Clinically Documented Infections Research Articles

Association of Vitamin A and D Deficiencies with Infectious Outcomes in Children Undergoing Intensive Induction Therapy for Acute Lymphoblastic Leukemia

To evaluate the association between deficiency of vitamin A or D at diagnosis of pediatric acute lymphoblastic leukemia (ALL) and subsequent infectious complications during induction therapy. We conducted an institutional review board-approved, retrospective cohort study of children with newly diagnosed ALL from 2007 to 2017 at St. Jude Children's Research Hospital. We measured vitamin D, vitamin D binding protein, retinol binding protein as a surrogate for vitamin A, and immunoglobulin isotypes in serum obtained at ALL diagnosis, and we assessed the association between vitamin deficiencies or levels and infection-related complications during the 6-week induction phase using Cox regression models. Among 378 evaluable participants, vitamin A and D deficiencies were common (43% and 17%, respectively). Vitamin D deficiency was associated with higher risks of febrile neutropenia (adjusted hazard ratio [aHR], 1.7; P=.0072), clinically documented infection (aHR, 1.73; P=.025), and likely bacterial infection (aHR, 1.86; P=.008). Conversely, vitamin A deficiency was associated solely with a lower risk of sepsis (aHR, 0.19; P=.027). In this retrospective study, vitamin D deficiency was associated with an increased risk of common infection-related complications during induction therapy for ALL. Additional studies are warranted to evaluate whether vitamin D supplementation could mitigate this effect.

Lenfoma ve Solid Tümörlü Çocuklarda Febril Nötropenide Sefaperazon-Sulbaktam Monoterapisinin Etkinliği

Objective: Monotherapy with a beta lactam or a cephalosporin has become the standard of care for the treatment of febrile neutropenia (FEN). We aimed to evaluate the efficacy of cefoperazone/sulbactam (CS) as empirical monotherapy for febrile neutropenia in children with solid tumors and lymphomas. Material and Methods: Children with FEN received cefaperazone-sulbactam (80 mg/kg/day, every 8 hours). Treatment responses (a) successful, complete resolution of all signs and symptoms of infection at 72 hours and after 7 days of CS treatment; (b) success with modification, change of therapy for viral, parasitic or fungal infection or addition of glycopeptides; (c) failure was defined as the emergence of a new or resistant infection, treatment-resistant bacteremia, the need to switch to carbapenems. Results: Our study included 157 patients and 350 febrile neutropenia episodes. The most common diagnoses were osteosarcoma (35%), Ewing sarcoma (30%), non-hodgkin lymphoma (13%) and rhabdomyosarcoma (9%), respectively. The origin of fever could not be determined in 223 (64%) of FEN episodes, 79 (22%) had microbiologically documented infection (MDI), and 48 (14%) had clinically documented infection (CDI). The success rate was 65% (229), the success rate with modification was 9% (31) and the failure rate was 26% (90). SC monotherapy was successful in 33% of attacks with MDI and in 60% of attacks with CDI. However, SC monotherapy was successful in 82% of febrile episodes of unknown origin. Conclusion: Cefoperazone/sulbactam is effective and safe in febrile neutropenic children with solid tumors and lymphomas for monotherapy.

Comparison of the Power of Procalcitonin and C-Reactive Protein to Differentiate between Different Etiologies of Febrile Neutropenia in Patients with Prolonged Profound Neutropenia

Background: The management of febrile neutropenia in case of prolonged profound neutropenia remains challenging as there are many possible infectious and non-infectious causes for fever in these patients. In more than 60% of cases there is no documented infectious etiology and unresolved febrile neutropenia often results in multiple empirical modifications of antibacterial therapy and/or addition of antifungal therapy. Unfortunately, indiscriminate use of broad-spectrum antibiotics can lead to important collateral damage including toxicity, selection of multidrug resistant pathogens and an increased predisposition to other infections such as Clostridium difficile or yeasts/fungi. In this study, we investigated whether procalcitonin (PCT) is superior to C-reactive protein (CRP) in discriminating between different etiologies of fever.Methods: CRP and PCT were tested daily during 93 neutropenic episodes in 66 patients (Table 1). A linear mixed model was performed to evaluate the effects of different variables on the values of CRP and PCT over time. A total of 121 febrile episodes occurred during this study period and were classified into four categories based on clinical and microbiological findings: microbiologically documented infection (MDI); clinically documented infection (CDI); proven or probable invasive fungal disease (IFD); fever of unknown origin (FUO). The values of PCT and CRP on day 2 after onset of fever were considered for analysis of their performance in distinguishing etiologies of fever in receiver operating characteristic (ROC) curves and by calculation of sensitivity, specificity, positive & negative predictive values and efficiency.Results: In 61 out of 93 neutropenic episodes (66.7%) the evolution of PCT and CRP was clearly different. CRP seemed to be a more volatile parameter, rising above its ULN (3 mg/dL) during every neutropenic episode. Its reactivity to stimuli was also quite pronounced with a median of 2 surges above 100 mg/dL per neutropenic episode. In contrast, PCT did not rise above its ULN (0.5 ng/mL) in 50 out of 93 neutropenic episodes (53.8%). The only confounding factor on the evolution of CRP and PCT with a clinically relevant large effect size was administration of antithymocyte globulin (ATG), which led to an 11-fold increase of PCT versus a 2-fold increase of CRP.On the day of fever onset no significant difference in PCT values was observed between different etiologies of fever (p=0.314), whereas median CRP values were significantly higher in IFD versus all other etiologies (median 98.8 mg/dL vs 28.8 mg/dL, p=0.027). Both PCT and CRP reached their peak at a median of 2 days after onset of febrile neutropenia. Median PCT values on day 2 showed no statistically significant difference when comparing etiologies of fever (Figure 1A). There was a tendency towards higher median PCT values in MDI and IFD where they rose > 0.25 ng/mL, while they did not in CDI or FUO without prior administration of ATG. Median CRP values on day 2 after fever onset were significantly higher in IFD versus all other etiologies (median 172 mg/dL vs 78.4 mg/dL, p=0.002). In MDI median CRP values rose > 100 mg/dL, whereas they did not in CDI or FUO (Figure 1B).The discriminatory power between IFD and FUO of CRP on day 2 after onset of febrile neutropenia was superior to that of PCT. With the cut-off set at 200 mg/dL, CRP has a positive predictive value of 66.7% and a negative predictive value of 97% for the diagnosis of IFD versus FUO, leading to an efficiency of 94.5%.Conclusions: Both CRP and PCT are not able to predict neither etiology nor severity of infection at the onset of fever. When performing reassessment of antibiotic therapy 2 days after onset of febrile neutropenia, CRP has the better discriminatory power between etiologies of fever and shows higher peak values in clinically severe infections. As such we conclude that PCT has no added value over CRP for clinical management of febrile neutropenia. In our study a CRP value above 200 mg/dL has a positive predictive value of 66.7% and a negative predictive value of 97% for the diagnosis of IFD versus FUO (when MDI and CDI were ruled out by diagnostic workup). A high CRP in the absence of a clear focus of infection might prompt earlier investigation for IFD, leading to earlier treatment initiation and lower mortality. In view of the low numbers of IFD in our study it is important to note that this finding should be confirmed in a larger patient population. [Display omitted] DisclosuresVerlinden:MSD - Merck: Research Funding. Gadisseur:Bayer: Research Funding.

