In vitro activity of ceftolozane/tazobactam against Gram-negative isolates collected from ICU patients with lower respiratory tract infections in seven Asian countries-SMART 2017-2019.

OBJECTIVES: Antimicrobial resistance is one of the top 10 global public-health threats. Especially high rates of resistance have been reported for isolates from ICU patients, requiring expanded treatment options in this setting. We evaluated the activity of ceftolozane/tazobactam and comparators against Gram-negative isolates collected from patients with lower respiratory tract infections (LRTIs) in ICUs in seven Asian countries. METHODS: In 2017-2019, up to 100 consecutive, aerobic Gram-negative LRTI isolates were collected per year at each of 37 hospitals. MICs were determined using the Clinical and Laboratory Standards Institute reference broth microdilution method. RESULTS: Overall, ceftolozane/tazobactam was active against 72% of 1408 Enterobacterales and 86% of 761 Pseudomonas aeruginosa isolates. Susceptibility to the non-carbapenem ß-lactam comparators, including piperacillin/tazobactam, was 52-67% among Enterobacterales isolates, and the activity of all ß-lactam comparators, including meropenem, was 57-70% among P. aeruginosa. Ceftolozane/tazobactam maintained activity against 61% of meropenem-nonsusceptible and 64% of piperacillin/tazobactam-nonsusceptible P. aeruginosa. At the country-level, ceftolozane/tazobactam activity ranged from >90% against Enterobacterales from Hong Kong and South Korea to <64% in Thailand and Vietnam, and from >90% against P. aeruginosa from South Korea, Malaysia, Philippines and Taiwan to <75% in Thailand and Vietnam. Correspondingly, the proportions of carbapenemase-positive isolates among Enterobacterales and P. aeruginosa isolates were highest in Thailand and Vietnam. CONCLUSION: Ceftolozane/tazobactam provides a potential treatment option for ICU patients in Asia, which is especially important considering the reduced activity of commonly used ß-lactams against the studied ICU isolates. Knowledge of local resistance patterns should inform empirical therapy decision-making.

In vitro activity of ceftazidime-avibactam against Enterobacterales and Pseudomonas aeruginosa isolates collected in Latin America as part of the ATLAS global surveillance program, 2017-2019.

The Antimicrobial Testing Leadership and Surveillance (ATLAS) global surveillance program collected clinical isolates of Enterobacterales (n = 8416) and Pseudomonas aeruginosa (n = 2521) from 41 medical centers in 10 Latin American countries from 2017 to 2019. In vitro activities of ceftazidime-avibactam and comparators were determined using the Clinical and Laboratory Standards Institute (CLSI) broth microdilution method. Overall, 98.1% of Enterobacterales and 86.9% of P. aeruginosa isolates were susceptible to ceftazidime-avibactam. When isolates were analyzed by country of origin, susceptibility to ceftazidime-avibactam for Enterobacterales ranged from 97.8% to 100% for nine of 10 countries (except Guatemala, 86.3% susceptible) and from 75.9% to 98.4% for P. aeruginosa in all 10 countries. For Enterobacterales, 100% of AmpC-positive, ESBL- and AmpC-positive, GES-type carbapenemase-positive, and OXA-48-like-positive isolates were ceftazidime-avibactam-susceptible as were 99.8%, 91.8%, and 74.7% of ESBL-positive, multidrug-resistant (MDR), and meropenem-nonsusceptible isolates. Among meropenem-nonsusceptible isolates of Enterobacterales, 24.4% (139/570) carried a metallo-ß-lactamase (MBL); 83.3% of the remaining meropenem-nonsusceptible isolates carried another class of carbapenemase and 99.4% of those isolates were ceftazidime-avibactam-susceptible. Among meropenem-non-susceptible isolates of P. aeruginosa (n = 835), 25.6% carried MBLs; no acquired ß-lactamase was identified in the majority of isolates (64.8%; 87.2% of those isolates were ceftazidime-avibactam-susceptible). Overall, clinical isolates of Enterobacterales collected in Latin America from 2017 to 2019 were highly susceptible to ceftazidime-avibactam, including isolates carrying ESBLs, AmpCs, and KPCs. Country-specific variation in susceptibility to ceftazidime-avibactam was more common among isolates of P. aeruginosa than Enterobacterales. The frequency of MBL-producers among Enterobacterales from Latin America was low (1.7% of all isolates; 146/8,416), but higher than reported in previous surveillance studies.

Ceftolozane/Tazobactam and Imipenem/Relebactam Cross-Susceptibility Among Clinical Isolates of Pseudomonas aeruginosa From Patients With Respiratory Tract Infections in ICU and Non-ICU Wards-SMART United States 2017-2019.

