J Infect Chemother 21 (2015) 623e633

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Surveillance

Japanese nationwide surveillance in 2011 of antibacterial susceptibility patterns of clinical isolates from complicated urinary tract infection cases Kiyohito Ishikawa a, b, *, Ryoichi Hamasuna a, c, Shinya Uehara a, d, Mitsuru Yasuda a, e, Shingo Yamamoto a, f, Hiroshi Hayami a, g, Satoshi Takahashi a, h, Tetsuro Matsumoto a, c, Shinichi Minamitani a, Jun-ichi Kadota i, Satoshi Iwata i, Mitsuo Kaku i, Akira Watanabe i, Keisuke Sunakawa i, Junko Sato i, Hideaki Hanaki j, Taiji Tsukamoto h, Hiroshi Kiyota k, Shin Egawa l, Takashi Deguchi e, Minori Matsumoto m, Kazushi Tanaka m, Soichi Arakawa m, Masato Fujisawa m, Hiromi Kumon d, Kanao Kobayashi n, Akio Matsubara n, Hironobu Wakeda o, Yoshinosuke Amemoto p, Shoichi Onodera q, Hirokazu Goto q, Hisao Komeda r, Masuo Yamashita s, Tadasu Takenaka t, Yoshinori Fujimoto u, Masaya Tsugawa v, Yoshito Takahashi w, Hiroshi Maeda x, Hiroyuki Onishi y, Satoshi Ishitoya y, Kazuo Nishimura z, Kenji Mitsumori z, Toru Ito aa, Yoshikazu Togo f, Ichiro Nakamura ab, Noriyuki Ito ac, Sojun Kanamaru ac, Takaoki Hirose ad, Takashi Muranaka ad, Daisuke Yamada ae, Satoshi Ishihara af, Hiroya Oka ag, Hisato Inatomi ah, Takashi Matsui ai, Makoto Kobuke aj, Yasuharu Kunishima ak, Takahiro Kimura l, Takaharu Ichikawa al, Ichiro Kagara am, Masanori Matsukawa an, Koichi Takahashi ao, Koji Mita ap, Masao Kato ap, Kazuhiro Okumura aq, Hiroaki Kawanishi aq, Takayuki Hashimura ar, Teruyoshi Aoyama ar, Masanobu Shigeta as, Shuntaro Koda as, Keisuke Taguchi at, Yohei Matsuda at a Urogenital Sub-committee and the Surveillance Committee of Japanese Society of Chemotherapy (JSC), The Japanese Association for Infectious Disease (JAID) and The Japanese Society for Clinical Microbiology (JSCM), Tokyo, Japan b Department of Urology, Fujita Health University School of Medicine, Aichi, Japan c Department of Urology, University of Occupational and Environmental Health, Fukuoka, Japan d Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan e Department of Urology, Graduate School of Medicine, Gifu University, Gifu, Japan f Department of Urology, Hyogo College of Medicine, Hyogo, Japan g Blood Purification Center, Kagoshima University Hospital, Kagoshima, Japan h Department of Urology, Sapporo Medical University School of Medicine, Sapporo, Japan i The Surveillance Committee of JSC, JAID and JSCM, Tokyo, Japan j Research Center for Anti-infectious Drugs, Kitasato Institute for Life Sciences, Kitasato University, Tokyo, Japan k Department of Urology, The Jikei University Katsushika Medical Center, Tokyo, Japan l Department of Urology, The Jikei University School of Medicine, Tokyo, Japan m Division of Urology, Kobe University Graduate School of Medicine, Hyogo, Japan n Department of Urology, Institute of Biomedical & Health Sciences Hiroshima University, Hiroshima, Japan o Department of Urology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan p Department of Urology, Minami Medical Health Cooperation, Aichi, Japan q Department of Urology, Fuji City General Hospital, Shizuoka, Japan r Department of Urology, Gifu Municipal Hospital, Gifu, Japan s Department of Urology, Shinko Hospital, Hyogo, Japan t Department of Urology, Japanese Red Cross Okayama Hospital, Okayama, Japan u Department of Urology, Ogaki Municipal Hospital, Gifu, Japan v Department of Urology, Okayama City Hospital, Okayama, Japan

* Corresponding author. Department of Urology, Fujita Health University School of Medicine, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake 470-1192, Aichi, Japan. Tel.: þ81 562 93 9257; fax: þ81 562 93 7863. E-mail address: [email protected] (K. Ishikawa). http://dx.doi.org/10.1016/j.jiac.2015.05.014 1341-321X/© 2015, Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

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w

Department of Urology, Gifu Prefectural General Medical Center, Gifu, Japan Department of Urology, Yodogawa Christian Hospital, Osaka, Japan y Department of Urology, Shiga Medical Center for Adults, Shiga, Japan z Department of Urology, Osaka Red Cross Hospital, Osaka, Japan aa Department of Urology, Nagoya Ekisaikai Hospital, Aichi, Japan ab Department of Urology, Kobe City Medical Center West Hospital, Hyogo, Japan ac Department of Urology, Nishi Kobe Medical Center, Hyogo, Japan ad Department of Urology, Japan Community Health Care Organization Hokkaido Hospital, Hokkaido, Japan ae Department of Urology, Mitoyo General Hospital, Kagawa, Japan af Department of Urology, Kizawa Memorial Hospital, Gifu, Japan ag Department of Urology, Nara Social Insurance Hospital, Nara, Japan ah Department of Urology, Munakata Suikokai General Hospital, Fukutsu, Japan ai Department of Urology, Japanese Red Cross Kobe Hospital, Hyogo, Japan aj Department of Urology, National Hospital Organization Iwakuni Clinical Center, Yamaguchi, Japan ak Department of Urology, Hokkaido Social Work Association Obihiro Hospital, Hokkaido, Japan al Department of Urology, Tottori Municipal Hospital, Tottori, Japan am Department of Urology, Kagoshima Prefectural Ohshima Hospital, Kagoshima, Japan an Department of Urology, Takikawa Municipal Hospital, Hokkaido, Japan ao Department of Urology, Fukuoka Shin Mizumaki Hospital, Fukuoka, Japan ap Department of Urology, Hiroshima City Asa Hospital, Hiroshima, Japan aq Department of Urology, Tenri Hospital, Nara, Japan ar Department of Urology, Kansai Electric Power Hospital, Osaka, Japan as Department of Urology, National Hospital Organization Kure Medical Center and Chugoku Cancer Center, Kure, Japan at Department of Urology, Oji General Hospital, Hokkaido, Japan x

a r t i c l e i n f o

a b s t r a c t

Article history: Received 12 December 2014 Received in revised form 27 May 2015 Accepted 29 May 2015 Available online 9 June 2015

