Antibiotic Treatment For Febrile Neutropenia Research Articles

Efficacy of extended infusion of β-lactam antibiotics for the treatment of febrile neutropenia in haematologic patients (BEATLE): a randomized, multicentre, open-label, superiority clinical trial

ObjectivesThe efficacy of extended infusions (EI) of β-lactam antibiotics for optimising outcomes in febrile neutropenia is unclear. We assessed whether the administration of β-lactams was more effective in EI than in intermittent infusion (II) for the treatment of febrile neutropenia. MethodsWe performed a randomized, open-label, superiority clinical trial of patients with febrile neutropenia at four Spanish university hospitals. Patients undergoing haematopoietic stem cell transplantation or with acute leukaemia receiving chemotherapy who required empirical antibiotic treatment for febrile neutropenia were randomly assigned (1:1) to receive EI of β-lactam or II after a first dose in bolus. The choice of antipseudomonal β-lactam was left to the discretion of the attending physician. The primary endpoint was treatment success at day 5, defined as defervescence without modifying the antibiotic treatment. Secondary endpoints included adverse events, attainment of the pharmacokinetic/pharmacodynamic target of 50%, 75%, and 100%ƒuT > MIC, and 30-day mortality. ResultsFrom November 19, 2019 to June 22, 2022, 295 patients were screened for eligibility, of whom 150 were randomly assigned to receive EI (n = 77) or II (n = 73) of the antipseudomonal β-lactam of choice. In the intention-to-treat analysis, treatment success at day 5 was achieved in 39/77 patients (50.6%) receiving EI versus 46/73 patients (63.0%) receiving II (risk difference, −12.4%; 95% CI, −29.4 to 4.7; p 0.17). The pharmacokinetic/pharmacodynamic targets of 75% and 100% ƒuT > MIC for empirical treatment were achieved more frequently in the EI group. No statistically significant differences were found between groups in terms of adverse events or 30-day mortality. DiscussionOur findings do not support the routine use of empirical EI of β-lactams in febrile neutropenia. Further studies should consider the clinical heterogeneity of febrile neutropenia and focus on patients with sepsis or septic shock and microbiologically documented infections, particularly those with infections caused by microorganisms less susceptible to β-lactams.

Application of the Weighted-Incidence Syndromic Combination Antibiogram (WISCA) to guide the empiric antibiotic treatment of febrile neutropenia in oncological paediatric patients: experience from two paediatric hospitals in Northern Italy

BackgroundGuidelines about febrile neutropenia in paediatric patients are not homogeneous; the best empiric treatment of this condition should be driven by local epidemiology. The Weighted-Incidence Syndromic Combination Antibiogram (WISCA) addresses the need for disease-specific local susceptibility evidence that could guide empiric antibiotic prescriptions based on outcome estimates of treatment regimens obtained as a weighted average of pathogen susceptibilities. This study developed a WISCA model to inform empirical antibiotic regimen selection for febrile neutropenia (FN) episodes in onco-haematological paediatric patients treated at two Italian paediatric tertiary centres.MethodsWe included blood cultures from patients with a bloodstream infection and neutropenia admitted to the Paediatric Haematology-Oncology wards in Padua and Genoa Hospitals from 2016 to 2021. WISCAs were developed by estimating the coverage of 20 antibiotics as monotherapy and of 21 combined regimens with a Bayesian probability distribution.ResultsWe collected 350 blood cultures, including 196 g-negative and 154 g-positive bacteria. Considering the most used antibiotic combinations, such as piperacillin–tazobactam plus amikacin, the median coverage for the pool of bacteria collected in the study was 78%. When adding a glycopeptide, the median coverage increased to 89%, while the replacement of piperacillin–tazobactam with meropenem did not provide benefits. The developed WISCAs showed that no monotherapy offered an adequate coverage rate for the identified pathogens.ConclusionsThe application of WISCA offers the possibility of maximizing the clinical utility of microbiological surveillance data derived from large hospitals to inform the choice of the best empiric treatment while contributing to spare broad-spectrum antibiotics.

