scholarly journals Antimicrobial Activity of Ceftazidime-Avibactam against Gram-Negative Organisms Collected from U.S. Medical Centers in 2012

2013 ◽  
Vol 58 (3) ◽  
pp. 1684-1692 ◽  
Author(s):  
Helio S. Sader ◽  
Mariana Castanheira ◽  
Robert K. Flamm ◽  
David J. Farrell ◽  
Ronald N. Jones
Keyword(s):  
The Novel ◽  
Gram Negative ◽  
Content Type ◽  
Class A ◽  
Medical Centers ◽  
Fixed Concentration ◽  
Clinically Significant ◽  
Gram Negative Organisms ◽  
Inhibitor Combination ◽  
Lactamase Inhibitor

ABSTRACTThe activities of the novel β-lactam–β-lactamase inhibitor combination ceftazidime-avibactam and comparator agents were evaluated against a contemporary collection of clinically significant Gram-negative bacilli. Avibactam is a novel non-β-lactam β-lactamase inhibitor that inhibits Ambler class A, C, and some D enzymes. A total of 10,928 Gram-negative bacilli—8,640Enterobacteriaceae, 1,967Pseudomonas aeruginosa, and 321Acinetobactersp. isolates—were collected from 73 U.S. hospitals and tested for susceptibility by reference broth microdilution methods in a central monitoring laboratory (JMI Laboratories, North Liberty, IA, USA). Ceftazidime was combined with avibactam at a fixed concentration of 4 μg/ml. Overall, 99.8% ofEnterobacteriaceaestrains were inhibited at a ceftazidime-avibactam MIC of ≤4 μg/ml. Ceftazidime-avibactam was active against extended-spectrum β-lactamase (ESBL)-phenotypeEscherichia coliandKlebsiella pneumoniae, meropenem-nonsusceptible (MIC ≥ 2 μg/ml)K. pneumoniae, and ceftazidime-nonsusceptibleEnterobacter cloacae. Among ESBL-phenotypeK. pneumoniaestrains, 61.1% were meropenem susceptible and 99.3% were inhibited at a ceftazidime-avibactam MIC of ≤4 μg/ml. AmongP. aeruginosastrains, 96.9% were inhibited at a ceftazidime-avibactam MIC of ≤8 μg/ml, and susceptibility rates for meropenem, ceftazidime, and piperacillin-tazobactam were 82.0, 83.2, and 78.3%, respectively. Ceftazidime-avibactam was the most active compound tested against meropenem-nonsusceptibleP. aeruginosa(MIC50/MIC90, 4/16 μg/ml; 87.3% inhibited at ≤8 μg/ml).Acinetobacterspp. (ceftazidime-avibactam MIC50/MIC90, 16/>32 μg/ml) showed high rates of resistance to most tested agents. In summary, ceftazidime-avibactam demonstrated potent activity against a large collection of contemporary Gram-negative bacilli isolated from patients in U.S. hospitals in 2012, including organisms that are resistant to most currently available agents, such asK. pneumoniaecarbapenemase (KPC)-producingEnterobacteriaceaeand meropenem-nonsusceptibleP. aeruginosa.

scholarly journals In VitroActivity of Aztreonam-Avibactam against a Global Collection of Gram-Negative Pathogens from 2012 and 2013

2015 ◽  
Vol 59 (7) ◽  
pp. 4239-4248 ◽  
Author(s):  
Douglas J. Biedenbach ◽  
Krystyna Kazmierczak ◽  
Samuel K. Bouchillon ◽  
Daniel F. Sahm ◽  
Patricia A. Bradford
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Clinical Isolates ◽  
Broth Microdilution ◽  
Gram Negative ◽  
Content Type ◽  
Class A ◽  
Medical Centers ◽  
Fixed Concentration ◽  
Class B

