scholarly journals In vitro Activity of Ceftazidime-Avibactam and Aztreonam-Avibactam Against Carbapenem-resistant Enterobacteriaceae Isolates Collected from Three Secondary Hospitals in Southwest China Between 2018 and 2019

2020 ◽  
Vol Volume 13 ◽  
pp. 3563-3568
Author(s):  
Chunhong Zou ◽  
Jie Wei ◽  
Baoju Shan ◽  
Xian Chen ◽  
Deqiang Wang ◽  
...  
Keyword(s):  
Southwest China ◽  
Vitro Activity ◽  
In Vitro Activity ◽  
Carbapenem Resistant

scholarly journals Cefepime/sulbactam as an enhanced antimicrobial combination therapy for the treatment of MDR Gram-negative infections

2019 ◽  
Author(s):  
David W Wareham ◽  
M H F Abdul Momin ◽  
Lynette M Phee ◽  
Michael Hornsey ◽  
Joseph F Standing
Keyword(s):  
Fixed Ratio ◽  
Vitro Activity ◽  
Definitive Treatment ◽  
High Dose ◽  
In Vitro Activity ◽  
Gram Negative ◽  
Pharmacodynamic Modelling ◽  
Carbapenem Resistant ◽  
Combination Regimens

Abstract Background β-Lactam (BL)/β-lactamase inhibitor (BLI) combinations are widely used for the treatment of Gram-negative infections. Cefepime has not been widely studied in combination with BLIs. Sulbactam, with dual BL/BLI activity, has been partnered with very few BLs. We investigated the potential of cefepime/sulbactam as an unorthodox BL/BLI combination against MDR Gram-negative bacteria. Methods In vitro activity of cefepime/sulbactam (1:1, 1:2 and 2:1) was assessed against 157 strains. Monte Carlo simulation was used to predict the PTA with a number of simulated cefepime combination regimens, modelled across putative cefepime/sulbactam breakpoints (≤16/≤0.25 mg/L). Results Cefepime/sulbactam was more active (MIC50/MIC90 8/8–64/128 mg/L) compared with either drug alone (MIC50/MIC90 128 to >256 mg/L). Activity was enhanced when sulbactam was added at 1:1 or 1:2 (P < 0.05). Reduction in MIC was most notable against Acinetobacter baumannii and Enterobacterales (MIC 8/8–32/64 mg/L). Pharmacokinetic/pharmacodynamic modelling highlighted that up to 48% of all isolates and 73% of carbapenem-resistant A. baumannii with a cefepime/sulbactam MIC of ≤16/≤8 mg/L may be treatable with a high-dose, fixed-ratio (1:1 or 1:2) combination of cefepime/sulbactam. Conclusions Cefepime/sulbactam (1:1 or 1:2) displays enhanced in vitro activity versus MDR Gram-negative pathogens. It could be a potential alternative to existing BL/BLI combinations for isolates with a cefepime/sulbactam MIC of 16/8 mg/L either as a definitive treatment or as a carbapenem-sparing option.

scholarly journals 1360. Antimicrobial Activity of Cefepime in Combination with VNRX-5133 Against a Global Collection of Enterobacteriaceae Including Resistant Phenotypes

2018 ◽  
Vol 5 (suppl_1) ◽  
pp. S416-S417 ◽  
Author(s):  
Meredith Hackel ◽  
Dan Sahm
Keyword(s):  
Vitro Activity ◽  
In Vitro Activity ◽  
First Line ◽  
First Line Therapy ◽  
Carbapenem Resistant ◽  
Line Therapy ◽  
Resistant Strains ◽  
Further Development ◽  
Dose Dependent

