avibactam and Escherichia-coli-Infections

The aim of this prospective phase II, randomized, investigator-blinded study (NCT00690378) was to compare the efficacy and safety of ceftazidime-avibactam and imipenem-cilastatin in hospitalized adults with serious complicated urinary tract infection (cUTI) due to Gram-negative pathogens.. Patients aged between 18 and 90 years with cUTI were enrolled and stratified by infection type (acute pyelonephritis or other cUTI) and randomized 1:1 to receive intravenous ceftazidime 500 mg plus avibactam 125 mg every 8 hours or imipenem-cilastatin 500 mg every 6 hours. Patients meeting pre-specified improvement criteria after 4 days could be switched to oral ciprofloxacin. Patients were treated for a total of 7-14 days. The primary efficacy objective was a favorable microbiological response at the test-of-cure (TOC) visit 5-9 days post-therapy in microbiologically evaluable (ME) patients.. Overall, 135 patients received study therapy (safety population); 62 were included in the ME population (ceftazidime-avibactam, n = 27; imipenem-cilastatin, n = 35). The predominant uropathogen was Escherichia coli. Favorable microbiological response was achieved in 70.4% of ME patients receiving ceftazidime-avibactam and 71.4% receiving imipenem-cilastatin at the TOC visit (observed difference -1.1% [95% CI: -27.2%, 25.0%]). Among ME patients with ceftazidime-resistant uropathogens, response was observed in 6/7 (85.7%) receiving ceftazidime-avibactam. Adverse events were observed in 67.6% and 76.1% of patients receiving ceftazidime-avibactam and imipenem-cilastatin, respectively. Limitations of the study include the small number of patients in the ME population.. The results suggest that the efficacy and safety of ceftazidime-avibactam may be similar to that of imipenem-cilastatin.

Topics: Acute Disease; Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Azabicyclo Compounds; Ceftazidime; Cilastatin; Drug Therapy, Combination; Escherichia coli; Escherichia coli Infections; Female; Humans; Imipenem; Male; Middle Aged; Prospective Studies; Protease Inhibitors; Pyelonephritis; Urinary Tract Infections

The burden of pulmonary fungal infection is increasing and often misdiagnosed as pulmonary tuberculosis in developing countries where the prevalence of pulmonary tuberculosis is high. |Therefore, the purpose of this study is to determine the spectrum of potential pulmonary fungal pathogens and the prevalence of the association between pulmonary tuberculosis and potential fungal pathogens.. A cross-sectional study was conducted between October 2018 and May 2019. Sputum was collected from 636 study participants. Part of the sputum was inoculated onto Brain Heart Infusion agar, and fungi were identified following standard microbiological procedures. The remaining part of the sample was used for the investigation of pulmonary tuberculosis.. High prevalence of potential pulmonary fungal pathogens and the association of tuberculosis and potential fungal pathogens recorded in this study will enforce health personnel to pay due attention to these conditions and arise the interest of researchers to conduct further work on the burden of the association between tuberculosis and potential fungal pathogens. Our study also revealed the need to employ conventional microbiology tests along with clinical and radiological evidence since clinical manifestations and radiological pictures of tuberculosis mimic that of pulmonary fungal infection.. Generate preclinical evidence confirming siponimod's CNS penetration and activity.. Siponimod's CNS penetration and distribution was explored in rodents and non-human primates (NHPs) using: Liquid Chromatography coupled to tandem Mass Spectrometry (LC-MS/MS), quantitative whole-body autoradiography (QWBA) using. In mice/rats, siponimod treatments achieved dose-dependent efficacy and dose-proportional increase in drug blood levels, with mean brain/blood drug-exposure ratio (. Findings demonstrate siponimod's CNS penetration and distribution across species, with high translational potential to human.. The online version contains supplementary material available at 10.1007/s13205-021-03020-2.. The IVIM-kurtosis model has potential value in the differential diagnosis of PCa and BPH/prostatitis. IVIM-kurtosis histogram analysis may provide more information in the grading of PCa than MEM.. We identified 60 consecutive patients treated with PCC between 2010 and 2016 at our institution. Thirty-one patients (52%) were ECOG-PS 2. Fifty-five patients (92%) were cisplatin ineligible. ORR was 43.3% (95% CI, 30.8-55.8), and disease control rate was 65% (95% CI, 52.9-77.1). With a median follow-up of 35.7 months (IQR 28.6-48.8), median PFS was 5.8 months (95% CI, 4.5-7.2), and median OS was 11.7 months (95% CI, 7.5-14.8). For ECOG-PS 0-1 patients, median OS was 14.8 months (95% CI, 12.2-21.7) while it was only 7.5 months (95%CI: 5.5-12.7) for ECOG-PS 2 patients (. The weekly PCC regimen seems to be an interesting option in cisplatin-unfit patients. This study shows favorable PFS and OS when compared with what is achieved with the EXTREME regimen and a high controlled disease rate with predictable and manageable toxicities even in the more fragile population.. Our results demonstrated that AUR potentiated the activities of CAZ-AVI and ATM-AVI against MBL-producing isolates

