Microbiologically Documented Infection Research Articles

Microbiologically Documented Infection-related Mortality in Children with Acute Leukemia: A Single-center Experience

Infections are a significant cause of morbidity and mortality of chemotherapy-induced neutropenia in children with acute leukemia. The aim of this study was to evaluate microbiologically documented infections (MDIs) during febrile neutropenia (FN) episodes and their relation to mortality. Four hundred eighty-seven FN episodes of 140 children were enrolled in this single-center study, and MDI in those FN episodes was retrospectively examined. Eighty-four patients (60%) had at least one positive peripheral blood, central line, or urine culture. MDIs were detected in 163 of 487 (33.4%) FN episodes of 84 children with leukemia. Gram-negative bacteria, Gram-positive bacteria, and fungal agents were isolated in 52.7%, 40.4%, and 6.9% of whole episodes. Coagulase-negative Staphylococci and Enterococci were the most detected Gram-positive bacteria. Klebsiella spp. and Escherichia coli were the most common Gram-negative bacteria isolated in the entire cohort. A central line was present in 145 MDI episodes, and catheter removal was required in 35 cases (17.7%) due to infection with Gram-negative bacteria, Gram-positive bacteria 43%, 28.5%, and fungus 28.5%, respectively. MDI-related mortality was 9.8%. The highest mortality rate (16.7%) was observed in Gram-negative bacteria and patients with relapsed and resistant leukemia. The most common infectious agent related to mortality was Klebsiella (31%). Resistance to third- or fourth-generation cephalosporins in Gram-negative bacteria was found to be over 50% of our cohort uri. Empirical antibiotic therapy at the onset of FN in neutropenic patients is crucial; therefore, the institution’s predominant pathogens and resistance patterns should guide the choice of empirical antimicrobials. To reduce mortality and morbidity, each center should know its local epidemiological data and antibiotic susceptibility.

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.

Density of antibiotic use and infectious complications in pediatric allogeneic hematopoietic cell transplantation.

Antibiotics, while an essential component of supportive care in allogeneic hematopoietic cell transplantation (allo-HCT), can have adverse effects and select for antibiotic resistance. Understanding of patterns of use will inform antimicrobial stewardship (AMS) interventions. Retrospective, single-center cohort of children undergoing first allo-HCT (n=125). Antibiotic prescription and infection data were included from the date conditioning was commenced until 30 days post allo-HCT. Antibiotic use was reported as length of therapy (LOT) (number of days a patient received an antibiotic) and days of therapy DOT (aggregating all antibiotics prescribed per day). Infections were classified as microbiologically documented infection (MDI) or clinically documented infections. At least one course of antibiotics was administered to 124 (99%) patients. The LOT was 636 per 1000 patient days and DOT was 959 per 1000 patient days. The median duration of cumulative antibiotic exposure per patient was 24 days (interquartile range [IQR] 20-30 days). There were 131 days of fever per 1000 patient days with patients febrile for a median of 4 days (IQR 1-7 days). Piperacillin-tazobactam was used for 116 (94%) of patients with an LOT of 532 per 1000 patient days. A total of 119 MDI episodes occurred in 74 (59%) patients, including blood stream infection in 30 (24%) and a proven/probable invasive fungal infection in 4 (3%). Pediatric HCT patients receive prolonged courses of broad-spectrum antibiotics relative to the frequency of fever and bacterial infections. This study has identified opportunities for AMS intervention to improve outcomes for our HCT patients.

Association of mannose-binding lectin 2 (MBL2) and suppressor of cytokine signaling-1 (SOCS1) gene variants in children with febrile neutropenia

