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Critical Care (London, England) Dec 2022Ceftolozane/tazobactam, a combination antibacterial agent comprising an anti-pseudomonal cephalosporin and β-lactamase inhibitor, is approved for the treatment of... (Randomized Controlled Trial)
Randomized Controlled Trial
Outcomes in participants with failure of initial antibacterial therapy for hospital-acquired/ventilator-associated bacterial pneumonia prior to enrollment in the randomized, controlled phase 3 ASPECT-NP trial of ceftolozane/tazobactam versus meropenem.
BACKGROUND
Ceftolozane/tazobactam, a combination antibacterial agent comprising an anti-pseudomonal cephalosporin and β-lactamase inhibitor, is approved for the treatment of hospital-acquired/ventilator-associated bacterial pneumonia (HABP/VABP) in adults. Participants in the ASPECT-NP trial received ceftolozane/tazobactam (3 g [2 g ceftolozane/1 g tazobactam] every 8 h) or meropenem (1 g every 8 h). Participants failing prior antibacterial therapy for the current HABP/VABP episode at study entry had lower 28-day all-cause mortality (ACM) rates with ceftolozane/tazobactam versus meropenem treatment. Here, we report a post hoc analysis examining this result.
METHODS
The phase 3, randomized, controlled, double-blind, multicenter, noninferiority trial compared ceftolozane/tazobactam versus meropenem for treatment of adults with ventilated HABP/VABP; eligibility included those failing prior antibacterial therapy for the current HABP/VABP episode at study entry. The primary and key secondary endpoints were 28-day ACM and clinical response at test of cure (TOC), respectively. Participants who were failing prior therapy were a prospectively defined subgroup; however, subgroup analyses were not designed for noninferiority testing. The 95% CIs for treatment differences were calculated as unstratified Newcombe CIs. Post hoc analyses were performed using multivariable logistic regression analysis to determine the impact of baseline characteristics and treatment on clinical outcomes in the subgroup who were failing prior antibacterial therapy.
RESULTS
In the ASPECT-NP trial, 12.8% of participants (93/726; ceftolozane/tazobactam, n = 53; meropenem, n = 40) were failing prior antibacterial therapy at study entry. In this subgroup, 28-day ACM was higher in participants who received meropenem versus ceftolozane/tazobactam (18/40 [45.0%] vs 12/53 [22.6%]; percentage difference [95% CI]: 22.4% [3.1 to 40.1]). Rates of clinical response at TOC were 26/53 [49.1%] for ceftolozane/tazobactam versus 15/40 [37.5%] for meropenem (percentage difference [95% CI]: 11.6% [- 8.6 to 30.2]). Multivariable regression analysis determined concomitant vasopressor use and treatment with meropenem were significant factors associated with risk of 28-day ACM. Adjusting for vasopressor use, the risk of dying after treatment with ceftolozane/tazobactam was approximately one-fourth the risk of dying after treatment with meropenem.
CONCLUSIONS
This post hoc analysis further supports the previously demonstrated lower ACM rate for ceftolozane/tazobactam versus meropenem among participants who were failing prior therapy, despite the lack of significant differences in clinical cure rates.
CLINICALTRIALS
gov registration NCT02070757 . Registered February 25, 2014, clinicaltrials.gov/ct2/show/NCT02070757 .
Topics: Adult; Humans; Anti-Bacterial Agents; Cephalosporins; Hospitals; Meropenem; Monobactams; Pneumonia, Bacterial; Pneumonia, Ventilator-Associated; Tazobactam; Vasoconstrictor Agents; Ventilators, Mechanical
PubMed: 36457059
DOI: 10.1186/s13054-022-04192-w -
PLoS Biology Dec 2023The emerging and global spread of a novel plasmid-mediated colistin resistance gene, mcr-1, threatens human health. Expression of the MCR-1 protein affects bacterial...
