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Annals of Clinical Microbiology and... Jun 2023Aztreonam-avibactam is an important option against Enterobacterales producing metallo-β-lactamases (MBLs). We obtained an aztreonam-avibactam-resistant mutant of an...
Aztreonam-avibactam is an important option against Enterobacterales producing metallo-β-lactamases (MBLs). We obtained an aztreonam-avibactam-resistant mutant of an MBL-producing Enterobacter mori strain by induced mutagenesis. Genome sequencing revealed an Arg244Gly (Ambler position) substitution of SHV-12 β-lactamase in the mutant. Cloning and susceptibility testing verified that the SHV-12 Arg244Gly substitution led to significantly reduced susceptibility to aztreonam-avibactam (MIC, from 0.5/4 to 4/4 mg/L) but with the loss of resistance to cephalosporins as tradeoff. Arg244 of SHV involves in the binding of avibactam by forming an arginine-mediated salt bridge and is a critical residue to interact with β-lactams. Molecular modeling analysis demonstrated that the Arg244Gly substitution hindered the binding of avibactam to SHV with higher binding energy (from - 5.24 to -4.32 kcal/mol) and elevated inhibition constant Ki (from 143.96 to 677.37 µM) to indicate lower affinity. This substitution, however, resulted in loss of resistance to cephalosporins as tradeoff by impairing substrate binding. This represents a new aztreonam-avibactam resistance mechanism.
Topics: Humans; Aztreonam; Anti-Bacterial Agents; beta-Lactamases; Cephalosporins; Enterobacter; Mutation; Microbial Sensitivity Tests; Drug Combinations; Ceftazidime
PubMed: 37365592
DOI: 10.1186/s12941-023-00605-y -
Annals of Medicine Dec 2023Antimicrobial resistance is a global health threat. Among Gram-negative bacteria, resistance to carbapenems, a class of β-lactam antibiotics, is usually a proxy for...
Antimicrobial resistance is a global health threat. Among Gram-negative bacteria, resistance to carbapenems, a class of β-lactam antibiotics, is usually a proxy for difficult-to-treat resistance, since carbapenem-resistant organisms are often resistant to many classes of antibiotics. Carbapenem resistance in the Gram-negative pathogen is mostly due to the production of carbapenemases, enzymes able to hydrolyze carbapenems, and carbapenemase (KPC)-type enzymes are overall the most prevalent carbapenemases in . In the last decade, the management of severe infections due to KPC-producing (KPC-Kp) in humans has presented many peculiar challenges to clinicians worldwide. In this perspective, we discuss how the treatment of severe KPC-Kp infections has evolved over the last decades, guided by the accumulating evidence from clinical studies, and how recent advances in diagnostics have allowed to anticipate identification of KPC-Kp in infected patients.KEY MESSAGESIn the last decade, the management of severe infections due to KPC-Kp has presented many peculiar challenges to clinicians worldwideFollowing the introduction in clinical practice of novel β-lactam/β-lactamase inhibitor combinations and novel β-lactams active against KPC-producing bacteria, the management of severe KPC-Kp infections has witnessed a remarkable evolutionTreatment of severe KPC-Kp infections is a highly dynamic process, in which the wise use of novel antimicrobials should be accompanied by a continuous refinement based on evolving clinical evidence and laboratory diagnostics.
Topics: Humans; Klebsiella pneumoniae; Carbapenems; Monobactams; Anti-Bacterial Agents; Lactams
PubMed: 36856521
DOI: 10.1080/07853890.2022.2152484 -
Microbiology Spectrum Dec 2023To our knowledge, this is the first study to report the activity of two novel antimicrobial drugs, including imipenem-relebactam (IMR) and aztreonam-avibactam (AZA),...
To our knowledge, this is the first study to report the activity of two novel antimicrobial drugs, including imipenem-relebactam (IMR) and aztreonam-avibactam (AZA), toward carbapenem-resistant and hypervirulent (CR-hvKP) strains. Our activity study revealed that only few antibacterial agents (including several novel agents) exhibit high antimicrobial activity toward carbapenem-resistant (CRKP) and CR-hvKP isolates. IMR and AZA may be promising therapeutic agents for the treatment of infections caused by CRKP and CR-hvKP isolates.
Topics: Humans; Aztreonam; Klebsiella pneumoniae; Bacterial Proteins; beta-Lactamases; Anti-Bacterial Agents; Carbapenem-Resistant Enterobacteriaceae; Imipenem; Carbapenems; Klebsiella Infections; Microbial Sensitivity Tests
PubMed: 37982631
DOI: 10.1128/spectrum.02806-23 -
Environmental Research Oct 2022The generic of antibiotics is considered to be a main reason for the generation of antibiotic resistance genes (ARGs) in wastewater treatment plants (WWTPs). However,...
