Review

Authors: Yuhang Wang, Jin Wang, Rui Wang...

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

Authors: Henry F Chambers, Heather R Cross, Maria Souli...

In this overview, we describe important contributions from the Antibacterial Resistance Leadership Group (ARLG) to patient care, clinical trials design, and mentorship while outlining future priorities. The ARLG research agenda is focused on 3 key areas: gram-positive infections, gram-negative infections, and diagnostics. The ARLG has developed an innovative approach to clinical trials design, the desirability of outcome ranking (DOOR), which uses an ordinal measure of global outcome to assess both benefits and harms. DOOR was initially applied to observational studies to determine optimal dosing of vancomycin for methicillin-resistant Staphylcococcus aureus bacteremia and the efficacy of ceftazidime-avibactam versus colistin for the treatment of carbapenem-resistant Enterobacterales infection. DOOR is being successfully applied to the analysis of interventional trials and, in collaboration with the US Food and Drug Administration (FDA), for use in registrational trials. In the area of diagnostics, the ARLG developed Master Protocol for Evaluating Multiple Infection Diagnostics (MASTERMIND), an innovative design that allows simultaneous testing of multiple diagnostic platforms in a single study. This approach will be used to compare molecular assays for the identification of fluoroquinolone-resistant Neisseria gonorrhoeae (MASTER GC) and to compare rapid diagnostic tests for bloodstream infections. The ARLG has initiated a first-in-kind randomized, double-blind, placebo-controlled trial in participants with cystic fibrosis who are chronically colonized with Pseudomonas aeruginosa to assess the pharmacokinetics and antimicrobial activity of bacteriophage therapy. Finally, an engaged and highly trained workforce is critical for continued and future success against antimicrobial drug resistance. Thus, the ARLG has developed a robust mentoring program targeted to each stage of research training to attract and retain investigators in the field of antimicrobial resistance research.

Topics: Humans; Anti-Bacterial Agents; Carbapenems; Ceftazidime; Colistin; Drug Resistance, Bacterial; Leadership; Microbial Sensitivity Tests

PubMed: 37843121
DOI: 10.1093/cid/ciad475

Review

Authors: Luying Xiong, Xueting Wang, Yuan Wang...

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

Authors: Junliang Zhu, Xiaohui Li, Yang Zhou...

Effective therapeutic modalities and drug administration strategies for the treatment of chronic obstructive pulmonary disease (COPD) exacerbations are lacking. Here, mucus and biofilm dual-penetrating immunoantimicrobials (IMAMs) are developed for bridging antibacterial therapy and pro-resolving immunotherapy of COPD. IMAMs are constructed from ceftazidime (CAZ)-encapsulated hollow mesoporous silica nanoparticles (HMSNs) gated with a charge/conformation-transformable polypeptide. The polypeptide adopts a negatively charged, random-coiled conformation, masking the pores of HMSNs to prevent antibiotic leakage and allowing the nebulized IMAMs to efficiently penetrate the bronchial mucus and biofilm. Inside the acidic biofilm, the polypeptide transforms into a cationic and rigid α helix, enhancing biofilm retention and unmasking the pores to release CAZ. Meanwhile, the polypeptide is conditionally activated to disrupt bacterial membranes and scavenge bacterial DNA, functioning as an adjuvant of CAZ to eradicate lung-colonizing bacteria and inhibiting Toll-like receptor 9 activation to foster inflammation resolution. This immunoantibacterial strategy may shift the current paradigm of COPD management.

Topics: Humans; Pulmonary Disease, Chronic Obstructive; Lung; Nanoparticles; Ceftazidime; Anti-Bacterial Agents; Peptides

PubMed: 38324682
DOI: 10.1126/sciadv.abd7904

Review

Authors: Evan J Zasowski, Jeffrey M Rybak, Michael J Rybak...

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

Authors: Christopher Fröhlich, Vidar Sørum, Nobuhiko Tokuriki...

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

Authors: Daisuke Ono, Maria F Mojica, Christopher R Bethel...

Taniborbactam (TAN; VNRX-5133) is a novel bicyclic boronic acid β-lactamase inhibitor (BLI) being developed in combination with cefepime (FEP). TAN inhibits both serine and some metallo-β-lactamases. Previously, the substitution R228L in VIM-24 was shown to increase activity against oxyimino-cephalosporins like FEP and ceftazidime (CAZ). We hypothesized that substitutions at K224, the homologous position in NDM-1, could impact FEP/TAN resistance. To evaluate this, a library of codon-optimized NDM K224X clones for minimum inhibitory concentration (MIC) measurements was constructed; steady-state kinetics and molecular docking simulations were next performed. Surprisingly, our investigation revealed that the addition of TAN restored FEP susceptibility only for NDM-1, as the MICs for the other 19 K224X variants remained comparable to those of FEP alone. Moreover, compared to NDM-1, all K224X variants displayed significantly lower MICs for imipenem, tebipenem, and cefiderocol (32-, 133-, and 33-fold lower, respectively). In contrast, susceptibility to CAZ was mostly unaffected. Kinetic assays with the K224I variant, the only variant with hydrolytic activity to FEP comparable to NDM-1, confirmed that the inhibitory capacity of TAN was modestly compromised (IC 0.01 µM vs 0.14 µM for NDM-1). Lastly, structural modeling and docking simulations of TAN in NDM-1 and in the K224I variant revealed that the hydrogen bond between TAN's carboxylate with K224 is essential for the productive binding of TAN to the NDM-1 active site. In addition to the report of NDM-9 (E149K) as FEP/TAN resistant, this study demonstrates the fundamental role of single amino acid substitutions in the inhibition of NDM-1 by TAN.

