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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 -
JAMA Jul 2023Meropenem is a widely prescribed β-lactam antibiotic. Meropenem exhibits maximum pharmacodynamic efficacy when given by continuous infusion to deliver constant drug...
IMPORTANCE
Meropenem is a widely prescribed β-lactam antibiotic. Meropenem exhibits maximum pharmacodynamic efficacy when given by continuous infusion to deliver constant drug levels above the minimal inhibitory concentration. Compared with intermittent administration, continuous administration of meropenem may improve clinical outcomes.
OBJECTIVE
To determine whether continuous administration of meropenem reduces a composite of mortality and emergence of pandrug-resistant or extensively drug-resistant bacteria compared with intermittent administration in critically ill patients with sepsis.
DESIGN, SETTING, AND PARTICIPANTS
A double-blind, randomized clinical trial enrolling critically ill patients with sepsis or septic shock who had been prescribed meropenem by their treating clinicians at 31 intensive care units of 26 hospitals in 4 countries (Croatia, Italy, Kazakhstan, and Russia). Patients were enrolled between June 5, 2018, and August 9, 2022, and the final 90-day follow-up was completed in November 2022.
INTERVENTIONS
Patients were randomized to receive an equal dose of the antibiotic meropenem by either continuous administration (n = 303) or intermittent administration (n = 304).
MAIN OUTCOMES AND MEASURES
The primary outcome was a composite of all-cause mortality and emergence of pandrug-resistant or extensively drug-resistant bacteria at day 28. There were 4 secondary outcomes, including days alive and free from antibiotics at day 28, days alive and free from the intensive care unit at day 28, and all-cause mortality at day 90. Seizures, allergic reactions, and mortality were recorded as adverse events.
RESULTS
All 607 patients (mean age, 64 [SD, 15] years; 203 were women [33%]) were included in the measurement of the 28-day primary outcome and completed the 90-day mortality follow-up. The majority (369 patients, 61%) had septic shock. The median time from hospital admission to randomization was 9 days (IQR, 3-17 days) and the median duration of meropenem therapy was 11 days (IQR, 6-17 days). Only 1 crossover event was recorded. The primary outcome occurred in 142 patients (47%) in the continuous administration group and in 149 patients (49%) in the intermittent administration group (relative risk, 0.96 [95% CI, 0.81-1.13], P = .60). Of the 4 secondary outcomes, none was statistically significant. No adverse events of seizures or allergic reactions related to the study drug were reported. At 90 days, mortality was 42% both in the continuous administration group (127 of 303 patients) and in the intermittent administration group (127 of 304 patients).
CONCLUSIONS AND RELEVANCE
In critically ill patients with sepsis, compared with intermittent administration, the continuous administration of meropenem did not improve the composite outcome of mortality and emergence of pandrug-resistant or extensively drug-resistant bacteria at day 28.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT03452839.
Topics: Humans; Female; Middle Aged; Male; Meropenem; Shock, Septic; Critical Illness; Double-Blind Method; Sepsis; Anti-Bacterial Agents; Monobactams; Hypersensitivity
PubMed: 37326473
DOI: 10.1001/jama.2023.10598 -
Archives of Razi Institute Feb 2023Aerobic vaginitis (AV) is a vaginal infectious condition characterized by abnormal vaginal discharge, high inflammatory response, signs of epithelial atrophy, an...
