mk-7655 and avibactam

With the current carbapenem-resistant organism crisis, conventional approaches to optimizing pharmacokinetic-pharmacodynamic parameters are frequently inadequate, and traditional salvage agents (eg, colistin, tigecycline, etc) confer high toxicity and/or have low efficacy. However, several β-lactam agents with activity against carbapenem-resistant organisms were approved recently by the US Food and Drug Administration, and more are anticipated to be approved in the near future. The primary goal of this review is to assist infectious disease practitioners with preferentially selecting 1 agent over another when treating patients infected with a carbapenem-resistant organism. However, resistance to some of these antibiotics has already developed. Antibiotic stewardship programs can ensure that they are reserved for situations in which other options are lacking and are paramount for the survival of these agents.

Topics: Anti-Bacterial Agents; Azabicyclo Compounds; Aztreonam; Boronic Acids; Carbapenems; Cefiderocol; Ceftazidime; Cephalosporins; Cilastatin, Imipenem Drug Combination; Drug Combinations; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Heterocyclic Compounds, 1-Ring; Meropenem; Tazobactam

As the incidence of Gram-negative bacterial infections for which few effective treatments remain increases, so does the contribution of drug-hydrolyzing β-lactamase enzymes to this serious clinical problem. This review highlights recent advances in β-lactamase inhibitors and focuses on agents with novel mechanisms of action against a wide range of enzymes. To this end, we review the β-lactamase inhibitors currently in clinical trials, select agents still in preclinical development, and older therapeutic approaches that are being revisited. Particular emphasis is placed on the activity of compounds at the forefront of the developmental pipeline, including the diazabicyclooctane inhibitors (avibactam and MK-7655) and the boronate RPX7009. With its novel reversible mechanism, avibactam stands to be the first new β-lactamase inhibitor brought into clinical use in the past 2 decades. Our discussion includes the importance of selecting the appropriate partner β-lactam and dosing regimens for these promising agents. This "renaissance" of β-lactamase inhibitors offers new hope in a world plagued by multidrug-resistant (MDR) Gram-negative bacteria.

Topics: Anti-Bacterial Agents; Azabicyclo Compounds; beta-Lactamase Inhibitors; Drug Resistance, Multiple, Bacterial; Enzyme Inhibitors; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Microbial Sensitivity Tests

Two of the three recently approved β-lactam agent (BL)/β-lactamase inhibitor (BLI) combinations have higher CLSI susceptibility breakpoints (ceftazidime/avibactam 8 mg/L; meropenem/vaborbactam 4 mg/L) compared with the BL alone (ceftazidime 4 mg/L; meropenem 1 mg/L). This can lead to a therapeutic grey area on susceptibility reports depending on resistance mechanism. For instance, a meropenem-resistant OXA-48 isolate (MIC 4 mg/L) may appear as meropenem/vaborbactam-susceptible (MIC 4 mg/L) despite vaborbactam's lack of OXA-48 inhibitory activity.. OXA-48-positive (n = 51) and OXA-48-negative (KPC, n = 5; Klebsiella pneumoniae wild-type, n = 1) Enterobacterales were utilized. Susceptibility tests (broth microdilution) were conducted with ceftazidime/avibactam, imipenem/relebactam and meropenem/vaborbactam, as well as their respective BL partner. Antimicrobial activity of all six agents was evaluated in the murine neutropenic thigh model using clinically relevant exposures. Efficacy was assessed as the change in bacterial growth at 24 h, compared with 0 h controls.. On average, the three BL/BLI agents resulted in robust bacteria killing among OXA-48-negative isolates. Among OXA-48-positive isolates, poor in vivo activity with imipenem/relebactam was concordant with its resistant phenotypic profile. Variable meropenem/vaborbactam activity was observed among isolates with a 'susceptible' MIC of 4 mg/L. Only 30% (7/23) of isolates at meropenem/vaborbactam MICs of 2 and 4 mg/L met the ≥1-log bacterial reduction threshold predictive of clinical efficacy in serious infections. In contrast, ceftazidime/avibactam resulted in marked bacterial density reduction across the range of MICs, and 96% (49/51) of isolates exceeded the ≥1-log bacterial reduction threshold.. Data demonstrate that current imipenem/relebactam and ceftazidime/avibactam CLSI breakpoints are appropriate. Data also suggest that higher meropenem/vaborbactam breakpoints relative to meropenem can translate to potentially poor clinical outcomes in patients infected with OXA-48-harbouring isolates.

