Documented Infection Research Articles

Risk Factors for the First Episode of Klebsiella pneumoniae Resistant to Carbapenems Infection in Critically Ill Patients: A Prospective Study

Objective. To identify risk factors for the first episode of Klebsiella Pneumonia resistant to carbapenems (KPRC) infection in critically ill patients. Design, Setting, and Methods. This prospective cohort study was conducted in a 12-bed general Intensive Care Unit (ICU) in a University Hospital on ICU patients who required mechanical ventilation (MV) for >48 hours during a 12-month period. Clinical and microbiologic data were studied. Characteristics of KPRC patients were compared with those of critically ill patients who presented nonmultidrug resistant (MDR) bacterial infections or no documented infection at all. Results. Twenty-five patients presented KPRC infection, 18 presented non-MDR bacterial infection, and 39 patients presented no infection. Compared to patients without documented infection or infected by non MDR bacteria, patients with KPRC infection had received more frequently or for longer duration antibiotics against Gram-negative bacteria (carbapenems, colistin P < 0.05). Duration of colistin administration prior to KPRC isolation was independently associated with increased frequency of KPRC infection (odds ratio, 1.156 per day; 95% confidence interval, 1.010 to 1.312; P = 0.025). KPRC patients stayed longer in the ICU and received mechanical ventilation and sedation for longer periods and presented increased mortality (P < 0.05). Conclusion. KPRC infection is an emerging problem which might be more common in patients with previous use of antibiotics and especially colistin.

Microbiologically documented infections in patients undergoing high‐dose melphalan and autologous stem cell transplantation for the treatment of light chain amyloidosis

Immunoglobulin light chain (AL) amyloidosis can be treated with high-dose melphalan and autologous stem cell transplantation (HDM/SCT). Risk factors for infections may include hyposplenism, hypogammaglobulinemia, treatment-related neutropenia, melphalan-induced mucositis, and nosocomial exposures. A review of 493 patients with AL amyloidosis undergoing treatment with HDM/SCT from August 1994 to August 2009 was performed. The objectives were to determine the rate and types of infections following HDM/SCT, to identify factors associated with microbiologically documented infections, and to assess the contribution of infections to all-cause treatment-related mortality (TRM; defined as deaths within 100days of SCT). Microbiologically documented infections after HDM/SCT occurred in 24% (n=119) of patients. TRM was 10% (n=48) overall, and 21% (n=25) in patients who had a documented infection. Thus, the relative risk of TRM in a patient with a documented infection was 3.42 (95% confidence interval [CI] 2.02-5.79). Infections were caused by gram-positive bacteria in 51%, anaerobic bacteria in 16%, gram-negative bacteria in 13%, and fungi in 9% of cases. Serum creatinine >2mg/dL was associated with increased risk of post-SCT infection (38% vs. 21%, P=0.0007) with an odds ratio of 2.27 (95% CI 1.40-3.68). No significant association for infection was found for age, gender, cardiac involvement, prior steroid therapy, dose of melphalan, multiorgan involvement, days to neutrophil engraftment, or dose of CD34+ cells infused. Serum creatinine >2mg/dL is a risk factor for infections in patients with AL amyloidosis undergoing HDM/SCT. The relative risk of TRM in a patient with a documented infection was increased >3-fold. A broad spectrum of infections, similar to that in other SCT patients, is seen in this population in the early post-SCT period.

Guidance for contact tracing of cases of Lassa fever, Ebola or Marburg haemorrhagic fever on an airplane: results of a European expert consultation

BackgroundTravel from countries where viral haemorrhagic fevers (VHF) are endemic has increased significantly over the past decades. In several reported VHF events on airplanes, passenger trace back was initiated but the scale of the trace back differed considerably. The absence of guidance documents to help the decision on necessity and scale of the trace back contributed to this variation.This article outlines the recommendations of an expert panel on Lassa fever, Ebola and Marburg haemorrhagic fever to the wider scientific community in order to advise the relevant stakeholders in the decision and scale of a possible passenger trace back.MethodThe evidence was collected through review of published literature and through the views of an expert panel. The guidance was agreed by consensus.ResultsOnly a few events of VHF cases during air travel are reported in literature, with no documented infection in followed up contacts, so that no evidence of transmission of VHF during air travel exists to date. Based on this and the expert opinion, it was recommended that passenger trace back was undertaken only if: the index case had symptoms during the flight; the flight was within 21 days after detection of the event; and for Lassa fever if exposure of body fluid has been reported. The trace back should only be done after confirmation of the index case. Passengers and crew with direct contact, seat neighbours (+/− 1 seat), crew and cleaning personal of the section of the index case should be included in the trace back.ConclusionNo evidence has been found for the transmission of VHF in airplanes. This information should be taken into account, when a trace back decision has to be taken, because such a measure produces an enormous work load. The procedure suggested by the expert group can guide decisions made in future events, where a patient with suspected VHF infection travelled on a plane. However, the actual decision on start and scale of a trace back always lies in the hands of the responsible people taking all relevant information into account.