The generic of antibiotics is considered to be a main reason for the generation of antibiotic resistance genes (ARGs) in wastewater treatment plants (WWTPs). However, little has been reported about the antibiotic biosynthesis by activated sludge. In this study, the distribution and expression of antibiotic biosynthetic genes (ABGs) in the floc sludge and biofilm from two WWTPs were deciphered using metagenomics and metatranscriptomics. The results showed that 2% of the community were in general well-linked to antibiotic production, indicating a non-negligible antibiotic synthetic ability of WWTPs. 93 ABGs belonging to 26 antibiotics were determined, among which aminoglycosides, β-lactams, ansamycins, peptides, macrolides were majority. The relative abundances of detected ABGs had a large interval, ranging from 0.000006% to 0.042%. The predominant antibiotic types of synthetic genes with higher relative expression levels were monobactams, penicillin & cephalosporins and streptomycin, primarily belonging to β-lactams and aminoglycosides. The hypothetical synthetic pathways of streptomycin synthesis and penicillin & cephalosporin synthesis were proposed. And the coexistence of ABGs and ARGs for these two antibiotics was also pronounced in activated sludge from meta-omics data. These findings for the first time demonstrated the antibiotic synthetic potential in activated sludges, revealing new sources of antibiotics and resistance genes in WWTPs, and thereby aggravating environmental pollution.
Topics: Aminoglycosides; Anti-Bacterial Agents; Genes, Bacterial; Penicillins; Sewage; Streptomycin; Wastewater; beta-Lactams
PubMed: 35750126
DOI: 10.1016/j.envres.2022.113741 -
The Journal of Antibiotics Mar 2024Cephalosporins comprise a β-lactam antibiotic class whose first members were discovered in 1945 from the fungus Cephalosporium acremonium. Their clinical use for... (Review)
Review
Cephalosporins comprise a β-lactam antibiotic class whose first members were discovered in 1945 from the fungus Cephalosporium acremonium. Their clinical use for Gram-negative bacterial infections is widespread due to their ability to traverse outer membranes through porins to gain access to the periplasm and disrupt peptidoglycan synthesis. More recent members of the cephalosporin class are administered as last resort treatments for complicated urinary tract infections, MRSA, and other multi-drug resistant pathogens, such as Neisseria gonorrhoeae. Unfortunately, there has been a global increase in cephalosporin-resistant strains, heteroresistance to this drug class has been a topic of increasing concern, and tolerance and persistence are recognized as potential causes of cephalosporin treatment failure. In this review, we summarize the cephalosporin antibiotic class from discovery to their mechanisms of action, and discuss the causes of cephalosporin treatment failure, which include resistance, tolerance, and phenomena when those qualities are exhibited by only small subpopulations of bacterial cultures (heteroresistance and persistence). Further, we discuss how recent efforts with cephalosporin conjugates and combination treatments aim to reinvigorate this antibiotic class.
Topics: Humans; Cephalosporin Resistance; Anti-Bacterial Agents; Cephalosporins; Gram-Negative Bacterial Infections; Neisseria gonorrhoeae; Monobactams
PubMed: 38114565
DOI: 10.1038/s41429-023-00687-y -
Antimicrobial Agents and Chemotherapy Sep 2020This study aimed to evaluate the antimicrobial activity of the novel monosulfactam 0073 against multidrug-resistant Gram-negative bacteria and and to characterize the...
This study aimed to evaluate the antimicrobial activity of the novel monosulfactam 0073 against multidrug-resistant Gram-negative bacteria and and to characterize the mechanisms underlying 0073 activity. The activities of 0073, aztreonam, and the combination with avibactam were assessed by MIC and time-kill assays. The safety of 0073 was evaluated using 3-(4,5-dimethylthizol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and acute toxicity assays. Murine thigh infection and pneumonia models were employed to define efficacy. A penicillin-binding protein (PBP) competition assay and confocal microscopy were conducted. The inhibitory action of 0073 against β-lactamases was evaluated by the half-maximal inhibitory concentration (IC), and resistance development was evaluated via serial passage. The monosulfactam 0073 showed promising antimicrobial activity against , , and isolates producing metallo-β-lactamases (MBLs) and serine β-lactamases. In preliminary experiments, compound 0073 exhibited safety both and In the murine thigh infection model and the pneumonia models in which infection was induced by and , 0073 significantly reduced the bacterial burden. Compound 0073 targeted several PBPs and exerted inhibitory effects against some serine β-lactamases. Finally, 0073 showed a reduced propensity for resistance selection compared with that of aztreonam. The novel monosulfactam 0073 exhibited increased activity against β-lactamase-producing Gram-negative organisms compared with the activity of aztreonam and showed good safety profiles both and The underlying mechanisms may be attributed to the affinity of 0073 for several PBPs and its inhibitory activity against some serine β-lactamases. These data indicate that 0073 represents a potential treatment for infections caused by β-lactamase-producing multidrug-resistant bacteria.
