scholarly journals Ceftazidime–avibactam and ceftolozane–tazobactam susceptibility of multidrug resistant Pseudomonas aeruginosa strains in Hungary

2020 ◽  
pp. 1-5 ◽  
Author(s):  
Dustin O'Neall ◽  
Emese Juhász ◽  
Ákos Tóth ◽  
Edit Urbán ◽  
Judit Szabó ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Inhibitory Concentration ◽  
Carbapenem Resistance ◽  
Multidrug Resistant ◽  
Test Results ◽  
Diffusion Test ◽  
Microdilution Method ◽  
Carbapenem Resistant ◽  
Gradient Diffusion ◽  
Broth Microdilution Method

Abstract Our objective was to compare the activity ceftazidime-avibactam (C/A) and ceftolozane–tazobactam (C/T) against multidrug (including carbapenem) resistant Pseudomonas aeruginosa clinical isolates collected from six diagnostic centers in Hungary and to reveal the genetic background of their carbapenem resistance. Two hundred and fifty consecutive, non-duplicate, carbapenem-resistant multidrug resistant (MDR) P. aeruginosa isolates were collected in 2017. Minimal inhibitory concentration values of ceftazidime, cefepime, piperacillin/tazobactam, C/A and C/T were determined by broth microdilution method and gradient diffusion test. Carbapenem inactivation method (CIM) test was performed on all isolates. Carbapenemase-encoding blaVIM, blaIMP, blaKPC, blaOXA-48-like and blaNDM genes were identified by multiplex PCR. Of the isolates tested, 33.6& and 32.4& showed resistance to C/A and C/T, respectively. According to the CIM test results, 26& of the isolates were classified as carbapenemase producers. The susceptibility of P. aeruginosa isolates to C/A and C/T without carbapenemase production was 89& and 91&, respectively. Of the CIM-positive isolates, 80& were positive for blaVIM and 11& for blaNDM. The prevalence of Verona integron-encoded metallo-beta-lactamase (VIM)-type carbapenemase was 20.8&. NDM was present in 2.8& of the isolates. Although the rate of carbapenemase-producing P. aeruginosa strains is high, a negative CIM result indicates that either C/A or C/T could be effective even if carbapenem resistance has been observed.

Evaluation of the in vitro interaction of fosfomycin and meropenem against metallo-β-lactamase–producing Pseudomonas aeruginosa using Etest and time-kill assay

2020 ◽  
pp. jim-2020-001573
Author(s):  
Sanjida Jahan ◽  
Heather Davis ◽  
Deborah S Ashcraft ◽  
George A Pankey
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Inhibitory Concentration ◽  
Multidrug Resistant ◽  
Resistance Mechanisms ◽  
Microdilution Method ◽  
Broth Microdilution Method ◽  
Time Kill ◽  
In Vitro Interaction ◽  
Antimicrobial Combinations

Pseudomonas aeruginosa is a nosocomial pathogen containing various resistance mechanisms. Among them, metallo-β-lactamase (MBL)–producing Pseudomonas are difficult to treat. Fosfomycin is an older antibiotic that has recently seen increased usage due to its activity against a broad spectrum of multidrug-resistant organisms. Our aim was to evaluate the combination of fosfomycin and meropenem against 20 MBL-producing P. aeruginosa (100% meropenem-resistant and 20% fosfomycin-resistant) using both an Etest minimal inhibitory concentration (MIC): MIC method and time-kill assay. MICs for fosfomycin and meropenem were determined by Etest and by broth microdilution method for the latter. The combination demonstrated synergy by Etest in 3/20 (15%) isolates and 5/20 (25%) isolates by time-kill assay. Results from the Etest method and time-kill assay were in agreement for 14/20 (70%) of isolates. No antagonism was found. Comparing both methods, Etest MIC: MIC method may be useful to rapidly evaluate other antimicrobial combinations.

