Search

Invasive pulmonary aspergillosis (IPA) has dire consequences in hemato-oncological patients. We report our experience with performing routine baseline chest computed tomography for early diagnosis of IPA. We found high rates of proven or probable IPA diagnosed on admission among patients with newly diagnosed acute myeloid leukemia.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is widely utilized as a curative treatment for malignant and non-malignant hematological conditions. Fluoroquinolone prophylaxis (FQ-P) is demonstrated to reduce the rate of blood stream infections (BSI) caused by gram-negative bacteria (GNB) during allo-HSCT and increases overall survival (OS), making this approach the standard of care. The available data show that during the transplantation period, the intestinal microbiome diversity profoundly decreases, which is associated with a significant increase in transplant-related mortality (TRM), acute graft-versus-host disease (aGVHD) related mortality and decrease in OS. FQ-P is reported to be a dominant factor in the perturbation of the gut microbiota, leading some centers to omit or modify transplant antibiotic prophylaxis regimens. The aim of the present study has been to evaluate the effects of FQ-P omission on the prevalence of gram-negative bacteria blood stream infections (GNB-BSI), GNB susceptibility to antibiotic treatment, mortality of patients with sepsis and overall TRM. This retrospective single-center study included all consecutive patients, admitted to the Rambam Department of Hematology for allo-HSCT between 01.01.2017 and 31.12.2019. The fact that at our center, FQ-P in allo-HSCT recipients was discontinued on 01.12.2018 allowed comparison of the outcomes in patients treated with and without such prophylaxis. GNB-BSI events registered within 30 days of admission were analyzed. The proportion of first-time GNB-BSI, the antibiotic susceptibility profile, day 30 and day 90 mortality among patients with GNB-BSI were compared. The assessment also included day 30 and day 90 overall TRM, mortality related to sepsis and aGVHD. During the evaluated period, 189 patients underwent allo-HSCT and were included in the analysis. FQ-P was administered to 125 patients and omitted in 64 individuals. GNB-BSI events occurred in 23 (18.4%) patients receiving FQ-P and in 17 (26.6%) patients who did not receive it (p=0.19). GNB susceptibility to FQ, piperacillin/tazobactam and meropenem increased from 38.1% to 58.8%, from 60% to 70.6% and from 85.7% to 94.1%, respectively, after FQ-P had been stopped (p=non-significant, NS). 30-day and 90-day mortality among patients with GNB-BSI did not increase in the post-FQ-P period (Table 1). Day 30 and day 90 overall TRM rates were 10.6% and 18.9%, respectively, with FQ-P versus 13.5% and 21.9%, respectively, without FQ-P (p=NS). Before FQ-P was stopped, sepsis was the cause of death in 56% of events and aGVHD in 16% and after FQ-P was stopped, the corresponding values were 46% and 23%, respectively (p=NS). FQ-P omission has not significantly increased the rate of GNB-BSI or affected the profile of GNB susceptibility to antibiotic treatment in patients undergoing allo-HSCT. Moreover, it has not significantly changed day 30 and day 90 mortality either among patients with GNB-BSI or in the entire study population. FQ-P omission in allo-HSCT recipients appears to be safe and its implementation could contribute to the preservation of intestinal microbiome diversity, potentially leading to improved post-transplant outcome. The findings of this study need to be further evaluated in large randomized trials. Disclosures No relevant conflicts of interest to declare.

