Management of fever and neutropenia in the adult patient with acute myeloid leukemia.

INTRODUCTION: Febrile neutropenia represents one of the most common treatment-associated complications in the management of acute myeloid leukemia (AML) and is considered an oncologic emergency. Rapid and detailed workup as well as the initiation of empiric broad-spectrum antibiotic therapy are critical to avoid sepsis and to reduce mortality. Although a definitive source of infection is frequently not identified, the severely immunosuppressed status of the AML patient undergoing cytotoxic therapy results in a high risk for a wide array of bacterial, fungal, and viral etiologies. AREAS COVERED: The authors herein review the diagnostic and therapeutic approach to the neutropenic leukemia patient based on the current knowledge. Special consideration is given to the rapidly changing therapeutic landscape in AML, creating new challenges in the management of infectious complications. EXPERT OPINION: Multidrug-resistant organisms pose a major challenge in the management of neutropenic fever patients with hematologic malignancies - including AML. Future directions to improve outcomes demand innovative treatment approaches as well as advances in biomarker research to facilitate diagnosis and disease monitoring. Recent achievements in AML-targeted therapy led to an increased incidence of differentiation syndrome, a potentially life-threatening side effect that frequently resembles clinical infection and requires prompt recognition and aggressive intervention.

Hallazgo inusual en la tinción de Gram de hemocultivos en una paciente con neutropenia febril prolongada y leucemia mieloide aguda / Unusual finding in Gram staining of blood cultures in a patient with prolonged febrile neutropenia and acute myeloid leukaemia

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Shock séptico por Leptotrichia buccalis en paciente neutropénico por quimioterapia / Septic shock caused by Leptotrichia buccalis in a neutropenic patient secondary to chemotherapy

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Hepatosplenic Fungal Infections in Children With Leukemia-Risk Factors and Outcome: A Multicentric Study.

BACKGROUND: Invasive fungal infections, including hepatosplenic fungal infections (HSFI), cause significant morbidity and mortality in children with leukemia. There are not enough data to support for the best approach to diagnosis of HSFI in children, nor for the best treatment. PROCEDURE: In this multicentric study, we assessed the demographic data, clinical and radiologic features, treatment, and outcome of 40 children with leukemia and HSFI from 12 centers. RESULTS: All cases were radiologically diagnosed with abdominal ultrasound, which was performed at a median of 7 days, of the febrile neutropenic episode. Mucor was identified by histopathology in 1, and Candida was identified in blood cultures in 8 patients. Twenty-two had fungal infection in additional sites, mostly lungs. Nine patients died. Four received a single agent, and 36 a combination of antifungals. CONCLUSIONS: Early diagnosis of HSFI is challenging because signs and symptoms are usually nonspecific. In neutropenic children, persistent fever, back pain extending to the shoulder, widespread muscle pain, and increased serum galactomannan levels should alert clinicians. Abdominal imaging, particularly an abdominal ultrasound, which is easy to perform and available even in most resource-limited countries, should be recommended in children with prolonged neutropenic fever, even in the absence of localizing signs and symptoms.

Blood Stream Infections and Antibiotic Utilization in Pediatric Leukemia Patients With Febrile Neutropenia.

BACKGROUND: Frequent surveillance of bacterial pathogens responsible for microbiologically defined-blood stream infections (MD-BSI), and their respective antibiotic susceptibilities is central to tailoring empiric antibiotic therapy in febrile neutropenia (FN) episodes in pediatric patients with leukemia. The safety of deescalating antibiotic therapy in pediatric patients with leukemia and neutropenia is incompletely understood. METHODS: A retrospective chart review of 194 FN episodes occurred between the years of 2013 and 2016 in 67 patients with leukemia. Clinical and microbiologic data were recorded. RESULTS: MD-BSI occurred in 36 of 194 (18%) of FN episodes. Deescalation of empiric antibiotic therapy based on antibiotic susceptibilities was possible in 25 of 36 (69.4%) episodes. In those 25 episodes, where there was an opportunity to deescalate the antibiotic spectrum, it was clinically appropriate to do so in 19. Deescalation occurred in 9 (47.4%) of these episodes without complication. The remaining 10 patients received a median of 20 additional days of broad-spectrum antibiotic therapy (range, 12 to 30 d). CONCLUSIONS: In our small cohort of patients, deescalation of antibiotic therapy based on antimicrobial susceptibilities did not result in complication. Larger prospective studies are needed to address the safety of deescalating antibiotic therapy in this population.