Geographic Patterns of Carbapenem-resistant Pseudomonas aeruginosa in the Asia-Pacific Region: Results from the Antimicrobial Testing Leadership and Surveillance (ATLAS) program, 2015–2019

2021 ◽  
Author(s):  
Yu-Lin Lee ◽  
Wen-Chien Ko ◽  
Po-Ren Hsueh
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Antimicrobial Agents ◽  
Carbapenem Resistance ◽  
Multidrug Resistant ◽  
Asia Pacific ◽  
Pacific Region ◽  
Asia Pacific Region ◽  
Carbapenem Resistant ◽  
Broth Microdilution Method ◽  
Resistance Patterns

Pseudomonas aeruginosa is a common pathogen that is associated with multidrug-resistant (MDR) and carbapenem-resistant (CR) phenotypes; therefore, we investigated its resistance patterns and mechanisms by using data from the Antimicrobial Testing Leadership and Surveillance (ATLAS) program in the Asia-Pacific region during 2015–2019. MICs were determined using the broth microdilution method. Genes encoding major extended-spectrum β-lactamases and carbapenemases were investigated by multiplex PCR assays. Susceptibility was interpreted using the Clinical and Laboratory Standards Institute (CLSI) breakpoints. A total of 6,349 P. aeruginosa isolates were collected in the ATLAS program between 2015 and 2019 from 14 countries. According to the CLSI definitions, the numbers (and rates) of CR and MDR P. aeruginosa were 1,198 (18.9%) and 1,303 (20.5%), respectively. For 747 of the CR P. aeruginosa strains that were available for gene screening, 253 β-lactamases genes were detected in 245 (32.8%) isolates. The most common gene was bla VIM (29.0, 71/245), followed by bla NDM (24.9%, 61/245) and bla VEB (20.8%, 51/245). The resistance patterns and associated genes varied significantly between the countries in the Asia-Pacific region. India had the highest rates of carbapenem resistance (29.3%, 154/525) and gene detection (17.7%, 93/525). Compared to those harboring either class A or B β-lactamase genes, the CR P. aeruginosa without detected β-lactamase genes had lower MICs for most of the antimicrobial agents, including ceftazidime/avibactam and ceftolozane/tazobactam. In conclusion, MDR and CR P. aeruginosa infections pose a major threat, particularly those with detected carbapenemase genes. Continuous surveillance is important for improving antimicrobial stewardship and antibiotic prescriptions.

scholarly journals Curcumin, a Natural Antimicrobial Agent with Strain-Specific Activity

2020 ◽  
Vol 13 (7) ◽  
pp. 153
Author(s):  
Artur Adamczak ◽  
Marcin Ożarowski ◽  
Tomasz M. Karpiński
Keyword(s):  
Inhibitory Concentration ◽  
Specific Activity ◽  
Curcuma Longa ◽  
Antimicrobial Properties ◽  
Antiviral Agent ◽  
Multidrug Resistant ◽  
Gram Negative Bacteria ◽  
Microdilution Method ◽  
Broth Microdilution Method ◽  
Bioactive Substance

Curcumin, a principal bioactive substance of turmeric (Curcuma longa L.), is reported as a strong antioxidant, anti-inflammatory, antibacterial, antifungal, and antiviral agent. However, its antimicrobial properties require further detailed investigations into clinical and multidrug-resistant (MDR) isolates. In this work, we tested curcumin’s efficacy against over 100 strains of pathogens belonging to 19 species. This activity was determined by the broth microdilution method and by calculating the minimum inhibitory concentration (MIC). Our findings confirmed a much greater sensitivity of Gram-positive than Gram-negative bacteria. This study exhibited a significantly larger variation in the curcumin activity than previous works and suggested that numerous clinical strains of widespread pathogens have a poor sensitivity to curcumin. Similarly, the MICs of the MDR types of Staphylococcus aureus, S. haemolyticus, Escherichia coli, and Proteus mirabilis were high (≥2000 µg/mL). However, curcumin was effective against some species and strains: Streptococcus pyogenes (median MIC = 31.25 µg/mL), methicillin-sensitive S. aureus (250 µg/mL), Acinetobacter lwoffii (250 µg/mL), and individual strains of Enterococcus faecalis and Pseudomonas aeruginosa (62.5 µg/mL). The sensitivity of species was not associated with its affiliation to the genus, and it could differ a lot (e.g., S. pyogenes, S. agalactiae and A. lwoffii, A. baumannii). Hence, curcumin can be considered as a promising antibacterial agent, but with a very selective activity.