Infectious Morbidity in Pediatric Patients Receiving Neoadjuvant Chemotherapy for Sarcoma.

Simple SummaryInfections are an important cause of morbidity and mortality in childhood cancer treatment. The aim of our retrospective study was to assess the infectious burden in pediatric sarcoma patients during neoadjuvant chemotherapy administered according to the EWING 2008, CWS SoTiSaR and EURAMOS clinical trial or registry. Our analyses indicate a substantial infectious morbidity in this group of patients, with 58.8% experiencing at least one episode of febrile neutropenia (FN) and 20.6% at least one microbiologically documented infection (MDI). We also identified parameters that impact on the occurrence of FN and MDIs, including treatment protocol, patient age, and mucositis. These findings may contribute to a better risk stratification for prevention and management of FN and infections as well as for maintaining quality of life, cost control, and optimum outcomes of anticancer treatment.The purpose of this retrospective, single-center cohort study was to assess the infectious burden in pediatric sarcoma patients during neoadjuvant chemotherapy. The review included all patients with a new diagnosis of Ewing sarcoma, osteosarcoma or soft tissue sarcoma between September 2009 and December 2018 who were enrolled in the EWING 2008, CWS SoTiSaR and EURAMOS clinical trial or registry. Primary endpoints were the occurrence of febrile neutropenia (FN) and microbiologically documented infection (MDI). Parameters with a potential impact on FN and MDI were also analyzed. A total of 170 sarcoma patients (median age: 13 years, range: 0–21; 96 m/74 f) received 948 chemotherapy courses (median: 6; range: 2–8). Of these patients, 58.8% had ≥1 FN episode and 20.6% ≥ 1 MDI. FN occurred in 272/948 courses (28.7%) with fever of unknown origin (FUO) in 231 courses and 45 MDI and 19 clinically documented infections (CDI) occurring in a total of 57 courses. Patients enrolled in EWING 2008 had significantly more FN (p < 0.001), infections (p = 0.02) and MDI (p = 0.035). No infection-related deaths were observed. Younger age, tumor type and localization, and higher median and maximum mucositis grades were significantly associated with higher numbers of FN (p < 0.001), and younger age (p = 0.024) and higher median mucositis grade (p = 0.017) with MDI. The study shows substantial infectious morbidity in sarcoma patients during neoadjuvant chemotherapy treatment and opportunities to improve prevention and management.

Outcomes of HIDAC 18g Versus IDAC 9g in Consolidation Therapy of Acute Myeloid Leukemia: A Retrospective Study.

Cytarabine based therapy has been the standard consolidation regimen for AML (acute myeloid leukemia) for decades. However, the optimal dose, regimen and schedule is not known. HIDAC (high dose cytarabine at 18g/m2) has been the conventional standard, however, recent studies have shown that intermediate doses of cytarabine (IDAC) have equal efficacy and lesser toxicities. We retrospectively analysed 75 AML patients who entered consolidation out of 167 patients who underwent induction therapy between 2014 and 2018. HIDAC (at 18g/m2) was given to 39 patients and 36 patients received IDAC at 9g/m2. Median age was 28years (range 2-60). Male: female ratio was 1.02. More courses were administered in out-patient setting in IDAC group 61% (n = 58/95 courses) than in HIDAC 29% (n = 29/101 courses); p < 0.001. Incidence of clinically documented infection (CDI) was higher in HIDAC group (23.7%) compared to IDAC (8.4%), p = 0.004, and diarrhea showed a higher trend in the HIDAC group (9.9% vs. 3.1%; p = 0.052). Other toxicities were similar in both groups. There were 4 consolidation deaths in HIDAC whereas 3 deaths in IDAC group (p = 0.775). Median OS was 19.7 vs. 16.2months and 3years OS was 49.1% vs. 34.7% in HIDAC and IDAC groups respectively (p = 0.570). Median LFS was 12.6 versus 11.8months; 3years LFS was 46.4% versus 31% in HIDAC and IDAC groups respectively (p = 0.278). For AML consolidation IDAC had lesser toxicity when compared with HIDAC though comparable efficacy needs to be confirmed with longer follow up and with prospective studies. The online version contains supplementary material available at 10.1007/s12288-021-01430-z.