Aerobic vaginitis (AV) is a vaginal infectious condition characterized by abnormal vaginal discharge, high inflammatory response, signs of epithelial atrophy, an increase in aerobic bacteria of intestinal origin and a decrease in the normal flora, especially . It is one of the most common reproductive tract infections among women. This study aimed to analyze the antimicrobial susceptibility levels of the dominant bacterial species found in the vaginae of women infected with AV. A total of 89 high vaginal swabs (HVS) were collected from women aged (18-50) years old attending some hospitals and private gynaecology clinics in Baghdad City. All obtained swabs were cultured on different culture media, and the primary diagnosis was performed according to standard laboratory diagnosis protocols. To confirm the diagnosis and to determine the antibiotic susceptibility profile of bacterial isolates, VITEK 2 Compact Automated System GP and GN colourimetric identification cards and AST GN and AST GP cards were used according to Manufacturer Company constructions (BioMérieux / France). Out of 89swabs, ninety-five pathogenic strains were obtained, including 62 isolates (65.2%), Grampositive and 33 isolates (34.7%), Gram-negative bacteria. (46.3%) The most represented active strain was (15.7%). All Gram-positive bacterial strains displayed the highest resistance rates (100%) toward penicillins and cephalosporins, while the highest sensitivity rates were toward daptomycin, followed by vancomycin and gentamicin (=0.001). Gram-negative bacteria displayed the highest resistance rates toward penicillins, beta-lactam combination, monobactam and cephalosporins, while the highest sensitivity rates were toward amikacin followed by imipenem meropenem and gentamicin (=0.001). It is worth mentioning that Gram-positive bacteria showed 100% sensitivity toward tigecycline. Thirty-eight (40 %) of all obtained bacterial strains were extensively drug-resistant XDR, 57 (60%) were multidrug resistance MDR and no pan-drug resistance PDR was reported. Gram-positive bacteria include 21% XDR and 44.2% MDR strains, while Gram-negative bacteria include 18.9% XDR and 15.7% MDR strains.
Topics: Female; Animals; Iraq; Vaginitis; Bacteria; Cephalosporins; Escherichia coli; Anti-Bacterial Agents
PubMed: 37312716
DOI: 10.22092/ARI.2022.358775.2307 -
Scientific Reports Jun 2023Carbapenem-resistant Acinetobacter baumannii (CRAb) is an urgent public health threat, according to the CDC. This pathogen has few treatment options and causes severe...
Carbapenem-resistant Acinetobacter baumannii (CRAb) is an urgent public health threat, according to the CDC. This pathogen has few treatment options and causes severe nosocomial infections with > 50% fatality rate. Although previous studies have examined the proteome of CRAb, there have been no focused analyses of dynamic changes to β-lactamase expression that may occur due to drug exposure. Here, we present our initial proteomic study of variation in β-lactamase expression that occurs in CRAb with different β-lactam antibiotics. Briefly, drug resistance to Ab (ATCC 19606) was induced by the administration of various classes of β-lactam antibiotics, and the cell-free supernatant was isolated, concentrated, separated by SDS-PAGE, digested with trypsin, and identified by label-free LC-MS-based quantitative proteomics. Thirteen proteins were identified and evaluated using a 1789 sequence database of Ab β-lactamases from UniProt, the majority of which were Class C β-lactamases (≥ 80%). Importantly, different antibiotics, even those of the same class (e.g. penicillin and amoxicillin), induced non-equivalent responses comprising various isoforms of Class C and D serine-β-lactamases, resulting in unique resistomes. These results open the door to a new approach of analyzing and studying the problem of multi-drug resistance in bacteria that rely strongly on β-lactamase expression.
Topics: Acinetobacter baumannii; Proteomics; Anti-Bacterial Agents; beta-Lactamases; Monobactams; Microbial Sensitivity Tests; beta-Lactam Resistance
PubMed: 37280269
DOI: 10.1038/s41598-023-36475-9 -
The Cochrane Database of Systematic... Jun 2023Respiratory tract infections with Pseudomonas aeruginosa occur in most people with cystic fibrosis (CF). Established chronic P aeruginosa infection is virtually... (Review)
Review
BACKGROUND
Respiratory tract infections with Pseudomonas aeruginosa occur in most people with cystic fibrosis (CF). Established chronic P aeruginosa infection is virtually impossible to eradicate and is associated with increased mortality and morbidity. Early infection may be easier to eradicate. This is an updated review.
