-
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 -
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 -
Tidsskrift For Den Norske Laegeforening... Dec 2008beta-lactams are our most valuable and frequently used antibiotics. Resistance towards them, in both Gram-positive and Gram-negative bacteria, challenges their... (Review)
Review
BACKGROUND
beta-lactams are our most valuable and frequently used antibiotics. Resistance towards them, in both Gram-positive and Gram-negative bacteria, challenges their antimicrobial effect. beta-lactamases are the most important resistance mechanism against beta-lactams in Gram-negative bacteria.
MATERIAL AND METHODS
This review is based on literature retrieved through a non-systematic search of Pubmed (with the terms "ESBL", "AmpC", and "carbapenemases"), as well as the authors' own research experience.
RESULTS AND INTERPRETATION
We now observe a global dissemination of particularly broad spectrum beta-lactamases; extended-spectrum beta-lactamases (ESBLs), plasmid-mediated AmpC, and carbapenemases. These beta-lactamases are hosted by multidrug-resistant clones of Enterobacteriaceae, Pseudomonas aeruginosa with few, if any, therapeutic alternatives. We have observed that this pandemic has reached Norway with an increase in ESBL-producing Escherichia coli in particular, but also pan-resistant carbapenemase-producing K. pneumoniae, P. aeruginosa OG A. baumannii during the last years. The latter ones have been associated with import after hospitalization abroad, but this situation may change due to the epidemic potential of these resistant clones. Rapid diagnostic service and targeted infection control measures are important to prevent them from spreading.
Topics: Anti-Bacterial Agents; Bacterial Proteins; Carbapenems; Cephalosporins; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Microbial Sensitivity Tests; Monobactams; Penicillins; Plasmids; beta-Lactam Resistance; beta-Lactamases; beta-Lactams
PubMed: 19079424
DOI: No ID Found -
Antimicrobial Agents and Chemotherapy Dec 2023is the most prevalent cystic fibrosis (CF) pathogen. Several phenotypes are associated with worsened CF clinical outcomes including methicillin-resistance and...
is the most prevalent cystic fibrosis (CF) pathogen. Several phenotypes are associated with worsened CF clinical outcomes including methicillin-resistance and small-colony-variants. The inoculum effect (IE) is characterized by reduced β-lactam susceptibility when assessed at high inoculum. The IE associates with worse outcomes in bacteremia and other high-density infections, and may therefore be relevant to CF. The prevalence of IE amongst a CF cohort (age ≥18 years), followed from 2013 to 2016, was investigated. Yearly methicillin-sensitive (MSSA) isolates were screened at standard (5 × 10 CFU/mL) and high (5 × 10 CFU/mL) inoculum against narrow-spectrum anti-Staphylococcal β-lactams and those with anti-pseudomonal activity common to CF. A ≥ 4-fold increase in minimum inhibitory concentration between standard and high inoculum defined IE. Isolates underwent sequencing and genotyping and were compared against published genomes. Fifty-six percent (99/177) of individuals had MSSA infection. MSSA was observed at ≥10 CFU/mL in 44.8% of entry sputum samples. The prevalence of the IE was 25.0%-cefazolin; 13.5%-cloxacillin; 0%-meropenem; 1.0%-cefepime; 5.2%-ceftazidime; and 34.4%-piperacillin-tazobactam amongst baseline MSSA isolates assessed. A associated with cefazolin IE ( = 0.0011), whereas C associated with piperacillin-tazobactam IE ( < 0.0001). Baseline demographics did not reveal specific risk factors for IE-associated infections, nor were long-term outcomes different. Herein, we observed the IE in CF-derived MSSA disproportionally for cefazolin and piperacillin-tazobactam and this phenotype strongly associated with underlying genotype. The confirmation of CF being a high density infection, and the identification of high prevalence of MSSA with IE in CF supports the need for prospective pulmonary exacerbation treatment studies to understand the impact of this phenotype.
