Ceftazidime-Avibactam and Comparator Agents Tested Against Urinary Tract Isolates from a Global Surveillance Program (2011) R.K. Flamm, H.S. Sader, R.N. Jones JMI Laboratories, North Liberty, Iowa, USA Selected References Bush K (2008). Extended-spectrum beta-lactamases in North America, 1987-2006. Clin Microbiol Infect 14 Suppl 1: 134-143. Clinical and Laboratory Standards Institute (2012). M07-A9. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically; approved standard: ninth edition. Wayne, PA: CLSI. Clinical and Laboratory Standards Institute (2013). M100-S23. Performance standards for antimicrobial susceptibility testing: 23rd informational supplement. Wayne, PA: CLSI. Ehmann DE, Jahic H, Ross PL, Gu RF, Hu J, Kern G, Walkup GK, Fisher SL (2012). Avibactam is a covalent, reversible, non-β-lactam β-lactamase inhibitor. Proc Natl Acad Sci USA 109: 11663-11668. European Committee on Antimicrobial Susceptibility Testing (2013). Breakpoint tables for interpretation of MICs and zone diameters. Version 3.0, January 2013. Available at: http://www.eucast.org/clinical_ breakpoints/. Accessed January 1, 2013. Foxman B (2010). The epidemiology of urinary tract infection. Nat Rev Urol 7: 653-660. Gupta K, Hooton TM, Naber KG, Wullt B, Colgan R, Miller LG, Moran GJ, Nicolle LE, Raz R, Schaeffer AJ, Soper DE (2011). International clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women: A 2010 update by the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases. Clin Infect Dis 52: e103-e120. Gupta N, Limbago BM, Patel JB, Kallen AJ (2011). Carbapenem-resistant Enterobacteriaceae: epidemiology and prevention. Clin Infect Dis 53: 60-67. Hooton TM, Bradley SF, Cardenas DD, Colgan R, Geerlings SE, Rice JC, Saint S, Schaeffer AJ, Tambayh PA, Tenke P, Nicolle LE, Infectious Diseases Society of A (2010). Diagnosis, prevention, and treatment of catheter-associated urinary tract infection in adults: 2009 International Clinical Practice Guidelines from the Infectious Diseases Society of America. Clin Infect Dis 50: 625-663. Livermore DM, Mushtaq S, Warner M, Miossec C, Woodford N (2008). NXL104 combinations versus Enterobacteriaceae with CTX-M extended-spectrum β-lactamases and carbapenemases. J Antimicrob Chemother 62: 1053-1056. Livermore DM, Mushtaq S, Warner M, Zhang J, Maharjan S, Doumith M, Woodford N (2011). Activities of NXL104 combinations with ceftazidime and aztreonam against carbapenemase-producing Enterobacteriaceae. Antimicrob Agents Chemother 55: 390-394. Mushtaq S, Warner M, Livermore DM (2010). In vitro activity of ceftazidime+NXL104 against Pseudomonas aeruginosa and other non-fermenters. J Antimicrob Chemother 65: 2376-2381. Vazquez JA, Gonzalez Patzan LD, Stricklin D, Duttaroy DD, Kreidly Z, Lipka J, Sable C (2012). Efficacy and safety of ceftazidime-avibactam versus imipenem-cilastatin in the treatment of complicated urinary tract infections, including acute pyelonephritis, in hospitalized