scholarly journals Results from the China Antimicrobial Surveillance Network (CHINET) in 2017 of the In Vitro Activities of Ceftazidime-Avibactam and Ceftolozane-Tazobactam against Clinical Isolates of Enterobacteriaceae and Pseudomonas aeruginosa

2019 ◽  
Vol 63 (4) ◽  
Author(s):  
Dandan Yin ◽  
Shi Wu ◽  
Yang Yang ◽  
Qingyu Shi ◽  
Dong Dong ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Clinical Isolates ◽  
Surveillance Network ◽  
Content Type ◽  
Highly Active ◽  
Microdilution Method ◽  
Carbapenem Resistant ◽  
Antimicrobial Surveillance ◽  
Broth Microdilution Method

ABSTRACT The in vitro activities of ceftazidime-avibactam (CZA), ceftolozane-tazobactam (C-T), and comparators were determined for 1,774 isolates of Enterobacteriaceae and 524 isolates of Pseudomonas aeruginosa collected by 30 medical centers from the China Antimicrobial Surveillance Network (CHINET) in 2017. Antimicrobial susceptibility testing was performed by the CLSI broth microdilution method, and blaKPC and blaNDM were detected by PCR for all carbapenem-resistant Enterobacteriaceae (CRE). Ceftazidime-avibactam demonstrated potent activity against almost all Enterobacteriaceae (94.6% susceptibility; MIC50, ≤0.25 mg/liter; MIC90, ≤0.25 to >32 mg/liter) and good activity against P. aeruginosa (86.5% susceptibility; MIC50/90, 2/16 mg/liter). Among the CRE, 50.8% (189/372 isolates) were positive for blaKPC-2, which mainly existed in ceftazidime-avibactam-susceptible Klebsiella pneumoniae isolates (92.1%, 174/189). Among the CRE, 17.7% (66/372 isolates) were positive for blaNDM, which mainly existed in strains resistant to ceftazidime-avibactam (71.7%, 66/92). Ceftolozane-tazobactam showed good in vitro activity against Escherichia coli and Proteus mirabilis (MIC50/90, ≤0.5/2 mg/liter; 90.5 and 93.8% susceptibility, respectively), and the rates of susceptibility of K. pneumoniae (MIC50/90, 2/>64 mg/liter) and P. aeruginosa (MIC50/90, 1/8 mg/liter) were 52.7% and 88.5%, respectively. Among the CRE strains, 28.6% of E. coli isolates and 85% of K. pneumoniae isolates were still susceptible to ceftazidime-avibactam, but only 7.1% and 1.9% of them, respectively, were susceptible to ceftolozane-tazobactam. The rates of susceptibility of the carbapenem-resistant P. aeruginosa isolates to ceftazidime-avibactam (65.7%) and ceftolozane-tazobactam (68%) were similar. Overall, both ceftazidime-avibactam and ceftolozane-tazobactam were highly active against clinical isolates of Enterobacteriaceae and P. aeruginosa recently collected across China, and ceftazidime-avibactam showed activity superior to that of ceftolozane-tazobactam against Enterobacteriaceae, whereas ceftolozane-tazobactam showed a better effect against P. aeruginosa.

scholarly journals Antimicrobial Activity of Ceftolozane-Tazobactam Tested against Enterobacteriaceae and Pseudomonas aeruginosa with Various Resistance Patterns Isolated in U.S. Hospitals (2011-2012)

2013 ◽  
Vol 57 (12) ◽  
pp. 6305-6310 ◽  
Author(s):  
David J. Farrell ◽  
Robert K. Flamm ◽  
Helio S. Sader ◽  
Ronald N. Jones
Keyword(s):  
Pseudomonas Aeruginosa ◽  
The United States ◽  
Multidrug Resistant ◽  
High Rate ◽  
Drug Resistant ◽  
Good Activity ◽  
Content Type ◽  
Microdilution Method ◽  
Medical Centers ◽  
Broth Microdilution Method