To investigate antimicrobial susceptibility patterns of various bacterial pathogens isolated from complicated urinary tract infection (UTI) cases, the Japanese Society of Chemotherapy, the Japanese Association of Infectious Disease, and the Japanese Society of Clinical Microbiology conducted the second nationwide surveillance from January to September 2011. With the cooperation of 42 medical institutions throughout Japan, 1036 strains belonging to 8 clinically relevant bacterial species were collected. Among methicillin-resistant Staphylococcus aureus (MRSA) strain, the vancomycin (VCM) MIC for 5.5% (3/55) of the strains was 2 mg/mL. Ampicillin, VCM, and linezolid were relatively active against 209 Enterococcus faecalis strains. The proportion of fluoroquinolone (FQ)-resistant strains was >20%. The MIC90 of FQs against the 382 Escherichia coli strains was 2e64 mg/L and the proportion resistant to FQs was approximately 30%. However, susceptibility of E. coli to sitafloxacin was still high (MIC90 ¼ 2 mg/ L). Fifty-eight (15.2%) of 382 E. coli, 6 (4.5%) of 132 Klebsiella pneumoniae, 1 (2.4%) of 41 Klebsiella oxytoca and 4 (6.8%) of 59 Proteus mirabilis strains were suspected of producing extended-spectrum beta-lactamase. Of 93 Pseudomonas aeruginosa strains, the proportions resistant to imipenem, amikacin, and ciprofloxacin were 21.5%, 4.3%, and 20.4%, respectively. Four strains (4.3%) were found to be multidrugresistant. In complicated UTI cases, all of MRSA and E. faecalis were susceptible to all anti-MRSA agents. Sitafloxacin was active against other FQ-resistant E. coli strains. The isolation of extended-spectrum betalactamase-producing and multidrug-resistant strains increased. © 2015, Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Keywords: Surveillance Susceptibility Complicated urinary tract infection

1. Introduction Complicated urinary tract infection (UTI) is defined as cystitis and pyelonephritis caused by uropathogenic bacteria in males and young or elderly females with underlying diseases. Its management is difficult because of increasing antibiotic resistance of the causative bacteria and multiple recurrences. Therefore, we must choose more effective antimicrobial agents to control complicated UTIs by chemotherapy. To investigate trends in the clinical isolation of various bacterial pathogens and the emergence of antimicrobial resistance in these pathogens, the Japanese Society of Chemotherapy (JSC) established the nationwide surveillance network. We conducted the first surveillance of bacterial urinary pathogens from January to June 2008 [1]. With the cooperation of 28 medical institutions throughout Japan, 715 strains belonging to 6 clinically relevant bacterial species (Enterococcus faecalis, Escherichia coli, Klebsiella pneumoniae,

Proteus mirabilis, Serratia marcescens, and Pseudomonas aeruginosa) were collected. The JSC, Japanese Association of Infectious Disease (JAID), and Japanese Society of Clinical Microbiology (JSCM) continued this work in a second nationwide surveillance to investigate trends over time. In the second surveillance, methicillin-resistant Staphylococcus aureus (MRSA) and Klebsiella oxytoca were added to the other 6 species to investigate multidrug-resistant pathogens. 2. Materials and methods 2.1. Patients and participating facilities Among the patients with complicated UTI who visited any of the 42 medical institutions throughout Japan (Table 1) from January to September 2011, those who had clinical symptoms and who met the inclusion criteria were enrolled.

K. Ishikawa et al. / J Infect Chemother 21 (2015) 623e633 Table 1 The 42 cooperative medical institutions throughout Japan participated in the surveillance from January to September 2011. Department of Urology, Sapporo Medical University School of Medicine Department of Urology, Hokkaido Social Insurance Hospital Department of Urology, Takikawa Municipal Hospital Department of Urology, Oji General Hospital Department of Urology, Hokkaido Social Work Association Obihiro Hospital Department of Urology, The Jikei University Katsushika Medical Center Department of Urology, Fuji City General Hospital, Department of Urology, Fujita Health University School of Medicine Department of Urology, Minami medical health cooperation Department of Urology, Nagoya Ekisaikai Hospital Department of Urology, Graduate School of Medicine, Gifu University Department of Urology, Ogaki Municipal Hospital Department of Urology, Gifu Prefectural General Medical Center Department of Urology, Kizawa Memorial Hospital Department of Urology, Gifu Municipal Hospital Division of Urology, Kobe University Graduate School of Medicine Department of Urology, Japanese Red Cross Kobe Hospital Department of Urology, Yodogawa Christian Hospital Department of Urology, Shinko Hospital Department of Urology, Kobe City Medical Center West Hospital Department of Urology, Hyogo College of Medicine Department of Urology, Nishi Kobe Medical Center Department of Urology, Tenri Hospital Department of Urology, Osaka Red Cross Hospital Department of Urology, Shiga Medical Center for Adults Department of Urology, Kansai Electric Power Hospital Department of Urology, Nara Social Insurance Hospital Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Department of Urology, Okayama Citizens' Hospital Department of Urology, Japanese Red Cross Okayama Hospital Department of Urology, Mitoyo General Hospital Department of Urology, National Hospital Organization Iwakuni Clinical Center Department of Urology, Tottori Municipal Hospital Department of Urology, Graduate School of Biomedical Sciences, Hiroshima University Department of Urology, Hiroshima City Asa Hospital Department of Urology, National Hospital Organization Kure Medical Center and Chugoku Cancer Center Department of Urology, University of Occupational and Environmental Health Department of Urology, Munakata Suikokai General Hospital Department of Urology, Fukuoka Shin Mizumaki Hospital Department of Urology, Nara Social Insurance Hospital Department of Urology, Faculty of Medicine, University of Miyazaki Blood Purification Center, Kagoshima University Hospital Department of Urology, Kagoshima Prefectural Ohshima Hospital

The objective criteria for UTI were (a) bacterial count of 105 colony-forming units (CFU)/mL and (b) 10 white blood cells/ high-power field in midstream urine [2]. The following symptoms were also considered as clinical criteria for UTIs: fever, painful micturition, pollakisuria, residual urine sensation, urgency, voiding disorder, lower abdominal disorder, lower abdominal pain, and lumbar pain [3], and having underlying diseases is essential criteria for diagnosis of complicated UTIs. Bacteria defined as uropathogens met the aforementioned criteria and potentially caused uropathogenicity. The protocol was prepared by the working group and approved by the governing board of the Japanese surveillance committee, consisting of the JSC, JAID, and JSCM. Ethics approval was the responsibility of each facility. The facilities that did not have their own ethics committee submitted the study to that of the non-profit organization CREC Net, Kitakyushu, Japan, for review. All participating facilities obtained approval from an ethics committee. Participating clinicians obtained written consent of each patient. Data were recorded in the study database with patient information remaining anonymous and confidential.

