scholarly journals In VitroAntibacterial Activity of the Ceftazidime-Avibactam (NXL104) Combination against Pseudomonas aeruginosa Clinical Isolates

2012 ◽  
Vol 56 (3) ◽  
pp. 1606-1608 ◽  
Author(s):  
Premavathy Levasseur ◽  
Anne-Marie Girard ◽  
Monique Claudon ◽  
Herman Goossens ◽  
Michael T. Black ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Antibacterial Activity ◽  
Content Type ◽  
Reference Treatment ◽  
Common Reference ◽  
Class A ◽  
Potent Inhibition ◽  
Efficient Protection ◽  
Lactamase Inhibitor

ABSTRACTThe β-lactamase inhibitor avibactam (NXL104) displays potent inhibition of both class A and C enzymes. Thein vitroantibacterial activity of the combination ceftazidime-avibactam was evaluated against a clinical panel ofPseudomonas aeruginosaisolates. Avibactam offered efficient protection from hydrolysis since 94% of isolates were susceptible to ceftazidime when combined with 4 μg/ml avibactam, compared with 65% susceptible to ceftazidime alone. Ceftazidime-avibactam also demonstrated better antipseudomonal activity than imipenem (82% susceptibility), a common reference treatment.

scholarly journals Structural Insight into Potent Broad-Spectrum Inhibition with Reversible Recyclization Mechanism: Avibactam in Complex with CTX-M-15 and Pseudomonas aeruginosa AmpC β-Lactamases

2013 ◽  
Vol 57 (6) ◽  
pp. 2496-2505 ◽  
Author(s):  
Sushmita D. Lahiri ◽  
Stefano Mangani ◽  
Thomas Durand-Reville ◽  
Manuela Benvenuti ◽  
Filomena De Luca ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Broad Spectrum ◽  
Reversible Inhibitor ◽  
Binding Modes ◽  
Content Type ◽  
Class A ◽  
Class C ◽  
Insight Into ◽  
Lactamase Inhibitor

ABSTRACTAlthough β-lactams have been the most effective class of antibacterial agents used in clinical practice for the past half century, their effectiveness on Gram-negative bacteria has been eroded due to the emergence and spread of β-lactamase enzymes that are not affected by currently marketed β-lactam/β-lactamase inhibitor combinations. Avibactam is a novel, covalent, non-β-lactam β-lactamase inhibitor presently in clinical development in combination with either ceftaroline or ceftazidime.In vitrostudies show that avibactam may restore the broad-spectrum activity of cephalosporins against class A, class C, and some class D β-lactamases. Here we describe the structures of two clinically important β-lactamase enzymes bound to avibactam, the class A CTX-M-15 extended-spectrum β-lactamase and the class CPseudomonas aeruginosaAmpC β-lactamase, which together provide insight into the binding modes for the respective enzyme classes. The structures reveal similar binding modes in both enzymes and thus provide a rationale for the broad-spectrum inhibitory activity of avibactam. Identification of the key residues surrounding the binding pocket allows for a better understanding of the potency of this scaffold. Finally, avibactam has recently been shown to be a reversible inhibitor, and the structures provide insights into the mechanism of avibactam recyclization. Analysis of the ultra-high-resolution CTX-M-15 structure suggests how the deacylation mechanism favors recyclization over hydrolysis.

scholarly journals Carbapenem-Nonsusceptible Pseudomonas aeruginosa Isolates from Intensive Care Units in the United States: a Potential Role for New β-Lactam Combination Agents

2019 ◽  
Vol 57 (8) ◽  
Author(s):  
Tomefa E. Asempa ◽  
David P. Nicolau ◽  
Joseph L. Kuti
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Intensive Care ◽  
Respiratory Tract ◽  
Potential Role ◽  
The United States ◽  
Content Type ◽  
New Antibiotics ◽  
Susceptibility Profiles ◽  
Lactamase Inhibitor