adults: results of a prospective, investigator-blinded, randomized study. Curr Med Res Opin 28: 1921-1931. Yong D, Toleman MA, Giske CG, Cho HS, Sundman K, Lee K, Walsh TR (2009). Characterization of a new metallo-beta-lactamase gene, bla NDM-1 , and a novel erythromycin esterase gene carried on a unique genetic structure in Klebsiella pneumoniae sequence type 14 from India. Antimicrob Agents Chemother 53: 5046-5054. C2-1631 Introduction Urinary tract infections are common in both the community and hospital settings. Increased morbidity and mortality may occur in complicated urinary tract infections (cUTIs), thus making the selection of appropriate initial therapy extremely important. Wide variation exists in the choice of antimicrobial agents and duration of treatment for cUTIs. These treatment differences occur due to concerns about bacterial resistance among uropathogens, drug availability and cost, expected efficacy and a desire to limit the effect of the antimicrobial on normal bacterial flora. Ceftazidime-avibactam is a combination agent consisting of the non-β-lactam β-lactamase inhibitor avibactam and the cephalosporin ceftazidime. Ceftazidime-avibactam administered at 500 mg of ceftazidime and 125 mg of avibactam every 8 hours was shown to have efficacy and safety similar to imipenem-cilastatin (500 mg every 6 hours) in a Phase II study of cUTI (Vazquez et al 2012). A favorable microbiologic outcome of 70.4% in the microbiologically evaluable population was shown for ceftazidime-avibactam compared to 71.4% for imipenem-cilastatin. Escherichia coli was the predominant uropathogen recovered from amongst these patients. In an effort to evaluate the activity of ceftazidime-avibactam against uropathogens on a global scale, the present study evaluated the activity of ceftazidime-avibactam and comparator agents against a contemporary collection of UTI isolates from the USA, Europe and Mediterranean region (EMR), Latin America (LATAM), and the Asia-Pacific and South Africa (APAC) regions. Robert K. Flamm, PhD JMI Laboratories 345 Beaver Kreek Ctr, Ste A North Liberty, Iowa, 52317, USA Phone: 319-665-3370 Fax: 319-665-3371 Email: robert-flamm@jmilabs.com Amended Abstract Background: Ongoing Phase III clinical trials for ceftazidime- avibactam (CAZ-AVI) include complicated urinary tract infection (UTI) and intra-abdominal infections. In this study, we report results of in vitro testing of CAZ-AVI and comparator agents against a contemporary collection of UTI isolates from the USA, Europe and Mediterranean region (EMR), Latin America (LATAM), and the Asia-Pacific and South Africa (APAC) regions. Methods: Clinical isolates (one per patient) were collected from hospitalized patients with a UTI during 2011. A total of 1,797 isolates were collected from 159 medical centers (no. of medical centers [no. of isolates]): 67 (821), USA; 46 (610), EMR; 16 (183), LATAM; and 30 (183), APAC. Isolates were processed at