Early infections after successful transcatheter aortic valve replacement are associated with increased short- and long-term mortality: A single-center study

BackgroundWe reviewed frequency, microbiological pattern, predictors, and outcomes of early infections following transcatheter aortic valve replacement (TAVR). MethodsFive hundred thirty-nine patients who underwent successful TAVR at a single, high-volume center between January 2014 and December 2019 were enrolled. We defined early infections as occurring within 30-day from TAVR. ResultsMean age was 83.5 ± 5.4 years; 230 (42.7%) patients were men. Median follow-up was 12.0 (5.7–18.3) months; 30-day and 1-year death rates were 8/539 (1.5%) and 30/539 (5.6%), respectively. Early infections occurred in 61/539 (11.3%) patients, of whom 2 had infections in two sites. Of the 63 infections, 10 were bloodstream infections (BSI), 5 urinary tract, 27 pulmonary (2 with sepsis), 6 access site infections, 1 enterocolitis, and 14 were clinically diagnosed (no specific site). We observed 31/63 (49.2%) microbiologically-documented infections: Gram+ bacteria were isolated in 12/31 (38.7%), Gram- in 17/31 (54.3%), both Gram+ and Gram- in 2/31 (6.5%); in thirty-two infections no specific pathogen could be isolated (clinically-documented infections).Early infections were more prevalent in patients who died within 30-day (8.2% vs. 0.6%, p < 0.001) or 1-year (14.8% vs. 4.4%, p < 0.001) from TAVR. At multivariable analysis, early infections were independently associated with 30-day (HR: 8.82, 95% CI: 1.11–19.83, p = 0.035) and 1-year mortality (HR: 2.10, 95%CI: 1.28–6.21, p = 0.041). The predictive value for 1-year mortality was maintained even restricting the analysis to documented infections only, or to more severe infections (BSI and pneumonia only) (all p < 0.05). ConclusionsEarly infections occur in 1/10th of TAVR and are associated with increased short- and long-term mortality. Whereas a causal relationship between early infections and the risk of death cannot be unequivocally proven, careful surveillance of infected patients may improve TAVR results.

Infectious Complications in Patients With Multiple Myeloma After High-Dose Chemotherapy Followed by Autologous Stem Cell Transplant: Nationwide Study of the Infectious Complications Study Group of the Polish Adult Leukemia Group

BackgroundMultiple myeloma (MM) has become a chronic disease in majority of patients, and remission consolidation with autologous hematopoietic stem cell transplant (ASCT) remains the backbone of treatment in transplant-eligible patients. ObjectiveThe aim of this multicenter cross-sectional nationwide retrospective study was to evaluate the epidemiology, etiology, and outcome of infections in patients with MM undergoing ASCT in 13 Polish transplant centers, carried out on behalf of the Infectious Complications Study Group of the Polish Adult Leukemia Group. MethodsA total number of consecutive 1374 patients with MM treated in Polish adult transplant centers from 2012 to 2014 were followed for infectious complications up to day +100 after ASCT in nationwide study. ResultsAltogether 490 infection episodes in 336 patients (49% male, aged 21-72 years) were reported, including 145 episodes of neutropenic fever (103 patients) and 34 episodes of clinically documented infections (CDIs) (27 patients). Among microbiologically confirmed infections there were 251 episodes of bacterial infections (180 patients), 42 episodes of fungal infections (38 patients), and 18 episodes of viral infections (17 patients). The overall incidence of infections reached 13.1% for bacterial, 3.6% for fungal, and 1.3% for viral infections. There were 16 cases of infection-related deaths after ASCT (1.2%). The mortality risk factors included multidrug-resistant bacteria etiology (odds ratio [OR], 3.5; P = .033), coexistence of bacterial and fungal infection (OR, 6.3; P = .002), and CDI (OR, 5.5; P = .007). ConclusionASCT in patients with MM was connected with low risk of life-threatening infections. However, multidrug-resistant bacteria bacterial etiology, mixed etiology, and CDI increased the risk of fatal outcome.

PB2041 UTILITY OF INFLAMMATORY MARKERS IN DISTINGUISHING VARIOUS INFECTIVE ETIOLOGIES OF FEVER IN FEBRILE NEUTROPENIC PATIENTS

Background:Febrile neutropenia is a common cause in morbidity and mortality during treatment of hematological neoplasms. This leads to unnecessary use of broad‐spectrum antibiotics adding to the cost of treatment, selection pressure amongst bacteria and side effects of antibiotics.Aims:To study the utility of Procalcitonin and CRP in differentiating various causes of fever in patients with febrile neutropenia.Methods:Subjects included all cases admitted under hematology department with febrile neutropenia from February to June 2018 (age ranged‐1‐60 years). Institutional Ethics Committee clearance was obtained for the conduct of this study.Etiology of febrile episodes classified according to International Immunocompromised Host Society (ICHS) into four groups:• Microbiologically documented infections (MDI)• Clinically documented infections (CDI)• Fever of unexplained origin (FUO)• Invasive fungal infections (IFI)Diagnostic work up for each febrile episode was done including Procalcitonin (PCT) and CRP. PCT and CRP was sent at fever onset 0,24,48hour, day 7 and day 14 or defervescence.Results:A total of 72 patients evaluated out of which 17 patients excluded either due to incomplete data or fever due to non‐ infective causes. Data was analyzed for 52 febrile episodes in 50 patients. At fever onset no significant difference was observed in the PCT &amp; CRP values amongst various etiologies. PCT cut off value at 24 hours of ≤1.2ng/ml had a sensitivity and specificity of 62.5% and 87.5% for discriminating IFI and MDI (p = 0.033). PCT had a negative predictive value of 70% for the diagnosis of IFI as compared to MDI. PCT cut‐off of 0.4ng/ml on day 7 had a sensitivity and specificity of 60.98% and 100% respectively for discriminating IFI and PUO (p = 0.0001). Procalcitonin was significantly higher in the pneumonia group compared to other site infections (median‐11.42; IQR‐6.170 ‐ 13.003; p &lt; 0.05). Patients who developed signs of severe infection like Septic shock, hypoxia were noticed to have significantly high median PCT value at 24 and 48 hours (p value‐ 0.007 for PCT 24 and 0.001 for PCT 48). Patients with only MDI infections had the highest PCT level over the course of febrile episode. CRP cut off &gt;160 mg/dl at 48 hours was suggestive of fever due to fungal infection rather than other causes, with a sensitivity of 100%, specificity of 48%, PPV of 33.3% and NPV of 100%. There was a significant rise from baseline in CRP values at 48 hours in the IFI group when compared to the other groups (median = 33.6; p = 0.045). The CRP values at 24 hours and 48 hours were significantly lower in the PUO (disease fever) group (p = 0.001) when compared to the other groups. There was a significant fall in the level of PCT by day 14(median fall in PCT of 10.8) in the group of patients who had both IFI+ MDI when compared to other groups (p = 0.047).Summary/Conclusion:PCT level at 24 and 48 hours can be a predictor of severity of infection. High PCT level throughout the course of febrile episode were more suggestive of blood culture positive bacterial infection. Regarding CRP, significant rise from baseline at 48 hrs or CRP&gt;160 mg/dl at 48 hrs were significantly indicative of fungal infection rather than bacterial. PCT or CRP may be a useful adjunct to step down or step up antimicrobials.

