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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 -
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 -
The Cochrane Database of Systematic... Nov 2022Inhaled antibiotics are commonly used to treat persistent airway infection with Pseudomonas aeruginosa that contributes to lung damage in people with cystic fibrosis.... (Review)
Review
BACKGROUND
Inhaled antibiotics are commonly used to treat persistent airway infection with Pseudomonas aeruginosa that contributes to lung damage in people with cystic fibrosis. Current guidelines recommend inhaled tobramycin for individuals with cystic fibrosis and persistent Pseudomonas aeruginosa infection who are aged six years or older. The aim is to reduce bacterial load in the lungs so as to reduce inflammation and deterioration of lung function. This is an update of a previously published review.
OBJECTIVES
To evaluate the effects of long-term inhaled antibiotic therapy in people with cystic fibrosis on clinical outcomes (lung function, frequency of exacerbations and nutrition), quality of life and adverse events (including drug-sensitivity reactions and survival).
SEARCH METHODS
We searched the Cochrane Cystic Fibrosis Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. We also searched ongoing trials registries. Date of last search: 28 June 2022.
SELECTION CRITERIA
We selected trials where people with cystic fibrosis received inhaled anti-pseudomonal antibiotic treatment for at least three months, treatment allocation was randomised or quasi-randomised, and there was a control group (either placebo, no placebo or another inhaled antibiotic).
DATA COLLECTION AND ANALYSIS
Two authors independently selected trials, judged the risk of bias, extracted data from these trials and judged the certainty of the evidence using the GRADE system.
MAIN RESULTS
The searches identified 410 citations to 125 trials; 18 trials (3042 participants aged between five and 45 years) met the inclusion criteria. Limited data were available for meta-analyses due to the variability of trial design and reporting of results. A total of 11 trials (1130 participants) compared an inhaled antibiotic to placebo or usual treatment for a duration between three and 33 months. Five trials (1255 participants) compared different antibiotics, two trials (585 participants) compared different regimens of tobramycin and one trial (90 participants) compared intermittent tobramycin with continuous tobramycin alternating with aztreonam. One trial (18 participants) compared an antibiotic to placebo and also to a different antibiotic and so fell into both groups. The most commonly studied antibiotic was tobramycin which was studied in 12 trials. Inhaled antibiotics compared to placebo We found that inhaled antibiotics may improve lung function measured in a variety of ways (4 trials, 814 participants). Compared to placebo, inhaled antibiotics may also reduce the frequency of exacerbations (risk ratio (RR) 0.66, 95% confidence interval (CI) 0.47 to 0.93; 3 trials, 946 participants; low-certainty evidence). Inhaled antibiotics may lead to fewer days off school or work (quality of life measure) (mean difference (MD) -5.30 days, 95% CI -8.59 to -2.01; 1 trial, 245 participants; low-certainty evidence). There were insufficient data for us to be able to report an effect on nutritional outcomes and there was no effect on survival. There was no effect on antibiotic resistance seen in the two trials that were included in meta-analyses. We are uncertain of the effect of the intervention on adverse events (very low-certainty evidence), but tinnitus and voice alteration were the only events occurring more often in the inhaled antibiotics group. The overall certainty of evidence was deemed to be low for most outcomes due to risk of bias within the trials and imprecision due to low event rates. Different antibiotics or regimens compared Of the eight trials comparing different inhaled antibiotics or different antibiotic regimens, there was only one trial for each unique comparison. We found no differences between groups for any outcomes except for the following. Aztreonam lysine for inhalation probably improved forced expiratory volume at one second (FEV) % predicted compared to tobramycin (MD -3.40%, 95% CI -6.63 to -0.17; 1 trial, 273 participants; moderate-certainty evidence). However, the method of defining the endpoint was different to the remaining trials and the participants were exposed to tobramycin for a long period making interpretation of the results problematic. We found no differences in any measure of lung function in the remaining comparisons. Trials measured pulmonary exacerbations in different ways and showed no differences between groups except for aztreonam lysine probably leading to fewer people needing treatment with additional antibiotics than with tobramycin (RR 0.66, 95% CI 0.51 to 0.86; 1 trial, 273 participants; moderate-certainty evidence); and there were fewer hospitalisations due to respiratory exacerbations with levofloxacin compared to tobramycin (RR 0.62, 95% CI 0.40 to 0.98; 1 trial, 282 participants; high-certainty evidence). Important treatment-related adverse events were not very common across comparisons, but were reported less often in the tobramycin group compared to both aztreonam lysine and colistimethate. We found the certainty of evidence for these comparisons to be directly related to the risk of bias within the individual trials and varied from low to high.
AUTHORS' CONCLUSIONS
Long-term treatment with inhaled anti-pseudomonal antibiotics probably improves lung function and reduces exacerbation rates, but pooled estimates of the level of benefit were very limited. The best evidence available is for inhaled tobramycin. More evidence from trials measuring similar outcomes in the same way is needed to determine a better measure of benefit. Longer-term trials are needed to look at the effect of inhaled antibiotics on quality of life, survival and nutritional outcomes.