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2.2. Bacteriological examination 2.2.1. Strains Urine samples were collected from patients with complicated UTI as midstream urine or via a catheter in accordance with the guidelines for clinical trials on genitourinary tract infections, version 1 [3]. Bacterial species were primarily identified at the local laboratory, suspended in preservation broth in Microbank® tubes (Asuka Junyaku, Tokyo, Japan) at 20  C, and sent to the Central Laboratory, Research Center for Anti-infective Drugs of Kitasato University. The microbiological data obtained were analyzed by clinical setting and patient profile. In total, 1036 strains were sent to the Central Laboratory and were stored at 80  C for future research. We investigated 997 evaluable strains (382 E. coli, 209 E. faecalis, 132 K. pneumoniae, 93 P. aeruginosa, 59 P. mirabilis, 55 MRSA, 41 K. oxytoca, and 26 S. marcescens). 2.2.2. Susceptibility testing and determination of minimal inhibitory concentration (MIC) The MICs of antimicrobial agents were determined by the microbroth dilution method according to the Clinical and Laboratory Standards Institute (CLSI) standards M7-A7 [4], M100-S22 [5], and M45-A [6] using a MIC2000 System (Eiken Chemical Co., Ltd. Tokyo, Japan). Briefly, Mueller-Hinton broth with an adjusted cation concentration (Ca2þ 25 mg/L, Mg2þ 12.5 mg/L; CA-MH broth) was used throughout. A 5 microL portion of test organism solution, grown to turbidity of McFarland number 0.5 and diluted 12-fold with saline was inoculated in the respective CA-MH broth to a final volume of 100 ± 20 microL. The final bacterial concentration was 5  104 CFU/ well (5  105 CFU/mL), and incubated at 35  C ± 2  C for 16e20 h. MICs were judged as the concentrations at which bacterial growth was completely inhibited and antibiotic susceptibility of each strain was categorized into 3 levels, namely susceptible, intermediate, or resistant, according to the MIC breakpoints recommended by CLSI standards M100-S22 [5]. 2.2.3. Quality control Accuracy of determination of the MIC of antimicrobial agents was achieved using the following control strains as recommended by the CLSI: S. aureus ATCC29213 for clinical isolates of S. aureus; E. faecalis ATCC29212 for those of E. faecalis; E. coli ATCC25922 for those of E. coli, K. pneumoniae, K. oxytoca, P. mirabilis, and S. marcescens; and E. coli ATCC25922 and P. aeruginosa ATCC27853 for those of P. aeruginosa. E. coli ATCC35218 was used as a control strain for the MIC determination of b-lactam antibiotics combined with b-lactamase inhibitors in all strains except S. aureus and E. faecalis. 2.2.4. Antimicrobial agents The antibiotic-impregnated microplates were purchased from Eiken Chemical. The bacterial strains were tested for susceptibility to the 42 antimicrobial agents (Table 2). 2.2.5. Detection of b-lactamase production To detect b-lactamase production in gram-negative bacteria, nitrocefin disks (Cefinase; Becton and Dickinson Company, Japan) were used according to the manufacturer's instructions. The CicaBeta Test (Kanto Chemical Co., Inc.) and the detection method of Clinical and Laboratory Standards Institute (CLSI) were used to detect extended-spectrum beta-lactamase (ESBL) and metallo-blactamase (MBL)-producing gram-negative bacteria by directly scraping the colony and applying it to the disk [7,8]. We had also

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Table 2 Antimicrobial agents (n ¼ 42) were used in susceptibility testing of bacterial strains isolated from patients with complicated urinary tract infection. Penicillins

Penicillins combined with b-lactamase inhibitors

Non-commercial penicillins available in Japan Oral cephalosporins

Parenteral cephalosporins

Cephamycin Oxacephem Carbapenems

Oral penem Monobactam Aminoglycosides

Fluoroquinolones

Tetracycline Glycopeptides Oxazolidinone Polypeptide Others

Ampicillin (ABPC) Piperacillin (PIPC) Pivmecillinam (Mecillinam) Clavulanic acid-amoxicillin (CVA/AMPC 1:2) Sulbactam-ampicillin (SBT/ABPC) Tazobactam-piperacillin-1 (TAZ/PIPC-1 1:4) Tazobactam-piperacillin-2 (TAZ/PIPC-2 1:8) Oxacillin (MPIPC) Cefaclor (CCL) Cefditoren (CDTR) Cefcapene (CFPN) Cefazolin (CEZ) Cefotiam (CTM) Ceftriaxone (CTRX) Ceftazidime (CAZ) Cefpirome (CPR) Cefepime (CFPM) Cefmetazole (CMZ) Flomoxef (FMOX) Imipenem (IPM) Panipenem (PAPM) Meropenem (MEPM) Biapenem (BIPM) Doripenem (DRPM) Faropenem (FRPM) Aztreonam (AZT) Gentamicin (GM) Isepamicin (ISP) Amikacin (AMK) Arbekacin (ABK) Ciprofloxacin (CPFX) Levofloxacin (LVFX) Tosufloxacin (TFLX) Sitafloxacin (STFX) Pazufloxacin (PZFX) Minocycline (MINO) Vancomycin (VCM) Teicoplanin (TEIC) Linezolid (LZD) Colistin (CL) Fosfomycin (FOM) Sulfamethoxazole-trimethoprim (ST) Nitrofurantoin (N-toin)

used added Double Disc Synergy Test to confirm the production of ESBLs. If we carry out genetic testing, the distinction of ESBL and K1-P-lactamase overproduction cannot be clearly distinguished. However, we distinguished the presents of ESBL and K1-P-lactamase overproduction in Cica-Beta Test, Double Disc Synergy Test, and antimicrobial susceptibility profile as simple methods. We also confirmed that ESBL-produced K. oxytoca is not a K1-b-lactamase overproduction strain. 3. Results 3.1. Description of patients We studied 997 evaluable bacterial strains isolated from patients diagnosed with UTIs complicating underlying diseases. Table 3 shows the clinical settings, profiles, background, and complicating underlying diseases of patients. In this study, we excluded the patients with urethral catheterization, nephrostomy, cystostomy, and urinary diversion using the intestinal tract. The mean age ± standard deviation was 73.3 ± 12.1 years for males and 69.5 ± 16.1 years for females, with patients aged >70 years