PS1268 CEFTAZIDIME/AVIBACTAM AND CEFTOLOZANE/TAZOBACTAM FOR THE TREATMENT OF FEBRILE NEUTROPENIA IN ALLOGENEIC TRANSPLANT RECIPIENTS

Background:Febrile neutropenia (FN) is a common life‐threatening complication in allogeneic HSCT recipients. The growing incidence of multi‐drug resistant Gram‐negative bacteria (MDR‐GNB) is a public health challenge worldwide. Two new antibiotics [ceftazidime/avibactam (C/A), ceftolozane/tazobactam (C/T)], active against carbapenem‐resistant (CR) GNB, have been introduced in clinical practice.Aims:Within an antimicrobial stewardship program, we aim to analyze the place in therapy of C/A and C/T, splinted up by indication [definite therapy (DT) of MDR‐GNB pre‐engraftment bloodstream infection (PE‐BSI) in MDR‐GNB carriers, empirical therapy (ET) of FN in MDR‐GNB carriers, ET of clinically documented infection (CDI) in non‐carriers]. Secondly, we describe PE‐BSI.Methods:From January to December 2018, we conducted a retrospective study on consecutive adult patients affected by high‐risk hematological diseases who received allogeneic HSCT in the Hematology and BMT Unit of our institute. According to institutional guidelines, all patients received levofloxacin prophylaxis and active weekly surveillance for MDR‐GNB colonization by rectal swab.Results:Seventy patients underwent HSCT, mainly for acute myeloid leukemia (55%): HLA‐matched related donor (n = 12), HLA‐matched unrelated donor (n = 33), haploidentical donor (n = 23) and cord blood (n = 2). The graft source was unmanipulated peripheral blood, using myeloablative conditioning and post‐transplant cyclophosphamide GvHD prophylaxis.Overall, 8/70 patients (11%) were MDR‐GNB carriers before HSCT [5 CR‐Klebsiella pneumoniae (Kp; 4/5 KPC producer), 3 CR‐Pseudomonas aeruginosa (Pa; 0/3 MBL producer, 2/3 resistant to C/T)] and 9/62 non‐carriers (15%) acquired colonization after HSCT [5 CR‐ Kp (4/5 KPC producer), 3 CR‐ Pa (0/3 MBL producer, 1/3 resistant to C/T), 1 CR‐Enterobacter cloacae MBL‐producer].Nine patients received C/A. Among pre‐HSCT CR‐Kp carriers, 3/5 (60%) developed KPC‐Kp PE‐BSI, receiving a combination DT with C/A [tigecyclin (n = 2), gentamycin (n = 1)], and 2/5 (40%) received C/A in the pre‐engraftment phase as ET for FN with a median time to de‐escalation of 8 days. Among post‐HSCT CR‐Kp carriers, 1/5 (20%) developed KPC‐Kp PE‐BSI, receiving C/A plus fosfomycin as DT, and 2/5 (40%) received C/A in the post‐engraftment phase as ET for FN (n = 1) and severe pneumonia (n = 1). Among non‐carriers, 1 patient received C/A in the post‐engraftment phase as ET for CDI (septic shock).Three patients received C/T, none as DT of PE‐BSI. Among pre‐HSCT CR‐Pa carriers, 1/3 (33%) developed CR‐Pa PE‐BSI resistant to C/T and 1/3 (33%) received C/T in the post‐engraftment phase as DT of CR‐Pa intra‐abdominal infection. Two non‐carriers received C/T in the post‐engraftment phase as ET for severe pneumonia.Overall, 22 PE‐BSI episodes occurred in 21 patients (30%): 10/22 by GNB [4 E. coli (50% ESBL‐producer), 4 Kp (100% KPC‐producer), 2 Pa (50% CR)] and 12/22 by gram‐positive bacteria (GPB) [3 E. faecalis, 7 E. faecium, 2 S. epidermidis].While infection‐related mortality (IRM) at 30 days was 0% among patients with GPB PE‐BSI, it was 30% in patients with GNB PE‐BSI (3/10): 2/4 patients with KPC‐Kp PE‐BSI died, in addition to the patient with CR‐Pa PE‐BSI resistant to C/T.Summary/Conclusion:A longitudinal monitoring of MDR‐GNB colonization, allow us to select carriers who benefit a prompt administration of new antibiotics, improving the outcome of HSCT procedure in a high‐risk population. MDR‐GNB PE‐BSI are the main determinant of IRM at 30 days and C/A is safe and effective in its containment.

