In Vitro Studies on Improvement of the Therapeutic Efficacy of Aminoglycoside Antibiotics

Abstract

The electrophoretic mobility of phosphatidyl inositol liposomes at pH 7.4, 25°C, was reduced by aminoglycoside(AG) antibiotics, neamine and several polyamines in general accordance with the number of basic nitrogenous groups on each molecule. There was good agreement between the relative position of the tested compounds on the mobility concentration plot and available information about their relative mammalian toxicities in vivo The slope of the plots for netilmicin and 86.038 were distinctively flat: comparative flat dose-response curves have been reported from in vivo studies of nephrotoxicity. Investigation of a homologous series of ∝,ω straight chain diaminoalkanes revealed that hydrophobicity did not contribute significantly to the observed interaction in this system. L-lysine showed the weakest effect amongst all compounds tested, supporting the view that the overall positive charge on the molecules was the major determinant of the observed effect. Whether antibiotics should be administered by continuous infusion or intermittent dosing is a matter of controversy. The efficacy of varying dosage regimes(continuous infusion and intermittent) of the AG gentamicin, simulated in an in vitro kinetic model, against Pseudomonas aeruginosa NCTC 6750 (WT) was investigated. No clear superiority of one type of regime over the other was’ found. Gentamicin resistant subpopulations were selected in all regimes. In some experiments multiply AG resistant small colony variants (SCV) were isolated. SCV had an altered outer membrane protein profile, compared to WT, and were biochemically and immunologically investigated to rule out the possibility of contamination. SCV were more resistant to polymyxin and AGs, but more susceptible to a range of antibiotics (hydrophobic and hydrophilic) with differing modes of action.