Topics: Animals; Anti-Bacterial Agents; Azabicyclo Compounds; Aztreonam; Enterobacteriaceae; Mice; Microbial Sensitivity Tests; beta-Lactamase Inhibitors; beta-Lactamases
PubMed: 32718961
DOI: 10.1128/AAC.00529-20 -
The Journal of Allergy and Clinical... Apr 2020Limited population-based data on penicillin-, carbapenem-, monobactam-, and clindamycin-associated reported adverse reactions exist.
BACKGROUND
Limited population-based data on penicillin-, carbapenem-, monobactam-, and clindamycin-associated reported adverse reactions exist.
OBJECTIVE
To collect data on penicillin, carbapenem, monobactam, and clindamycin usage and associated adverse reactions.
METHODS
Data from January 1, 2009, to December 31, 2017, in Kaiser Permanente Southern California were collected.
RESULTS
There were 6,144,422 unique individuals, mean age 33.6 ± 21.1 years, 52.2% females, with at least 1 health care visit during the 9-year study interval, for a total of 37,387,313 patient-years of follow-up. This population was exposed to 5,617,402 courses of oral penicillins, 370,478 courses of parenteral penicillins, 59,645 courses of parenteral carbapenems or monobactams, 817,232 courses of oral clindamycin, and 215,880 courses of parenteral clindamycin. New penicillin allergies were reported more commonly after parenteral (0.85%) compared with oral (0.74%) exposures (P < .0001). There were 22 cases (1 in 255,320) of oral penicillin-associated anaphylaxis and 3 cases (1 in 123,792) of parenteral penicillin-associated anaphylaxis (P < .001). There were 2 clindamycin-associated anaphylaxis cases, 1 (1 in 817,232) oral and 1 (1 in 215,880) parenteral. There were 2 (1 in 2,993,940) penicillin-associated serious cutaneous adverse reaction (SCAR) cases, but both also had co-trimoxazole coexposure within 45 days. There was 1 (1 in 1,033,112) clindamycin-associated SCAR. Clostridioides difficile infection was more common after parenteral exposures, and with extended-spectrum penicillins, beta-lactamase combinations, carbapenems, monobactam, and clindamycin exposures compared with oral penicillins or clindamycin.
CONCLUSIONS
Only 1 of 1543 (0.065%) oral and 1 of 1030 (0.097%) parenteral penicillin-associated allergy reports were confirmed to be anaphylaxis. C. difficile was more common after parenteral versus oral penicillin, carbapenem, monobactam, and clindamycin exposures, and with broader spectrum antibiotic exposures.
Topics: Adolescent; Adult; Anti-Bacterial Agents; Carbapenems; Child; Clindamycin; Clostridioides difficile; Drug Hypersensitivity; Female; Humans; Male; Middle Aged; Monobactams; Penicillins; Retrospective Studies; Young Adult
PubMed: 31821919
DOI: 10.1016/j.jaip.2019.11.035 -
International Journal of Antimicrobial... May 2024To analyse the impact of the most clinically relevant β-lactamases and their interplay with low outer membrane permeability on the activity of cefiderocol,...
Activity of cefiderocol and innovative β-lactam/β-lactamase inhibitor combinations against isogenic strains of Escherichia coli expressing single and double β-lactamases under high and low permeability conditions.
OBJECTIVES
To analyse the impact of the most clinically relevant β-lactamases and their interplay with low outer membrane permeability on the activity of cefiderocol, ceftazidime/avibactam, aztreonam/avibactam, cefepime/enmetazobactam, cefepime/taniborbactam, cefepime/zidebactam, imipenem/relebactam, meropenem/vaborbactam, meropenem/xeruborbactam and meropenem/nacubactam against recombinant Escherichia coli strains.
METHODS
We constructed 82 E. coli laboratory transformants expressing the main β-lactamases circulating in Enterobacterales (70 expressing single β-lactamase and 12 producing double carbapenemase) under high (E. coli TG1) and low (E. coli HB4) permeability conditions. Antimicrobial susceptibility testing was determined by reference broth microdilution.
RESULTS
Aztreonam/avibactam, cefepime/zidebactam, cefiderocol, meropenem/xeruborbactam and meropenem/nacubactam were active against all E. coli TG1 transformants. Imipenem/relebactam, meropenem/vaborbactam, cefepime/taniborbactam and cefepime/enmetazobactam were also highly active, but unstable against most of MBL-producing transformants. Combination of β-lactamases with porin deficiency (E. coli HB4) did not significantly affect the activity of aztreonam/avibactam, cefepime/zidebactam, cefiderocol or meropenem/nacubactam, but limited the effectiveness of the rest of carbapenem- and cefepime-based combinations. Double-carbapenemase production resulted in the loss of activity of most of the compounds tested, an effect particularly evident for those E. coli HB4 transformants in which MBLs were present.
