Bloodstream infections in patients with hematological malignancies

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

Multiple myeloma and infections: a population-based study on 9253 multiple myeloma patients.

Infections are a major cause of morbidity and mortality in patients with multiple myeloma. To estimate the risk of bacterial and viral infections in multiple myeloma patients, we used population-based data from Sweden to identify all multiple myeloma patients (n=9 253) diagnosed from 1988 to 2004 with follow-up to 2007 and 34 931 matched controls. Cox proportional hazard models were used to estimate the risk of infections. Overall, multiple myeloma patients had a 7-fold (hazard ratio =7.1; 95% confidence interval = 6.8-7.4) risk of developing any infection compared to matched controls. The increased risk of developing a bacterial infection was 7-fold (7.1; 6.8-7.4), and for viral infections 10-fold (10.0; 8.9-11.4). Multiple myeloma patients diagnosed in the more recent calendar periods had significantly higher risk of infections compared to controls (p<0.001). At one year of follow-up, infection was the underlying cause in 22% of deaths in multiple myeloma patients. Mortality due to infections remained constant during the study period. Our findings confirm that infections represent a major threat to multiple myeloma patients. The effect on infectious complications due to novel drugs introduced in the treatment of multiple myeloma needs to be established and trials on prophylactic measures are needed

Bacterial Landscape of Bloodstream Infections in Neutropenic Patients via High Throughput Sequencing

<div><p>Background</p><p>Bloodstream infection (BSI) is a common and potentially life-threatening complication in patients with hematological malignancies and therapy-induced neutropenia. Administration of broad spectrum antibiotics has substantially decreased the mortality rate in febrile neutropenia, but bacterial infection is documented in only one-third or fewer of the cases. BSI is typically diagnosed by blood culture; however, this method can detect only culturable pathogens.</p><p>Methods</p><p>In the present study, a total of 130 blood samples from hematological patients receiving dose-intensive antitumoural treatment were subjected to 16S rRNA PCR and 62 of them were cultured. PCR positive samples were processed to high throughput sequencing by amplifying the V1-V3 regions of the 16S rRNA gene to obtain a full spectrum of bacteria present in BSI.</p><p>Results</p><p>Five phyla and 30 genera were identified with sequencing compared to 2 phyla and 4 genera with culture. The largest proportion of bacteria detected by sequencing belonged to Proteobacteria (55.2%), Firmicutes (33.4%) and Actinobacteria (8.6%), while Fusobacteria (0.4%) and Bacteroidetes (0.1%) were also detected. Ninety-eight percent of the bacteria identified by sequencing were opportunistic human pathogens and 65% belonged to the normal human microbiota.</p><p>Conclusions</p><p>The present study indicates that BSIs in neutropenic hosts contain a much broader diversity of bacteria, likely with host origin, than previously realized. The elevated ratio of Proteobacteria in BSI corroborates the results found in other systemic inflammatory diseases, such as inflammatory bowel disease or mucosal infections. This knowledge may become of value for tailoring antimicrobial drug administration.</p></div

Composition of microbiota from different parts of the body classified by four major bacterial phyla.

<p>The graph was reconstructed based on the data from [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0135756#pone.0135756.ref044" target="_blank">44</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0135756#pone.0135756.ref045" target="_blank">45</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0135756#pone.0135756.ref051" target="_blank">51</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0135756#pone.0135756.ref053" target="_blank">53</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0135756#pone.0135756.ref055" target="_blank">55</a>]. Axes show percentages.</p

Schematic representation of microorganisms detected by sequencing on the species level.

<p>Pink nodes represent the given genera connected to the species. Green lines indicate the most prevalent species. Color lines from Bacteria to genera indicate phyla (Proteobacteria-yellow, Firmicutes-light blue, Actinobacteria-dark blue, Bacteroidetes-purple, Fusobacterium-orange). Species nodes indicate infectious properties: yellow-normal microbiota, red-human pathogen, blue-typically occurs in immunocompromised patients and/or nosocomial infections, white: taxonomy unclear/recently changed or environmental bacteria.</p

Bloodstream infections in patients with chronic lymphocytic leukemia: a longitudinal single-center study.