Safety and Efficacy of Abbreviated Induction with Oral Fludarabine (F) and Cyclophosphamide (C) Combined with Dose-Dense IV Rituximab (R) in Previously Untreated Patients with Chronic Lymphocytic Leukemia (CLL) Aged > 65 years : Results of a Multicenter Trial (LLC 2007 SA) On Behalf of the French Goelams/Fcgcll-WM Intergroup

AbstractAbstract 434 Introduction:The German CLL8 trial has demonstrated that addition of R to FC improves quality and durability of response in CLL (Hallek et al, 2010), which has led to the recommendation of FCR as first line therapy for fit patients. Although elderly patients were included in the CLL8 trial (up to 81 y-old), the median age of the cohort was 61 y, thus at least 10 y younger than median age at CLL diagnosis. The elderly population is underrepresented in clinical trials and it is still not clear how FCR should be applied in this subgroup. In December 2007, the French intergroup launched the LLC 2007 SA trial (NCT00645606) in which CLL patients aged > 65 y receive an induction with abbreviated FCR followed by randomization between observation or maintenance with rituximab. We now report the safety and efficacy of the induction part in the first 200 patients enrolled in this study. Patients and methods:Stage B or C previously untreated fit (CIRS ≤ 6, CCR ≥ 60 ml/min, PS ≤ 1) CLL patients aged > 65 y needing treatment (NCI criteria) were included. Patients with del17p and/or Matutes scoring < 4 were excluded. From these 200 first patients included, 6 were removed because of incorrect inclusion (n=4) or consent withdrawal (n=2). In total, 194 patients (included between Dec/07 and Feb/10) were analyzed. FCR consisted of four monthly cycles of oral FC (F 40 mg/msq/d and C 250 mg/msq/d, × 3d) and iv R (375 mg/msq d1 cycle 1, 500 mg/msq d14 cycle 1, d1 and 14 of cycle 2, and d1 of cycles 3 and 4). Response was assessed by NCI criteria. MRD analysis was done using 6-color FCM in PB and BM. No later than 90 d after the last FCR, patients were further randomized as per protocol. Disease outcome after randomization remains completely blinded to date. Results:The median age was 71 y (range 65–85) and 65% were males. 83% had CIRS between 0 and 3. Binet stage was B in 127 (65.5%) and C in 67 (34.5%). Median (n=143) Beta-2-microglobulin was 4 mg/L (range 2–8). Fifty-six % had unmutated IgVH and FISH revealed 18% with del11q, 15% with trisomy 12, and 57% with del13q. Karyotype (ODN+IL2-stimulated) was abnormal in 67%. Balanced and unbalanced translocations were seen in 16% and 17%, respectively. Complex (>2 abn) karyotype occurred in 14% of the patients. Toxicity:167 (86%) received all four cycles of FCR. Only 4.6% and 3.2% of patients did not receive d14 rituximab at cycle 1 and 2, respectively. 158 patients (81%) could proceed to the randomization (the main reason for failure was insufficient marrow recovery). Dose delay (by ≥ 1 w) and dose reduction (by ≥ 25% of F and C) for cycles 2, 3, and 4 were 12% and 7%, 14% and 8%, 15% and 11%, respectively. Neutropenia g3/4 occurred after cycle 1, 2, 3 and 4, in 46% (19% g4), 50% (21% g4), 53% (29% g4), and 46% (26% g4) of the patients. G-CSF was given in 32%, 46%, 48%, and 52% of them after cycles 1, 2, 3, and 4. G4 thrombocytopenia occurred in less than 2% of the cycles. G3/4 anemia was seen in 11%, 7%, 6%, and 3% of the patients after cycle 1, 2, 3, and 4, respectively. G 3/4 infectious events occurred in 6.2%, 4.8%, 7.6%, and 6.2% of the patients after each of the 4 cycles. Seventy SAE (including 46 febrile neutropenia and/or documented infection) were declared in 53 patients during the induction and the period of recovery prior to randomization. In total, 6.3% of the 732 cycles were followed by febrile neutropenia or infection qualified as SAE. Six deaths (all infections) occurred during induction, corresponding to a 3.1% (6/194) death rate from immediate toxicity. Efficacy:Among 188 evaluable patients, complete responses (CR) were observed in 19.7%, nodular partial response (PR) in 2.7%, and PR in 73.9%, for an ORR of 96.3%, using stringent criteria. According to the updated guidelines of 2008 (Hallek), CR, CRi, and PR rates were 19.7%, 13.3%, and 63.3%, respectively. Conclusion:Four cycles of oral FC combined with 6 doses of R appear feasible in elderly patients with CLL; only 14% cannot receive the 4 courses and only 19% cannot proceed to randomization planned at day 90 post FCR4. Dose reduction and treatment interruption are unusual despite strict stopping criteria. Grade 3/4 neutropenia is frequent but rarely translates into serious infection. The response rate is high, and further analysis of MRD eradication is ongoing and will be presented. In conclusion, this approach could enable the safe administration of FCR to elderly fit CLL patients in first line. Long-term toxicity, occurring after randomization, will be scrutinized. Disclosures:Dartigeas:Roche: Consultancy. Van Den Neste:Roche: Consultancy. Leblond:Mundipharma: Honoraria; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Honoraria.