Topics: Animals; Anti-Bacterial Agents; Azabicyclo Compounds; beta-Lactamase Inhibitors; beta-Lactamases; Ceftazidime; Drug Combinations; Genotype; Imipenem; Lactams; Meropenem; Mice; Microbial Sensitivity Tests; Phenotype

To describe and characterize the emergence of resistance to ceftolozane/tazobactam, ceftazidime/avibactam and imipenem/relebactam in a patient receiving ceftazidime/avibactam treatment for an MDR Pseudomonas aeruginosa CNS infection.. One baseline (PA1) and two post-exposure (PA2 and PA3) isolates obtained before and during treatment of a nosocomial P. aeruginosa meningoventriculitis were evaluated. MICs were determined by broth microdilution. Mutational changes were investigated through WGS. The impact on β-lactam resistance of mutations in blaPDC and mexR was determined through cloning experiments and complementation assays.. Isolate PA1 showed baseline resistance mutations in DacB (I354A) and OprD (N142fs) conferring resistance to conventional antipseudomonals but susceptibility to ceftazidime/avibactam, ceftolozane/tazobactam and imipenem/relebactam. Post-exposure isolates showed two divergent ceftazidime/avibactam-resistant phenotypes associated with distinctive mutations affecting the intrinsic P PDC β-lactamase (S254Ins) (PA2: ceftolozane/tazobactam and ceftazidime/avibactam-resistant) or MexAB-OprM negative regulator MexR in combination with modification of PBP3 (PA3: ceftazidime/avibactam and imipenem/relebactam-relebactam-resistant). Cloning experiments demonstrated the role of PDC modification in resistance to ceftolozane/tazobactam and ceftazidime/avibactam. Complementation with a functional copy of the mexR gene in isolate PA3 restored imipenem/relebactam susceptibility.. We demonstrated how P. aeruginosa may simultaneously develop resistance and compromise the activity of new β-lactam/β-lactamase inhibitor combinations when exposed to ceftazidime/avibactam through selection of mutations leading to PDC modification and up-regulation of MexAB-OprM-mediated efflux.

Topics: Anti-Bacterial Agents; Azabicyclo Compounds; beta-Lactamase Inhibitors; Ceftazidime; Cephalosporinase; Cephalosporins; Drug Combinations; Humans; Imipenem; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Pseudomonas Infections; Tazobactam

Nosocomial infection caused by Carbapenem-Resistant Acinetobacter baumannii (CR-A. baumannii) has become a challenge in clinical practice. Acting as the last resort antibacterial agents for the treatment of CR-A. baumannii infection, polymyxins have high risk of nephrotoxicity and poor clinical efficacy. Ceftazidime/avibactam, imipenem/relebactam and meropenem/vaborbactam are three β-lactam/β-lactamase inhibitor combination complexes that newly approved by the Food and Drug Administration for the treatment of carbapenem-resistant Gram-negative bacterial infection. In this study, we analyzed the in vitro activity of those novel antibacterial agents alone or in combination with polymyxin B against the CR-A. baumannii obtained from a Chinese tertiary hospital. Our results suggest that those novel antibacterial agents should not be used alone for the treatment of CR-A. baumannii infection, as they cannot prevent the regrowth of bacteria at the clinical achievable blood concentration. Imipenem/relebactam and meropenem/vaborbactam should not be used as the substitutes of imipenem and meropenem for polymyxin B based combination therapy against CR-A. baumannii, since they have no edge over imipenem and meropenem on antibacterial activity when in combination with polymyxin B. Ceftazidime/avibactam may be more suitable than ceftazidime for polymyxin B based combination therapy against CR-A. baumannii, as it has a higher synergistic rate with polymyxin B, and the antibacterial activity of ceftazidime/avibactam is much higher than that of ceftazidime when tested in combination with polymyxin B. Ceftazidime/avibactam may also be the better choice than imipenem and meropenem for polymyxin B based combination therapy against CR-A. baumannii, as it has a higher synergistic rate with polymyxin B.

