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Journal of Global Antimicrobial... Sep 2020Ceftazidime-avibactam (CAZ-AVI) is a novel synthetic β-lactamase inhibitor combination. Although the combination has been available clinically for only a few years,... (Review)
Review
OBJECTIVE
Ceftazidime-avibactam (CAZ-AVI) is a novel synthetic β-lactamase inhibitor combination. Although the combination has been available clinically for only a few years, cases of resistance to CAZ-AVI have already been reported.
METHODS
In the present review, we summarize the distribution of CAZ-AVI-resistant strains and the possible resistance mechanisms.
RESULTS
There are no significant differences in CAZ-AVI resistance rates across different regions. CAZ-AVI maintains good activity against Gram-negative bacteria, especially Enterobacteriaceae. Pseudomonas aeruginosa is less susceptible to CAZ-AVI compared with Enterobacteriaceae, with a resistance rate ranging from 2.9 to 18%. The resistance to CAZ-AVI exceeds 50% in Acinetobacter baumannii. A higher resistance rate to CAZ-AVI is associated with carbapenem resistance. Moreover, β-lactamase-related amino acid substitutions are the main mechanisms that lead to CAZ-AVI resistance. Membrane protein amino acid substitutions and efflux pumps also play important roles in CAZ-AVI resistance.
CONCLUSIONS
To maintain its efficacy, CAZ-AVI should not be used for pathogens that are naturally resistant to it. For CAZ-AVI-resistant strains, other effective antibacterial agents or CAZ-AVI in combination with other antibacterial agents should be considered.
Topics: Azabicyclo Compounds; Ceftazidime; Drug Combinations; Microbial Sensitivity Tests
PubMed: 31863899
DOI: 10.1016/j.jgar.2019.12.009 -
WIREs Mechanisms of Disease Nov 2022Ceftazidime/avibactam (CAZ/AVI), a combination of ceftazidime and a novel β-lactamase inhibitor (avibactam) that has been approved by the U.S. Food and Drug... (Review)
Review
Ceftazidime/avibactam (CAZ/AVI), a combination of ceftazidime and a novel β-lactamase inhibitor (avibactam) that has been approved by the U.S. Food and Drug Administration, the European Union, and the National Regulatory Administration in China. CAZ/AVI is used mainly to treat complicated urinary tract infections and complicated intra-abdominal infections in adults, as well as to treat patients infected with Carbapenem-resistant Enterobacteriaceae (CRE) susceptible to CAZ/AVI. However, increased clinical application of CAZ/AVI has resulted in the development of resistant strains. Mechanisms of resistance in most of these strains have been attributed to bla mutations, which lead to amino acid substitutions in β-lactamase and changes in gene expression. Resistance to CAZ/AVI is also associated with reduced expression and loss of outer membrane proteins or overexpression of efflux pumps. In this review, the prevalence of CAZ/AVI-resistance bacteria, resistance mechanisms, and selection of detection methods of CAZ/AVI are demonstrated, aiming to provide scientific evidence for the clinical prevention and treatment of CAZ/AVI resistant strains, and provide guidance for the development of new drugs. This article is categorized under: Infectious Diseases > Molecular and Cellular Physiology.