CONCLUSIONS
Our findings highlight the promising activity that cefiderocol and new β-lactam/β-lactamase inhibitors have against recombinant E. coli strains expressing widespread β-lactamases, including when these are combined with low permeability or other enzymes. Aztreonam/avibactam, cefiderocol, cefepime/zidebactam and meropenem/nacubactam will help to mitigate to some extent the urgency of new compounds able to resist MBL action, although NDM enzymes represent a growing challenge against which drug development efforts are still needed.
Topics: Escherichia coli; beta-Lactamases; Cephalosporins; Microbial Sensitivity Tests; beta-Lactamase Inhibitors; Azabicyclo Compounds; Anti-Bacterial Agents; Drug Combinations; Cyclooctanes; Cefiderocol; Ceftazidime; Cefepime; Boronic Acids; Meropenem; Aztreonam; Imipenem; Bacterial Proteins; Heterocyclic Compounds, 1-Ring; Cell Membrane Permeability; Borinic Acids; Carboxylic Acids; Lactams; Triazoles
PubMed: 38513748
DOI: 10.1016/j.ijantimicag.2024.107150 -
The Journal of Antimicrobial... Sep 2023
Topics: Humans; Meropenem; Aztreonam; Klebsiella pneumoniae; Anti-Bacterial Agents; beta-Lactamases; Drug Combinations; Microbial Sensitivity Tests; Klebsiella Infections
PubMed: 37392133
DOI: 10.1093/jac/dkad206 -
Microbiology Spectrum Jun 2023Aztreonam-avibactam, eravacycline, and cefoselis are three novel antimicrobial agents for the treatment of serious infections caused by Gram-negative bacteria. We...
Aztreonam-avibactam, eravacycline, and cefoselis are three novel antimicrobial agents for the treatment of serious infections caused by Gram-negative bacteria. We evaluated the activities of the above-mentioned three antimicrobial agents against clinical isolates. A total of 1,202 isolates, including 10 genera or species, were collected from 26 hospitals that cover seven regions of China. The susceptibilities of the 30 antimicrobial agents were interpreted based on the combination of U.S. Food and Drug Administration and Clinical and Laboratory Standards Institute guidelines. The results indicated that all isolates showed high susceptibility to aztreonam-avibactam (98.25%), eravacycline (85.69%), and cefoselis (62.73%). The first two antimicrobial agents also demonstrated potent activities against multidrug-resistant and carbapenem-resistant independent of antimicrobial resistance mechanisms. The rates of susceptibility to aztreonam-avibactam, eravacycline, and cefoselis were lowest in spp. (84.42%), Proteus spp. (33.65%), and Escherichia coli (40.14%), respectively. In general, the lower rates of susceptibility to eravacycline and cefoselis were in the older inpatient group. The strains isolated from urinary tract exhibited the lowest rate of susceptibility (78.97%) to eravacycline, and the lowest rate of susceptibility (45.83%) to cefoselis was observed in nervous system specimens. The strains isolated from intensive care unit (ICU) wards showed significantly reduced susceptibility to cefoselis compared with those isolated from non-ICU wards. The MIC values of aztreonam-avibactam and ceftazidime-avibactam have poor consistency (weighted kappa = 0.243), as did eravacycline and tigecycline (weighted kappa = 0.478). Cefoselis and cefepime showed highly similar activities against (weighted kappa = 0.801). Our results support the clinical development of aztreonam-avibactam, eravacycline, and cefoselis to treat infections caused by . Infections caused by multidrug-resistant (MDR) , especially carbapenem-resistant (CRE), have been a challenging clinical problem due to the limited therapeutic options. Therefore, the need to develop novel antimicrobial agents and evaluate their activities against is urgent. Our results show that the novel antimicrobial agents aztreonam-avibactam and eravacycline retain activities against MDR and CRE isolates, including carbapenemase producers and non-carbapenemase producers. Further analysis combined with clinical information on the strains tested revealed that no significant differences were observed in susceptibility rates of strains with different demographic parameters to aztreonam-avibactam. Age, specimen source, and department were associated with the susceptibility of strains to eravacycline and cefoselis ( ≤ 0.01). Compared with ceftazidime-avibactam, aztreonam-avibactam has its advantages and limitations against . The potent activity of eravacycline against was higher than that of tigecycline. Cefoselis and cefepime showed a highly consistent activity against .
Topics: Aztreonam; Anti-Bacterial Agents; Tigecycline; Cefepime; beta-Lactamases; Carbapenems; Microbial Sensitivity Tests
PubMed: 37184411
DOI: 10.1128/spectrum.04873-22