Topics: Acinetobacter baumannii; Anti-Bacterial Agents; Azabicyclo Compounds; beta-Lactamase Inhibitors; Carbapenems; Ceftazidime; Drug Combinations; Imipenem; Meropenem; Microbial Sensitivity Tests; Polymyxin B

The study aimed to investigate prevalence of carbapenem-resistant Klebsiella pneumoniae (CRKP) blood culture isolates and their susceptibility to two new antibiotics, imipenem/relebactam and ceftazidime/avibactam. Out of 765 isolates recovered from blood cultures in a tertiary care hospital in Serbia between 2020 and 2023, 143 non-repetitive K. pneumoniae strains were included in this study. Minimum inhibitory concentration (MIC) values of the examined antimicrobial drugs was determined by VITEK 2 system, MIC test strip (imipenem/relebactam and ceftazidime/avibactam), and broth microdilution method (tigecycline and colistin). Carbapenemase-encoding genes (blaKPC, blaOXA-48-like, blaNDM, blaVIM, blaIMP) were detected using a multiplex-PCR assay, the BioFire-Blood Culture Identification 2-panel. This closed molecular assay is designed for the BioFire® FilmArray® system, enabling automated sample preparation, amplification, detection, and analysis (bioMérieux, France). Results revealed that K. pneumoniae was the most common isolate from blood cultures in 2022. The prevalence of K. pneumoniae was about 11.6% in 2020 and 2021, while in 2022 it raised to over 30%. Also, the frequency of CRKP increased from 11.76% in 2020, through 15.29% in 2021 to 72.94% in 2022. The majority of CRKP carried blaOXA-48-like (60.0%), followed by blaKPC (16.47%), and blaNDM (8.24%) genes, while 14.12% harboured both blaOXA-48-like and blaNDM genes. Only 25.88% of CRKP isolates were resistant to ceftazidime/avibactam, while 51.76% were resistant to imipenem/relebactam and colistin. The rapid spread of CRKP is particularly concerning because therapeutic options are limited to a few antibiotics. While imipenem/relebactam and colistin showed similar antimicrobial activity against CRKP clinical isolates, ceftazidime/avibactam proved to be the most effective antibiotic.

Topics: Anti-Bacterial Agents; Bacterial Proteins; beta-Lactamases; Blood Culture; Carbapenem-Resistant Enterobacteriaceae; Carbapenems; Ceftazidime; Colistin; Drug Combinations; Hospitals, University; Humans; Imipenem; Klebsiella Infections; Klebsiella pneumoniae; Microbial Sensitivity Tests; Serbia

Topics: Anti-Bacterial Agents; Azabicyclo Compounds; beta-Lactamase Inhibitors; beta-Lactamases; Carbapenems; Drug Combinations; Imipenem; Microbial Sensitivity Tests; Mycobacterium abscessus

Antimicrobial resistance in Pseudomonas aeruginosa is complex and multifaceted. While the novel β-lactamase inhibitors (BLIs) avibactam, relebactam and vaborbactam inhibit serine-based β-lactamases, the comparative potency of the novel β-lactam (BL)/BLI combinations against serine carbapenemase-producing P. aeruginosa is unknown.. To compare the in vitro activity of ceftazidime/avibactam, ceftazidime, imipenem/relebactam, imipenem, meropenem/vaborbactam and meropenem against serine β-lactamase-producing P. aeruginosa.. Carbapenem-resistant P. aeruginosa were collated through the Enhancing Rational Antimicrobials against Carbapenem-resistant P. aeruginosa (ERACE-PA) Global Surveillance. Isolates positive for serine-based carbapenemases were assessed. MICs were determined by broth microdilution to each novel BL/BLI and BL alone.. GES was the most common carbapenemase identified (n = 59) followed by KPC (n = 8). Ceftazidime/avibactam had MIC50/MIC90 values of 4/8 mg/L and 91% of isolates were susceptible. Conversely, ceftazidime alone was active against only 3% of isolates. The MIC50/MIC90 of imipenem/relebactam were 16/>16 mg/L and 13% of all isolates were defined as susceptible. Of the KPC-producing isolates, 38% were susceptible to imipenem/relebactam, compared with 0% to imipenem. The meropenem/vaborbactam MIC50/MIC90 were >16/>16 mg/L, and 6% of isolates were susceptible, which was similar to meropenem alone (MIC50/90, >8/>8 mg/L; 3% susceptible) suggesting the addition of vaborbactam cannot overcome co-expressed, non-enzymatic resistance mechanisms.. Among the novel BL/BLIs, ceftazidime/avibactam displayed better in vitro activity and thus is a rational treatment option for serine carbapenemase-harbouring P. aeruginosa. While imipenem/relebactam displayed some activity, particularly against isolates with blaKPC, meropenem/vaborbactam exhibited poor activity, with MICs similar to meropenem alone.