Real-life evaluation of a human immunodeficiency virus screening algorithm using a single combined p24 antigen–antibody assay

Since May 2010, human immunodeficiency virus (HIV) screening in France has been performed using a single combined fourth-generation assay. One of our major concerns is to verify that this screening strategy is able to diagnose HIV primary infection as soon as possible. Thus, the sensitivity and specificity of this strategy were evaluated on 49,623 serum samples, including 29 primary infections, received for routine HIV testing between September 2010 and November 2011. Specimens were screened using the Enzygnost HIV Integral II enzyme-linked immunosorbent assay (ELISA) kit. All positive sera, according to the manufacturer's recommendations [signal-to-cutoff ratio (S/CO) ≥ 1] were retested using the Architect HIV Ag/Ab Combo. Moreover, we defined a grey zone (0.5 < S/CO < 1) and sera within this grey zone were retested using the VIDAS HIV DUO Ultra test and HIV-1 RNA was checked by the Abbott RealTime PCR kit. Screening tests were positive for all primary infections. All samples within the grey zone proved VIDAS HIV DUO Ultra and HIV-1 RNA negative. Overall, the ELISA test sensitivity and specificity were 100 and 99.79 %, respectively. The false-positive rate was higher when S/CO was in the low range (1 to 5). Adding a second screening test for positive sera reduced the false-positive rate from 0.20 to 0.02 %. HIV screening with a single combined assay did not miss any documented primary infection during this evaluation period, even without extending the positivity zone.

Metaphyseal locking compression plate as an external fixator for the distal tibia

PurposeRecently we coined the term supercutaneous plating using a locking compression plate (LCP) as an external fixator. The use of this technique in peri-articular areas is facilitated by the development of anatomical plates with various screw sizes. The purpose of this report is to describe our results using the metaphyseal locking plate (LCP) as an external fixator in the treatment of infected post-traumatic problems of the distal tibia.MethodsBetween August 2008 and January 2012 a total of seven patients underwent external plating (“supercutaneous plating”) of the distal tibia using a metaphyseal locking plate. Average age was 43 years (range 20–79). Six out of seven patients had a documented infection at the time of external plate application. All patients in this cohort were followed prospectively at regular intervals by the senior author (PK).ResultsThe plate was in situ for an average of 17.5 weeks (range 6–60). There were no clinically significant pin site infections. In four patients the plate was kept in place until there was complete consolidation. In three patients the external plate was exchanged for formal internal fixation once the infection had subsided. At the latest follow-up (average 12.8 months, range 4–31), all patients were fully weight bearing with a fully healed tibia. All patients were infection-free with well-healed wounds.ConclusionInfection of the distal tibia after treatment of traumatic and post-traumatic problems is a challenging problem. It is common practice that after initial debridement and hardware removal, temporary bony stabilisation is provided by external fixation. Most external frames for the lower leg are bulky and cumbersome, causing significant problems for the patient. To circumvent these issues, we have successfully used an anatomically-contoured metaphyseal locking compression plate as external fixator in a series of seven patients for acute or post-traumatic problems of the tibia.

Can procalcitonin distinguish infectious fever from tumor‐related fever in non‐neutropenic cancer patients?

Procalcitonin (PCT) has been proposed as a marker of infection and was studied in neutropenic patients. This study investigated its role in non-neutropenic febrile cancer patients (NNCPs). Between July 2009 and July 2010, a total of 248 NNCPs with fever were studied. PCT was measured in plasma within 24 hours of fever onset and 4 to 7 days thereafter, using a Kryptor system with a lower limit of quantitation of 0.075 ng/mL. Patients' clinical, microbiological, and radiological data were reviewed to make the diagnosis and were correlated with PCT levels. This study included 30 patients with bloodstream infection (BSI), 60 with localized bacterial infection, 141 with no documented infection, and 8 with tumor-related fever. Most patients (98%) were inpatients or admitted to the hospital during the study. Patients with BSI had significantly higher PCT levels than did those with documented localized infections (P = .048) and no documented infection (P = .011). PCT levels were significantly higher in septic patients than in those without sepsis (P = .012). Patients with stage IV disease or metastasis had significantly higher baseline PCT levels than did those with early stages of cancer (P < .05). PCT levels dropped significantly in patients with bacterial infections in response to antibiotics (P < .0001). Baseline PCT levels are predictive of BSI and sepsis in NNCPs. They may be predictors of metastasis and advanced cancer. Subsequent decrease in PCT levels in response to antibiotics is suggestive of bacterial infection. Larger trials are needed to confirm the results of this pilot study.