BACKGROUND: Carbapenem-nonsusceptible and multidrug-resistant (MDR) P. aeruginosa, which are more common in patients with lower respiratory tract infections (LRTIs) and in patients in intensive care units (ICUs), pose difficult treatment challenges and may require new therapeutic options. Two ß-lactam/ß-lactamase inhibitor combinations, ceftolozane/tazobactam (C/T) and imipenem/relebactam (IMI/REL), are approved for treatment of hospital-acquired/ventilator-associated bacterial pneumonia. METHODS: The Clinical and Laboratory Standards Institute-defined broth microdilution methodology was used to determine minimum inhibitory concentrations (MICs) against P. aeruginosa isolates collected from patients with LRTIs in ICUs (n = 720) and non-ICU wards (n = 914) at 26 US hospitals in 2017-2019 as part of the Study for Monitoring Antimicrobial Resistance Trends (SMART) surveillance program. RESULTS: Susceptibility to commonly used ß-lactams including carbapenems was 5-9 percentage points lower and MDR rates 7 percentage points higher among isolates from patients in ICUs than those in non-ICU wards (P < .05). C/T and IMI/REL maintained activity against 94.0% and 90.8% of ICU isolates, respectively, while susceptibility to all comparators except amikacin (96.0%) was 63%-76%. C/T and IMI/REL inhibited 83.1% and 68.1% of meropenem-nonsusceptible (n = 207) and 71.4% and 65.7% of MDR ICU isolates (n = 140), respectively. Among all ICU isolates, only 2.5% were nonsusceptible to both C/T and IMI/REL, while 6.7% were susceptible to C/T but not to IMI/REL and 3.5% were susceptible to IMI/REL but not to C/T. CONCLUSIONS: These data suggest that susceptibility to both C/T and IMI/REL should be considered for testing at hospitals, as both agents could provide important new options for treating patients with LRTIs, especially in ICUs where collected isolates show substantially reduced susceptibility to commonly used ß-lactams.

Epidemiology of Carbapenem Resistance Determinants Identified in Meropenem-Nonsusceptible Enterobacterales Collected as Part of a Global Surveillance Program, 2012 to 2017.

To estimate the incidence of carbapenem-resistant Enterobacterales (CRE), a global collection of 81,781 surveillance isolates of Enterobacterales collected from patients in 39 countries in five geographic regions from 2012 to 2017 was studied. Overall, 3.3% of isolates were meropenem-nonsusceptible (MIC ≥2 µg/ml), ranging from 1.4% (North America) to 5.3% (Latin America) of isolates by region. Klebsiella pneumoniae accounted for the largest number of meropenem-nonsusceptible isolates (76.7%). The majority of meropenem-nonsusceptible Enterobacterales carried KPC-type carbapenemases (47.4%), metallo-ß-lactamases (MBLs; 20.6%) or OXA-48-like ß-lactamases (19.0%). Forty-three carbapenemase sequence variants (8 KPC-type, 4 GES-type, 7 OXA-48-like, 5 NDM-type, 7 IMP-type, and 12 VIM-type) were detected, with KPC-2, KPC-3, OXA-48, NDM-1, IMP-4, and VIM-1 identified as the most common variants of each carbapenemase type. The resistance mechanisms responsible for meropenem-nonsusceptibility varied by region. A total of 67.3% of all carbapenemase-positive isolates identified carried at least one additional plasmid-mediated or intrinsic chromosomally encoded extended-spectrum ß-lactamase, AmpC ß-lactamase, or carbapenemase. The overall percentage of meropenem-nonsusceptible Enterobacterales increased from 2.7% in 2012 to 2014 to 3.8% in 2015 to 2017. This increase could be attributed to the increasing proportion of carbapenemase-positive isolates that was observed, most notably among isolates carrying NDM-type MBLs in Asia/South Pacific, Europe, and Latin America; OXA-48-like carbapenemases in Europe, Middle East/Africa, and Asia/South Pacific; VIM-type MBLs in Europe; and KPC-type carbapenemases in Latin America. Ongoing CRE surveillance combined with a global antimicrobial stewardship strategy, sensitive clinical laboratory detection methods, and adherence to infection control practices will be needed to interrupt the spread of CRE.

Molecular characterization of clinical isolates of Enterobacterales with elevated MIC values for aztreonam-avibactam from the INFORM global surveillance study, 2012-2017.

OBJECTIVES: While aztreonam-avibactam is a potent ß-lactam-ß-lactamase-inhibitor combination, reduced in vitro activity against some Enterobacterales isolates has been reported. In this study, globally collected clinical isolates of Enterobacterales with elevated minimum inhibitory concentrations (MICs) for aztreonam-avibactam were examined for potential resistance mechanisms. METHODS: Isolates with aztreonam-avibactam MICs ≥8 µg/mL (n = 55: Escherichia coli, n = 38; Enterobacter cloacae, n = 10; Klebsiella pneumoniae, n = 3; others, n = 4) and <8 µg/mL (n = 18) collected for the INFORM global surveillance programme were characterized by short read whole-genome sequencing. Sequences were inspected for the presence of ß-lactamase genes, penicillin-binding protein (PBP) mutations, and disruptions in the coding sequences of porin genes. RESULTS: All isolates of E. coli testing with aztreonam-avibactam MIC values ≥8 µg/mL carried a previously documented four-amino-acid insertion in PBP3 at position 333 of YRI(K/N/P). Such mutations were absent in isolates with MICs <2 µg/mL (n = 6). Among other species, carriage of PER- or VEB-type ß-lactamases was identified in 10/17 (58.8%) of isolates testing with aztreonam-avibactam MICs ≥8 µg/mL, but no isolates with lower MIC values (n = 11). CONCLUSIONS: PBP3 mutations are known to confer resistance to aztreonam in E. coli, providing a rationale for the elevated MIC values for aztreonam-avibactam in these isolates. Elevated MICs in other isolates were associated with the carriage of PER-type ß-lactamases, which have been previously shown to be inhibited less effectively by avibactam than other Class A ß-lactamases and may contribute to this phenotype. Other resistance mechanisms contributing to poor in vitro activity for aztreonam-avibactam in some of these isolates are not yet elucidated.

