piperidines and Pseudomonas-Infections

To evaluate the activity of cefiderocol, imipenem/relebactam, cefepime/taniborbactam and cefepime/zidebactam against a clinical and laboratory collection of ceftolozane/tazobactam- and ceftazidime/avibactam-resistant Pseudomonas aeruginosa β-lactamase mutants.. The activity of cefiderocol, imipenem/relebactam, cefepime/taniborbactam, cefepime/zidebactam and comparators was evaluated against a collection of 30 molecularly characterized ceftolozane/tazobactam- and/or ceftazidime/avibactam-resistant P. aeruginosa isolates from patients previously treated with cephalosporins. To evaluate how the different β-lactamases in the clinical isolates affected the resistance to these agents, a copy of each blaPDC, blaOXA-2 and blaOXA-10 ancestral and mutant allele from the clinical isolates was cloned in pUCp24 and expressed in dual blaPDC-oprD (for blaPDC-like genes) or single oprD (for blaOXA-2-like and blaOXA-10-like genes) PAO1 knockout mutants. MICs were determined using reference methodologies.. For all isolates, MICs were higher than 4 and/or 8 mg/L for ceftolozane/tazobactam and ceftazidime/avibactam, respectively. Cefiderocol was the most active agent, showing activity against all isolates, except one clinical isolate that carried an R504C substitution in PBP3 (MIC = 16 mg/L). Imipenem/relebactam was highly active against all isolates, except two clinical isolates that carried the VIM-20 carbapenemase. Cefepime/zidebactam and cefepime/taniborbactam displayed activity against most of the isolates, but resistance was observed in some strains with PBP3 amino acid substitutions or that overexpressed mexAB-oprM or mexXY efflux pumps. Evaluation of transformants revealed that OXA-2 and OXA-10 extended-spectrum variants cause a 2-fold increase in the MIC of cefiderocol relative to parental enzymes.. Cefiderocol, imipenem/relebactam, cefepime/taniborbactam and cefepime/zidebactam show promising and complementary in vitro activity against ceftolozane/tazobactam- and ceftazidime/avibactam-resistant P. aeruginosa. These agents may represent potential therapeutic options for ceftolozane/tazobactam- and ceftazidime/avibactam-resistant P. aeruginosa infections.

Topics: Anti-Bacterial Agents; Azabicyclo Compounds; beta-Lactamases; Borinic Acids; Carboxylic Acids; Cefepime; Cefiderocol; Ceftazidime; Cephalosporins; Cyclooctanes; Humans; Imipenem; Piperidines; Pseudomonas aeruginosa; Pseudomonas Infections; Tazobactam

Topics: Adenine; Aged; Ecthyma; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Piperidines; Pseudomonas aeruginosa; Pseudomonas Infections; Skin; Staphylococcal Skin Infections; Staphylococcus aureus

Herein, we report a case of a 68-year-old woman receiving ibrutinib for chronic lymphocytic leukaemia, who presented with septic shock and a progressive necrotic lesion on her nose. Surgical pathology of the nasal lesion revealed evidence of tissue necrosis, and both tissue and blood culture grew

Topics: Adenine; Aged; Ecthyma; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Necrosis; Piperidines; Pseudomonas aeruginosa; Pseudomonas Infections; Sepsis

Chronic suppurative otitis media (CSOM) is a widespread, debilitating problem with poorly understood immunology. Here, we assess the host response to middle ear infection over the course of a month post-infection in a mouse model of CSOM and in human subjects with the disease. Using multiparameter flow cytometry and a binomial generalized linear machine learning model, we identified Ly6G, a surface marker of mature neutrophils, as the most informative factor of host response driving disease in the CSOM mouse model. Consistent with this, neutrophils were the most abundant cell type in infected mice and Ly6G expression tracked with the course of infection. Moreover, neutrophil-specific immunomodulatory treatment using the neutrophil elastase inhibitor GW 311616A significantly reduces bacterial burden relative to ofloxacin-only treated animals in this model. The levels of dsDNA in middle ear effusion samples are elevated in both humans and mice with CSOM and decreased during treatment, suggesting that dsDNA may serve as a molecular biomarker of treatment response. Together these data strongly implicate neutrophils in the ineffective immune response to P. aeruginosa infection in CSOM and suggest that immunomodulatory strategies may benefit drug-tolerant infections for chronic biofilm-mediated disease.

