Interaction of drug- and granulocyte-mediated killing of Pseudomonas aeruginosa in a murine pneumonia model.
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 × 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.


CONCLUSIONS
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.
Institute for Therapeutic Innovation, Department of Medicine, College of Medicine, University of Florida Research and Academic Center, Lake Nona.
George Louis
GL
Drusano
Institute for Therapeutic Innovation, Department of Medicine, College of Medicine, University of Florida Research and Academic Center, Lake Nona.
Weiguo
W
Liu
Institute for Therapeutic Innovation, Department of Medicine, College of Medicine, University of Florida Research and Academic Center, Lake Nona.
Steven
S
Fikes
Achaogen, San Francisco, California.
Ryan
R
Cirz
Institute for Therapeutic Innovation, Department of Medicine, College of Medicine, University of Florida Research and Academic Center, Lake Nona.
Nichole
N
Robbins
Institute for Therapeutic Innovation, Department of Medicine, College of Medicine, University of Florida Research and Academic Center, Lake Nona.
Stephanie
S
Kurhanewicz
Institute for Therapeutic Innovation, Department of Medicine, College of Medicine, University of Florida Research and Academic Center, Lake Nona.
Jaime
J
Rodriquez
Institute for Therapeutic Innovation, Department of Medicine, College of Medicine, University of Florida Research and Academic Center, Lake Nona.
David
D
Brown
Institute for Therapeutic Innovation, Department of Medicine, College of Medicine, University of Florida Research and Academic Center, Lake Nona.
Dodge
D
Baluya
Institute for Therapeutic Innovation, Department of Medicine, College of Medicine, University of Florida Research and Academic Center, Lake Nona.
Arnold
A
Louie
D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D024881:Drug Resistance, Bacterial; D005260:Female; D006098:Granulocytes / Q000502:physiology*; D051379:Mice; D008826:Microbial Sensitivity Tests; D018410:Pneumonia, Bacterial / Q000188:drug therapy / Q000276:immunology / Q000382:microbiology*; D011552:Pseudomonas Infections / Q000188:drug therapy / Q000276:immunology / Q000382:microbiology*; D011550:Pseudomonas aeruginosa / Q000502:physiology*; D012853:Sisomicin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use
D000900:Anti-Bacterial Agents; C550938:plazomicin; D012853:Sisomicin
P. aeruginosa pneumonia; antimicrobial therapy; mathematical modeling