ABSTRACTThe combination of aztreonam plus avibactam is being developed for use in infections caused by metallo-β-lactamase-producingEnterobacteriaceaestrains that also produce serine β-lactamases. Thein vitroactivities of aztreonam-avibactam and comparator antimicrobials were determined against year 2012 and 2013 clinical isolates ofEnterobacteriaceae,Pseudomonas aeruginosa, andAcinetobacter baumanniiusing the broth microdilution methodology recommended by the Clinical and Laboratory Standards Institute (CLSI). A total of 28,501 unique clinical isolates were obtained from patients in 190 medical centers within 39 countries. MIC90values of aztreonam and aztreonam-avibactam against all collected isolates ofEnterobacteriaceae(n= 23,516) were 64 and 0.12 μg/ml, respectively, with 76.2% of the isolates inhibited by ≤4 μg/ml of aztreonam (the CLSI breakpoint) and 99.9% of the isolates inhibited by ≤4 μg/ml of aztreonam-avibactam using a fixed concentration of 4 μg/ml of avibactam. The MIC90was 32 μg/ml for both aztreonam and aztreonam-avibactam againstP. aeruginosa(n= 3,766). Aztreonam alone or in combination with avibactam had noin vitroactivity against isolates ofA. baumannii. PCR and sequencing were used to characterize 5,076 isolates for β-lactamase genes. Aztreonam was not active against mostEnterobacteriaceaeisolates producing class A or class C enzymes alone or in combination with class B metallo-β-lactamases. In contrast, >99% ofEnterobacteriaceaeisolates producing all observed Ambler classes of β-lactamase enzymes were inhibited by ≤4 μg/ml aztreonam in combination with avibactam, including isolates that produced IMP-, VIM-, and NDM-type metallo-β-lactamases in combination with multiple serine β-lactamases.

scholarly journals Beyond Piperacillin-Tazobactam: Cefepime and AAI101 as a Potent β-Lactam−β-Lactamase Inhibitor Combination

2019 ◽  
Vol 63 (5) ◽  
Author(s):  
Krisztina M. Papp-Wallace ◽  
Christopher R. Bethel ◽  
Jocelyne Caillon ◽  
Melissa D. Barnes ◽  
Gilles Potel ◽  
...  
Keyword(s):  
Phase Iii ◽  
Cell Penetration ◽  
Gram Negative ◽  
Resistance Determinants ◽  
Class A ◽  
Penicillanic Acid ◽  
Inhibitor Combination ◽  
Unique Mechanism ◽  
Lactamase Inhibitor

ABSTRACTImpeding, as well as reducing, the burden of antimicrobial resistance in Gram-negative pathogens is an urgent public health endeavor. Our current antibiotic armamentarium is dwindling, while major resistance determinants (e.g., extended-spectrum β-lactamases [ESBLs]) continue to evolve and disseminate around the world. One approach to attack this problem is to develop novel therapies that will protect our current agents. AAI101 is a novel penicillanic acid sulfone β-lactamase inhibitor similar in structure to tazobactam, with one important difference. AAI101 possesses a strategically placed methyl group that gives the inhibitor a net neutral charge, enhancing bacterial cell penetration. AAI101 paired with cefepime, also a zwitterion, is in phase III of clinical development for the treatment of serious Gram-negative infections. Here, AAI101 was found to restore the activity of cefepime against class A ESBLs (e.g., CTX-M-15) and demonstrated increased potency compared to that of piperacillin-tazobactam when tested against an established isogenic panel. The enzymological properties of AAI101 further revealed that AAI101 possessed a unique mechanism of β-lactamase inhibition compared to that of tazobactam. Additionally, upon reaction with AAI101, CTX-M-15 was modified to an inactive state. Notably, thein vivoefficacy of cefepime-AAI101 was demonstrated using a mouse septicemia model, indicating the ability of AAI101 to bolster significantly the therapeutic efficacy of cefepimein vivo. The combination of AAI101 with cefepime represents a potential carbapenem-sparing treatment regimen for infections suspected to be caused byEnterobacteriaceaeexpressing ESBLs.

scholarly journals Avibactam and Inhibitor-Resistant SHV β-Lactamases

2015 ◽  
Vol 59 (7) ◽  
pp. 3700-3709 ◽  
Author(s):  
Marisa L. Winkler ◽  
Krisztina M. Papp-Wallace ◽  
Magdalena A. Taracila ◽  
Robert A. Bonomo
Keyword(s):  
Alternative Pathway ◽  
Proton Acceptor ◽  
Hydroxyl Group ◽  
The Novel ◽  
Content Type ◽  
Class A ◽  
Important Amino Acid ◽  
Class D ◽  
Continued Use ◽  
Lactamase Inhibitor

