Pseudomonas aeruginosa is a well-known cause of severe and potentially life-threatening infections among hematological patients. A prospective epidemiological surveillance program ongoing at our Hematology Unit revealed an increase over time of P. aeruginosa bloodstream infections (BSI). Their impact on outcome and antibiotic susceptibility was analyzed. BSI which consecutively occurred at our institution during a 70-month period were evaluated and correlated with type of pathogen, status of underlying disease, neutropenia, previous antibiotic therapy, resistance to antibiotics, and outcome. During the observation period, 441 BSI were recorded. Frequency of Gram-negative BSI was higher than that of other pathogens (57.3%). Overall, 66 P. aeruginosa BSI were recorded; 22 out of 66 were multiresistant (MR P. aeruginosa). Thirty-day mortality for all BSI was 11.3%; it was 27.3% for P. aeruginosa BSI and 36.4% for MR P. aeruginosa. At multivariate analysis, only active hematological disease and P. aeruginosa BSI were associated to an increased risk of death. For MR P. aeruginosa, BSI mortality was 83.3% vs. 18.8% when empiric therapy included or not an antibiotic with in vitro activity against P. aeruginosa (p=0.011). Together with active disease, the emergence of P. aeruginosa BSI, particularly if multiresistant, was responsible for an increased risk of death among hematological patients at our institution. In this scenario, reconsidering the type of combination antibiotic therapy to be used as empiric treatment of neutropenic fever was worthwhile.

Although rare, nocardiosis should be considered in the differential diagnosis of pulmonary and central nervous system lesions among hematological patients. Lymphoproliferative disorders, prolonged steroid treatment, lymphopenia, and active hematological disease are the conditions that are worth considering as predisposing factors for the development of this disease.

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Acute leukemia (AL) patients may experience more than one episode of bloodstream infection (BSI) caused by the same pathogen during the entire chemotherapy program. In order to identify factors influencing BSI recurrence (R-BSI) during subsequent phases of treatment, we analyzed all BSIs occurring to consecutively treated AL patients during a period of active epidemiologic surveillance at our institution between 2004 and 2011. Two hundred and fifty BSIs were observed in 138 patients receiving more than 1 cycle of chemotherapy. BSI due to the same pathogen recurred in 39/138 (28.3 %) patients. Gram-negative rods (GNRs) accounted for 59.6 % and Gram-positive cocci (GPCs) for 34.4 % of BSI. Four pathogens were involved in R-BSI: Escherichia coli, Pseudomonas aeruginosa, coagulase-negative staphylococci, and Streptococcus viridans. GNRs were significantly more frequent among R-BSI compared to non-relapsing BSI (nR-BSI) [69/94 (73.4 %) vs 70/156 (50.6 %), p < 0.0001]; in particular, E. coli accounted for 67 % of R-BSI vs 32.1 % of nR-BSI (p < 0.0001). Receiving more than four chemotherapy courses and having an extended spectrum β-lactamase (ESBL)-producing E. coli BSI at any time of treatment were significantly associated to R-BSI. A trend toward a higher mortality among R-BSI patients in comparison with nR-BSI was observed (17.9 and 7.1 %, respectively, p = 0.12). Among AL patients, R-BSI is a frequent phenomenon, which may contribute to the shift of epidemiology toward GNR and to a higher mortality. This should significantly impact the strategies of antibiotic prophylaxis and treatment in patients with AL.