the medical centers and forwarded to a central laboratory (JMI Laboratories, North Liberty, Iowa, USA) for confirmatory identification and susceptibility (S) testing using CLSI methods. AVI was tested at a fixed concentration of 4 μg/mL. Results: CAZ-AVI was highly active against Gram-negative (GN) bacteria including Enterobacteriaceae (ENT) and P. aeruginosa (PSA). In the USA, EMR, LATAM and APAC there were 560, 470, 130 and 137 ENT isolates, respectively. The MIC 90 values for ENT in the USA, EMR and LATAM regions were 0.25-0.5 μg/mL; APAC MIC 90 was 1 μg/mL. In the USA, all ENT MIC values were ≤2 μg/mL; 99.4% of values in the EMR were ≤4 μg/mL (CLSI S breakpoint for CAZ alone). In LATAM and APAC, 99.2 (129/130) and 94.9% (130/137) of ENT MIC values were ≤4 μg/mL. A total of 6.1% (8/131) of E. coli in the USA, 23.5% (43/183) in the EMR, 61.2% (30/49) in LATAM, and 75.0% (9/12) in APAC showed an ESBL-phenotype. The MIC 90 values for all E. coli in the USA and EMR were 0.12 and 0.25 μg/mL, respectively, while for CAZ alone the MIC 90 values were 0.5 and 32 μg/mL. A total of 1.6% (2/129) of K. pneumoniae isolates in the USA were meropenem-non-susceptible (MER-NS, MIC ≥2 μg/mL) and 10.3% (10/97) in the EMR. All isolates (17) of PSA in the USA and 80.9% (38/47) in the EMR were inhibited at a MIC of ≤8 μg/mL compared to 88.2% (15/17) and 61.7% (29/47) for CAZ alone. The 9 EMR PSA isolates with CAZ-AVI MIC values ≥32 μg/mL were from Romania (5), Portugal (3) and Poland (1). Conclusions: CAZ-AVI demonstrated in vitro activity against GN bacteria from patients with UTI, including activity against multidrug-resistant organisms. Table 1. Cumulative MIC distribution values for ceftazidime-avibactam when tested against selected UTI isolates from all regions (2011) No. of isolates No. of isolates (cumulative %) inhibited at MIC (μg/mL) of: Organism/resistant subset ≤0.06 0.12 0.25 0.5 1 2 4 8 16 ≥32 MIC 50 MIC 90 Enterobacteriaceae 1,297 640 (49.3) 364 (77.4) 178 (91.1) 64 (96.1) 23 (97.8) 14 (98.9) 3 (99.2) 0 (99.2) 0 (99.2) 11 (100.0) 0.12 0.25 Escherichia coli 375 244 (65.1) 96 (90.7) 30 (98.7) 4 (99.7) 0 (99.7) 0 (99.7) 1 (100.0) – – – 0.06 0.12 ESBL-phenotype 90 34 (37.8) 31 (72.2) 20 (94.4) 4 (98.9) 0 (98.9) 0 (98.9) 1 (100.0) – – – 0.12 0.25 Klebsiella pneumoniae 254 103 (40.6) 86 (74.4) 33 (87.4) 18 (94.5) 6 (96.9) 7 (99.6) 1 (100.0) – – – 0.12 0.5 ESBL-phenotype 84 10 (11.9) 25 (41.7) 20 (65.5) 15 (83.3) 6 (90.5) 7 (98.8) 1 (100.0) – – – 0.25 1 MER-non-susceptible (MIC, ≥2 μg/mL) 12 – 2 (16.7) 1 (25.0) 4 (58.3) 1 (66.7) 3 (91.7) 1 (100.0) – – – 0.5 2 Klebsiella oxytoca 42 21 (50.0) 10 (73.8) 6 (88.1) 5 (100.0) – – – – – – 0.06 0.5 Morganella morganii 127 105 (82.7) 12 (92.1) 9 (99.2) 1 (100.0) – – – – – – 0.06 0.12 Citrobacter spp. 176 53 (30.1) 59 (63.6) 41 (86.9) 14 (94.9) 4 (97.2) 1 (97.7) 1 (98.3) 0 (98.3) 0 (98.3) 3 (100.0) 0.12 0.5 Enterobacter spp. 159 26 (16.4) 64 (56.6) 37 (79.9) 14 (88.7) 10 (95.0) 5 (98.1) 0 (98.1) 0 (98.1) 0 (98.1) 3 (100.0) 0.12 1 Serratia marcescens 67 2 (3.0) 30 (47.8) 20 (77.6) 8 (89.6) 3 (94.0) 1 (95.5) 0 (95.5) 0 (95.5) 0 (95.5) 3 (100.0) 0.25 1 Pseudomonas aeruginosa 80 – – 1 (1.3) 1 (2.5) 25 (33.8) 24 (63.7) 10 (76.3) 6 (83.8) 2 (86.3) 11 (100.0) 2 32 MER-non-susceptible (MIC, ≥4 μg/mL) 26 – – – – 1 (3.8) 4 (19.2) 3 (30.8) 6 (53.8) 1 (57.7) 11 (100.0) 8 >32 CAZ-non-susceptible (MIC, ≥16 μg/mL) 26 – – – – 1 (3.8) 3 (15.4) 4 (30.8) 5 (50.0) 2 (57.7) 11 (100.0) 8 >32 Staphylococcus aureus 88 – – – – – – 12 (13.6) 30 (47.7) 9 (58.0) 37 (100.0) 16 >32 β-haemolytic streptococci 177 – 11 (6.2) 18 (16.4) 147 (99.4) 1 (100.0) – – – – – 0.5 0.5 CAZ, ceftazidime; MER, meropenem Table 2. Activity by geographic region for ceftazidime-avibactam and comparator agents when tested against selected UTI Gram-negative clinical isolates (2011) USA EMR LATAM APAC Antimicrobial agent (N) MIC 50 b MIC 90 b CLSI a %S / %R EUCAST a %S / %R MIC 50 b MIC 90 b CLSI a %S / %R EUCAST a %S / %R MIC 50 b MIC 90 b CLSI a %S / %R EUCAST a %S / %R MIC 50 b MIC 90 b CLSI a %S / %R EUCAST a %S / %R Enterobacteriaceae N=560 N=470 N=130 N=137 Ceftazidime-avibactam 0.06 0.25 – / – – / – 0.06 0.5 – / – – / – 0.12 0.25 – / – – / – 0.12 1 – / – – / – Ceftazidime 0.12 2 91.1 / 8.4 89.5 / 8.9 0.25 >32 73.2 / 23.6 69.6 / 26.8 2 >32 55.4 / 38.5 46.9 / 44.6 0.5 >32 65.0 / 32.8 58.4 / 35.0 Cefepime ≤0.5 ≤0.5 97.5 / 1.4 93.9 / 2.9 ≤0.5 >16 80.9 / 18.3 74.7 / 21.3 ≤0.5 >16 67.7 / 27.7 56.9 / 39.2 ≤0.5 >16 79.6 / 16.8 73.7 / 23.4 Ciprofloxacin ≤0.03 >4 86.6 / 11.1 85.0 / 13.4 0.06 >4 65.5 / 32.3 63.2 / 34.5 0.25 >4 54.6 / 40.0 51.5 / 45.4 0.12 >4 68.6 / 28.5 67.2 / 31.4 Meropenem ≤0.06 ≤0.06 98.8 / 0.9 99.1 / 0.2 ≤0.06 0.12 97.0 / 2.8 97.2 / 1.7 ≤0.06 ≤0.06 99.2 / 0.8 99.2 / 0.0 0.06 0.25 94.9 / 3.7 96.4 / 2.9 Piperacillin-tazobactam 2 8 94.3 / 3.2 92.7 / 5.7 2 64 82.3 / 9.0 78.9 / 17.7 4 32 83.8 / 4.6 73.8 / 16.2 2 64 81.0 / 9.5 75.9 / 19.0 Escherichia coli N=131 N=183 N=49 N=12 Ceftazidime-avibactam 0.06 0.12 – / – – / – 0.06 0.25 – / – – / – 0.06 0.25 – / – – / – 0.12 0.5 – / – – / – Ceftazidime 0.12 0.5 96.9 / 2.3 94.7 / 3.1 0.25 32 80.9 / 15.8 77.0 / 19.1 8 32 44.9 / 44.9 42.9 / 55.1 4 >32 50.0 / 41.7 25.0 / 50.0 Cefepime ≤0.5 ≤0.5 97.7 / 1.5 93.9 / 3.1 ≤0.5 >16 84.2 / 14.2 78.7 / 16.9 >16 >16 46.9 / 51.0 38.8 / 59.2 16 >16 41.7 / 41.7 25.0 / 75.0 Ciprofloxacin ≤0.03 >4 77.9 / 22.1 77.9 / 22.1 ≤0.03 >4 60.7 / 39.3 59.6 / 39.3 >4 >4 34.7 / 65.3 34.7 / 65.3 >4 >4 25.0 / 75.0 25.0 / 75.0 Meropenem ≤0.06 ≤0.06 100.0 / 0.0 100.0 / 0.0 ≤0.06 ≤0.06 100.0 / 0.0 100.0 / 0.0 ≤0.06 ≤0.06 100.0 / 0.0 100.0 / 0.0 ≤0.06 ≤0.06 100.0 / 0.0 100.0 / 0.0 Piperacillin-tazobactam 2 4 96.9 / 1.5 94.7 / 3.1 2 16 92.3 / 2.2 87.9 / 7.7 4 16 91.8 / 2.0 81.6 / 8.2 4 16 91.7 / 8.3 75.0 / 8.3 Klebsiella pneumoniae N=129 N=97 N=25 N=3 c Ceftazidime-avibactam 0.06 0.25 – / – – / – 0.12 1 – / – – / – 0.12 0.25 – / – – / – – – – – Ceftazidime 