Topics: Anti-Bacterial Agents; Azabicyclo Compounds; beta-Lactamase Inhibitors; beta-Lactamases; Carbapenems; Ceftazidime; Drug Combinations; Imipenem; Lactams; Meropenem; Microbial Sensitivity Tests; Pseudomonas aeruginosa

Two out of the three recently approved β-lactam (BL)/β-lactamase inhibitors (BLIs) have higher CLSI susceptibility breakpoints (ceftazidime/avibactam 8 mg/L; meropenem/vaborbactam 4 mg/L) compared with the BL alone (ceftazidime 4 mg/L; meropenem 1 mg/L). This can lead to a therapeutic grey area on susceptibility reports depending on resistance mechanism. For instance, a meropenem-resistant OXA-48 isolate (MIC 4 mg/L) may appear as meropenem/vaborbactam-susceptible (MIC 4 mg/L) despite vaborbactam's lack of OXA-48 inhibitory activity.. OXA-48-positive (n = 51) and OXA-48-negative (KPC, n = 5; Klebsiella pneumoniae WT, n = 1) Enterobacterales were utilized. Susceptibility tests (broth microdilution) were conducted with ceftazidime/avibactam, imipenem/relebactam and meropenem/vaborbactam, as well as their respective BL partner. Antimicrobial activity of all six agents was evaluated in the murine neutropenic thigh model using clinically relevant exposures. Efficacy was assessed as the change in bacterial growth at 24 h, compared with 0 h controls.. On average, the three BL/BLI agents resulted in robust bacteria killing among OXA-48-negative isolates. Among OXA-48-positive isolates, poor in vivo activity with imipenem/relebactam was concordant with its resistant phenotypic profile. Variable meropenem/vaborbactam activity was observed among isolates with a 'susceptible' MIC of 4 mg/L. Only 30% (7/23) of isolates at meropenem/vaborbactam MICs of 2 and 4 mg/L met the ≥1 log bacterial reduction threshold predictive of clinical efficacy in serious infections. In contrast, ceftazidime/avibactam resulted in marked bacterial density reduction across the range of MICs and 73% (37/51) of isolates exceeded the ≥1 log bacterial reduction threshold.. Data demonstrate that current imipenem/relebactam and ceftazidime/avibactam CLSI breakpoints are appropriate. Data also suggest that higher meropenem/vaborbactam breakpoints relative to meropenem can translate to potentially poor clinical outcomes in patients infected with OXA-48-harbouring isolates.

Topics: Animals; Anti-Bacterial Agents; Azabicyclo Compounds; beta-Lactamase Inhibitors; beta-Lactamases; Boronic Acids; Ceftazidime; Drug Combinations; Genotype; Imipenem; Lactams; Meropenem; Mice; Microbial Sensitivity Tests; Phenotype

The novel carbapenem/β-lactamase inhibitor combination imipenem/cilastatin/relebactam has been developed for the treatment of infections due to carbapenemase-producing Enterobacteriaceae (CPE). Herein, we describe the in vivo evolution of imipenem/cilastatin/relebactam resistance in longitudinal intra-patient Klebsiella pneumoniae carbapenemase (KPC)-producing Klebsiella pneumoniae (KPC-Kp) strains isolated from a patient following ceftazidime/avibactam-based treatments.. WGS analysis was performed on KPC-Kp strains isolated at different times and during antimicrobial treatments from the same patient. Genome assemblies were performed using a hybrid approach using Illumina iSeq 100 and Minion Oxford Nanopore platforms. Subpopulation analysis and allele frequency determination was performed by mapping Illumina reads to blaKPC.. During antimicrobial treatment, resistance to ceftazidime/avibactam was observed following 16 days of antimicrobial therapy. WGS results showed that all KPC-Kp exhibited a low SNP rate of divergence, belonged to ST512 and shared similar antimicrobial resistance and porin gene patterns. Genetic analysis demonstrated that the first ceftazidime/avibactam-resistant KPC-Kp strain harboured a blaKPC-53 gene in a Tn4401 transposon moved from IncFII(K) to a 43 kb IncX3 plasmid, while a imipenem/cilastatin/relebactam-resistant strain exhibited two copies of the Tn4401 transposon in IncFII(K) and IncX3 plasmids, resulting in an increased blaKPC copy number. Of note, frequency analysis demonstrated that imipenem/cilastatin/relebactam-resistant KPC-Kp consisted of mixed subpopulations harbouring blaKPC-40 and blaKPC-53 alleles.. Our results show the in vivo evolution of genetic rearrangement conferring resistance to imipenem/relebactam in a patient with KPC-Kp infection and treated with different ceftazidime/avibactam-based treatments. The rapid development of mutations and the high adaptability of its genome highlight the potential threat of KPC-Kp.