Epidemiology of infections in children with acquired aplastic anaemia: a retrospective multicenter study in Italy

Infection is a significant cause of death in patients with aplastic anaemia (AA). However, few studies have examined the characteristics of infections in patients with AA, especially in children. The aim of this retrospective study was to evaluate the incidence and types of infections in a large cohort of paediatric patients with AA referred to eight AIEOP (Italian Association of Paediatric Oncology and Haematology) centres in Italy. The study included 78 patients, 45 boys and 33 girls, median age 9.29 yrs (1st-3rd quartile 3.59-13.09) diagnosed with AA. During the study period, 111 infectious episodes were observed in 42 (54%) patients. Fifty-one (46%) episodes were fever of unknown origin and 60 (54%) were documented infections (DI). In this group, microbiologically documented infection (MDI) with bacteremia accounted for 23 (38%) episodes, MDI without bacteremia for 7 (12%), clinically documented infection for 25 (42%) and invasive fungal diseases for 5 (8%). The rate (episodes/1000 d at risk) was similar in severe aplastic anemia and very severe aplastic anemia both before and after day 120. During the first 120 d from diagnosis, the cumulative risk of a DI was 21% (95% CI 12-29) with the last episode at day 117, but the 50% of episodes were observed in the first 24 d. After day 120, the cumulative risk of DI was again 21% (95% CI 12-29), with the last episode at day 445 of follow-up, with 50% of episodes observed in the first 120 d of observation (240 d from the diagnosis of AA). We found a statistically significant association between the grade of aplasia at diagnosis and the incidence of IEs (P = 0.0002). No association was found between gender, age at diagnosis, response at day +120 and at day +180, use of G-CSF and occurrence of IEs. The actuarial overall survival at 5 yrs was 90% ± 3.6. The mortality rate attributable to infection complication was 9%. This is a large paediatric cohort study reporting the epidemiology of infectious complications in children with AA and that allow us to compare the epidemiological data in this diseases with that of the most recent studies in neutropenic children with cancer. Our findings confirm that infections represent the main cause of death in patients with AA and they are important for the design of management strategies of febrile neutropenia in these patients.

Clinical Outcomes with Ertapenem as a First-Line Treatment Option of Infections Caused by Extended-Spectrum β-Lactamase Producing Gram-Negative Bacteria

Infections caused by extended-spectrum β-lactamase (ESBL)-producing gram-negative organisms are a growing concern in hospitalized patients. Traditionally, these infections can be effectively treated by the carbapenem class of drugs. In 2005, our institution initiated a protocol for use of ertapenem, a carbapenem, as the first-line treatment option for these infections. It is unknown whether ertapenem is associated with similar clinical response and microbiologic cure rates as those achieved with group 2 carbapenems (imipenem, meropenem, doripenem). To describe clinical response and microbiologic cure rates associated with ertapenem as first-line treatment of infections caused by ESBL-producing organisms. This case series included patients who received ertapenem for more than 48 hours to treat a documented infection with a positive culture for an ESBL-producing organism. Efficacy was determined by the clinical response and microbiologic cure rates achieved with ertapenem. Seventy-three patients received ertapenem for a mean (SD) of 10.7 (5.9) days. The most common (59%) infection site was urine. The most common causative organisms were ESBL-producing Klebsiella pneumoniae (47%) and Escherichia coli (48%). Clinical response was observed in 78% of patients. Microbiologic cure was achieved in 92% of the evaluable population (n = 50). There were no significant differences in clinical or microbiologic cure rates across important subgroups. Patients treated with ertapenem achieved favorable clinical response and microbiologic cure rates. Our data suggest that ertapenem can be used as an alternative to group 2 carbapenems for the treatment of infections caused by ESBL-producing gram-negative organisms.

In Vitro Activities of Ertapenem and Imipenem against Clinical Extended Spectrum Beta-Lactamase-Producing Enterobacteriaceae Collected in Military Teaching Hospital Mohammed V of Rabat

Objective. To study the sensitivity level of extended spectrum beta-lactamase-producing Enterobacteriaceae to Carbapenems (Imipenem, Ertapenem) marketed in Morocco and discusses the place of Ertapenem in the treatment of extended spectrum-beta-lactamase-producing. Materials and Methods. A retrospective study of 110 extended spectrum beta-lactamase-producing Enterobacteriaceae. Isolates obtained from blood cultures, superficial and deep pus, and catheters were conducted. The minimum inhibitory concentrations of Imipenem and Ertapenem were done by the E-test. The modified Hodge test was conducted for resistant or intermediate strains. Results. 99.1% of isolates were susceptible to Imipenem. For Ertapenem, 4 were resistant and 4 intermediate. The modified Hodge test was positive for all 08 isolates. A minimum inhibitory concentration comparison of K. pneumoniae, E. cloacae, and E. coli for Imipenem has noted a significant difference between E. cloacae on one hand and E. coli, K. pneumoniae on the other hand (P < 0.01). No significant difference was noted for minimum inhibitory concentration of Ertapenem. Conclusion. Our results confirm in vitro effectiveness of Ertapenem against extended spectrum beta-lactamase-producing Enterobacteriaceae as reported elsewhere. However, the emergence of resistance to Carbapenems revealed by production of carbapenemases in this study confirmed a necessary bacteriological documented infection before using Ertapenem.