Background Fosmanogepix (FMGX) is a first-in-class antifungal agent, with a unique MOA targeting the fungal enzyme Gwt1, that has broad-spectrum activity against both yeasts, molds, and dimorphic fungi, including fungi resistant to other antifungal agents. FMGX has a favorable safety profile, reduced potential for clinically significant drug-drug interactions, and is formulated for IV and oral administration. Methods This global, multicenter, open-label, non-comparative study evaluated the safety and efficacy of FMGX for first-line treatment of candidemia. Patients with a recent diagnosis of candidemia defined as positive blood culture for Candida spp. within 96 hrs prior to study entry, with ≤2 days of prior antifungal treatment were eligible. Patients with neutropenia, C. krusei infection, or deep-seated Candida infections were excluded. Patients were treated with FMGX for up to 14 days: 1000 mg IV BID for 1 day, then 600 mg IV QD for at least 2 days, followed by either 600 mg IV QD or 700 mg PO QD. Short-term fluconazole (or appropriate alternative) could follow if treatment was required beyond 14 days. Patients with a diagnosis of candidemia within 96 hrs of start of study drug who received at least 1 dose of FMGX were included in the mITT population. The primary efficacy endpoint was outcome at end of study treatment (EOST) as determined by an independent data review committee (DRC). Successful outcome was defined as clearance of Candida from blood cultures with no additional antifungal treatment and survival at EOST. All Candida isolates were tested for antifungal susceptibility. Results A total of 21 subjects were enrolled in the study: 20 were included in the mITT. Median duration of FMGX was 11 days (range 5–14). All subjects received IV FMGX, 48% (10/21) received PO FMGX. The DRC-assessed success rate at EOST was 80% (16/20). Survival at day 30 was 85% (17/20); 3 deaths were not related FMGX. FMGX was well-tolerated with no treatment-related serious adverse events or discontinuations. FMGX had potent in vitro activity against all study Candida spp. (EUCAST MIC range 0.001–0.03 µg/ml) including those resistant to other antifungal agents. Conclusion FMGX was safe, well-tolerated, and demonstrated proof of concept with a high level of treatment success in patients with candidemia. Disclosures Peter Pappas, MD, SCYNEXIS, Inc. (Consultant, Advisor or Review Panel member, Research Grant or Support) Bart Jan Kullberg, MD, FRCP, FIDSA, Amplyx (Advisor or Review Panel member) Galia Rahav, MD, AstraZeneca (Scientific Research Study Investigator) Mickaël Aoun, MD, Amplyx Pharmaceuticals (Scientific Research Study Investigator) Pierre Bulpa, MD, Amplyx Pharmaceuticals (Scientific Research Study Investigator) Ricard Ferrer, MD, PhD, Shionogi B.V. (Advisor or Review Panel member) Todd P. McCarty, MD, Amplyx (Scientific Research Study Investigator)Cidara (Scientific Research Study Investigator) Sara Barbat, BSN, RN, Amplyx Pharmaceuticals (Employee) Pamela Wedel, BSc, Amplyx Pharmaceuticals (Employee) Iwonka Oborska, PhD, Amplyx Pharmaceuticals (Consultant, Independent Contractor) Haran T. Schlamm, MD, Amplyx (Consultant) Michael Hodges, BSc. MD, Amplyx Pharmaceuticals Inc. (Employee)

Background: This study aimed to evaluate the diagnostic role of PCR detection of Aspergillus DNA in the broncho-alveolar lavage (BAL) fluid in a large cohort of patients suspected to have invasive pulmonary aspergillosis (IPA). Methods: Consecutive immunocompromised patients who underwent bronchoscopy with BAL sampling and PCR detection of Aspergillus DNA for the diagnosis of pulmonary infiltrates were included in the study. Galactomannan (GM) antigen testing in BAL and serum and BAL fungal culture were also performed. Patients were classified as having IPA (proven/probable/possible) or no-IPA according to the EORTC/MSG diagnostic criteria. Results: During 12 years (2005–2016), 1248 bronchoscopies were performed for 1072 patients. 77% had hematological malignancy, of them 40% had AML and 35.6% underwent HSCT. IPA was diagnosed in 531 patients (42.5%), 7-proven, 280-probable and 244-possible. PCR was positive in 266 cases, of them 213 had IPA, indicating a true positive rate of 80% (213/266) and a false positive rate of 20% (53/266). These results establish the diagnostic performance of PCR to have sensitivity of 40%, specificity of 93%, PPV- 80% and NPV-68%. Of 244 patients with possible IPA, 80 had positive PCR. Including PCR in the diagnostic criteria would move 80 cases from the possible group to the probable one. A combination of positive PCR and/or BAL-GM increases sensitivity to 74%, while positivity of both tests elevates PPV to 99.4%. Conclusions: Inclusion PCR for the detection of Aspergillus-DNA in BAL in the mycological criteria of the EORTC/MSG definitions increases the rate and the certainty of IPA diagnosis. Keywords: PCR, Bronchoalveolar lavage, Diagnosis, Invasive pulmonary aspergillosis

Background Fosmanogepix (FMGX) is a first-in-class antifungal agent, with a unique MOA targeting the fungal enzyme Gwt1, and broad-spectrum activity against yeasts and molds, including fungi resistant to other antifungal agents. Patients with candidemia often have underlying renal insufficiency or are receiving medications that affect renal function. This analysis evaluated outcomes in patients with varying degrees of renal insufficiency. Methods This global, multicenter, open-label, non-comparative study evaluated the safety and efficacy of FMGX for first-line treatment of candidemia. Patients with a recent diagnosis of candidemia defined as positive blood culture for Candida spp within 96 hrs prior to study entry with ≤ 2 days of prior antifungal treatment were eligible, including those with renal insufficiency. Patients with neutropenia, C. krusei infection, deep-seated Candida infections or receiving hemodialysis were excluded. Subjects were treated with FMGX for up to 14 days: 1000 mg IV BID for 1 day, then 600 mg IV QD for at least 2 days, followed by either 600 mg IV QD or 700 mg PO QD. Patients requiring antifungal treatment beyond 14 days received fluconazole. The primary efficacy endpoint was outcome at end of study treatment (EOST) as determined by an independent data review committee. Successful outcome was defined as survival with clearance of Candida from blood cultures with no additional antifungal treatment. Results 14/21 (66%) subjects had some degree of renal insufficiency: 7 had mild renal insufficiency (GFR:60-89), 5 had moderate renal insufficiency (GFR:30-59), and 2 had severe renal insufficiency (GFR:15-29). 12/14 (86%) completed study treatment, and treatment was successful at EOST in 12/14 (86%) subjects. Decline in renal function was not observed at EOST. 4 had worsening of renal function during the follow-up period; none required dialysis. Renal impairment did not increase exposure of FMGX. There were no treatment-related adverse events. Conclusion FMGX demonstrated high level treatment success with no evidence of drug-related nephrotoxicity, with no dose adjustments required. These preliminary data support the continued evaluation of FMGX in patients with candidemia and renal dysfunction as an alternative to potentially nephrotoxic antifungal agents. Disclosures Pierre Bulpa, MD, Amplyx Pharmaceuticals (Scientific Research Study Investigator) Galia Rahav, MD, AstraZeneca (Scientific Research Study Investigator) Mickaël Aoun, MD, Amplyx Pharmaceuticals (Scientific Research Study Investigator) Peter Pappas, MD, SCYNEXIS, Inc. (Consultant, Advisor or Review Panel member, Research Grant or Support) Bart Jan Kullberg, MD, FRCP, FIDSA, Amplyx (Advisor or Review Panel member) Sara Barbat, BSN, RN, Amplyx Pharmaceuticals (Employee) Pamela Wedel, BSc, Amplyx Pharmaceuticals (Employee) Haran T. Schlamm, MD, Amplyx (Consultant) Michael Hodges, BSc. MD, Amplyx Pharmaceuticals Inc. (Employee)

