Impact of iron limitation on in vitro and in vivo activity of ceftazidime against A. baumannii

Acinetobacter baumannii (AB) is known to have high rates of multidrug resistance (MDR); new treatment options are critically needed to prevent further spread and mortality. Deferiprone, a metal chelator, has been shown to induce transient growth inhibition in previous studies, and this could be potentially exploited for therapeutic purposes. This study was to examine the impact of iron limitation on the in vitro and in vivo activity of ceftazidime against four clinical MDR AB isolates. Ceftazidime minimal inhibitory concentration was determined by microbroth dilution in the presence of deferiprone. In vitro growth profiles were discerned longitudinally over 20 hours. The effect of deferiprone (1000μM) and ceftazidime (128μg/ml) on bacterial growth was studied either alone or in combination. A neutropenic pneumonia mouse model was used for in vivo validation; mice were infected with approximately 6 log CFU (with and without deferiprone). A humanized regimen of ceftazidime was used to mimic a human dose of 2g. The bacterial burden of lung tissue was determined immediately and 8h post-infection. Ceftazidime MIC was reduced from > 256μg/mL to 1μg/mL, in the presence 1500μM of deferiprone. In vitro, a combination of ceftazidime and deferiprone resulted in minimal growth over time. The lung bacterial burden of the ceftazidime alone group increased significantly, while the combination group (ceftazidime + deferiprone) stayed comparable to baseline. Limiting iron has the potential to be a novel approach to treating MDR AB infections and further research is warranted.