ABSTRACTβ-Lactamase enzymes (EC 3.5.2.6) are a significant threat to the continued use of β-lactam antibiotics to treat infections. A novel non-β-lactam β-lactamase inhibitor with activity against many class A and C and some class D β-lactamase variants, avibactam, is now available in the clinic in partnership with ceftazidime. Here, we explored the activity of avibactam against a variety of characterized isogenic laboratory constructs of β-lactamase inhibitor-resistant variants of the class A enzyme SHV (M69I/L/V, S130G, K234R, R244S, and N276D). We discovered that the S130G variant of SHV-1 shows the most significant resistance to inhibition by avibactam, based on both microbiological and biochemical characterizations. Using a constant concentration of 4 mg/liter of avibactam as a β-lactamase inhibitor in combination with ampicillin, the MIC increased from 1 mg/liter forblaSHV-1to 256 mg/liter forblaSHV S130Gexpressed inEscherichia coliDH10B. At steady state, thek2/Kvalue of the S130G variant when inactivated by avibactam was 1.3 M−1s−1, versus 60,300 M−1s−1for the SHV-1 β-lactamase. Under timed inactivation conditions, we found that an approximately 1,700-fold-higher avibactam concentration was required to inhibit SHV S130G than the concentration that inhibited SHV-1. Molecular modeling suggested that the positioning of amino acids in the active site of SHV may result in an alternative pathway of inactivation when complexed with avibactam, compared to the structure of CTX-M-15–avibactam, and that S130 plays a role in the acylation of avibactam as a general acid/base. In addition, S130 may play a role in recyclization. As a result, we advance that the lack of a hydroxyl group at position 130 in the S130G variant of SHV-1 substantially slows carbamylation of the β-lactamase by avibactam by (i) removing an important proton acceptor and donator in catalysis and (ii) decreasing the number of H bonds. In addition, recyclization is most likely also slow due to the lack of a general base to initiate the process. Considering other inhibitor-resistant mechanisms among class A β-lactamases, S130 may be the most important amino acid for the inhibition of class A β-lactamases, perhaps even for the novel diazabicyclooctane class of β-lactamase inhibitors.

scholarly journals In VivoEfficacy of Humanized Exposures of Ceftazidime-Avibactam in Comparison with Ceftazidime against Contemporary Enterobacteriaceae Isolates

2014 ◽  
Vol 58 (11) ◽  
pp. 6913-6919 ◽  
Author(s):  
Shawn H. MacVane ◽  
Jared L. Crandon ◽  
Wright W. Nichols ◽  
David P. Nicolau
Keyword(s):  
Gram Negative ◽  
Content Type ◽  
Carbapenem Resistant ◽  
Class D ◽  
Variable Activity ◽  
Resistant Strains ◽  
The Impact ◽  
Inhibitor Combination ◽  
Lactamase Inhibitor

