-
The European Respiratory Journal May 2022Recent randomised clinical trials in bronchiectasis have failed to reach their primary end-points, suggesting a need to reassess how we measure treatment response.... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Recent randomised clinical trials in bronchiectasis have failed to reach their primary end-points, suggesting a need to reassess how we measure treatment response. Exacerbations, quality of life (QoL) and lung function are the most common end-points evaluated in bronchiectasis clinical trials. We aimed to determine the relationship between responses in terms of reduced exacerbations, improved symptoms and lung function in bronchiectasis.
METHODS
We evaluated treatment response in three randomised clinical trials that evaluated mucoactive therapy (inhaled mannitol), an oral anti-inflammatory/antibiotic (azithromycin) and an inhaled antibiotic (aztreonam). Treatment response was defined by an absence of exacerbations during follow-up, an improvement of QoL above the minimum clinically important difference and an improvement in forced expiratory volume in 1 s (FEV) of ≥100 mL from baseline.
RESULTS
Cumulatively the three trials included 984 patients. Changes in FEV, QoL and exacerbations were heterogeneous in all trials analysed. Improvements in QoL were not correlated to changes in FEV in the azithromycin and aztreonam trials (r= -0.17, p=0.1 and r=0.04, p=0.4, respectively) and weakly correlated in the mannitol trial (r=0.22, p<0.0001). An important placebo effect was observed in all trials, especially regarding improvements in QoL. Clinical meaningful lung function improvements were rare across all trials evaluated, suggesting that FEV is not a responsive measure in bronchiectasis.
CONCLUSIONS
Improvements in lung function, symptoms and exacerbation frequency are dissociated in bronchiectasis. FEV is poorly responsive and poorly correlated with other key outcome measures. Clinical parameters are poorly predictive of treatment response, suggesting the need to develop biomarkers to identify responders.
Topics: Anti-Bacterial Agents; Azithromycin; Aztreonam; Bronchiectasis; Humans; Mannitol; Quality of Life
PubMed: 34675045
DOI: 10.1183/13993003.00777-2021 -
Frontiers in Cellular and Infection... 2023β-lactam antibiotics are the most frequently used drugs and the most common drugs that cause allergic reactions in pediatrics. The occurrence of some allergic reactions... (Review)
Review
β-lactam antibiotics are the most frequently used drugs and the most common drugs that cause allergic reactions in pediatrics. The occurrence of some allergic reactions can be predicted by skin testing, especially severe adverse reactions such as anaphylactic shock. Thus, penicillin and cephalosporin skin tests are widely used to predict allergic reactions before medication in pediatrics. However, false-positive results from skin tests were more often encountered in pediatrics than in adults. In fact, many children labeled as allergic to β-lactam are not allergic to the antibiotic, leading to the use of alternative antibiotics, which are less effective and more toxic, and the increase of antibiotic resistance. There has been controversy over whether β-lactam antibiotics should be tested for skin allergies before application in children. Based on the great controversy in the implementation of β-lactam antibiotic skin tests, especially the controversial cephalosporin skin tests in pediatrics, the mechanism and reasons of anaphylaxis to β-lactam antibiotics, the significance of β-lactam antibiotic skin tests, the current state of β-lactam antibiotic skin tests at home and abroad, and the problems of domestic and international skin tests were analyzed to determine a unified standard of β-lactam antibiotic skin tests in pediatrics to prevent and decrease adverse drug reactions, avoid waste of drugs, and a large amount of manpower and material resource consumption.
Topics: Adult; Child; Humans; Drug Hypersensitivity; Skin Tests; Anti-Bacterial Agents; beta-Lactams; Penicillins; Monobactams; Cephalosporins; Anaphylaxis; Pediatrics
PubMed: 37396306
DOI: 10.3389/fcimb.2023.1147976 -
Bioorganic & Medicinal Chemistry Letters May 2021Monobactams play an important role in antibiotic drug discovery. Based on the structural characteristics of aztreonam and its biological targets, six new monobactam...
Monobactams play an important role in antibiotic drug discovery. Based on the structural characteristics of aztreonam and its biological targets, six new monobactam derivatives (2a-c and 3a-c) were synthesized and their in vitro antibacterial activities were investigated. Compounds 2a-c showed higher activities against tested gram-negative bacteria than that of parent aztreonam. Monobactam 2c exhibited the most potent activities, with MIC ranging from 0.25 to 2 μg/mL against most bacteria.
Topics: Anti-Bacterial Agents; Dose-Response Relationship, Drug; Gram-Negative Bacteria; Microbial Sensitivity Tests; Molecular Structure; Monobactams; Structure-Activity Relationship
PubMed: 33636305
DOI: 10.1016/j.bmcl.2021.127878 -
The Journal of Allergy and Clinical... Apr 2020
Topics: Anti-Bacterial Agents; Carbapenems; Clindamycin; Humans; Monobactams; Penicillins; Retrospective Studies
PubMed: 32276693
DOI: 10.1016/j.jaip.2020.01.027 -
The Journal of Antimicrobial... May 2023Aztreonam/avibactam is one of the last therapeutic options for treating infections caused by NDM-like-producing Enterobacterales. However, PBP3-modified and...