Summary Objectives The identification of the specific pathogen responsible for a respiratory infection in patients with hematological malignancies (HM) would ensure relevant treatment and prevent toxicity associated with anti-infective therapy. This large-scale study aimed to explore the clinical impact of fiberoptic bronchoscopy with bronchoalveolar lavage (FOB-BAL) in conjunction with molecular analysis on the diagnosis and management of respiratory infections in hemato-oncological patients. Methods All consecutive patients with HM and pulmonary infiltrates, who underwent FOB-BAL between January 2008 and January 2013, were included in the analysis. Clinical characteristics, FOB-BAL results, and treatment adjustments were recorded, and factors predicting a positive BAL were assessed. Results Four hundred and twenty-five FOB-BAL procedures were analyzed. BAL revealed a specific diagnosis in 219 (51.5%) patients, 208 of them with a pulmonary infection. Infectious etiological agents found were mainly Aspergillus spp ( n =142), bacterial species ( n =44), and Pneumocystis jirovecii ( n =34). Multivariate analysis showed that a lymphoproliferative disease, ≥2 symptoms (dyspnea/cough/hemoptysis/pleuritic pain), and less than 4 days between symptom appearance and FOB-BAL, predicted a positive FOB-BAL result. BAL results prompted a treatment modification in 48% of subjects. Conclusions FOB-BAL in conjunction with molecular assays is efficient in the rapid detection of life-threatening infections, allowing for adjustment of anti-infective therapy, which may result in better outcomes and reduce treatment-related toxicity.

Data regarding treatment of rare invasive fungal diseases (IFDs) are scarce. We documented the efficacy and safety of isavuconazole for treatment of uncommonly diagnosed IFDs. VITAL was a single-arm, international, open-label study evaluating the efficacy and safety of isavuconazole (200 mg orally or intravenously every 8 hours for 48 hours, then once daily). The primary outcome was overall response at Day 42; key secondary outcomes were overall responses at Day 84 and end of treatment (EOT), mortality at Days 42 and 84, and safety. This analysis includes patients with IFD caused by rare or unidentified pathogens. Twenty-six patients with IFDs caused by rare moulds (n = 17), non-Candida yeasts (n = 2), or unidentified moulds (n = 7) were enrolled (median treatment duration [range], 114.5 [1-496]) days. Overall treatment success was observed in 11/26 (42.3%), 10/26 (38.5%), and 15/26 (57.7%) patients at Days 42, 84, and EOT, respectively. All-cause mortality rates were 2/26 patients (7.7%) at Day 42 and 4/26 patients (15.4%) at Day 84; another two patients died after Day 84. All patients had ≥1 treatment-emergent adverse event (TEAE); 15 patients (57.7%) had serious TEAEs, and TEAEs led to discontinuation of isavuconazole in four patients (15.4%). Isavuconazole may be efficacious for treatment of a range of rare IFDs.