PS1269 AUTOIMMUNE NEUTROPENIA OF INFANCY- UNEXPECTED PREVALENCE OF PSEUDOMONAS SKIN INFECTIONS

Background: Febrile neutropenia (FN) is a common life-threatening complication in allogeneic HSCT recipients. The growing incidence of multi-drug resistant Gram-negative bacteria (MDR-GNB) is a public health challenge worldwide. Two new antibiotics [ceftazidime/avibactam (C/A), ceftolozane/tazobactam (C/T)], active against carbapenem-resistant (CR) GNB, have been introduced in clinical practice. Aims: Within an antimicrobial stewardship program, we aim to analyze the place in therapy of C/A and C/T, splinted up by indication [definite therapy (DT) of MDR-GNB pre-engraftment bloodstream infection (PE-BSI) in MDR-GNB carriers, empirical therapy (ET) of FN in MDR-GNB carriers, ET of clinically documented infection (CDI) in non-carriers]. Secondly, we describe PE-BSI. Methods: From January to December 2018, we conducted a retrospective study on consecutive adult patients affected by high-risk hematological diseases who received allogeneic HSCT in the Hematology and BMT Unit of our institute. According to institutional guidelines, all patients received levofloxacin prophylaxis and active weekly surveillance for MDR-GNB colonization by rectal swab. Results: Seventy patients underwent HSCT, mainly for acute myeloid leukemia (55%): HLA-matched related donor (n = 12), HLA-matched unrelated donor (n = 33), haploidentical donor (n = 23) and cord blood (n = 2). The graft source was unmanipulated peripheral blood, using myeloablative conditioning and post-transplant cyclophosphamide GvHD prophylaxis. Overall, 8/70 patients (11%) were MDR-GNB carriers before HSCT [5 CR-Klebsiella pneumoniae (Kp; 4/5 KPC producer), 3 CR-Pseudomonas aeruginosa (Pa; 0/3 MBL producer, 2/3 resistant to C/T)] and 9/62 non-carriers (15%) acquired colonization after HSCT [5 CR- Kp (4/5 KPC producer), 3 CR- Pa (0/3 MBL producer, 1/3 resistant to C/T), 1 CR-Enterobacter cloacae MBL-producer]. Nine patients received C/A. Among pre-HSCT CR-Kp carriers, 3/5 (60%) developed KPC-Kp PE-BSI, receiving a combination DT with C/A [tigecyclin (n = 2), gentamycin (n = 1)], and 2/5 (40%) received C/A in the pre-engraftment phase as ET for FN with a median time to de-escalation of 8 days. Among post-HSCT CR-Kp carriers, 1/5 (20%) developed KPC-Kp PE-BSI, receiving C/A plus fosfomycin as DT, and 2/5 (40%) received C/A in the post-engraftment phase as ET for FN (n = 1) and severe pneumonia (n = 1). Among non-carriers, 1 patient received C/A in the post-engraftment phase as ET for CDI (septic shock). Three patients received C/T, none as DT of PE-BSI. Among pre-HSCT CR-Pa carriers, 1/3 (33%) developed CR-Pa PE-BSI resistant to C/T and 1/3 (33%) received C/T in the post-engraftment phase as DT of CR-Pa intra-abdominal infection. Two non-carriers received C/T in the post-engraftment phase as ET for severe pneumonia. Overall, 22 PE-BSI episodes occurred in 21 patients (30%): 10/22 by GNB [4 E. coli (50% ESBL-producer), 4 Kp (100% KPC-producer), 2 Pa (50% CR)] and 12/22 by gram-positive bacteria (GPB) [3 E. faecalis, 7 E. faecium, 2 S. epidermidis]. While infection-related mortality (IRM) at 30 days was 0% among patients with GPB PE-BSI, it was 30% in patients with GNB PE-BSI (3/10): 2/4 patients with KPC-Kp PE-BSI died, in addition to the patient with CR-Pa PE-BSI resistant to C/T. Summary/Conclusion: A longitudinal monitoring of MDR-GNB colonization, allow us to select carriers who benefit a prompt administration of new antibiotics, improving the outcome of HSCT procedure in a high-risk population. MDR-GNB PE-BSI are the main determinant of IRM at 30 days and C/A is safe and effective in its containment.

Comparison of the Power of Procalcitonin and C-Reactive Protein to Discriminate between Different Aetiologies of Fever in Prolonged Profound Neutropenia: A Single-Centre Prospective Observational Study.

Management of fever in prolonged, profound neutropenia remains challenging with many possible infectious and non-infectious causes. We investigated whether procalcitonin (PCT) is superior to C-reactive protein (CRP) in discriminating between different aetiologies of fever in this setting.CRP and PCT were tested daily during 93 neutropenic episodes in 66 patients. During this study period, 121 febrile episodes occurred and were classified into four categories based on clinical and microbiological findings: microbiologically documented infection (MDI); clinically documented infection (CDI); proven or probable invasive fungal disease (IFD); fever of unknown origin (FUO). Values of PCT and CRP at fever onset as well as two days later were considered for analysis of their performance in distinguishing aetiologies of fever.At fever onset, no significant difference in PCT values was observed between different aetiologies of fever, whereas median CRP values were significantly higher in case of IFD (median 98.8 mg/L vs 28.8 mg/L, p=0.027). Both PCT and CRP reached their peak at a median of 2 days after fever onset. Median PCT values on day 2 showed no significant difference between the aetiologies of fever. Median CRP values on day 2 were significantly higher in IFD (median 172 mg/L versus 78.4 mg/L, p=0.002). In MDI median CRP values rose > 100 mg/L, whereas they did not in CDI or FUO.PCT has no added value over CRP for clinical management of fever in prolonged, profound neutropenia. When performing reassessment 2 days after fever onset, CRP has better discriminatory power between aetiologies of fever.

Cefepime vs. cefoperazone/sulbactam in combination with amikacin as empirical antibiotic therapy in febrile neutropenia.

