Details

Autor(en) / Beteiligte

• Drusano, George Louis
• Liu, Weiguo
• Fikes, Steven
• Cirz, Ryan
• Robbins, Nichole
• Kurhanewicz, Stephanie
• Rodriquez, Jaime
• Brown, David
• Baluya, Dodge
• Louie, Arnold

Titel

Interaction of Drug- and Granulocyte-Mediated Killing of Pseudomonas aeruginosa in a Murine Pneumonia Model

Ist Teil von

• The Journal of infectious diseases, 2014-10, Vol.210 (8), p.1319-1324

Ort / Verlag

United States: Oxford University Press

Erscheinungsjahr

2014

Link zum Volltext

Quelle

Oxford Journals 2020 Medicine

Beschreibungen/Notizen

• Background. 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. Methods. 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. Results. The mean bacterial burden (±SD) at which granulocyte-mediated kill was half saturable was 2.45 x 10⁶ ± 6.84 x 10⁵ 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. Conclusions. For patients with large bacterial burdens (eg, individuals with ventilator-requiring hospitalacquired pneumonia), it is imperative to kill ≥2 log₁₀ CFU/g early after treatment initiation, to allow the granulocytes to contribute optimally to bacterial clearance.