Compared to available inhibitors for clinical use, DBOs are more potent, have a broader spectrum, and have a different mechanism of action. ceftazidime nonsusceptible), 99.8% of the isolates, including 99.3% of the ceftazidime-nonsusceptible isolates, were ceftazidime-avibactam susceptible. Only 23 of 36,380 (0.06%) isolates were ceftazidime-avibactam nonsusceptible, including 9 metallo–lactamase producers and 2 KPC-producing strains with porin alteration; the remaining 12 strains showed negative results for all -lactamases tested. Ceftazidime-avibactam showed potent activity against (MIC50/90, 2/4 g/ml; 97.1% susceptible), including MDR (MIC50/90, 4/16 g/ml; 86.5% susceptible) isolates, and inhibited 71.8% of isolates nonsusceptible to meropenem, piperacillin-tazobactam, and ceftazidime (= 628). In summary, ceftazidime-avibactam demonstrated potent activity against a large collection (= 44,248) of contemporary Gram-negative bacilli isolated from U.S. patients, including organisms resistant to most currently available agents, such as CRE and meropenem-nonsusceptible carbapenemase (KPC) (2, 11). The wide dissemination of these -lactamases has left clinicians and patients with very few treatment options for infections caused by MDR (12, 13). Ceftazidime-avibactam is a combination agent consisting of the -lactamase inhibitor avibactam and the broad-spectrum cephalosporin ceftazidime (14, 15). Avibactam is a member of a novel class of non–lactam -lactamase inhibitors, the diazabicyclooctanes Rabbit Polyclonal to SRPK3 (DBO), and acts as a reversible, covalent inhibitor. Compared to available inhibitors for clinical use, DBOs are more potent, have a broader spectrum, and have a different mechanism of action. A unique feature of avibactam compared to earlier -lactamase inhibitors is that avibactam binds reversibly to -lactamases, allowing for recyclization and inhibition of additional -lactamase molecules. Avibactam effectively inactivates class A (ESBLs and KPC), class C (AmpC), and some class D (such as OXA-48) -lactamases (16). Ceftazidime-avibactam was approved by the U.S. Food and Drug Administration (FDA) and by the European Medicine Agency (EMA) to treat complicated intra-abdominal infection in combination with metronidazole, as Vinpocetine well as complicated urinary tract infections, including pyelonephritis (17, 18). Ceftazidime-avibactam is also approved to treat nosocomial pneumonia in Europe and has been studied in pediatric patients (“type”:”clinical-trial”,”attrs”:”text”:”NCT01893346″,”term_id”:”NCT01893346″NCT01893346) (19). As part of the International Network for Optimal Resistance Monitoring (INFORM) surveillance program, we evaluated the activity of ceftazidime-avibactam against a large collection of contemporary (2013 to 2016) MDR Gram-negative organisms causing infections in patients from U.S. medical centers. RESULTS Ceftazidime-avibactam inhibited 99.9% of all isolates (= 36,380) at the susceptible breakpoint of 8 g/ml (Tables 1 and ?and2)2) and was highly active against MDR isolates (= 2,953; MIC50/90, 0.25/1 g/ml; 99.2% susceptible), extensively drug-resistant (XDR) isolates (= 448; MIC50/90, 0.5/2 g/ml; 97.8% susceptible), and carbapenem-resistant (CRE) isolates (= 513; MIC50/90, 0.5/2 g/ml; 97.5% susceptible; Tables 1 and ?and2)2) isolates. Amikacin (MIC50/90, 2/4 g/ml; 99.2% susceptible according to the Clinical and Laboratory Standards Institute [CLSI] criteria), tigecycline (MIC50/90, 0.25/1 g/ml; 98.0% susceptible according to the FDA), and meropenem (MIC50/90, 0.06/0.06 g/ml; 98.5% susceptible according to the CLSI) were also very active against the entire collection of isolates, but these antimicrobial agents exhibited limited activity against MDR, XDR, and CRE isolates (Table 2). TABLE 1 Antimicrobial activity of ceftazidime-avibactam tested against antimicrobial resistant and Vinpocetine