Gallium maltolate: safety in neonatal foals following multiple enteral administrations

Abstract

Gallium maltolate (GaM) has been proposed as a new agent for the prevention and control of foal pneumonia caused by the intracellular bacterium Rhodococcus equi. This proposal is based on the observed antimicrobial effectiveness of GaM on R. equi (Harrington. et al., 2006; Martens et al., 2007a), and the known pharmacokinetics of GaM in neonatal foals (Martens et al., 2007b). The use of GaM represents a novel approach to combating infections: the exploitation of a major stress already imposed on an organism by the host s environment. Adequate availability of ferric iron (Fe) is essential for the growth of most pathogenic bacteria, including R. equi (Jordan et al., 2003), which rely on Fe-dependent enzyme systems (Bullen et al., 2005). A major host innate antimicrobial defense mechanism is the sequestration of available Fe by host plasma proteins, primarily transferrin and lactoferrin. Rhodococcus equi, however, can acquire and utilize transferrinand lactoferrin-bound iron, thereby circumventing this defense mechanism (Jordan et al., 2003). Gallium, a trivalent semi-metal that shares many chemical similarities with Fe and functions as a ferric iron mimic, has been used to control various microorganisms by exploiting their iron dependency (Bernstein, 1998; Oyebode et al., 2000; Harrington et al., 2006; Kaneko et al., 2007). Gallium competes with Fe for uptake by bacteria and is incorporated into crucial Fe-dependent enzyme systems. Trivalent gallium, unlike Fe, is unable to undergo redox-cycling, which leads to inactivation of some Fe-dependent enzymes (particularly ribonucleotide reductase), causing bacterial stasis and death (Bernstein, 1998). Gallium salts (e.g., gallium chloride, gallium nitrate) are not well absorbed orally (Bernstein, 1998). In the only reports of an herbivore species or a neonate in which Ga administration has been assessed, neonatal calves treated with oral gallium chloride developed severe intestinal lesions, alterations in enteric microflora, and diarrhea (Fettman et al., 1987a,b). A citrate-chelated gallium nitrate solution for injection (Ganite , Genta Inc., Berkeley Heights, NJ, USA), which is FDA-approved for treatment of human cancer-related hypercalcemia, is associated with renal toxicity when administered as an IV bolus (Bernstein, 2005). Gallium maltolate, a coordination complex of Ga and maltol, developed by a co-author (LRB), has high oral bioavailability in humans and a variety of other species (Bernstein et al., 2000), and attains potentially therapeutic serum concentrations in neonatal foals (Martens et al., 2007b). Adverse responses to enteral GaM have not been reported in humans or laboratory animal species, but safety studies have not been reported for either neonates or horses. During the neonatal period (first days-to-weeks of life) most mammals have immature or inefficient organ systems and are undergoing a variety of physiologic adaptations that can impact their pharmacologic and toxicologic responsiveness (Koterba, 1990). This report assesses the safety of GaM in neonatal foals by comparing clinical and clinicopathologic parameters of foals that received five daily doses of enteral GaM or distilled water. The authors believe that this is the first report on the safety of GaM therapy in neonates of any species. Rhodococcus equi is a facultative intracellular bacterium that causes severe bronchopneumonia in foals and immunocompromised people (Giguere & Prescott, 1997). Most foals appear to become infected within the first few days of life (Horowitz et al., 2001), when they may have immature or ineffective immune responses (Boyd et al., 2003; Chaffin et al., 2004). Because the J. vet. Pharmacol. Therap. 33, 208–212, doi: 10.1111/j.1365-2885.2009.01121.x. SHORT COMMUNICATION