Abstract Background VNRX-5133 is a novel cyclic boronate-based broad-spectrum β-lactamase inhibitor with potent and selective direct inhibitory activity against both serine- and metallo-β-lactamases (Ambler Classes A, B, C, and D). In this analysis, we evaluated the activity of cefepime (FEP) in combination with VNRX-5133 and comparators against 1,120 recent Enterobacteriaceae clinical isolates, including carbapenem-resistant strains. Methods MICs of FEP with VNRX-5133 fixed at 4 µg/mL (FEP/VNRX-5133) were determined following CLSI M07-A10 guidelines against 1,120 Enterobacteriaceae from community and hospital infections collected globally in 2012–2013. Resistant phenotypes were based on 2017 CLSI breakpoints. As FEP/VNRX-5133 breakpoints have not yet been established, the FEP 2 g q8h susceptible dose-dependent (SDD) breakpoint of ≤8 µg/mL was considered for comparative purposes. Results FEP/VNRX-5133 showed potent in vitro activity against drug-resistant subsets of Enterobacteriaceae, with MIC90 values ranging from 1 µg/mL against ceftazidime-, levofloxacin-, or piperacillin–tazobactam-nonsusceptible isolates, to 8 µg/mL against meropenem-nonsusceptible isolates. FEP/VNRX-5133 inhibited &gt;93% of all resistant subsets at ≤8 µg/mL. Conclusion Cefepime in combination with VNRX-5133 demonstrated potent in vitro activity against Enterobacteriaceae, including cephalosporin-, fluoroquinolone- and carbapenem-resistant (CRE) isolates. Because this drug combination exhibited substantial potential for the treatment of infections caused by isolates often resistant to first-line therapy, further development is warranted. Disclosures M. Hackel, IHMA, Inc.: Employee, Salary. VenatoRx: Consultant, Consulting fee. D. Sahm, IHMA, Inc.: Employee, Salary. VenatoRx: Consultant, Consulting fee.

scholarly journals 1348. In vitro Activity of Plazomicin, a Next-Generation Aminoglycoside, Against Carbapenemase-Producing Klebsiella pneumoniae

2018 ◽  
Vol 5 (suppl_1) ◽  
pp. S412-S413
Author(s):  
Michael R Jacobs ◽  
Caryn E Good ◽  
Ayman M Abdelhamed ◽  
Daniel D Rhoads ◽  
Kristine M Hujer ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
Carbapenem Resistance ◽  
Vitro Activity ◽  
In Vitro Activity ◽  
Next Generation ◽  
Aminoglycoside Resistance ◽  
Carbapenem Resistant ◽  
Carbapenemase Gene ◽  
Research Grant

Abstract Background Plazomicin is a next-generation aminoglycoside with in vitro activity against multidrug-resistant Gram-negative species, including carbapenem-resistant isolates. The Consortium on Resistance Against Carbapenems in Klebsiella and other Enterobacteriaceae (CRACKLE) is a federally funded, prospective multicenter consortium of 20 hospitals from nine US healthcare systems to track carbapenem-resistant Enterobacteriaceae. Methods Minimum inhibitory concentrations (MICs) of plazomicin were determined by broth microdilution according to current CLSI guidelines against a collection of 697 carbapenem-resistant Klebsiella pneumoniae with defined carbapenem resistance mechanisms, including KPC and OXA carbapenemases. Isolates were submitted by participating CRACKLE centers. Results Carbapenemases present in study isolates included KPC-2 (n = 323), KPC-3 (n = 364), KPC-4 (n = 2), OXA-48 like (n = 7), and NDM (n = 1). Plazomicin MICs ranged from ≤0.12 to &gt;32 mg/L, with MIC50 and MIC90 values of 0.25 and 1 mg/L, respectively (figure). MICs of 689 (98.8%) isolates were ≤4 mg/L, while MICs of the remaining eight isolates were &gt;32 mg/L. Plazomicin MICs were related to specific carbapenemases present in isolates: of eight isolates with MICs &gt;32 mg/L, seven contained OXA-48 like and one contained KPC-3, suggesting that these isolates possess an aminoglycoside-resistance mechanism on the same plasmid as their carbapenemase gene, such as a 16S ribosomal RNA methyltransferase, against which plazomicin is not active. Conclusion Plazomicin has good in vitro potency against a collection of carbapenemase-producing K. pneumoniae, with MIC90 value of 1 mg/L and MICs of ≤4 mg/L for 98.9% of isolates. Disclosures M. R. Jacobs, Achaogen: Investigator, Research grant. Shionogi: Investigator, Research grant. L. Connolly, Achaogen, Inc.: Consultant, Consulting fee. K. M. Krause, Achaogen: Employee, Salary. S. S. Richter, bioMerieux: Grant Investigator, Research grant. BD Diagnostics: Grant Investigator, Research grant. Roche: Grant Investigator, Research grant. Hologic: Grant Investigator, Research grant. Diasorin: Grant Investigator, Research grant. Accelerate: Grant Investigator, Research grant. Biofire: Grant Investigator, Research grant. D. Van Duin, achaogen: Scientific Advisor, Consulting fee. shionogi: Scientific Advisor, Consulting fee. Allergan: Scientific Advisor, Consulting fee. Astellas: Scientific Advisor, Consulting fee. Neumedicine: Scientific Advisor, Consulting fee. Roche: Scientific Advisor, Consulting fee. T2 Biosystems: Scientific Advisor, Consulting fee.