Longitudinal analysis of ESBL and carbapenemase carriage among Enterobacterales and Pseudomonas aeruginosa isolates collected in Europe as part of the International Network for Optimal Resistance Monitoring (INFORM) global surveillance programme, 2013-17.

OBJECTIVES: To determine the spread of ESBLs and carbapenemases in Enterobacterales and Pseudomonas aeruginosa in Europe. METHODS: 45 335 Gram-negative bacilli were collected in 18 European countries as part of the International Network for Optimal Resistance Monitoring (INFORM) global surveillance programme from 2013 to 2017. Antimicrobial susceptibility was determined using broth microdilution, and 9546 isolates were screened for ß-lactamase genes by PCR and sequencing. RESULTS: ESBLs were identified in 35.5% of Klebsiella pneumoniae and 18.5% of Escherichia coli. ESBL carriage was lowest among isolates in Northern/Western Europe and highest in Eastern Europe. CTX-M-15 was the dominant ESBL in all countries except Greece, where SHV-type ESBLs were more common. Carbapenemases (KPC, OXA-48-like, GES, NDM and VIM) were found in 3.4% of Enterobacterales and were most common among K. pneumoniae (10.5% of those collected). Carbapenemase carriage was lowest in Northern/Western and highest in Southern Europe. KPC-positive Enterobacterales were most abundant but the percentages of OXA-48-like-, NDM- and VIM-positive isolates increased over time and were correlated with an increase in meropenem non-susceptibility. Carbapenemases (VIM, IMP, NDM and GES) were also identified in 5.1% of P. aeruginosa and were commonly found in Eastern Europe. Carbapenemase carriage and meropenem non-susceptibility among P. aeruginosa fluctuated over the 5 years studied and were not well correlated. CONCLUSIONS: ESBL and carbapenemase carriage varied by species and European subregion. Meropenem non-susceptibility in European isolates of Enterobacterales can be attributed to carbapenemase carriage and is increasingly caused by MBLs and OXA-48-like carbapenemases. Carbapenemases or other ß-lactamases are not a common cause of meropenem non-susceptibility in P. aeruginosa in Europe.

In vitro activity of ceftolozane/tazobactam against phenotypically defined extended-spectrum ß-lactamase (ESBL)-positive isolates of Escherichia coli and Klebsiella pneumoniae isolated from hospitalized patients (SMART 2016).

The Clinical and Laboratory Standards Institute (CLSI)-defined broth microdilution testing method (M07, 11th edition, 2018) was used to determine MICs for ceftolozane/tazobactam and eight comparator agents against 21,952 isolates of Enterobacteriaceae submitted by 161 clinical laboratories in 51 countries in 2016 as a part of the SMART global surveillance program. MICs were interpreted using CLSI breakpoints (M100 29th edition, 2019). 89.7% of isolates of Enterobacteriaceae were susceptible to ceftolozane/tazobactam, compared to 70.0%, 76.3%, 77.7%, 84.7%, 93.6%, and 96.4%, respectively, for ceftriaxone, ceftazidime, cefepime, piperacillin-tazobactam, ertapenem, and meropenem. 82.4% of isolates of ESBL-positive, carbapenemase-negative Enterobacteriaceae were susceptible to ceftolozane/tazobactam, compared to 1.5%, 7.8%, 20.3%, 71.1%, 94.7%, and 98.7%, respectively, for ceftriaxone, cefepime, ceftazidime, piperacillin-tazobactam, ertapenem, and meropenem. In vitro susceptibility to ceftolozane/tazobactam was >60% higher than susceptibility to other advanced-generation cephalosporins among all Enterobacteriaceae and >10% higher than susceptibility to piperacillin-tazobactam among ESBL-positive Enterobacteriaceae collected globally in 2016.

Escherichia coli strains possessing a four amino acid YRIN insertion in PBP3 identified as part of the SIDERO-WT-2014 surveillance study.

