<i>In Vitro</i>
            Activity of Ceftolozane-Tazobactam, Imipenem-Relebactam, Ceftazidime-Avibactam, and Comparators against Pseudomonas aeruginosa Isolates Collected in United States Hospitals According to Results from the SMART Surveillance Program, 2018 to 2020

Karlowsky, James A.; Lob, Sibylle; DeRyke, C Andrew; Hilbert, David W.; Wong, Michael; Young, Katherine; Siddiqui, Fakhar; Motyl, Mary; Sahm, Daniel F.

doi:10.1128/aac.00189-22

Cited by 26 publications

(21 citation statements)

References 35 publications

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“…The rate of susceptibility for CZA amongst multidrug-resistant (MDR) isolates was 63.3% in P. aeruginosa. However, a raise of MIC for CZA amongst all isolates, exceeding the susceptibility-breakpoint, was observed from 2018 to 2020, whereas only a minority of the isolates carried an MBL (Karlowsky et al, 2022b), suggesting adaptive resistance mechanisms as causative for the CZA-resistance. In a 5-year survey, from 2014 to 2019, of more than 7000 P. aeruginosa isolates, the annual percent susceptibility rates from North America were higher for CZA (96-99.6%) than for isolates from Europe (90.3-93.1%), 25% of the distinct carbapenem-resistant isolates were also CZAresistant (Karlowsky et al, 2022a), however, no data was acquired on prevalence of carbapenemases in these specific isolates.…”

Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 95%

“…We did not detect carbapenemases in any of the isolates. In a two-years surveillance of more than 2000 P. aeruginosa isolates from the United States, carbapenemases were detected only in 5.9% and 1.0% of 781 IPM- and 119 CZA-resistant isolates respectively ( Karlowsky et al., 2022b ). The rate of susceptibility for CZA amongst multidrug-resistant (MDR) isolates was 63.3% in P. aeruginosa.…”

Section: Discussionmentioning

confidence: 99%

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Multifactorial resistance mechanisms associated with resistance to ceftazidime-avibactam in clinical Pseudomonas aeruginosa isolates from Switzerland

Flury

Bösch

Gisler

et al. 2023

Front. Cell. Infect. Microbiol.

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BackgroundIncreasing reports of multidrug resistance (MDR) in clinical Pseudomonas aeruginosa have led to a necessity for new antimicrobials. Ceftazidime-avibactam (CZA) is indicated for use against MDR P. aeruginosa across a broad range of infection types and particularly those that are carbapenem resistant. This study sought to determine the molecular mechanisms of CZA and imipenem (IPM)-resistance in clinical P. aeruginosa isolates obtained from Swiss hospitals.MethodsClinical P. aeruginosa isolates were obtained from inpatients in three hospitals in Switzerland. Susceptibility was determined by either antibiotic disc testing or broth microdilution according to EUCAST methodology. AmpC activity was determined using cloxacillin and efflux activity was determined using phenylalanine-arginine β-naphthylamide, in agar plates. Whole Genome Sequencing was performed on 18 clinical isolates. Sequence types (STs) and resistance genes were ascertained using the Centre for Genomic Epidemiology platform. Genes of interest were extracted from sequenced isolates and compared to reference strain P. aeruginosa PAO1.ResultsSixteen different STs were identified amongst the 18 isolates in this study indicating a high degree of genomic diversity. No carbapenemases were detected but one isolate did harbor the ESBL blaPER-1. Eight isolates were CZA-resistant with MICs ranging from 16-64 mg/L, and the remaining ten isolates had either low/wildtype MICs (n=6; 1-2 mg/L) or elevated, but still susceptible, MICs (n=4; 4-8 mg/L). Ten isolates were IPM-resistant, seven of which had mutations resulting in truncations of OprD, and the remaining nine IPM-susceptible isolates had intact oprD genes. Within CZA-R isolates, and those with reduced susceptibility, mutations resulting in ampC derepression, OprD loss, mexAB overexpression and ESBL (blaPER-1) carriage were observed in various combinations and one harbored a truncation of the PBP4 dacB gene. Within the six isolates with wildtype-resistance levels, five had no mutations that would affect any antimicrobial resistance (AMR) genes of interest when compared to PAO1.ConclusionThis preliminary study highlights that CZA-resistance in P. aeruginosa is multifactorial and could be caused by the interplay between different resistance mechanisms including ESBL carriage, increased efflux, loss of permeability and derepression of its intrinsic ampC.

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Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

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Multifactorial resistance mechanisms associated with resistance to ceftazidime-avibactam in clinical Pseudomonas aeruginosa isolates from Switzerland

Flury

Bösch

Gisler

et al. 2023

Front. Cell. Infect. Microbiol.

