achn-490 and Pneumonia--Bacterial

Topics: Anti-Bacterial Agents; Bacteremia; Carbapenem-Resistant Enterobacteriaceae; Colistin; Creatinine; Drug Resistance, Bacterial; Enterobacteriaceae Infections; Healthcare-Associated Pneumonia; Humans; Intention to Treat Analysis; Kaplan-Meier Estimate; Pneumonia, Bacterial; Pneumonia, Ventilator-Associated; Sample Size; Sisomicin

Topics: Administration, Inhalation; Amikacin; Anti-Bacterial Agents; Antifungal Agents; Cross Infection; Drug Approval; Drug Resistance, Microbial; Drug Therapy, Combination; Extensively Drug-Resistant Tuberculosis; Humans; Liposomes; Mycobacterium avium Complex; Mycobacterium avium-intracellulare Infection; Nitroimidazoles; Pneumonia, Bacterial; Pneumonia, Ventilator-Associated; Sisomicin; United States; United States Food and Drug Administration

Killing of bacterial pathogens by granulocytes is a saturable process, as previously demonstrated. There is virtually no quantitative information about how granulocytes interact with antimicrobial chemotherapy to kill bacterial cells.. We performed a dose-ranging study with the aminoglycoside plazomicin against Pseudomonas aeruginosa ATCC27853 in a granulocyte-replete murine pneumonia model. Plazomicin was administered in a humanized fashion (ie, administration of decrementing doses 5 times over 24 hours, mimicking a human daily administration profile). Pharmacokinetic profiling was performed in plasma and epithelial lining fluid. All samples were simultaneously analyzed with a population model. Mouse cohorts were treated for 24 hours; other cohorts treated with the same therapy were observed for another 24 hours after therapy cessation, allowing delineation of the therapeutic effect necessary to reduce the bacterial burden to a level below the half-saturation point.. The mean bacterial burden (±SD) at which granulocyte-mediated kill was half saturable was 2.45 × 10(6) ± 6.84 × 10(5) colony-forming units of bacteria per gram of tissue (CFU/g). Higher levels of plazomicin exposure reduced the bacterial burden to <5 log10 CFU/g, allowing granulocytes to kill an additional 1.0-1.5 log CFU/g over the subsequent 24 hours.. For patients with large bacterial burdens (eg, individuals with ventilator-requiring hospital-acquired pneumonia), it is imperative to kill ≥2 log10 CFU/g early after treatment initiation, to allow the granulocytes to contribute optimally to bacterial clearance.

Topics: Animals; Anti-Bacterial Agents; Dose-Response Relationship, Drug; Drug Resistance, Bacterial; Female; Granulocytes; Mice; Microbial Sensitivity Tests; Pneumonia, Bacterial; Pseudomonas aeruginosa; Pseudomonas Infections; Sisomicin