BACKGROUND: In addition to carbapenemases, dissemination of recently reported Escherichia coli lineages possessing a four amino acid insertion in PBP3 (encoded by ftsI) that confers reduced susceptibility to PBP3-targeted ß-lactams, such as ceftazidime, can pose a threat of antimicrobial resistance. OBJECTIVES: To evaluate genotypic and phenotypic characteristics of E. coli possessing the mutated PBP3 collected during SIDERO-WT-2014 surveillance. METHODS: A subset of 65 E. coli clinical isolates with MICs ≥2 mg/L for ceftazidime/avibactam, ceftolozane/tazobactam or cefiderocol, among a total of 1529 isolates from the multinational surveillance study, were subjected to gene analysis and antimicrobial susceptibility testing. Isogenic PBP3 mutants were constructed to confirm experimentally an impact on antimicrobial susceptibility. RESULTS: Eleven strains possessing a YRIN-inserted PBP3 were identified, consisting of nine strains collected from the same hospital in Turkey (ST1284) and one each from the USA and Italy (ST361). Strains associated with each ST lineage possessed similar genetic backgrounds including ß-lactamase genotypes; all nine strains from Turkey carried CMY-42, OXA-1 and the OXA-181 carbapenemase (five strains additionally carried CTX-M-15 ESBL), whereas the two other strains carried CMY-42 and TEM-1, indicating dissemination driven by selective pressure. The presence of the YRIN insertion contributed to reduced susceptibility to aztreonam, ceftazidime, cefepime and ceftolozane/tazobactam, although the strains remained susceptible to ceftazidime/avibactam despite relatively high MICs. CONCLUSIONS: E. coli strains of both ST1284 and ST361 lineages, possessing YRIN-inserted PBP3, are disseminating in several regions. The YRIN insertion in PBP3 occurred with multiple ß-lactamases, which indicates frequent cross-resistance to other ß-lactams.

In vitro activity of imipenem/relebactam against Enterobacteriaceae and Pseudomonas aeruginosa isolated from intraabdominal and urinary tract infection samples: SMART Surveillance United States 2015-2017.

OBJECTIVES: Antimicrobial resistance, including multidrug-resistance (MDR), is increasing, especially among Gram-negative bacilli. New agents are needed to treat infections caused by these pathogens. This report assessed the activity of imipenem/relebactam against Gram-negative bacilli from intraabdominal infections (IAIs) and urinary tract infections (UTIs) submitted to the SMART (Study for Monitoring Antimicrobial Resistance Trends) global surveillance programme in the United States from 2015 to 2017. METHODS: Broth microdilution MICs for imipenem/relebactam and comparators were determined by a central laboratory against isolates of non-Proteeae Enterobacteriaceae (NPE) and Pseudomonas aeruginosa (P. aeruginosa). Imipenem/relebactam MICs were interpreted using United States Food and Drug Administration (FDA) breakpoints. RESULTS: 99.5% of NPE isolates collected from patients with IAIs (n=3633) and UTIs (n=3038) were susceptible to imipenem/relebactam, as were 77.9% of imipenem-nonsusceptible, 96.3% of Klebsiella pneumoniae carbapenemase (KPC)-positive, and 98.7% of MDR isolates from IAIs and UTIs combined. A total of 96.7% of IAI isolates (n=486) and 96.4% of UTI isolates (n=360) of P. aeruginosa were susceptible to imipenem/relebactam, as were 85.0% of imipenem-nonsusceptible and 87.3% of MDR isolates from IAIs and UTIs combined. Percent susceptibility to imipenem/relebactam for cefepime-, ceftazidime-, and piperacillin-tazobactam-nonsusceptible isolates was 98.3-98.8% for NPE and 87.3-90.0% for P. aeruginosa. CONCLUSIONS: Imipenem/relebactam demonstrated potent in vitro activity against NPE and P. aeruginosa isolates from IAIs and UTIs, including against resistant subsets, and will provide important coverage for IAIs and UTIs caused by ß-lactam-resistant, MDR, and KPC-positive Gram-negative bacilli.

In-vitro activity of imipenem/relebactam and key ß-lactam agents against Gram-negative bacilli isolated from lower respiratory tract infection samples of intensive care unit patients - SMART Surveillance United States 2015-2017.

ß-lactam- and multi-drug-resistant (MDR) Gram-negative bacilli frequently cause lower respiratory tract infections (LRTIs) in patients housed in intensive care units (ICUs). Relebactam, a novel diazabicyclooctane inhibitor of Ambler class A and C ß-lactamases, in combination with imipenem-cilastatin was approved by the US Food and Drug Administration in July 2019 for the treatment of adults with complicated intra-abdominal infections and complicated urinary tract infections. A phase III study of imipenem/relebactam for the treatment of patients with respiratory tract infections, including antimicrobial-resistant Gram-negative infections, has also been completed. The Clinical and Laboratory Standards Institute's broth microdilution methodology was used to determine minimum inhibitory concentrations against non-Proteeae Enterobacteriaceae (NPE) and Pseudomonas aeruginosa collected from ICU patients with LRTIs at 26 US hospitals in 2015-2017. Percent susceptibilities to imipenem/relebactam were 97.0%, 66.4% and 98.1%, respectively, for all NPE (n=1298), imipenem-non-susceptible NPE (n=113, of which 71% were Serratia marcescens) and MDR NPE (n=206), and 92.2%, 77.2% and 79.6%, respectively, for all P. aeruginosa (n=638), imipenem-non-susceptible P. aeruginosa (n=219) and MDR P. aeruginosa (n=225). Percent susceptibilities to imipenem/relebactam were 98.0-98.6% for cefepime-, ceftazidime- and piperacillin-tazobactam-non-susceptible NPE and 77.8-82.5% for cefepime-, ceftazidime- and piperacillin-tazobactam-non-susceptible P. aeruginosa. Generally, only slight variations in susceptibility were observed across US census regions. Imipenem/relebactam may provide a valuable therapeutic option for the treatment of ICU patients with LRTI caused by Gram-negative bacilli resistant to commonly used ß-lactams, as it demonstrated potent in-vitro activity against the majority of tested ß-lactam-non-susceptible and MDR Gram-negative bacilli from ICU patients with LRTIs in US hospitals.