Topics: Anti-Bacterial Agents; Azabicyclo Compounds; Bacterial Proteins; beta-Lactamases; Ceftazidime; Cilastatin; Drug Combinations; Humans; Imipenem; Klebsiella; Klebsiella Infections; Klebsiella pneumoniae; Microbial Sensitivity Tests

Carbapenemase-producing Enterobacterales (CPE) represent a public health concern. The limited antimicrobial options against CPE have led to the development of novel antimicrobial molecules. In the present study, we characterized the genetic determinants associated with the resistance to ceftazidime/avibactam (CAZ-AVI), meropenem/vaborbactam (MER-VAB), imipenem/relebactam (IMI-REL) and cefiderocol (CFD) in a carbapenemase-producing Klebsiella pneumoniae strain isolated from a critically ill patient.. Genomic DNA was sequenced using Illumina iSeq 100 and Minion Oxford Nanopore platforms. Assemblies were performed with a de novo approach using short-read, hybrid and long-lead assembly approaches. Final assembly was manually curated and carefully verified. Circular elements were screened for antimicrobial-resistance genes, porins, virulence factors and prophage regions.. KPC-Kp (KPC-producing Klebsiella pneumoniae) BO743 was resistant to all novel β-lactams including CAZ-AVI, MER-VAB, IMI-REL and CFD. The genome of strain BO743 is composed of a single chromosome of 5 347 606 bp and three circular plasmids of 363 634 bp (pBO743-363Kb), 120 290 bp (pBO743-120Kb) and 54 339 bp (pBO743-54Kb). Sequence analysis demonstrated that KPC-Kp BO743 co-harboured bla. The description of the genome of KPC-Kp cross-resistant to novel βL-βLICs and cefiderocol reveals the presence of numerous antimicrobial resistance genes including bla

Topics: Anti-Bacterial Agents; Azabicyclo Compounds; Boronic Acids; Cefiderocol; Ceftazidime; Cephalosporins; Critical Illness; Humans; Imipenem; Klebsiella pneumoniae; Meropenem; Microbial Sensitivity Tests

To evaluate the activity of cefiderocol, imipenem/relebactam, cefepime/taniborbactam and cefepime/zidebactam against a clinical and laboratory collection of ceftolozane/tazobactam- and ceftazidime/avibactam-resistant Pseudomonas aeruginosa β-lactamase mutants.. The activity of cefiderocol, imipenem/relebactam, cefepime/taniborbactam, cefepime/zidebactam and comparators was evaluated against a collection of 30 molecularly characterized ceftolozane/tazobactam- and/or ceftazidime/avibactam-resistant P. aeruginosa isolates from patients previously treated with cephalosporins. To evaluate how the different β-lactamases in the clinical isolates affected the resistance to these agents, a copy of each blaPDC, blaOXA-2 and blaOXA-10 ancestral and mutant allele from the clinical isolates was cloned in pUCp24 and expressed in dual blaPDC-oprD (for blaPDC-like genes) or single oprD (for blaOXA-2-like and blaOXA-10-like genes) PAO1 knockout mutants. MICs were determined using reference methodologies.. For all isolates, MICs were higher than 4 and/or 8 mg/L for ceftolozane/tazobactam and ceftazidime/avibactam, respectively. Cefiderocol was the most active agent, showing activity against all isolates, except one clinical isolate that carried an R504C substitution in PBP3 (MIC = 16 mg/L). Imipenem/relebactam was highly active against all isolates, except two clinical isolates that carried the VIM-20 carbapenemase. Cefepime/zidebactam and cefepime/taniborbactam displayed activity against most of the isolates, but resistance was observed in some strains with PBP3 amino acid substitutions or that overexpressed mexAB-oprM or mexXY efflux pumps. Evaluation of transformants revealed that OXA-2 and OXA-10 extended-spectrum variants cause a 2-fold increase in the MIC of cefiderocol relative to parental enzymes.. Cefiderocol, imipenem/relebactam, cefepime/taniborbactam and cefepime/zidebactam show promising and complementary in vitro activity against ceftolozane/tazobactam- and ceftazidime/avibactam-resistant P. aeruginosa. These agents may represent potential therapeutic options for ceftolozane/tazobactam- and ceftazidime/avibactam-resistant P. aeruginosa infections.