ABSTRACT Pseudomonas aeruginosa, a frequent pathogen in the intensive care unit (ICU), has the propensity to develop antibiotic resistance. In particular, carbapenem-nonsusceptible (NS) P. aeruginosa poses tremendous challenges, and new antibiotics will be needed to treat this phenotype. Here we determine carbapenem nonsusceptibility rates for contemporary P. aeruginosa isolates from U.S. ICUs and in vitro activities of new β-lactam combination agents. Between July 2017 and June 2018, consecutive nonduplicate P. aeruginosa isolates from blood and respiratory tract sources were recovered from patients admitted to the ICUs of 36 geographically diverse U.S. hospitals. Antimicrobial susceptibility to the following antipseudomonal agents was tested: ceftazidime, imipenem, meropenem, ceftazidime-avibactam, and imipenem-relebactam (an investigational β-lactam/β-lactamase inhibitor). MICs and susceptibility rates were measured using Clinical and Laboratory Standards Institute reference broth microdilution methodology. Among the 538 consecutive ICU P. aeruginosa isolates collected, carbapenem nonsusceptibility was observed for 35% of the isolates and was more common among respiratory tract versus bloodstream specimens. Susceptibility rates, MIC50 values, and MIC90 values were as follows: ceftazidime-avibactam, 92.8%, 2 μg/ml, and 8 μg/ml; imipenem-relebactam, 91.5%, 0.25 μg/ml, and 2 μg/ml; ceftazidime, 77.1%, 4 μg/ml, and 64 μg/ml; meropenem, 72.7%, 1 μg/ml, and 16 μg/ml; imipenem, 67.1%, 2 μg/ml, and 16 μg/ml. Most (>75%) of the carbapenem-NS isolates were susceptible to ceftazidime-avibactam and imipenem-relebactam. In these U.S. hospital ICUs, carbapenem-NS P. aeruginosa isolates from respiratory sources were frequently observed. Novel β-lactam combination agents appear to retain active in vitro susceptibility profiles against these isolates and may play a role in the treatment of infections caused by carbapenem-NS P. aeruginosa strains.

scholarly journals 709. In Vitro Antibacterial Activity and In Vivo Efficacy of Sulbactam–Durlobactam (ETX2514SUL) Against Pathogenic Burkholderia Species

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S319-S319
Author(s):  
John O’Donnell ◽  
Alita Miller ◽  
Douglas Lane ◽  
Rekha Panchal ◽  
John P Mueller
Keyword(s):  
Antibacterial Activity ◽  
Preclinical Model ◽  
In Vivo Efficacy ◽  
Class A ◽  
Clinical Resistance ◽  
In Vitro Antibacterial Activity ◽  
Acinetobacter Spp ◽  
Lactamase Inhibitor

Abstract Background The genus Burkholderia contains several pathogenic species with distinct etiologies, including Burkholderia pseudomallei the biothreat pathogen responsible for melioidosis and Burkholderia mallei which causes glanders. β-Lactams, such as ceftazidime and meropenem, are important therapeutic options for these infections. However, clinical resistance to β-lactams, which is primarily mediated by multiple types of β-lactamases in these species, is a growing concern. Durlobactam (ETX2514, DUR) is a novel β-lactamase inhibitor with broad-spectrum activity against Ambler class A, C, and D β-lactamases. Sulbactam (SUL) is an Ambler Class A β-lactamase inhibitor with intrinsic antibacterial activity against a limited number of species, including Acinetobacter spp. SUL-DUR is currently in Phase 3 clinical testing for the treatment of carbapenem-resistant infections caused by Acinetobacter spp. In this study, SUL-DUR was tested for in vitro antibacterial activity against B. pseudomallei and B. mallei as well as for in vivo efficacy in a preclinical model of melioidosis. Methods The antibacterial activity of SUL alone or in combination with DUR (fixed at 4 mg/L) against B. pseudomallei (n = 30) and B. mallei (N = 28) was determined following CLSI guidelines. In vivo efficacy was tested in an acute murine model of melioidosis in which 4 × 104 cfu Bp K96423 (SUL-DUR MIC = 1 mg/L) was administered intranasally to BalbC mice. SUL-DUR (100/200 or 400/200 mg/kg) was administered q4h subcutaneously 4 hours post-challenge for 6 days and murine survival was monitored for 45 days. Doxycycline (DOX) and ciprofloxacin (CIP) were dosed as positive controls at 40 mg/kg q12 h for 6 days. Results The addition of DUR effectively lowered the SUL MIC50/90 from 8/16 to 0.25/0.5 mg/L vs. B. pseudomallei and from 8/8 to 1/2 mg/L for B. mallei. All untreated mice in the melioidosis model succumbed to infection within 3 days of challenge. 60% survival was observed for both dose arms of SUL-DUR as compared with 40% survival observed for both CIP and DOX. Conclusion Preliminary preclinical data demonstrating robust in vitro and in vivo antibacterial activity of SUL-DUR against Burkholderia spp. suggests this combination may be an effective new therapy for the treatment of these challenging pathogens. Disclosures All authors: No reported disclosures.