BACKGROUND
Aztreonam/avibactam is one of the last therapeutic options for treating infections caused by NDM-like-producing Enterobacterales. However, PBP3-modified and NDM-producing Escherichia coli strains that co-produce CMY-42 have been shown to be resistant to this drug combination. The aim of our study was to assess the in vitro activity of cefepime/taniborbactam and cefepime/zidebactam against such aztreonam/avibactam-resistant E. coli strains.
METHODS
MIC values of aztreonam, aztreonam/avibactam, cefepime, cefepime/taniborbactam, cefepime/zidebactam and zidebactam alone were determined for 28 clinical aztreonam/avibactam-resistant E. coli isolates. Those isolates produced either NDM-5 (n = 24), NDM-4 (n = 2) or NDM-1 (n = 2), and they all co-produced CMY-42 (n = 28). They all harboured a four amino acid insertion in PBP-3 (Tyr-Arg-Ile-Asn or Tyr-Arg-Ile-Lys).
RESULTS
All strains were resistant to aztreonam/avibactam and cefepime, as expected. The resistance rate to cefepime/taniborbactam was 100%, with MIC50 and MIC90 being at 16 mg/L and 64 mg/L, respectively. Conversely, all strains were susceptible to cefepime/zidebactam, with both MIC50 and MIC90 at 0.25 mg/L. Notably, all strains showed low MICs for zidebactam alone, with MIC50 and MIC90 at 0.5 mg/L and 1 mg/L.
CONCLUSIONS
Our data highlighted the excellent in vitro performance of the newly developed β-lactam/β-lactamase inhibitor combination cefepime/zidebactam against aztreonam/avibactam-resistant E. coli strains, suggesting that this combination could be considered as an efficient therapeutic option in this context. Our study also highlights the cross-resistance between acquired resistance to aztreonam/avibactam and the cefepime/taniborbactam combination.
Topics: Aztreonam; Cefepime; Escherichia coli; Anti-Bacterial Agents; beta-Lactamases; Cephalosporins; Azabicyclo Compounds; beta-Lactamase Inhibitors; Microbial Sensitivity Tests
PubMed: 36921067
DOI: 10.1093/jac/dkad061 -
Antimicrobial Agents and Chemotherapy Nov 2023- complex (ABC) causes severe infections that are difficult to treat due to pre-existing antibiotic resistance. Sulbactam-durlobactam (SUL-DUR) is a targeted...
- complex (ABC) causes severe infections that are difficult to treat due to pre-existing antibiotic resistance. Sulbactam-durlobactam (SUL-DUR) is a targeted β-lactam/β-lactamase inhibitor combination antibiotic designed to treat serious infections caused by , including multidrug- and carbapenem-resistant strains. In a recent global surveillance study of 5,032 ABC clinical isolates collected from 2016 to 2021, less than 2% of ABC isolates had SUL-DUR MIC values >4 µg/mL. Molecular characterization of these isolates confirmed the primary drivers of resistance are metallo-β-lactamases or penicillin-binding protein 3 (PBP3) mutations, as previously described. In addition, this study shows that certain common PBP3 variants, such as A515V, are insufficient to confer sulbactam resistance and that the efflux of durlobactam by AdeIJK is likely to play a role in a subset of strains.
Topics: Sulbactam; Acinetobacter baumannii; Anti-Bacterial Agents; Azabicyclo Compounds; beta-Lactamase Inhibitors; Monobactams; Microbial Sensitivity Tests
PubMed: 37843305
DOI: 10.1128/aac.00665-23 -
The Journal of Antimicrobial... Dec 2022To evaluate the in vitro activity of aztreonam in combination with novel β-lactamase inhibitors, namely avibactam, nacubactam, taniborbactam and zidebactam, against MDR...
In vitro activity of aztreonam in combination with newly developed β-lactamase inhibitors against MDR Enterobacterales and Pseudomonas aeruginosa producing metallo-β-lactamases.
OBJECTIVES
To evaluate the in vitro activity of aztreonam in combination with novel β-lactamase inhibitors, namely avibactam, nacubactam, taniborbactam and zidebactam, against MDR MBL-producing Enterobacterales and Pseudomonas aeruginosa clinical isolates.
METHODS
MIC values of aztreonam, aztreonam/β-lactam inhibitor but also cefiderocol as comparator were determined for 64 and 39 clinical Enterobacterales or P. aeruginosa isolates, respectively, producing representative MBLs, i.e. derivatives of NDM (n = 64), VIM (n = 32), IMP (n = 8) and SPM (n = 2). MICs were also determined for Escherichia coli TOP10 and P. aeruginosa PAO1 harbouring recombinant plasmids producing the different β-lactamases under isogenic backgrounds (n = 22 and n = 11, respectively). Fifty percent inhibitory concentrations were additionally determined for the abovementioned β-lactamase inhibitors using β-lactamase crude extracts.