Topics: Anti-Bacterial Agents; Azabicyclo Compounds; beta-Lactamases; Borinic Acids; Carboxylic Acids; Cefepime; Cefiderocol; Ceftazidime; Cephalosporins; Cyclooctanes; Humans; Imipenem; Piperidines; Pseudomonas aeruginosa; Pseudomonas Infections; Tazobactam

A catalytic asymmetric total synthesis of avibactam and relebactam, two marketed diazabicyclooctane (DBO) β-lactamase inhibitors (BLIs), has been accomplished. An important feature of this study is the creation of a stereogenic center by using Rh-catalysed asymmetric hydrogenation, affording the crucial α-amino acid ester derivative with high-level enantiocontrol (99% ee). Furthermore, the adoption of flow technologies for the assembly of a majority of intermediates significantly achieves a faster preparation and greater synthetic efficiency than corresponding batch procedures.

Topics: Amino Acids; Anti-Bacterial Agents; Azabicyclo Compounds; beta-Lactamase Inhibitors; beta-Lactamases; Esters; Microbial Sensitivity Tests

The limited armamentarium against multidrug-resistant Gram-negative bacilli led to the development of a new generation of β-lactam/β-lactamase inhibitor combinations (BL/BLI).. To evaluate the in vitro activity of ceftazidime/avibactam, ceftolozane/tazobactam, meropenem/vaborbactam, and imipenem/relebactam against Pseudomonas aeruginosa isolates recovered from patients hospitalized with skin and soft tissue infections (SSTIs) in several countries around the world.. A total of 360 P. aeruginosa isolates were consecutively collected from 47 medical centers located in Western Europe, Eastern Europe, the Asia-Pacific region, and Latin America. Susceptibility testing was performed by broth microdilution method at a monitoring laboratory. EUCAST breakpoints were applied.. Ceftazidime/avibactam (98.3% susceptible), ceftolozane/tazobactam (98.6% susceptible), and imipenem/relebactam (98.3% susceptible) were the most active compounds after colistin (100.0% susceptible) and retained activity against isolates nonsusceptible to piperacillin/tazobactam, meropenem, imipenem, and/or ceftazidime. Meropenem-vaborbactam was active against 94.2% of isolates. Ceftazidime/avibactam was the most active BL/BLI against meropenem-nonsusceptible (92.6% susceptible) and imipenem-resistant (93.8% susceptible) isolates, whereas ceftolozane/tazobactam was the most active BL/BLI against piperacillin/tazobactam-resistant (91.1% susceptible) and ceftazidime-resistant (91.7% susceptible) isolates.. The recently approved BL/BLIs demonstrated potent activity and broad coverage against contemporary P. aeruginosa isolates from patients with SSTIs.

Topics: Anti-Bacterial Agents; Azabicyclo Compounds; Boronic Acids; Ceftazidime; Cephalosporins; Drug Combinations; Drug Resistance, Multiple, Bacterial; Humans; Imipenem; Meropenem; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Pseudomonas Infections; Soft Tissue Infections; Tazobactam

