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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 -
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 -
Expert Opinion on Therapeutic Patents 2023β-Lactams, which include monobactams, remain the most important class of antibiotics worldwide. Aztreonam, the only monobactam in clinical use, has remarkable activity... (Review)
Review
INTRODUCTION
β-Lactams, which include monobactams, remain the most important class of antibiotics worldwide. Aztreonam, the only monobactam in clinical use, has remarkable activity against many Gram-negative bacteria, but limited activity against some of the most problematic multidrug-resistant (MDR) pathogens, such as MDR and co-expressing extended-spectrum- and metallo-β-lactamases, which can inactivate aztreonam by hydrolysis.
AREAS COVERED
Structurally novel siderophore-conjugated aztreonam derivatives with improved antibacterial properties against several high-priority pathogens are claimed. This invention reports that sidechain extension of aztreonam is tolerated; the coupling of its aminothiazoloxime carboxylic acid part with a siderophore mimetic significantly improved the antibacterial activity against several problematic strains, including MDR isolates with carbapenemase/cephalosporinase activity.
EXPERT OPINION
Finding new strategies to tackle bacterial resistance to β-lactam antibiotics is critical. Considering that β lactams are validated and safe drugs, this research may stimulate the field to develop new ideas in the arena of antimicrobial drug discovery, particularly with respect to siderophore mimetics.
Topics: Humans; Monobactams; Aztreonam; Siderophores; Patents as Topic; Anti-Bacterial Agents; beta-Lactams; beta-Lactamases; Microbial Sensitivity Tests
PubMed: 37902072
DOI: 10.1080/13543776.2023.2262135 -
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 -
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... Apr 2023Metallo-β-lactamase (MBL)-producing Enterobacterales are of particular concern because they are widely disseminated and difficult to treat, being resistant to almost...
Metallo-β-lactamase (MBL)-producing Enterobacterales are of particular concern because they are widely disseminated and difficult to treat, being resistant to almost all β-lactam antibiotics. Aztreonam is not hydrolysed by MBLs but is labile to serine β-lactamases (SBLs), which are usually co-produced by MBL-producing Enterobacterales. This study investigated the activity of aztreonam in combination with novel β-lactamase inhibitors (BLIs) against a national multi-centre study collection of strains co-producing MBLs and SBLs. Fifty-five clinical isolates co-producing MBLs (41 VIM producers, 10 NDM producers and 4 IMP producers) and SBLs were selected, and whole-genome sequencing (WGS) was performed. The minimum inhibitory concentration (MIC) values of aztreonam, aztreonam/avibactam, aztreonam/relebactam, aztreonam/zidebactam, aztreonam/taniborbactam, aztreonam/vaborbactam and aztreonam/enmetazobactam were determined. β-lactam/BLI resistance mechanisms were analysed by WGS. All BLIs decreased the MIC values of aztreonam for strains that were not susceptible to aztreonam. Aztreonam/zidebactam (MIC ≤1 mg/L for 96.4% of isolates), aztreonam/avibactam (MIC ≤1 mg/L for 92.7% of isolates) and aztreonam/taniborbactam (MIC ≤1 mg/L for 87.3 % of isolates) were the most active combinations. For other aztreonam/BLI combinations, 50-70% of the isolates yielded MIC values ≤1 mg/L. WGS data revealed that mutations in PBP3, defective OmpE35/OmpK35 porins, and the presence of extended-spectrum β-lactamases and class C β-lactamases were some of the resistance mechanisms involved in reduced susceptibility to aztreonam/BLIs. Combinations of aztreonam with new BLIs show promising activity against Enterobacterales co-producing MBLs and SBLs, particularly aztreonam/zidebactam, aztreonam/avibactam and aztreonam/taniborbactam. The present results show that these novel drugs may represent innovative therapeutic strategies by their use in yet-unexplored combinations as solutions for difficult-to-treat infections.
Topics: Aztreonam; beta-Lactamase Inhibitors; Anti-Bacterial Agents; beta-Lactamases; Spain; Azabicyclo Compounds; Microbial Sensitivity Tests; Drug Combinations
PubMed: 36736925
DOI: 10.1016/j.ijantimicag.2023.106738 -
International Microbiology : the... May 2020Presence of extended-spectrum β-lactamase (ESBL-E), AmpC-producing and carbapenemase-producing (CPE) Enterobacteriaceae has been observed not only in the clinical...
Presence of extended-spectrum β-lactamase (ESBL-E), AmpC-producing and carbapenemase-producing (CPE) Enterobacteriaceae has been observed not only in the clinical environment, but also in the out-of-hospital environment. The objective of this study was to isolate and characterize strains of ESBL, AmpC, and CPE present in feces of healthy carriers in Navarra (n = 125). Despite the fact that no CPE strains were isolated, 16% and 11.2% of the studied population were ESBL-E and AmpC carriers, respectively. No significant differences were found by gender or age; young people (5-18 years old) showed the highest ESBL-E prevalence (31.8%). The isolates corresponded to E. coli (57.1%), Enterobacter spp. (28.6%), and Citrobacter freundii (14.3%), and all strains showed multidrug-resistant profiles. High resistance against cephalosporins, penicillins, and monobactams, and sensitivity to carbapenems, quinolones, and aminoglycosides were observed. With respect to ESBL producers, 52.4% were CTX-M-type (19.0% CTX-M-14, 9.5% CTX-M-1, and 28.6% CTX-M-15) and 47.6% were TEM-type (38.1% TEM-171). These results confirm the extensive dissemination of these resistances among a healthy population and pose the need to implement control measures and strategies according to the One Health approach in order to prevent the increase of severe and untreatable infections in a not far future.
Topics: Adolescent; Adult; Aged; Anti-Bacterial Agents; Bacterial Proteins; Cephalosporins; Child; Child, Preschool; Citrobacter freundii; Drug Resistance, Multiple, Bacterial; Enterobacter; Enterobacteriaceae; Escherichia coli; Feces; Female; Healthy Volunteers; Humans; Male; Microbial Sensitivity Tests; Middle Aged; Monobactams; Multilocus Sequence Typing; Penicillins; Prevalence; Young Adult; beta-Lactamases
PubMed: 31218538
DOI: 10.1007/s10123-019-00087-z -
Journal of Clinical Microbiology Apr 2024Traditionally, cephalothin susceptibility results were used to predict the susceptibility of additional cephalosporins; however, in 2013-2014, the Clinical and... (Review)
Review
Traditionally, cephalothin susceptibility results were used to predict the susceptibility of additional cephalosporins; however, in 2013-2014, the Clinical and Laboratory Standards Institute (CLSI) revisited this practice and determined that cefazolin is a more accurate proxy than cephalothin for uncomplicated urinary tract infections (uUTIs). Therefore, a cefazolin surrogacy breakpoint was established to predict the susceptibility of seven oral cephalosporins for , , and in the context of uUTIs. Clinical microbiology laboratories face several operational challenges when implementing the cefazolin surrogacy breakpoint, which may lead to confusion for the best path forward. Here, we review the historical context and data behind the surrogacy breakpoints, review PK/PD profiles for oral cephalosporins, discuss challenges in deploying the breakpoint, and highlight the limited clinical outcome data in this space.
Topics: Humans; Cefazolin; Cephalosporins; Cephalothin; Anti-Bacterial Agents; Microbial Sensitivity Tests; Urinary Tract Infections; Escherichia coli; Monobactams
PubMed: 38457194
DOI: 10.1128/jcm.00788-21 -
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