Analysis of bacteremia at first-line antibiotic treatment for febrile neutropenia in children and adolescents: A retrospective, single-center analysis

BackgroundControl of bacterial and fungal infections is critical to improving outcomes in hematological neoplastic diseases of children and adolescents. In this study, a retrospective analysis of our previous studies on febrile neutropenia was performed to investigate bacteremia. ProcedureFrom August 2008 to December 2023, five antibiotic studies were performed for febrile and neutropenic pediatric patients who had been treated with chemotherapy, immunosuppressive therapy, or had received stem cell transplantation in the pediatric unit at Sapporo Hokuyu Hospital. The rate of positive blood culture, detected bacteria, and susceptibility of several types of antibiotics in febrile episodes were investigated. ResultsBlood culture was positive in 133 of 1604 febrile episodes of 329 patients. Detected bacteria were Gram-positive cocci (61.2 %), Gram-negative bacilli (27.6 %), Gram-negative cocci (0.7 %), and Gram-positive bacilli (10.4 %). The incidence of bacteremia over time showed a decreasing trend with each passing year. In particular, the incidence of bacteremia was around 10 % in 2008–2013, whereas it was often below 5 % after 2020; this decrease was statistically significant. Although almost all detected bacteria and their susceptibilities to antibiotics (piperacillin/tazobactam, meropenem, ceftazidime, and cefozopran) did not change over time, all Escherichia coli detected after 2014 were extended-spectrum β-lactamase-producing bacteria.

Bloodstream Infections in Hematologic Malignancy Patients With Fever and Neutropenia: Are Empirical Antibiotic Therapies in the United States Still Effective?

BackgroundRising antimicrobial resistance rates may impact the efficacy of empirical antibiotic treatment for febrile neutropenia in high-risk cancer patients. Lacking contemporary data about the epidemiology, antibiotic resistance patterns, and clinical outcomes from bloodstream infections (BSIs) in US cancer patients, it is unclear if current guidelines remain relevant.MethodsIn a cross-sectional study, 14 US cancer centers prospectively identified BSIs in high-risk febrile neutropenic (FN) patients, including those receiving chemotherapy for hematologic malignancies or hematopoietic stem cell transplantation.ResultsAmong 389 organisms causing BSI in 343 patients, there was an equal distribution of gram-negative (GN) and gram-positive (GP) bacteria, with variability across centers. Cefepime and piperacillin-tazobactam were the most commonly prescribed empirical antibiotics for FN, at 62% and 23%, respectively; a GP-directed agent was empirically included in nearly half of all FN episodes within the first 24 hours. Susceptibility to fluoroquinolones, cefepime, piperacillin-tazobactam, and carbapenems was 49%, 84%, 88%, and 96%, respectively, among GN isolates. Critical illness (CrI), defined as a new requirement for mechanical ventilation, vasopressor, or death within 30 days, occurred in 15% and did not correlate with fluoroquinolone prophylaxis, organism type, initial antibiotics, or adequacy of coverage. Only severity of illness at presentation, signified by a Pitt bacteremia score ≥2, predicted for critical illness within 30 days. Mortality was 4% by day 7 and 10% overall.ConclusionsIn accordance with US guidelines, cefepime or piperacillin-tazobactam remain effective agents or empirical treatment for high-risk cancer patients with FN who are stable at presentation, maintaining high GN pathogen susceptibility and yielding excellent outcomes.

Association of an emergency department febrile neutropenia intervention protocol with time to initial antibiotic treatment.