scholarly journals In VitroAntibacterial Activity of the Ceftazidime-Avibactam Combination against Enterobacteriaceae, Including Strains with Well-Characterized β-Lactamases

2015 ◽  
Vol 59 (4) ◽  
pp. 1931-1934 ◽  
Author(s):  
Premavathy Levasseur ◽  
Anne-Marie Girard ◽  
Christine Miossec ◽  
John Pace ◽  
Ken Coleman
Keyword(s):  
Antibacterial Activity ◽  
Antimicrobial Agents ◽  
The Novel ◽  
Content Type ◽  
Class A ◽  
Fixed Weight ◽  
Class D ◽  
Resistant Strains ◽  
Esbl Producers

ABSTRACTThe novel β-lactamase inhibitor avibactam is a potent inhibitor of class A, class C, and some class D enzymes. Thein vitroantibacterial activity of the ceftazidime-avibactam combination was determined for a collection ofEnterobacteriaceaeclinical isolates; this collection was enriched for resistant strains, including strains with characterized serine β-lactamases. The inhibitor was added either at fixed weight ratios to ceftazidime or at fixed concentrations, with the latter type of combination consistently resulting in greater potentiation of antibacterial activity. In the presence of 4 μg/ml of avibactam, the ceftazidime MIC50and MIC90(0.25 and 2 μg/ml, respectively) were both below the CLSI breakpoint for ceftazidime. Further comparisons with reference antimicrobial agents were performed using this fixed inhibitor concentration. Against most ceftazidime-susceptible and -nonsusceptible isolates, the addition of avibactam resulted in a significant increase in ceftazidime activity, with MICs generally reduced 256-fold for extended-spectrum β-lactamase (ESBL) producers, 8- to 32-fold for CTX-M producers, and >128-fold for KPC producers. Overall, MICs of a ceftazidime-avibactam combination were significantly lower than those of the comparators piperacillin-tazobactam, cefotaxime, ceftriaxone, and cefepime and similar or superior to those of imipenem.

scholarly journals New β-Lactam–β-Lactamase Inhibitor Combinations

2020 ◽  
Vol 34 (1) ◽  
Author(s):  
Dafna Yahav ◽  
Christian G. Giske ◽  
Alise Grāmatniece ◽  
Henrietta Abodakpi ◽  
Vincent H. Tam ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Treatment Option ◽  
Clinical Data ◽  
Multidrug Resistant ◽  
Drug Resistant ◽  
Content Type ◽  
Carbapenem Resistant ◽  
Class D ◽  
Lactamase Inhibitor