Topics: Adult; Humans; Ceftazidime; Microbial Sensitivity Tests; Anti-Bacterial Agents; beta-Lactamases
PubMed: 35891616
DOI: 10.1002/wsbm.1571 -
British Medical Journal Dec 1964
Topics: Anti-Bacterial Agents; Cephaloridine; Drug Resistance; Drug Resistance, Microbial; Escherichia coli; Humans; Proteus; Urinary Tract Infections
PubMed: 14214202
DOI: 10.1136/bmj.2.5423.1530 -
Pharmacotherapy Aug 2015Gram-negative resistance has reached a crucial point, with emergence of pathogens resistant to most or all available antibiotics. Ceftazidime-avibactam is a newly... (Review)
Review
Gram-negative resistance has reached a crucial point, with emergence of pathogens resistant to most or all available antibiotics. Ceftazidime-avibactam is a newly approved agent combining ceftazidime and a novel β-lactamase inhibitor with activity against multidrug-resistant gram-negative bacteria. Avibactam has increased potency and expanded spectrum of inhibition of class A and C β-lactamases relative to available β-lactamase inhibitors, including extended-spectrum β-lactamases, AmpC, and Klebsiella pneumoniae carbapenemase (KPC) enzymes. Avibactam expands ceftazidime's spectrum of activity to include many ceftazidime- and carbapenem-resistant Enterobacteriaceae and Pseudomonas aeruginosa. Early clinical data indicate that ceftazidime-avibactam is effective and well tolerated in patients with complicated urinary tract infections (cUTIs) and complicated intraabdominal infections (cIAI). In a phase II trial of patients with cUTIs, ceftazidime-avibactam produced similar rates of clinical and microbiologic success compared with imipenem-cilastatin (70.5% and 71.4% microbiologic success rates, respectively). Likewise, patients receiving ceftazidime-avibactam plus metronidazole in a phase II study of patients with cIAI had similar response rates to those receiving meropenem (91.2% and 93.4% clinical success rates, respectively). Based on available in vitro, in vivo, and phase II trial data, as well as preliminary phase III trial results in ceftazidime-resistant, gram-negative cUTI and cIAI, ceftazidime-avibactam received U.S. Food and Drug Administration approval for treatment of cUTI, including pyelonephritis, and cIAI, in combination with metronidazole, in adult patients with limited or no alternative treatment options. The approved dosage, ceftazidime 2 g-avibactam 0.5 g administered as a 2-hour infusion every 8 hours, was selected based on pharmacodynamic analysis and available clinical data. This dosage is under further investigation in patients with cUTI, cIAI, and nosocomial or ventilator-associated pneumonia. The current body of evidence suggests that ceftazidime-avibactam is a promising addition to our therapeutic armamentarium with potential to answer an urgent unmet medical need. Further data in highly resistant gram-negative infections, particularly those caused by KPC-producing Enterobacteriaceae, are needed. As it is introduced into clinical use, careful stewardship and rational use are essential to preserve ceftazidime-avibactam's potential utility.
Topics: Anti-Bacterial Agents; Azabicyclo Compounds; Ceftazidime; Clinical Trials, Phase II as Topic; Drug Combinations; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacteria; Gram-Positive Bacteria; Humans; Randomized Controlled Trials as Topic; beta-Lactamase Inhibitors
PubMed: 26289307
DOI: 10.1002/phar.1622 -
The Journal of Antimicrobial... Aug 2022Cefiderocol is a novel siderophore β-lactam with improved hydrolytic stability toward β-lactamases, including carbapenemases, achieved by combining structural moieties...
BACKGROUND
Cefiderocol is a novel siderophore β-lactam with improved hydrolytic stability toward β-lactamases, including carbapenemases, achieved by combining structural moieties of two clinically efficient cephalosporins, ceftazidime and cefepime. Consequently, cefiderocol represents a treatment alternative for infections caused by MDR Gram-negatives.
OBJECTIVES
To study the role of cefiderocol on resistance development and on the evolution of β-lactamases from all Ambler classes, including KPC-2, CTX-M-15, NDM-1, CMY-2 and OXA-48.
METHODS
Directed evolution, using error-prone PCR followed by selective plating, was utilized to investigate how the production and the evolution of different β-lactamases cause changes in cefiderocol susceptibility determined using microbroth dilution assays (MIC and IC50).