Earlier initial antibiotic treatment for febrile neutropenia is associated with improved clinical outcomes. This study was conducted to evaluate the association of an emergency department (ED) intervention protocol with time to initial antibiotic treatment for febrile neutropenia patients. We conducted a cohort study of adult ED febrile neutropenia patients before and after implementation of an intervention protocol. Analyses included comparison of means and medians, Kaplan-Meier estimates, multivariable regression analyses, interrupted time-series analyses, and causal mediation analyses. The intervention protocol included specific triage and process-of-care actions to reduce the primary outcome of time to initial antibiotic treatment. There were 69 patients in the 12-month preintervention period and 52 patients in the 8-month postintervention period. The mean (±SD) times to initial antibiotics were 197.6 (±85.4)min for the preintervention group and 97.7 (±51.0)min for the postintervention group (difference of 99.9min with 95% confidence interval [CI]= 73.5 to 126.4, p<0.001). The patients' probability for receiving initial antibiotics within 90min was severalfold greater (adjusted risk ratio= 10.31, 95% CI= 4.99 to 21.30, p<0.001) for the postintervention group versus preintervention group. ED length of stay, hospital length of stay, 30-day readmissions, and 30-day all-cause mortality were not different between the study groups. The association of the intervention protocol with time to initial antibiotics appeared to be mediated through times to treatment room placement, report of absolute neutrophil count, and initial antibiotic order. The intervention protocol was associated with a significant reduction in time to initial antibiotics for ED patients with febrile neutropenia. This association appears to be facilitated through specific intermediate process-of-care variables. A larger multicenter study is needed to assess the potential effects of an ED febrile neutropenia protocol on patient-centered clinical outcomes and resource utilization.

Stopping antibiotic therapy after 72h in patients with febrile neutropenia following intensive chemotherapy for AML/MDS (safe study): A retrospective comparative cohort study.

BackgroundInduction chemotherapy for acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) is almost universally complicated by febrile neutropenia(FN). Empirical broad-spectrum antibiotic therapy (EBAT) strategies advocated by guidelines result in long periods of broad-spectrum antibiotic therapy. We compared the outcome of AML/MDS patients treated with a 3-day versus a prolonged (until neutrophil recovery) regimen.MethodsThis is a retrospective comparative cohort study in AML or MDS patients undergoing remission-induction chemotherapy from 2011 to 2019, comparing 2 tertiary care hospitals with different strategies regarding antibiotic treatment for FN. At Erasmus University medical center(EMC), EBAT was stopped after 3 days of FN, in absence of a clinically or microbiologically documented infection. In the University Hospitals Leuven(UZL), a prolonged strategy was used, where EBAT was given until neutrophil recovery. The primary endpoint was a serious medical complication(SMC) defined as death or ICU admission in the 30 days after the start of chemotherapy.Findings305 and 270 AML or MDS patients received chemotherapy at EMC and UZL, respectively. Broad-spectrum antibiotic treatment was given for a median of 19 days (IQR13-25) at UZL versus 9 days at EMC (IQR5–13) (p <0·001). With the 3-day EBAT strategy, an SMC was observed in 12·5% versus 8·9% with the prolonged strategy (p = 0·17). The hazard ratio for an SMC was not significantly higher with the 3-day strategy (HR 1·357,95%CI 0·765–2·409).InterpretationThis study suggests that during remission induction chemotherapy it is safe to stop antibiotics after 3 days of FN in absence of infection. A comparison of both strategies in a prospective trial should be pursued.