Topics: Animals; Antigens, Ly; Disease Models, Animal; Drug Synergism; Female; Flow Cytometry; Humans; Machine Learning; Male; Mice; Neutrophils; Ofloxacin; Otitis Media, Suppurative; Piperidines; Proteinase Inhibitory Proteins, Secretory; Pseudomonas aeruginosa; Pseudomonas Infections

WCK 5222 combines cefepime with zidebactam, a β-lactam enhancer that binds PBP2 and inhibits class A and C β-lactamases. The efficacy of human-simulated bronchopulmonary exposures of WCK 5222 against MDR Pseudomonas aeruginosa was investigated in a neutropenic murine pneumonia model.. Nineteen MDR isolates of P. aeruginosa (cefepime MICs ≥64 mg/L) were studied. MICs of zidebactam and WCK 5222 ranged from 4 to 512 mg/L and from 4 to 32 mg/L, respectively. Dosing regimens of cefepime and zidebactam alone and in combination that achieved epithelial lining fluid (ELF) exposures in mice approximating human ELF exposures after doses of 2 g of cefepime/1 g of zidebactam every 8 h (1 h infusion) were utilized; controls were vehicle-dosed. Lungs were intranasally inoculated with 107-108 cfu/mL bacterial suspensions. Mice were dosed subcutaneously 2 h after inoculation for 24 h, then lungs were harvested.. In vitro MIC was predictive of in vivo response to WCK 5222 treatment. Mean±SD changes in bacterial density at 24 h compared with 0 h controls (6.72±0.50 log10 cfu/lungs) for 13 isolates with WCK 5222 MICs ≤16 mg/L were 1.17±1.00, -0.99±1.45 and -2.21±0.79 log10 cfu/lungs for cefepime, zidebactam and WCK 5222, respectively. Against these isolates, zidebactam yielded >1 log10 cfu/lungs reductions in 8/13, while activity was enhanced with WCK 5222, producing >2 log10 cfu/lungs reductions in 10/13 and >1 log10 cfu/lungs reductions in 12/13. Among isolates with WCK 5222 MICs of 32 mg/L, five out of six showed a bacteriostatic response.. Human-simulated bronchopulmonary exposure of WCK 5222 is effective against MDR P. aeruginosa at MIC ≤16 mg/L in a murine pneumonia model. These data support the clinical development of WCK 5222 for pseudomonal lung infections.

Topics: Animals; Anti-Bacterial Agents; Azabicyclo Compounds; Cefepime; Cephalosporins; Cyclooctanes; Disease Models, Animal; Drug Resistance, Multiple, Bacterial; Drug Therapy, Combination; Female; Healthy Volunteers; Humans; Lung; Mice; Microbial Sensitivity Tests; Neutropenia; Piperidines; Pneumonia, Bacterial; Pseudomonas aeruginosa; Pseudomonas Infections; Specific Pathogen-Free Organisms

The combination of cefepime and zidebactam (WCK5222), a novel β-lactam enhancer, has demonstrated activity against a wide variety of Gram-negative pathogens and is currently under clinical evaluation.. To examine the activity of cefepime/zidebactam against: (i) a contemporary collection of Gram-negative isolates from New York City; (ii) a collection of carbapenem-resistant clinical isolates; and (iii) a collection of isolates with characterized resistance mechanisms.. Susceptibility tests were performed using broth microdilution for cefepime, zidebactam and cefepime/zidebactam (1:1).. More than 99% of a contemporary collection of Escherichia coli, Klebsiella pneumoniae and Enterobacter spp. had cefepime/zidebactam MICs ≤2 mg/L, the susceptibility breakpoint for cefepime. For K. pneumoniae, the acquisition of blaKPC resulted in increased MICs, although MICs remained ≤2 mg/L for 90% of KPC-possessing isolates. Overall for Pseudomonas aeruginosa, 98% of isolates had MICs ≤8 mg/L and MICs were affected by increased expression of ampC. For carbapenem-resistant P. aeruginosa, 78% of isolates had cefepime/zidebactam MICs ≤8 mg/L. The activity of cefepime/zidebactam against Acinetobacter baumannii was lower, with 85% of all isolates and 34% of carbapenem-resistant isolates with MICs ≤8 mg/L (cefepime interpretative criteria).. Cefepime/zidebactam demonstrated excellent activity against Enterobacteriaceae and P. aeruginosa, although activity was reduced in carbapenem-non-susceptible isolates. The activity against A. baumannii was reduced and studies examining the therapeutic efficacy in strains with high cefepime/zidebactam MICs are warranted.

Topics: Acinetobacter baumannii; Acinetobacter Infections; Anti-Bacterial Agents; Azabicyclo Compounds; Cefepime; Cyclooctanes; Drug Interactions; Endemic Diseases; Enterobacteriaceae; Enterobacteriaceae Infections; Health Facilities; Humans; Microbial Sensitivity Tests; New York City; Piperidines; Pseudomonas aeruginosa; Pseudomonas Infections