To investigate the susceptibility of imipenem-non-susceptible Escherichia coli (INS-EC), Klebsiella pneumoniae (INS-KP), Acinetobacter baumannii (INS-AB) and Pseudomonas aeruginosa (INS-PA) to novel antibiotics.. MICs were determined using the broth microdilution method. Carbapenemase and ESBL phenotypic testing and PCR for genes encoding ESBLs, AmpCs and carbapenemases were performed.. Zidebactam, avibactam and relebactam increased the respective susceptibility rates to cefepime, ceftazidime and imipenem of 17 INS-EC by 58.8%, 58.8% and 70.6%, of 163 INS-KP by 77.9%, 88.3% and 76.1% and of 81 INS-PA by 45.7%, 38.3% and 85.2%, respectively. Vaborbactam increased the meropenem susceptibility of INS-EC by 41.2% and of INS-KP by 54%. Combinations of β-lactams and novel β-lactamase inhibitors or β-lactam enhancers (BLI-BLE) were inactive against 136 INS-AB. In 58 INS-EC and INS-KP with exclusively blaKPC-like genes, zidebactam, avibactam, relebactam and vaborbactam increased the susceptibility of the partner β-lactams by 100%, 96.6%, 84.5% and 75.9%, respectively. In the presence of avibactam, ceftazidime was active in an additional 85% of 20 INS-EC and INS-KP with exclusively blaOXA-48-like genes while with zidebactam, cefepime was active in an additional 75%. INS-EC and INS-KP with MBL genes were susceptible only to cefepime/zidebactam. The β-lactam/BLI-BLE combinations were active against INS-EC and INS-KP without detectable carbapenemases. For INS-EC, INS-KP and INS-AB, tigecycline was more active than omadacycline and eravacycline but eravacycline had a lower MIC distribution. Lascufloxacin and delafloxacin were active in <35% of these INS isolates.. β-Lactam/BLI-BLE combinations were active in a higher proportion of INS-EC, INS-KP and INS-PA. The susceptibility of novel fluoroquinolones and tetracyclines was not superior to that of old ones.

Topics: Anti-Bacterial Agents; Azabicyclo Compounds; Bacterial Proteins; beta-Lactamases; Boronic Acids; Cefepime; Ceftazidime; Cyclooctanes; Drug Combinations; Humans; Imipenem; Meropenem; Microbial Sensitivity Tests; Piperidines; Taiwan

To evaluate the potential clinical in vitro efficacy of novel β-lactam/β-lactamase-inhibitor combinations - including imipenem-relebactam (IPM-REL) and cefepime-AAI101 (enmetazobactam) (FEP-AAI) - against contemporary multidrug-resistant (MDR) Enterobacteriaceae.. Agar-based MIC screening against MDR Enterobacteriaceae (n = 264) was used to evaluate the in vitro efficacy of IPM-REL and FEP-AAI, to compare the results with established combinations, and to investigate alternative β-lactam partners for relebactam (REL) and enmetazobactam (AAI). The inhibition activities of REL, AAI and the comparators avibactam (AVI) and tazobactam, against isolated recombinant β-lactamases covering representatives from all four Ambler classes of β-lactamases, were tested using a fluorescence-based assay.. Using recombinant proteins, all four inhibitors were highly active against the tested class A serine β-lactamases (SBLs). REL and AVI showed moderate activity against the Class C AmpC from Pseudomonas aeruginosa and the Class D OXA-10/-48 SBLs, but outperformed tazobactam and AAI. All tested inhibitors lacked activity against Class B metallo-β-lactamases (MBLs). In the presence of REL and IPM, but not AAI, susceptibility increased against Klebsiella pnuemoniae carbapenemase (KPC)-positive and OXA-48-positive isolates. Both aztreonam-AVI and ceftolozane-tazobactam were more effective than IPM-REL. In all the tested combinations, AAI was a more effective inhibitor of class A β-lactamases (ESBLs) than the established inhibitors.. The results lead to the proposal of alternative combination therapies involving REL and AAI to potentiate the use of β-lactams against clinical Gram-negative isolates expressing a variety of lactamases. They highlight the potential of novel combinations for combating strains not covered by existing therapies.

Topics: Anti-Bacterial Agents; Azabicyclo Compounds; beta-Lactamase Inhibitors; beta-Lactamases; Carbapenem-Resistant Enterobacteriaceae; Cefepime; Drug Combinations; Enterobacteriaceae Infections; Humans; Imipenem; Microbial Sensitivity Tests; Tazobactam; Triazoles

Extended-spectrum β-lactamases (ESBLs) present a serious challenge in the treatment of Gram-negative bacterial infections. ESBLs mediate resistance to most β-lactams, which may be reversed with the addition of an active β-lactamase inhibitor (such as tazobactam, relebactam and avibactam). However, various ESBLs may exhibit different susceptibilities to these inhibitors, which could impact efficacy. We proposed a framework for comparing the efficacy of these inhibitors when combined with the same β-lactam.. In all scenarios, piperacillin MIC reductions were well characterized with increasing inhibitor concentrations. As predicted by %fT > MIC. We illustrated a practical approach to compare the performance of different inhibitors. This platform may be used clinically to identify the optimal pairing of various β-lactams and β-lactamase inhibitors for individual isolates producing ESBLs.