ABSTRACTCeftazidime-avibactam is a β-lactam β-lactamase inhibitor combination under investigation for the treatment of serious Gram-negative infections. When combined with avibactam, a novel non-β-lactam β-lactamase inhibitor, ceftazidime has activity against isolates that produce Ambler class A, class C, and some class D β-lactamases. However, little is known of thein vivoefficacy of the combination against these targeted ceftazidime- and carbapenem-resistantEnterobacteriaceae. Using humanized exposures in the murine thigh model, we evaluated the efficacy of ceftazidime-avibactam againstEnterobacteriaceaeexhibiting MICs of ≥8 μg/ml to aid in the assignment of interpretive susceptibility criteria. Eighteen clinicalEnterobacteriaceaeisolates, including nine carbapenem-resistant strains, were evaluated against ceftazidime-avibactam (2,000 mg/500 mg) as a 2-h infusion every 8 h. To highlight the impact of avibactam, 13 select isolates were tested in the neutropenic model against a humanized regimen of 2,000 mg ceftazidime every 8 h (2-h infusion). Additionally, nine isolates were evaluated in immunocompetent animals. The efficacy was evaluated as the change in log10CFU compared with that of 0-h controls after 24 h. The vast majority (17/18, 94%) of the isolates were resistant to ceftazidime alone. The ceftazidime monotherapy failed to have activity against 10 of 13 isolates, while ceftazidime-avibactam produced reductions in bacterial density against 16 of 18 isolates. Ceftazidime-avibactam (2,000 mg/500 mg) every 8 h (2-h infusion) displayed dependable activity against theEnterobacteriaceaeisolates, exhibiting MICs of ≤16 μg/ml (free drug concentration above the MIC [fT>MIC] of ≥62%) and variable activity was noted at an MIC of 32 μg/ml (fT>MICof 34%). The presence of a functioning immune system enhanced the efficacy for both regimens against all tested isolates. These data support further examination of the use of ceftazidime-avibactam as an effective therapy against infections due to Gram-negative infections, including carbapenem-resistantEnterobacteriaceae.

scholarly journals Probing the Mechanism of Inactivation of the FOX-4 Cephamycinase by Avibactam

2018 ◽  
Vol 62 (5) ◽  
pp. e02371-17 ◽  
Author(s):  
Michiyoshi Nukaga ◽  
Krisztina M. Papp-Wallace ◽  
Tyuji Hoshino ◽  
Scott T. Lefurgy ◽  
Christopher R. Bethel ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Hydrogen Bonding ◽  
Single Amino Acid ◽  
Content Type ◽  
Class A ◽  
Hydrogen Bonding Interactions ◽  
Extended Spectrum ◽  
Inhibitor Combination ◽  
Lactamase Inhibitor ◽  
Inhibition Analysis

ABSTRACTCeftazidime-avibactam is a “second-generation” β-lactam–β-lactamase inhibitor combination that is effective againstEnterobacteriaceaeexpressing class A extended-spectrum β-lactamases, class A carbapenemases, and/or class C cephalosporinases. Knowledge of the interactions of avibactam, a diazabicyclooctane with different β-lactamases, is required to anticipate future resistance threats. FOX family β-lactamases possess unique hydrolytic properties with a broadened substrate profile to include cephamycins, partly as a result of an isoleucine at position 346, instead of the conserved asparagine found in most AmpCs. Interestingly, a single amino acid substitution at N346 in theCitrobacterAmpC is implicated in resistance to the aztreonam-avibactam combination. In order to understand how diverse active-site topologies affect avibactam inhibition, we tested a panel of clinicalEnterobacteriaceaeisolates producingblaFOXusing ceftazidime-avibactam, determined the biochemical parameters for inhibition using the FOX-4 variant, and probed the atomic structure of avibactam with FOX-4. Avibactam restored susceptibility to ceftazidime for most isolates producingblaFOX; two isolates, one expressingblaFOX-4and the other producingblaFOX-5, displayed an MIC of 16 μg/ml for the combination. FOX-4 possessed ak2/Kvalue of 1,800 ± 100 M−1· s−1and an off rate (koff) of 0.0013 ± 0.0003 s−1. Mass spectrometry showed that the FOX-4–avibactam complex did not undergo chemical modification for 24 h. Analysis of the crystal structure of FOX-4 with avibactam at a 1.5-Å resolution revealed a unique characteristic of this AmpC β-lactamase. Unlike in thePseudomonas-derived cephalosporinase 1 (PDC-1)–avibactam crystal structure, interactions (e.g., hydrogen bonding) between avibactam and position I346 in FOX-4 are not evident. Furthermore, another residue is not observed to be close enough to compensate for the loss of these critical hydrogen-bonding interactions. This observation supports findings from the inhibition analysis of FOX-4; FOX-4 possessed the highestKd(dissociation constant) value (1,600 nM) for avibactam compared to other AmpCs (7 to 660 nM). Medicinal chemists must consider the properties of extended-spectrum AmpCs, such as the FOX β-lactamases, for the design of future diazabicyclooctanes.