Antibiotic Treatment of Febrile Neutropenia in Patients with Acute Leukemia

Aim. To estimate the efficacy of antibiotic treatment of febrile neutropenia in patients with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). Materials &amp; Methods. The prospective study (2013 to 2015) included 66 AML and 44 ALL patients receiving 480 chemotherapy cycles within the period of 6 months. Results. Febrile neutropenia was registered during 242 (50 %) chemotherapy cycles occurring more frequently in AML than in ALL patients (93 % vs. 18 %, p &lt; 0.0001). In AML patients infections were more common during induction and consolidation (98 and 89 %) phases compared to ALL patients who most commonly had infection during induction phase (55 %). Compared to ALL patients, AML patients had lower recovery rates after first-line antibiotic monotherapy (24 % vs. 57 %, p &lt; 0.0001), compared to combination therapy (37 % vs. 18 %, p = 0.01). The use of beta-lactam antibiotics in ALL patients was associated with lower recovery rates during the induction phase compared to consolidation phase (47 % vs. 72 %, p = 0.0004). In cases of granulocytopaenia longer that 14 days the clinical recovery rate with administration of the first-line antibiotics and carbapenems accounted for 23-24 % compared to 47 % with other antimicrobials, more commonly with antifungal (21 %) administration. In patients with fever of unknown origin the monotherapy with first-line antibiotics proved to be successful (45 %). In patients with clinically and microbiologically defined infections the best results were achieved by the combined treatment with the beta-lactam antibiotics and other drugs (43 %). Conclusion. Antibiotic escalation has proved to be the optimal strategy in treatment of ALL patients and in cases of fever of unknown origin. The efficacy of the beta-lactam antibiotic monotherapy was lower in AML patients during the induction phase as well as in cases of continuous neutropenia (&gt; 14 days) and clinically and microbiologically diagnosed infections. The adding of other antimicrobial administration resulted in the recovery in 37-48 % of cases.

Timing of initial antibiotic treatment for febrile neutropenia in the emergency department: the need for evidence-based guidelines.

Guidelines for the treatment of febrile neutropenia (FN) universally recommend the prompt initiation (<60 minutes) of antibiotic therapy for patients with this complication presenting to medical settings. Unfortunately, administration delays exist in emergency departments where patients with FN frequently seek care. Future guidelines should be based on investigations that clearly indicate the effectiveness of rapid antibiotic therapy. If definitive investigations identify an optimal time period for the initial administration of antibiotics for patients with FN, administrative efforts will be developed to improve the emergency department care of these critically ill patients with cancer.

A prospective, controlled, randomized, non-blind, comparative study of the efficacy and safety of a once daily high dose of ceftriaxone plus ciprofloxacin versus thrice daily ceftazidime plus amikacin in empirical therapy for febrile neutropenic patients

BackgroundEmpirical antibiotic treatment for febrile neutropenia is well established. The best regimen is still controversial. The purpose of this study was to evaluate the efficacy, safety, and cost of a once daily high dose of ceftriaxone plus ciprofloxacin versus thrice daily ceftazidime plus amikacin in neutropenic febrile patients. MethodsNinety-five patients with febrile neutropenia were included in a prospective, controlled, randomized, non-blind, comparative study. Patients were randomly assigned to one of the treatment groups (63 to the ceftriaxone/ciprofloxacin group and 32 to the ceftazidime/amikacin group) and evaluated as successes or failures according to defined criteria. Daily assessments were made of all patients and all adverse events were recorded. ResultsThe overall incidence of documented infections was 45.9%: 24/47 (51.1%) in the ceftriaxone/ciprofloxacin group and 10/27 (37%) in the ceftazidime/amikacin group. There was a significant difference in clinical efficacy between the groups (p=0.011) at the end of therapy. The ceftriaxone/ciprofloxacin group had an overall incidence of resolution and improvement of 95.7% in comparison to 75% in the ceftazidime/amikacin group. Thirty-nine organisms were isolated, 26 (66.67%) gram-negative and 13 (33.33%) gram-positive. There was a low incidence of adverse events in both groups. ConclusionThe combination of a single, high dose of ceftriaxone plus ciprofloxacin daily was more effective than the standard combination of thrice daily ceftazidime plus amikacin with no significant adverse events in either group.