To access publisher's full text version of this article click on the hyperlink at the bottom of the pageInfectious complications in chronic lymphocytic leukemia (CLL) represent a major cause of morbidity and mortality. The aim of the study was to investigate temporal trends in bloodstream infections (BSIs) among patients with CLL. Individuals with blood cultures were linked to Swedish Cancer Registry and divided into three time periods (1988-1993, 1994-1999, and 2000-2006) according to year of CLL diagnosis. CLL patients (n = 275) with 1092 blood culture episodes were identified and linked to the nationwide Cause of Death Registry and Swedish Patient Registry (to retrieve information on splenectomies). The most common causes of BSI among CLL patients were Escherichia coli (11/43, 15/78, and 9/33), Streptococcus pneumoniae (7/43, 13/78, and 6/33), Pseudomonas aeruginosa (2/43, 8/78, and 3/33), Staphylococcus aureus (1/43, 6/78, and 6/33), and Viridans streptococci (5/43, 6/78, and 2/33). Coagulase-negative staphylococci was the most frequent microorganism found in blood cultures (22/70, 23/106, and 5/41, respectively) but is a frequent contaminant. Based on the largest study to date on BSI in CLL patients, we found a stable proportion of Gram-positive to Gram-negative bacteria and no temporal change of distribution was observed for BSIs 1988-2006

Heat map showing 3 pairs of samples before and after antibiotic treatment with the corresponding clinical characteristics (follow up: 1 day for samples 48/49 and 54/55, 5 days for samples 120/129).

<p>Bacteria were detected in all cases, but in 2 pairs (48–49, 120–129), the composition of bacteria changed, while in one patient (54–55), the composition of bacteria remained the same despite of antibiotic treatment. Blue ellipses indicate culture results. N/A: not available.</p

Representation of the distribution of phyla with sequencing in all samples (a) and in individual samples (b). Detected phyla per sample with blood culture (c).

<p>Representation of the distribution of phyla with sequencing in all samples (a) and in individual samples (b). Detected phyla per sample with blood culture (c).</p

Occurrence of genera in 19 samples identified by sequencing (a). A genus was included if it reached or exceeded 0.5% of the total number of filtered reads in at least one sample. Distribution of OTU-assigned reads per genera in all samples in percentage (b). Diagram shows the pathogenicity and natural habitat of the detected genera based on read percentages (c). Over 96% of the identified reads belonged to opportunistic human pathogens (black stripes), while 64% belonged to the normal human microbiota (grey background).

<p>Occurrence of genera in 19 samples identified by sequencing (a). A genus was included if it reached or exceeded 0.5% of the total number of filtered reads in at least one sample. Distribution of OTU-assigned reads per genera in all samples in percentage (b). Diagram shows the pathogenicity and natural habitat of the detected genera based on read percentages (c). Over 96% of the identified reads belonged to opportunistic human pathogens (black stripes), while 64% belonged to the normal human microbiota (grey background).</p

Idelalisib (PI3Kδ inhibitor) therapy for patients with relapsed/refractory chronic lymphocytic leukemia : A Swedish nation-wide real-world report on consecutively identified patients

Objectives We examined the efficacy and toxicity of the PI3Kδ inhibitor idelalisib in combination with rituximab salvage therapy in consecutively identified Swedish patients with chronic lymphocytic leukemia (CLL). Methods and Results Thirty-seven patients with relapsed/refractory disease were included. The median number of prior lines of therapy was 3 (range 1–11); the median age was 69 years (range 50–89); 22% had Cumulative Illness Rating Scale (CIRS) &gt;6 and 51% had del(17p)/TP53 mutation. The overall response rate was 65% (all but one was partial response [PR]). The median duration of therapy was 9.8 months (range 0.9–44.8). The median progression-free survival was 16.4 months (95% CI: 10.4–26.3) and median overall survival had not been reached (75% remained alive at 24 months of follow-up). The most common reason for cessation of therapy was colitis (n = 8, of which seven patients experienced grade ≥3 colitis). The most common serious adverse event was grade ≥3 infection, which occurred in 24 patients (65%). Conclusions Our real-world results suggest that idelalisib is an effective and relatively safe treatment for patients with advanced-stage CLL when no other therapies exist. Alternative dosing regimens and new PI3K inhibitors should be explored, particularly in patients who are double-refractory to inhibitors of BTK and Bcl-2