SUMMARY The limited armamentarium against drug-resistant Gram-negative bacilli has led to the development of several novel β-lactam–β-lactamase inhibitor combinations (BLBLIs). In this review, we summarize their spectrum of in vitro activities, mechanisms of resistance, and pharmacokinetic-pharmacodynamic (PK-PD) characteristics. A summary of available clinical data is provided per drug. Four approved BLBLIs are discussed in detail. All are options for treating multidrug-resistant (MDR) Enterobacterales and Pseudomonas aeruginosa. Ceftazidime-avibactam is a potential drug for treating Enterobacterales producing extended-spectrum β-lactamase (ESBL), Klebsiella pneumoniae carbapenemase (KPC), AmpC, and some class D β-lactamases (OXA-48) in addition to carbapenem-resistant Pseudomonas aeruginosa. Ceftolozane-tazobactam is a treatment option mainly for carbapenem-resistant P. aeruginosa (non-carbapenemase producing), with some activity against ESBL-producing Enterobacterales. Meropenem-vaborbactam has emerged as treatment option for Enterobacterales producing ESBL, KPC, or AmpC, with similar activity as meropenem against P. aeruginosa. Imipenem-relebactam has documented activity against Enterobacterales producing ESBL, KPC, and AmpC, with the combination having some additional activity against P. aeruginosa relative to imipenem. None of these drugs present in vitro activity against Enterobacterales or P. aeruginosa producing metallo-β-lactamase (MBL) or against carbapenemase-producing Acinetobacter baumannii. Clinical data regarding the use of these drugs to treat MDR bacteria are limited and rely mostly on nonrandomized studies. An overview on eight BLBLIs in development is also provided. These drugs provide various levels of in vitro coverage of carbapenem-resistant Enterobacterales, with several drugs presenting in vitro activity against MBLs (cefepime-zidebactam, aztreonam-avibactam, meropenem-nacubactam, and cefepime-taniborbactam). Among these drugs, some also present in vitro activity against carbapenem-resistant P. aeruginosa (cefepime-zidebactam and cefepime-taniborbactam) and A. baumannii (cefepime-zidebactam and sulbactam-durlobactam).

scholarly journals A Novel Anti-PcrV Antibody Providing Enhanced Protection against Pseudomonas aeruginosa in Multiple Animal Infection Models

2014 ◽  
Vol 58 (8) ◽  
pp. 4384-4391 ◽  
Author(s):  
Paul Warrener ◽  
Reena Varkey ◽  
Jessica C. Bonnell ◽  
Antonio DiGiandomenico ◽  
Maria Camara ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Host Cells ◽  
Content Type ◽  
Mechanically Ventilated ◽  
Potent Inhibition ◽  
Infection Models ◽  
High Risk Populations ◽  
Hospital Acquired

ABSTRACTPseudomonas aeruginosais a major cause of hospital-acquired infections, particularly in mechanically ventilated patients, and it is the leading cause of death in cystic fibrosis patients. A key virulence factor associated with disease severity is theP. aeruginosatype III secretion system (T3SS), which injects bacterial toxins directly into the cytoplasm of host cells. The PcrV protein, located at the tip of the T3SS injectisome complex, is required for T3SS function and is a well-validated target in animal models of immunoprophylactic strategies targetingP. aeruginosa. In an effort to identify a highly potent and protective monoclonal antibody (MAb) that inhibits the T3SS, we generated and characterized a panel of novel anti-PcrV MAbs. Interestingly, some MAbs exhibiting potent inhibition of T3SSin vitrofailed to provide protection in a mouse model ofP. aeruginosainfection, suggesting that effectivein vivoinhibition of T3SS with anti-PcrV MAbs is epitope dependent. V2L2MD, while not the most potent MAb as assessed byin vitrocytotoxicity inhibition assays, provided strong prophylactic protection in several murine infection models and a postinfection therapeutic model. V2L2MD mediated significantly (P< 0.0001) betterin vivoprotection than that provided by a comparator antibody, MAb166, a well-characterized anti-PcrV MAb and the progenitor of a clinical candidate, KB001-A. The results described here support further development of a V2L2MD-containing immunotherapeutic and may suggest even greater potential than was previously recognized for the prevention and treatment ofP. aeruginosainfections in high-risk populations.

scholarly journals Emergence of Ceftolozane-Tazobactam-Resistant Pseudomonas aeruginosa during Treatment Is Mediated by a Single AmpC Structural Mutation

2017 ◽  
Vol 61 (12) ◽  
Author(s):  
Shawn H. MacVane ◽  
Ruchi Pandey ◽  
Lisa L. Steed ◽  
Barry N. Kreiswirth ◽  
Liang Chen
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Wound Infection ◽  
Clinical Isolates ◽  
Content Type ◽  
Structural Mutation ◽  
Inhibitor Combination ◽  
Lactamase Inhibitor