Introduction Treatment options for carbapenem-resistant Enterobacteriaceae (CRE) infections are limited and CRE infections remain associated with high clinical failure and mortality rates, particularly in vulnerable patient populations. A Phase 3, multinational, open-label, randomized controlled trial (TANGO II) was conducted from 2014 to 2017 to evaluate the efficacy/safety of meropenem–vaborbactam monotherapy versus best available therapy (BAT) for CRE. Methods A total of 77 patients with confirmed/suspected CRE infection (bacteremia, hospital-acquired/ventilator-associated bacterial pneumonia, complicated intra-abdominal infection, complicated urinary tract infection/acute pyelonephritis) were randomized, and 47 with confirmed CRE infection formed the primary analysis population (microbiologic-CRE-modified intent-to-treat, mCRE-MITT). Eligible patients were randomized 2:1 to meropenem–vaborbactam (2 g/2 g over 3 h, q8h for 7–14 days) or BAT (mono/combination therapy with polymyxins, carbapenems, aminoglycosides, tigecycline; or ceftazidime-avibactam alone). Efficacy endpoints included clinical cure, Day-28 all-cause mortality, microbiologic cure, and overall success (clinical cure + microbiologic eradication). Safety endpoints included adverse events (AEs) and laboratory findings. Results Within the mCRE-MITT population, cure rates were 65.6% (21/32) and 33.3% (5/15) [95% confidence interval (CI) of difference, 3.3% to 61.3%; P = 0.03)] at End of Treatment and 59.4% (19/32) and 26.7% (4/15) (95% CI of difference, 4.6% to 60.8%; P = 0.02) at Test of Cure;.Day-28 all-cause mortality was 15.6% (5/32) and 33.3% (5/15) (95% CI of difference, − 44.7% to 9.3%) for meropenem–vaborbactam versus BAT, respectively. Treatment-related AEs and renal-related AEs were 24.0% (12/50) and 4.0% (2/50) for meropenem–vaborbactam versus 44.0% (11/25) and 24.0% (6/25) for BAT. Exploratory risk–benefit analyses of composite clinical failure or nephrotoxicity favored meropenem–vaborbactam versus BAT (31.3% [10/32] versus 80.0% [12/15]; 95% CI of difference, − 74.6% to − 22.9%; P

OBJECTIVES Carbapenem-resistant Gram-negative bacteria (CRGNB) pose a clinical challenge. We attempted to estimate the mortality burden of CRGNB among haematological cancer patients. METHODS This was a retrospective cohort study. We included adult patients hospitalized in the haemato-oncological/bone marrow transplantation departments for chemotherapy, between 2008 and 2014, with Gram-negative aerobic bacteraemia. We compared patients with CRGNB and carbapenem-susceptible Gram-negative bacteraemia (CSGNB). The primary outcome was 14 day all-cause mortality. In addition, we assessed 1 year survival. Multivariable logistics regression analysis and adjusted Cox regression analysis were conducted. Analyses were adjusted to the propensity for CRGNB bacteraemia. RESULTS The cohort included mostly young patients (mean age 50.1 years) with acute leukaemia (264/423, 62.4%) and the median absolute neutrophil count at bacteraemia onset was 0 × 10(9)/L. The unadjusted 14 day mortality rate was higher for patients with CRGNB compared with CSGNB [45.6% (47/103) versus 15% (48/320), respectively (P

Recent exposure to azoles is an important risk factor for infection with fluconazole-resistant Candida spp., but little is known about the role of antibacterial drug exposure in the emergence of drug-resistant Candida . We did a prospective nationwide surveillance study of candidemia in Israel and analyzed the propensity score-adjusted association between antifungal and antibacterial drug exposure and bloodstream infection with C. glabrata and fluconazole-resistant Candida isolates. Four hundred forty-four episodes of candidemia (450 Candida isolates, 69 [15%] C. glabrata isolates, and 38 [8.5%] fluconazole-resistant isolates) from 18 medical centers in Israel were included. C. glabrata bloodstream infection was strongly associated with recent metronidazole exposure (odds ratio [OR], 3.2; P < 0.001). Infection with a fluconazole-resistant isolate was associated with exposure to carbapenems, trimethoprim-sulfamethoxazole, clindamycin, and colistin (odds ratio, 2.8; P = 0.01). The inclusion of antibacterial drug exposure in a multivariable model significantly enhanced the model's predictive accuracy for fluconazole-resistant Candida bloodstream infection. Our findings may be relevant to the selection of empirical antifungal treatment and broaden the scope of antibiotic-associated collateral damage.

Following an outbreak of carbapenem resistant Klebsiella pneumoniae (CRKP) bacteremia among inpatients in the Hemato-oncology and BMT unit, we studied the course of this infection in patients undergoing intensive chemotherapy and SCT. In addition, we conducted a pilot study aimed to eradicate CRKP colonization in the gastrointestinal tract, using oral gentamicin. Adult patients admitted to the BMT unit, identified as CRKP carriers on surveillance rectal cultures, were included in the study. Oral gentamicin at a dose of 80 mg q.i.d. was administered to all identified carriers until eradication. Among 15 colonized patients included in the study, the eradication rate achieved was 66% (10/15); discontinuation of persistent bacteremia occurred in 62.5% (5/8) and nosocomial spread of CRKP carrier state ceased. Administration of intensive chemotherapy and SCT is feasible, although associated with increased risk. Hematological patients in need of intensive chemotherapy/SCT should not be denied the required treatment on the basis of being CRKP carriers. Oral gentamicin treatment for eradication of CRKP from the gastrointestinal reservoir could serve as additional tool in the combat against the nosocomial spread and severe infections caused by this difficult-to-treat organism.

