Distribution of anti-infective agents in ischaemic peripheries

Abstract

The aims of the study were to analyse the distribution of gentamicin in patients with different degrees of peripheral artery disease (PAD) and to develop pharmacokinetic equations to predict gentamicin concentrations in patients with PAD. Patients undergoing debridement of a wound or an amputation procedure were included. Patients received a 120mg or 240mg intravenous dose of gentamicin once daily. Patients were classified according to the degree of PAD. Tissue and serum samples were collected at the time of intervention. Gentamicin was extracted from the tissue samples by optimising a sodium hydroxide method described by Brown et al. Gentamicin concentrations were determined by Fluorescence Polarization Immunoassay (FPIA). Blood and tissue samples were obtained from 61 patients, 41 male and 20 female. Nineteen patients were free from the disease or had borderline PAD, 9 patients had mild or moderate PAD and 26 patients had severe PAD. The degree of PAD was not known in 7 cases. Forty-eight patients had Type 2 diabetes, 8 patients had Type 1 diabetes and 5 patients were non-diabetic. The concentration of gentamicin in peripheral skeletal muscle tissue was dependent on the serum concentration, degree of PAD, gender and age. For patients with ischaemic lower extremity wounds (patients with mild or moderate and severe PAD), the concentration of gentamicin was significantly lower (p=0.010) than the concentration in non-ischaemic wounds and the concentration in female patients was also significantly lower than in male patients (p=0.047). The pharmacokinetic equation for gentamicin concentrations in skeletal muscle tissue was: Expected Cmuscle = -15.709 + 0.624 Cserum + 0.216 Age + PAD + 2.402 Gender* The concentration in peripheral subcutaneous tissue was 0.663 times the concentration in skeletal muscle tissue (p=0.000). The pharmacokinetic equation for gentamicin subcutaneous tissue concentrations was: Expected Csubcutaneous = 0.663 Cmuscle - 0.220* Gentamicin showed greatest penetration in male patients without PAD. For patients with severe PAD, higher doses of gentamicin may be required to achieve the same effect. 1. Brown SA, Newkirk OR, Hunter RP, Smith GG, Sugimoto K. Extraction methods for quantification of gentamicin residues from tissues using fluorescence polarization immunoassay. J Assoc Off Anal Chem 1990; 73(3): 479-483. * Where: Cmuscle = Skeletal muscle tissue concentration CJlg/g) Csubcutaneous = Subcutaneous tissue concentration CJlg/g) Cserum = Serum concentration CJlg/mL) Age = Age in years PAD = 3.881 for patients with nil or borderline PAD PAD = 1.813 for patients with mild or moderate PAD PAD = 0 for patients with severe PAD Gender - 1 for male patients Gender = 0 for female patients