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Background Neutropenic fever (NF) occurs in >70% of hematopoietic cell transplant (HCT) recipients, without a documented cause in most cases. Antibiotics used to prevent and treat NF disrupt the gut microbiota; these disruptions predict a higher posttransplantation mortality rate. We hypothesized that specific features in the gut microbial community may mediate the risk of NF. Methods We searched a large gut microbiota database in allogeneic HCT recipients (12 546 stool samples; 1278 patients) to find pairs with NF (cases) versus without NF (controls) on the same day relative to transplantation and with a stool sample on the previous day. A total of 179 such pairs were matched as to the underlying disease and graft source. Several other important clinical variables were similar between the groups. Results The gut microbiota of cases on the day before NF occurrence had a lower abundance of Blautia than their matched controls on the same day after transplantation, suggesting a protective role for Blautia. Microbiota network analysis did not find any differences in community structure between the groups, suggesting a single-taxon effect. To identify putative mechanisms, we searched a gut microbiome and serum metabolome database of patients with acute leukemia receiving chemotherapy and identified 139 serum samples collected within 24 hours after a stool sample from the same patient. Greater Blautia abundances predicted higher levels of next-day citrulline, a biomarker of total enterocyte mass. Conclusions These findings support a model in which Blautia protects against NF by improving intestinal health. Therapeutic restoration of Blautia may help prevent NF, thus reducing antibiotic exposures and transplantation-related deaths. [ABSTRACT FROM AUTHOR]

Background With increased use of antibiotics in high-risk patients, the investigation of new antibiotics to cover potentially resistant pathogens is warranted. In this prospective randomized trial, we compared ceftolozane/tazobactam (C/T), a new cephalosporin/β-lactamase inhibitor, to the standard of care (SOC) for the empiric treatment of neutropenia and fever in patients with hematological malignancies. Methods We enrolled 100 patients to receive intravenous (IV) C/T or SOC antibiotics (cefepime, piperacillin/tazobactam, or meropenem) in combination with gram-positive antibacterial agents. We evaluated responses at the end of IV therapy (EOIV), test of cure (TOC; days 21–28), and late follow-up (LFU; days 35–42). Results We analyzed 47 C/T patients and 50 SOC patients. C/T patients had a higher rate of favorable clinical response at EOIV (87% vs 72%). A 1-sided noninferiority analysis indicated that C/T was at least not inferior to the SOC for favorable clinical response at EOIV (P  = .002), TOC (P  = .004), and LFU (P  = .002). Superiority tests showed that C/T led to significantly lower rates of clinical failure at TOC (6% vs 30%; P  = .003) and LFU (9% vs 30%; P  = .008). C/T and SOC patients with documented infections had similar rates of favorable microbiological response. Serious adverse events leading to drug discontinuation (2% vs 0%; P  = .48) and overall mortality (6% vs 4%; P  = .67) were similar in both groups. Conclusions The empiric use of C/T in high-risk patients with hematological malignancies and febrile neutropenia is safe and associated with better clinical outcomes than SOC antimicrobial agents. Clinical Trials Registration NCT03485950. [ABSTRACT FROM AUTHOR]

Background Neutropenic fever (NF) is associated with significant morbidity and mortality for patients receiving cancer treatment in sub-Saharan Africa (sSA). However, the antibiotic management of NF in sub-Saharan Africa has not been well described. We evaluated the timing and selection of antibiotics for patients with NF at the Uganda Cancer Institute (UCI). Methods We conducted a retrospective chart review of adults with acute leukemia admitted to UCI from 1 January 2016 to 31 May 2017, who developed NF. For each NF event, we evaluated the association of clinical presentation and demographics with antibiotic selection as well as time to both initial and guideline-recommended antibiotics. We also evaluated the association between ordered antibiotics and the in-hospital case fatality ratio (CFR). Results Forty-nine NF events occurred among 39 patients. The time to initial antibiotic order was <1 day. Guideline-recommended antibiotics were ordered for 37 (75%) NF events. The median time to guideline-recommended antibiotics was 3 days. Fever at admission, a documented physical examination, and abdominal abnormalities were associated with a shorter time to initial and guideline-recommended antibiotics. The in-hospital CFR was 43%. There was no difference in in-hospital mortality when guideline-recommended antibiotics were ordered as compared to when non-guideline or no antibiotics were ordered (hazard ratio, 0.51 [95% confidence interval {CI},.10–2.64] and 0.78 [95% CI,.20–2.96], respectively). Conclusions Patients with acute leukemia and NF had delayed initiation of guideline-recommended antibiotics and a high CFR. Prospective studies are needed to determine optimal NF management in sub-Saharan Africa, including choice of antibiotics and timing of antibiotic initiation. [ABSTRACT FROM AUTHOR]