In Vitro Activity of Ceftazidime-Avibactam against Clinical Isolates of Enterobacteriaceae and Pseudomonas aeruginosa Collected in Latin American Countries: Results from the INFORM Global Surveillance Program, 2012 to 2015.

The International Network for Optimal Resistance Monitoring (INFORM) global surveillance program collected clinical isolates of Enterobacteriaceae (n = 7,665) and Pseudomonas aeruginosa (n = 1,794) from 26 medical centers in six Latin American countries from 2012 to 2015. The in vitro activity of ceftazidime-avibactam and comparators was determined for the isolates using the Clinical and Laboratory Standards Institute (CLSI) reference broth microdilution method. Enterobacteriaceae were highly susceptible (99.7%) to ceftazidime-avibactam, including 99.9% of metallo-ß-lactamase (MBL)-negative isolates; 87.4% of all P. aeruginosa isolates and 92.8% of MBL-negative isolates were susceptible to ceftazidime-avibactam. Susceptibility to ceftazidime-avibactam ranged from 99.4% to 100% for Enterobacteriaceae and from 79.1% to 94.7% for P. aeruginosa when isolates were analyzed by country of origin. Ceftazidime-avibactam inhibited 99.6% to 100% of Enterobacteriaceae isolates that carried serine ß-lactamases, including extended-spectrum ß-lactamases (ESBLs), AmpC cephalosporinases, and carbapenemases (KPC and OXA-48-like) as well as 99.7%, 99.6%, 99.5%, and 99.2% of MBL-negative isolates demonstrating ceftazidime-nonsusceptible, multidrug-resistant (MDR), meropenem-nonsusceptible, and colistin-resistant phenotypes, respectively. Among carbapenem-nonsusceptible isolates of P. aeruginosa (n = 750), 14.7% carried MBLs with or without additional acquired serine ß-lactamases, while in the majority of isolates (70.0%), no acquired ß-lactamase was identified. Ceftazidime-avibactam inhibited 89.5% of carbapenem-nonsusceptible P. aeruginosa isolates in which no acquired ß-lactamase was detected. Overall, clinical isolates of Enterobacteriaceae collected in Latin America from 2012 to 2015 were highly susceptible to ceftazidime-avibactam, including isolates that exhibited resistance to ceftazidime, meropenem, colistin, or an MDR phenotype. Country-specific variations were noted in the susceptibility of P. aeruginosa isolates to ceftazidime-avibactam.

In vitro activity of cefiderocol, a siderophore cephalosporin, against a recent collection of clinically relevant carbapenem-non-susceptible Gram-negative bacilli, including serine carbapenemase- and metallo-ß-lactamase-producing isolates (SIDERO-WT-2014 Study).

Cefiderocol is a siderophore cephalosporin in development for treatment of infections caused by Gram-negative bacilli, including carbapenem-resistant and multidrug-resistant isolates. ß-Lactamase carriage and in vitro activity of cefiderocol were determined against 1272 meropenem-non-susceptible isolates of Enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacter baumannii collected as part of the SIDERO-WT-2014 surveillance study. Minimum inhibitory concentration (MIC) values for cefiderocol were ≤4 µg/mL against 97.7% of tested isolates, including 100% of IMP-positive (range, 1-2 µg/mL), OXA-58-positive (MIC90, 1 µg/mL), KPC-positive (MIC90, 2 µg/mL), VIM-positive (MIC90, 2 µg/mL), and OXA-48-like-positive (MIC90, 4 µg/mL) isolates; 99.3% of carbapenemase-negative isolates (MIC90, 1 µg/mL); 97.2% of OXA-23-positive isolates (MIC90, 1 µg/mL); 95.2% of OXA-24-positive isolates (MIC90, 1 µg/mL); 91.7% of GES-positive isolates (MIC90, 4 µg/mL); and 64.3% of NDM-positive isolates (MIC90, 8 µg/mL). A total of 29 isolates (2.3%; 15 OXA-23-producers, 6 OXA-24-producers, 5 NDM-producers, and 3 carbapenemase-negative isolates) exhibited cefiderocol MIC ≥8 µg/mL, confirming there was no clear correlation between carriage of ß-lactamases included in the molecular testing algorithm and elevated cefiderocol MICs. Similarly, no correlation was observed between cefiderocol MICs and truncation or loss of porin proteins in meropenem-non-susceptible isolates of E. coli and K. pneumoniae. Cefiderocol MICs were also ≤4 µg/mL against 99.3% of 136 colistin-resistant Enterobacteriaceae collected as part of the SIDERO-WT-2014 study, including isolates carrying mcr-1 (MIC90, 2 µg/mL). Cefiderocol demonstrated potent in vitro activity against a collection of carbapenemase-producing and carbapenemase-negative meropenem-non-susceptible Gram-negative bacilli for which few treatment options are available, including the majority of metallo-ß-lactamase producing isolates identified.

In Vitro Activity of Ceftazidime-Avibactam and Aztreonam-Avibactam against OXA-48-Carrying Enterobacteriaceae Isolated as Part of the International Network for Optimal Resistance Monitoring (INFORM) Global Surveillance Program from 2012 to 2015.

