Abstract
Critically ill patients often present with low serum iron levels or anemia. We evaluated the impact of iron levels and iron homeostasis on the efficacy and safety of cefiderocol, an iron-chelator siderophore cephalosporin, in patients with nosocomial pneumonia in a post hoc analysis of the randomized, double-blind, Phase 3 APEKS-NP study (NCT03032380). Patients with Gram-negative nosocomial pneumonia received cefiderocol 2 g, 3-h infusion, q8h, or high-dose, extended-infusion meropenem 2 g, 3-h infusion, q8h, for 7–14 days. Efficacy and safety parameters, including specific iron homeostasis parameters (i.e., hepcidin, iron, total iron binding capacity, transferrin saturation), were analyzed according to baseline iron levels. In the cefiderocol and meropenem arms, 79.1% (117/148) and 83.3% (125/150) randomized patients, respectively, had low baseline serum iron levels. Rates of 14-day (12.3% [14/114] vs 11.6% [14/121]) and 28-day all-cause mortality (20.5% [23/112] vs 19.0% [23/121]), clinical cure (63.2% [72/114] vs 67.2% [82/122]), and microbiological eradication (43.6% [41/94] vs 48.1% [51/106]) at test of cure were similar in cefiderocol vs meropenem arms, respectively. In the overall safety population, rates of anemia-related adverse events were similar (cefiderocol arm 18.2% [27/148], meropenem arm 18.7% [28/150]). Changes from baseline to test of cure in hepcidin, iron, total iron binding capacity, and transferrin saturation were similar between treatment arms. Cefiderocol treatment did not affect iron homeostasis, and its efficacy and safety were not influenced by baseline serum iron levels. Clinicaltrials.gov registration: NCT03032380. Date of registration: 26 January 2017.
Highlights
Iron is an essential nutrient for both humans under physiological conditions and for pathogenic bacteria during infection [1,2,3]
298 patients were randomized in the ITT/safety population in the APEKS-NP study
In the subgroup of patients with available baseline iron levels, there were some numerical differences at baseline between low and normal iron level groups (Table 1), with low iron levels being more common among males, patients ventilated at randomization, and patients admitted to the intensive care unit
Summary
Iron is an essential nutrient for both humans under physiological conditions and for pathogenic bacteria during infection [1,2,3]. Iron is mainly stored intracellularly in erythrocytes, or is bound in the plasma to transferrin, which has a high affinity for ferric iron (Fe3+) [1, 3]. Following an insult, such as an infection, iron homeostasis is disrupted, and nutritional immunity is enhanced [1, 4]. Reduced iron availability at the infection site has the potential to decrease growth and virulence of pathogenic bacteria [1]
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