scholarly journals Evaluation of theIn VitroActivity of Eravacycline against a Broad Spectrum of Recent Clinical Anaerobic Isolates

2018 ◽  
Vol 62 (5) ◽  
Author(s):  
David R. Snydman ◽  
Laura A. McDermott ◽  
Nilda V. Jacobus ◽  
Kathryn Kerstein ◽  
Trudy H. Grossman ◽  
...  
Keyword(s):  
Specific Resistance ◽  
Multidrug Resistant ◽  
The Novel ◽  
Gram Negative ◽  
Content Type ◽  
Resistance Determinants ◽  
Serious Infections ◽  
Aerobic And Anaerobic ◽  
Lactamase Inhibitor

ABSTRACTThe novel fluorocycline antibiotic eravacycline is in development for use in the treatment of serious infections caused by susceptible and multidrug-resistant (MDR) aerobic and anaerobic Gram-negative and Gram-positive pathogens. Eravacycline and 11 comparator antibiotics were tested against recent anaerobic clinical isolates, including MDRBacteroidesspp. andClostridium difficile. Eravacycline was potentin vitroagainst all the isolates tested, including strains with tetracycline-specific resistance determinants and MDR anaerobic pathogens resistant to carbapenems and/or β-lactam–β-lactamase inhibitor combinations.

scholarly journals Activity of NXL104 in Combination with β-Lactams against Genetically Characterized Escherichia coli and Klebsiella pneumoniae Isolates Producing Class A Extended-Spectrum β-Lactamases and Class C β-Lactamases

2011 ◽  
Vol 55 (5) ◽  
pp. 2434-2437 ◽  
Author(s):  
P. R. S. Lagacé-Wiens ◽  
F. Tailor ◽  
P. Simner ◽  
M. DeCorby ◽  
J. A. Karlowsky ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Klebsiella Pneumoniae ◽  
The Novel ◽  
Content Type ◽  
E Coli ◽  
Class A ◽  
Extended Spectrum ◽  
Class C ◽  
Lactamase Inhibitor

ABSTRACTThe novel non-β-lactam β-lactamase inhibitor NXL104, in combination with cefepime, ceftazidime, ceftriaxone, amdinocillin, and meropenem, was tested against 190 extended-spectrum β-lactamase (ESBL)-producingEscherichia coliandKlebsiella pneumoniaeisolates, 94 AmpC-hyperproducingE. coliisolates, and 8 AmpC/ESBL-coexpressingE. coliisolates. NXL104 restored 100% susceptibility to the partner cephalosporins for all isolates tested. Amdinocillin and meropenem MICs were modestly improved (2 to 32 times lower) by NXL104. These results suggest that NXL104 may be useful in combination with β-lactams for the treatment of infections caused by ESBL- and AmpC-producingEnterobacteriaceae.

Activity of imipenem/relebactam against carbapenemase-producing Enterobacteriaceae with high colistin resistance

2019 ◽  
Vol 74 (11) ◽  
pp. 3260-3263 ◽  
Author(s):  
Jessica Carpenter ◽  
Nick Neidig ◽  
Alex Campbell ◽  
Tanner Thornsberry ◽  
Taylor Truex ◽  
...  
Keyword(s):  
Serratia Marcescens ◽  
Antimicrobial Agents ◽  
Time Frame ◽  
Resistance Mechanisms ◽  
Broth Microdilution ◽  
Colistin Resistance ◽  
Gram Negative ◽  
Class A ◽  
Inhibitor Combination ◽  
Lactamase Inhibitor

