Bacteremia in patients with hematological malignancies and neutropenia

Abstract

For hematological cancer patients, the risk of blood stream infection by bacterial pathogens is increased. Studies on pathogen panorama, efficacy of antimicrobial prophylaxis and antimicrobial resistance are important efforts to decrease morbidity, mortality and the risk of delays or reduction of intensity in cancer treatment. There is a need for continuous development of new techniques for diagnosing infections. In this research project we seek to expand the knowledge base to future improvements in clinical management of bacterial bloodstream infections during neutropenia, The studies focus on local bacterial distribution and antibiotic resistance patterns by applying new means for diagnostics with Next Generation Sequencing (NGS) and evaluates the effects of prophylactic antibiotic treatment.

Study I: Totally, 142 episodes of fever from 124 neutropenic patients with different hematological malignancies were analyzed, and bacterial blood stream infections were found in 27% of the cases. In 58% of these Gram-positive bacteria could be isolated and Viridans streptococci, CoNS and E. coli were most common. A negative association between bacterial blood stream infection and non-Hodgkin´s lymphoma as underlying diagnosis were noted (p = 0.01). The bacterial distribution was coherent to contemporary reports from Scandinavia and antimicrobial resistance levels were lower compared to centers in Europe. No significant protective effect of antibiotic prophylaxis with ciprofloxacin could be detected in this heterogenous material, which led to a more comprehensive investigation in Study II: Aiming to further evaluate the effects of ciprofloxacin prophylaxis during the course of cancer treatment, 666 episodes (235 with and 431 without prophylactic ciprofloxacin treatment) of treatment-induced neutropenia in 245 Swedish adult Acute Myeloid Leukemia patients were compared. Ciprofloxacin seemed to have good prophylactic effect with reduced incidence of fever and bacteremia in this group and should be considered at least in the initial cycles of chemotherapy.

In Study III, 130 blood samples from 33 hematological cancer patients with intensive chemotherapy were included prospectively. Samples from different time points during febrile neutropenia were collected and analyzed with 16S rRNA amplicon sequencing. For 62 samples, blood culture findings were compared with sequencing results. The high-throughput sequencing yielded reads with slight overweight to Gram negative bacteria (55.7%). In total, the reads detected were distributed over 55% Proteobacteria, 33% Firmicutes, 9% Actinobacteria. 0.4% Fusobacteria and 0.1% Bacteroidetes. A more diversified bacterial panorama than expected was revealed but, with low concordance between blood cultures and NGS, and, the results indicate that bacterial translocation is important as etiological factor in febrile neutropenia.

Study IV: In this study Shotgun metagenomics were applied for 27 blood samples collected during febrile neutropenia in nine acute leukemia patients. Even though the applied method needs development on several points, the study indicates the techniques applicability for diagnostics in bloodstream infections and reveals pathogenic dynamics during fever episodes that may become of value for more targeted antimicrobial strategies for this patient group.