accounting for 65.9%; 54.4% of the patients were male. Among all patients, 160 (16%) were hospitalized with preexisting disease at the time of participation in the study. The proportion of hospitalized patients for each pathogen was: MRSA, 25.5%; E. faecalis, 19.6%; E. coli, 13.6%; K. pneumoniae, 9.8%; K. oxytoca, 10%; P. mirabilis, 11.9%; S. marcescens, 7.7%; and P. aeruginosa, 29%. 3.2. Causative bacteria Table 4 summarizes the antimicrobial potency and spectrum for the 42 selected antimicrobial agents against the 8 most frequent complicated UTI pathogens. We investigated 997 evaluable strains (382 E. coli, 209 E. faecalis, 132 K. pneumoniae, 93 P. aeruginosa, 59 P. mirabilis, 55 MRSA, 41 K. oxytoca, and 26 S. marcescens). 3.2.1. Antimicrobial susceptibility of MRSA Strains with MICs for VCM of 2 mg/mL accounted for a small proportion, 5.5% (3 of 55 strains), and strains with MICs for TEIC of 8 mg/mL accounted for 1.8% (1/55 strains). Takesue et al. demonstrated that the efficacy of glycopeptides as 1st line therapy in patients infected with 2 mg/ml strains was significantly lower than that for patients infected with 1 mg/ml strains (30.0 vs. 78.8%, p < 0.001) in bacteremia and the mortality was 65.8% in patients with 2 mg/ml strains and 19.5% in patients with 1 mg/ml strains (p < 0.001) [9]. Although some of the meta-analysis are scattered about the clinical effectiveness of strains of high vancomycin MIC, the evaluation is controversial, yet [10e12]. Furthermore, many of these studies compared several characteristics of VCM MIC S2 mg/mL strains isolated from bacteremia. Unfortunately, sufficient evaluation regarding the clinical efficacy of VCM against urinary tract infection is not performed. However, pyelonephritis is an infectious disease to merge bacteremia in more than 30% [13]. If you encounter the severe pyelonephritis that strains of VCM MIC S 2 mg/mL has been detected, you should decide to change or continue VCM therapy in according to look at the clinical response carefully. However, no strains were resistant to VCM, TEIC, and LZD. Only 1 strain with a MIC of 16 mg/mL was resistant to ABK. MINO was relatively inactive against MRSA and the susceptibility rate was only 36.4%. 3.2.2. Antimicrobial susceptibility of E. faecalis The MIC90 of ABPC against 209 E. faecalis strains was 2 mg/mL and all strains were susceptible. PIPC and TAZ/PIPC were relatively active and the MIC90 was 8 mg/mL. Four times as many strains were susceptible to IPM and PAPM as to MEPM, BIPM, and DRPM. The MIC90 of CPFX and LVFX were 32 and 64 mg/mL, respectively and the proportion of strains susceptible were 55.0% and 78.9%, respectively. Among the fluoroquinolones (FQs), STFX had the most activity with a MIC90 of only 2 mg/mL. The MIC cumulative curves of FQs had 2 peaks, demonstrating that E. faecalis had strains that were susceptible to FQs and others that were resistant. No VCMresistant strains (VRE) were detected. 3.2.3. Antimicrobial susceptibility of E. coli E. coli was the most common species among the evaluable strains. The proportions of strains susceptible to ABPC and PIPC were 57.3% and 62.3%, respectively, while the proportions for the penicillins (PCs) with b-lactamase inhibitors (BLI) CVA/AMPC and SBT/ABPC were 83% and 76.7%, respectively. The proportions of strains with MIC 8 mg/mL for the 3 oral cephalosporins (CEPs) CCL, CDTR, and CFPN, which might be expected to be relatively active, were 78.5%, 82.5%, and 84.8%, respectively. More than 10% of strains were resistant to oral CEPs. The proportion of strains susceptible to the parenteral CEPs CEZ, CTRX, CAZ, and CFPM were 66.8%, 82.5%, 90.8%, and 93.7%, respectively. The antimicrobial susceptibility

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Table 3 The clinical settings, profiles, background, and complicating underlying diseases of patients.

1. No. of strains No. of strains enrolled No. of strains evaluated 2. Gender Male Female Unknown Total 3. Age (years) 20e29 30e39 40e49 50e59 60e69 70e79 80 Total 4. Outpatients/inpatients Outpatients Inpatients Total 5. Underlying diseases Neurogenic bladder Benign prostatic hyperplasia Bladder cancer Prostate cancer Ureteral stone Renal stone Hydronephrosis Ureteral stenosis Disorder of the bladder Vesical stone Malignancy Disorder of the urethra Disorder of the ureter Disorder of the kidney Others Unknown Total

