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Abstract Carbapenem-resistant Enterobacterales and Pseudomonas aeruginosa are being isolated from patient specimens with increasing frequency in Latin America and worldwide. The current study provides an initial description of the in vitro activity of imipenem/relebactam (IMR) against non-Morganellaceae Enterobacterales (NME) and P. aeruginosa infecting hospitalized patients in Latin America. From 2018 to 2020, 37 clinical laboratories in nine Latin American countries participated in the SMART global surveillance program and contributed 15,466 NME and 3408 P aeruginosa isolates. MICs for IMR and seven comparators were determined using CLSI broth microdilution and interpreted by CLSI M100 (2022) breakpoints. β-lactamase genes were identified in selected isolate subsets. IMR (96.9% susceptible), amikacin (95.9%), meropenem (90.7%), and imipenem (88.7%) were the most active agents against NME. Among piperacillin/tazobactam-nonsusceptible NME (n= 4124), 90.4% of isolates were IMR-susceptible (range by country, 97.2 [Chile] to 67.0% [Guatemala]) and among meropenem-nonsusceptible NME isolates (n= 1433), 74.0% were IMR-susceptible (94.1% [Puerto Rico] to 5.1% [Guatemala]). Overall, 6.3% of all collected NME isolates carried a KPC (metallo-β-lactamase [MBL]-negative), 1.8% an MBL, 0.4% an OXA-48-like carbapenemase (MBL-negative), and 0.1% a GES carbapenemase (MBL-negative). Amikacin (85.2% susceptible) and IMR (80.1%) were the most active agents against P. aeruginosa; only 56.5% of isolates were imipenem-susceptible. Relebactam increased susceptibility to imipenem by 22.0% (from 23.9% to 45.9%) in piperacillin/tazobactam-nonsusceptible isolates (n= 1031) and by 35.5% (from 5.5% to 41.0%) in meropenem-nonsusceptible isolates (n= 1128). Overall, 7.6% of all collected P. aeruginosa isolates were MBL-positive and 0.7% carried a GES carbapenemase. In conclusion, in 2018‒2020, almost all NME (97%) and most P. aeruginosa(80%) isolates from Latin America were IMR-susceptible. Continued surveillance of the in vitro activities of IMR and comparator agents against Gram-negative pathogens, and monitoring for β-lactamase changes (in particular for increases in MBLs), is warranted. Carbapenemresistant Carbapenem resistant worldwide imipenemrelebactam relebactam (IMR nonMorganellaceae non Morganellaceae (NME 201 2020 3 15466 15 466 15,46 340 M M10 2022 (2022 breakpoints βlactamase β lactamase subsets 96.9% 969 96 9 (96.9 susceptible, susceptible , 95.9%, 959 95.9% 95 (95.9%) 90.7%, 907 90.7% 90 7 (90.7%) 88.7% 887 88 (88.7% piperacillin/tazobactamnonsusceptible piperacillintazobactamnonsusceptible piperacillin/tazobactam nonsusceptible piperacillin tazobactam n= n (n 4124, 4124 4124) 904 4 90.4 IMRsusceptible range country 972 97 2 97. Chile [Chile 670 67 0 67.0 Guatemala [Guatemala] meropenemnonsusceptible 1433, 1433 1433) 740 74 74.0 94.1% 941 94 1 (94.1 Puerto Rico 51 5 5.1 Guatemala. . Overall 63 6 6.3 metalloβlactamase metallo MBLnegative, MBLnegative MBL negative [MBL]-negative) 18 8 1.8 04 0.4 OXA48like OXAlike OXA 48 like (MBL-negative) 01 0.1 MBLnegative. 85.2% 852 85 (85.2 80.1% 801 80 (80.1% 565 56 56.5 imipenemsusceptible. imipenemsusceptible susceptible. imipenem-susceptible 220 22 22.0 239 23 23.9 45.9% 459 45 1031 355 35 35.5 55 5.5 41.0% 410 41 1128. 1128 1128) 76 7.6 MBLpositive positive 07 0.7 conclusion 20182020 2018‒2020 97% (97% aeruginosa80% aeruginosa80 80% aeruginosa(80% IMRsusceptible. Gramnegative Gram pathogens MBLs, MBLs MBLs) warranted 20 202 1546 46 15,4 34 M1 (202 96.9 (96. 95.9 (95.9% 90.7 (90.7% 88.7 (88.7 tazobactamnonsusceptible piperacillintazobactam 412 90. 67. [Guatemala 143 74. 94.1 (94. 5. 6. [MBL]-negative 1. 0. (MBL-negative 85.2 (85. 80.1 (80.1 56. 22. 23. 45.9 103 35. 41.0 112 7. 2018202 2018‒202 (97 aeruginosa8 aeruginosa(80 154 15, (20 96. (96 95. (95.9 (90.7 88. (88. 14 94. (94 85. (85 80. (80. 45. 10 41. 11 201820 2018‒20 (9 aeruginosa(8 (2 (95. (90. (88 (8 (80 20182 2018‒2 ( aeruginosa( (95 (90 2018‒