Background.Carbapenem resistance among isolates of Klebsiella pneumoniae has been unusual.Objectives.To identify risk factors for infection with carbapenem-resistant K. pneumoniae (CRKP) and to characterize microbiological aspects of isolates associated with these infections.Design.Retrospective case-control study.Setting.A 900-bed tertiary care hospital.Results.From January 2006 through April 2007, K. pneumoniae was isolated from 461 inpatients; 88 had CRKP infection (case patients), whereas 373 had carbapenem-susceptible K. pneumoniae infection (control subjects). The independent risk factors for infection with CRKP were prior fluoroquinolone use (odds ratio [OR], 1.87 [95% confidence interval {CI}, 1.07–3.26]; P = .026), previous receipt of a carbapenem drug (OR, 1.83 [95% CI, 1.02–3.27]; P = .042), admission to the intensive care unit (OR, 4.27 [95% CI, 2.49–7.31]; P < .001), and exposure to at least 1 antibiotic drug before isolation of K. pneumoniae (OR, 3.93 [95% CI, 1.15–13.47]; P = .029). All CRKP isolates carried the blaKPC gene. Approximately 90% of the tested isolates carried the blaKPC-2 allele, suggesting patient-to-patient transmission. Almost all CRKP isolates were resistant to all antibiotics, except to Colistin (resistance rate, 4.5%), gentamicin (resistance rate, 7%), and tigecycline (resistance rate, 15%).Conclusions.CRKP should be regarded as an emerging clinical threat. Because these isolates are resistant to virtually all commonly used antibiotics, control of their spread is crucial.

Extended application of allogeneic stem cell transplantation (alloSCT) is expected to increase the frequency of JC polyomavirus (JCPyV)-related progressive multifocal leukoencephalopathy (PML). The aim of this study was to assess frequency, risk factors and course of JCPyV reactivation in allografted hematology patients. This retrospective study included consecutive adult patients, treated with alloSCT between January 2008 and December 2011. Quantitative JCPyV-PCR analysis was performed on whole blood DNA samples, originally drawn for cytomegalovirus detection since transplant date. The study included 164 patients diagnosed with hematological malignancies. Patients received reduced-intensity conditioning (n=74) or myeloablative conditioning (n=90), followed by alloSCT. Twenty patients developed transient and 20 had persistent JCPyV reactivation. Two of the patients with persistent reactivation showed a gradual increase in JCPyV levels, preceding PML development by 96 and 127 days. Cessation of immunosuppression resulted in complete resolution of neurological symptoms in one patient, while the other died of PML. Seventy percent of the 'persistently reactivating' patients died. Multivariate analysis confirmed age to be the only significant predictive factor for JCPyV reactivation. In conclusion, JCPyV reactivation occurs in a quarter of allografted patients. Preemptive detection of JCPyV reactivation in high-risk subjects and early discontinuation of immunosuppressive therapy may prevent development of lethal PML.

We present a case of progressive disseminated histoplasmosis in an immunocompetent traveler. Histoplasmosis was acquired in South America; its manifestations included prolonged fever, splinter hemorrhages, erythema multiforme, arthritis, and mediastinal lymphadenopathy. To the best of our knowledge no splinter hemorrhages had previously been reported in a patient with histoplasmosis.

Between March 1997 and January 2002, 18 consecutive patients (18-47 years) with hematological malignancies and previous proven invasive fungal infection underwent stem cell transplantation (SCT) (10 matched sibling allograft, 6 autograft, and 2 haploidentical). All patients had full myeloablative conditioning. The fungal pathogens diagnosed were Aspergillus (14), Fusarium (2), Mucor (1), Exserohilum (1), and Candida (1), involving the lungs (15), sinuses (5), and liver (1). All patients were treated pre- and during transplant with systemic antifungal therapy. Eleven out of 18 (61%) patients survived the transplant. Only 1 of 5 patients who transplanted with an active fungal infection accompanied with active leukemia survived the transplant, compared with 10/13 (84%) survivals in patients who had no clinical and radiological signs of infection or active leukemia (P < 0.025). None of the autografted patients has died, compared with 7/12 allografted patients, of whom 5 underwent transplant with active hematological/active fungal disease. In only 3 patients was the cause of death reactivation of previous fungal infection. Both active fungal infection and active leukemia place patients at a very high risk for procedure-related mortality. Pre-transplant therapy of fungal infection, aiming to achieve a clinically undetectable state of infection, followed by an antifungal treatment during transplant may allow the SCT with no fungal reactivation in selected patients.

A nosocomial outbreak of pneumonia caused by Legionella pneumophila serogroup 3 occurred in four patients following hematopoietic stem cell transplantation (HSCT) in a new bone marrow transplantation (BMT) unit during a 2 week period. The causative organism was recovered from the water supply system to the same unit just before the outbreak. Nineteen other BMT patients were hospitalized in the same unit at the same time, giving a frequency of proven infection of 4/23 = 17%. Immediately after recognition of the outbreak, use of tap water was forbidden, humidifiers were disconnected, and ciprofloxacin prophylaxis was started for all patients in the unit, until decontamination of the water was achieved. No other cases were detected. In conclusion, contamination of the hospital water supply system with legionella carries a high risk for legionella pneumonia among BMT patients. Early recognition of the outbreak, immediate restrictions of water use, antibiotic prophylaxis for all non-infected patients, and water decontamination, successfully terminated the outbreak.