0.12 0.5 93.8 / 5.4 93.8 / 6.2 32 >32 42.3 / 53.6 40.2 / 57.7 4 >32 64.0 / 32.0 40.0 / 36.0 – – – – Cefepime ≤0.5 ≤0.5 95.3 / 3.1 93.8 / 4.7 8 >16 50.5 / 48.5 41.2 / 53.6 8 >16 60.0 / 32.0 48.0 / 52.0 – – – – Ciprofloxacin ≤0.03 0.5 94.6 / 5.4 92.2 / 5.4 >4 >4 42.3 / 55.7 41.2 / 57.7 1 >4 56.0 / 24.0 48.0 / 44.0 – – – – Meropenem ≤0.06 ≤0.06 98.5 / 1.6 98.5 / 0.8 ≤0.06 2 89.7 / 9.3 90.7 / 7.2 ≤0.06 ≤0.06 100.0 / 0.0 100.0 / 0.0 – – – – Piperacillin-tazobactam 2 8 96.9 / 3.1 95.3 / 3.1 8 >64 56.7 / 23.7 50.5 / 43.3 8 >64 76.0 / 12.0 64.0 / 24.0 – – – – Enterobacter spp. N=67 N=44 N=17 N=31 Ceftazidime-avibactam 0.12 0.25 – / – – / – 0.12 0.5 – / – – / – 0.25 1 – / – – / – 0.25 2 – / – – / – Ceftazidime 0.25 4 91.0 / 9.0 88.1 / 9.0 0.5 >32 63.6 / 34.1 61.4 / 36.4 32 >32 17.6 / 76.5 11.8 / 82.4 16 >32 41.9 / 58.1 35.5 / 58.1 Cefepime ≤0.5 ≤0.5 95.5 / 3.0 91.0 / 4.5 ≤0.5 8 93.2 / 6.8 79.5 / 13.6 1 >16 82.4 / 11.8 58.8 / 23.5 ≤0.5 >16 71.0 / 25.8 67.7 / 29.0 Ciprofloxacin ≤0.03 0.25 92.5 / 6.0 92.5 / 7.5 ≤0.03 >4 77.3 / 18.2 72.7 / 22.7 0.25 >4 64.7 / 35.3 58.8 / 35.3 0.12 >4 58.1 / 38.7 54.8 / 41.9 Meropenem ≤0.06 ≤0.06 95.5 / 3.0 97.0 / 0.0 ≤0.06 0.12 97.7 / 2.3 97.7 / 2.3 ≤0.06 0.12 100.0 / 0.0 100.0 / 0.0 ≤0.06 1 90.3 / 6.5 93.5 / 6.5 Piperacillin-tazobactam 4 8 94.0 / 4.5 92.5 / 6.0 4 >64 72.7 / 15.9 72.7 / 27.3 16 64 52.9 / 5.9 29.4 / 47.1 8 >64 58.1 / 29.0 51.6 / 41.9 Citrobacter spp. N=93 N=37 N=11 N=35 Ceftazidime-avibactam 0.12 0.25 – / – – / – 0.12 0.5 – / – – / – 0.12 0.5 – / – – / – 0.12 0.5 – / – – / – Ceftazidime 0.25 >32 79.6 / 20.4 79.6 / 20.4 0.25 32 78.4 / 18.9 75.7 / 21.6 0.5 >32 63.6 / 27.3 54.5 / 36.4 0.5 >32 65.7 / 34.3 62.9 / 34.3 Cefepime ≤0.5 1 97.8 / 0.0 92.5 / 3.2 ≤0.5 8 91.9 / 8.1 89.2 / 10.8 ≤0.5 1 90.9 / 9.1 90.9 / 9.1 ≤0.5 >16 82.9 / 14.3 77.1 / 20.0 Ciprofloxacin ≤0.03 0.25 93.5 / 3.2 92.5 / 6.5 ≤0.03 >4 86.5 / 10.8 86.5 / 13.5 ≤0.03 0.25 90.9 / 9.1 90.9 / 9.1 0.06 4 80.0 / 17.1 80.0 / 20.0 Meropenem ≤0.06 ≤0.06 97.8 / 1.1 98.9 / 0.0 ≤0.06 ≤0.06 100.0 / 0.0 100.0 / 0.0 ≤0.06 ≤0.06 90.9 / 9.1 90.9 / 0.0 ≤0.06 ≤0.06 94.3 / 2.9 97.1 / 0.0 Piperacillin-tazobactam 2 64 82.8 / 6.5 79.6 / 17.2 2 64 2 32 81.8 / 9.1 72.7 / 18.2 4 64 77.1 / 2.9 74.3 / 22.9 Morganella morganii N=51 N=36 N=11 N=29 Ceftazidime-avibactam 0.06 0.25 – / – – / – ≤0.03 0.12 – / – – / – ≤0.03 0.12 – / – – / – 0.06 0.06 – / – – / – Ceftazidime 0.12 32 78.4 / 19.6 72.5 / 21.6 0.25 8 88.9 / 5.6 80.6 / 11.1 0.25 2 90.9 / 9.1 72.7 / 9.1 0.12 16 82.8 / 13.8 72.4 / 17.2 Cefepime ≤0.5 ≤0.5 100.0 / 0.0 96.1 / 0.0 ≤0.5 ≤0.5 100.0 / 0.0 100.0 / 0.0 ≤0.5 16 81.8 / 0.0 81.8 / 8.2 ≤0.5 1 100.0 / 0.0 93.1 / 0.0 Ciprofloxacin ≤0.03 >4 68.6 / 23.5 62.7 / 31.4 ≤0.03 1 91.7 / 5.6 80.6 / 8.3 >4 >4 27.3 / 63.6 27.3 / 72.7 0.06 >4 69.0 / 24.1 65.5 / 31.0 Meropenem ≤0.06 0.12 100.0 / 0.0 100.0 / 0.0 ≤0.06 0.12 100.0 / 0.0 100.0 / 0.0 ≤0.06 0.12 100.0 / 0.0 100.0 / 0.0 0.12 0.12 100.0 / 0.0 100.0 / 0.0 Piperacillin-tazobactam ≤0.5 2 