IntroductionFebrile neutropenia (FEN) was reported in patients with solid malignancies at a rate of 5–10% and in patients with hematological malignancies at a rate of 20–25%. In our study, we aimed to investigate the effects of mannose-binding lectin 2 (MBL2) (rs1800450) and suppressor of cytokine signaling-1 (SOCS1) (rs33989964) gene variants on patients with FEN. MethodsA total of 123 patients who applied to pediatric emergency department between December 2019–12/2020 included in the study. Thirteen patients were excluded from the study due to the inability to obtain DNA. Demographic-clinical features at initial diagnosis and genotype distributions were recorded. The control group consisted of volunteers with the same ethnicity, age and gender, no active infection, and no consanguinity. ResultsCA/CA genotype of SOCS1 was found to be significantly higher in the healthy control group (p = 0.028). AB/BB genotype of MBL2 was significantly higher in FEN patients with a MASCC score of high risk, AA genotype was found to be higher in patients with low risk (p = 0.001). While the rate of microbiologically documented infection (MDI) was significantly lower in patients with the AA genotype of MBL2, it was significantly higher in patients with AA/BB genotypes (p = 0.025). MDI rate in patients with the del/del genotype of SOCS1 was found to be significantly lower than in patients with CA/CA + CA/del genotypes (p = 0.026). ConclusionsIn this study, it was revealed that low expression-related MBL2 genotypes were riskier for FEN and also, gene variants associated with high SOCS1 transcription were both protective against FEN and increased the rate of culture-negativity.

Characteristics and recognition of early infections in patients treated with commercial anti-CD19 CAR-T cells.

The characteristics of infections following chimeric antigen receptor T (CAR-T) cells targeting CD19 in real-word population are obscure. We analyzed infections' characteristics in the first month among consecutive patients with diffuse large B-cell lymphoma (DLBCL) (n=60, median age, 69.3years), treated with commercial CAR-T cells. ECOG performance status (PS) was 2-3 in most patients (58%). Infections were observed in 45% of patients (16, 27%, bacterial infections, and 14, 23%, viral infections). Bacterial infection included clinically documented infection in 7 (Pneumonia, n=5; periodontal infection, n=1; and cellulitis, n=1) and microbiology documented infection (MDI) in 9 patients (Gram-negative rod, n=5; Gram-positive cocci, n=3, bacteremia; polymicrobial, n=1). The most common viral infection was cytomegalovirus (CMV) reactivation (n=10, 17%) leading to initiation of anti-CMV treatment in 6 (60%) among these patients. None had CMV disease. In univariate analysis, immune effector cell-associated neurotoxicity syndrome (ICANS) was associated with higher incidence of bacterial infection (OR=4.5, P=.018), while there was a trend for lower incidence of bacterial infections in patients with chemosensitive disease to bridging therapy (OR=0.375, P=.074). Age or PS was not associated with increased risk of bacterial infection. Increase in C-reactive protein (CRP) prior to fever onset was associated with microbiologically documented infections. We conclude that infections are common in the first month following CAR-T-cell administration, however, were not increased in elderly patients or those presenting with poorer PS. Increase in CRP prior to fever onset could support infection over cytokine release syndrome.

Bolus Versus Prolonged Infusion of Broad-Spectrum Beta-Lactams for Patients with Hematologic Malignancies and High Risk Febrile Neutropenia - a Single Center Prospective Unblinded Randomized Trial