Beta lactams are standard empirical therapy for febrile neutropenia (FN). The aim of this study was to evaluate the efficacy and safety of cefepime monotherapy compared with cefoperazone/sulbactam plus amikacin (CS + A) for empirical treatment of high risk FN. One hundred seventy-five patients with 336 FN episodes were randomized to receive either cefepime (2g q8h for adults and 50mg/kg q8h for children) or CS (2g q8h for adults and 50mg/kg q8h for children) plus amikacin (15mg/kg once a day). Positive response was defined as afebrile within 72h of starting antibiotics, persistent afebrile status more than 48h and no requirement of second-line antibiotics and antifungal agents. Three hundred thirty-six episodes were assessable for efficacy (168 cefepime, 168 CS + A). The positive response to antibiotics was identical for cefepime (53%) and CS + A (53%). Positive response was similar in MDI (microbiologically documented infection), 50 vs. 35% (p = 0.248), CDI (clinically documented infection), 50 vs. 35% (p = 0.259), combination CDI + MDI, 25 vs. 15% (p = 0.400), FUO (fever of unknown origin), 68 vs. 72% (p = 0.577) respectively in the two groups. The successful discontinuation of antibiotics at 72h in FUO was similar in both groups (60 vs. 59%, p = 0.544). Total drug-related adverse events were similar in both groups (8 vs. 6%) except renal dysfunction was high in CS + A (1 vs. 7 events). Mortality was the same between two groups (8 vs 7%). Cefepime monotherapy and CS + A had similar efficacy as first-line therapy for FN. Discontinuation of empirical antibiotics is safe and feasible approach in selected group of FUO patients.

The diagnostic and prognostic value of angiopoietins compared with C-reactive protein and procalcitonin in children with febrile neutropenia.

Mimaroğlu E, Çıtak EÇ, Kuyucu N, Eskendari G. The diagnostic and prognostic value of angiopoietins compared with C-reactive protein and procalcitonin in children with febrile neutropenia. Turk J Pediatr 2017; 59: 418-425. In this study, we aimed to determine serum angiopoetin (Ang) levels and compare them with levels of C-reactive protein (CRP) and procalcitonin (PCT). Cancer patients (aged 0-18 years) who experienced febrile neutropenia attacks were included in the study. Ang-1, Ang-2, CRP, and PCT were analyzed at admission and 2nd day. Ninety-four episodes of febrile neutropenia that developed in 62 patients were analyzed in this study. The mean age of the patients was 7.56 ± 4.8 (0.5-17) years. The patients had lymphoma (33.9%), solid tumors (48.4%), and other cancer (17.7%). The percentages of the patients with fever of unknown origin (FUO), clinically documented infection (CDI), and microbiologically documented infection (MDI) categories were 45.7%, 22.3%, and 31.9%, respectively. During the study period 11 patients were lost to follow-up. The levels of CRP, PCT and Ang-2 were significantly higher; and that of Ang-1 was significantly lower, compared to the controls. The differentiation cannot be made between the groups by CRP and PCT levels. The level of Ang-1 was the lowest in MDI group; the level of Ang-2 and the ratio of Ang-2/Ang-1 were high in each group. Ang-1, Ang-2 and the ratio of Ang-2/Ang-1 were significantly associated with mortality. Angs correlated with the severity of infection.

A clinical evaluation of efficacy and safety of cefepime monotherapy versus piperacillin-tazobactam in patients of paediatric age group with febrile neutropenia in a tertiary care centre of north India

To evaluate clinically the efficacy and safety in northern India of cefepime monotherapy versus piperacillin-tazobactam in patients of paediatric age group with febrile neutropenia. Children aged ≤18 years admitted febrile with chemotherapy-induced neutropenia were randomised into two groups comprising 20 cases in each group viz. CEF (receiving cefepime only) and PIP-TAZO (receiving piperacillin-tazobactam). Based on clinical and laboratory tests, patients were classified into: microbiologically documented infections (MDI); clinically documented infections (CDI); and unexplained fever (UF). They were assessed for clinical signs and symptoms as well as laboratory parameters at the time of enrolment and subsequently on days 3 and 7. Incidence of MDI, CDI and UF were 22.5%, 47.5% and 30%, respectively. The mean duration of neutropenia (in days) was 5.45 ± 2.1 in the PIP-TAZO group and 5.5 ± 1.5 in the CEF group (P = 0.305). The success rate defined as clearing infection effectively and improvement of neutropenia was comparable (P = 0.705). There was a mortality rate of 20% in the PIP-TAZO group as compared to 10% in the CEF group. We conclude that cefepime monotherapy and piperacillin-tazobactam are equally efficacious and safe in treating patients with febrile neutropenia. Empirical monotherapy with cefepime would prevent an unnecessary extra economic burden as well as avoiding the serious adverse or toxic effects of multi-drug regimes, especially in low- and middle-income countries.

Adrenomedullin—A New Marker in Febrile Neutropenia: Comparison With CRP and Procalcitonin

In this study, we aimed to determine serum adrenomedullin levels and compare them with levels of C-reactive protein (CRP) and procalcitonin (PCT). Cancer patients aged 0–18 years who experienced febrile neutropenia attacks were included in the study. Adrenomedullin, CRP, and PCT were analyzed at admission, day 3, and days 7–10 later. Fifty episodes of febrile neutropenia that developed in 37 patients were analyzed in this study. The mean age of the patients was 7.5 ± 4.7 (1–18) years. The patients had leukemia (73%), solid tumors (19%), and lymphoma (8%). The percentages of the patients in the clinically documented infection (CDI), fever of unknown origin (FUO), sepsis, and microbiological documented infection (MDI) categories were 34%, 34%, 20%, and 12%, respectively. During the study period, four patients were lost. In the MDI group, adrenomedullin levels on day 3 were significantly higher than those in the CDI and FUO groups. PCT levels were significantly higher in the sepsis group than those in the CDI group at admission, day 3, and days 7–10. In the sepsis group, PCT levels on days 7–10 days were significantly higher than those in the sepsis group. PCT values from the deceased patients on days 7–10 were significantly higher than those from patients who survived. CRP levels did not differ significantly among the febrile neutropenia groups. First, in our study, adrenomedullin was used as a biomarker in the febrile neutropenia episodes of children with cancer. Among adrenomedullin, CRP, and PCT, procalcitonin demonstrates the highest correlation with the severity of infection.

