Increase of microcirculatory blood flow enhances penetration of ciprofloxacin into soft tissue

Abstract

The present study addressed the effect of microcirculatory blood flow on the ability of ciprofloxacin to penetrate soft tissues. Twelve healthy male volunteers were enrolled in an analyst-blinded, clinical pharmacokinetic study. A single intravenous dose of 200 mg of ciprofloxacin was administered over a period of approximately 20 min. The concentrations of ciprofloxacin were measured in plasma and in the warmed and contralateral nonwarmed lower extremities. The microdialysis technique was used for the assessment of unbound ciprofloxacin concentrations in subcutaneous adipose tissue. Microcirculatory blood flow was measured by use of laser Doppler flowmetry. Warming of the extremity resulted in an increase of microcirculatory blood flow by approximately three- to fourfold compared to that at the baseline (P < 0.05) in subcutaneous adipose tissue. The ratio of the maximum concentration (C(max)) of ciprofloxacin for the warmed thigh to the C(max) for the nonwarmed thigh was 2.10 +/- 0.90 (mean +/- standard deviation; P < 0.05). A combined in vivo pharmacokinetic (PK)-in vitro pharmacodynamic (PD) simulation based on tissue concentration data indicated that killing of Pseudomonas aeruginosa (ATCC 27853 and two clinical isolates) was more effective by about 2 log(10) CFU/ml under the warmed conditions than under the nonwarmed conditions (P < 0.05). The improvement of microcirculatory blood flow due to the warming of the extremity was paralleled by an increased ability of ciprofloxacin to penetrate soft tissue. Subsequent PK-PD simulations based on tissue PK data indicated that this increase in tissue penetration was linked to an improved antimicrobial effect at the target site.

FIG. 1.

Time-concentration profiles of ciprofloxacin for the interstitial space fluid of subcutaneous adipose tissue of warmed (up triangles) and reference (down triangles) tissue following administration of a single intravenous dose of 200 mg over a period of 20 min (n = 12). The shaded horizontal bar indicates the duration of infusion. Results are presented as means ± SDs.

FIG. 2.

Relative change in laser Doppler flowmetry measurements after the start of heating of the lower limbs versus that at the baseline. Data are shown as means ± SDs.

FIG. 3.

Time-kill curves for selected Pseudomonas aeruginosa strains with MICs of 0.12 mg/liter, 0.5 mg/liter, and 2 mg/liter. The bacteria were exposed in vitro to the PK profile determined in vivo in the nonwarmed and warmed extremities. Data are shown as means ± SDs.