Zidebactam is a β-lactam enhancer antibiotic with a dual mechanism of action involving binding to Gram-negative PBP2 and β-lactamase inhibition. Cefepime combined with zidebactam (WCK 5222) is under clinical development for treatment of Gram-negative infections.. To evaluate the in vitro activities of cefepime and zidebactam separately and combined at 1:1 and 2:1 ratios when tested against Gram-negative organisms producing the most clinically relevant β-lactamase types.. β-Lactamase-producing (193) and WT (71) isolates were tested for susceptibility by broth microdilution method against cefepime/zidebactam, cefepime and zidebactam.. Cefepime/zidebactam (1:1) was very active against Enterobacteriaceae producing CTX-M-15 (21; MIC 50/90 0.25/1 mg/L), SHV (20; MIC 50/90 0.12/0.25 mg/L), other ESBLs (20, including GES-18, OXA-1/30 and OXY-, PER-, TEM- and VEB-like; MIC 50/90 0.25/1 mg/L), plasmidic AmpC (10; MIC 50/90  ≤0.06/≤0.06 mg/L), derepressed AmpC (23; MIC 50/90 0.12/0.5 mg/L), KPC (35; MIC 50/90 0.25/1 mg/L) and metallo-β-lactamases (MBLs; 20 including VIM, IMP and NDM; MIC 50/90 0.5/8 mg/L). Cefepime/zidebactam (1:1) was also active against Pseudomonas aeruginosa with overexpression of AmpC (21; MIC 50/90 4/8 mg/L) and MBLs [12 (VIM and IMP); MIC 50/90 4/8 mg/L]. Zidebactam alone exhibited potent in vitro activity against some Enterobacteriaceae and P. aeruginosa , including β-lactamase-producing strains. Cefepime/zidebactam MIC values were lower than those of each agent tested alone for many β-lactamase-producing strains, indicating synergy. Cefepime/zidebactam showed moderate activity against OXA-23/24/58-producing Acinetobacter baumannii [MIC 50/90 32 mg/L (1:1)].. Cefepime/zidebactam showed potent activities against Enterobacteriaceae and P. aeruginosa producing various clinically relevant β-lactamases, including ESBLs, KPCs, AmpC and MBLs for which limited treatment options are currently available.

Topics: Acinetobacter baumannii; Acinetobacter Infections; Anti-Bacterial Agents; Azabicyclo Compounds; beta-Lactamase Inhibitors; beta-Lactamases; Cefepime; Cephalosporins; Cyclooctanes; Drug Synergism; Enterobacteriaceae; Enterobacteriaceae Infections; Humans; Microbial Sensitivity Tests; Piperidines; Pseudomonas aeruginosa; Pseudomonas Infections

A series of 4-oxo-4H-pyrido[1,2-a]pyrimidine derivatives, substituted at the 2-position with piperidines bearing quaternary ammonium salt side chains, were synthesized and evaluated for their ability to potentiate the activity of the fluoroquinolone levofloxacin (LVFX) and the beta-lactam aztreonam (AZT) in Pseudomonas aeruginosa. Attachment of the charged entity using an N-ethylcarbamoyloxy linker led to the discovery of the highly soluble compound 22 (D13-9001), which maintained good potency in vitro and displayed excellent activity in vivo in a rat pneumonia model of P. aeruginosa.

Topics: Animals; Anti-Bacterial Agents; Bacterial Outer Membrane Proteins; Drug Evaluation, Preclinical; Drug-Related Side Effects and Adverse Reactions; Female; Haplorhini; Infusions, Intravenous; Male; Membrane Transport Proteins; Microbial Sensitivity Tests; Molecular Structure; Piperidines; Pseudomonas aeruginosa; Pseudomonas Infections; Quaternary Ammonium Compounds; Rats; Rats, Sprague-Dawley; Solubility; Stereoisomerism

Individuals who have suffered severe trauma, such as burns, have a high incidence of infection associated with impaired host resistance. Nonspecific stimulators of host defense mechanisms, i.e., immunomodulators, may be of benefit in such situations. A small animal model (guinea pigs) was developed to study the efficacy of immunomodulators in burns. Anesthetized animals received a 20% total body surface area, full-thickness, scald burn. There was no mortality associated with this injury, but these animals were highly susceptible to challenge with Pseudomonas aeruginosa strain 1244 by direct injection into the burn wound within 24 hours of injury. This susceptibility persisted about 7 days. The standard model adopted was to injure animals, then challenge with 1 median lethal dose (LD50) of P. aeruginosa 96 hours after injury. Using this model, six synthetic immunomodulators were tested: CP-20,961, CP-46,665, muramyl dipeptide, thymopoietin pentapeptide (TP-5), levamisole, and lithium. Drug administration began 24 hours after injury and ended prior to challenge with P. aeruginosa at 96 hours. CP-20,961, muramyl dipeptide, levamisole, and lithium all had no beneficial effect on survival. A single dosage (0.3 mg/kg, I.V.) of CP-46,665, administered 24 hours postinjury, increased the survival rate from 50% to 85% and mean survival time (MST) from 8.2 days to 12.4 days. TP-5, given in four doses (0.1 mg/kg, I.V. each) every 24 hours, increased the survival rate from 40% to 80% and MST from 6.9 days to 11.6 days. These data show that immunomodulators could be of benefit in burns, but also that not all agents are effective in this particular situation.

Topics: Acetylmuramyl-Alanyl-Isoglutamine; Adjuvants, Immunologic; Animals; Burns; Diamines; Evaluation Studies as Topic; Female; Guinea Pigs; Lethal Dose 50; Levamisole; Lithium; Peptide Fragments; Piperidines; Pseudomonas aeruginosa; Pseudomonas Infections; Thymopentin; Thymopoietins; Time Factors