Enterobacteriaceae producing the Ambler class D OXA-48 carbapenemase, combined with additional resistance mechanisms, such as permeability defects or cocarriage of class A, B, or C ß-lactamases, can become highly resistant to most ß-lactams currently in use, including carbapenems. A total of 45,872 Enterobacteriaceae clinical isolates collected in 39 countries as part of the International Network for Optimal Resistance Monitoring (INFORM) global surveillance study in 2012 to 2015 were tested for susceptibility to ß-lactams and comparator agents using the Clinical and Laboratory Standards Institute broth microdilution methodology and screened for the presence of ß-lactamases. The blaOXA-48 and blaOXA-48-like genes were detected in 333 isolates across 14 species of Enterobacteriaceae collected in 20 countries across the globe. Few agents tested were effective in vitro against the overall collection of OXA-48-producers (n = 265), with tigecycline (MIC90, 2 µg/ml; 92.5% susceptible), ceftazidime-avibactam (MIC90, 4 µg/ml; 92.5% susceptible), and aztreonam-avibactam (MIC90, 0.5 µg/ml; 99.6% of isolates with MIC ≤8 µg/ml) demonstrating the greatest activity. Similarly, colistin (MIC90, 1 µg/ml; 94.2% susceptible), tigecycline (MIC90, 2 µg/ml; 92.6% susceptible), ceftazidime-avibactam (MIC90, >128 µg/ml; 89.7% susceptible), and aztreonam-avibactam (MIC90, 4 µg/ml; 100% of isolates with MIC ≤8 µg/ml) were most active against OXA-48-like-positive isolates (n = 68). The in vitro activity of ceftazidime-avibactam was improved against the subset of metallo-ß-lactamase (MBL)-negative, OXA-48- and OXA-48-like-positive isolates (99.2% and 100% susceptible, respectively). The data reported here support the continued investigation of ceftazidime-avibactam and aztreonam-avibactam for the treatment of infections caused by carbapenem-resistant Enterobacteriaceae carrying OXA-48 and OXA-48-like ß-lactamases in combination with serine- or metallo-ß-lactamases.

In vitro activity of ceftazidime/avibactam against isolates of Enterobacteriaceae collected in European countries: INFORM global surveillance 2012-15.

Objectives: The activity of ceftazidime/avibactam was assessed against 24 750 isolates of Enterobacteriaceae collected from 96 medical centres in 18 European countries as part of the International Network for Optimal Resistance Monitoring (INFORM) global surveillance programme from 2012 to 2015. Activity was analysed against subsets of isolates based on resistant phenotypes and ß-lactamase content. Methods: Antimicrobial susceptibility testing was performed using broth microdilution and the presence of ß-lactamase genes in isolates of interest was determined using PCR and sequencing. Results: Ceftazidime/avibactam was the most active agent, compared with all other tested comparator agents, against the overall collection of Enterobacteriaceae isolates (99.4% susceptible) and against subsets of ceftazidime-non-susceptible (97.7% susceptible), colistin-resistant (98.2% susceptible), MDR (96.7% susceptible) and meropenem-non-susceptible, MBL-negative (98.5% susceptible) isolates. At the country level, susceptibility to ceftazidime/avibactam ranged from 96.3% to 100% among Enterobacteriaceae isolates, with decreased susceptibilities only observed in countries where MBLs were more frequently encountered (e.g. Greece and Romania). Ceftazidime/avibactam was active against 99.7% of Enterobacteriaceae isolates that carried serine ß-lactamases, including ESBLs, AmpC cephalosporinases and carbapenemases (KPC, GES and OXA-48-like) in all combinations. As expected, ceftazidime/avibactam was not active against isolates carrying MBLs. Conclusions: The data show that ceftazidime/avibactam is highly potent in vitro against clinical isolates of Enterobacteriaceae collected in European countries, including isolates that exhibit resistance to ceftazidime, meropenem and colistin and combined resistance to agents from multiple drug classes.

In vitro activity of ceftazidime/avibactam against isolates of Pseudomonas aeruginosa collected in European countries: INFORM global surveillance 2012-15.

Objectives: The activity of ceftazidime/avibactam was assessed against 5716 Pseudomonas aeruginosa isolates collected from 96 medical centres in 18 European countries as part of the International Network for Optimal Resistance Monitoring (INFORM) global surveillance programme from 2012 to 2015. Activity was analysed against subsets of isolates based on resistance phenotypes and ß-lactamase content. Methods: Antimicrobial susceptibility testing was performed by broth microdilution and ß-lactamase genes were detected by PCR screening and sequencing. Results: Ceftazidime/avibactam was highly active in vitro against the overall collection of P. aeruginosa isolates and colistin-resistant isolates (92.4% and 92.9% susceptible, respectively). Although activity was slightly reduced against MBL-negative subsets of ceftazidime-non-susceptible (79.6% susceptible), meropenem-non-susceptible (85.1% susceptible) and MDR (81.6% susceptible) P. aeruginosa, ceftazidime/avibactam remained the second most active entity, after colistin, compared with all other comparator agents tested. At the country level, susceptibility to ceftazidime/avibactam ranged from 74.6% to 99.6%, with decreased susceptibilities only observed in countries where MBLs are more frequently encountered, such as the Czech Republic, Greece, Romania and Russia. Ceftazidime/avibactam was also active in vitro against 87.6% of meropenem-non-susceptible isolates in which no acquired ß-lactamases were detected by molecular methods; these isolates were assumed to hyperproduce the chromosomally encoded AmpC in combination with alterations in OprD or drug efflux. As expected, ceftazidime/avibactam was not active against isolates carrying MBLs. Conclusions: The data show that ceftazidime/avibactam is highly potent in vitro against clinical isolates of P. aeruginosa collected in European countries, including isolates that exhibit resistance to ceftazidime, meropenem and colistin and combined resistance to agents from multiple drug classes.