RESULTS
We found that the expression of blaOXA-48 did not affect cefiderocol susceptibility. On the contrary, the expression of blaKPC-2, blaCMY-2, blaCTX-M-15 and blaNDM-1 substantially reduced cefiderocol susceptibility by 4-, 16-, 8- and 32-fold, respectively. Further, directed evolution on these enzymes showed that, with the acquisition of only 1-2 non-synonymous mutations, all β-lactamases were evolvable to further cefiderocol resistance by 2- (NDM-1, CTX-M-15), 4- (CMY-2), 8- (OXA-48) and 16-fold (KPC-2). Cefiderocol resistance development was often associated with collateral susceptibility changes including increased resistance to ceftazidime and ceftazidime/avibactam as well as functional trade-offs against different β-lactam drugs.
CONCLUSIONS
The expression of contemporary β-lactamase genes can potentially contribute to cefiderocol resistance development and the acquisition of mutations in these genes results in enzymes adapting to increasing cefiderocol concentrations. Resistance development caused clinically important cross-resistance, especially against ceftazidime and ceftazidime/avibactam.
Topics: Anti-Bacterial Agents; Azabicyclo Compounds; Ceftazidime; Cephalosporins; Drug Combinations; Microbial Sensitivity Tests; beta-Lactamases; Cefiderocol
PubMed: 35815680
DOI: 10.1093/jac/dkac221 -
British Medical Journal Nov 1964
Topics: Cephaloridine
PubMed: 14205525
DOI: 10.1136/bmj.2.5419.1211 -
Canadian Medical Association Journal Jul 1971
Topics: Cephaloridine; Cephalosporins; Cephalothin; Drug Hypersensitivity; Humans; Infections; Injections, Intramuscular; Injections, Intravenous; Kidney; Kidney Diseases; Thrombophlebitis
PubMed: 5092516
DOI: No ID Found -
International Archives of Allergy and... 2023Neutrophilic granulocytes represent the first line of defense against microorganisms. Granulocytes phagocytose microorganisms and specifically synthesize oxygen radicals...
INTRODUCTION
Neutrophilic granulocytes represent the first line of defense against microorganisms. Granulocytes phagocytose microorganisms and specifically synthesize oxygen radicals against them, which eventually kills the invaders.
METHODS
Neutrophilic granulocytes were isolated from peripheral blood of healthy volunteer donors. Putative interference of new-generation antibiotics with neutrophil function was tested using a collection of granulocyte-stimulating agents and Amplex™ Red-based plate assay and flow cytometry-based respiratory burst assays. In addition, phagocytosis of E. coli, IL-8 production, bactericidal activity, and CD62L expression of granulocytes were evaluated.
RESULTS
Of note, we found that the two glycopeptide antibiotics dalbavancin and teicoplanin inhibited ROS production upon granulocyte activation via different signaling pathways in a dose-dependent manner. Dalbavancin also blocked the PMA-induced shedding of CD62L. In contrast, the oxazolidinone antibiotics tedizolid and linezolid had no effect on neutrophil function, while the combination of ceftazidime/avibactam dose dependently inhibited the fMLP/Cytochalasin B-induced granulocyte burst in a dose-dependent manner. Additionally, we showed that dalbavancin and teicoplanin as well as sulfametrole/trimethoprim and ceftazidime/avibactam inhibited baseline and PMA-induced IL-8 production by neutrophilic granulocytes. Moreover, dalbavancin impaired the bactericidal activity of neutrophilic granulocytes.
CONCLUSION
We here identified hitherto unknown inhibitory effects of several classes of antibiotics on the effector functions of neutrophilic granulocytes.
Topics: Humans; Neutrophils; Ceftazidime; Teicoplanin; Escherichia coli; Interleukin-8; Anti-Bacterial Agents
PubMed: 37321197
DOI: 10.1159/000530865 -
Nature Communications Aug 2023The cell envelope of Gram-negative bacteria belonging to the Burkholderia cepacia complex (Bcc) presents unique restrictions to antibiotic penetration. As a consequence,...