Urine cultures at the onset of febrile neutropenia rarely impact antibiotic management in asymptomatic adult cancer patients.

PURPOSE: There is a paucity of data regarding the utility of routine urine cultures in adults with febrile neutropenia (FN) without urinary symptoms receiving protocolised antibiotics. This is reflected by inconsistent recommendations in international and regional FN guidelines. We addressed this issue by retrospectively reviewing the impact of routine urine cultures on antibiotic management in haematology cancer inpatients at a tertiary hospital. METHODS: All haematology inpatients over a 5-year period (2011-2015) were retrospectively reviewed for episodes of FN (neutrophil count < 0.5 × 109/L and fever > 37.5 °C). For each episode, demographic data, urinary tract symptoms and signs (absence of which was termed 'asymptomatic'), urinalysis and urine culture results, antibiotic therapy and duration, and patient outcomes were collected. A urine culture was considered positive if > 105 colony forming units (CFU)/L were detected. Empiric antibiotic therapy for FN consisted of intravenous piperacillin/tazobactam in stable patients, with the addition of vancomycin and a single dose of gentamicin if systemically compromised. RESULTS: Four hundred and thirty-three episodes of FN were identified in 317 patients. Urine cultures were performed in 362 (84%) episodes. Cultures were positive in 9 of 48 (19%) symptomatic episodes versus 8 of 314 (2.5%) asymptomatic episodes (RR = 7.4, p < 0.0001). A change in antibiotic management due a positive urine culture occurred in only 5 episodes (1.4%): 3 of 48 (6.3%) symptomatic and 2 of 314 (0.6%) asymptomatic episodes respectively (RR = 9.8, p = 0.01). CONCLUSION: Routine urine cultures in FN patients without urinary symptoms who are already receiving protocolised broad spectrum antibiotics rarely impact subsequent antibiotic management.

Phenotypic screening and molecular characterization of carbapenemase-producing Gram-negative bacilli recovered from febrile neutropenic pediatric cancer patients in Egypt.

AIM: Infections with carbapenem-resistant Gram-negative bacteria (GNB) are among the most frequent complications in the immunocompromised cancer patients because of their considerable morbidity and mortality. Therefore, the aim of the current study was to characterize the prevalence of carbapenemase-producing GNB recovered from febrile neutropenic pediatric cancer patients in Egypt. METHODS: Standard methods were used for identification, sensitivity testing (Kirby-Bauer and broth microdilution method according to CLSI guidelines). Standard methods were applied for both phenotypic and genotypic detection of the carbapenemase-producing GNB. RESULTS: A total of 185 GNB were recovered from different clinical specimens, Escherichia (E.) coli (86; 46.48%), followed by Klebsiella spp. (71; 38.37%), Acinetobacter (A.) baumannii (7; 3.78%) and others including Pseudomonas spp., Enterobacter (Ent.) cloacae and Proteus spp. (21; 11.35%). It is a matter of concern that 116 out of 171 enterobacterial isolates (94.15%) showed resistance to three or more antimicrobial classes and were considered multidrug resistant. Additionally, the rate of carbapenem-resistance displayed a worrisome trend as 113 out of 171 enterobacterial isolates (66.08%) and 12 out of 14 non fermenting bacilli (85.71%) showed resistance pattern to at least one of the tested carbapenems. After performing a series of phenotypic tests for initial screening of potential carbapenemase producers, molecular characterization to the 29 extracted plasmids were subjected to PCR (using 5 common carbapenemase primers). The results revealed that blaOXA-48 was the most prevalent 17 (58.62%), followed by blaNDM 8(27.58%), then blaVIM 3 (10.3%) and blaKPC 2 (6.89%). CONCLUSION: These results are an alarming threat to public health that calls for urgent application of antimicrobial stewardship programs along with routine surveillance for controlling outbreaks.

One percent chlorhexidine-alcohol for preventing central venous catheter-related infection during intensive chemotherapy for patients with haematologic malignancies.