Significance of Interleukin-6 (IL-6) and C-reactive Protein (CRP) in Children and Young Adults With Febrile Neutropenia During Chemotherapy for Cancer

We evaluated the usefulness of interleukin-6 (IL-6) and C-reactive protein (CRP) at the onset of febrile neutropenia and 72 hours later, in identifying risk groups and assessing response to antibiotic therapy. All episodes of febrile neutropenia were divided in 3 study groups-microbiologically documented infection (MDI), clinically documented infection (CDI), and fever of unknown origin (FUO). Three outcome groups were defined as those responding to first-line antibiotics (R1), those responding to second-line antibiotics (R2), and those requiring antifungal therapy (RAF). Median values of IL-6 and CRP were compared between the groups. There were 57 episodes of febrile neutropenia among 26 patients younger than 25 years during 1 year of study period. On day 1, median IL-6 level was significantly lower in FUO group compared with CDI+MDI groups combined (P < 0.001). Rise in CRP on day 3 was highly significant to differentiate MDI group from other 2 groups (P < 0.001). The CRP also increased significantly on day 3 in RAF (P < 0.001) and R2 (P = 0.002) groups than in R1 group. Low level of IL-6 may help differentiate patients with FUO from those with documented infections. A rising CRP is indicative of serious infection.

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.

Infectious Events In Patients with Chronic Myeloid Leukemia Treated with Nilotinib as a Front Line Therapy and After Imatinib Failure

AbstractAbstract 1233 Background:Different tyrosine kinase inhibitors have different effect on various kinases. Dasatinib and bosutinib inhibt Src, an effect that has been suggested could have an immunosuppressive effect. Others, such as imatinib and nilotinib, have no discernible effect on Src. All agents however can cause myelosuppression. Because of these effects, and in view of long-term us of these agent, infectious complications may occur during therapy. The risk of infectious complications with nilotinib therapy has not been reported. Aim: To investigate the frequency and characteristics of infectious events in patients (pts) with chronic myeloid leukemia (CML) treated with Nilotinib as a front line therapy (FL) or after Imatinib failure (IF). Methods:Retrospective review of medical records of patients who received Nilotinib between Jun 2004 and Jun 2010, either as FL therapy or as salvage therapy after IF. Results:The total number of pts treated were 169, including 90 FL pts and 79 IF pts. Overall, 132 pts (78%) were in chronic phase and 37 pts (22%) were in accelerated phase. The median age was 53 (20 - 87) years and 57% of the pts were male. Median follow up for all patients was 30 months. Among the FL therapy group, 9 (10%) pts developed any infection, whereas 29 of 79 (37%) pts treated with nilotinib after IF developed any infection. Table 1 shows the types of infections for both groups.Of the 43 infections in the IF group, 26 (60%) were clinically documented infections (CDI), 8 FUO (19%), 3 bacterial (7%), 5 viral (12%) [Zoster (2), influenza (2), RSV (1)] and 1 (2%) fungal infections. Nine (21%) of these infectious episodes occurred with neutropenia and 24/43 episodes (56%) required hospitalization. In the FL group, 6 (60%) of the events were CDI, 2 (20%) were FUO, 1 (10%) was bacterial and 1 (10%) was viral [zoster]. None of the FL group events were associated with neutropenia and only 2/10 episodes required hospitalization. We also studied the relationship of infectious events according to the nilotinib doses at the moment of the infection. In IF group, 46% of the events occurred at 800mg/day, 30% at 400mg/day, 14% at 1200 mg/day and 10% at 200mg/day or less. In the FL group, 6 (60%) events occurred at 800mg/day and 40% at 400mg/day. There was no statistically significant association between infectious event rate and the nilotinib starting dose. Overall mortality at 30 months was 22% (29/169), 35 (44%) of the IF group died and 2 (2%) of the FL died. Three of the deaths in the IF group and none in the FT group were due to infection. Conclusions:Although several patients developed infectious complications during nilotinib therapy, particularly when used after imatinib failure, these episodes were common infections that responded rapidly to adequate intervention. Atypical infections were not seen. Further research is needed to determine predisposing factor and measures to prevent infections. Disclosures:Cortes:Novartis: Research Funding; BMS: Research Funding; Pfizer: Research Funding; Pfizer: Consultancy. Kantarjian:BMS, Pfizer and Novartis: Research Funding; Novartis: Consultancy. O'Brien:Novartis: Research Funding; BMS: Research Funding.

Analysis of Infections In Acute Leukemia According to the Different Phases of Treatment Reveals Marked Differences Potentially Useful for Tailored Prophylactic and Empiric Antimicrobial Treatments