The Role of PET-CT for the Diagnosis of Infections in Hemato-Oncological Patients with Persistent Febrile Neutropenia

Abstract 4289 Background and aims:Patients with hematological malignancies and prolonged febrile neutropenia are at high risk for bacterial and invasive fungal infections (IFIs). We aimed to evaluate the role of PET-CT for detection of such infections among these patients. Methods:Prospective cohort study of patients with hematological malignancies given intensive conventional chemotherapy and hematopoietic-cell transplantation (HCT) at our center. All consecutive, consenting patients with neutropenia (<500/mm3) and persistent or breakthrough fever despite broad spectrum antibiotics (>5days) had a PET-CT examination. The CT component of the PET-CT was a contrast-enhanced diagnostic CT. Results were available to clinicians in real time. Blinded evaluation of chest and sinus CT and the full PET-CT scan (i.e.chest, sinus CT, abdominal CT, and FDG uptake) were compared with the final clinical diagnosis 30 days after neutropenia resolution, as determined by an expert panel consisting of a hematologist and an infectious diseases expert. Patients were included more than once in the study for different episodes of persistent febrile neutropenia and each episode could receive more than one diagnosis at 30 days. Episodes concluding in no documented infection or other pathological process were classified as fever of unknown origin (FUO). Results:Between January 2008 and January 2011, 91 PET-CT examinations were performed in 79 patients. Median age was 56 (range: 21–85) years. PET-CT was performed after a median of 10 days from last chemotherapy (range: 0–255). Patients were neutropenic for a median of 11 (range:1–100) days.Most patients had acute leukemia (71 episodes), 7 patients underwent allogeneic HCT and 6 patients with lymphoma underwent autologous HCT.The types and number of individual diagnoses are listed in the table. Of the 91 PET-CT examinations, 23 episodes had two or more diagnoses, most commonly a combination of bacterial and fungal infection. Of 28 microbiologically documented infections (MDIs), bacteremia was the diagnosis in 20 episodes, most commonly without a focal source. In the primary analysis we considered FUO as “no disease” and all else as “disease”.Table– Characteristics of diagnosesDiagnostic CategoryNumber of diagnoses (total 117)Positive findings on PET/CT (positive FDG uptake)Positive findings on chest/sinus CTFUO =no disease156 (3)5Disease (Infectious causes):• Clinically documented infection (CDI)3431 (25)14• microbiologically documented infection (MDI)2816 (13)9• Possible invasive fungal infection (IFI)2020 (16)19• Probable/proven IFI77 (7)7Disease due to primary malignancy or non-infectious causes1313 (10)12The sensitivity to detect any infection or non-infectious pathology in chest/sinus CT, was 58.8% (60 /102 diagnoses). The respective sensitivity for PET- CT was 85.3% (87/102). The difference in sensitivity was 26.5% (95% confidence interval 21.4% to 31.6%), matched sample p<0.001. The specificities of CT and PET-CT were not significantly different, 66.7% (10/15 episodes of FUO) and 60% (9/15), respectively. Of note, all 7 proven or probable fungal infections were FDG- positive.In 28 cases, PET-CT demonstrated findings which were not detected on chest/sinus CT (27.5% of diagnoses).These were mainly abdominal infections (as appendicitis, diverticulitis, etc.) and abscesses (perianal, splenic, etc.).When we compared PET-CT to total body (chest, sinus and abdominal) CT, we found that 7 of these cases were found only on PETCT. The sensitivity of total body CT to detect disease was 78.4% (80/102).PET-CT resulted in modifications of patients' management in 46 (55%) cases. These included change in antibiotics (14 cases), change in antifungals (14), change in both (5), an invasive diagnostic procedure (7), a surgical procedure (appendectomy, 3) and abscess drainage (4). Conclusions:PET-CT has a higher sensitivity with no loss of specificity compared to chest/sinus CT in patients with persistent febrile neutropenia. The increase in sensitivity afforded by PET-CT was mainly due to the addition of abdominal CT. Thus, PET-CT has a potential role for the diagnosis of infections in neutropenic patients with persistent fever. Disclosures:No relevant conflicts of interest to declare.

Documented Infection Load In Patients with Neutropenia; a Survey From the Italian Registry of Neutropenias