The clinical impact of a rapid PCR identification assay for Klebsiella pneumoniae in positive blood cultures was prospectively evaluated. Multivariate analysis identified the rapid PCR assay as the only significant factor in decreasing the time lapse preceding the initiation of appropriate antimicrobial therapy (hazards ratio, 3.03; confidence interval, 1.62 to 5.68; P , 0.001).

A gram-positive rod with a restriction pattern closely related to the published nucleotide sequence ofMycobacterium mucogenicumwas isolated from 6 of 45 units of peripheral blood stem cell products. The source of the contamination was traced to ice cubes used in processing the peripheral blood stem cell products. Substituting reusable ice trays for ice from an ice machine terminated the outbreak.

Herpesvirus 6 (HHV-6) infection is a common complication during immunosuppression. Its significance for multiple myeloma (MM) patients undergoing autologous stem cell transplantation (ASCT) after treatment with novel agents affecting immune system remains undetermined. Data on 62 consecutive MM patients receiving bortezomib-dexamethasone (VD) (; 66%) or thalidomide-dexamethasone (TD) (, 34%) induction, together with melphalan 200 mg/m2 autograft between 01.2005 and 09.2010, were reviewed. HHV-6 reactivation was diagnosed in patients experiencing postengraftment unexplained fever (PEUF) in the presence of any level of HHHV-6 DNA in blood. There were no statistically significant differences in patient characteristics between the groups, excluding dexamethasone dosage, which was significantly higher in patients receiving TD. Eight patients in TD and 18 in VD cohorts underwent viral screening for PEUF. HHV-6 reactivation was diagnosed in 10 patients of the entire series (16%), accounting for 35% of those screened; its incidence was 19.5% () in the VD group versus 9.5% () in the TD group. All patients recovered without sequelae. In conclusion, HHV-6 reactivation is relatively common after ASCT, accounting for at least a third of PEUF episodes. Further studies are warranted to investigate whether bortezomib has an impact on HHV-6 reactivation development.

Introduction: The significance of viral respiratory infections (VRI) and efficacy of anti-flu vaccine in patients (pts) with lymphoproliferative malignancies (LPM) have not been fully elucidated. The current large comprehensive study was designed to evaluate the incidence of respiratory infections in LPM pts, define clinical significance of VRI and assess the impact of anti-flu vaccine on RI prevention in this population. Methods: All consecutive pts, diagnosed either with non-Hodgkin lymphoma (NHL) or multiple myeloma (MM), followed at the Rambam Hematology Outpatient Unit between 01/2011 and 03/2012 (during or after anti-cancer therapy or untreated) were evaluated. Data regarding anti-lymphoma/MM therapy used, respiratory infections occurring during the study period, tests performed to assess these infections (focusing on viral ones), administration of anti-flu vaccine and infection-related outcome were recorded. Samples of nasopharyngeal aspirate (NPA) or bronchoalveolar lavage (BAL) were evaluated for VRI pathogens using both immunofluorescence and polymerase chain reaction (PCR) methods. Results: Five hundred and sixty two respiratory infection episodes were reported in 369 pts. In 224 (40%) episodes, VRI investigation was performed using either NPA (n=180) or BAL (n=44) samples. The decision regarding the sample source was taken based on the respiratory infection severity. The cohort screened for VRI included a larger proportion of pts receiving anti-cancer therapy during the study period than the non-screened cohort (70% vs 30%, respectively, p Fever was the most common clinical symptom in screened episodes (n=111, 50%), followed by cough (n=91, 41%), dyspnea (n= 87, 39%), runny nose (n=47, 21%), respiratory distress (n=45, 20%): with decreased O2 saturation (n=35, 16%) and mechanical ventilation (n=10, 4%). In 12% and 23% of episodes, respectively, neutropenia and significant hypogammaglobinemia (IgG VRI were identified in 66/224 episodes (29%), 59 episodes were viral infections and 7 - co-infections (viral with another pathogen). Sixty viral episodes were diagnosed in pts with upper respiratory tract infections and 6 in pts with pneumonia. Cough, abnormal lung physical findings and hypogammaglobinemia were statistically more frequent in pts with viral infections vs those with other respiratory infections. Viral infections were treated according to pathogens recognized. Tamiflu was prescribed for influenza infections and ribavirin was given for part of the respiratory syncytial virus (RSV) infections. Supportive treatment only was given for parainfluensa and metapneumovirus infections. Twelve episodes of VRI, developed outside of hospital, required hospitalization (5%) and 2 of these episodes resulted in death. The most frequent viral infection was Influenza A (22 cases), followed by RSV (14 cases), parainfluenza and metapneumovirus (11 cases each). Less frequent viral pathogens were Influenza B (6 cases), and adenovirus (2 cases). Seven cases (10%) were accompanied with a secondary bacterial or fungal infection. Notably, 3 of the 10 pts diagnosed with RSV infection had a concurrent Aspergillus infection. Data regarding anti-flu vaccination were available in 701 pts; 431 pts (61%) were vaccinated. In a univariate analysis, anti-flu vaccination was found to have no impact on the respiratory infection frequency (51% vs 48.9%, p=0.752). Among pts with VRI, 49% did and 45% did not previously receive anti-flu vaccination (p=0.95). This vaccination had no effect on the VRI incidence in the investigated episodes. Conclusions: VRI, although frequent, are usually associated with a good outcome in LPM pts. Presence of cough and abnormal pulmonary examination were found to predict a positive screen for a viral pathogen. Influenza and RSV, both potentially treatable with Tamiflu and ribavirin, respectively, were responsible for 55% of VRI episodes, justifying a wider use of viral screening in LPM pts. Anti-flu vaccination has not proved its efficacy either in preventing viral infections or in reducing the entire incidence of respiratory infections in these pts. Disclosures No relevant conflicts of interest to declare.