from U.S. hospitals (2013 to 2016)(36,380)1,3344,42811,13912,3424,8151,631448142631513190.120.253.715.846.580.493.698.199.399.799.999.9 99.9 99.9100.0????CRE (513)165133576137138592014090.523.14.16.613.528.355.081.993.497.397.598.298.2100.0????MDR (2,953)98217428597587525296116531313190.2513.310.725.245.465.383.093.197.098.899.299.799.7100.0????XDR (448)169202553126117442354060.523.65.610.015.627.555.681.791.596.797.898.798.7100.0(12,942)1,0241,4634,5974,5501,0661863613310030.060.257.919.254.789.998.199.699.899.9 99.9 99.9 99.9 99.9100.0????Ceftriaxone-NS (1,750)100632477364441083312310030.120.255.79.323.465.590.997.098.999.699.899.899.899.8100.0????MEM-NS (27)11358411000030.25 323.77.418.537.066.781.585.288.988.988.988.988.9100.0(7,511)1373642,5232,950957364137581701030.120.251.86.740.379.592.397.198.999.799.999.9 99.9 99.9100.0????MEM-NS (382)1557215611199481601030.523.95.27.112.627.256.382.294.899.099.099.299.2100.0????Ceftriaxone-NS (1,063)392367259242229127561701030.2513.75.812.136.559.380.892.898.099.699.699.799.7100.0????Colistin-NS (205)94224930363213900010.2524.46.317.141.055.673.288.895.199.599.599.599.5100.0(1,902)89382370917474145110.120.250.45.348.685.995.098.999.699.999.9100.0(2,818)421,5681,1028314330110010.030.061.557.196.299.299.799.899.999.999.9 99.9 99.9 99.9100.0(3,740)33262151,5941,18447716433803120.250.50.91.67.349.981.694.498.799.699.899.899.999.9100.0????CAZ-NS (831)13374422934514630803120.511.61.92.88.135.677.194.798.399.399.399.699.8100.0(1,384)2947352605256751045010.120.252.15.530.974.693.198.699.399.699.999.9100.0????CAZ-NS (279)107176411349945010.250.53.66.112.235.175.693.296.497.899.699.6100.0(1,059)23704891204025921010.060.120.235.181.392.696.498.899.699.899.999.9100.0(777)34943732056010010.060.124.416.564.590.998.699.999.9100.0(1,026)121517147322598232610.120.51.22.619.365.487.396.999.199.399.9100.0(1,715)4497206682333151220.250.50.23.145.184.097.699.499.799.899.9100.0(418)318618538240.060.120.745.289.598.699.0100.0spp. (872)516418423114974141918950.120.50.619.440.567.084.192.594.296.398.499.4100.0(7,868)1413882,7712,7791,1374261344349241.86.741.977.391.797.198.899.4100.0????CAZ-NS (1,204)1179331734421613343494160.10.20.78.534.863.481.392.495.9100.0????MEM-NS (1,471)4812138248528210737454160.30.89.035.068.087.294.496.9100.0????P-T-NS (1,497)211510836046733612539444160.10.21.28.432.563.786.194.597.1100.0????CAZ, MEM, and P-T-NS (628)2210617414910135418323.520.448.171.887.993.5100.0????MDR (1,562)81812938449831412242474160.51.79.934.566.486.594.397.0100.0????XDR (717)101321261901949336448320.10.10.34.722.348.875.988.893.9100.0 Open in a separate window aAbbreviations: CRE, carbapenem-resistant (1,063)(205)????????Ceftazidime-avibactam0.25299.50.5*99.50.5????????Ceftriaxone 8 842.955.642.955.6????????Ceftazidime32 3242.057.140.058.0????????Cefepime16 1646.751.146.751.1????????Piperacillin-tazobactam16 6451.245.941.048.8????????Meropenem0.06 862.437.662.431.2????????Levofloxacin 4 446.850.242.054.1????????Gentamicin1 869.825.965.930.2????????Amikacin23277.67.366.822.4????????Tigecycline0.5299.50.0*89.30.5????????Colistin 8 80.0100.0????Ceftazidime-nonsusceptible (8 g/ml) (831)(= 59), (= 1), (= 42), (= 119), species complex (= 153), (= 797), (= 3), (= 55), (= 793), (= 174), (= 426), (= 5), group (= 1), (= 17), (= 191), (= 1), (= 1), (= 112), sp. (= 2), and sp. (= 1). dXDR organisms included the following: (= 9), (= 1), (= 44), (= 12), (= 8), (= 297), (= 17), (= 19), (= 18), (= 1), (= 21), and sp. (= 1). eThe Vinpocetine results of the molecular characterization of these isolates are shown in Table 3. CRE organisms included the following: (= 6), (= 13), (= 5), species complex (= 50), (= 24), (= 16), (= 368), (= 4), (= 2), (= 1), (= 22), and sp. (= 2). fAccording to CLSI criteria; 2 g/ml (33). gAccording to CLSI criteria; 8 g/ml (33). The most active compound tested against MDR and.