Abstract Objectives Imipenem/relebactam, an investigational β-lactam/β-lactamase inhibitor combination for treatment of Gram-negative infections, and comparators including ceftazidime/avibactam, piperacillin/tazobactam and colistin were tested for activity against representative carbapenemase-producing Enterobacteriaceae (CPE) isolates. Methods MICs of the antimicrobial agents were determined using standard broth microdilution methodology for CPE isolates collected from Indiana patients, primarily during the time frame of 2013–17 (n = 199 of a total of 200 isolates). Inhibitors were tested at 4 mg/L in all combinations. Results Of the CPE in the study, 199 produced plasmid-encoded KPC class A carbapenemases; 1 Serratia marcescens isolate produced the SME-1 chromosomal class A carbapenemase. MIC50/MIC90 values of imipenem/relebactam were ≤0.25/0.5 mg/L, whereas MIC50/MIC90 values of ceftazidime/avibactam were 1/2 mg/L. Resistance to colistin was observed in 54% (n = 97) of 180 non-Serratia isolates tested (MIC50 of 4 mg/L). Colistin resistance mechanisms included production of a plasmid-encoded mcr-1-like gene (n = 2) or an inactivated mgrB gene. Conclusions Imipenem/relebactam was the most potent agent tested against CPE in this study and may be a useful addition to the antimicrobial armamentarium to treat infections caused by these pathogens.

scholarly journals Antimicrobial Activity of Ceftazidime-Avibactam against Gram-Negative Bacteria Isolated from Patients Hospitalized with Pneumonia in U.S. Medical Centers, 2011 to 2015

2017 ◽  
Vol 61 (4) ◽  
Author(s):  
Helio S. Sader ◽  
Mariana Castanheira ◽  
Robert K. Flamm
Keyword(s):  
Multidrug Resistant ◽  
Gram Negative Bacteria ◽  
Gram Negative ◽  
Content Type ◽  
Negative Results ◽  
Highly Active ◽  
Microdilution Method ◽  
Medical Centers ◽  
Broth Microdilution Method ◽  
Gram Negative Organisms

ABSTRACT Bacterial isolates were collected from patients hospitalized with pneumonia (PHP), including ventilator-associated pneumonia (VAP), from 76 U.S. medical centers in 2011 to 2015. The Gram-negative organisms (n = 11,185, including 1,097 from VAP) were tested for susceptibility to ceftazidime-avibactam and comparators by the broth microdilution method. β-Lactamase-encoding genes were screened using a microarray-based assay on selected isolates. Pseudomonas aeruginosa and Klebsiella spp. were the most common Gram-negative bacteria isolated from PHP and VAP. Ceftazidime-avibactam was very active against P. aeruginosa (n = 3,402; MIC50/MIC90, 2 and 4 μg/ml; 96.6% susceptible), including isolates nonsusceptible to meropenem (86.3% susceptible to ceftazidime-avibactam), piperacillin-tazobactam (85.6% susceptible), or ceftazidime (80.6% susceptible). Ceftazidime-avibactam was also highly active against Enterobacteriaceae (MIC50/MIC90, 0.12 and 0.5 μg/ml; 99.9% susceptible), including carbapenem-resistant Enterobacteriaceae (CRE) (n = 189; MIC50/MIC90, 0.5 and 2 μg/ml; 98.0% susceptible) and multidrug-resistant (MDR) (n = 674; MIC50/MIC90, 0.25 and 1 μg/ml; 98.8% susceptible) and extensively drug-resistant (XDR) (n = 156; MIC50/MIC90, 0.5 and 2 μg/ml; 98.1% susceptible) Enterobacteriaceae isolates, as well as Klebsiella species isolates showing an extended-spectrum β-lactamase (ESBL) screening-positive phenotype (n = 433; MIC50/MIC90, 0.25 and 1 μg/ml; 99.5% susceptible). Among Enterobacter spp. (24.8% ceftazidime nonsusceptible), 99.8% of the isolates, including 99.4% of ceftazidime-nonsusceptible isolates, were susceptible to ceftazidime-avibactam. The most common β-lactamases detected among Klebsiella pneumoniae and E. coli isolates were K. pneumoniae carbapenemase (KPC)-like and CTX-M-15, respectively. Only 8 of 6,209 Enterobacteriaceae isolates (0.1%) were ceftazidime-avibactam nonsusceptible, three NDM-1-producing strains with ceftazidime-avibactam MIC values of >32 μg/ml and five isolates with ceftazidime-avibactam MIC values of 16 μg/ml and negative results for all β-lactamases tested. Susceptibility rates among isolates from VAP were generally similar or slightly higher than those from all PHP.

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