98.0 / 2.0 98.0 / 2.0 ≤0.5 2 100.0 / 0.0 100.0 / 0.0 ≤0.5 2 100.0 / 0.0 100.0 / 0.0 ≤0.5 4 100.0 / 0.0 93.1 / 0.0 Pseudomonas aeruginosa N=17 N=47 N=13 N=3 c Ceftazidime-avibactam 2 4 – / – – / – 2 32 – / – – / – 2 16 – / – – / – – – – – Ceftazidime 2 32 88.2 / 11.8 88.2 / 11.8 4 32 61.7 / 31.9 61.7 / 38.3 8 32 61.5 / 23.1 61.5 / 38.5 – – – – Cefepime 4 16 88.2 / 5.9 88.2 / 11.8 8 >16 66.0 / 21.3 66.0 / 34.0 8 >16 61.5 / 23.1 61.5 / 38.5 – – – – Ciprofloxacin 0.5 >4 64.7 / 35.3 52.9 / 35.3 0.5 >4 51.1 / 44.7 51.1 / 48.9 0.5 >4 61.5 / 38.5 53.8 / 38.5 – – – – Meropenem 0.25 8 88.2 / 11.8 88.2 / 5.9 0.5 >8 61.7 / 29.8 61.7 / 23.4 2 >8 61.5 / 30.8 61.5 / 30.8 – – – – Piperacillin-tazobactam 8 >64 76.5 / 11.8 76.5 / 23.5 16 >64 57.4 / 25.5 57.4 / 42.6 16 >64 53.8 / 15.4 53.8 / 46.2 – – – – a Criteria as published by the CLSI (2013) and EUCAST (2013). As there are currently no established susceptibility criteria for ceftazidime-avibactam, no susceptibility interpretation was provided. b Units in μg/mL. c Susceptibility values were not presented when the number of isolates was <10. Conclusions • Ceftazidime-avibactam was highly active against Gram-negative bacteria isolated from UTI from a global surveillance program conducted during 2011. • Against the Enterobacteriaceae, ceftazidime-avibactam demonstrated activity against a variety of resistant and multidrug-resistant bacteria, including ESBL- and KPC- phenotype strains. A total of 99.2% of all Enterobacteriaceae exhibited a ceftazidime-avibactam MIC of ≤4 μg/mL (the CLSI susceptible breakpoint for ceftazidime alone), a marked improvement over ceftazidime alone (78.3%). • Ceftazidime-avibactam was more active than ceftazidime alone against P. aeruginosa strains, including those that were non-susceptible to meropenem or ceftazidime. • The potent activity shown by ceftazidime-avibactam against Gram-negative bacteria from UTI that occurred in the USA, EMR, LATAM and Asia-Pacific regions demonstrates that clinical study in patients with UTI, including those with multi-drug-resistant strains, is merited. Materials and Methods Organism Collection: A total of 1,797 isolates were identified as UTI pathogens (including pathogens from both complicated and uncomplicated infections) based on the infection site and/or specimen type recorded by the participant laboratory. Isolates were collected from patients at 159 medical centers (no. of medical centers [no. of isolates]): 67 (821), USA; 46 (610), EMR; 16 (183), LATAM; and 30 (183), APAC. Isolates were processed at the respective medical centers and forwarded to a coordinating laboratory (JMI Laboratories, North Liberty, Iowa, USA; Australian isolates, South Australia Pathology, Women’s & Children’s Hospital, Adelaide, Australia) for confirmatory identification and susceptibility testing using Clinical and Laboratory Standards Institute (CLSI) methods. Avibactam was tested at a fixed concentration of 4 μg/mL. Susceptibility