Background. There is marked interest in using DNA-based methods to detect antimicrobial resistance (AMR), with targeted polymerase chain reaction (PCR) approaches increasingly being incorporated into clinical care. Whole-genome sequencing (WGS) could offer significant advantages over targeted PCR for AMR detection, particularly for species where mutations are major drivers of AMR. Methods. Illumina MiSeq WGS and broth microdilution (BMD) assays were performed on 90 bloodstream isolates of the 4 most common gram-negative bacteria causing bloodstream infections in neutropenic patients. The WGS data, including both gene presence/absence and detection of mutations in an array of AMR-relevant genes, were used to predict resistance to 4 ß-lactams commonly used in the empiric treatment of neutropenic fever. The genotypic predictions were then compared to phenotypic resistance as determined by BMD and by commercial methods during routine patient care. Results. Of 133 putative instances of resistance to the β-lactams of interest identified by WGS, only 87 (65%) would have been detected by a typical PCR-based approach. The sensitivity, specificity, and positive and negative predictive values for WGS in predicting AMR were 0.87, 0.98, 0.97, and 0.91, respectively. Using BMD as the gold standard, our genotypic resistance prediction approach had a significantly higher positive predictive value compared to minimum inhibitory concentrations generated by commercial methods (0.97 vs 0.92; P = .025). Conclusions. These data demonstrate the potential feasibility of using WGS to guide antibiotic treatment decisions for patients with life-threatening infections for an array of medically important pathogens. [ABSTRACT FROM AUTHOR]

Objectives Information on the efficacy of extended meropenem administration in neutropenic patients is scarce. Our objective was to determine whether the administration of meropenem in a 4 h extended infusion (EI) leads to a better clinical outcome in patients with febrile neutropenia than the conventional short infusion (SI). Methods This was a retrospective observational study. The subjects were neutropenic patients who presented with fever after receiving haematopoietic stem-cell transplantation or induction chemotherapy for acute myeloid leukaemia. The primary endpoint was the success of treatment after 5 days of meropenem therapy, defined as follows: the disappearance of fever leading to a maintained (≥24 h) feverless state; the resolution or improvement of the clinical signs and symptoms of infection; the absence of persistent or breakthrough bacteraemia; and no additional antibiotics prescribed because of an unsatisfactory clinical evolution. Results Eighty-eight patients received meropenem (1 g/8 h) in SI and 76 received the same dose in EI. Treatment success on day 5 was superior in the EI group [52/76 (68.4%) versus 36/88 (40.9%); P < 0.001]. Meropenem administered in EI was independently associated with success (OR 3.13, 95% CI 1.61–6.10). Fewer additional antibiotics were prescribed in the EI group during the first 5 days of treatment [20/76 (26.3%) versus 44/88 (50.0%); P = 0.002]. Using Kaplan–Meier survival analysis a more prompt defervescence and a faster decrease in C-reactive protein concentration were observed in the EI group (P = 0.021 and P = 0.037, respectively). There were no significant differences in the length of hospital stay and in the mortality rate. Conclusions Meropenem administration in EI results in a better clinical outcome for febrile neutropenia episodes, with fewer additional antibiotics needed. [ABSTRACT FROM PUBLISHER]

Objectives We aimed to improve the microbial diagnosis of first episodes of febrile neutropenia (FEFNs) since <30% of episodes are microbiologically documented. Consequently patients are usually treated by empirical antibiotic therapy. Methods A prospective study evaluated a new workflow combining: (i) one 40 mL blood culture (BC) sampled from the central venous catheter; (ii) immediate incubation in an automated BC system on the ward; (iii) direct detection of microbial DNA in blood; and (iv) identification and susceptibility testing using rapid methods performed directly on positive BC bottles. Patients were also sampled for the standard workflow with two BC sets incubated in the central laboratory and assessed by classical procedures. Results One hundred and twenty consecutive FEFNs were included (February 2008–March 2009). The new workflow was as sensitive as the standard workflow, with BC positivity rates of 30% (36/120) and 28% (34/120), respectively (McNemar's χ2 = 0.67, P = 0.41). Direct DNA detection was positive in nine episodes (7.5%) that were also positive in BC. The new workflow provided microbiological results significantly earlier than the standard workflow, with a shorter time to BC positivity (median 12 h 31 min, range 7 h 55 min–25 h 37 min versus median 13 h 01 min, range 9 h 31 min–43 h 33 min, P = 0.004) and shorter turnaround times for identification and susceptibility testing, with most of the results obtained <24 h after BC sampling. We retrospectively estimated that the new workflow would lead to earlier adequacy of antimicrobial therapy in 30% of documented cases. Conclusions Our new process improved the microbiological diagnosis in FEFNs. Cost effectiveness needs to be tested. [ABSTRACT FROM AUTHOR]