▪Background: Neutropenic fever is a life-threatening condition which is common in patients with hematologic malignancies, and prompt initiation of appropriate antibiotics is of great importance.Empirical treatment includes monotherapy with a beta-lactam containing anti-pseudomonal activity. Theoretically, time-dependent antibiotics are most active when administered as a continuous infusion, but evidence is lacking in cases of febrile neutropenia. This study examines the optimal dosing regimen (bolus infusion vs. prolonged 4 hour-infusion) for high risk patients undergoing hematopoietic cell transplantation or patients with acute leukemia and febrile neutropenia.Methods: This was a single center, prospective, unblinded randomized study, of 123 hospitalized hematologic patients enrolled between July 2015 and March 2017. The primary outcome was a successful response to treatment, defined as the combination of- defervescence at 96 hours after initiation of broad spectrum beta-lactams (pipracillin/tazobactam or ceftazidime) or before, sterile cultures after 72-96 hours, and no requirement of additional aminoglycoside therapy after 48 hours. Secondary outcomes included breakthrough fever or additional infection after 5 days from initiation of treatment, death within 30 days of study enrollment, duration of hospitalization, duration of neutropenia, occurrence of renal failure (doubling of serum creatinine levels) within 5 days, and requirement for noradrenaline due to hypotension. Patients were randomized using a computerized random number program and allocation was concealed by sequentially numbered sealed and opaque envelopes. All patients signed informed consent and the study was approved by the Tel Aviv Medical Center Institutional Review Board.Results: 123 patients were randomized to bolus infusion (n=63) and prolonged infusion (n=60). Febrile neutropenia occurred in 87% of the patients, and these patients were eligible for the intention-to-treat analysis (ITT). 73% of the patients were given at least one dose of antibiotic according to the allocation arm and were eligible for the per-protocol analysis, Figure. The patients' baseline characteristics were well-balanced between the 2 groups, Table 1. In the ITT analysis (Table 2), there was a higher success rate in patients allocated to the prolonged infusion arm, compared to those allocated to the bolus infusion arm (76% vs. 55%, p= .03). This was also true for the subgroups of patients with microbiologically documented infections (MDI) - (55.6% vs. 7.7%, p=.013) and blood stream infections, (BSI) - (67% vs. 8.3%, p=.009). Similarly, in the per-protocol analysis, the success rate was higher in patients allocated to the prolonged infusion arm who had MDI (62.5% vs. 12.5%, p=.039) or BSI (80% vs. 14.3%, p=.023). There was no difference in the secondary endpoint outcomes between the 2 groups. 30-day death rate was similarly low in both groups. Prolonged beta-lactam infusion was associated with significantly higher treatment success in a logistic regression model that included either BSI (odds ratio of 2.4, 95% CI 0.97-6.1, p=.058) or MDI (OR 2.8, 95% CI 1.1-7.4, p=.032) .Conclusions: This is the first randomized study showing superior treatment outcomes in patients with high-risk febrile neutropenia treated with prolonged versus bolus beta-lactam infusion. Optimization of beta-lactam dosing is a widely available and cost-effective strategy to improve treatment outcomes in patients with high risk febrile neutropenia. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

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.

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.

Interleukin-6 versus C-reactive protein as markers for early detection of bacteremia in febrile neutropenia in pediatric population

Abstract Introduction: Systemic infection leading to multiorgan failure during neutropenia is one of the leading causes of treatment-related mortality among children receiving chemotherapy. Reliable markers are needed to diagnose or rule out infection, to reduce the empirical use of broad-spectrum antibiotic therapy. Aims and Objectives: The aim is to compare the role of interleukin-6 versus C-reactive protein (CRP) as markers of sepsis in febrile neutropenia in pediatric patients while on chemotherapy for malignancy. Materials and Methods: This was a prospective observational study carried out in the Department of Paediatrics of a tertiary care Hospital in South India. All children with malignancy in the age group from 1 month to 18 years diagnosed to have febrile neutropenia during any phase of chemotherapy were included in the study. Multiple episodes of febrile neutropenia in the same child were analyzed as separate episodes. Results: Thirty-two episodes of febrile neutropenia were analyzed. There were 7 microbiologically documented infections (MDI), 19 clinically documented infections and 6 episodes of fever of unknown origin. Out of the 7 MDI, 5 were Gram-negative sepsis and 2 were Gram-positive sepsis. Gram-negative sepsis had a much higher median IL-6 value (169) than Gram-positive sepsis (17.5) and sterile blood cultures (52). However, median value of CRP was only slightly higher in Gram-positive sepsis (85.5) than in Gram-negative sepsis (60.7) and sterile blood cultures (44.2). Conclusion: In this study, higher IL-6 values predicted Gram-negative sepsis better than CRP.

Comparison of CRP and procalcitonin for etiological diagnosis of fever during febrile neutropenia in hematology patients- an experience from a tertiary care center in Northern India

IntroductionFebrile neutropenia is a common cause in morbidity and mortality during treatment of hematological neoplasms. MethodsSubjects included all cases admitted under hematology department with febrile neutropenia from February to June 2018. Each febrile episode was investigated by standard investigations (Blood culture, Chest x ray etc.); Procalcitonin (PCT) and c reactive protein (CRP) was sent at fever onset 0, 24, 48 h, day 7 and day 14. ResultsData was analyzed for 52 febrile episodes in 50 patients. PCT cut off value at 24 h of ≤1.2 ng/ml had a sensitivity and specificity of 62.5% and 87.5% for discriminating Invasive fungal infection (IFI) and Microbiologically documented infection (MDI) (p = 0.033). PCT had a negative predictive value of 70% for the diagnosis of IFI as compared to MDI. CRP cut off >160 mg/dl at 48 h was suggestive of fever due to fungal infection with a sensitivity of 100%, specificity of 48%, PPV of 33.3% and NPV of 100%. CRP at 24 and 48 h of fever was useful to distinguish non-infectious causes of fever from infectious causes. ConclusionPCT at 24 h and CRP at 48 h was useful in identifying fungal infection. CRP was a better marker when compared to PCT for identifying disease fever.