A survey of the antibiotic treatment of febrile neutropenia in haematology units in the United Kingdom

We performed a nationwide survey to define the different practices in managing febrile neutropenia in haematology units. A questionnaire was sent out to a named haematologist in each of 220 haematology units in the UK. Questions were asked regarding antibiotics of choice in managing febrile neutropenia and the use of antibiotic prophylaxis. Responses were received from 167 (76%) haematology units. Combination therapy with piperacillin-tazobactam and gentamicin is used first-line in febrile neutropenia by 72% of units. Piperacillin-tazobactam monotherapy is used first-line by 5% of units. When response to initial empirical therapy does not occur after 24-48 h, 32% of haematology units add a glycopeptide (vancomycin or teicoplanin) and 31% change to a carbapenem and a glycopeptide. Seventy-one percent of units use oral fluoroquinolone prophylaxis for all neutropenic patients. The antibiotic treatment of febrile neutropenia in haematology patients, and the use of antibiotic prophylaxis, vary significantly across the UK. This survey is the first to examine the prescribing of UK haematology units in this area, and could help in the formulation of practice guidelines.

Control of glycopeptide-resistant enterococci in an oncology unit.

Enterococci are responsible for 10-12% of nosocomial infections. Since 1987 the incidence of glycopeptide-resistant enterococci (GRE; termed vancomycin-resistant enterococci in the United States) has increased dramatically. The mechanism of GRE is well understood and involves mutation of a single terminal amino acid in a peptidoglycan precursor leading to reduced vancomycin affinity. Studies implicated antibiotic selection pressure as a major risk factor for GRE infection and colonization. In the hematology unit of a London hospital, GRE emerged in December 1993, with 38% of patients positive in a point prevalence study. Between December 1993 and June 1995, 13 patients acquired GRE bacteremia, five of whom died. Between 1995 and 1996 a prospective sequential study was undertaken to determine the effect of changing antibiotic treatment of febrile neutropenia (FN). All patients admitted to the hematology unit were enrolled in the study. In phase 1, treatment continued with ceftazidime monotherapy. In phase 2, piperacillin-tazobactam replaced ceftazidime, and enhanced infection control measures were encouraged. In phase 3, therapy returned to ceftazidime. In phase 1, 57% of patients became colonized or infected with GRE. Phase 2, which was divided into two 4-month cohorts, showed a significant reduction in GRE acquisition, falling to 8% colonization and no clinical infections in the second 4 months. In phase 3, despite heightened infection control procedures, the acquisition rate rose to 36%.

New Strategies in the Treatment of Infectious Complications in Haematology and Oncology:Is There a Role for Out-Patient Antibiotic Treatment of Febrile Neutropenia?

Febrile neutropenia is associated with a significant risk of complications and mortality. Patients with neutropenia secondary to cytostatic chemotherapy who develop fever are normally admitted to hospital and treated promptly with broad-spectrum antibiotics. Over the last 10 years, chemotherapy for solid tumours has been shifting out of the hospital setting into the ambit of community-based oncologists, and out-patient treatment with complex multidrug protocols is becoming increasingly common. In North America high-dose protocols combined with peripheral blood stem cell transfusion are already being administered on an out-patient basis. With the increase in the numbers of out-patients undergoing multidrug chemotherapy, there has been a corresponding rise in the severity and duration of neutropenia and in the incidence of associated infections. Patients with neutropenia of short duration (<7 days) and fever are at a relatively low risk for complications, and in these circumstances, out-patient antibiotic treatment is an alternative to costly hospitalisation. Drugs, whose antimicrobial coverage and pharmacokinetics make them particularly suitable for out-patient treatment of febrile neutropenia, include intravenous and oral quinolones and, for once-daily dosing, intravenous glycopeptides, ceftriaxone and intravenous aminoglycosides. Response rates of 60–95% have been achieved with such regimens in clinical trials, with hospital admission avoided in 75–95% of the cases. There is no doubt that out-patient treatment improves the quality of life of cancer patients. In Europe, however, there is a need for randomised clinical trials to support the establishment of out-patient-based treatment of febrile neutropenia. Out-patient antibiotic treatment of febrile neutropenia is still not standard practice, and community-based providers of such treatment must be adequately equipped and experienced in the management of this condition.