ABSTRACT Ceftolozane-tazobactam is a cephalosporin-β-lactamase inhibitor combination that exhibits potent in vitro activity against Pseudomonas aeruginosa, including strains that are resistant to other β-lactams. The emergence of ceftolozane-tazobactam resistance among clinical isolates of P. aeruginosa has rarely been described. Here we characterized ceftolozane-tazobactam-resistant P. aeruginosa strains recovered from a patient who was treated with this agent for 6 weeks for a recurrent wound infection. The results showed that the resistance was mediated by a single AmpC structural mutation.

scholarly journals In VitroActivity of Imipenem-Relebactam Alone or in Combination with Amikacin or Colistin againstPseudomonas aeruginosa

2019 ◽  
Vol 63 (9) ◽  
Author(s):  
Tomefa E. Asempa ◽  
David P. Nicolau ◽  
Joseph L. Kuti
Keyword(s):  
Potential Role ◽  
Multidrug Resistant ◽  
Synergistic Activity ◽  
Content Type ◽  
Class A ◽  
Susceptible Isolate ◽  
Time Kill ◽  
Lactamase Inhibitor

ABSTRACTRelebactam is a novel class A/C β-lactamase inhibitor that restores imipenemin vitroactivity against multidrug-resistant and carbapenem-nonsusceptiblePseudomonas aeruginosa. Time-kill analyses were performed to evaluate the potential role of imipenem-relebactam in combination with amikacin or colistin againstP. aeruginosa. Ten clinicalP. aeruginosaisolates (9 imipenem nonsusceptible) with imipenem-relebactam MICs ranging from 1/4 to 8/4 μg/ml were included. The isolates had varied susceptibilities to imipenem (1 to 32 μg/ml), amikacin (4 to 128 μg/ml), and colistin (0.5 to 1 μg/ml). Duplicate 24-h time-kill studies were conducted using the average steady-state concentrations (Cssavg) observed after the administration of imipenem-relebactam at 500 mg/250 mg every 6 hours (q6h) alone and in combination with theCssavgof 25 mg/kg of body weight/day amikacin and 360 mg/day colistin in humans. Imipenem-relebactam alone resulted in 24-h bacterial densities of −2.93 ± 0.38, −1.67 ± 0.29, +0.38 ± 0.96, and +0.15 ± 0.65 log10CFU/ml at imipenem-relebactam MICs of 1/4, 2/4, 4/4, and 8/4 μg/ml, respectively. No synergy was demonstrated against the single imipenem-susceptible isolate. Against the imipenem-nonsusceptible isolates (n = 9), imipenem-relebactam combined with amikacin resulted in synergy (−2.61 ± 1.50 log10CFU/ml) against all amikacin-susceptible isolates and in two of three amikacin-intermediate (i.e., MIC, 32 μg/ml) isolates (−2.06 ± 0.19 log10CFU/ml). Synergy with amikacin was not observed when the amikacin MIC was >32 μg/ml. Imipenem-relebactam combined with colistin demonstrated synergy in eight out of the nine imipenem-resistant isolates (−3.17 ± 1.00 log10CFU/ml). Against these 10 P. aeruginosaisolates, imipenem-relebactam combined with either amikacin or colistin resulted in synergistic activity against the majority of strains. Further studies evaluating combination therapy with imipenem-relebactam are warranted.

scholarly journals Potency of Vaborbactam Is Less Affected than That of Avibactam in Strains Producing KPC-2 Mutations That Confer Resistance to Ceftazidime-Avibactam

2020 ◽  
Vol 64 (4) ◽  
Author(s):  
Ruslan Tsivkovski ◽  
Olga Lomovskaya
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Inhibitory Concentration ◽  
Fold Increase ◽  
Clinical Settings ◽  
Bacterial Cells ◽  
Wild Type ◽  
Content Type ◽  
Carbapenem Resistant ◽  
Lactamase Inhibitor