Identifying Factors That Predict for Unplanned Readmissions for Acute Myeloid Leukemia Patients Receiving Consolidation Cytarabine Based Therapies

Background: Younger patients (pts) with acute myeloid leukemia (AML) who enter a remission after intensive induction chemotherapy routinely receive at least one cycle of consolidation therapy with high dose cytarabine (HiDAC). This is commonly administered over a five-day inpatient stay, after which pts are discharged home as their blood counts nadir. It is thus a natural consequence of therapy that readmission for febrile neutropenia (FN) occurs, which can impact measures of quality and value in this population. Precise descriptions of incidence, type, and severity of infection, if identified, are lacking, and thus it is unknown to what standard cancer centers should be held for anticipated readmission. We measured these rates, and attempted to identify predictive factors for readmission. Methods: Adult AML pts ≥ 18 years of age who received at least one cycle of HiDAC consolidation (1000-3000 mg/m2 for six doses) in 2009-2019 were included. Our primary aim was to identify predictive factors for readmission after the first cycle of consolidation chemotherapy. The following pt characteristics and co-morbid conditions were analyzed: age, gender, body mass index (BMI), smoking status, AML cytogenetic risk status, history of diabetes, peripheral vascular disease, cardiovascular disease, chronic pulmonary disease, hepatic impairment, and other cancers. Secondary aims included: estimating rates of all-cause readmissions among all HiDAC cycles, defining the rate of FN readmissions, estimating rates of intensive care unit (ICU) admissions, clinical (e.g., probable pneumonia per imaging) and microbiologically-documented infections, prophylactic (ppx) medications used, and mortality. Statistical analyses interrogated potential risk factors for evidence of association with hospital readmission after the first cycle of consolidation chemotherapy. Results: We identified 182 AML pts who fit inclusion criteria. The median age was 50 years (range 19-73); 55% were female and 45% were male. Statistical analyses revealed no association with readmission after cycle 1 for cytogenetic risk (p=0.85), history of heart failure (p= 0.67), chronic pulmonary disease (p=1), connective tissue disease (p=0.53), cerebrovascular accident (p=0.63), diabetes (p=0.63), gender (p=0.07), history of lymphoma (p=0.53), other solid tumors (p=0.53), liver disease (p=1), myocardial infarction (p=0.71), peripheral vascular disease (p=1), or smoking status (p= 0.52). For 480 HiDAC cycles analyzed (88% at 3000 mg/m2), the overall readmission rate was 50% (242/480), of which 85% (205/242) were for FN. Those readmissions which were not FN were for cardiac complications (chest pain, EKG changes), non-neutropenic fevers or infections, neurotoxicity, bleeding or clotting events, or other symptoms associated with chemotherapy (nausea/vomiting, pain, etc.). Median time to FN hospital admission was 18 days (range 6-27) from the start of HiDAC. Of the 205 FN readmissions, 57% had documented infections. Of these infections, 41% were bacteremia, 23% fungal, 16% sepsis, 12% other bacterial, and 8% viral. Of 480 HiDAC cycles, ppx medications prescribed included: 92% fluoroquinolone (442/480), 81% anti-viral (389/480), 30 % anti-fungal (142/480), and 3% colony stimulating factor (14/480). Only 7% (14/205) of FN readmissions resulted in an ICU admission, and 1% (3/205) resulted in death. Conclusions: Approximately half of patients treated with consolidation therapy following intensive induction therapy can be expected to be readmitted to the hospital. The majority of FN readmissions were associated with clinical or microbiologically documented infections and are not avoidable, however ICU admission and death associated with these complications are rare. Readmission of AML pts following HiDAC is expected, and therefore, should be excluded from measures of value and quality. Disclosures Waldron: Amgen: Consultancy. Hobbs:Amgen: Research Funding; SimulStat Inc.: Consultancy. Advani:Macrogenics: Research Funding; Abbvie: Research Funding; Kite Pharmaceuticals: Consultancy; Pfizer: Honoraria, Research Funding; Amgen: Research Funding; Glycomimetics: Consultancy, Research Funding. Nazha:Incyte: Speakers Bureau; Abbvie: Consultancy; Daiichi Sankyo: Consultancy; Jazz Pharmacutical: Research Funding; Novartis: Speakers Bureau; MEI: Other: Data monitoring Committee; Tolero, Karyopharma: Honoraria. Gerds:Imago Biosciences: Research Funding; Roche: Research Funding; Celgene Corporation: Consultancy, Research Funding; Pfizer: Consultancy; CTI Biopharma: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Sierra Oncology: Research Funding. Sekeres:Syros: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees. Mukherjee:Partnership for Health Analytic Research, LLC (PHAR, LLC): Consultancy; McGraw Hill Hematology Oncology Board Review: Other: Editor; Projects in Knowledge: Honoraria; Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees.