The mortality rate of 60-90% in invasive pulmonary aspergillosis (IPA) is partly explained by diagnostic delay due to the limitation of current diagnostic tests. We assessed the influence of Aspergillus species (ASP) DNA detection by PCR from bronchoalveolar lavage (BAL) fluid, a new tool for diagnosing IPA, on the outcome of this disease in immune-compromised patients. The study population comprised 107 consecutive patients with hematological malignancies from a single medical center with IPA diagnosed between 1998 and 2005. Clinical variables and mortality rates were compared between two groups diagnosed according to traditional criteria without and with PCR-based ASP DNA detection in BAL fluid. The overall mortality rate during the study period was 38.3%. The addition of PCR to the diagnostic criteria shifted 31 patients from possible to probable IPA. Patients diagnosed with probable IPA according to traditional microbiological methods had significantly higher mortality rates compared to their counterparts who had in addition a PCR-based diagnosis (80 vs 35.6%, P=0.003). This study demonstrates that PCR-based ASP DNA detection for a diagnosis of IPA from BAL fluid has a significant effect on the outcome of patients with IPA, probably related to earlier diagnosis.

Fluconazole antifungal prophylaxis is standard care in allogeneic hematopoietic stem cell transplant (HSCT) recipients, but this drug lacks anti-Aspergillus activity, the primary cause of invasive fungal infection (IFI) in many transplantation centers. We performed a randomized trial to compare itraconazole vs fluconazole, for prevention of IFIs in patients with acute leukemia (AL) and HSCT recipients. One hundred and ninety-five patients were randomly assigned to either fluconazole or itraconazole antifungal prophylaxis, after stratification into high-risk and low-risk groups. Antifungal prophylaxis was started at the beginning of chemotherapy and continued until resolution of neutropenia, or until amphotericin B treatment was started. IFI occurred in 11 (11%) of itraconazole, and in 12 (12%) fluconazole recipients. Invasive candidiasis (IC) developed in two (2%) itraconazole and one (1%) fluconazole recipients, while invasive aspergillosis (IA) developed in nine (9%) itraconazole and 11(11%) fluconazole recipients. There was no difference in the incidence of total IFI, IC and IA between the two study arms. However, there was a nonsignificant trend towards reduced mortality among patients who developed IA while receiving itraconazole prophylaxis (3/9=33% vs 8/11=73%, P=0.095).

Between September 1993 and December 1993, during extensive hospital construction and indoor renovation, a nosocomial outbreak of invasive pulmonary aspergillosis occurred in acute leukemia patients treated in a regular ward that has only natural ventilation. The observed infection rate was 50%. Chemoprophylaxis with intravenous continuous low-dose amphotericin B was then instituted as a preventive measure. During the next 18 months invasive pulmonary aspergillosis developed in 43% of acute leukemia patients. After that period a new hematology ward was opened with an air filtration system through high-efficiency particulate air filtration (HEPA) filters, and a bone marrow transplantation program was started on the hematology service. During the following three years, none of the acute leukemia or bone marrow transplantation patients who were hospitalized exclusively in the hematology ward developed invasive pulmonary aspergillosis, although 29% of acute leukemia patients who were housed in a regular ward, because of shortage of space in the new facility, still contracted invasive pulmonary aspergillosis. Overall, 31 patients were diagnosed with invasive pulmonary aspergillosis during almost five years: 74% of patients recovered from invasive pulmonary aspergillosis, and 42% are long-term survivors; 26% of patients died of resistant leukemia with aspergillosis, but no one died of invasive pulmonary aspergillosis alone. In conclusion, during an on-going construction period, an extremely high incidence rate of invasive pulmonary aspergillosis in acute leukemia patients undergoing intensive chemotherapy was observed. Institution of low-dose intravenous amphotericin B prophylaxis marginally reduced the incidence rate of invasive pulmonary aspergillosis. Keeping patients in a special ward with air filtration through a HEPA system eliminated invasive pulmonary aspergillosis completely. Among patients who developed invasive pulmonary aspergillosis, early diagnosis and treatment are probably the explanation for the favorable outcome.