scholarly journals 681. In vitro Activity of the β-Lactamase Inhibitor QPX7728 in Combination with Several β-Lactams Against Acinetobacter baumannii (AB) and Pseudomonas aeruginosa (PSA)

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S310-S311 ◽  
Author(s):  
Olga Lomovskaya ◽  
Jill Lindley ◽  
Debora Rubio-Aparicio ◽  
Kirk J Nelson ◽  
Mariana Castanheira
Keyword(s):  
Resistance Mechanisms ◽  
Vitro Activity ◽  
Clinical Isolates ◽  
In Vitro Activity ◽  
Microdilution Method ◽  
Carbapenem Resistant ◽  
Broth Microdilution Method ◽  
Data Representative ◽  
Lactamase Inhibitor

Abstract Background QPX7728 (QPX) is a novel broad-spectrum boron-containing inhibitor of serine- and metallo-β-lactamases (MBLs). We evaluated the in vitro activity of QPX combined with several β-lactams against carbapenem-resistant AB (CRAB) and PSA clinical isolates with varying β-lactam resistance mechanisms. Methods A total of 503 CRAB (meropenem [MEM] MIC ≥8 µg/mL) and 762 PSA clinical isolates were tested by the reference broth microdilution method against β-lactams alone and combined with QPX (4 µg/mL and 8 µg/mL). PSA isolates were selected to represent the normal distribution of MEM, ceftazidime–avibactam (CAZ-AVI), and ceftolozane-tazobactam (TOL-TAZ) resistance according to 2017 surveillance data (representative panel). Additionally, 262 PSA isolates that were either nonsusceptible (NS) to MEM (MIC, ≥4 µg/mL) or to TOL-TAZ (MIC, ≥8 µg/mL), or resistant (R) to CAZ-AVI (MIC, ≥16 µg/mL) (challenge panel) were also tested. Within this 262 strain challenge set, 56 strains carried MBLs and the majority also had nonfunctional OprD. Results Against CRAB, QPX at 4 and 8 µg/mL increased the potency of all β-lactams tested. MEM-QPX was the most potent combination (table) displaying MIC50/MIC90 at 1/8 and 0.5/4 µg/mL with QPX at fixed 4 and 8 µg/mL, respectively. Susceptibility (S) to MEM was restored in >95% of strains. Against the 500 PSA from the representative panel, S for all QPX combinations was >90%. For the challenge panel, TOL-QPX and piperacillin (PIP)-QPX were the most potent combinations, restoring S in 76–77% of strains. TOL-QPX and MEM-QPX or cefepime (FEP)-QPX restored the MIC values to S rates when applying the CLSI breakpoint for the compound alone (comparison purposes only) in ~90% and ~75% of non-MBL-producing strains, respectively, vs. 60–70% for TOL-TAZ and CAZ-AVI. PIP-QPX reduce the MIC values to S values for PIP-TAZ in ~60% of MBL-producing strains vs. 20–30% and 3–7% for other QPX combinations and non-QPX tested combinations, respectively. Conclusion Combinations of QPX with various β-lactam antibiotics displayed potent activity against CRAB and resistant PSA isolates and warrant further investigation. Disclosures All authors: No reported disclosures.

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