A central venous catheter (CVC) is a catheter placed into a large vein, and is used for chemotherapy administration. However, there is little confirmatory data on which antiseptic-such as chlorhexidine or povidone-iodine (PI) -is more protective against CVC-related infectious complications in patients receiving intensive chemotherapy. We aimed to compare the effectiveness of 1% chlorhexidine gluconate in 70% alcohol (CH) vs. PI for skin disinfection before CVC insertion in patients receiving intensive chemotherapy. Methods We used either CH or 10% PI as skin antiseptics before CVC insertion, and assessed which agent was more protective against CVC-related infection. The participants were 112 patients with haematologic malignancies who underwent chemotherapy; a total of 292 CVCs were inserted over this period. Blood cultures were obtained when febrile neutropenia occurred. The CVC was removed and the catheter-tip qualitatively cultured when catheter-related infection was suspected. The cumulative incidence of febrile neutropenia, microbial growth from blood or catheter-tip culture, and catheter-related blood stream infection (CRBSI) was evaluated retrospectively. A univariate Cox proportional hazards model showed that CH significantly alleviated infectious complications. Notably, no case of CRBSI occurred in the CH group. Multivariate analysis, adjusted for prolonged neutropenia (>15 days) and older age (>52 years), also showed significant reduction in the cumulative incidence of microbial growth from catheter-tips in the CH group (hazard ratio = 0.146, 95% confidence interval: 0.023-0.502, p = 0.0008). Disinfection using CH, compared with PI, can potentially decrease catheter-related infection without causing adverse skin reactions in patients with haematologic malignancies.

Does ciprofloxacin prophylaxis during chemotherapy induce intestinal microflora resistance to ceftazidime in children with cancer?

To determine the susceptibility and minimal inhibitory concentrations (MIC) of ceftazidime, the commonly used empirical antibiotic in patients with febrile neutropenia, in Escherichia coli and Klebsiella pneumoniae isolated from the intestinal microflora of pediatric patients with cancer, who received ciprofloxacin prophylaxis during chemotherapy, children younger than 18 years with acute lymphoblastic leukemia or lymphoma scheduled to undergo chemotherapy were randomized to receive oral ciprofloxacin 20 mg/kg/day or placebo from the beginning of their chemotherapy. Rectal swab cultures were taken before (R0) and at 1 (R1), 2 (R2), and 3 (R3) weeks during the intervention. The antimicrobial susceptibilities and MICs of ceftazidime and ciprofloxacin were determined via the E test. Of the total 87 patients enrolled, 44 received ciprofloxacin and 43 placebo. A total of 350 isolates were obtained, 62, 49, 46 and 22 from the ciprofloxacin group and 68, 54, 38 and 11 from the placebo group at R0, R1, R2 and R3, respectively. The percentages of ceftazidime susceptibility did not show significantly greater decreases from R0 to R1-R3 in the ciprofloxacin group compared to the placebo group. The MIC50s of ceftazidime showed significantly greater increases after ciprofloxacin prophylaxis during R1-R3 compared to R0 in the intervention group compared to the placebo group (R0, 0.12 vs. 0.12; R1, 0.19 vs. 0.12; R2, 0.19 vs. 0.12 and R3, 0.38 vs. 0.09 µg/mL, respectively). Due to the increasing MIC50 of ceftazidime over time after ciprofloxacin prophylaxis, the use of ceftazidime in patients who have previously had ciprofloxacin prophylaxis needs to be closely monitored.

Acute Oncology Care: A narrative review of the acute management of neutropenic sepsis and immune-related toxicities of checkpoint inhibitors.

Cancer care has become increasingly specialized and advances in therapy have resulted in a larger number of patients receiving care. There has been a significant increase in the number of patients presenting with cancer related emergencies including treatment toxicities and those directly related to the malignancy. Suspected neutropenic sepsis is an acute medical emergency and empirical antibiotic therapy should be administered immediately. The goal of empirical therapy is to cover the most likely pathogens that will cause life-threatening infections in neutropenic patients. Patients with febrile neutropenia are a heterogeneous group with only a minority of treated patients developing significant medical complications. Outpatient management of low risk febrile neutropenia patients identified by the MASCC score is a safe and effective strategy. Immunotherapy with "checkpoint inhibitors" has significantly improved outcomes for patients with metastatic melanoma and evidence of benefit in a wide range of malignancies is developing. Despite these clinical benefits a number of immune related adverse events have been recognised which can affect virtually all organ systems and are potentially fatal. The timing of the onset of the adverse events is dependent on the organ system affected and unlike anti-neoplastic therapy can be delayed significantly after initiation or completion of therapy. The field of Acute Oncology is changing rapidly. Alongside, the traditional challenge of neutropenic sepsis there are many emerging toxicities. Further research into the optimal management, strategies and pathways of acutely unwell patients with cancer is required.