Topics: Anti-Bacterial Agents; Azabicyclo Compounds; beta-Lactamase Inhibitors; beta-Lactamases; Dose-Response Relationship, Drug; Drug Synergism; Enterobacteriaceae; Escherichia coli; Humans; Klebsiella pneumoniae; Microbial Sensitivity Tests; Piperacillin; Tazobactam

The new diazabicyclooctane-based β-lactamase inhibitors avibactam and relebactam improve the

Topics: Anti-Bacterial Agents; Azabicyclo Compounds; beta-Lactamase Inhibitors; beta-Lactams; Cefepime; Cyclooctanes; Microbial Sensitivity Tests; Mycobacterium abscessus; Piperidines

Reported herein is a relebactam-derived fluorogenic reagent for covalent labeling of serine β-lactamases (SBLs), which are the major causes of bacterial resistance to β-lactam antibiotics. This highly selective imaging reagent generates over 300-fold stronger near-infrared fluorescence signals upon covalently bonding to SBLs, allowing wash-free visualization of live antimicrobial-resistant bacteria.

Topics: Affinity Labels; Azabicyclo Compounds; beta-Lactamase Inhibitors; beta-Lactamases; Enterobacter cloacae; Fluoresceins; Fluorescent Dyes; Indoles

There is urgent need for new therapeutic strategies to fight the global threat of antibiotic resistance. The focus of this Perspective is on chemical agents that target the most common mechanisms of antibiotic resistance such as enzymatic inactivation of antibiotics, changes in cell permeability, and induction/activation of efflux pumps. Here we assess the current landscape and challenges in the treatment of antibiotic resistance mechanisms at both bacterial cell and community levels. We also discuss the potential clinical application of chemical inhibitors of antibiotic resistance mechanisms as add-on treatments for serious drug-resistant infections. Enzymatic inhibitors, such as the derivatives of the β-lactamase inhibitor avibactam, are closer to the clinic than other molecules. For example, MK-7655, in combination with imipenem, is in clinical development for the treatment of infections caused by carbapenem-resistant Enterobacteriaceae and Pseudomonas aeruginosa, which are difficult to treat. In addition, other molecules targeting multidrug-resistance mechanisms, such as efflux pumps, are under development and hold promise for the treatment of multidrug resistant infections.

Topics: Azabicyclo Compounds; beta-Lactamase Inhibitors; Drug Resistance, Microbial; Enterobacteriaceae Infections; Humans; Imipenem; Pseudomonas Infections

Diazabicyclooctanes, e.g. avibactam and relebactam, are a new class of β-lactamase inhibitors. Their spectrum includes AmpC enzymes, but it is important to understand whether they also induce these enzymes.. Levels of ampC mRNA were measured by RT-PCR during 4 h of exposure of Enterobacter cloacae, Citrobacter freundii and Pseudomonas aeruginosa (n = 5 strains per species) to avibactam, relebactam and cefoxitin at 0, 1, 4 and 32 mg/L. The method had low precision compared with conventional specific-activity-based induction assays, which are impracticable for inhibitors. Accordingly, induction was only considered to be significant if induction ratios >10 were found at two consecutive time intervals, with 'strong induction' if one or more of these ratios was >100.. Cefoxitin, as expected, gave concentration-dependent induction for all strains, with strong induction for 13/15. At the other extreme, relebactam caused no significant induction for any strain. Avibactam gave strain-variable results, with strong concentration-dependent induction for 2/5 E. cloacae and 2/5 P. aeruginosa, but little or no induction for the other strains, including all the C. freundii strains.. Avibactam, but not relebactam, had some strain-variable ability to induce AmpC enzymes, though at concentrations (32 mg/L) above those reached in the patient.

Topics: Azabicyclo Compounds; Bacterial Proteins; beta-Lactamase Inhibitors; beta-Lactamases; Citrobacter freundii; Enterobacter cloacae; Gene Expression Profiling; Gene Expression Regulation, Bacterial; Humans; Pseudomonas aeruginosa; Real-Time Polymerase Chain Reaction; RNA, Messenger