Background: Broad-spectrum antibiotics are often used for suspected infections in patients with hematologic malignancies due to the risk of severe infections. Although antibiotic use can lead to antimicrobial resistance and microbiome dysbiosis, the effects of antibiotics on the microbiome and resistome in patients with acute myeloid leukemia (AML) undergoing remission induction chemotherapy (RIC) are not well understood. Methods: Various statistical models were utilized to examine the effects of antibiotic administration on the microbiome and resistome over time, as well as differences in AR-infection (ARI) and colonization (ARC) by important CDC-threats in 119 AML patients. Results: A greater number of unique antibiotic classes administered correlated with a loss of unique antibiotic resistance genes (ARGs) (R = −0.39, p = 0.008). Specifically, although a greater number of oxazolidinone administrations was correlated with a greater loss of diversity (R = −0.58, p < 0.001), each additional day of linezolid reduced the risk of ARC by ~30% (HR: 0.663, p = 0.047) and decreased the odds of acquiring genes predicted to confer macrolide (HR: 0.50, p = 0.026) resistance. Conclusions: The number of antibiotic administrations and the types of antibiotics used can influence the risk of antibiotic resistance gene (ARG) expansion and ARC events in AML patients undergoing RIC. While certain antibiotics may reduce microbial diversity, they are not always linked to an increase in ARGs or ARC events.

Bloodstream infections (BSIs) are a major cause of morbidity and mortality in acute myeloid leukemia (AML) patients undergoing induction chemotherapy. Staphylococcus epidermidis, typically a skin commensal, is increasingly recognized as a pathogen in these vulnerable individuals. This study investigated whether genomic differences exist between infectious and gastrointestinal colonizing S. epidermidis isolates from AML patients and how these compare to colonizing and infectious isolates from other patient groups and biogeographic sites. We analyzed 114 isolates—44 from AML patients (23 infections, 21 GI colonizers) and 70 from public datasets (34 infections, 36 colonizers). Stool samples underwent 16S rRNA sequencing and culture to identify colonization, while bloodstream isolates were sequenced and compared. Genomic profiling using Roary, Scoary, Phyre2, and InterProScan revealed that infectious and GI-colonizing AML isolates were phylogenetically close but genomically distinct. Infectious isolates from AML patients were significantly enriched for resistance genes (e.g., mecA, mecR1, mecI, ANT(4′)-Ib) and the biofilm-associated gene icaA. AML infectious isolates harbored more resistance genes and mobile elements than non-AML strains but lacked widespread classical virulence factors. These results suggest that S. epidermidis pathogenicity in immunocompromised hosts is driven by genomic adaptability and antibiotic tolerance rather than traditional virulence mechanisms.