Human herpesvirus-6 encephalitis following chemotherapy induction for acute myelogenous leukemia.

We report a case of human herpesvirus-6 (HHV-6) encephalitis in a neutropenic patient who had undergone chemotherapy induction for acute myelogenous leukemia while on broad-spectrum antimicrobial therapy. The patient displayed symptoms of confusion, amnesia, and lethargy. Diagnosis was made via polymerase chain reaction analysis of cerebrospinal fluid. Electroencephalogram and magnetic resonance imaging of the brain were unremarkable. Following diagnosis, the patient was successfully treated with ganciclovir. HHV-6 encephalitis should be considered in immunocompromised patients who become encephalopathic.

A therapeutic benefit of daptomycin against glycopeptide-resistant gram-positive cocci bloodstream infections under neutropenia.

Antibiotic-resistant infections remain to be a major issue for all over the world. Although appropriate diagnosis and rapid treatment initiation are crucially important particularly in immunocompromised patients, selection of antibiotics without identification of causative bacteria is often challenging. A 44-year-old woman with acute myeloid leukemia (AML) under myelosuppression suffered from teicoplanin-resistant gram-positive cocci bacteremia. Taking severe neutropenia due to chemotherapy and glycopeptide-resistance into account, teicoplanin was empirically substituted with daptomycin, which led to prompt defervescence. This microorganism later turned out to be Leuconostoc lactis (L. Lactis), and daptmycin was continued to use based on antimicrobial susceptibility tests. As a result, empiric use of daptomycin successfully controlled glycopeptide-resistant gram-positive cocci bacteremia under neutropenia. This is the first report of daptomycin treatment for L. lactis bacteremia in a patient with AML under neutropenia. Our findings suggest that daptomycin would be a suitable treatment option for glycopeptide-resistant gram-positive cocci bloodstream infections, especially in myelosuppressive patients.

Repeated Blood Cultures in Pediatric Febrile Neutropenia: Would Following the Guidelines Alter the Outcome?

BACKGROUND: The Infectious Diseases Society of America (IDSA) guidelines recommend collecting blood cultures for the first 3 days of febrile neutropenia (FN) in the clinically stable oncology patient with persistent fevers. Nonetheless, many physicians send daily blood cultures beyond 3 days, and the impact of that practice is uncertain. PROCEDURE: We reviewed pediatric FN episodes from July 2009 to May 2014 at University of Chicago Comer Children's Hospital. For each positive culture, we determined if it was a pathogen or a contaminant. We reviewed episode and patient demographics to identify risk factors for subsequent positive blood cultures in the setting of an initially negative culture. RESULTS: We identified 381 episodes of FN in 162 patients. Of those, 87 had a positive blood culture on day 1 (21.0% incidence of bacteremia). Of 294 episodes with a negative blood culture on day 1, six (2.04%, 95% confidence interval [CI] 0.42-3.67) had a positive culture after day 3. Of those, three were pathogens (1.02%, 95%CI -0.14 to 2.18), and only one was found in a hemodynamically stable patient (0.34%, 95%CI -0.33 to 1.01) with new mucositis. In the other two patients, Escherichia coli was isolated from blood cultures after day 10 in the setting of significant hemodynamic changes. Risk factor analysis performed in stable patients yielded nonsignificant results. CONCLUSIONS: Of 294 FN episodes with an initial negative blood culture, only one episode of bacteremia occurred without hemodynamic changes past day 3, supporting the IDSA guidelines to discontinue blood cultures in stable FN patients after day 3.

[Chemotherapy-induced febrile neutropenia: About 186 episodes. Clinical, microbiological and therapeutic characteristics]. / Les neutropénies fébriles chimio-induites: A propos de 186 épisodes Aspects épidémiologiques, diagnostiques et thérapeutiques.