Topics: Adolescent; Adult; Child; Child, Preschool; Humans; Middle Aged; Young Adult; Anti-Bacterial Agents; Aztreonam; Cystic Fibrosis; Lysine; Quality of Life; Tobramycin; Randomized Controlled Trials as Topic
PubMed: 36373968
DOI: 10.1002/14651858.CD001021.pub4 -
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 -
Brazilian Journal of Biology = Revista... 2023Bloodstream infections are among the most serious and frequent infections, and the people most exposed are patients in the Intensive Care Unit (ICU). ESBL...
Bloodstream infections are among the most serious and frequent infections, and the people most exposed are patients in the Intensive Care Unit (ICU). ESBL (extended-spectrum beta-lactate) are resistant bacteria to penicillins, cephalosporins and monobactams. It´s necessary to know how often and which microorganisms are involved, checking their susceptibility. This study was carried out at the University Hospital. Data collection was performed in the Adult and Newborn ICUs, with assessment of microorganisms and their resistance profile. During six-month period, 156 samples were studied, and 42 were positive with microorganism isolation. Isolated species include Staphylococcus aureus, Staphylococcus epidermidis and Klebsiella pneumoniae. Many resistant to carbapenem.
Topics: Infant, Newborn; Adult; Humans; Anti-Bacterial Agents; Brazil; Carbapenems; Intensive Care Units; Hospitals, Teaching; Microbial Sensitivity Tests
PubMed: 37194825
DOI: 10.1590/1519-6984.269571 -
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 -
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 -
Clinical Therapeutics Aug 2020The objective of this communication was to determine the intravenous compatibility of ceftazidime/avibactam and aztreonam using simulated and actual Y-site...
PURPOSE
The objective of this communication was to determine the intravenous compatibility of ceftazidime/avibactam and aztreonam using simulated and actual Y-site administration.
METHODS
Ceftazidime-avibactam was reconstituted and diluted to concentrations of 8, 25, and 50 mg/mL in 0.9% sodium chloride. Aztreonam was reconstituted and diluted to concentrations of 10 and 20 mg/mL. Each combination of concentrations was tested for compatibility using visual, Tyndall beam, microscopy, turbidity, and pH assessments. Microscopy results were compared to those from sodium chloride 0.9% in water, pH was compared to that at time 0, and turbidity of combinations was compared to that of individual agents. Actual Y-site mixing was conducted over 2-h infusions with samples collected at 0, 1, and 2 h. Test results were evaluated at 0, 1, 2, 4, 8, and 12 h after mixing. All experiments were completed in triplicate.
FINDINGS
Across simulated and actual Y-site experiments, no evidence of incompatibility between combinations of ceftazidime-avibactam + aztreonam was observed. Visual and microscopic tests revealed no particulate matter, color changes, or turbidity. Tyndall beam tests were negative with all combinations. No evidence of incompatibility was observed in turbidity testing. The pH values were consistent across each of the 6 combinations, from immediately after mixing until 12 h after mixing. When the addition of agents was reversed in simulated Y-site experiments, no differences in compatibility were observed. No differences in compatibility between actual and simulated Y-site administration were observed, and there was minimal variability across all replicate experiments.
IMPLICATIONS
Ceftazidime-avibactam, at concentrations of 8, 25, and 50 mg/mL, appeared compatible with aztreonam at concentrations of 10 and 20 mg/mL.
Topics: Anti-Bacterial Agents; Azabicyclo Compounds; Aztreonam; Ceftazidime; Computer Simulation; Drug Combinations; Drug Incompatibility; Infusions, Intravenous
PubMed: 32684326
DOI: 10.1016/j.clinthera.2020.06.005 -
Antibiotics (Basel, Switzerland) Mar 2024Since the discovery of penicillin, β-lactam antibiotics have commonly been used to treat bacterial infections. Unfortunately, at the same time, pathogens can develop... (Review)
Review
Since the discovery of penicillin, β-lactam antibiotics have commonly been used to treat bacterial infections. Unfortunately, at the same time, pathogens can develop resistance to β-lactam antibiotics such as penicillins, cephalosporins, monobactams, and carbapenems by producing β-lactamases. Therefore, a combination of β-lactam antibiotics with β-lactamase inhibitors has been a promising approach to controlling β-lactam-resistant bacteria. The discovery of novel β-lactamase inhibitors (BLIs) is essential for effectively treating antibiotic-resistant bacterial infections. Therefore, this review discusses the development of innovative inhibitors meant to enhance the activity of β-lactam antibiotics. Specifically, this review describes the classification and characteristics of different classes of β-lactamases and the synergistic mechanisms of β-lactams and BLIs. In addition, we introduce potential sources of compounds for use as novel BLIs. This provides insights into overcoming current challenges in β-lactamase-producing bacteria and designing effective treatment options in combination with BLIs.
PubMed: 38534695
DOI: 10.3390/antibiotics13030260