Acinetobacter Baumannii Response to Cefiderocol Challenge in Human Urine

Abstract Cefiderocol (CFDC) is a novel chlorocatechol-substituted siderophore cephalosporin, approved by the Food and Drug Administration (FDA) for treating complicated urinary tract infections and for hospital-acquired and ventilator-acquired pneumonia. In previous work, human serum, human serum albumin,HSA, and human pleural fluid, HPF, were shown to increase the minimum inhibitory concentration (MICs) of Acinetobacter baumannii against CFDC. These fluids are also associated with a reduction in the expression of genes related to iron uptake systems, which could explain the need for higher concentrations of CFDC to exert inhibitory action. Herein, we analyzed the impact of human urine (HU), which contains low albumin concentrations, on the expression of iron-uptake related genes and MIC values of two carbapenem-resistant A. baumannii. Levels of resistance to CFDC were not modified by HU in strain AMA40 but were reduced in the case of strain AB5075. Testing other carbapenem-resistant A. baumannii isolates showed that the CFDC MICs were unmodified or reduced in the presence of HU. The expression of piuA, pirA, bauA, and bfnH determined by qRT-PCR was enhanced in both strains when HU was present in the culture medium. All four tested genes are involved in recognizing ferric siderophore complexes or internalization into the cell’s cytosol. In contrast, the effect of HU on genes associated with resistance to β-lactams, antibiotics commonly used to treat urinary tract infections caused by A. baumannii, was variable; the transcriptional analysis of pbp1, pbp3, blaOXA−51−like, blaADC, and blaNDM−1 showed significant variation. In summary, HU, probably due to the albumin and free iron content, does not adversely impact or slightly improves the activity of CFDC when tested against A. baumannii in urine in contrast to other human bodily fluids.