The cell envelope of Gram-negative bacteria belonging to the Burkholderia cepacia complex (Bcc) presents unique restrictions to antibiotic penetration. As a consequence, Bcc species are notorious for causing recalcitrant multidrug-resistant infections in immunocompromised individuals. Here, we present the results of a genome-wide screen for cell envelope-associated resistance and susceptibility determinants in a Burkholderia cenocepacia clinical isolate. For this purpose, we construct a high-density, randomly-barcoded transposon mutant library and expose it to 19 cell envelope-targeting antibiotics. By quantifying relative mutant fitness with BarSeq, followed by validation with CRISPR-interference, we profile over a hundred functional associations and identify mediators of antibiotic susceptibility in the Bcc cell envelope. We reveal connections between β-lactam susceptibility, peptidoglycan synthesis, and blockages in undecaprenyl phosphate metabolism. The synergy of the β-lactam/β-lactamase inhibitor combination ceftazidime/avibactam is primarily mediated by inhibition of the PenB carbapenemase. In comparison with ceftazidime, avibactam more strongly potentiates the activity of aztreonam and meropenem in a panel of Bcc clinical isolates. Finally, we characterize in Bcc the iron and receptor-dependent activity of the siderophore-cephalosporin antibiotic, cefiderocol. Our work has implications for antibiotic target prioritization, and for using additional combinations of β-lactam/β-lactamase inhibitors that can extend the utility of current antibacterial therapies.
Topics: Humans; Anti-Bacterial Agents; Ceftazidime; beta-Lactamase Inhibitors; Meropenem; beta-Lactamases; Drug Combinations; Microbial Sensitivity Tests
PubMed: 37558695
DOI: 10.1038/s41467-023-40494-5 -
Clinical Microbiology and Infection :... May 2023Ceftazidime-avibactam (CAZ-AVI)-based treatments have been associated with the emergence of resistance in KPC-producing Klebsiella pneumoniae (KPC-Kp) isolates after...
OBJECTIVES
Ceftazidime-avibactam (CAZ-AVI)-based treatments have been associated with the emergence of resistance in KPC-producing Klebsiella pneumoniae (KPC-Kp) isolates after antimicrobial exposure. Here, we evaluated the CAZ-AVI resistance development in KPC-Kp isolated from patients treated with CAZ-AVI-based therapy.
METHODS
We enrolled adult patients treated with CAZ-AVI-based regimens between January 2020 and January 2021. Carbapenemase-producing isolates collected from clinical samples and rectal swabs were evaluated for CAZ-AVI resistance development after antimicrobial exposure. KPC-Kp developing CAZ-AVI resistance and parental susceptible strains were genomically characterized. Whole genome sequencing was performed by using the Illumina iSeq100 platform and genomes were analyzed for antimicrobial-resistance genes, plasmid and porins sequences.
RESULTS
We enrolled 90 patients treated with CAZ-AVI-based therapy and 62.2% (56/90) of them were colonized by KPC-producers before CAZ-AVI-based treatment and 6.6% acquired colonization during therapy. Six (6.6%) patients developed infections because of resistant KPC-Kp after CAZ-AVI exposure and 3 (3.3%) of them developed CAZ-AVI resistance in the rectum. Development of resistance among KPC in the rectum occurred after 32 (IQR, 9-35) days of therapy and after 30 (IQR, 22-40) days in clinical specimens. Genetic analysis demonstrated that the development of CAZ-AVI resistance was associated with mutated bla (bla, bla, bla, and bla) and phylogenetic analysis demonstrated a close genomic relationship between KCP-Kp collected from rectum and clinical samples of the same patient.
DISCUSSION
Antimicrobial exposure induce a higher incidence of CAZ-AVI resistance development in the blood and respiratory tract than in the rectum (6.7% vs. 3.3%) of CAZ-AVI-treated patients and genome analysis showed that resistance was associated with mutated bla variants.
Topics: Adult; Humans; Ceftazidime; Anti-Bacterial Agents; Klebsiella pneumoniae; Critical Illness; Phylogeny; Drug Combinations; Bacterial Proteins; beta-Lactamases; Microbial Sensitivity Tests; Klebsiella Infections
PubMed: 36716999
DOI: 10.1016/j.cmi.2023.01.012