RESULTS
The susceptibility rate for aztreonam was 17.1% among MBL-producing Enterobacterales, while it was very high with aztreonam/zidebactam (98.4%), and to a lower extent with aztreonam/nacubactam (84.4%) and aztreonam/taniborbactam (75%), compared with aztreonam/avibactam (70.3%) and cefiderocol (39.1%). Among MBL-producing P. aeruginosa isolates, the susceptibility rates were 53.8% with aztreonam, 66.7% with aztreonam/nacubactam and aztreonam/taniborbactam combinations, and 69.2% with aztreonam/avibactam, aztreonam/zidebactam and cefiderocol.
CONCLUSIONS
Altogether, these results showed that combinations including aztreonam and novel β-lactamase inhibitors, such as zidebactam, nacubactam or taniborbactam, have a very significant in vitro activity against MDR MBL-producing Enterobacterales clinical isolates, the aztreonam/zidebactam combination being the best option. On the other hand, aztreonam/zidebactam is equivalent to aztreonam/avibactam and cefiderocol among MBL-producing P. aeruginosa isolates.
Topics: Aztreonam; beta-Lactamase Inhibitors; Pseudomonas aeruginosa; Anti-Bacterial Agents; beta-Lactamases; Pseudomonas; Azabicyclo Compounds; Microbial Sensitivity Tests; Cefiderocol
PubMed: 36308322
DOI: 10.1093/jac/dkac360 -
PLoS Pathogens Jul 2023Central metabolic pathways control virulence and antibiotic resistance, and constitute potential targets for antibacterial drugs. In Staphylococcus aureus the role of...
Central metabolic pathways control virulence and antibiotic resistance, and constitute potential targets for antibacterial drugs. In Staphylococcus aureus the role of the pentose phosphate pathway (PPP) remains largely unexplored. Mutation of the 6-phosphogluconolactonase gene pgl, which encodes the only non-essential enzyme in the oxidative phase of the PPP, significantly increased MRSA resistance to β-lactam antibiotics, particularly in chemically defined media with physiologically-relevant concentrations of glucose, and reduced oxacillin (OX)-induced lysis. Expression of the methicillin-resistance penicillin binding protein 2a and peptidoglycan architecture were unaffected. Carbon tracing and metabolomics revealed extensive metabolic reprogramming in the pgl mutant including increased flux to glycolysis, the TCA cycle, and several cell envelope precursors, which was consistent with increased β-lactam resistance. Morphologically, pgl mutant cells were smaller than wild-type with a thicker cell wall and ruffled surface when grown in OX. The pgl mutation reduced resistance to Congo Red, sulfamethoxazole and oxidative stress, and increased resistance to targocil, fosfomycin and vancomycin. Levels of lipoteichoic acids (LTAs) were significantly reduced in pgl, which may limit cell lysis, while the surface charge of pgl cells was significantly more positive. A vraG mutation in pgl reversed the increased OX resistance phenotype, and partially restored wild-type surface charge, but not LTA levels. Mutations in vraF or graRS from the VraFG/GraRS complex that regulates DltABCD-mediated d-alanylation of teichoic acids (which in turn controls β-lactam resistance and surface charge), also restored wild-type OX susceptibility. Collectively these data show that reduced levels of LTAs and OX-induced lysis combined with a VraFG/GraRS-dependent increase in cell surface positive charge are accompanied by significantly increased OX resistance in an MRSA pgl mutant.
Topics: Methicillin-Resistant Staphylococcus aureus; Pentose Phosphate Pathway; Anti-Bacterial Agents; Oxacillin; Cell Wall; Monobactams; beta-Lactam Resistance; Bacterial Proteins; Microbial Sensitivity Tests
PubMed: 37486930
DOI: 10.1371/journal.ppat.1011536 -
Annals of Allergy, Asthma & Immunology... Oct 2023Antibiotic allergies are frequently encountered in clinical practice, and delabeling of these allergies has individual and public health benefits. This review focuses on... (Review)
Review
Antibiotic allergies are frequently encountered in clinical practice, and delabeling of these allergies has individual and public health benefits. This review focuses on the evidence supporting graded challenges without preceding skin testing in adult and pediatric patients to the major groups of antibiotics including penicillins, cephalosporins, sulfamethoxazole, fluoroquinolones, tetracyclines, macrolides, metronidazole, carbapenems, and aztreonam. The cost savings, time savings, and evidence for performing graded challenges outside of an allergy/immunology office are also reviewed for graded challenges to penicillins.
Topics: Adult; Humans; Child; Anti-Bacterial Agents; Penicillins; Aztreonam; Cephalosporins; Drug Hypersensitivity; Hypersensitivity
PubMed: 37031773
DOI: 10.1016/j.anai.2023.03.033 -
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