Abstract 4724Documented Infection Load In Patients With Neutropenia; a survey from the Italian Registry of Neutropenias.Fioredda F, Calvillo M, Caviglia I, Tucci F, Pusiol A, Bonanomi S, Ghilardi R, Martire B, Mastrodicasa E, Barone A, Farruggia P, Caso M, Castagnola E, Dufour C on behalf of the marrow failure Study Group of the AIEOP (Associazione Italiana Emato-Oncologia Pediatrica). Background:Children with severe congenital (SCN), autoimmune (AN) and idiopathic (IN) neutropenia may have infectious complications with high rate of morbidity/mortality. In spite of this scarce data on the incidence and type of documented infections are available in the literature Aims:To describe incidence and type of documented infections in a large population of patients with different types of neutropenia. Patients and Methods:Patients affected with SCN, AN and IN followed from 2000 to 2009 in Centres of the Italian Registry of Neutropenia (IRN) entered the study. Anagraphics and disease–realated data were extracted from the IRN, while details about infections were collected through a dedicated CRF containing uniform criteria to define infection type that was sent to each centre.The occurrence of infections was calculated during a period “at risk” defined as person-days at risk (pdr). The infection rate (IR) was calculated by dividing the number of events by the pdr and expressed as episodes/1000 pdr (95% CI) and was use to compare infection load of neutropenic patients with that of other haematological diseases. Results:Seventy three patients (28 females and 45 males) of whom 12 (16%) with SCN, 38 (52%) with AN and 23 (32%) with IN were analyzed. At least one infectious episode was observed in 100% of SCN and in 30% of both AN and IN. Overall 2/73 patients died (2,7%). They were both SCN subjects: one deceased from haplo-identical HSCT related complication that was performed for loss of response to G-CSF and the other from sepsis after the parents decided to stop G-CSF treatment.In the overall study population from birth to last follow-up, a total of 108 infections occurred in 31/73 subjects (42%). Sixty-nine episodes were observed in 12/12 patients with SCN, 25 infections were concentrated in 12/38 AI patients, and 14 episodes in 7/23 IN subjects. Skin/subcutaneous infections (49%) and pneumonia (18%) were the most frequent localizations. Othomastoiditis, tonsillar phlegmons, osteomyelitis occurred in 10% and deep abdominal infections in 5% of subjects, who were almost exclusively SCN patients. Microbiological characterization was possible in only 25% of the episodes and showed a slight prevalence of Gram-negatives without differences according to the type of neutropenia. Fungal infections were diagnosed only in two different SCN subjects. G-CSF was used in all SCN patients, in 26% of AN and 4% of IN. The IR in SCN was significantly higher than in IN/AN along the entire period of observation (p<0.001). In the whole population and in each subgroup, the IR of the time-span from birth to the diagnosis of neutropenia (coinciding with the start of G-CSF treatment in those patients who received this drug) was significantly higher vs IR calculated from the diagnosis to the last follow up (p<0.01). ConclusionAmong neutropenic children the highest infectious load was observed in SCN, but was not negligible in AN and IN. Skin was the main involved site whereas deep infections are characteristic of SCN. The incidence of infections in SCN is comparable with that of aplastic anemia and slighty lower than in acute lymphoblastic laeukemia receiving aggressive treatments.The significant decrease of IR after diagnosis of neutropenia can probably be attributed to the increased awareness of the patients/family, to early antibiotic intervention and to the G-CSF therapy. Overall these data suggest that also non SCN patients may benefit of specific monitoring/follow up programmes. Disclosures:No relevant conflicts of interest to declare.

RAD001: A Clinico-Biological Phase I GOELAMS trial of Everolimus Association with High Dose Chemotherapy in Late Relapsing AML Patients Under 65 Years of Age