Introduction Elevated frequency of JC virus (JCV) associated progressive multifocal leukoencephalopathy (PML) was recently reported in immunocompromised patients. Current extended use of allogeneic stem cell transplantation (alloSCT) may further increase the incidence of this disorder. While the paucity of therapeutic options makes PML a lethal disease, immune restoration is deemed to be potentially effective in the management of this condition. The aim of the present study was to assess the frequency, risk factors and course of JCV reactivation in allografted patients, focusing on the potential impact of its preemptive identification on patients' outcome. Methods This study, approved by the Rambam IRB (# RMB 0097-12), included all consecutive patients (aged ≥ 17 years) with hematological malignancies who underwent alloSCT at Rambam between January 2008 and December 2011. Required clinical data were obtained from computerized patient charts. Quantitative JCV-PCR analysis was employed to assess JCV reactivation in whole blood DNA samples monthly drawn for CMV detection, beginning with transplant date up to the end of immunosuppressive therapy. In JCV positive patients, additional DNA samples were weekly drawn and analyzed. The incidence, clinical significance and risk factors of JCV reactivation were evaluated. Results The study included 164 patients (mean age 43.4 years; range 17.5-71.8) diagnosed with acute leukemia (n=108), myelosdysplasia (n=10), lymphoproliferative disorder (LPD) (n=37), multiple myeloma (n=5) and myeloproliferative disorders (n=4) and treated with alloSCT during the study period. Median time from diagnosis to alloSCT was 7.1 months (range 0-181.1).Thirty patients previously received rituximab and 36 failed to respond to high-dose therapy. Ninety four patients had a matched related, 61 a matched unrelated and 9 had a cord blood (CB) transplant, receiving either a conventional conditioning regimen (CC) (n=90), or reduced intensity conditioning regimen (RIC) (n=74). Anti-thymocyte globulin was used in 66 patients. Fifty five patients had prolonged GvHD requiring therapy beyond one year after transplant. Forty patients developed JCV reactivation: 20 anecdotal (appearing only once) and 20 persistent (reported at least in 2 tests). In124 patients, consecutive tests were negative. The maximal JCV load in patients with anecdotal JCV reactivation was60: HR= 8.933, 95% CI: 1.694-47.101, p=0.01 in reference to age Multivariate analysis confirmed age to be the most significant predictive factor for JCV reactivation. Additionally, prolonged GvHD predicted an increased risk of developing persistent versus anecdotal JCV reactivation (p=0.04). Conclusions The findings of the current study suggest that JCV reactivation is relatively uncommon. JCV reactivation is associated with older age and tends to be persistent in patients with prolonged GvHD, in whom it is more likely to eventually progress to PML. Preemptive detection of JCV reactivation in high risk patients, entailing early discontinuation of immunosuppressive therapy, may prevent the development of lethal PML. Disclosures: No relevant conflicts of interest to declare.

Mycobacterium kansasii is a relatively common cause of nontuberculous mycobacterial pulmonary infection. Septic arthritis caused by Mycobacterium kansasii , on the other hand, is rare. Reported here for the first time is the case of an 82-year-old patient with an infection of a prosthetic knee joint with Mycobacterium kansasii .

Human herpesvirus type 6 (HHV-6), a newly recognized human herpesvirus first described in 1986, is morphologically similar to other herpesviruses but is distinguishable from all of them by some unique in vitro biological effects, specific antigenic analysis, and patterns of endonuclease restriction digests of DNA. In vitro HHV-6 exhibits tropism mainly for T lymphocytes, but it also infects other cells, including B lymphocytes, monocytes-macrophages, glial cells, and fibroblasts. Because HHV-6 causes frequent infection in infants and children, a seroprevalence rate of antibody to this virus of up to 80% has been reported in the United States. Infection in infancy develops as levels of maternal antibody wane, thus resulting in either subclinical infection or an acute febrile illness termed exanthema subitum. Primary infection acquired later in life causes a disease resembling acute infectious mononucleosis. Since HHV-6 shares the capacity to establish latent infection with other herpesviruses, frequent viral reactivation is probably the explanation for the high incidence of serologically proven active HHV-6 infection found simultaneously with active infection due to other herpesviruses as well as in the presence of various immune deficiency conditions.

SummaryWe report the case of a 28-year-old previously healthy male who presented with a 1-week history of fever, headache, vomiting, and jaundice. Blood cultures were positive for group G streptococci and transesophageal echocardiography demonstrated vegetations on the aortic valve, leading to a definitive diagnosis of infective endocarditis. The combination of fever, splenomegaly, anemia, thrombocytopenia, hypertriglyceridemia, elevated ferritin level, low natural killer (NK) cell activity, and hemophagocytosis in bone marrow aspirate confirmed the diagnosis of hemophagocytic syndrome (hemophagocytic lymphohistiocytosis). Antibiotic treatment and intravenous immunoglobulins were administered and the patient made a full recovery.