ABSTRACTCeftolozane/tazobactam, a novel antimicrobial agent with activity againstPseudomonas aeruginosa(including drug-resistant strains) and other common Gram-negative pathogens (including most extended-spectrum-β-lactamase [ESBL]-producingEnterobacteriaceaestrains), and comparator agents were susceptibility tested by a reference broth microdilution method against 7,071Enterobacteriaceaeand 1,971P. aeruginosaisolates. Isolates were collected consecutively from patients in 32 medical centers across the United States during 2011 to 2012. Overall, 15.7% and 8.9% ofP. aeruginosaisolates were classified as multidrug resistant (MDR) and extensively drug resistant (XDR), and 8.4% and 1.2% ofEnterobacteriaceaewere classified as MDR and XDR. No pandrug-resistant (PDR)Enterobacteriaceaeisolates and only one PDRP. aeruginosaisolate were detected. Ceftolozane/tazobactam was the most potent (MIC50/90, 0.5/2 μg/ml) agent tested againstP. aeruginosaand demonstrated good activity against 310 MDR strains (MIC50/90, 2/8 μg/ml) and 175 XDR strains (MIC50/90, 4/16 μg/ml). Ceftolozane/tazobactam exhibited high overall activity (MIC50/90, 0.25/1 μg/ml) againstEnterobacteriaceaeand retained activity (MIC50/90, 4/>32 μg/ml) against many 601 MDR strains but not against the 86 XDR strains (MIC50, >32 μg/ml). Ceftolozane/tazobactam was highly potent (MIC50/90, 0.25/0.5 μg/ml) against 2,691Escherichia coliisolates and retained good activity against most ESBL-phenotypeE. coliisolates (MIC50/90, 0.5/4 μg/ml), but activity was low against ESBL-phenotypeKlebsiella pneumoniaeisolates (MIC50/90, 32/>32 μg/ml), explained by the high rate (39.8%) of meropenem coresistance observed in this species phenotype. In summary, ceftolozane/tazobactam demonstrated high potency and broad-spectrum activity against many contemporaryEnterobacteriaceaeandP. aeruginosaisolates collected in U.S. medical centers. Importantly, ceftolozane/tazobactam retained potency against many MDR and XDR strains.

scholarly journals 1589. Ceftolozane–Tazobactam Activity Against Difficult-to-Treat Resistance in Pseudomonas aeruginosa from Bloodstream Infections in US Hospitals

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S580-S580
Author(s):  
Dee Shortridge ◽  
S J Ryan Arends ◽  
Leonard R Duncan ◽  
Jennifer M Streit ◽  
Robert K Flamm
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Bloodstream Infections ◽  
The United States ◽  
Multidrug Resistant ◽  
First Line ◽  
Microdilution Method ◽  
Drug Classes ◽  
Broth Microdilution Method ◽  
Tract Infections ◽  
Abdominal Infections

Abstract Background Infections caused by Pseudomonas aeruginosa (PSA) resistant to first-line agents are difficult to treat and require using more toxic antimicrobials, such as amikacin (AMK) and colistin (COL). Kadri et al. recently described the category of difficult-to-treat resistance (DTR) as intermediate or resistant to all tested first-line agents (fluoroquinolones, carbapenems, and extended-spectrum cephalosporins). Ceftolozane–tazobactam (C-T) is an antibacterial combination of an antipseudomonal cephalosporin and a β-lactamase inhibitor. C-T has been approved in >60 countries to treat complicated urinary tract infections, acute pyelonephritis, and complicated intra-abdominal infections. The filing is in progress for treatment of hospital-acquired pneumonia, including ventilator-associated pneumonia. The Program to Assess Ceftolozane–Tazobactam Susceptibility (PACTS) monitors gram-negative (GN) isolates resistant to C-T worldwide. In this study, the activity of C-T and comparators against PSA bloodstream isolates that are DTR, multidrug-resistant (MDR), or extensively drug-resistant (XDR) were analyzed. Methods A total of 922 PSA isolates from BSI were collected between 2011 and 2018 from 35 PACTS hospitals in the United States. Isolates were tested for C-T susceptibility (S) by the CLSI broth microdilution method. Other antibiotics tested included cefepime (FEP), ceftazidime (CAZ), ciprofloxacin, levofloxacin (LEV), doripenem, imipenem, meropenem (MEM), piperacillin–tazobactam (PIP-TAZ), AMK and COL. Antibiotic-resistant phenotypes analyzed using CLSI (2019) breakpoints included MDR (nonsusceptible to ≥ 1 agent in ≥ 3 drug classes), XDR (susceptible to ≤ 1 agent in ≤ 2 drug classes), or DTR. Results The percent of DTR isolates was 4.8% when compared with 15.2% MDR and 9.3% XDR. The %S for C-T and other first- and second-line agents are shown in the table for each phenotype. Conclusion C-T demonstrated 97.1%S overall for BSI isolates, similar to AMK (97.8%) and COL (99.5%). C-T had better coverage than first-line drugs against MDR (81.4%) and XDR (72.1%), and 50% for the DTR isolates, which represented only 4.8% of isolates. Only AMK and COL had > 75%S for DTR isolates. Disclosures All authors: No reported disclosures.