Testing: Isolates were susceptibility tested against ceftazidime-avibactam and comparator agents by CLSI reference broth microdilution methods. CLSI interpretative criteria were applied per M100-S23, European Committee on Antimicrobial Susceptibility Testing (EUCAST) interpretations were based on EUCAST breakpoint tables version 3.0, January 2013. USA-FDA breakpoint criteria for tigecycline were also used. Isolates were tested in cation- adjusted Mueller-Hinton broth (CA-MHB). CA-MHB supplemented with 2.5-5% lysed horse blood was used for the fastidious streptococci. Extended spectrum β-lactamase (ESBL)-phenotype was defined as a MIC of ≥2 μg/mL for ceftazidime or ceftriaxone or aztreonam (CLSI, 2013). Concurrent quality control (QC) testing was performed including the following strains: Staphylococcus aureus ATCC 29213, Enterococcus faecalis ATCC 29212, Streptococcus pneumoniae ATCC 49619 and E. coli ATCC 25922 and 35218; and all QC results were within published CLSI ranges. Results • Ceftazidime-avibactam was highly active against Enterobacteriaceae from UTI with MIC 50 and MIC 90 values for all isolates at 0.12 and 0.25 μg/mL (Table 1). The MIC 90 value for ceftazidime alone tested against these organisms was 128-fold higher (32 μg/mL) than that for ceftazidime-avibactam. • Enterobacteriaceae isolates from the APAC region had the highest ceftazidime-avibactam MIC 90 at 1 μg/mL (>32 μg/mL for ceftazidime alone; Table 2). In the USA, all ceftazidime- avibactam MIC values for Enterobacteriaceae were ≤2 μg/mL; 99.4% and 99.2% of values in the EMR and LATAM were ≤4 μg/mL, respectively (CLSI susceptibility breakpoint for ceftazidime alone; data not shown). • Ciprofloxacin resistance among all Enterobacteriaceae was at 23.5/26.1% (CLSI/EUCAST) and meropenem resistance at 1.9/1.0% (data not shown). Regional ciprofloxacin resistance varied from a low of 11.1/13.4% (CLSI/EUCAST) in the USA to a high of 40.0/45.4% in LATAM (Table 2). Meropenem resistance varied from a low of 0.8/0.0% in LATAM to a high of 3.7/2.9% in APAC (Table 2). • The MIC 50 and MIC 90 for ceftazidime-avibactam tested against all E. coli from UTI were 0.06 and 0.12 μg/mL, respectively, compared to 0.25 and 32 μg/mL for ceftazidime alone (Table 1). Regional ceftazidime-avibactam MIC 90 values were 0.12 μg/mL (USA), 0.25 μg/mL (EMR), 0.25 μg/mL (LATAM), and 0.5 μg/mL (APAC; Table 2). • The overall ESBL-phenotype rate for E. coli was 24.0% (Table 1). When analyzed by region, 6.1% (8/131) of E. coli in the USA, 23.5% (43/183) in the EMR, 61.2% (30/49) in LATAM, and 75.0% (9/12) in APAC showed an ESBL-phenotype (data not shown). • Ciprofloxacin resistance among all E. coli was at 37.9/37.9% (CLSI/EUCAST) and there was no meropenem resistance (data not shown). Regional ciprofloxacin resistance rates varied from a low of 22.1/22.1% in the USA (CLSI/EUCAST) to a high of 75.0/75.0% in APAC (Table 2). • The MIC 90 for ceftazidime-avibactam tested