Topics: Adult; Humans; Adolescent; Methicillin; Cefazolin; Staphylococcus aureus; Anti-Bacterial Agents; Prospective Studies; Cystic Fibrosis; Staphylococcal Infections; Monobactams; Piperacillin, Tazobactam Drug Combination; Ceftazidime; beta Lactam Antibiotics; Microbial Sensitivity Tests
PubMed: 37966229
DOI: 10.1128/aac.00136-23 -
Chronic Respiratory Disease May 2017To provide an update on efficacy and safety of antibiotic treatments for stable non-cystic fibrosis (CF) bronchiectasis (BE). Systematic review based on the Preferred... (Review)
Review
To provide an update on efficacy and safety of antibiotic treatments for stable non-cystic fibrosis (CF) bronchiectasis (BE). Systematic review based on the Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines was done. Twenty-six studies (1.898 patients) fulfilled the inclusion criteria. Studies of inhaled tobramycin have revealed conflicting results regarding quality of life (QoL), exacerbations and admissions, but may result in sputum cultures negative for Pseudomonas aeruginosa, whereas studies investigating the effect of inhaled gentamycin have shown positive effects on sputum bacterial density, decrease in sputum cultures positive for P. aeruginosa, QoL and exacerbation rate, but no improvement in forced expiratory volume in first second (FEV). Oral azithromycin can reduce exacerbations, together with minor improvements in QoL and FEV. Furthermore, oral erythromycin reduces exacerbations, but has no effect on lung function, symptoms or QoL. Inhaled ciprofloxacin may reduce P. aeruginosa in sputum cultures, but without changes in lung function, exacerbations or QoL. Although with limited evidence, inhaled colistin may have effects on P. aeruginosa density, exacerbations and QoL, whereas studies on aztreonam revealed no significant clinical improvements in the outcomes of interest, including exacerbation rate. Adverse events, including bronchospasm, have been reported in association with tobramycin and aztreonam. Several antibiotic treatment regimens have been shown to improve QoL and exacerbation rate, whereas findings regarding sputum production, lung function and admissions have been conflicting. Evidence-based treatment algorithms for antibiotic treatment of stable non-CF BE will have to await large-scale, long-term controlled studies.
Topics: Aminoglycosides; Anti-Bacterial Agents; Aztreonam; Bronchiectasis; Ciprofloxacin; Colistin; Disease Progression; Forced Expiratory Volume; Humans; Macrolides; Pseudomonas Infections; Pseudomonas aeruginosa; Quality of Life; Sputum
PubMed: 27507832
DOI: 10.1177/1479972316661923 -
The Medical Clinics of North America Jul 1995Aztreonam is a monocyclic beta-lactam antibiotic that is active exclusively against the aerobic gram-negative bacilli. It is not ototoxic or nephrotoxic and so is used... (Review)
Review
Aztreonam is a monocyclic beta-lactam antibiotic that is active exclusively against the aerobic gram-negative bacilli. It is not ototoxic or nephrotoxic and so is used as an alternative to aminoglycosides in a variety of clinical situations. In polymicrobial infections or when used for empiric therapy, aztreonam must be combined with other antimicrobial agents active against gram-positive and anaerobic species. Aztreonam is often effective against resistant strains of gram-negative organisms, which are often involved in nosocomial infections. Overuse of aztreonam should be avoided to prevent the emergence of resistant P. aeruginosa strains. Except in the treatment of P. aeruginosa infections, aztreonam should not be added to beta-lactam regimens for additional gram-negative coverage.
Topics: Aztreonam; Gram-Negative Bacterial Infections; Humans; Microbial Sensitivity Tests
PubMed: 7791420
DOI: 10.1016/s0025-7125(16)30036-0 -
Medicina (Kaunas, Lithuania) Mar 2023: Vancomycin combined with piperacillin/tazobactam (vancomycin + piperacillin/tazobactam) has a higher risk of acute kidney injury (AKI) than vancomycin combined with... (Meta-Analysis)
Meta-Analysis Review
Evaluating the Nephrotoxicity of Area-under-the-Curve-Based Dosing of Vancomycin with Concomitant Antipseudomonal Beta-Lactam Antibiotics: A Systematic Review and Meta-Analysis.
: Vancomycin combined with piperacillin/tazobactam (vancomycin + piperacillin/tazobactam) has a higher risk of acute kidney injury (AKI) than vancomycin combined with cefepime or meropenem. However, it is uncertain if applying area under the curve (AUC)-based vancomycin dosing has less nephrotoxicity than trough-based dosing in these combinations. : We searched PubMed, Embase, Cochrane Library, and ClinicalTrials.gov from inception to December 2022. We examined the odds ratio (OR) of AKI between vancomycin + piperacillin/tazobactam and the control group. The control group was defined as vancomycin combined with antipseudomonal beta-lactam antibiotics, except for piperacillin-tazobactam. : The OR for AKI is significantly higher in vancomycin + piperacillin/tazobactam compared with the control group (3 studies, 866 patients, OR of 3.861, 95% confidence interval of 2.165 to 6.887, < 0.05). In the sample population of patients who received vancomycin + piperacillin/tazobactam (2 studies, 536 patients), the risk of AKI (OR of 0.715, 95% CI of 0.439 to 1.163, = 0.177) and daily vancomycin dose (standard mean difference-0.139, 95% CI-0.458 to 0.179; = 0.392) are lower by AUC-based dosing than trough-based dosing, although it is not statistically significant. : Nephrotoxicity is higher when combined with piperacillin/tazobactam than other antipseudomonal beta-lactam antibiotics (cefepime or meropenem) using the AUC-based dosing. However, applying the AUC-based dosing did not eliminate the risk of AKI or significantly reduce thedaily vancomycin dose compared with the trough-based dosing in the available literature.