AbstractAbstract 2773 Introduction.Infections during chemotherapy-induced aplasia are still a problem in the management of acute leukemia (AL) patients (pts), causing potentially life-threatening consequences and treatment delays. Adequate empiric antibiotic therapy is crucial for a favourable clinical evolution. In order to better define the best antimicrobial management for AL pts during different phases of treatment, we analyzed all infectious events occurring to consecutively treated AL pts at our Institute during a period of six years. Patients and Methods.Since June 2004 a program of active epidemiological surveillance is ongoing at our Institute. Data concerning infections occurring during chemotherapy-induced cytopenia in AL pts were analysed. All pts showing fever or signs/symptoms of infection underwent thorax X-ray and culture of any other fluid/drainage obtained from a suspected infection site. CT scan of thorax was performed when fever persisted >48h. An infection was considered clinically documented (CDI) when pertinent symptoms, objective signs, or diagnostic radiological findings were present and microbiologically documented (MDI) when microorganisms were isolated. Results.From June 2004 to May 2010, 210 cases of AL (154 acute myeloid leukemia [AML], 53 acute lymphoblastic leukemia [ALL], and 3 blastic plasmacytoid dendritic cell leukemia), were diagnosed and treated with at least one induction cycle followed by consolidation and with reinduction cycles in relapsing/refractory pts. Overall, 1014 chemotherapy cycles were delivered, subdivided as induction (I) (210), consolidation (C) (708) and salvage (S) (96) treatment. Overall 309 clinically documented infections (CDI) were observed (30.5%). Incidence of CDI was higher during S therapy in comparison with I or C (77.1% vs 41.9% and 20.7%, p<0.0001). Incidence of pneumonia was similar in S and I phase (18.7% vs 17.6%) and significantly higher than in C (1.8%, p<0.0001). Incidence of bloodstream infections (BSI) was similar during I and C phase (20% and 15%, p=0.09) and significantly lower than in S (54.2%, p<0.0001). MDI were diagnosed in 270/1014 cycles (26.6%). Isolates were Gram negative (G-) in 54.8%, Gram-positive (G+) in 32.6% and fungi (F, moulds only) in 2,6% of cases; in 27 cases (10%) a mixed infection was documented. Frequency of fungal infections was higher during I therapy (6.9%) than in C+S (1%, p=0.016). Epidemiological distribution of G+ and G- infections during different phases was similar, with the exception of a lower frequency of G- during I (41.7%) vs C+S (59.6%, p=0.012). Mixed infections were more frequent during I (16.7%) than C+S (7.6%, p=0.038). Overall, 297 pathogens were isolated. S. aureus (9/270, 3.3%) and coagulase-negative staphylococci (43/270, 15.9%) were more frequent during I than C+S (respectively: 6.9% vs 2%, p=0.059 and 25% vs 12.6%, p=0.02); E. coli infections (92/270, 34.1%) were predominant during C (52.5%) in comparison with I+S (25.7%, p=0.004). Enterococci (30/270, 11.1%) and P. aeruginosa infections (52/270, 19.6%) were uniformly distributed during different phases. Death occurred in 19 cases (6 and 13 during I and S, respectively). At univariate analysis, S phase (p<0.0001), P. aeruginosa and S. aureus, alone or in association with other pathogens, emerged as poor prognostic factors (p=0.002 and 0.016, respectively). Two of the 7 cases of probable aspergillosis died during I. Conclusions.The S phase has the highest infectious risk, particularly for BSI. Both prophylactic and empiric antibiotic therapy guided by epidemiological data seem warranted. In the I phase pneumonia, particularly of mycotic origin, is relatively more frequent, confirming the appropriateness of an effective antifungal prophylaxis. The C phase carries a very limited risk of life-threatening infections and a relatively high incidence of E. coli. Therefore, the need for antimicrobial and antifungal prophylaxis during C may be reconsidered. Overall the frequency of bacterial infections largely outweighs that of fungal infections and is responsible for 84% of infectious deaths. Among bacteria, P. aeruginosa ranks as the second more frequent microorganism after E. coli and carries the highest risk of death. Given its intrinsic ability of developing antibiotic resistance, it should be presently considered as the most threatening infectious agent in AL against which empiric antibiotic therapy should be tailored. Disclosures:No relevant conflicts of interest to declare.

The Use of Intravenous Antibiotics at the Onset of Neutropenia In Patients Receiving Hematopoietic Stem Cell Transplants: A Pre-Emptive Strategy.

AbstractAbstract 4516 Background:Hematopoietic Stem Cell Transplant (HSCT) recipients are at risk for fatal bacterial infections during the engraftment period. Empirical antibiotic(s) at the onset of febrile neutropenia remain the standard of care. HSCT recipients began receiving intravenous once daily ceftriaxone at the onset of neutropenia (neutrophils< 1.0) regardless of fever as part of The Ottawa Hospital Blood and Marrow Outpatient Programme policy from Jan 2009; “pre-emptive” approach. We examined the impact of this policy on HSCT recipient outcomes. Methods:A retrospective “before-after” study was conducted to compare 2 cohorts [Jan 2008 - Dec 2008 (Empiric strategy) vs. Jan 09 - Dec 2009 (Pre-emptive strategy)] of patients receiving HSCT. Baseline characteristics between the groups were compared with 2 sample tests. Categorical variables and continuous variables were compared using Chi-squared and Wilcoxan rank-sum tests respectively. Results:There were 238 HSCTs performed between Jan 2008 and Dec 2009 with 127 and 111 in the earlier and later cohorts respectively. Baseline characteristics between the cohorts were similar. Infection related mortality at 100 days after HSCT and during the engraftment period was similar with a pre-emptive strategy compared to an empiric strategy (7.2% vs 10.2%; p=0.41 and 3.6% vs 7.1%; p=0.24) respectively. Further, there were no differences in ICU admissions or length of hospital stay. Both microbiologically (MDI) and clinically documented infections (CDI) were reduced (11.7% vs 29.1%; p=0.001 and 18.2% vs33.9%; p=0.007) with the pre-emptive strategy compared with an empiric strategy. Importantly, recipients of autologous HSCT appear to have a lower infection related mortality and reduced infection related ICU admissions during the engraftment period with the pre-emptive strategy compared to an empiric strategy (0% vs 6.8%; p=0.03 and 2.9% vs 12.2% p= 0.04). The need for escalation of antimicrobial treatments, resistance pattern of MDIs and cost of antimicrobial treatment were not different between the two groups. Conclusion:The use of once daily intravenous ceftriaxone at the onset of neutropenia in patients receiving HSCT is safe and effective particularly in patients receiving autologous HSCT. Further studies are warranted to study the impact of this “pre-emptive” strategy. Disclosures:No relevant conflicts of interest to declare.