The emerging and global spread of a novel plasmid-mediated colistin resistance gene, mcr-1, threatens human health. Expression of the MCR-1 protein affects bacterial fitness and this cost correlates with lipid A perturbation. However, the exact molecular mechanism remains unclear. Here, we identified the MCR-1 M6 variant carrying two-point mutations that conferred co-resistance to β-lactam antibiotics. Compared to wild-type (WT) MCR-1, this variant caused severe disturbance in lipid A, resulting in up-regulation of L, D-transpeptidases (LDTs) pathway, which explains co-resistance to β-lactams. Moreover, we show that a lipid A loading pocket is localized at the linker domain of MCR-1 where these 2 mutations are located. This pocket governs colistin resistance and bacterial membrane permeability, and the mutated pocket in M6 enhances the binding affinity towards lipid A. Based on this new information, we also designed synthetic peptides derived from M6 that exhibit broad-spectrum antimicrobial activity, exposing a potential vulnerability that could be exploited for future antimicrobial drug design.
Topics: Humans; Colistin; Anti-Bacterial Agents; beta Lactam Antibiotics; Lipid A; Antimicrobial Peptides; Monobactams; Plasmids; Drug Resistance, Bacterial; Escherichia coli Proteins; Microbial Sensitivity Tests
PubMed: 38091366
DOI: 10.1371/journal.pbio.3002433 -
European Journal of Clinical... Mar 2024Relebactam is a novel β-lactamase inhibitor, which, when combined with imipenem/cilastatin, is active against both class A and class C β-lactamases. To evaluate in...
PURPOSE
Relebactam is a novel β-lactamase inhibitor, which, when combined with imipenem/cilastatin, is active against both class A and class C β-lactamases. To evaluate in vitro antimicrobial activity of imipenem/relebactam against a collection of recent clinical isolates of carbapenem-non-susceptible P. aeruginosa and K. pneumoniae ST258 and ST512 KPC producers belonging to different lineages from hospitals in Southern Spain.
METHODS
Six hundred and seventy-eight isolates were tested: 265 K. pneumoniae (230 ST512/KPC-3 and 35 ST258/KPC-3) and 413 carbapenem-non-susceptible P. aeruginosa. Imipenem, piperacillin/tazobactam, ceftazidime, cefepime, aztreonam, ceftolozane/tazobactam, meropenem, amikacin, ciprofloxacin, colistin, and ceftazidime/avibactam were used as comparators against P. aeruginosa. Against K. pneumoniae ceftazidime, cefepime, aztreonam, and ceftolozane/tazobactam were not tested, and tigecycline was studied instead. MICs were determined in duplicate by broth microdilution according to EUCAST guidelines.
RESULTS
Imipenem/relebactam displayed potent in vitro activity against both sequence types of KPC-3-producing K. pneumoniae. MIC and MIC values were 0.25 mg/L and 1 mg/L, respectively, with percent of susceptible isolates >97%. Only three K. pneumoniae ST512/KPC-3 isolates and one ST258/KPC-3 were resistant to imipenem/relebactam. Relebactam sensitized 98.5% of K. pneumoniae isolates resistant to imipenem. The activity of imipenem/relebactam against P. aeruginosa was moderate (susceptibility rate: 62.7%). Analysis of the acquired and mutational resistome of isolates with high levels of resistance to imipenem/relebactam has not shown a clear association between them.
CONCLUSION
Imipenem/relebactam showed excellent activity against K. pneumoniae KPC-3. The activity of imipenem/relebactam against imipenem-resistant P. aeruginosa was moderate.