Topics: Humans; Vancomycin; Anti-Bacterial Agents; Cefepime; Meropenem; Drug Therapy, Combination; Retrospective Studies; Piperacillin, Tazobactam Drug Combination; Monobactams; Acute Kidney Injury
PubMed: 37109649
DOI: 10.3390/medicina59040691 -
International Journal of Antimicrobial... Mar 2024Enterobacterales with carbapenemase-independent resistance to carbapenems are sometimes selected during therapy and, on rare occasions, cause outbreaks. Most have...
Enterobacterales with carbapenemase-independent resistance to carbapenems are sometimes selected during therapy and, on rare occasions, cause outbreaks. Most have extended-spectrum or AmpC β-lactamases, together with changes to permeability or penicillin-binding proteins (PBPs). Newer β-lactam-β-lactamase inhibitor combinations may present useful options for infections due to these organisms. Accordingly, Clinical and Laboratory Standards Institute/European Committee on Antimicrobial Susceptibility Testing broth-microdilution was used to measure the minimum inhibitory concentrations (MICs) of ceftazidime/avibactam and aztreonam/avibactam for 51 carbapenemase-negative Enterobacterales with resistance or reduced susceptibility to carbapenems: genomic sequencing of the least-susceptible organisms was also undertaken. MICs of the two avibactam combinations cross-correlated closely, but with fewer MICs (2/51 vs. 10/51) exceeding 8+4 mg/L in the case of ceftazidime/avibactam. Raised MICs for Escherichia coli were associated with PBP3 inserts together with CMY-42 β-lactamase; correlates among Enterobacter cloacae complex isolates remain elusive, with AmpC and PBP3 sequences found to be species specific. In the case of Klebsiella spp., no MICs exceeding 2 mg/L were seen for either combination. It appears that these avibactam combinations have potential against Enterobacterales with carbapenemase-independent carbapenem resistance or reduced susceptibility, with ceftazidime/avibactam being more reliably active than aztreonam/avibactam.
Topics: Aztreonam; Ceftazidime; beta-Lactamases; Carbapenems; Escherichia coli; Bacterial Proteins; Azabicyclo Compounds
PubMed: 38176458
DOI: 10.1016/j.ijantimicag.2023.107081 -
Annals of Clinical Microbiology and... May 2023Bloodstream infection (BSI) caused by Carbapenem-Resistant Enterobacteriaceae (CRE) are associated with poor outcomes in hematological patients. The aim of this study...
PURPOSE
Bloodstream infection (BSI) caused by Carbapenem-Resistant Enterobacteriaceae (CRE) are associated with poor outcomes in hematological patients. The aim of this study was to identify risk factors for mortality and evaluate the value of epidemiological feature of carbapenemases in guiding antimicrobial treatment options.
METHODS
Hematological patients with monomicrobial CRE BSI between January 2012 and April 2021 were included. The primary outcome was all-cause mortality 30 days after BSI onset.
RESULTS
A total of 94 patients were documented in the study period. Escherichia coli was the most common Enterobacteriaceae, followed by Klebsiella pneumoniae. 66 CRE strains were tested for carbapenemase genes, and 81.8% (54/66) were positive, including NDM (36/54), KPC (16/54), IMP (1/54). Besides, one E. coli isolate was found to express both NDM and OXA-48-like genes. Overall, 28 patients received an antimicrobial treatment containing ceftazidime-avibactam (CAZ-AVI), of which 21 cases were combined with aztreonam. The remaining 66 patients were treated with other active antibiotics (OAAs). The 30-day mortality rate was 28.7% (27/94) for all patients, and was only 7.1% ((2/28) for patients treated with CAZ-AVI. In multivariate analysis, the presence of septic shock at BSI onset (OR 10.526, 95% CI 1.376-76.923) and pulmonary infection (OR 6.289, 95% CI 1.351-29.412) were independently risk factors for 30-day mortality. Comparing different antimicrobial regimens, CAZ-AVI showed a significant survive benefit than OAAs (OR 0.068, 95% CI 0.007-0.651).
CONCLUSION
CAZ-AVI-containing regimen is superior to OAAs for CRE BSI. As the predominance of blaNDM in our center, we recommend the combination with aztreonam when choose CAZ-AVI.
Topics: Humans; Carbapenem-Resistant Enterobacteriaceae; Aztreonam; Escherichia coli; Ceftazidime; Anti-Bacterial Agents; Klebsiella pneumoniae; Enterobacteriaceae Infections; Drug Combinations; Sepsis; Risk Factors; Microbial Sensitivity Tests
PubMed: 37202758
DOI: 10.1186/s12941-023-00586-y -
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