OBJECTIVES
Does giving antibiotics for P aeruginosa infection in people with CF at the time of new isolation improve clinical outcomes (e.g. mortality, quality of life and morbidity), eradicate P aeruginosa infection, and delay the onset of chronic infection, but without adverse effects, compared to usual treatment or an alternative antibiotic regimen? We also assessed cost-effectiveness.
SEARCH METHODS
We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and conference proceedings. Latest search: 24 March 2022. We searched ongoing trials registries. Latest search: 6 April 2022.
SELECTION CRITERIA
We included randomised controlled trials (RCTs) of people with CF, in whom P aeruginosa had recently been isolated from respiratory secretions. We compared combinations of inhaled, oral or intravenous (IV) antibiotics with placebo, usual treatment or other antibiotic combinations. We excluded non-randomised trials and cross-over trials.
DATA COLLECTION AND ANALYSIS
Two authors independently selected trials, assessed risk of bias and extracted data. We assessed the certainty of the evidence using GRADE.
MAIN RESULTS
We included 11 trials (1449 participants) lasting between 28 days and 27 months; some had few participants and most had relatively short follow-up periods. Antibiotics in this review are: oral - ciprofloxacin and azithromycin; inhaled - tobramycin nebuliser solution for inhalation (TNS), aztreonam lysine (AZLI) and colistin; IV - ceftazidime and tobramycin. There was generally a low risk of bias from missing data. In most trials it was difficult to blind participants and clinicians to treatment. Two trials were supported by the manufacturers of the antibiotic used. TNS versus placebo TNS may improve eradication; fewer participants were still positive for P aeruginosa at one month (odds ratio (OR) 0.06, 95% confidence interval (CI) 0.02 to 0.18; 3 trials, 89 participants; low-certainty evidence) and two months (OR 0.15, 95% CI 0.03 to 0.65; 2 trials, 38 participants). We are uncertain whether the odds of a positive culture decrease at 12 months (OR 0.02, 95% CI 0.00 to 0.67; 1 trial, 12 participants). TNS (28 days) versus TNS (56 days) One trial (88 participants) comparing 28 days to 56 days TNS treatment found duration of treatment may make little or no difference in time to next isolation (hazard ratio (HR) 0.81, 95% CI 0.37 to 1.76; low-certainty evidence). Cycled TNS versus culture-based TNS One trial (304 children, one to 12 years old) compared cycled TNS to culture-based therapy and also ciprofloxacin to placebo. We found moderate-certainty evidence of an effect favouring cycled TNS therapy (OR 0.51, 95% CI 0.31 to 0.82), although the trial publication reported age-adjusted OR and no difference between groups. Ciprofloxacin versus placebo added to cycled and culture-based TNS therapy One trial (296 participants) examined the effect of adding ciprofloxacin versus placebo to cycled and culture-based TNS therapy. There is probably no difference between ciprofloxacin and placebo in eradicating P aeruginosa (OR 0.89, 95% CI 0.55 to 1.44; moderate-certainty evidence). Ciprofloxacin and colistin versus TNS We are uncertain whether there is any difference between groups in eradication of P aeruginosa at up to six months (OR 0.43, 95% CI 0.15 to 1.23; 1 trial, 58 participants) or up to 24 months (OR 0.76, 95% CI 0.24 to 2.42; 1 trial, 47 participants); there was a low rate of short-term eradication in both groups. Ciprofloxacin plus colistin versus ciprofloxacin plus TNS One trial (223 participants) found there may be no difference in positive respiratory cultures at 16 months between ciprofloxacin with colistin versus TNS with ciprofloxacin (OR 1.28, 95% CI 0.72 to 2.29; low-certainty evidence). TNS plus azithromycin compared to TNS plus oral placebo Adding azithromycin may make no difference to the number of participants eradicating P aeruginosa after a three-month treatment phase (risk ratio (RR) 1.01, 95% CI 0.75 to 1.35; 1 trial, 91 participants; low-certainty evidence); there was also no evidence of any difference in the time to recurrence. Ciprofloxacin and colistin versus no treatment A single trial only reported one of our planned outcomes; there were no adverse effects in either group. AZLI for 14 days plus placebo for 14 days compared to AZLI for 28 days We are uncertain whether giving 14 or 28 days of AZLI makes any difference to the proportion of participants having a negative respiratory culture at 28 days (mean difference (MD) -7.50, 95% CI -24.80 to 9.80; 1 trial, 139 participants; very low-certainty evidence). Ceftazidime with IV tobramycin compared with ciprofloxacin (both regimens in conjunction with three months colistin) IV ceftazidime with tobramycin compared with ciprofloxacin may make little or no difference to eradication of P aeruginosa at three months, sustained to 15 months, provided that inhaled antibiotics are also used (RR 0.84, 95 % CI 0.65 to 1.09; P = 0.18; 1 trial, 255 participants; high-certainty evidence). The results do not support using IV antibiotics over oral therapy to eradicate P aeruginosa, based on both eradication rate and financial cost.