scholarly journals 2291. Evaluation of Multidrug-Resistant Pseudomonas aeruginosa Isolates in Patients Receiving Ceftolozane/tazobactam

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S785-S785
Author(s):  
Emily C Bodo ◽  
Aisling Caffrey ◽  
Vrishali Lopes ◽  
Jaclyn A Cusumano ◽  
Laura A Puzniak ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Antibiotic Resistance ◽  
Retrospective Study ◽  
Carbapenem Resistance ◽  
Multidrug Resistant ◽  
Veterans Affairs ◽  
Carbapenem Resistant ◽  
Clinical Culture ◽  
Resistance Rates ◽  
Lactamase Inhibitor

Abstract Background Multidrug-resistant (MDR) Pseudomonas aeruginosa is a challenging pathogen to treat. Ceftolozane/tazobactam (C/T) is a combination cephalosporin and β-lactamase inhibitor that has demonstrated activity against MDR P. aeruginosa, including carbapenem-resistant isolates. The objective of this study was to evaluate multidrug resistance in P. aeruginosa isolates obtained from patients treated with C/T across the Veterans Affairs (VA) Healthcare System nationally. Methods Hospitalized patients who received at least 1 dose of CT between January 2015 and April 2018 and had a positive P. aeruginosa culture were included in this retrospective study. Culture source and antimicrobial susceptibility reports were assessed for each P. aeruginosa isolate. Isolates were categorized as multidrug-resistant based on the Centers for Disease Control (CDC) definition. Resistance rates were categorized by source of culture. Results We identified 174 positive P. aeruginosa cultures among 154 patients who received at least one dose of C/T during the study period. The most common sources of isolates were lung (40% of patients), urine (21%), skin and soft tissue (15%), blood (14%), and bone/joint (14%). Most patients (98.1%) had isolates that were MDR, with high rates of carbapenem (84.4%), extended-spectrum cephalosporin (82.5%), and fluoroquinolone (79.9%) resistance. In this cohort, 50.6% of patients received at least one antibiotic prior to initiating C/T to which their clinical culture was not susceptible. Conclusion Antibiotic resistance was high in this cohort of patients with P. aeruginosa, and as a result, use of non-susceptible antibiotics occurred in 50.6% of patients before C/T was started. The high carbapenem resistance rates are of great clinical concern, but highlight an area of utilization for C/T given its activity against carbapenem-resistant P. aeruginosa. Disclosures All authors: No reported disclosures.

scholarly journals The Prevalence of Metallo-β-Lactamases and Efflux-Mediated Mechanisms in Carbapenem Nonsusceptible Nosocomial Pseudomonas aeruginosa Isolated in Moscow in 2012–2015

2015 ◽  
Vol 70 (6) ◽  
pp. 679-683
Author(s):  
Anna Valer'evna Lazareva ◽  
Ol'ga Andreevna Kryzhanovskaya ◽  
Yuliya Aleksandrovna Bocharova ◽  
Igor' Viktorovich Chebotar' ◽  
Nikolay Andreevich Mayanskiy
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Carbapenem Resistance ◽  
Opportunistic Pathogen ◽  
Resistance Mechanisms ◽  
Active Efflux ◽  
Minimal Inhibitory Concentrations ◽  
Highly Active ◽  
Microdilution Method ◽  
Broth Microdilution Method ◽  
Carbonyl Cyanide