Topics: Humans; Imipenem; Ceftazidime; Pseudomonas aeruginosa; Klebsiella pneumoniae; Cefepime; Aztreonam; Anti-Bacterial Agents; Pseudomonas Infections; Tazobactam; beta-Lactamases; Drug Combinations; Microbial Sensitivity Tests; Cephalosporins; Azabicyclo Compounds
PubMed: 38157139
DOI: 10.1007/s10096-023-04735-1 -
Antimicrobial Agents and Chemotherapy Dec 2022To report on the therapy used for penicillin- and cephalosporin-resistant pneumococcal meningitis, we conducted an observational cohort study of patients admitted to our... (Observational Study)
Observational Study
To report on the therapy used for penicillin- and cephalosporin-resistant pneumococcal meningitis, we conducted an observational cohort study of patients admitted to our hospital with pneumococcal meningitis between 1977 and 2018. According to the European Committee on Antimicrobial Susceptibility Testing (EUCAST) recommendations, we defined pneumococci as susceptible and resistant to penicillin with MIC values of ≤0.06 mg/L and > 0.06 mg/L, respectively; the corresponding values for cefotaxime (CTX) were ≤0.5 mg/L and >0.5 mg/L. We treated 363 episodes of pneumococcal meningitis during the study period. Of these, 24 had no viable strain, leaving 339 episodes with a known MIC for inclusion. Penicillin-susceptible strains accounted for 246 episodes (73%), penicillin-resistant strains for 93 (27%), CTX susceptible for 58, and CTX resistant for 35. Nine patients failed or relapsed and 69 died (20%), of whom 22% were among susceptible cases and 17% were among resistant cases. During the dexamethasone period, mortality was equal (12%) in both susceptible and resistant cases. High-dose CTX (300 mg/Kg/day) helped to treat failed or relapsed cases and protected against failure when used as empirical therapy ( = 0.02), even in CTX-resistant cases. High-dose CTX is a good empirical therapy option for pneumococcal meningitis in the presence of a high prevalence of penicillin and cephalosporin resistance, effectively treating pneumococcal strains with MICs up to 2 mg/L for either penicillin or CTX.
Topics: Humans; Cephalosporins; Meningitis, Pneumococcal; Penicillins; Ceftriaxone; Cohort Studies; Cefotaxime; Streptococcus pneumoniae; Microbial Sensitivity Tests; Monobactams; Penicillin Resistance; Mitomycin; Anti-Bacterial Agents
PubMed: 36326246
DOI: 10.1128/aac.00820-22 -
Journal of Bacteriology Mar 2023Antibiotic tolerance, the ability of bacteria to sustain viability in the presence of typically bactericidal antibiotics for extended time periods, is an understudied...
Antibiotic tolerance, the ability of bacteria to sustain viability in the presence of typically bactericidal antibiotics for extended time periods, is an understudied contributor to treatment failure. The Gram-negative pathogen Vibrio cholerae, the causative agent of cholera, becomes highly tolerant to β-lactam antibiotics (penicillin and related compounds) in a process requiring the two-component system VxrAB. VxrAB is induced by exposure to cell wall damaging conditions, which results in the differential regulation of >100 genes. While the effectors of VxrAB are relatively well known, VxrAB environment-sensing and activation mechanisms remain a mystery. Here, we used transposon mutagenesis to screen for mutants that spontaneously upregulate VxrAB signaling. This screen was answered by genes known to be required for proper cell envelope homeostasis, validating the approach. Unexpectedly, we also uncovered a new connection between central carbon metabolism and antibiotic tolerance in Vibrio cholerae. Inactivation of ( coding for glucose-6-phosphate isomerase) resulted in an intracellular accumulation of glucose-6-phosphate and fructose-6-phosphate, concomitant with a marked cell envelope defect, resulting in VxrAB induction. Deletion of also increased sensitivity to β-lactams and conferred a growth defect on salt-free LB, phenotypes that could be suppressed by deleting sugar uptake systems and by supplementing cell wall precursors in the growth medium. Our data suggest an important connection between central metabolism and cell envelope integrity and highlight a potential new target for developing novel antimicrobial agents. Antibiotic tolerance (the ability to survive exposure to antibiotics) is a stepping stone toward antibiotic resistance (the ability to grow in the presence of antibiotics), an increasingly common cause of antibiotic treatment failure. The mechanisms promoting tolerance are poorly understood. Here, we identified central carbon metabolism as a key contributor to antibiotic tolerance and resistance. A strain with a mutation in a sugar utilization pathway accumulates metabolites that likely shut down the synthesis of cell wall precursors, which weakens the cell wall and thus increases susceptibility to cell wall-active drugs. Our results illuminate the connection between central carbon metabolism and cell wall homeostasis in V. cholerae and suggest that interfering with metabolism may be a fruitful future strategy for the development of antibiotic adjuvants.
Topics: Vibrio cholerae; Mutation; Penicillins; Anti-Bacterial Agents; Monobactams; beta-Lactams
PubMed: 36840595
DOI: 10.1128/jb.00476-22 -
The Journal of Antibiotics Feb 1987New monobactams, PB-5266 A, B and C were isolated from the culture filtrate of Cytophaga johnsonae PB-5266 by various types of column chromatography and preparative...