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“…An antimicrobial was paired with an AR event if the antimicrobial was typically active against the AR organism and was frequently used to treat the AR organism in clinical practice. The following AU/AR ratios were identified (in alphabetical order by antimicrobial): ceftazidime‐avibactam/carbapenem‐resistant Enterobacterales, 17 ceftazidime‐avibactam/multidrug‐resistant P. aeruginosa , 18 ceftolozane‐tazobactam/multidrug‐resistant P. aeruginosa , 19 colistin/carbapenem‐nonsusceptible Acinetobacter , 20 daptomycin/vancomycin‐resistant Enterococcus , 21 linezolid/vancomycin‐resistant Enterococcus , 22 meropenem/ESBL Enterobacterales, 23 and intravenous vancomycin/methicillin‐resistant S. aureus 24 . All AU/AR ratios were expressed as the number of antimicrobial therapy days per AR event per month.…”

Section: Methodsmentioning

confidence: 99%

Computing antimicrobial use/antimicrobial resistance ratios: A novel way to assess inpatient antimicrobial utilization using current National Healthcare Safety Network metrics

Santos

Martinez

Won

et al. 2022

Transplant Infectious Dis

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Background Current methods for benchmarking inpatient antimicrobial use (AU) could benefit from combining AU with antimicrobial resistance (AR) information to provide metrics benchmarked to microbiological data; this may yield more instructive and better risk‐adjusted measurements than AU and AR in isolation. Methods In this retrospective single‐center study, we computed facility‐wide AU/AR ratios from 2019 to 2020 for specific antimicrobial agents and corresponding AR events, and compared median monthly AU/AR ratios between March 2019 through December 2019 (pre‐COVID period) and March 2020 through December 2020 (COVID period). Aggregate AU was expressed as a ratio to aggregate AR events for antimicrobials that typically have activity against the AR organism and are frequently used to treat the AR organism in clinical practice. We also computed AU/AR ratios in our surgical intensive care unit in the pre‐COVID period. Results High‐median facility‐wide monthly AU/AR ratios were observed for intravenous vancomycin/methicillin‐resistant Staphylococcus aureus, with 130.0 in the pre‐COVID period and 121.3 in the COVID period (p =.520). Decreases in facility‐wide median monthly AU/AR ratios were observed between periods for meropenem/ESBL Enterobacterales (20.9 vs. 7.9, p < .001), linezolid/vancomycin‐resistant Enterococcus (48.5 vs. 15.8, p =.004), and daptomycin/vancomycin‐resistant Enterococcus (32.2 vs. 4.8, p = .002). Increases in facility‐wide median monthly AU/AR ratios were observed between periods for ceftazidime‐avibactam/carbapenem‐resistant Enterobacterales (0.0 vs. 3.2, p = .020) and ceftazidime‐avibactam/multidrug‐resistant Pseudomonas aeruginosa (0.0 vs. 4.0, p = .017). The AU/AR ratio for intravenous vancomycin/methicillin‐resistant S. aureus in the surgical intensive care unit was 191.5 in the pre‐COVID period. Conclusions AU/AR ratios may be used to supplement current AU and AR metrics. Future directions should include the development of more AU metrics benchmarked to microbiological information. AU metrics more specific to transplant infectious diseases should be developed.

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“…The combination of IMI/CILA/RELE plus aztreonam was tested against MBL-producing OprD-deficient P. aeruginosa isolates and it presented synergy [ 63 ]. IMI/CILA/RELE can retain activity against many ceftazidime-avibactam- and ceftolozane-tazobactam-resistant P. aeruginosa isolates [ 51 , 64 ].…”

Section: Recently Approved Antimicrobial Agentsmentioning

confidence: 99%

Novel Antimicrobial Agents for Gram-Negative Pathogens

et al. 2023

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Gram-negative bacterial resistance to antimicrobials has had an exponential increase at a global level during the last decades and represent an everyday challenge, especially for the hospital practice of our era. Concerted efforts from the researchers and the industry have recently provided several novel promising antimicrobials, resilient to various bacterial resistance mechanisms. There are new antimicrobials that became commercially available during the last five years, namely, cefiderocol, imipenem-cilastatin-relebactam, eravacycline, omadacycline, and plazomicin. Furthermore, other agents are in advanced development, having reached phase 3 clinical trials, namely, aztreonam-avibactam, cefepime-enmetazobactam, cefepime-taniborbactam, cefepime-zidebactam, sulopenem, tebipenem, and benapenem. In this present review, we critically discuss the characteristics of the above-mentioned antimicrobials, their pharmacokinetic/pharmacodynamic properties and the current clinical data.

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In Vitro Activity of Ceftolozane-Tazobactam, Imipenem-Relebactam, Ceftazidime-Avibactam, and Comparators against Pseudomonas aeruginosa Isolates Collected in United States Hospitals According to Results from the SMART Surveillance Program, 2018 to 2020

Cited by 26 publications

References 35 publications

Multifactorial resistance mechanisms associated with resistance to ceftazidime-avibactam in clinical Pseudomonas aeruginosa isolates from Switzerland

Multifactorial resistance mechanisms associated with resistance to ceftazidime-avibactam in clinical Pseudomonas aeruginosa isolates from Switzerland

Computing antimicrobial use/antimicrobial resistance ratios: A novel way to assess inpatient antimicrobial utilization using current National Healthcare Safety Network metrics

Novel Antimicrobial Agents for Gram-Negative Pathogens

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