Background. Pseudomonas aeruginosa, the major nosocomial opportunistic pathogen, is an important cause of infectious morbidity and mortality among immunocompromised patients.Objective. To establish the role of metallo-β-lactamases (MBL) and efflux-mediated mechanisms in conferring carbapenem resistance in nosocomial isolates of P. aeruginosa.Methods. We analyzed carbapenem nonsusceptible nosocomial P. aeruginosa isolates obtained from pediatric and adult patients at three hospitals in Moscow in 2012–2015. Carbapenem susceptibility was assessed using the E-test. In addition, minimal inhibitory concentrations (MICs) of meropenem were tested by the broth microdilution method. The presence of MBL was determined using the EDTA-mediated suppression test. Efflux-dependent resistance was measured using an assay based on MIC modification by an ionophore carbonyl cyanide 3-chlorophenyl hydrazine (CCCP).Results. A total of 54 carbapenem nonsusceptible P. aeruginosa isolates was examined. The presence of an MBL was detected in 37 (69%) isolates, 29 (54%) isolates had efflux-mediated resistance. In 10 (19%) isolates neither MBL nor efflux activity was found. Five out of 6 isolates (83%) with highly active efflux were MBL-positive. Among isolates with low efflux activity, 74% (17/23) possessed MBL, whereas in isolates with no efflux the rate of MBL-positivity was 60% (15/25).Conclusion. The prevalence of MBL- and efflux-mediated carbapenem resistance in nosocomial P. aeruginosa is high. Moreover, our results reveal that several resistance mechanisms may combine at the isolate level. These data may contribute to the development of novel strategies in combating carbapenem resistance.

scholarly journals 1598. Antimicrobial Activity of the Novel β-Lactam Enhancer Combination Cefepime–Zidebactam (WCK-5222) Tested Against Gram-Negative Bacteria Isolated in United States Medical Centers from Patients with Bloodstream Infections

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S583-S583
Author(s):  
Mariana Castanheira ◽  
Michael D Huband ◽  
Robert K Flamm ◽  
Helio S Sader
Keyword(s):  
Bloodstream Infections ◽  
Multidrug Resistant ◽  
High Dose ◽  
Gram Negative ◽  
Highly Active ◽  
Microdilution Method ◽  
Medical Centers ◽  
Carbapenem Resistant ◽  
Broth Microdilution Method ◽  
Dual Mechanism

Abstract Background Zidebactam (ZID) is a β-lactam enhancer antibiotic with a dual mechanism of action: high binding affinity to gram-negative PBP2 and β-lactamase (BL) inhibition. We evaluated the activity of cefepime (FEP) combined with ZID against contemporary clinical isolates of gram-negative bacilli (GNB) causing bloodstream infections (BSIs) in the US hospitals. Methods 1,239 GNB were consecutively collected (1/patient) from 34 US medical centers in 2018. Susceptibility (S) testing against FEP-ZID (1:1 ratio) and comparators were performed by reference broth microdilution method in a central laboratory. The FEP S breakpoint of ≤ 8 mg/L (CLSI, high dose) was applied to FEP-ZID for comparison purposes. An FEP-ZID S breakpoint of ≤ 64 mg/L has been proposed for non-fermentative GNB based on pharmacokinetic/pharmacodynamic target attainment and was also applied. Selected Enterobacterales (ENT) isolates were evaluated by whole-genome sequencing. Results FEP-ZID was highly active against ENT (MIC50/MIC90, 0.03/0.12 mg/L; highest MIC, 4 mg/L; Table), including multidrug-resistant (MDR, MIC50/MIC90, 0.12/0.25 mg/L) and carbapenem-resistant isolates (n = 7; MIC50, 0.5 mg/L). The highest FEP-ZID MIC values among E. coli, K. pneumoniae, and E. cloacae were 1, 2, and 0.25 mg/L, respectively. The most active comparators tested against MDR ENT were ceftazidime–avibactam (CAZ-AVI; MIC50/MIC90, 0.25/1 mg/L; 98.0%S), meropenem (MEM; MIC50/MIC90, 0.03/0.12 mg/L; 93.1%S) and amikacin (AMK; MIC50/MIC90, 4/16 mg/L; 92.1%S). The most active agents tested against P. aeruginosa were FEP-ZID (MIC50/MIC90, 1/4 mg/L; highest MIC, 8 mg/L), colistin (MIC50/MIC90, 0.5/1 mg/L; 100.0%S), and AMK (MIC50/MIC90, 4/8 mg/L; 99.2%S); whereas CAZ-AVI and ceftolozane–tazobactam were active against 96.5–96.7% of isolates. FEP-ZID exhibited good activity against Acinetobacter spp. (MIC50/MIC90, 2/8 mg/L) and S. maltophilia (MIC50/MIC90, 4/32 mg/L). S. maltophilia displayed low S rates to most comparators. Conclusion FEP-ZID demonstrated potent activity against a large collection GNB from BSI, including isolates resistant to other BL inhibitor combinations and/or carbapenems. These results support further clinical development of FEP-ZID. Disclosures All authors: No reported disclosures.

