • Kravchick S.
      • Cytron S.
      • Agulansky L.
      • Ben-Dor D.
      Acute prostatitis in middle- aged men: a prospective study.
      ]. Transrectal ultrasonography is useful for screening for prostate abscess [
      • Horcajada J.P.
      • Vilana R.
      • Moreno-Martínez A.
      • Alvarez-Vijande R.
      • Bru C.
      • Bargalló X.
      • et al.
      Transrectal prostatic ultrasonog- raphy in acute bacterial prostatitis: findings and clinical impli- cations.
      ]. In patients who have developed urinary retention, it is optimal to perform a cystostomy (suprapubic), with urethral catheterization as an option when a cystostomy is not available (BIII). Severe acute prostatitis with sepsis is treated similarly to urosepsis.
      • Mild/moderate acute prostatitis
      First choices
      • LVFX, oral, 500 mg, once a day for 14 days
      • CPFX, oral, 200 mg, 3 times a day for 14 days
      • TFLX, oral, 150 mg, 3 times a day for 14 days
      • STFX, oral, 100 mg, twice a day for 14 days
      Alternatives
      • SBTPC, oral, 375 mg, 3 times a day for 14–28 days
      • SMZ-TMP, oral, T = 160 mg/S = 800 mg, twice a day for 14 days
      not covered by Japanese national health insurance
      • Severe prostatitis
      Empiric therapy should be performed for 3 days and then switched to definitive therapy based on the results of culture testing of the initial urine sample and antimicrobial susceptibility testing. Following remission of symptoms, the treatment is switched to oral antibacterial therapy (see antimicrobials noted above for mild/moderate acute prostatitis). The total treatment period is 14–28 days.
      First choices
      • CTM, intravenous, 1 g, 2 to 4 times a day for 3–7 days
      • CAZ, intravenous, 1 g, 2 to 4 times a day for 3–7 days
      • FMOX, intravenous, 1 g, 2 to 4 times a day for 3–7 days
      Alternatives
      • TAZ/PIPC, intravenous, 4.5 g, 3 times a day for 3–7 days
      • PZFX, intravenous, 500 mg, twice a day for 3–7 days
      • LVFX, intravenous, 500 mg, once a day for 3–7 days

      3.2 Acute epididymitis

      Executive summary
      • Neisseria gonorrhoeae and Chlamydia trachomatis, causative microorganisms of urethritis, must be kept in mind for sexually active males aged 35 years or younger. For other age groups, consideration of lower urinary tract infection causative microorganisms such as E. coli is important [
        • Manavi K.
        • Turner K.
        • Scott G.R.
        • Stewart L.H.
        Audit on the management of epididymo-orchitis by the department of urology in edinburgh.
        ,
        • Redfern T.R.
        • English P.J.
        • Baumber C.D.
        • McGhie D.
        The aetiology and man- agement of acute epididymitis.
        ].
      • Testicular torsion is the most important differential diagnosis in younger males. If testicular torsion can not be excluded, the case should be treated as acute scrotum (BIV) [
        • Trojian T.H.
        • Lishnak T.S.
        • Heiman D.
        Epididymitis and orchitis: an overview.
        ].
      Commentary
      Acute epididymitis causes pain and swelling due to inflammation of the epididymis. It generally shows acute onset and occurs by mechanism that infection of the bladder, urethra, or prostate reaches the epididymis via the ejaculatory duct and vas deferens.
      In children, the disease is often related to a urinary tract infection and lower urinary tract anomaly, or phimosis [
      • Luzzi G.A.
      • O'Brien T.S.
      Acute epididymitis.
      ]. In middle-aged and older patients, prostate hypertrophy, urinary tract infection, and urethral catheterization are among the most frequent causes [
      • Luzzi G.A.
      • O'Brien T.S.
      Acute epididymitis.
      ]. The most frequent causative microorganism of acute bacterial epididymitis in children, as well as middle-aged and older patients is E. coli [
      • Luzzi G.A.
      • O'Brien T.S.
      Acute epididymitis.
      ]. On the other hand, in sexually active ages, particularly 14–35 years of age, the most frequent cause of epididymitis is urethritis, and the most frequently isolated microorganisms are N. gonorrhoeae and C. trachomatis (III) [
      • Manavi K.
      • Turner K.
      • Scott G.R.
      • Stewart L.H.
      Audit on the management of epididymo-orchitis by the department of urology in edinburgh.
      ,
      • Redfern T.R.
      • English P.J.
      • Baumber C.D.
      • McGhie D.
      The aetiology and man- agement of acute epididymitis.
      ].
      As for laboratory findings, urinalysis is revealed by pyuria if cystitis or urethritis is present, while blood test results show signs of inflammation, such as leukocytosis, and elevated CRP, PCT, and ESR. Similarly to urinary tract infection, urine culture and antimicrobial susceptibility testing are performed to identify the causative microorganism. In sexually active ages, examinations for N. gonorrhoeae and C. trachomatis should be performed using first-catch urine (CIII) [
      • Luzzi G.A.
      • O'Brien T.S.
      Acute epididymitis.
      ].
      • Disease characteristics
      In patients with acute epididymitis, swelling and intense pain in the scrotal region are usually observed along with fever. The most important differential diagnosis is testicular torsion in younger males, and if that cannot be excluded, the case should be treated as acute scrotum (BIV) [
      • Trojian T.H.
      • Lishnak T.S.
      • Heiman D.
      Epididymitis and orchitis: an overview.
      ].
      • Causative microorganisms
      Treatment of acute epididymitis in sexually active males aged 35 years or younger should be designed with N. gonorrhoeae and C. trachomatis, the causative microorganisms of urethritis, in mind. When treating males in other age groups, E. coli, the causative microorganism of lower urinary tract infection, should be considered (CIII) [

