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Current Microbiology Nov 2022Lungs of cystic fibrosis patients are often colonized or infected with organisms, such as Pseudomonas aeruginosa and other emerging pathogenic bacteria such as...
Lungs of cystic fibrosis patients are often colonized or infected with organisms, such as Pseudomonas aeruginosa and other emerging pathogenic bacteria such as Achromobacter xylosoxidans. Further, it is well established that infections of the cystic fibrosis lung airways are caused by polymicrobial infections, although its composition and diversity may change throughout the patient's life. In the present study, we investigated the effects of N-acetylcysteine (NAC) and amikacin, aztreonam, ciprofloxacin, and tobramycin alone and in combination against single- and dual-species biofilms of P. aeruginosa and A. xylosoxidans, in vitro and in the Caenorhabditis elegans infection model. Results showed that tobramycin and ciprofloxacin were the most effective antibiotics, while aztreonam was the least effective antibiotic against both single- and dual-species biofilms of P. aeruginosa and A. xylosoxidans. However, NAC showed little effect on both single- and dual-species, even with a combination of antibiotics. Increased survival was observed in C. elegans when treated with NAC in combination with tobramycin or ciprofloxacin, compared to no treatment or NAC alone. Tobramycin and ciprofloxacin were found effective in biofilms, but more research is needed to better understand the effects of NAC and antibiotics against single- and dual-species biofilms.
Topics: Animals; Humans; Pseudomonas aeruginosa; Achromobacter denitrificans; Anti-Bacterial Agents; Acetylcysteine; Aztreonam; Cystic Fibrosis; Caenorhabditis elegans; Biofilms; Tobramycin; Ciprofloxacin
PubMed: 36434296
DOI: 10.1007/s00284-022-03122-x -
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 -
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 -
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 -
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 -
International Journal of Antimicrobial... Nov 2023Acquired β-lactamase-encoding genes are typically carried by large plasmids in Gram-negative bacteria, which also commonly carry multi-copy small plasmids. This study...
Acquired β-lactamase-encoding genes are typically carried by large plasmids in Gram-negative bacteria, which also commonly carry multi-copy small plasmids. This study found that mobile genetic elements carrying antimicrobial resistance genes are capable of hijacking small plasmids. This study focused on aztreonam-avibactam (ATM-AVI) as this combination can be used to effectively counter almost all β-lactamases produced by bacteria, and has been recommended against carbapenem-resistant Enterobacterales. A clinical strain (085003) of carbapenem-resistant Escherichia coli was investigated, and mutants (085003R32 and 085003R512) able to grow under 32/4 and 512/4 mg/L of ATM-AVI were obtained as representatives of low- and high-level resistance, respectively, by induction. Comparative genomics showed that 085003R32 and 085003R512 had a single nucleotide mutation of β-lactamase gene bla, encoding a novel CMY with a Thr319Ile substitution, assigned 'CMY-2R'. Cloning and enzyme kinetics were used to verify that CMY-2R conferred ATM-AVI resistance by compromising binding of AVI and subsequent protection of ATM. Mechanisms for the discrepant resistance between 085003R32 and 085003R512 were investigated. Three tandem copies of bla were identified on a self-transmissible IncP1 plasmid of 085003R32 due to IS1294 misrecognizing its end terIS and rolling-circle replication. 085003R512 had only a single copy of bla on the IncP1 plasmid, but possessed anther bla on an already present 4-kb small plasmid. IS1294-mediated mobilization on to this multi-copy small plasmid increased the copy number of bla significantly, rendering higher resistance. This study shows that bacteria can employ multiple approaches to accommodate selection pressures imposed by exposure to varied concentrations of antimicrobial agents.
Topics: Aztreonam; Ceftazidime; Azabicyclo Compounds; Drug Combinations; Plasmids; Escherichia coli; beta-Lactamases; Carbapenems; Anti-Bacterial Agents; Microbial Sensitivity Tests
PubMed: 37769749
DOI: 10.1016/j.ijantimicag.2023.106985