Topics: Anti-Bacterial Agents; Molecular Docking Simulation; Carboxylic Acids; Borinic Acids; Ceftazidime; beta-Lactamase Inhibitors; beta-Lactamases; Microbial Sensitivity Tests

PubMed: 38174924
DOI: 10.1128/aac.01332-23

Authors: Paul Ettel, Al Nasar Ahmed Sehgal, Nicole Harrison...

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

Authors: Sylvain Goutelle, Vincent Jullien, Jean-Pierre Bru...

BACKGROUND

The new definitions of antimicrobial susceptibility categories proposed by EUCAST in 2020 require the definition of standard and high dosages of antibiotic. For injectable β-lactams, standard and high dosages have been proposed for short-infusion regimens only.

OBJECTIVES

To evaluate dosages for β-lactams administered by prolonged infusion (PI) and continuous infusion (CI).

METHODS

Monte Carlo simulations were performed for seven injectable β-lactams: aztreonam, cefepime, cefotaxime, cefoxitin, ceftazidime, piperacillin and temocillin. Various dosage regimens based on short infusion, PI or CI were simulated in virtual patients. Pharmacokinetic (PK) profiles and PTAs were obtained based on reference population PK models, as well as PK/pharmacodynamic targets and MIC breakpoints proposed by EUCAST. Alternative dosage regimens associated with PTA values similar to those of recommended dosages up to the breakpoints were considered acceptable.

RESULTS

Adequate PTAs were confirmed for most EUCAST short-infusion dosage regimens. A total of 9 standard and 14 high dosages based on PI (3 to 4 h) or CI were identified as alternatives. For cefepime and aztreonam, only PI and CI regimens could achieve acceptable PTAs for infections caused by Pseudomonas spp.: 2 g q8h as PI of 4 h or 6 g/24 h CI for cefepime; 2 g q6h as PI of 3 h or 6 g/24 h CI for aztreonam.

CONCLUSIONS

These alternative standard and high dosage regimens are expected to provide antibiotic exposure compatible with new EUCAST definitions of susceptibility categories and associated MIC breakpoints. However, further clinical evaluation is necessary.

Topics: Humans; Cefepime; Aztreonam; Anti-Bacterial Agents; Ceftazidime; Piperacillin; Microbial Sensitivity Tests; Monte Carlo Method

PubMed: 37796958
DOI: 10.1093/jac/dkad300

Comparative Study

Cephaloridine induces translocation of protein kinase C delta into mitochondria and enhances mitochondrial generation of free radicals in the kidney cortex of rats causing renal dysfunction.

Authors: Yuka Kohda, Munekazu Gemba

We have previously reported that the enhancement of free radical generation in mitochondria isolated from the kidney cortex of rats exposed to cephaloridine (CER) is probably mediated by the activation of protein kinase C (PKC). We examined which isoenzymes of PKC might be involved in the development of nephrotoxicity induced by CER in rats. The CER-induced renal dysfunction observed 24 h after its injection was prevented by a potent antioxidant DPPD and well-known PKC inhibitors like H-7 and rottlerin. At 1.5 and 3.5 h after the CER injection, the free radical generation was increased markedly and this was associated with translocation of PKCdelta into the mitochondria of renal cortex tissue. Pretreatment of rats with H-7, a PKC inhibitor, significantly inhibited the CER-derived increase in mitochondrial generation of free radicals, suggesting that H-7 probably gets into the mitochondria and inhibits the activity of translocated PKC within the mitochondria. It was also shown that pretreatment of rats with rottlerin, a specific inhibitor of PKCdelta, suppressed the early translocation of PKCdelta into mitochondria and inhibited the CER-derived development of renal dysfunction. These results suggest that the CER-derived early translocation of PKCdelta into mitochondria probably leads to the enhanced production of free radicals through the mitochondrial respiratory chain during the development of the nephrotoxicity caused by CER. Understanding the role of PKCdelta in mitochondria may provide an important clue to the molecular mechanisms of mitochondrial production of reactive oxygen species and the free radical-induced renal failure in rats treated with CER.

Topics: Animals; Cephaloridine; Free Radicals; Kidney Cortex; Kidney Diseases; Male; Mitochondria; Protein Kinase Inhibitors; Protein Transport; Rats; Rats, Sprague-Dawley

PubMed: 15879677
DOI: 10.1254/jphs.fp0040926