      Grabe M, Bjerklund-Johansen TE, Botto H, Cek M, Naber KG, Pickard RS, et al. Guidelines on Urological Infections 2013. European Association of Urology Guidelines. http://www.uroweb.org/guidelines/eau-clinical-guidelines/.

      ].
      The effectiveness of empiric therapy is generally evaluated at 3 days after beginning antibacterial therapy, then the treatment is switched to definitive therapy when results of culture testing become available.
      • Key points
      In severe cases, inflammation extends to the testis and advances to the epididymo-orchitis. In addition, abscess may develop, which will require surgical excision or drainage.
      • Mild/moderate cases
      First choices
      • LVFX, oral, 500 mg, once a day for 14 days
      • CPFX, oral, 200 mg, 3 times a day for 14 days
      • TFLX, oral, 150 mg, 3 times a day for 14 days
      • STFX, oral, 100 mg, twice a day for 14 days
      Alternatives
      • MINO, oral, 100 mg, twice a day for 14 days
      • CDTR-PI, oral, 200 mg, 3 times a day for 14 days∗ ∗∗ †
      *Not indicated for C. trachomatis.
      **When the disease is suspected to be caused by other than C. trachomatis.
      not covered by Japanese national health insurance.
      • Severe cases
      Empiric therapy should be performed for 3 days, then the treatment is switched to definitive therapy based on first urine sample culture results and antimicrobial susceptibility testing. Following remission of symptoms, the treatment is changed to oral antibacterial therapy (see antimicrobials for mild to moderate cases noted above). The total treatment period is 14–21 days.
      First choices
      • CTRX, intravenous, 1–2 g, 1 to 2 times a day for 3–7 days
      • CZOP, intravenous, 1 g, 2 to 3 times a day for 3–7 days
      Alternatives
      • LVFX, intravenous, 500 mg, once a day for 3–7 days
      • SBT/ABPC, intravenous, 1.5–3 g, 4 times a day for 3–7 days
      When C. trachomatis infection is suspected
      • MINO, intravenous, 100 mg, twice a day for 3–5 days (Following resolution of fever and swelling of scrotal contents: MINO, oral, 100 mg, twice a day, for 14 days in total)
      not covered by Japanese national health insurance

      Conflict of interest

      Shingo Yamamoto: Speaker's honorarium from Astellas Pharma Inc. and Pfizer Japan Inc.
      Soichi Arakawa: Speaker's honorarium from Taisho Toyama Pharmaceutical Co., Ltd.
      Isao Miyairi: Grant from Janssen Pharmaceutical K.K.
      Hiroshi Kiyota: Donation from AstraZeneca K.K., Daiichi Sankyo Co., Ltd. and Asahi Kasei co.
      Shingo Yamamoto: Donation from Astellas Pharma Inc., Pfizer Japan Inc, Takeda Pharmaceutical Co., Ltd., and Daiichi Sankyo Co., Ltd. and Asahi Kasei co.
      Kazushi Tanaka: Donation from Adachi Co., Ltd.

      Appendix A. Supplementary data

      The following is the supplementary data related to this article:

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