Investigation of the Pharmacokinetics and Local and Systemic Morbidity of a Gentamicin Impregnated Collagen Sponge Implanted in the Canine Stifle

INVESTIGATION OF THE PHARMACOKINETICS AND LOCAL AND SYSTEMIC MORBIDITY OF A GENTAMICIN IMPREGNATED COLLAGEN SPONGE IMPLANTED IN THE CANINE STIFLE Galina Merete Hayes Advisors: University of Guelph, 2013 Dr Tom Gibson Dr Noel Moens This thesis is an investigation of a gentamicin impregnated collagen sponge (GICS) product implanted into an inflamed canine stifle joint. Project goals were to determine the duration for which drug concentrations remained above minimal inhibitory concentrations within the joint following sponge implantation; to determine whether there was systemic exposure to the drug following local implantation; to evaluate the impact of the sponge on local joint inflammation and lameness; and to evaluate whether sponge use resulted in any renal injury. The study design was a randomized controlled experimental trial (2 x n=9) performed with research hounds. GICS were arthroscopically implanted at a dose of 6mg/kg. Pharmacokinetic parameters were modeled using statistical moment analyses. Joint inflammation was measured by synovial fluid cell counts and cytokine concentrations, lameness was measured by force plate asymmetry indices, and renal function was measured by glomerular filtration rate (GFR) study using technetium 99 plasma clearance. The prevalence of lesions associated with aminoglycoside nephrotoxicity was assessed by renal biopsy and electronmicroscopy. Intra-articular gentamicin concentrations fell to sub-MIC for Staphylococcus sp. (4ug/ml) by 22.4hrs (95% CI=18.6-26.2) following sponge implantation. Cmax synovial was 2397ug/ml (95% CI=1161-3634 ug/ml) at 1.2 hrs (95% CI=0.5-1.8hrs). Plasma gentamicin concentrations achieved levels of Cmax plasma =8.0ug/ml (95% CI=6.1-10.0 ug/ml) at 1.5hrs (95% CI=0.8-2.1) following GICS placement and fell below target trough of 2.0ug/ml by 5.6hrs (95% CI=4.76.5hrs) following GICS placement. GICS implantation caused joint inflammation (p<0.01), lameness (p=0.04), and decreased GFR (p=0.04). No dog developed clinical renal failure. No difference was observed in the prevalence of renal lesions on biopsy between treatment and control group (p=0.49). Intra-articular gentamicin concentration following GICS placement at an IV-equivalent dose reached high levels and declined rapidly. The maximum plasma levels attained were approximately 1/3 of the recommended sub-toxic target for human patients following parenteral gentamicin administration. GICS implantation in the inflamed joint caused additional inflammation and joint dysfunction that is likely to be of clinical relevance. GICS implantation affected renal function at the dose assessed. Renal effects may be exacerbated in septic patients, and care should be taken with GICS dosing in clinical patients.