MRSA

E. faecalis

E. coli

K. pneumoniae

K. oxytoca

P. mirabilis

S. marcescens

P. aeruginosa

Total

58 55

216 209

390 382

140 132

42 41

60 59

28 26

102 93

1036 997

43 12

149 230 3 382

58 71 3 132

25 16

21 38

24 2

67 26

55

155 52 2 209

41

59

26

93

542 447 8 997

1 3 1 7 30 13 55

1 4 6 15 35 77 71 209

12 12 12 34 70 121 121 382

1 4 6 8 24 52 37 132

1 2 3 1 7 18 9 41

1 1 2 6 12 20 17 59

1 1 2 4 6 7 5 26

2 1 3 12 16 29 30 93

19 26 37 81 177 354 303 997

41 14 55

168 41 209

330 52 382

119 13 132

37 4 41

52 7 59

24 2 26

66 27 93

837 160 997

22 16 6 3 5 3 5 5

45 72 30 25 14 10 12 14 6 5 4 4 3

186 65 40 22 29 22 24 12 13 2 1 1 1 2 1 20 441

71 34 10 5 4 6 2 4 9 1 2 3 2 1 1 3 158

23 15 1 2

27 10 5 1 7 7 2 2 3 2 1

13 8 1 4 2 1

30 29 9 7 4 10 4 8 2 2 3 2 2 1 1 6 120

417 249 102 69 65 60 52 46 36 14 13 11 8 5 5 40 1192

2

1 2 70

4 248

rate was increased in proportion to their generation, e.g., second generation drugs were more effective than first generation drugs. The carbapenems (CBPs) showed the strongest antimicrobial activity, with MIC90 of 0.06e0.125 mg/mL. As for the aminoglycosides (AGs), GM and AMK had a MIC90 of 2 and 8 mg/mL, respectively and the proportion of susceptible strains was 92.9% and 100%, respectively. For FQs, the susceptible rates for CPFX and LVFX were 67.8% and 68.6%, respectively. However, the MIC90 of STFX was only 2 mg/mL and the proportion of strains with MIC 1 mg/mL, which might indicate relatively high activity, was 86.4%. The MIC cumulative curves showed 2 peaks and the pattern was similar to that of E. faecalis. We found 58 ESBL-producing strains (15.2%) among the E. coli strains, and the proportion increased with time. 3.2.4. Antimicrobial susceptibility of K. pneumoniae All of the 132 K. pneumoniae strains were susceptible to 18 antibacterial agents, with susceptibility rates of >90% except for PIPC. We detected 6 ESBL producing stains. 3.2.5. Antimicrobial susceptibility of K. oxytoca The proportion of strains susceptible to PCs with BLI was nearly 80%. CEZ was inactive and the proportion of susceptible strains was 90% of strains showing susceptibility. One (2.4%) of the 41 strains produced ESBL.

1 3 1 3

2

1 1

50

4 72

1 1 33

3.2.6. Antimicrobial susceptibility of P. mirabilis The MIC90 of ABPC against the 59 P. mirabilis strains were >256 mg/mL, but 84.7% of strains were susceptible. As expected, PCs with BLI were effective. P. mirabilis was relatively susceptible to many other antimicrobial agents except CEZ and MINO. The proportion of susceptible strains for CEZ and MINO were 55.9% and 1.7%, respectively. The CLSI breakpoint for IPM was a MIC of 2 mg/mL and 32 (54.2%) of 59 strains were under this MIC level. Therefore, although the proportion of strains susceptible to IPM was only 28.8%, the MIC90 was 4 mg/mL. MEPM and DRPM showed strong activity with MIC90 of 0.125e0.5 mg/mL and there were some differences in the MIC cumulative curves among these 3 CBPs. The MIC90 of the 3 FQs was 1e4 mg/mL and the FQ-resistant rates were about 10%. Four (6.8%) of 59 P. mirabilis strains were suspected of producing ESBL. 3.2.7. Antimicrobial susceptibility of S. marcescens Analysis of the susceptibility of 26 S. marcescens to 14 antimicrobial agents demonstrated that the proportion of strains susceptible to PCs, CEPs, CBPs, AGs, FQs, AZT, and FOM ranged from 80% to 100%. MINO was relatively active. No strain was identified as ESBL-producing or multidrugeresistant. 3.2.8. Antimicrobial susceptibility of P. aeruginosa More than 10% of the 93 P. aeruginosa strains were resistant to PIPC and CAZ. The proportion of strains susceptible to the 4th generation CEP CFPM was 77.4%. Among the CBPs, more strains

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Table 4 The MIC50, MIC90, range of MICs for antimicrobial agents, and antimicrobial susceptibility patterns of eight most frequent complicated UTI pathogens. Antibacterial agent

1. MRSA n ¼ 55 MPIPC ABK MINO VCM TEIC LZD ST 2. Enterococcus faecalis n ¼ 209 ABPC SBT/ABPC PIPC TAZ/PIPC-1 TAZ/PIPC-2 CPR IPM PAPM MEPM BIPM DRPM FRPM CPFX LVFX TFLX STFX PZFX MINO VCM TEIC LZD ST 3. Escherichia coli n ¼ 382 ABPC CVA/AMPC SBT/ABPC PIPC TAZ/PIPC-1 TAZ/PIPC-2 PMPC CCL CDTR CFPN CEZ CMZ CTM FMOX CTRX CAZ CPR CFPM IPM PAPM MEPM BIPM DRPM FRPM GM ISP AMK ABK CPFX LVFX TFLX STFX PZFX MINO AZT FOM ST CL

MIC(mg/mL)

%

50%

90%

Range

Susceptible

256 1 16 1 0.5 2 0.06

256 2 16 1 2 2 0.125

4 0.125 0.125 0.5 0.25 0.5 0.03

e e e e e e e

256 16 16 2 8 2 0.25

1 1 4 4 4 16 1 1 4 4 2 1 1 2 0.5 0.125 2 8 1 0.25 2 0.125

2 2 8 8 8 64 2 2 8 8 8 4 32 64 32 2 128 16 2 0.5 2 16

0.5 0.25 1 1 1 1 0.25 0.25 1 0.25 0.5 0.5 0.5 1 0.125 0.06 1 0.06 0.5 0.125 0.5 0.015

e e e e e e e e e e e e e e e e e e e e e e

8 4 16 16 16 256 8 8 16 16 16 16 128 128 32 4 256 32 2 0.5 2 16

4 4 4 2 2 2 0.25 1 0.25 0.5 2 1 0.125 0.06 0.06 0.25 0.125 0.06 0.125 0.125 0.06 0.06 0.06 0.5 1 1 2 1 0.06 0.25 0.06 0.06 0.06 1 0.06 1 0.125 0.25

256 16 32 256 4 16 4 256 128 32 256 4 64 0.25 64 4 32 8 0.25 0.25 0.06 0.06 0.06 1 2 4 8 2 64 16 32 2 16 4 8 8 16 0.5

0.25 0.5 0.25 0.125 0.25 0.25 0.06 0.125 0.06 0.06 0.5 0.125 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.125 0.25 0.5 1 0.5 0.06 0.06 0.06 0.06 0.06 0.25 0.06 0.25 0.03 0.125

e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e

256 64 256 256 256 128 256 256 128 256 256 64 256 64 256 32 256 256 1 1 0.125 1 0.125 8 256 8 16 16 128 256 32 8 128 128 256 256 16 8