BACKGROUND: One of the major side effects of anti-proliferative treatment is their medullar toxicity. This toxicity is particularly important in neutrophils and leads to a neutropenia. Fever during these episodes of neutropenia is a frequent complication but remains of indeterminate origin in 60% of cases. It's a medical emergency because of rapid evolution and a significant increase in mortality up to 10%. Thus, these episodes should be prevented and treated in priority with un empiric and large spectrum antibiotherapy, taking into account the bacterial ecology of each hospital. AIM: The aim of this study was to determinate the clinical, therapeutic and evolutive characteristics of febrile neutropenia (FN). METHODS: This retrospective study concerned 186 episodes of FN in 136 patients treated for solid tumors and lymphoma in the department of medical oncology of Sfax from january 2006 to December 2010. RESULTS: Mean age was 40 years (1 to 81) and sex ratio at 0.97. They were trated mainly solid tumors in 86.02%. Median time to onset of FN was 11 days and the mean duration of neutropenia was 5 days. 24.2% had a neutrophil count (ANC) <100 / mm3. Fever was clinically documented in 33.87%. Patients have mainly ORL clinical manifestations (38.46%) and specially mucositis (50%). Only 17.2% of cases were microbiologically documented and a bacteria was isolated in 76.46% of them in blood cultures, Gram-negative bacilli (GNB) accounted for the majority of organisms isolated in different samples in 66.66% of cases. Enterobacteriaceae were the most frequent dominated by Klebsiella spp, followed by Escherichia coli. Pseudomonas aeruginosa ranked second after the Enterobacteriaceae (21.21%). The Gram-positive cocci (GPC) were found in 24.24% mainly Staphylococcus aureus. The first line of empirical antibiotic therapy was associated in 88.7% of ceftazidime and amikacin or a fluoroquinolone that has to have an efficiency of 72.12%. The rate of death due to infection in our series was 9.14%. CONCLUSION: Our results are consistent with data in the literature concerning the short duration of neutropenia, causing fever and mortality, but our bacterial epidemiology is different from the current literature, where there is a predominance of CGP unlike our predominantly the BGN. And prescribing empiric antibiotic therapy must take into account the epidemiological and ecological particularities of each country, each hospital or each department.

A Prospective Observational Study of Antibiotic Therapy in Febrile Neutropenia Patients with Hematological Malignances from Multiple centers in Northeast China.

OBJECTIVES: Febrile neutropenia (FN) is a common but lethal complication of chemotherapy in hematological malignance. The aim of this study was to identify the prognostic risk factors for antibiotic treatment outcome in PN patients, and provide the optimal choice for the initial empirical antibiotic treatment. METHODS: 227 consecutive FN hematologic malignancies from four hospitals in Northeast China were enrolled. The outcome of antibiotic therapy was investigated until 14 days after the onset of FN. The factors affecting antibiotic therapy outcome were evaluated using Univariate analysis and Multivariate logistic regression analysis. RESULTS: Among all patients, 27 patients did not achieve favorable outcome either clinically or bacteriologically. It was shown that the risk factors for poor FN therapy outcome were associated with prolonged duration of neutropenia over 9 days during FN (P=0.019), slow neutrophil recovery (P=0.039), respiratory infection (P=0.005), and that initial monotherapy with drugs recommended by the guidelines indicated better outcome (P=0.009). Additionally, patients with multi-bacterial infection, as well as further ANC decrease after fever, had a poor prognosis. CONCLUSIONS: Our results indicate that early application of antibiotics and prevention of respiratory infection as well as good clinical care are able to improve clinical outcomes from empirical antibiotic treatment in FN patients with hematological malignances.

Value of lipopolysaccharide binding protein as diagnostic marker of infection in adult cancer patients with febrile neutropenia: comparison with C-reactive protein, procalcitonin, and interleukin 6.

PURPOSE: Early detection of infection is essential for initial management of cancer patients with chemotherapy-associated febrile neutropenia in the emergency department. In this study, we evaluated lipopolysaccharide binding protein (LBP) as predictor for infection in febrile neutropenia and compared with other biomarkers previously studied: C-reactive protein (CRP), procalcitonin (PCT), and interleukin (IL)-6. METHODS: A total of 61 episodes of chemotherapy-associated febrile neutropenia in 58 adult cancer patients were included. Serum samples were collected on admission at emergency department and CRP, LBP, PCT, and IL-6 were measured. Patients were classified into fever of unknown origin and infection, including microbiologically and clinically documented infection, groups. Receiver operating characteristic (ROC) curve analysis was performed for each biomarker for the diagnosis of infection. RESULTS: Thirty-two of the 61 episodes were classified as infection. On admission, CRP, PCT, IL-6, and LBP were significantly increased in patients with infection compared to fever of unknown origin group. Area under the ROC curve (AUC ROC) of CRP, PCT, IL-6, and LBP for discriminating both groups was 0.77, 0.88, 0.82, and 0.82, respectively, without significant difference between them. The combination of IL-6 and PCT or LBP did not lead to a significant improvement of the diagnostic accuracy of PCT or LBP alone. CONCLUSIONS: On admission, LBP has a similar diagnostic accuracy than PCT or IL-6 for the diagnosis of infection and might be used as additional diagnostic tool in adult cancer patients with chemotherapy-associated febrile neutropenia.

