Dosing regimen matters: the importance of early intervention and rapid attainment of the pharmacokinetic/pharmacodynamic target

Abstract

To date, the majority of pharmacokinetic/pharmacodynamic (PK/PD) discussions have focused on PK/PD relationships evaluated at steady-state drug concentrations. However, a concern with reliance upon steady-state drug concentrations is that it ignores events occurring while the pathogen is exposed to intermittent suboptimal systemic drug concentrations prior to the attainment of a steady state. Suboptimal (inadequate) exposure can produce amplification of resistant bacteria. This minireview provides an overview of published evidence supporting the positions that, in most situations, it is the exposure achieved during the first dose that is relevant for determining the therapeutic outcome of an infection, therapeutic intervention should be initiated as soon as possible to minimize the size of the bacterial burden at the infection site, and the duration of drug administration should be kept as brief as clinically appropriate to reduce the risk of selecting for resistant (or phenotypically nonresponsive) microbial strains. To support these recommendations, we briefly discuss data on inoculum effects, persister cells, and the concept of time within some defined mutation selection window.

Fig 1

Resistant populations at 48 h under various levels of drug exposure (56). The data at an AUC/MIC ratio of 0 represent the densities of the resistant subpopulation at baseline (time zero). All other data points denote the densities of the resistant subpopulation present at 48 h. KP, Klebsiella pneumoniae ATCC 13883; MRSA, methicillin-resistant S. aureus; MRSA-CS, ciprofloxacin-susceptible MRSA; MRSA-CR, ciprofloxacin-resistant MRSA.

Fig 2

Emergence of resistance to meropenem (A) and tobramycin (B) in a wild-type strain of P. aeruginosa (PAO1) and emergence of resistance to meropenem (C) and tobramycin (D) in MexAB efflux pump-overexpressing mutant strain PAO1(MexAB) after incubation in respective combinations of meropenem and tobramycin concentrations as indicated on the plots (18).

Fig 3

Impact of differing durations of garenoxacin therapy on susceptible and resistant bacterial subpopulations subjected to a regimen with an AUC/MIC ratio of 100 (reproduced from reference with permission).

Fig 4

Calculations of the total bacterial population size, the garenoxacin-susceptible subpopulation size, and the garenoxacin-resistant subpopulation size. A, no-treatment control; B, 4 drug doses; C, 5 drug doses; D, 6 drug doses. Obs, observed; Sim, simulated (reproduced from reference with permission).

Fig 5

Interacting factors that can influence the success of antimicrobial intervention.