Treatment-emergent cefiderocol resistance in carbapenem-resistant Acinetobacter baumannii is associated with insertion sequence ISAba36 in the siderophore receptor pirA.

We report the emergence of cefiderocol resistance in a blaOXA-72 carbapenem-resistant Acinetobacter baumannii isolate from a sacral decubitus ulcer. Cefiderocol was initially used; however, a newly approved sulbactam-durlobactam therapy with source control and flap coverage was successful in treating the infection. Laboratory investigation revealed cefiderocol resistance mediated by ISAba36 insertion into the siderophore receptor pirA.

Exploration of the Role of the C-Terminal Domain of Human DNA Topoisomerase IIα in Catalytic Activity.

Human topoisomerase IIα (TOP2A) is a vital nuclear enzyme involved in resolving knots and tangles in DNA during replication and cell division. TOP2A is a homodimer with a symmetrical, multidomain structure. While the N-terminal and core regions of the protein are well-studied, the C-terminal domain is poorly understood but is involved in enzyme regulation and is predicted to be intrinsically disordered. In addition, it appears to be a major region of post-translational modification and includes several Ser and Thr residues, many of which have not been studied for biochemical effects. Therefore, we generated a series of human TOP2A mutants where we changed specific Ser and Thr residues in the C-terminal domain to Ala, Gly, or Ile residues. We designed, purified, and examined 11 mutant TOP2A enzymes. The amino acid changes were made between positions 1272 and 1525 with 1-7 residues changed per mutant. Several mutants displayed increased levels of DNA cleavage without displaying any change in plasmid DNA relaxation or DNA binding. For example, mutations in the regions 1272-1279, 1324-1343, 1351-1365, and 1374-1377 produced 2-3 times more DNA cleavage in the presence of etoposide than wild-type TOP2A. Further, several mutants displayed changes in relaxation and/or decatenation activity. Together, these results support previous findings that the C-terminal domain of TOP2A influences catalytic activity and interacts with the substrate DNA. Furthermore, we hypothesize that it may be possible to regulate the enzyme by targeting positions in the C-terminal domain. Because the C-terminal domain differs between the two human TOP2 isoforms, this strategy may provide a means for selectively targeting TOP2A for therapeutic inhibition. Additional studies are warranted to explore these results in more detail.

Safety, Efficacy, and Effectiveness of Delabeling in Patients with Multiple Drug Allergy Labels.

BACKGROUND: Patients with multiple drug allergy labels (MDALs) present a challenging barrier to patient care. OBJECTIVE: To assess the efficacy, safety, and effectiveness of removing MDALs in a single clinic visit. METHODS: Retrospective chart review was performed from October 1, 2014, to October 31, 2018, on patients with MDALs who had electronic health record (EHR) allergy label to 2 or more drugs and who were delabeled to 1 or more drug. Our primary outcome was the number of allergy labels tested and removed, at a single or multiple visits. Postvisit surveys were administered to patients, their pharmacies, and primary care physicians for patients delabeled following an EHR transition from November 2, 2017, to October 31, 2018 (n = 184). RESULTS: Among 536 patients meeting inclusion criteria, 916 of 943 (97.1%) tested allergy labels were removed from the EHR. Most patients, 461 of 536 (86.0%), were tested, challenged, and delabeled in a single visit, to 1 or more drug, although 134 of 536 (25%) still had evidence of 1 or more label at 1 year. In surveys, 90 of 171 (52.6%) responding pharmacies and 122 of 168 (72.6%) primary care physicians contacted had removed drug labels from the EHR as a result of the recommendations from the patient's drug allergy evaluation. Overall, 91 of 142 (64.1%) MDAL patient survey respondents were willing to take the drugs to which they had been delabeled. CONCLUSIONS: Patients with MDALs can be safely delabeled to multiple drugs in 1 visit; however, effectiveness barriers were identified. Reinforcement of drug allergy label removal information to patients, pharmacies, and primary care providers presents a targeted area for improvement.