AUTHORS' CONCLUSIONS
We found that nebulised antibiotics, alone or with oral antibiotics, were better than no treatment for early infection with P aeruginosa. Eradication may be sustained in the short term. There is insufficient evidence to determine whether these antibiotic strategies decrease mortality or morbidity, improve quality of life, or are associated with adverse effects compared to placebo or standard treatment. Four trials comparing two active treatments have failed to show differences in rates of eradication of P aeruginosa. One large trial showed that intravenous ceftazidime with tobramycin is not superior to oral ciprofloxacin when inhaled antibiotics are also used. There is still insufficient evidence to state which antibiotic strategy should be used for the eradication of early P aeruginosa infection in CF, but there is now evidence that intravenous therapy is not superior to oral antibiotics.
Topics: Child; Child, Preschool; Humans; Infant; Anti-Bacterial Agents; Azithromycin; Ceftazidime; Ciprofloxacin; Colistin; Cystic Fibrosis; Monobactams; Pseudomonas aeruginosa; Pseudomonas Infections; Tobramycin
PubMed: 37268599
DOI: 10.1002/14651858.CD004197.pub6 -
Frontiers in Public Health 2023serovar Typhi (. Typhi) is a major cause of morbidity and mortality in developing countries, contributing significantly to the global disease burden.
INTRODUCTION
serovar Typhi (. Typhi) is a major cause of morbidity and mortality in developing countries, contributing significantly to the global disease burden.
METHODS
In this study, . Typhi strains were isolated from 100 patients exhibiting symptoms of typhoid fever at a tertiary care hospital in Pakistan. Antimicrobial testing of all isolates was performed to determine the sensitivity and resistance pattern. Three MDR strains, namely QS194, QS430, and QS468, were subjected to whole genome sequencing for genomic characterization.
RESULTS AND DISCUSSION
MLST analysis showed that QS194, belonged to ST19, which is commonly associated with . In contrast, QS430 and QS468, belonged to ST1, a sequence type frequently associated with . Typhi. PlasmidFinder identified the presence of and plasmids in QS194, while was found in QS468. No plasmid was detected in QS430. CARD-based analysis showed that the strains were largely resistant to a variety of antibiotics and disinfecting agents/antiseptics, including fluoroquinolones, cephalosporins, monobactams, cephamycins, penams, phenicols, tetracyclines, rifamycins, aminoglycosides, etc. The . Typhi strains possessed various virulence factors, such as etc. The sequencing data indicated that the strains had antibiotic resistance determinants and shared common virulence factors. Pangenome analysis of the selected . Typhi strains identified 13,237 genes, with 3,611 being core genes, 2,093 shell genes, and 7,533 cloud genes. Genome-based typing and horizontal gene transfer analysis revealed that the strains had different evolutionary origins and may have adapted to distinct environments or host organisms. These findings provide important insights into the genetic characteristics of . Typhi strains and their potential association with various ecological niches and host organisms.