Individual participant data validation of the PICNICC prediction model for febrile neutropenia

BackgroundRisk-stratified approaches to managing cancer therapies and their consequent complications rely on accurate predictions to work effectively. The risk-stratified management of fever with neutropenia is one such very common area...

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.

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.

Risk Factors for Microbiologically-documented Infections, Mortality and Prolonged Hospital Stay in Children with Febrile Neutropenia

To analyze the risk factors for microbiologically documented infection, mortality and hospital stay more than 5 days in children with febrile neutropenia. Cross-sectional study (July 2013-September 2014). Government-run, tertiary-care, university hospital in Chandigarh, Northern India. 414 episodes in 264 children aged <12 years, not undergoing stem-cell transplantation. Predictors for 'high-risk' febrile neutropenia. Microbiologically-documented infections were observed in 82 children (19.8%); bacterial 14.2%, fungal 4.3%, polymicrobial 9.7%. Complications were documented in 109 (26%) children. 43 (10.3%) died: 8 due to fungal and 35 due to bacterial sepsis. Children admitted within 7 days of the last chemotherapy (P<0.01) and having a non-upper respiratory focus of infection (P<0.02) were at risk of developing microbiologically-documented infections and death. Platelet count <20000/uL (P=0.03) was an additional predictor for microbiologically-documented infections, while albumin <2.5 g/dL (P=0.04) and C-reactive protein >90 mg/L (P=0.02) were risk factors predicting mortality. The median (IQR) duration of hospital stay was 5 (3,8) days. Hospital stay <5 days was seen in 144 (35%) children. Children with acute myeloid leukaemia (P<0.01) and admitted within 7 days of chemotherapy (P=0.02) were likely to have a prolonged hospital stay >5 days. Febrile neutropenic children admitted within 7 days of completion of chemotherapy, those with a non-upper respiratory focus of infection, CRP >90 mg/dL, platelet <20000/uL and albumin <2.5 g/dL need to be considered as 'high risk' for complications and mortality.

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 Impact of Nutritional Status and Complete Blood Count Parameters on Clinical Outcome in Geriatric Critically Ill Patients.

BackgroundThe geriatric population in intensive care units (ICUs) has recently increased. The aim of this study was to analyse the impact of initial complete blood count (CBC)-related parameters and nutritional status on morbidity and mortality in geriatric ICU patients.MethodsA retrospective analysis was made of geriatric patients admitted to our tertiary adult ICU for 1 year. Patients with a length of stay (LOS) of < 48 h, with hematological malignancy or age < 65 years age were excluded from the study. Initial albumin level was considered to reflect nutritional status. The prevelance and risk factors of mortality and microbiologically documented infection (MDI) were analysed.ResultsThe study included a total of 243 patients with a mean age of 78.96 ± 6.62 years. The overall mortality rate was 40.7%. The most common cause for admission was acute respiratory failure and sepsis (17.2% vs. 16.8%). The most common MDI sources were lower respiratory tract, bloodstream, and urinary tract infections. Patients with thrombocytopenia on admission had a higher mortality rate than patients with normal platelet count (P = 0.019). The initial albumin level of non-survivors was significantly lower than that of survivors (P = 0.001). There was a significant negative correlation between albumin level and LOS (r = -0.157; P = 0.000). Patients with hypoalbuminemia (albumin < 3.2 g/dL) at the time of diagnosis had higher mortality, LOS and MDI rates than those with normal albumin levels (P < 0.05). There was no significant relationship between any other CBC-related parameter and infection and mortality (P > 0.05).ConclusionsThrombocytopenia and hypoalbuminemia may be considered as major risk factors for morbidity and mortality in critically ill elderly patients.