Introduction The efficacy of posaconazole prophylaxis against invasive fungal infection (IFI) in acute myeloid leukemia (AML) patients during induction therapy has been demonstrated both in randomized and real-life studies. Absorption of posaconazole is enhanced by food intake, which may be impaired by gastrointestinal mucositis. However, correlation between posaconazole serum levels and breakthrough IFI has not been clearly demonstrated and the usefulness of therapeutic drug monitoring (TDM) is still a matter of debate. Aims In order to clarify the role of posaconazole TDM in preventing opportunistic infections, we correlated posaconazole serum levels with the incidence of breakthrough proven/probable IFI and the need for empiric/pre-emptive/targeted antifungal therapy among AML induction patients. A comparative analysis with an historical cohort receiving mainly itraconazole prophylaxis was also performed. Patients and Methods Since June 2004 a program of active epidemiological surveillance is ongoing at our Institute. Posaconazole prophylaxis was routinely introduced among AML induction patients on July 2011; data concerning incidence of IFI during AML induction were extracted from two consecutive periods (Jul2009-Jun2011 and Jul2011-Jun2013). Patients received posaconazole at 200 mg three times a day; 1st serum posaconazole level was determined on day 7 and repeated every 7 days. A serum level ≥500 ng/mL was considered adequate. Serum galactomannan (GM) was monitored two times a week; thorax CT scan was performed within 3 days from the onset of fever. Systemic antifungal therapy was started empirically, in the case of persistent fever, with or without radiological signs of fungal infections. Results Overall, 120 AML patients were evaluated, 60 in both periods. The two cohorts did not differ in median age, M/F ratio and type of treatment. During the 1st period 9/60 (15%) breakthrough IFI (2 candidemia, 7 aspergillosis) were observed, as compared to 2/60 (3.3%) in the 2nd period (1 candidemia and 1 aspergillosis), p=0.027 (Chi-square test). In all but one cases of aspergillosis, GM positivity was the microbiological criterion to meet the diagnosis of probable/proven IFI. The need for systemic antifungal therapy was similar in both periods (40% and 38.3%, respectively). Posaconazole serum levels was available in 50/60 patients (83%) during the 2nd period. Mean serum concentration did not change significantly over time (mean value±SE: 551±48.7 543±64, 643±107.4, 698±164.7 at 1st, 2nd, 3rd, 4th week of therapy respectively, p=0.64). Adequate serum levels throughout the induction period were maintained in 19 cases (38%). None of them developed IFI. Posaconazole serum level was below the therapeutic threshold in the patient developing candidemia and not evaluable in the one who developed pulmonary aspergillosis 3 days after starting posaconazole prophylaxis. Systemic antifungal therapy, was given to 4/19 (21.1%) patients with persistently adequate posaconazole serum levels as compared to 13/31 (41.3%) patients with at least 1 posaconazole serum level below the therapeutic threshold (p=0.13). Conclusions Our study confirms that posaconazole prophylaxis significantly reduces the incidence of proven/probable breakthrough IFI, particularly aspergillosis, in a “real life” setting. No patient with persistently adequate posaconazole serum levels developed IFI. In this subgroup the need for systemic antifungal therapy was halved compared to patients with below-target posaconazole serum levels. Weather the reduced sensitivity of diagnostic biomarker tests due to azole prophylaxis may contribute to underestimate a diagnosis of IFI remains an open question. Disclosures: No relevant conflicts of interest to declare.

Background: Although a complete remission (CR) can be achieved in 70-80% of newly diagnosed acute myeloid leukemia (AML) patients, relapses occur in up to the 50% of cases. Thus, minimal residual disease (MRD) monitoring is a major issue for early detection of patients at high-risk of treatment failure and relapse. Aim: to dynamically evaluate WT1 pan-leukemic molecular marker of MRD in patients with AML. Matherial and methods: 107 newly diagnosed AML patients consecutively treated between 2010 and 2013 were monitored with quantitative WT-1 from bone marrow (BM) and peripheral blood (PB) at baseline, after induction, after the first consolidation course, before allogeneic stem cell transplantation (allo-SCT), at the 3rd and the 6th month after transplantation Results: At diagnosis, 104/107 (97%) had increased PB and BM WT1 levels assessed according to the ELN assay. Eighty-eight out of 107 patients (82%) achieved a complete remission (CR) after induction, 30/88 (34%) relapsed during follow up and 24/107 (22%) were addressed to allogeneic stem cell transplantation (allo-SCT). By univariate analysis, PB-WT > 50x10^4/ABL and BM-WT1 > 250x10^4/ABL after induction (PB: p=0.02; BM: p=0.04), after consolidation (PB: p=0.003), at the end of treatment (PB and BM: p=0.001), at 3rd month of follow up (PB and BM: p=0.005) and at 6th month of follow up (PB: p=0.005) were associated with a reduced overall survival (OS). By multivariate analysis, a BM-WT1 > 250 x 10^4/ABL at the end of treatment was significantly associated with a reduced OS. In order to adapt the cut-off of WT1 in our series of patients, we considered WT1 levels as continuous variables and categorized them at approximately the 25th, 50th, and 75th percentile. A cut-off of PB-WT1 > 25x10^4/ABL and BM-WT1 > 125x10^4/ABL at the end of the treatment program was identified as correlated with reduced leukemia-free survival (LFS) and OS (p=0.001). Similarly, and restricting the analysis on the 24 patients allo-transplanted in CR, 8/11 (73%) with pre-transplant PB-WT1 ≥ 5 and 4/13 (31%) with PB-WT1 < 5 relapsed, respectively (p=0.04). The incidence of relapse was higher in AML patients with PB-WT1 ≥ 5 measured at 3rd (56% vs 38%; p=0.43) and 6th month (71% vs 20%; p=0.03) after allo-SCT. Interestingly, 5/5 (100%) patients with pre-transplant PB-WT1 ≥ 5 who never reduced this level at 3rd or 6th month after allo-SCT experienced a disease recurrence. Conclusions: our data, although retrospectively collected, show that WT1 monitoring may be useful to predict the relapse in AML patients. Acknowledgments: This work was supported in part by Banca di Credito Cooperativo di Pompiano e Franciacorta and Lions Club Bassa Bresciana Association. Disclosures Russo: Celgene: Research Funding; Gilead: Research Funding; Novartis: Consultancy.

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