against all Klebsiella pneumoniae isolated from UTI was >64-fold lower than for ceftazidime alone (0.5 compared to >32 μg/mL; Table 1). Regional ceftazidime-avibactam MIC 90 values were 0.25 μg/mL (USA), 1 μg/mL (EMR), and 0.25 μg/mL (LATAM; Table 2). • The overall ESBL-phenotype rate for K. pneumoniae was 33.1% (Table 1). A total of 6.2% (8/129) of K. pneumoniae in the USA, 61.9% (60/97) in the EMR, 60.0% (15/25) in LATAM, and 33.3% (1/3) in APAC showed an ESBL-phenotype. Ciprofloxacin resistance among all K. pneumoniae was 26.4/29.1% (CLSI/EUCAST) and meropenem resistance was 4.3/3.2% (data not shown). • Regional ciprofloxacin resistance (CLSI/EUCAST) for K. pneumoniae varied from a low of 5.4/5.4% in the USA to a high of 55.7/57.7% in the EMR (excluding APAC where only three isolates were recovered; Table 2). There were no meropenem-resistant K. pneumoniae in LATAM and APAC; however, in the USA the rate was 1.6/0.8% and in the EMR it was 9.3/7.2% (Table 2). All meropenem-non- susceptible K. pneumoniae strains in the USA and EMR exhibited a ceftzidime-avibactam MIC ≤4 μg/mL (Table 1). • Against all Pseudomonas aeruginosa strains, ceftazidime- avibactam exhibited a MIC 50 that was two-fold lower than ceftazidime alone (2 vs 4 μg/mL; Table 1). The MIC 90 value for both ceftazidime-avibactam and ceftazidime alone was 32 μg/mL (Table 1). A total of 83.8% (ceftazidime-avibactam) and 67.5% (ceftazidime alone) of isolates exhibited MIC values at ≤8 μg/mL (Table 1). Ceftazidime-avibactam was more active against meropenem-non-susceptible and ceftazidime- non-susceptible strains than ceftazidime alone (Table 1). The MIC 50 and MIC 90 values for ceftazidime-avibactam against meropenem-non-susceptible P. aeruginosa were 8 and >32 μg/mL, while for ceftazidime alone the values were 32 and >32 μg/mL, respectively (Table 1). A total of 53.8% of meropenem-non-susceptible and 50.0% of ceftazidime-non-susceptible isolates exhibited a MIC value of ≤8 μg/mL, respectively, for ceftazidime-avibactam (Table 1). • All P. aeruginosa isolates in the USA and 80.9% (38/47) in the EMR were inhibited at a ceftazidime-avibactam MIC of ≤8 μg/mL compared to 88.2% (15/17) and 61.7% (29/47), respectively, for ceftazidime alone (data not shown). • In the EMR, all nine P. aeruginosa isolates with ceftazidime- avibactam MIC values ≥32 μg/mL were from Romania (5), Portugal (3) and Poland (1), indicating national differences for these resistant isolates. This study was funded by AstraZeneca and Forest/Cerexa, and JMI Laboratories received compensation fees for services in relation to preparing the abstract/poster, which was also funded by AstraZeneca. Poster typesetting and printing was provided by Prime Medica Ltd, Knutsford, Cheshire UK, funded by AstraZeneca Presented at the 53rd Interscience Conference on Antimicrobial Agents and Chemotherapy, September 10–13, 2013, Denver, CO, USA AZ130242H ICAAC JMI UTI poster.indd 1 29/08/2013 17:01