Intermediate

Resistant

100 36.4 100 100 100 100

10.9

52.7

55.0 78.9

26.8 3.3

18.2 17.7

33.5 100 100 100

33.0

33.5

57.3 83.0 76.7 62.3 97.9

0 10.5 11.5 2.1 0.8

42.7 6.5 11.8 35.6 1.3

95.0 78.5

1.3 0.8

3.7 20.7

66.8 98.2

6.8 1.0

26.4 0.8

82.5 90.8

0.5 4.2

17.0 5.0

93.7 100

2.1

4.2

0.3

6.8

67.8 68.6

0.8 1.8

31.4 29.6

91.1 88.0 98.4 80.9

3.7 4.7 1.0

5.2 7.3 0.5 19.1

100

100 100 92.9 100

K. Ishikawa et al. / J Infect Chemother 21 (2015) 623e633

629

Table 4 (continued ) Antibacterial agent

MIC(mg/mL) 50%

N-toin 4. Klebsiella pneumoniae n ¼ 132 CVA/AMPC SBT/ABPC PIPC TAZ/PIPC-1 TAZ/PIPC-2 CCL CDTR CFPN CEZ CMZ CTM FMOX CTRX CAZ CPR CFPM IPM PAPM MEPM BIPM DRPM FRPM GM ISP AMK ABK CPFX LVFX TFLX STFX PZFX MINO AZT ST CL 5. Klebsiella oxytoca n ¼ 41 CVA/AMPC SBT/ABPC PIPC TAZ/PIPC-1 TAZ/PIPC-2 CCL CDTR CFPN CEZ CMZ CTM FMOX CTRX CAZ CPR CFPM IPM PAPM MEPM BIPM DRPM FRPM GM ISP AMK ABK CPFX LVFX TFLX STFX PZFX MINO AZT

% 90%

8

16

Range

Susceptible

Intermediate

Resistant

0.25

e

64

99.7

0.3

0

95.5 92.4 88.6 97.7

3.0 2.3 0.8 0

1.5 5.3 10.6 2.3

93.9

0

6.1

90.9 100

3.0

6.1

95.5 97.0

0 0.8

4.5 2.3

97.7 100

1.5

0.8

0.8

0.8

91.7 93.9

2.3 3.0

6.1 3.0

89.4 96.2 90.9

3.8 0.8

6.8 3.0 9.1

87.8 78.0 80.5 87.8

0 9.8 4.9 2.4

12.2 12.2 14.6 9.8

85.4

0

14.6

24.4 97.6

22.0 0

53.7 2.4

87.8 97.6

0 2.4

12.2 0

100 97.6

2.4

0

92.7 92.7

0 2.4

7.3 4.9

92.7 87.8

2.4 0

4.9 12.2

2 4 4 2 2 0.5 0.25 0.5 1 0.5 0.125 0.06 0.06 0.125 0.06 0.06 0.125 0.125 0.06 0.125 0.06 0.5 0.5 0.5 1 0.5 0.06 0.25 0.06 0.06 0.06 2 0.06 0.125 0.25

4 8 128 4 8 1 0.5 1 2 2 0.5 0.125 0.125 0.5 0.25 0.25 0.5 0.25 0.06 0.5 0.06 1 0.5 1 2 1 0.5 1 0.5 0.25 0.25 8 0.125 2 1

0.5 1 0.06 0.06 0.125 0.06 0.06 0.06 0.25 0.25 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.25 0.125 0.125 0.25 0.25 0.06 0.06 0.06 0.06 0.06 1 0.06 0.03 0.125

e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e

32 256 256 256 256 256 128 256 256 16 256 1 256 128 256 64 1 0.5 0.125 1 0.125 8 64 2 4 2 128 64 32 32 64 128 256 16 64

4 4 8 2 4 0.5 0.25 0.5 8 0.5 0.25 0.06 0.125 0.125 0.06 0.06 0.125 0.125 0.06 0.125 0.06 0.5 0.5 1 2 1 0.06 0.125 0.06 0.06 0.06 1 0.125

32 64 256 64 128 256 2 2 256 2 32 0.06 4 0.5 4 2 0.25 0.5 0.06 0.5 0.06 2 0.5 1 2 1 0.125 0.25 0.06 0.06 0.125 4 16

1 0.5 1 0.5 1 0.25 0.06 0.125 0.5 0.25 0.125 0.06 0.06 0.06 0.06 0.06 0.06 0.125 0.06 0.06 0.06 0.25 0.25 0.5 1 0.5 0.06 0.06 0.06 0.06 0.06 1 0.06

e e e e e e e e e e e e e e e e e e

64 256 256 256 256 256 128 16 256 128 256 0.5 32 8 16 8 2 2

e e e e e e e e e e e e e e

0.5 0.125 8 2 4 4 2 16 16 32 2 4 256 128

100 100 98.5 100

100 100 100 100

(continued on next page)

630

K. Ishikawa et al. / J Infect Chemother 21 (2015) 623e633

Table 4 (continued ) Antibacterial agent

MIC(mg/mL) 50%

ST CL 6. Proteus mirabilis n ¼ 59 ABPC CVA/AMPC SBT/ABPC PIPC TAZ/PIPC-1 TAZ/PIPC-2 CCL CDTR CFPN CEZ CMZ CTM FMOX CTRX CAZ CPR CFPM IPM PAPM MEPM BIPM DRPM FRPM GM ISP AMK ABK CPFX LVFX TFLX STFX PZFX MINO AZT FOM ST CL 7. Serratia marcescens n ¼ 26 PIPC TAZ/PIPC-1 TAZ/PIPC-2 CDTR CFPN CMZ CTM FMOX CTRX CAZ CPR CFPM IPM PAPM MEPM BIPM DRPM FRPM GM ISP AMK ABK CPFX LVFX TFLX STFX PZFX MINO AZT FOM CL

% 90%

0.125 0.25

Range 0.25 0.5

Susceptible

0.015 0.125

e e

16 1

92.7

84.7 93.2 93.2 89.8 100

1 1 1 0.25 0.25 0.25 1 0.06 0.06 2 2 0.25 0.25 0.06 0.06 0.125 0.125 2 1 0.06 2 0.25 2 1 4 4 2 0.06 0.25 0.25 0.06 0.06 16 0.06 4 0.25 64

256 8 8 128 1 4 256 32 2 256 4 64 0.5 0.5 0.5 1 1 4 2 0.125 4 0.5 4 2 8 16 4 4 4 32 1 1 32 0.125 128 4 64

0.25 0.25 0.25 0.06 0.06 0.125 0.125 0.06 0.06 0.5 1 0.125 0.125 0.06 0.06 0.06 0.06 0.125 0.06 0.06 0.06 0.06 0.25 0.5 2 1 1 0.06 0.06 0.06 0.06 0.06 4 0.06 0.5 0.004

e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e

256 64 32 256 2 32 256 128 128 256 8 256 32 256 4 256 256 8 4 0.25 4 2 8 64 16 16 8 128 128 32 8 64 128 256 256 16 64