New monobactams, PB-5266 A, B and C were isolated from the culture filtrate of Cytophaga johnsonae PB-5266 by various types of column chromatography and preparative reverse phase HPLC. PB-5266 A, B and C exhibited weak antibacterial activity against a sensitive mutant of Escherichia coli to beta-lactam antibiotics.
Topics: Anti-Bacterial Agents; Biochemical Phenomena; Biochemistry; Chromatography; Cytophaga; Monobactams
PubMed: 3570960
DOI: 10.7164/antibiotics.40.135 -
Annales de Biologie Clinique 2006The acquired resistance against the wide-spectrum and highly stable beta-lactams including third-generation cephalosporins (3GC) and carbapenems is constinuously... (Review)
Review
The acquired resistance against the wide-spectrum and highly stable beta-lactams including third-generation cephalosporins (3GC) and carbapenems is constinuously increasing and widespead with the discovery of various plasmid-encoded, or genes cassette or integrons coding for a novel beta-lactamase, always a major mechanism of resistance. To explain resistance against 3GC, with the continuing story with TEM and SHV mutated enzymes, several types of ESBL (class A) emerge the CTX-M type, at least CTX-M-40, but also other non predominant types intitled BES, GES, PLA, PER, VEB. The wider resistance including 3GC, cephamycins and beta-lactamase inhibitor is correlated to synthesis of transferable cephalosporinases (class C) usually located in the chromosome but mobilized from Enterobacter spp., Citrobacter freundii, Hafnia alvei, Morganella morganii, Aeromonas caviae. Such genes encoded the following types: ACC-1, ACT-1, CFE-1, CMY group, DHA-1, FOX group, MIR-1, MOX-1. Finally the resistance against carbapemens e.g. imipenem originally restricted to Pseudomonas aeruginosa, then to Acinetobacter baumannii and finally to enterobacteria is related to production of novel enzymes (classes B, D and A) denominated IMP, VIM SME, GIM, OXA, KPC. A striking exemple of evolution towards more and more resistance is given by Salmonella, even from animal origins, a great threat fo public health. So far it appears necessary to perform molecular approaches to identify such enzymatic production. Finally because the absence of real new drugs, the discovery of some progenitors of the gene beta-lactamase, a strict control of beta-lactam antibiotics must be provide not only in medecine or veterinary field but also in agriculture, including aquaculture for example.
Topics: Animals; Drug Resistance, Bacterial; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Monobactams; Salmonella Infections; Zoonoses; beta-Lactamases
PubMed: 16420989
DOI: No ID Found -
European Journal of Clinical... Feb 2024To evaluate the different present and future therapeutic β-lactam/β-lactamase inhibitor (BL/BLI) alternatives, namely aztreonam-avibactam, imipenem-relebactam,...
PURPOSE
To evaluate the different present and future therapeutic β-lactam/β-lactamase inhibitor (BL/BLI) alternatives, namely aztreonam-avibactam, imipenem-relebactam, meropenem-vaborbactam, cefepime-zidebactam, cefepime-taniborbactam, meropenem-nacubactam, and sulbactam-durlobactam against clinical isolates showing reduced susceptibility or resistance to cefiderocol in Enterobacterales, Acinetobacter baumannii, and Pseudomonas aeruginosa.
METHODS
MIC values of aztreonam, aztreonam-avibactam, cefepime, cefepime-taniborbactam, cefepime-zidebactam, imipenem, imipenem-relebactam, meropenem, meropenem-vaborbactam, meropenem-nacubactam, sulbactam-durlobactam, and cefiderocol combined with a BLI were determined for 67, 9, and 11 clinical Enterobacterales, P. aeruginosa or A. baumannii isolates, respectively, showing MIC values of cefiderocol being ≥1 mg/L. If unavailable, the respective β-lactam breakpoints according to EUCAST were used for BL/BLI combinations.