Topics: Animals; Anti-Bacterial Agents; Antibodies, Protozoan; Antifungal Agents; Auranofin; Azabicyclo Compounds; Aztreonam; beta-Lactamases; Canada; Candida; China; Clostridioides difficile; Cresols; Cross-Sectional Studies; Decarboxylation; Drug Resistance, Bacterial; Drug Resistance, Fungal; Escherichia coli; Escherichia coli Infections; Escherichia coli Proteins; Extraintestinal Pathogenic Escherichia coli; Female; Food Microbiology; Gastrointestinal Microbiome; Genomics; HIV Infections; Humans; Immunoglobulin G; Immunoglobulin M; Immunotherapy; Listeria monocytogenes; Listeriosis; Malaria; Male; Melanoma; Memory T Cells; Mice; Mice, Inbred C57BL; Microbial Sensitivity Tests; Mink; Mitogen-Activated Protein Kinase Kinases; Molecular Epidemiology; Multilocus Sequence Typing; Pharmaceutical Preparations; Phenylacetates; Phylogeny; Plasmodium berghei; Pneumonia; Pregnancy; Proto-Oncogene Proteins B-raf; Risk Factors; RNA, Ribosomal, 16S; Saccharomycetales; Seroepidemiologic Studies; Toxoplasmosis; Virulence

The spread of NDM-1 amongst Enterobacteriaceae has highlighted a significant threat to the clinical management of serious infections. The combination of aztreonam and avibactam, a non-β-lactam β-lactamase inhibitor, may provide a much-needed therapeutic alternative. This combination was potent against most NDM-containing Enterobacteriaceae, although activity was diminished against many Escherichia coli isolates. These E. coli isolates were characterized to elucidate the mechanism of decreased susceptibility to aztreonam/avibactam.. MIC determinations were performed using broth microdilution, and whole-genome sequencing was performed to enable sequence-based analyses.. The decreased susceptibility was not due to avibactam being unable to inhibit the serine β-lactamases found in the E. coli isolates. Rather, it was manifested by a four-amino-acid insertion in PBP3. This same insertion was also found in non-NDM-containing E. coli that had reduced susceptibility to aztreonam/avibactam. Construction of an isogenic mutant confirmed that this insertion resulted in decreased susceptibility to aztreonam and several cephalosporins, but had no impact on carbapenem potency. Structural analysis suggests that this insertion will impact the accessibility of the β-lactam drugs to the transpeptidase pocket of PBP3.. The acquisition of β-lactamases is the predominant mechanism of β-lactam resistance in Enterobacteriaceae. We have demonstrated that small PBP3 changes will affect the susceptibility to a broad range of β-lactams. These changes were identified in multiple MLST lineages of E. coli, and were enriched in NDM-containing isolates. However, they were not present in other key species of Enterobacteriaceae despite significant conservation among the PBP3 proteins.

Topics: Anti-Bacterial Agents; Azabicyclo Compounds; Aztreonam; beta-Lactam Resistance; beta-Lactamases; Computational Biology; Escherichia coli; Escherichia coli Infections; Genome, Bacterial; Humans; Microbial Sensitivity Tests; Mutagenesis, Insertional; Penicillin-Binding Proteins; Sequence Analysis, DNA

Secondary to the stability of aztreonam against metallo-β-lactamases, coupled with avibatam's neutralizing activity against often coproduced extended-spectrum β-lactamases (ESBLs) or AmpC enzymes, the combination of aztreonam and avibactam has been proposed as a principal candidate for the treatment of infections with metallo-β-lactamase-producing Gram-negative organisms. Using the neutropenic-mouse thigh infection model, we evaluated the efficacy of human simulated doses of aztreonam-avibactam and aztreonam against 14 Enterobacteriaceae and 13 Pseudomonas aeruginosa isolates, of which 25 produced metallo-β-lactamases. Additionally, six P. aeruginosa isolates were also evaluated in immunocompetent animals. A humanized aztreonam dose of 2 g every 6 h (1-h infusion) was evaluated alone and in combination with avibactam at 375 or 600 mg every 6 h (1-h infusion), targeting the percentage of the dosing interval in which free-drug concentrations remained above the MIC (fT>MIC). Efficacy was evaluated as the change in bacterial density after 24 h compared with the bacterial density at the initiation of dosing. Aztreonam monotherapy resulted in reductions of two of the Enterobacteriaceae bacterial isolates (aztreonam MIC, ≤ 32 μg/ml; fT>MIC, ≥ 38%) and minimal activity against the remaining isolates (aztreonam MIC, ≥ 128 μg/ml; fT>MIC, 0%). Alternatively, aztreonam-avibactam therapy resulted in the reduction of all 14 Enterobacteriaceae isolates (aztreonam-avibactam MICs, ≤16 μg/ml; fT>MIC, ≥ 65%) and no difference between the 375- and 600-mg doses of avibactam was noted. Similar pharmacodynamically predictable activity against P. aeruginosa was noted in studies with neutropenic and immunocompetent mice, with activity occurring when the MICs were ≤ 16 μg/ml and variable efficacy noted when the MICs were ≥ 32 μg/ml. Again, no difference in efficacy between the 375- and 600-mg doses of avibactam was observed. Aztreonam-avibactam represents an attractive treatment option for infections with metallo-β-lactamase-producing Gram-negative pathogens that coproduce ESBLs or AmpC.

Topics: Animals; Anti-Bacterial Agents; Azabicyclo Compounds; Aztreonam; Bacterial Proteins; beta-Lactamases; Enterobacteriaceae Infections; Escherichia coli; Escherichia coli Infections; Humans; Klebsiella Infections; Klebsiella pneumoniae; Mice; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Pseudomonas Infections