scholarly journals In Vitro Activity of WCK 5222 (Cefepime-Zidebactam) against Worldwide Collected Gram-Negative Bacilli Not Susceptible to Carbapenems

2020 ◽  
Vol 64 (12) ◽  
Author(s):  
James A. Karlowsky ◽  
Meredith A. Hackel ◽  
Samuel K. Bouchillon ◽  
Daniel F. Sahm
Keyword(s):  
Antimicrobial Agents ◽  
Multidrug Resistant ◽  
Limiting Factor ◽  
Gram Negative ◽  
Content Type ◽  
Microdilution Method ◽  
Carbapenem Resistant ◽  
Broth Microdilution Method ◽  
Universal Stability

ABSTRACT WCK 5222 (cefepime-zidebactam, 2 g + 1g, every 8 h [q8h]) is in clinical development for the treatment of infections caused by carbapenem-resistant and multidrug-resistant (MDR) Gram-negative bacilli. We determined the in vitro susceptibility of 1,385 clinical isolates of non-carbapenem-susceptible Enterobacterales, MDR Pseudomonas aeruginosa (also non-carbapenem susceptible), Stenotrophomonas maltophilia, and Burkholderia spp. collected worldwide (49 countries) from 2014 to 2016 to cefepime-zidebactam (1:1 ratio), ceftazidime-avibactam, imipenem-relebactam, ceftolozane-tazobactam, and colistin using the CLSI broth microdilution method. Cefepime-zidebactam inhibited 98.5% of non-carbapenem-susceptible Enterobacterales (n = 1,018) at ≤8 μg/ml (provisional cefepime-zidebactam-susceptible MIC breakpoint). Against the subset of metallo-β-lactamase (MBL)-positive Enterobacterales (n = 214), cefepime-zidebactam inhibited 94.9% of isolates at ≤8 μg/ml. Further, it inhibited 99.6% of MDR P. aeruginosa (n = 262) isolates at ≤32 μg/ml (proposed cefepime-zidebactam-susceptible pharmacokinetic/pharmacodynamic MIC breakpoint), including all MBL-positive isolates (n = 94). Moreover, cefepime-zidebactam was active against the majority of isolates of Enterobacterales (≥95%) and P. aeruginosa (99%) that were not susceptible to ceftazidime-avibactam, ceftolozane-tazobactam, imipenem-relebactam, and colistin. Most isolates (99%) of S. maltophilia (n = 101; MIC50, 8 μg/ml; MIC90, 32 μg/ml) and Burkholderia spp. (n = 4; MIC range, 16 to 32 μg/ml) were also inhibited by cefepime-zidebactam at ≤32 μg/ml. The activity of cefepime-zidebactam against carbapenem-resistant Gram-negative bacteria is ascribed to its β-lactam enhancer mechanism of action (i.e., zidebactam binding to penicillin binding protein 2 [PBP2] and its universal stability to both serine β-lactamases and MBLs). The results from this study support the continued development of cefepime-zidebactam as a potential therapy for infections caused by Enterobacterales, P. aeruginosa, and other nonfermentative Gram-negative bacilli where resistance to marketed antimicrobial agents is a limiting factor.

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