Bloodstream infections in patients with hematological malignancies

Abstract: Patients with hematological malignancies have an increased risk of infectious complications. These complications can be caused by disease-specific factors or be treatment-related. Bloodstream infections increase the risk of morbidity, mortality, have a negative impact on quality of life, and may lead to reductions in treatment intensity. Surveillance studies on infectious complications and new technologies in diagnosing bloodstream infections are two important fields in improving management of patients with hematological malignancies. Paper I: This is a retrospective study of positive blood cultures from patients mainly treated with dose-intensive antitumoural treatment between 2002 and 2008. Bacterial distribution, bacterial resistance and mortality from 667 fever episodes are presented. Results are compared with historical, previous published, material from the same institution and setting. Subsequently, temporal trends from 1980 to 2008 could be analysed. In a setting with very low use of fluoroquinolone-prophylaxis it can be concluded that; the distribution of Gram-positive bacteremia is stable, the crude mortality remains low in an international perspective and acquired resistance is uncommon but a significant increase in ciprofloxacin resistance in Escherichia coli is observed. The five most common bacteria in the study are; E. coli, coagulase-negative staphylococci, viridans streptococci, Klebsiella spp., and Staphylococcus aureus. Paper II: This is a retrospective study that investigated temporal trends in bloodstream infections in patients with chronic lymphocytic leukemia between 1988-2008. We find a decrease in positive blood cultures over time and speculate if this could be due to more effective antitumoural treatment in recent years. Moreover a bloodstream infection is, as intuitively foreseen, associated with worse prognosis. Dominating pathogens in the study are; E. coli, Streptococcus pneumoniae, P. aeruginosa, S. aureus, and viridans streptococci. Coagulase-negative staphylococcus, a common skin contaminant, is the most frequently detected bacteria. Paper III: This is a prospective study of 33 patients with aggressive hematological malignancies in need of dose-intensive chemotherapy. One hundred thirty blood samples were collected at different time points during episodes with neutropenia and fever between 2013 and 2014. Conventional blood culture findings were compared with a method applicable also for unculturable bacteria, 16S rRNA amplicon sequencing. Sequencing yielded reads belonging to Proteobacteria (55.2%), Firmicutes (33.4%), Actinobacteria (8.6%), Fusobacteria (0.4%), and Bacteroidetes (0.1%). The results display a much broader diversity of bacteria in bloodstream infections than expected. Changes in the relative abundance in the sequence data after commencement of antibiotics could be suggestive for a new method for estimating antibiotic efficacy. Lastly, the results are indicative for translocation, especially of gut microbiota, playing an important etiological factor in fever episodes in the neutropenic host. Paper IV: This is a prospective study of 9 patients with acute leukemia in which we applied shotgun metagenomics for 27 blood samples collected during episodes of neutropenia and fever between 2013 and 2014. Shotgun metagenomics can characterize DNAemia and reconstruct unculturable microbial communities, resistance markers and gene ontology. The study confirms the method’s applicability in bloodstream infections demonstrating bacteria, viruses and fungi. Furthermore, the observed dynamics of microbe sequences during fever episodes as well as gene ontology makes this diagnostic approach appealing for exploring the fever episodes in this patient category.