Abstract 945 Background:The mTORC1 signaling pathway is activated in nearly 100% of AML and is one of the key pathway of blast proliferation. RAD001 (Everolimus) is a specific mTORC1 inhibitor with demonstrated clinical activity in solid tumor. We present here a clinico-biological phase I trial combining RAD001 and chemotherapy in younger AML patients (NCT 01074086). Methods:Patients (pts) less than 65 years old with relapsing AML at least one year after CR following prior chemotherapy +/− auto or alloSCT were recruited from the GOELAMS centers from March 2008 to July 2011. The treatment regimen consisted of escalating doses of oral RAD001 at D1 and D7 + daunorubicin 60mg/m2 D1-3 and cytarabine CIV 200 mg/m2/d D1-7. In the absence of dose-limiting toxicity (DLT) after the inclusion of 3 patients, the RAD001 doses were escalated by 10mg over 7 dose levels (DL) from 10mg to 70mg. If there were more than 5% of bone marrow blasts on D15, a second course of induction chemotherapy was administered with daunorubicin 35mg/m2 on D17-D18 and cytarabine 1000mg/m2 BID on D17-D20. A plasma inhibitory activity (PIA) test reflecting the % of inhibition of p70S6K phosphorylation (a direct substrate of mTORC1) in MOLM-14 cells by the serum of the patients was performed. H0, H4, H24 and D7 serum samples were obtained for the DL 10 mg to 40mg and supplementary D3 and D5 samples were collected for the DL 50 and 60mg. Results:Twenty one pts have been included in this trial. Their median age was 50.3y (range 20–65); AML FAB subtypes were as follows: AML0=1, AML1=4, AML2=4, AML4=4, AML5=5, secondary AML=3. Cytogenetics evidenced 1 inv(16), 2 pts with abnormal intermediate risk, 14 normal, 3 poor risk cytogenetics while 1 patient had no available karyotypic information. Documented infections occurred in 16 subjects with grade 3 or more infections in 3 cases. Liver and lung mucormycosis along with appendicitis mass and a septic shock was observed in one patient at 10mg of RAD001. A Fournier gangrene occurred in another one at D40 at DL 50mg. Finally, for another pt, a Candida parapsilosis sepsis occurred on D20 of treatment on a central catheter at DL 50. Two grade 3 oral stomatites at the DL of 20mg and 30mg were observed, as well as 1 grade 3 digestive toxicity at DL 10mg, 2 grade 3 hemorragic events at DL 20mg and 30mg, 2 grade 3 total body erythema at DL 10 and 20mg, 2 grade 3 hepatic cytotoxicity at DL 20mg and 50mg, resolving in less than 14 days and 2 grade 2 renal toxicity at DL 20 and 60mg. None of these effects were considered to be directly related with RAD001. For each DL from 10mg to 40mg and 60mg, 3 pts were included according to the classical 3+3 inclusion schema. For DL 50mg, 6 pts were included as 2 grade>3 SAE have been observed at this level (hepatic dysfunction and fungal sepsis which resolved within 28 days of induction). Hematological toxicities duration were reported as usual (mean neutropenia duration 38 days (range 20–45), mean thrombocytopenia duration 40 days (range 30–65d)). The MTD was not attained at 60mg and accrual is ongoing at 70mg. Four deaths occurred in the study after D40 of induction but none in relation to RAD001 administration.Overall, 15/21 pts achieved CR (71%), among which 9 pts required a second induction course at D15. Four pts were allo-transplanted in CR. Clinical responses occurred across all dose levels but 8/9 pts obtained CR for DL 50mg and 60mg.As shown in Figure 1, the global exposure to RAD001 (as expressed by the area under the curve, AUC) increased with the dose. Using a PIA test in MOLM-14 cells (Figure 2), we observed that there was an excellent inhibition of p70S6K phosphorylation in almost all samples 4 hours after administration of RAD001 whatever the DL (mean decrease of 93%). However, this strong inhibition seems to be maintained until D1 only with 50mg and 60mg of RAD001 (mean decrease of 63% with 10 to 40mg of RAD001 vs 93% with 50 and 60mg). As expected, an increase of RAD001 DL induces an extended inhibition of the mTORC1 signaling pathway until D3 (decrease of 94% with 60mg vs 57% with 50mg). In contrast, at D5 and D7, phosphorylation of p70S6K is only barely affected. Conclusion:In this trial testing the association of RAD001 + chemotherapy, the MTD for RAD001 was not attained at DL 60mg. The CR rate was 71% and the PIA with 60mg of RAD001 seems to be promising. We conclude that these results could be improved with an increased DL of RAD001. The trial is therefore still ongoing with a DL of 70mg and updated results will be presented at the meeting. [Display omitted] [Display omitted] Disclosures:Park:Amgen: Honoraria; Janssen-Cilag: Honoraria; Celgene: Honoraria; Novartis: Research Funding. Off Label Use: RAD001. Merlat:Novartis: Employment.

Risk Factors for 30-Day Hospital Readmission following Myeloablative Allogeneic Hematopoietic Cell Transplantation (allo-HCT)

Patient readmission within 30 days from discharge has been perceived by the Centers for Medicare and Medical Services as an indicator of poor healthcare quality for specific high-cost medical conditions. Patients who undergo allogeneic hematopoietic cell transplantation (allo-HCT) are often being readmitted. Our study identified the risk factors for 30-day readmission among 618 adult recipients of myeloablative allo-HCT from 1990 to 2009. Two hundred forty-two (39%) of 618 patients (median age = 42 years [range: 18-66]) were readmitted a median of 10 days (range: 1-30) from their hospital discharge. Median duration of readmission was 8 days (range: 0-103). Infections (n = 68), fever with or without identified source of infection (n= 63), gastrointestinal complications (n = 44), graft-versus-host disease (GVHD) (n = 38), and other reasons (n = 29) accounted for 28%, 26%, 18%, 16%, and 12% of readmissions, respectively. During their index admission, patients who were subsequently readmitted had more documented infections (P < .001), higher hematopoietic cell transplantation comorbidity index (HCT-CI) (P < .01), total body irridiation (TBI)-based conditioning (P < .001), unrelated donor (P < .001), and peripheral stem cell (P = .014) transplantation. In multivariable analysis, HCT-CI (odds ratio [OR] = 1.78; 95% confidence interval [CI], 1.25-2.52), TBI-based preparative regimen (OR = 2.63; 95% CI, 1.67-4.13), and infection during admission for allo-HSCT (OR = 2.00; 95% CI, 1.37-2.92) predicted 30-day readmission. Thirty-day readmission itself was an independent predictor of all-cause mortality (hazard ratio [HR](Adj) = 1.66; 95% CI, 1.36-2.10). Our data emphasize the importance of a risk-standardized approach to 30-day hospital readmission if it is used as a quality-of-care metric for bone marrow transplantation.

Infection fongique invasive en oncologie et hématologie pédiatrique : analyse de la littérature et étude médicoéconomique des coûts de prise en charge

Invasive fungal infections are an important cause of mortality in oncology and haematology unit care. Immunosuppression allows the occurrence of Candida or Aspergillus infectious disease. Treatment is based on antifungal agents (liposomal amphotericin B, azoles and caspofungin) administrated alone. The lack of study does not yet validate the combination of two drugs which are not recommended in medical practice. The aim of this pharmacoeconomics study is to assess different therapeutic strategies compared to standard treatment. Health care system point of view is used. Results show that liposomal amphotericin B is the reference standard drug during no documented infection in term of cost. But, voriconazole does not have significative cost variation for Aspergillus disease. Same conclusion can be showed, in case of candidosis for caspofungin. The sensitivity analysis shows that daily cost treatment and body weight are variables with important impact on results. This preliminary analysis must be continued by a clinical study in order to assess different antifungal treatments.

