PK-PD Modeling of Biofilm Infections

Accurate pharmacokinetic–pharmacodynamic (PK-PD) models of biofilm treatment could be used to guide formulation and administration strategies to better control bacterial lung infections. To this end, we developed a detailed pharmacodynamic model of P. aeruginosa treatment with the front-line antibiotics, tobramycin and colistin, and validated it on a detailed dataset of killing dynamics. A compartmental model structure was developed in which the key features are the diffusion of the drug through a boundary layer to the bacteria, concentration-dependent interactions with bacteria, and the passage of the bacteria through successive transit states before death. Current efforts are focused on coupling this PD model with a PK model that describes distribution to and from the lungs to provide an integrated PK-PD description relevant to treatment of bacterial lung infections. This can be used to optimize administration and timing protocols for single- and multiple-drug regimens to eradicate emerging and persistent infections.

Pharmacodynamic model structure for tobramycin. The pharmacodynamic model for

response to tobramycin (subscript ‘t’) tracks the transit of biofilm cells going from a viable (B) to

nonviable state (Xt) following administration of tobramycin at bulk concentration C0t. There is a flux,

J(D) of drug from the bulk to the biofilm cells, where the local concentration is Ct. For tobramycin,

there are five transit compartments (D1t, D2t, D3t, D4t, and D5t) mediating the cellular response to

drug. Growth is governed by a specific growth rate, m; the coupled diffusion and pharmacodynamic

response are subject to parameters α, β, and γ; and the transit rate to subsequent compartments is

given by ktt.