Causative Pathogens of Febrile Neutropaenia in Children Treated for Acute Lymphoblastic Leukaemia.

INTRODUCTION: Treatment of acute lymphoblastic leukaemia (ALL) using intensive chemotherapy has resulted in high cure rates but also substantial morbidity. Infective complications represent a significant proportion of treatment-related toxicity. The objective of this study was to describe the microbiological aetiology and clinical outcome of episodes of chemotherapy-induced febrile neutropaenia in a cohort of children treated for ALL at our institution. MATERIALS AND METHODS: Patients with ALL were treated with either the HKSGALL93 or the Malaysia-Singapore (Ma-Spore) 2003 chemotherapy protocols. The records of 197 patients who completed the intensive phase of treatment, defined as the period of treatment from induction, central nervous system (CNS)-directed therapy to reinduction from June 2000 to January 2010 were retrospectively reviewed. RESULTS: There were a total of 587 episodes of febrile neutropaenia in 197 patients, translating to an overall rate of 2.98 episodes per patient. A causative pathogen was isolated in 22.7% of episodes. An equal proportion of Gram-positive bacteria (36.4%) and Gram-negative bacteria (36.4%) were most frequently isolated followed by viral pathogens (17.4%), fungal pathogens (8.4%) and other bacteria (1.2%). Fungal organisms accounted for a higher proportion of clinically severe episodes of febrile neutropaenia requiring admission to the high-dependency or intensive care unit (23.1%). The overall mortality rate from all episodes was 1.5%. CONCLUSION: Febrile neutropaenia continues to be of concern in ALL patients undergoing intensive chemotherapy. The majority of episodes will not have an identifiable causative organism. Gram-positive bacteria and Gram-negative bacteria were the most common causative pathogens identified. With appropriate antimicrobial therapy and supportive management, the overall risk of mortality from febrile neutropaenia is extremely low.

Cefozopran, meropenem, or imipenem-cilastatin compared with cefepime as empirical therapy in febrile neutropenic adult patients: A multicenter prospective randomized trial.

We conducted an open-label, randomized study to evaluate the clinical efficacy of cefozopran, meropenem or imipenem-cilastatin using cefepime as a control in febrile neutropenia (FN) patients. Three hundred and seventy-six patients received cefepime, cefozopran, meropenem or imipenem-cilastatinas initial therapy for FN. The primary endpoint was the non-inferiority of response rates including modification at day 7 in cefozopran, meropenem or imipenem-cilastatin patients compared with cefepime in the per-protocol population (delta = 10%). The response rates for cefozopran, meropenem and imipenem-cilastatin were not significantly different compared with cefepime (cefozopran: 54/90 (60%), meropenem: 60/92 (65%), and IPM/CS: 63/88 (72%) versus cefepime: 56/85 (66%) (p = 0.44, 1.0 and 0.51, respectively)), and the differences in treatment success for cefozopran, meropenem and imipenem-cilastatin compared with cefepime were -5.9% (95% confidence interval (CI): -20.1-8.4), -0.7% (95% CI: -14.6-13.3), and 5.7% (95% CI: -8.1-19.4), respectively. The same tendency was seen in the modified intention-to-treat population. Based on the evaluation of initial drug efficacy performed on days 3-5, there was no significant difference between the four drugs. In the subgroup with an absolute neutrophil count ≤ 100 × 10(6)/L for longer than seven days, there was significantly better efficacy in the carbapenem arm compared to 4th generation beta-lactams (52% versus 27% at days 3-5, p = 0.006, and 76% versus 48% at day 7, p = 0.002). Our results suggest that the effects of these four drugs as empiric therapy were virtually the same for adult FN patients, although non-inferiority was shown only in imipenem-cilastatin compared with cefepime (clinical trial number: UMIN000000462).