2 2 4 2 2 8 256 2 0.5 0.5 0.25 0.25 0.5 0.5 0.06 1 0.125 8 0.5 2 2 2 0.125 0.5 0.25 0.125 0.125 4 0.125 8 64

64 64 64 128 16 64 256 32 16 2 1 2 1 1 0.125 1 0.25 32 1 4 4 4 4 4 8 1 1 16 4 64 64

1 1 1 0.5 0.5 4 4 0.25 0.125 0.125 0.125 0.06 0.25 0.25 0.06 0.125 0.06 2 0.125 0.25 0.5 0.25 0.06 0.06 0.06 0.06 0.06 1 0.06 2 1

e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e

256 256 128 128 32 128 256 32 32 8 2 8 4 2 0.25 2 0.5 64 2 4 8 4 32 32 16 4 32 32 8 256 64

Intermediate

Resistant 7.3

0 1.7 3.4 0

15.3 5.1 3.4 10.2

88.1

0

11.9

55.9 100

30.5

13.6

93.2 100

0

6.8

93.2 28.8

0 54.2

6.8 16.9

98.3

1.7

0

96.6

0

3.4

100

100 81.4 88.1

6.8 3.4

11.9 8.5

1.7 96.6

13.6 0

84.7 3.4

86.4

13.6

84.6 88.5

7.7 7.7

7.7 3.8

61.5

23.1

15.4

76.9 96.2

3.8 3.8

19.2 0

100 92.3

3.8

3.8

76.9 88.5

11.5 7.7

11.5 3.8

61.5 96.2

26.9 3.8

11.5 0

100 100 100 100

K. Ishikawa et al. / J Infect Chemother 21 (2015) 623e633

631

Table 4 (continued ) Antibacterial agent

MIC(mg/mL) 50%

8. Pseudomonas aeruginosa n ¼ 93 PIPC TAZ/PIPC-1 TAZ/PIPC-2 CTRX CAZ CPR CFPM IPM PAPM MEPM BIPM DRPM GM ISP AMK ABK CPFX LVFX TFLX STFX PZFX MINO AZT FOM CL

8 8 8 128 4 8 4 1 8 0.5 0.5 0.5 2 4 4 2 0.25 2 0.5 0.25 0.5 16 8 64 0.5

% 90%

Range

256 128 128 256 32 64 16 16 32 8 8 4 4 8 8 4 16 32 32 4 16 64 32 256 1

0.5 0.25 0.5 4 1 0.5 0.5 0.5 1 0.06 0.25 0.06 0.125 0.5 0.5 0.25 0.06 0.25 0.06 0.06 0.06 1 0.25 4 0.125

were susceptible to DRPM compared to the other 2 CBPs. Two AGs, GM and AMK, were active, with >90% of strains showing susceptibility. More than 20% of strains were resistant to the CPFX and LVFX. The numbers of resistant strains to IPM, AMK, and CPFX were 20, 4, and 19, respectively. Four (4.3%) of 93 strains were found to be multidrug-resistant (MDRP), to these 3 antimicrobial agents. The four strains had been collected from 3 different facilities. So we have determined that MDRP had not integrated by facilities. Five MBL-producing strains were detected. 4. Discussion Complicated UTI is a common infectious disease, particularly among the elderly, both male and female. However, we sometimes encounter refractory cases of complicated UTIs. To select the correct antimicrobial agents, it is important to determine the causative bacteria and confirm its drug susceptibilities. Unfortunately, many physicians prescribe medication immediately before drug sensitivity can be assessed. To obtain a high cure rate, we need to know the most recent information on the drug sensitivity profiles of causative bacteria. To investigate antimicrobial susceptibility patterns of various bacterial pathogens isolated from complicated UTI and the emergence of antimicrobial resistance among them, the JSC, JAID, and JSCM conducted the second nationwide surveillance in 2011. For MRSA cases, the trend of an increasing number of strains with low susceptibility to anti-MRSA agents is a problem in clinical practice. The recent MIC creep is of concern and strains with MIC values for VCM of 2 mg/mL are sometimes found. However, the proportion of MRSA strains isolated from urine with MICs for VCM of 2 mg/mL was low in this study. When MRSA is detected in clinical specimens, the distinction between infection and colonization is often difficult. Careful judgment is necessary to decide whether to administer an anti-MRSA agent when MRSA is isolated from urine; we must aim to decrease the incidence of resistant strains.

Susceptible

e e e e e e e e e e e e e e e e e e e e e e e e e

256 256 256 256 128 256 256 128 256 256 256 128 256 256 128 32 128 256 32 32 256 256 256 256 1

Intermediate

Resistant

80.6 80.6

6.5 7.5

12.9 11.8

83.9

3.2

12.9

77.4 73.1

12.9 5.4

9.7 21.5

81.7

4.3

14.0

86.0 90.3

4.3 1.1

9.7 8.6

95.7

0

4.3

74.2 65.6

5.4 11.8

20.4 22.6

63.4

15.1

21.5

100

For E. faecalis, ABPC is currently the first-line drug; we did not find strains resistant to ABPC. We did not detect VRE, and there were strains with low susceptibility to other anti-MRSA drugs. Eleven strains (7.8%) with MIC of 4 mg/mL for LZD, which showed an intermediate resistance to LZD, were detected in the previous surveillance period [1]. In Japan, enterococci tolerance to antiMRSA drugs does not appear to have increased. Additionally, Khair et al. proposed that VCM resistance had no influence on the outcome of enterococcal bacteriuria [14] and the clinical significance of UTIs caused by VRE has been questioned. Since the proportion of strains of E. coli susceptible to PCs reduced to about 60%, it would be difficult to expect good clinical results using these drugs. The rationale of selecting PCs with blactamase inhibitors as recommended by the guidelines in complicated UTI has been demonstrated in this study [15e17]. Because at least 10% of strains were resistant to oral cephalosporin, we should choose these drugs carefully due to the detection of resistant strains in outpatients. The increase in the proportion of FQ-resistant E. coli strains has been viewed as a clinical problem for several decades. The results of recent surveillance data demonstrated that the proportion of strains not susceptible to FQs isolated from patients with complicated UTIs was 29.3% in 2008 [1] and 32.0% in this study. The proportion among patients with acute uncomplicated cystitis was 12.3% [18]. We observed regional differences in the proportion of FQ-resistant strains in our data (data not shown). Various risk factors for resistant strains are described [19e23]; however, it is important to know the resistant rate of the host facility to use an appropriate drug. We found some reports of excellent antimicrobial susceptibility of STFX [18,24,25] and it is expected us to the clinical efficacy of STFX against FQ-resistant strains. Matsumoto et al. studied the mechanism [26], but cross-resistance of FQs might contribute to antimicrobial resistance to STFX. In 2011, 58 (15.2%) of 382 strains were ESBL-producers; this value is higher than that in our previous surveillance [1]. In Taiwan, ESBL-producing strains identified in community-onset UTIs have

