Abstract 1678: Systemic gallium nitrate therapy results in sustained sputum concentrations that may be therapeutic for biofilm-associated pulmonary bacterial infections

Abstract

Abstract Background: The formation of polymeric biofilms represents an important defense mechanism evolved by planktonic bacteria. Bacteria living in biofilms may resist killing by standard antiinfective agents despite nominal in vitro sensitivity owing in part to reduced drug penetration. Elemental iron is an essential nutrient for most infectious organisms. Agents that sequester iron have been tested experimentally with initially favorable results in serious infections, including Pseudomonas aeruginosa. Kaneko et al (J Clin Invest 117;877, 2007) proposed the use of ionic gallium as a potential antiinfective that interferes with iron metabolism and showed that gallium solutions (0.5-10 μM; 1 μg/ml=14.5 μM) disrupted biofilms produced by P. aeruginosa and resulted in collapse of resistant bacterial colonies. They speculated that an aerosolized gallium solution might be useful for P. aeruginosa pulmonary infections. Due to variability of drug dispersion within diseased pulmonary tissue, we speculated that systemic therapy with a gallium-containing solution could achieve potentially therapeutic levels in sputum of infected patients. Methods: A 31-year old man with end-stage cystic fibrosis lung disease (FEV1 20%) and highly resistant P. aeruginosa was treated on an investigational basis with several cycles of gallium nitrate (Ganite®), an agent for the treatment of hypercalcemia of malignancy. The drug was given by continuous IV infusion for 5 days at doses ranging from approximately 100 to 250 mg/m2/d. In 2 cycles, serial samples of expectorated sputum and whole blood or plasma were obtained and assayed for gallium concentration by ICP/MS. Informed consent and ethical approval were obtained. Results: After the first drug infusion (150 mg/m2/d for 5 days), sputum gallium concentration from a single sample was unexpectedly high (2.2 μg/ml) relative to previously reported blood concentrations. Approximately 1 month later, a sputum concentration was still measurable (0.32 μg/ml), and the patient was retreated at a dose of 200 mg/m2/d for 5 days. Paired sputum samples on day 5 showed gallium levels of 2.13 and 2.65 μg/ml, respectively, whereas simultaneous measurements of gallium in plasma and whole blood were 1.35 and 1.64 μg/ml, respectively. Despite a previously reported plasma T1/2 ∼ 12 h, serial measurements after the drug infusion showed a progressive increase in sputum gallium concentration on days 6, 7, 9, and 11 (1.83, 2.04, 4.35, and 4.78 μg/ml, respectively). Conclusions: Gallium appears to be preferentially concentrated in infected sputum. This effect increases and remains sustained post therapy, suggesting that transport across a gradient can be maintained for a prolonged period. Systemic gallium therapy achieves sputum drug levels that may be therapeutic for highly resistant bacteria associated with biofilm formation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1678.