Background Once daily dosing (ODD) of aminoglycosides has become a standard of care for most patient populations. However, the use of ODD of aminoglycosides has not been clarified in febrile neutropenia. Methods We performed a systematic review and meta-analysis of randomized controlled trials (RCTs) that compared the effectiveness and safety of ODD versus multiple daily dosing (MDD) of aminoglycosides in patients with febrile neutropenia. We searched the PubMed, Scopus, Cochrane Central Register of Trials and clinicaltrials.gov databases up to July 2010. Results A total of five and eight RCTs were included in the effectiveness and safety analyses, respectively. We observed a trend towards better effectiveness of the ODD regimen in the clinically evaluable population {five RCTs, 403 patient-episodes, risk ratio (RR) = 1.18 [95% confidence interval (95% CI): 0.98, 1.42]}, but not in the microbiologically evaluable population [three RCTs, 119 patient-episodes, RR = 1.11 (95% CI: 0.84, 1.48)]. The occurrence of nephrotoxicity was similar between the two groups [seven RCTs, 1643 patient-episodes, RR = 0.74 (95% CI: 0.36, 1.50)], as was ototoxicity [six RCTs, 862 patient-episodes, RR = 1.05 (95% CI: 0.51, 2.19)]. There was no difference in mortality [four RCTs, 403 patient-episodes, RR = 0.77 (95% CI: 0.21, 2.78)]. Conclusions Although the generalization of our findings may be restricted by the relatively small sample size and other methodological limitations of the included RCTs, ODD appears to be at least as effective and as safe as MDD in patients with febrile neutropenia. RCTs comparing ODD versus MDD in patients with bacteraemia and profound or prolonged neutropenia would be of additional value. [ABSTRACT FROM PUBLISHER]

Purpose. Febrile neutropenia (FN) is a common, costly, and potentially fatal complication in oncology. While FN in the inpatient setting has been extensively studied, only one study has evaluated emergency department (ED) care for FN cancer patients. That study found that 96% of patients survived the complication. We evaluated clinical and economic outcomes for cancer patients with chemotherapy-associated FN treated in an ED. Methods. ED records for consecutive oncology patients with FN were reviewed for information on death, intensive care unit (ICU) use, blood cultures, and costs. Results. Forty-eight patients (n = 57 visits) were evaluated. Six patients died from FN (12%) and four received ICU care within 2 weeks and survived (8%). Blood cultures were positive for 37% of the ED visits. The median ED time was 3.3 hours. In 91% of visits, i.v. antibiotics were administered in the ED, ordered at a median of 1.7 hours from triage (interquartile range [IQR], 1.2-2.8 hours). All patients with death or ICU in 2 weeks and all but one patient with positive blood cultures received antibiotics. The median per patient ED costs were $1,455 (IQR, $1,300-$1,579)--42.4% for hospital/nursing, 23.5% for radiology, 20.8% for physician services, 10.9% for diagnostic tests, and 2.4% for antibiotics. Conclusions. Cancer patients with FN in this sample presenting to the ED frequently had no identified source of infection. One third of the patients had positive ED blood cultures and one fifth died or required ICU care within 2 weeks. Costs of ED care were similar to the cost of a single day of inpatient care. [ABSTRACT FROM AUTHOR]

Implementation of Biofire FilmArray Blood Culture Identification Multiplex PCR panel (BCID) at a cancer hospital was associated with reduced time to appropriate antimicrobial therapy. Additional reductions were not observed when BCID was coupled with antimicrobial stewardship intervention. [ABSTRACT FROM AUTHOR]

Background Antimicrobial stewardship in allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients remains underutilized in North America. European guidelines advise de-escalation of broad-spectrum therapy after 72 hours in select patients with neutropenic fever of unknown origin. This is not commonplace in the United States, as current guidelines recommend broad-spectrum therapy until neutrophil engraftment. If de-escalating after at least 5 days of broad-spectrum therapy and defervescence in neutropenic allo-HSCT recipients does not predispose them to recurrent fever or infection, the practice could afford several benefits. Methods The primary end point was rate of recurrent fever. Secondary outcomes included Clostridium difficile –associated infections, length of stay, intensive care unit (ICU) admission incidence, in-hospital mortality rate, need for re-escalation of therapy, rate of positive blood cultures for patients who had recurrent fevers, overall antimicrobial utilization from neutropenic fever onset, and pharmacoeconomic impact. Results A total of 120 patients were assessed in 2 groups as cohort 1 (n = 46), which received early de-escalation, and cohort 2 (n = 74), which did not. The primary end point met criteria for noninferiority, as 7 patients (15%) in cohort 1 had recurrent fever within the specified time frame compared with 14 (19%) in cohort 2 (90% CI, –0.0878 to 0.1629, P =.026). Patients in cohort 1 received significantly less gram-positive broad-spectrum antimicrobials, with trends toward lower use of broad-spectrum gram-negative agents and lower associated costs and no differences in length of stay, ICU admission incidence, need for re-escalation of therapy, rate of culture-positive bacteremia after de-escalation or discontinuation of broad-spectrum therapy, or in-hospital mortality rate. Conclusions De-escalating after at least 5 days of broad-spectrum therapy and defervescence did not appear to affect the rate of recurrent fever. This allowed for significant reductions in gram-positive broad-spectrum antimicrobial utilization, with trends toward lower use of broad-spectrum gram-negative agents and associated costs and no difference in clinical outcomes compared with those continuing such therapy until neutrophil engraftment. [ABSTRACT FROM AUTHOR]