Topics: Humans; Salmonella typhi; Multilocus Sequence Typing; Pakistan; Anti-Bacterial Agents; Virulence Factors; Whole Genome Sequencing; Drug Resistance, Multiple
PubMed: 37261234
DOI: 10.3389/fpubh.2023.1151805 -
Antimicrobial Agents and Chemotherapy Jul 2023The impact of broad-spectrum β-lactamases on the susceptibility to novel β-lactamase/β-lactamase inhibitor combinations was evaluated both in Pseudomonas aeruginosa...
Impact of Acquired Broad Spectrum β-Lactamases on Susceptibility to Novel Combinations Made of β-Lactams (Aztreonam, Cefepime, Meropenem, and Imipenem) and Novel β-Lactamase Inhibitors in Escherichia coli and Pseudomonas aeruginosa.
The impact of broad-spectrum β-lactamases on the susceptibility to novel β-lactamase/β-lactamase inhibitor combinations was evaluated both in Pseudomonas aeruginosa and Escherichia coli using isogenic backgrounds. Cefepime-zidebactam displayed low MICs, mainly due to the significant intrinsic antibacterial activity of zidebactam. Cefepime-taniborbactam showed excellent activity against recombinant E. coli strains, including metallo-β-lactamase producers, whereas aztreonam-avibactam remained the best therapeutic option against class B β-lactamase-producing P. aeruginosa.
Topics: Cefepime; beta-Lactamase Inhibitors; Meropenem; beta-Lactams; Aztreonam; Imipenem; Pseudomonas aeruginosa; Escherichia coli; beta-Lactamases; Anti-Bacterial Agents; Azabicyclo Compounds; Microbial Sensitivity Tests
PubMed: 37255469
DOI: 10.1128/aac.00339-23 -
Frontiers in Cellular and Infection... 2023Biofilm formation is the major pathogenicity of , which enhances bacterial resistance to antibiotics. Isookanin has potential inhibitory activity on biofilm.
INTRODUCTION
Biofilm formation is the major pathogenicity of , which enhances bacterial resistance to antibiotics. Isookanin has potential inhibitory activity on biofilm.
METHOD
The inhibiting mechanisms of isookanin against biofilm formation through surface hydrophobicity assay, exopolysaccharides, eDNA, gene expression analysis, microscopic visualization, and molecular docking were explored. Additionally, the combination of isookanin and β-lactam antibiotics were evaluated by the broth micro-checkerboard assay.
RESULTS
The results showed that isookanin could decrease the biofilm formation of by ≥85% at 250 μg/mL. The exopolysaccharides, eDNA and surface hydrophobicity were reduced after treatment with isookanin. Microscopic visualization analysis showed that there were fewer bacteria on the surface of the microscopic coverslip and the bacterial cell membrane was damaged after treatment with isookanin. The down-regulation of and up-regulation of were observed after treatment with isookanin. Additionally, the RNAIII gene was significantly up-regulated ( < 0.0001) at the mRNA level. Molecular docking showed that isookanin could bind to biofilm-related proteins. This indicated that isookanin can affect biofilm formation at the initial attachment phase and the aggregation phase. The FICI index showed that the combination of isookanin and β-lactam antibiotics were synergistic and could reduce doses of antibiotics by inhibiting biofilm formation.
DISCUSSION
This study improved the antibiotic susceptibility of through inhibition of the biofilm formation, and provided a guidance for the treatment of antibiotic resistance caused by biofilm.
Topics: Staphylococcus epidermidis; Anti-Bacterial Agents; Down-Regulation; Molecular Docking Simulation; Biofilms; Monobactams; Microbial Sensitivity Tests
PubMed: 37234778
DOI: 10.3389/fcimb.2023.1139796