Predicting Infectious ComplicatioNs in Children with Cancer: an external validation study

Background:The aim of this study was to validate the ‘Predicting Infectious ComplicatioNs in Children with Cancer’ (PICNICC) clinical decision rule (CDR) that predicts microbiologically documented infection (MDI) in children with cancer and fever and neutropenia (FN). We also investigated costs associated with current FN management strategies in Australia.Methods:Demographic, episode, outcome and cost data were retrospectively collected on 650 episodes of FN. We assessed the discrimination, calibration, sensitivity and specificity of the PICNICC CDR in our cohort compared with the derivation data set.Results:Using the original variable coefficients, the CDR performed poorly. After recalibration the PICNICC CDR had an area under the receiver operating characteristic (AUC-ROC) curve of 0.638 (95% CI 0.590–0.685) and calibration slope of 0.24. The sensitivity, specificity, positive predictive value and negative predictive value of the PICNICC CDR at presentation was 78.4%, 39.8%, 28.6% and 85.7%, respectively. For bacteraemia, the sensitivity improved to 85.2% and AUC-ROC to 0.71. Application at day 2, taking into consideration the proportion of MDI known (43%), further improved the sensitivity to 87.7%. Length of stay is the main contributor to cost of FN treatment, with an average cost per day of AUD 2183 in the low-risk group.Conclusions:For prediction of any MDI, the PICNICC rule did not perform as well at presentation in our cohort as compared with the derivation study. However, for bacteraemia, the predictive ability was similar to that of the derivation study, highlighting the importance of recalibration using local data. Performance also improved after an overnight period of observation. Implementation of a low-risk pathway, using the PICNICC CDR after a short period of inpatient observation, is likely to be safe and has the potential to reduce health-care expenditure.

Hospital readmission rate for febrile neutropenia (FN) following high dose cytarabine (HiDAC) consolidation chemotherapy for acute myeloid leukemia (AML).

e18513 Background: FN is an anticipated complication of consolidation with HiDAC for AML, though precise descriptions of incidence, type, and severity of infection leading to FN are lacking. Since AML patients (pts) with FN after HiDAC are routinely readmitted to the hospital, there is a likely impact on measures of quality and value in this population. Methods: Our primary aim was to define the rate of FN inpatient readmissions among all HiDAC cycles. Secondary aims included: estimating rates of all-cause readmissions, clinical (e.g., probable pneumonia per imaging) and microbiologically-documented infections, and identify pts-specific risk factors associated with readmission. Readmission per patient were modeled using Poisson regression, with means proportional to total cycles exposed, and logistic regression for the probability of FN per treatment cycle. Results: We identified 150 AML pts ≥ 18 years of age, who received at least one cycle of HiDAC consolidation (1000-3000 mg/m2 for six doses) in 2009-2016. The median age was 50 (range 19-69); 55% were female and 45% were male. For 417 HiDAC cycles analyzed (87% at 3000 mg/m2), all pts received flouroquinalone prophylaxis and the overall readmission rate was 49% (203/417), of which 86% (174/203) were for FN. Median time to FN hospital admission was 18 days (range 10-22) from the start of HiDAC. Of the 174 FN readmissions, 60% had documented infections. Of these infections, 35% were bacteremia, 29% other bacterial, 24% fungal, 6% sepsis, and 6% viral. Females had higher FN readmission rates (RR 1.7 (1.3, 2.4) p = 0.007), as did pts with higher BMI (RR 1.06 (1.01, 1.09) p = 0.005), while age and HiDAC dose were not associated with readmission. Only 34% of all readmissions were in the absence of a documented infection. Conclusions: The majority of FN readmissions were associated with clinical or microbiologically documented infections and are not avoidable. Females and pts with higher BMI were more likely to be readmitted. Readmission of AML pts following HiDAC is expected, and therefore, should be excluded from measures of value and quality.