The Ideal Use of the Power Injectable Peripherally Inserted Central Catheter in the Pediatric Population

IntroductionThe peripherally inserted central catheter (PICC) is being used more frequently in pediatric populations in both hospital and home care settings in order to provide secure vascular access. In 2007, the Power PICC was introduced to pediatric populations. In contrast to traditional PICCs, the power injectable PICC withstands higher flow rates and can deliver contrast injections. Although effectiveness studies of power injectable PICCs have been performed in adults, only limited published research is available regarding pediatric populations. PurposeThis study aimed to develop criteria for identifying the ideal pediatric candidate for the power injectable PICC. A secondary aim was to identify contraindications and barriers to power injectable catheter use in pediatric populations. MethodsRetrospective and prospective chart reviews were used to analyze complication rates for 97 power injectable PICCs placed in patients aged 4 months to 17 years. ResultsA low incidence of catheter complications was identified during and post- insertion. Our documented infection rate of 1.30 per 1000 catheter days was similar to the infection rate of 1.27 per 1000 catheter days found in the Abedin & Kapoor (2008) study. DiscussionThe introduction into a pediatric hospital of power injectable PICCs for power injection scans for contrast injection was safe and effective in patients with many disease processes. ConclusionIn properly selected pediatric patients, the power injectable PICC is not associated with an increased risk to thrombosis or infection and can improve patient outcome.

Kingella infections in children – a child with small ventricular septal defect and endocarditis

AimTo study the prevalence of Kingella infections in children under 18 years in a District General Hospital in the UK.MethodsThe records of the microbiology laboratory over a 10-year period (2001–2010)...

Pandemic 2009 H1N1 influenza virus vaccination in lung transplant recipients: Coverage, safety and clinical effectiveness in the Zurich cohort

Pandemic 2009 H1N1 influenza virus (H1N1) infection is considered harmful to lung transplant recipients (LTRs). Vaccination against this virus is recommended for LTRs, but little is known about associated benefits and risks. Our aim in this study is to document the safety and clinical effectiveness of the H1N1 vaccine in LTRs. All LTRs received an informational letter on the H1N1 pandemic that included hygiene and vaccination recommendations. After completing a questionnaire, volunteering LTRs received Pandemrix (H1N1 2009 Monovalent AS03-Adjuvanted Vaccine; GSK). Adverse events (AEs) were documented at short-term follow-up visits and by telephone. Any flu-like symptoms were reported and a low threshold for performing nasal/pharyngeal swabs for virus detection was maintained. Of 168 eligible LTRs (107 already vaccinated for 2009 seasonal influenza), 148 (88%) received at least one vaccination with the H1N1 vaccine and 115 received a second dose. After the first vaccination, 44% had no AEs. Six self-limiting, severe AEs occurred, and the remainder were minor to moderate, predominantly injection-site reactions. After the second vaccination, AEs were clearly less frequent. All AEs resolved completely. Documented H1N1 infection occurred in 2 of 148 vaccinated LTRs, in contrast to 5 infections in 20 non-vaccinated LTRs. H1N1 vaccination is generally well tolerated with mild to moderate, predominantly local AEs in most LTRs and few self-limiting severe events. Clinical effectiveness is good.

Short-Lived IFN-γ Effector Responses, but Long-Lived IL-10 Memory Responses, to Malaria in an Area of Low Malaria Endemicity

Immunity to malaria is widely believed to wane in the absence of reinfection, but direct evidence for the presence or absence of durable immunological memory to malaria is limited. Here, we analysed malaria-specific CD4+ T cell responses of individuals living in an area of low malaria transmission in northern Thailand, who had had a documented clinical attack of P. falciparum and/or P. vivax in the past 6 years. CD4+ T cell effector memory (CD45RO+) IFN-γ (24 hours ex vivo restimulation) and cultured IL-10 (6 day secretion into culture supernatant) responses to malaria schizont antigens were detected only in malaria-exposed subjects and were more prominent in subjects with long-lived antibodies or memory B cells specific to malaria antigens. The number of IFN-γ-producing effector memory T cells declined significantly over the 12 months of the study, and with time since last documented malaria infection, with an estimated half life of the response of 3.3 (95% CI 1.9–10.3) years. In sharp contrast, IL-10 responses were sustained for many years after last known malaria infection with no significant decline over at least 6 years. The observations have clear implications for understanding the immunoepidemiology of naturally acquired malaria infections and for malaria vaccine development.

Salvage therapy for refractory rejection and persistence of donor-specific antibodies after intestinal transplantation using the proteasome inhibitor bortezomib

Salvage therapy for refractory rejection and persistence of donor-specific antibodies after intestinal transplantation using the proteasome inhibitor bortezomib