ABSTRACT Resistance to ceftazidime-avibactam due to mutations in KPC genes has been reported both in vitro and in clinical settings. The most frequently reported mutation leads to the amino acid substitution D179Y in the Ω loop of the enzyme. Bacterial cells that carry mutant KPC acquire a higher level of ceftazidime resistance, become more sensitive to other cephalosporins, and almost completely lose resistance to carbapenems. In this study, we demonstrated that two substitutions in KPC-2, D179Y and L169P, reduce the ability of avibactam to enhance the activity of ceftazidime, cefepime, or piperacillin against isogenic efflux-deficient strains of Pseudomonas aeruginosa, 8- to 32-fold and 4- to 16-fold for the D179Y and L169P variants, respectively, depending on the antibiotic. In contrast, the potency of vaborbactam, the structurally unrelated β-lactamase inhibitor that was recently approved by the FDA in combination with meropenem, is reduced no more than 2-fold. Experiments with purified enzymes demonstrate that the D179Y substitution causes an ∼20-fold increase in the 50% inhibitory concentration (IC50) for inhibition of ceftazidime hydrolysis by avibactam, versus 2-fold for vaborbactam, and that the L169P substitution has an ∼4.5-fold-stronger effect on the affinity for avibactam than for vaborbactam. In addition, the D179Y and L169P variants hydrolyze ceftazidime with 10-fold and 4-fold-higher efficiencies, respectively, than that of wild-type KPC-2. Thus, microbiological and biochemical experiments implicate both decreased ability of avibactam to interact with KPC-2 variants and an increase in the efficiency of ceftazidime hydrolysis in resistance to ceftazidime-avibactam. These substitutions have a considerably lesser effect on interactions with vaborbactam, making the meropenem-vaborbactam combination a valuable agent in managing infections due to KPC-producing carbapenem-resistant Enterobacteriaceae.

scholarly journals Molecular Basis for the Potent Inhibition of the Emerging Carbapenemase VCC-1 by Avibactam

2019 ◽  
Vol 63 (4) ◽  
Author(s):  
Chand S. Mangat ◽  
Grishma Vadlamani ◽  
Viktor Holicek ◽  
Mitchell Chu ◽  
Veronica L. C. Larmour ◽  
...  
Keyword(s):  
Molecular Basis ◽  
Tertiary Structure ◽  
Human Consumption ◽  
Content Type ◽  
New Class ◽  
Class A ◽  
Potent Inhibition ◽  
Canadian Isolate ◽  
Functional Biology

ABSTRACT In 2016, we identified a new class A carbapenemase, VCC-1, in a nontoxigenic Vibrio cholerae strain that had been isolated from retail shrimp imported into Canada for human consumption. Shortly thereafter, seven additional VCC-1-producing V. cholerae isolates were recovered along the German coastline. These isolates appear to have acquired the VCC-1 gene (blaVCC-1) independently from the Canadian isolate, suggesting that blaVCC-1 is mobile and widely distributed. VCC-1 hydrolyzes penicillins, cephalothin, aztreonam, and carbapenems and, like the broadly disseminated class A carbapenemase KPC-2, is only weakly inhibited by clavulanic acid or tazobactam. Although VCC-1 has yet to be observed in the clinic, its encroachment into aquaculture and other areas with human activity suggests that the enzyme may be emerging as a public health threat. To preemptively address this threat, we examined the structural and functional biology of VCC-1 against the FDA-approved non-β-lactam-based inhibitor avibactam. We found that avibactam restored the in vitro sensitivity of V. cholerae to meropenem, imipenem, and ertapenem. The acylation efficiency was lower for VCC-1 than for KPC-2 and akin to that of Pseudomonas aeruginosa PAO1 AmpC (k2/Ki = 3.0 × 103 M−1 s−1). The tertiary structure of VCC-1 is similar to that of KPC-2, and they bind avibactam similarly; however, our analyses suggest that VCC-1 may be unable to degrade avibactam, as has been found for KPC-2. Based on our prior genomics-based surveillance, we were able to target VCC-1 for detailed molecular studies to gain early insights that could be used to combat this carbapenemase in the future.

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