Pharmacokinetics of [18F]fleroxacin in patients with acute exacerbations of chronic bronchitis and complicated urinary tract infection studied by positron emission tomography

Abstract

The pharmacokinetics of fleroxacin, a new broad-spectrum fluoroquinolone, were measured by positron emission tomography (PET) with [18F]fleroxacin in five patients with acute bacterial exacerbations of chronic bronchitis and in five patients with symptomatic, complicated urinary tract infection. Two studies were performed with each patient, one within 24 h of the initiation and one within 24 h of the completion of a 7-day course of fleroxacin, 400 mg/day. For each study, the patient received an infusion of that day's therapeutic dose of fleroxacin (400 mg) supplemented with approximately 740 MBq of [18F]fleroxacin, and serial PET images and blood samples were collected for 6 to 8 h starting at the initiation of the infusion. Between studies, the drug was administered orally. In all infected tissues, there was rapid accumulation of radiolabeled drug, with stable levels achieved within 1 h after completion of the infusion. In kidneys, accumulation was greater in the presence of active infection (P < 0.01), while in lungs, accumulation was lower (P < 0.02). Infection of the lung or urinary tract had no effect on drug delivery to uninvolved tissues. Also, there was no difference between the results obtained at the beginning and the end of therapy. Overall, peak concentrations of drug many times the MIC at which 90% of the infecting organisms are inhibited (MIC90) were achieved in the kidneys (> 30 micrograms/g), prostate glands (> 11 micrograms/g), and lungs (> 14 micrograms/g). Plateau concentrations (2 to 8 h; given as mean micrograms per gram +/- standard error of the mean) of drug in kidneys (15.11 +/- 0.55), prostate glands (5.08 +/- 0.19), and lungs (5.75 +/- 0.22) were also well above the MIC90 for most relevant pathogens. All patients had a good therapeutic response to fleroxacin.

Regional Pharmacokinetics of Orally Administered PET Tracers

“…Compared with other imaging modalities such as X-ray computed tomography (CT), ultrasound (US), magnetic resonance imaging (MRI) and single photon radionuclide imaging (planar and SPECT), PET combines the important characteristics of: (a) absolute quantitation, (b) short half-lives of PET radionuclides permit repetitive studies before and after interventions, (c) resolutions of <5 mm (FWHM) can be achieved in almost any tissue of the body, (d) procedures developed in animal studies are readily applied to human studies and most importantly, (e) almost any drug can be radiolabeled with 11 C, 13 N or 18 [1][2][3][4], antimicrobials [5][6][7][8], antineoplastics [9][10][11], etc., have been studied using PET techniques. In general PET measurements of tissue pharmacokinetics can be divided into two broad categories; direct and indirect approaches.…”

Pharmacokinetics of 18F-labeled trovafloxacin in normal and Escherichia coli-infected rats and rabbits studied with positron emission tomography

“… Objective: To measure tissue pharmacokinetics of trovafloxacin (CP 99,219) in normal and infected animals by both direct tissue radioactivity measurements and positron emission tomography (PET). Method: Concentrations of [ 18 ]Ftrovafloxacin were measured in normal and infected rats ( n =6/group), at 10, 30, 60, and 120 min after injection, by radioactivity measurements. In normal rabbits ( n =4) and rabbits with Escherichia coli thigh infection ( n =4), tissue concentrations of drug were measured over 2 h with PET.…”

“…In normal rabbits ( n =4) and rabbits with Escherichia coli thigh infection ( n =4), tissue concentrations of drug were measured over 2 h with PET. After acquiring the final images, the rabbits were killed and tissue concentrations measured with PET were compared to the results of direct tissue radioactivity measurements. Results: In both species, there was rapid distribution of [ 18 ]F trovafloxacin in most peripheral organs. Peak concentrations of more than five times the MIC 90 of most Enterobacteriaceae and anaerobes (>100‐fold for most organisms) were achieved in all tissues and remained above this level for >2 h. Particularly high peak concentrations were achieved in the kidney (>75 μg/g), liver (>100 μg/g), blood (>40 μg/g), and lung (>10 μg/g).…”

“…Method: Concentrations of [ 18 ]Ftrovafloxacin were measured in normal and infected rats ( n =6/group), at 10, 30, 60, and 120 min after injection, by radioactivity measurements. In normal rabbits ( n =4) and rabbits with Escherichia coli thigh infection ( n =4), tissue concentrations of drug were measured over 2 h with PET.…”

“…Results: In both species, there was rapid distribution of [ 18 ]F trovafloxacin in most peripheral organs. Peak concentrations of more than five times the MIC 90 of most Enterobacteriaceae and anaerobes (>100‐fold for most organisms) were achieved in all tissues and remained above this level for >2 h. Particularly high peak concentrations were achieved in the kidney (>75 μg/g), liver (>100 μg/g), blood (>40 μg/g), and lung (>10 μg/g).…”