In Vitro Activity of Ceftazidime-Avibactam against Clinical Isolates of Enterobacteriaceae and Pseudomonas aeruginosa Collected in Asia-Pacific Countries: Results from the INFORM Global Surveillance Program, 2012 to 2015.

The in vitro activities of ceftazidime-avibactam and comparators against 9,149 isolates of Enterobacteriaceae and 2,038 isolates of Pseudomonas aeruginosa collected by 42 medical centers in nine countries in the Asia-Pacific region from 2012 to 2015 were determined as part of the International Network for Optimal Resistance Monitoring (INFORM) global surveillance program. Antimicrobial susceptibility testing was conducted by Clinical and Laboratory Standards Institute (CLSI) broth microdilution, and isolate subset analysis was performed on the basis of the resistant phenotypes and ß-lactamase content. Ceftazidime-avibactam demonstrated potent in vitro activity (MIC, ≤8 µg/ml) against all Enterobacteriaceae tested (99.0% susceptible) and was the most active against isolates that were metallo-ß-lactamase (MBL) negative (99.8% susceptible). Against P. aeruginosa, 92.6% of all isolates and 96.1% of MBL-negative isolates were susceptible to ceftazidime-avibactam (MIC, ≤8 µg/ml). The rates of susceptibility to ceftazidime-avibactam ranged from 97.0% (Philippines) to 100% (Hong Kong, South Korea) for Enterobacteriaceae and from 83.1% (Thailand) to 100% (Hong Kong) among P. aeruginosa isolates, with lower susceptibilities being observed in countries where MBLs were more frequently encountered (Philippines, Thailand). Ceftazidime-avibactam inhibited 97.2 to 100% of Enterobacteriaceae isolates, per country, that carried serine ß-lactamases, including extended-spectrum ß-lactamases, AmpC cephalosporinases, and carbapenemases (KPC, GES, OXA-48-like). It also inhibited 91.3% of P. aeruginosa isolates that were carbapenem nonsusceptible in which no acquired ß-lactamase was detected. Among MBL-negative Enterobacteriaceae isolates that were ceftazidime nonsusceptible, meropenem nonsusceptible, colistin resistant, and multidrug resistant, ceftazidime-avibactam inhibited 96.1, 87.7, 100, and 98.8% of isolates, respectively, and among MBL-negative P. aeruginosa isolates that were ceftazidime nonsusceptible, meropenem nonsusceptible, colistin resistant, and multidrug resistant, ceftazidime-avibactam inhibited 79.6, 83.6, 83.3, and 68.2% of isolates, respectively. Overall, clinical isolates of Enterobacteriaceae and P. aeruginosa collected in nine Asia-Pacific countries from 2012 to 2015 were highly susceptible to ceftazidime-avibactam.

In Vitro Activity of Imipenem-Relebactam against Clinical Isolates of Gram-Negative Bacilli Isolated in Hospital Laboratories in the United States as Part of the SMART 2016 Program.

Relebactam is a non-ß-lactam, bicyclic diazabicyclooctane ß-lactamase inhibitor of class A and class C ß-lactamases, including Klebsiella pneumoniae carbapenemases (KPCs). It is in phase 3 clinical development in combination with imipenem/cilastatin. The in vitro activities of imipenem-relebactam, imipenem, and comparators were determined using the Clinical and Laboratory Standards Institute (CLSI) reference broth microdilution method for isolates of Enterobacteriaceae (n = 3,419) and Pseudomonas aeruginosa (n = 896) collected in 2016 by 21 U.S. hospital laboratories participating in the SMART (Study for Monitoring Antimicrobial Resistance Trends) global surveillance program. Relebactam was tested at a fixed concentration of 4 µg/ml. Imipenem-relebactam MICs were interpreted using CLSI breakpoints for imipenem. Rates of susceptibility to imipenem-relebactam and imipenem for non-ProteeaeEnterobacteriaceae (n = 3,143) and P. aeruginosa were 99.1% (3,115/3,143) and 95.9% (3,013/3,143) and were 94.4% (846/896) and 74.7% (669/896), respectively. Relebactam restored imipenem susceptibility to 78.5% (102/130) of imipenem-nonsusceptible non-ProteeaeEnterobacteriaceae and to 78.0% (177/227) of imipenem-nonsusceptible P. aeruginosa isolates. Susceptibility to imipenem-relebactam was 98.2% (444/452) and 82.2% (217/264) for multidrug-resistant (MDR) non-ProteeaeEnterobacteriaceae and MDR P. aeruginosa, respectively. Given the ability of relebactam to restore susceptibility to imipenem in nonsusceptible isolates of both non-ProteeaeEnterobacteriaceae and P. aeruginosa and to demonstrate potent activity against current MDR isolates of both non-ProteeaeEnterobacteriaceae and P. aeruginosa, further development of imipenem-relebactam appears warranted.