632

K. Ishikawa et al. / J Infect Chemother 21 (2015) 623e633

increased. It was reported that 13.5% of uropathogenic Enterobacteriaceae were phenotypically positive for ESBL production [27]. The researchers demonstrated that nasogastric tube placement and hospitalization within the previous 3 months were independently associated with the acquisition of ESBL-producing pathogens in community-onset UTIs. So we speculate that intestinal bacteria in patients with these risk factors are easy to substitute for ESBL-producing strains. We need to be careful for intestinal bacteria in these patients. For K. pneumoniae, susceptibility to most antibiotics was maintained, a result similar to that of the SMART study [28]. We detected 6 ESBL-producing stains. Another study in Japan also reported an increase in their detection [29]. In general, this is a species that easily becomes an infection control problem in hospitals and, thus, it is necessary to continue surveillance. In respiratory tract infections, the emergence and rapid spread of CBP-resistant Klebsiella spp. (CRK) strains has become a problem. In a multivariate analysis, prior use of IPM, ICU stay, and receiving H2 receptor antagonist were independently associated with CBP resistance [30]. Strains highly resistant to other antibiotics, except for CL and tigecycline, limit therapeutic options and can lead to increased mortality. In UTIs, emergence of CRK strains may occur in the near future. For UTIs, the prevalence of MDR-bacterial isolates has increased in the last few years, affecting the prognosis and survival of hospitalized patients. Cohen-Nahum et al. observed that prior TAZ/ PIPC and empirical CBP use were independent risk factors for infection with MDR-strains. All MDR P. mirabilis urinary isolates at their institution were ESBL-producers [31]. Only 4 (6.8%) of 59 P. mirabilis strains were suspected of producing ESBL in our study. P. aeruginosa has a tendency to exhibit resistance to various antibiotics and has been a problem in the clinical setting as an opportunistic infection. Currently, a small percentage of clinical isolates of P. aeruginosa have acquired resistance to AMK. On the other hand, they have acquired resistance to CBPs such as IPM and the resistance rate has increased to about 20%. The SMART study demonstrated that IPM resistance ranges from 20% to 40% in various regions of the world [28]. Additionally, P. aeruginosa has commonly acquired resistance to FQs, with about 20% of strains showing resistance [32]. The resistance of P. aeruginosa to FQs has significantly increased over time in North America from 22% in 2005 to 33% in 2010 [28]. The relative susceptibilities of antimicrobial agents are inconsistent among different regions of the world. Our surveillance data demonstrated that the proportion P. aeruginosa strains resistant to IPM, AMK and CPFX were 22.5%, 4.3%, and 20.4%, respectively and the results were almost identical to those in the Infectious Disease Weekly Report [32]. 5. Conclusions Surveillance data of current antimicrobial agents are essential for optimal management of UTI patients. Results of our second nationwide surveillance did not differ significantly from those of the first, conducted 3 years earlier. However, in terms of treatment, it is important to verify that there is no change in antimicrobial susceptibility of uropathogenic microorganisms; it may confirm that no major changes in the use of antibiotics are needed at this time. These data will be a useful reference for future periodic surveillance studies, as well as for studies to control antimicrobialresistant pathogens. Conflict of interests Mitsuru Yasuda has received donation from Astellas Pharma Inc. Jun-ichi Kadota has received speaker’s honorarium from Taisho Toyama Pharmaceutical Co., Ltd., Pfizer Japan Inc., MSD K.K., Kyorin

Pharmaceutical Co.,Ltd., Daiichi Sankyo Co., Ltd., Glaxo SmithKline K.K., payments for a manuscript drafting and editing from Nankodo Co., Ltd. and donation from Astellas Pharma Inc. Satoshi Iwata has received speaker's honorarium from Astellas Pharma Inc., Pfizer Japan Inc., Taisho Toyama Pharmaceutical Co., Ltd., MSD K.K., Meiji Seika Pharma Co., Ltd., Daiichi Sankyo Co., Ltd. and Japan Vaccine Co., Ltd., donation from Taisho Toyama Pharmaceutical Co., Ltd. and supported, in part, by a fund from Nikon Corporation. Mitsuo Kaku has received speaker's honorarium from Taisho Toyama Pharmaceutical Co., Ltd., Shionogi & Co., Ltd., Pfizer Japan Inc. and Sumitomo Dainippon Pharma Co., Ltd. and donation from Astellas Pharma Inc. Akira Watanabe has received speaker's honorarium from MSD K.K., Glaxo SmithKline K.K., Shionogi & Co., Ltd., Daiichi Sankyo Co.,Ltd., Taisho Toyama Pharmaceutical Co., Ltd. and Pfizer Japan Inc.; grant support from Kyorin Pharmaceutical Co., Ltd., Shionogi & Co.,Ltd., Taisho Pharmaceutical Co.,Ltd., Toyama Chemical Co., Ltd., Daiichi Sankyo Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Taiho Pharmaceutical Co.,Ltd. and Meiji Seika Pharma Co., Ltd. Keisuke Sunakawa has received speaker's honorarium from Taisho Toyama Pharmaceutical Co., Ltd., Toyama Chemical Co., Ltd. and Meiji Seika Pharma Co., Ltd. Hideaki Hanaki is a member of a laboratory endowed chair from Kohjin Bio Co., Ltd. Taiji Tsukamoto has received speaker's honorarium from Astellas Pharma Inc., and payments for a manuscript drafting and editing from RichHill Medical Inc. Shin Egawa has received donation from Takeda Pharmaceutical Co., Ltd., Astellas Pharma Inc., Asahi Kasei Corp. and Euro Meditech Co., Ltd. Takashi Deguchi has received donation from Astellas Pharma Inc. Soichi Arakawa has received speaker's honorarium from Taisho Toyama Pharmaceutical Co., Ltd.

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Japanese nationwide surveillance in 2011 of antibacterial susceptibility patterns of clinical isolates from complicated urinary tract infection cases.

To investigate antimicrobial susceptibility patterns of various bacterial pathogens isolated from complicated urinary tract infection (UTI) cases, the...
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