RESULTS
For Enterobacterales, the susceptibility rates for aztreonam, cefepime, imipenem, and meropenem were 7.5%, 0%, 10.4%, and 10.4%, respectively, while they were much higher for cefepime-zidebactam (91%), cefiderocol-zidebactam (91%), meropenem-nacubactam (71.6%), cefiderocol-nacubactam (74.6%), and cefiderocol-taniborbactam (76.1%), as expected. For P. aeruginosa isolates, the higher susceptibility rates were observed for imipenem-relebactam, cefiderocol-zidebactam, and meropenem-vaborbactam (56% for all combinations). For A. baumannii isolates, lower susceptibility rates were observed with commercially or under development BL/BLI combos; however, a high susceptibility rate (70%) was found for sulbactam-durlobactam and when cefiderocol was associated to some BLIs.
CONCLUSIONS
Zidebactam- and nacubactam-containing combinations showed a significant in vitro activity against multidrug-resistant Enterobacterales clinical isolates with reduced susceptibility to cefiderocol. On the other hand, imipenem-relebactam and meropenem-vaborbactam showed the highest susceptibility rates against P. aeruginosa isolates. Finally, sulbactam-durlobactam and cefiderocol combined with a BLI were the only effective options against A. baumannii tested isolates.
Topics: Humans; Cefiderocol; Meropenem; Cefepime; Aztreonam; Anti-Bacterial Agents; Cephalosporins; Imipenem; beta-Lactamase Inhibitors; Microbial Sensitivity Tests; beta-Lactamases; Carboxylic Acids; Piperidines; Lactams; Boronic Acids; Cyclooctanes; Azabicyclo Compounds; Borinic Acids
PubMed: 38095831
DOI: 10.1007/s10096-023-04732-4 -
Antimicrobial Resistance and Infection... Apr 2023Rapid emergence of multidrug resistant Staphylococcus aureus has resulted to difficulty in treatment of infections caused by such strains. The aim of this meta-analysis... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Rapid emergence of multidrug resistant Staphylococcus aureus has resulted to difficulty in treatment of infections caused by such strains. The aim of this meta-analysis study was to determine the pooled prevalence of resistance of S. aureus to different antibiotics in Nigeria.
METHODS
Literature search for studies was done using Google scholar, PubMed, Science direct, and African Journal Online. The prevalence of S. aureus resistance to different antibiotics was evaluated using the meta-analysis proportion command in MedCalc software version 20.0 adopting a rand effect model. I statistic and Egger test in MedCalc was used to evaluate the heterogeneity and the presence of publication bias among studies respectively.
RESULTS
A total of 40, 682 studies were retrieved through the database search of which 98 studies met the study inclusion criteria. Prevalence of resistance of S. aureus to different antibiotics ranges from 13 to 82%. Results showed a very high degree of resistance to penicillin G (82% [95% confidence interval (CI) 61%, 0.96%]), cloxacillin (77% [95% CI 64%, 88%]), amoxacillin (74% [95% CI 66%, 81%]), cefuroxime (69% [95% CI 51%, 85%]), ampicillin (68% [95% CI 53%, 81%]). Moderately resistance to erythromycin (47% [95% CI 40%, 53%]), chloramphenicol (47% [95% CI 37%, 56%]), methicillin (46% [95% CI 37%, 56%]), ofloxacin (24% [95% CI 18%, 31%]) and rifampicin 24% [95% CI 6%, 48%]). Low resistance was observed in vancomycin 13% (95% CI 7%, 21%). For each individual meta-analysis, high heterogeneity was observed with I range (79.36-98.60%) at p-values ≤ 0.01). Egger's tests for regression intercept in funnel plots indicated no evidence of publication bias.
CONCLUSION
This meta-analysis study established that S. aureus in Nigeria has developed resistance to commonly used antibiotics such as the beta-lactam class antibiotics, sulphonamides, tetracyclines, chloramphenicol, and vancomycin. Hence it is imperative to develop programs to promote rational use of antimicrobial agents, infection prevention and control to reduce the incidence of antimicrobial resistance.
Topics: Humans; Anti-Bacterial Agents; Staphylococcus aureus; Vancomycin; Methicillin-Resistant Staphylococcus aureus; Prevalence; Nigeria; Staphylococcal Infections; Chloramphenicol; Monobactams
PubMed: 37098614
DOI: 10.1186/s13756-023-01243-x -
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