In vitro activity of imipenem/relebactam against Gram-negative ESKAPE pathogens isolated in 17 European countries: 2015 SMART surveillance programme.

Objectives: Relebactam is an inhibitor of class A ß-lactamases, including KPC ß-lactamases, and class C ß-lactamases, and is currently under clinical development in combination with imipenem. The objective of the current study was to evaluate the in vitro activity of imipenem/relebactam against Gram-negative ESKAPE pathogens (Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter spp.) submitted by clinical laboratories in 17 European countries to the Study for Monitoring Antimicrobial Resistance Trends (SMART) global surveillance programme in 2015. Methods: MICs were determined using the CLSI standard broth microdilution method and interpreted using EUCAST clinical breakpoints. Relebactam was tested at a fixed concentration of 4 mg/L in combination with doubling dilutions of imipenem. Imipenem/relebactam MICs were interpreted using breakpoints for imipenem. Results: Rates of susceptibility to imipenem and imipenem/relebactam for isolates of P. aeruginosa (n = 1705), K. pneumoniae (n = 1591) and Enterobacter spp. (n = 772) were 72.0/94.7%, 88.7/94.8% and 95.6/96.8%, respectively. Relebactam restored imipenem susceptibility to 81.1%, 54.2% and 26.5% of imipenem-non-susceptible isolates of P. aeruginosa (n = 477), K. pneumoniae (n = 179) and Enterobacter spp. (n = 34). Most imipenem/relebactam-non-susceptible isolates carried MBLs, OXA-48 or GES carbapenemases. Relebactam did not increase the number of isolates of A. baumannii (n = 486) susceptible to imipenem. Conclusions: Relebactam restored susceptibility to imipenem for the majority of imipenem-non-susceptible isolates of P. aeruginosa and K. pneumoniae tested as well as some isolates of imipenem-non-susceptible Enterobacter spp. Based on our results, imipenem/relebactam appears to be a promising therapeutic option for treating patients with infections caused by antimicrobial-resistant Gram-negative bacilli.

Prevalence of mcr-type genes among colistin-resistant Enterobacteriaceae collected in 2014-2016 as part of the INFORM global surveillance program.

A set of 908 clinically derived colistin-resistant Enterobacteriaeae isolates collected worldwide in 2014-2016 were screened for the presence of the plasmid-borne mcr-1, mcr-2, mcr-3, mcr-4 and mcr-5 genes. In total 3.2% (29/908) of the collection were positive for mcr, including 27 Escherichia coli, 1 Klebsiella pneumoniae and 1 Enterobacter cloacae. Twenty-four isolates possessed genes from the mcr-1 family, including the original mcr-1 (n = 22), as well as mcr-1.2 (n = 1) and mcr-1.5 (n = 1), which each differ from mcr-1 by encoding single amino acid variations. Genes from the mcr-3 family were found in isolates from Thailand, including mcr-3.1 (n = 3) and mcr-3.2 (n = 1). An E. coli isolated from a patient with a urinary tract infection in Colombia contained the recently discovered mcr-5. The full colistin-resistant collection was tested against a panel of antimicrobial agents with ceftazidime-avibactam and tigecycline exhibiting the highest activity.

Global survey of Klebsiella pneumoniae major porins from ertapenem non-susceptible isolates lacking carbapenemases.

PURPOSE: To understand the diversity of porin disruption in Klebsiella pneumoniae, the major outer membrane protein (OMP) porins, OmpK35 and OmpK36, were examined in a set of isolates that did not harbour traditional carbapenem-hydrolysing enzymes, but nevertheless tested non-susceptible to ertapenem. METHODS: A world-wide collection of Klebsiella pneumoniae isolates that were part of the Study for Monitoring Antimicrobial Resistance Trends (SMART) surveillance project over the years 2008-2014 were characterised with regard to their ß-lactamase gene carriage and potential permeability defects. Four hundred and eighty-seven isolates that did not carry carbapenemase genes, but were non-susceptible to ertapenem, were investigated by sequence analysis of the genes encoding OmpK35 and OmpK36. Isolates without obvious genetic lesions in either major porin gene were further examined by outer membrane protein SDS-PAGE. RESULTS: The majority of isolates, 83.0 % (404/487), exhibited clear genetic disruption in either or both of the ompK35 and ompK36 genes. Among the proportion of the collection with the highest ertapenem MIC value (>4 mg l-1), 60.5 % (115/190) showed mutation in both porin genes. Isolates without obvious genetic mutations were examined by SDS-PAGE, and 90.4 % (75/83) were found to lack or show altered expression of at least one of the major OMPs when compared to an ertapenem sensitive control strain. CONCLUSION: This study illustrates that porin deficiency in Klebsiella pneumoniae is a widespread phenomenon, and in combination with ESBLs and/or AmpC enzymes, likely accounts for the elevated ertapenem MICs observed in this study.