Antibiotic Therapy For Febrile Neutropenia Research Articles

FREQUENCY OF BACTEREMIA CAUSED BY EXTENDED SPECTRUM BETALACTAMASE (ESBL)-PRODUCING ENTEROBACTERIA IN FEBRILE NEUTROPENIC PATIENTS WITH A PREVIOUS EPISODE OF ESBL BACTEREMIA

Bacteremia caused by ESBL-producing enterobacteria may require treatment with a carbapenem. We evaluated the frequency of bacteremia caused ESBL during febrile neutropenia (FN) in patients with a bacteremia by ESBL documented in a previous episode of FN. In this retrospective study we identified all patients with bacteremia by ESBL-producing enterobacteria during an episode of FN and looked at microbiologic documentation infection in subsequent episodes of FN. From 2001 to 2020 we recorded 1624 episodes of FN occurring in 1045 patients, with 64 episodes of FN with ESBL bacteremia occurring in 40 patients. Fourteen patients had at least another episode of FN after the documentation of ESBL bacteremia (median of 1 episode per patient, range 1 – 8). Four of the 14 patients (28.6%) had ESBL bacteremia in a subsequent episode of FN. The agents of bacteremia were Escherichia coli in 2 patients, and Enterobacter cloacae and Klebsiella pneumoniae (1 each). The time from the first to the second bacteremia by ESBL was 2 months, 7 months, 9 months and 10 months, respectively. One patient had an episode of FN without bacteremia between the two episodes with ESBL. Two patients received meropenem as empiric antibiotic therapy in the second episode and survived. Two patients received cefepime. One switched to piperacillin-tazobactam and survived. The other developed ESBL bacteremia on day 6 of cefepime, switched to meropenem but died on day 10 of meropenem. Considering that the initiation of inappropriate empiric antibiotic therapy in FN results in poor outcome, and given the high frequency of recurrence (28.6%) of ESBL (and 1 in 4 deaths), patients who develop a subsequent episode of FN should receive empiric antibiotic therapy with activity against the ESBL identified in the previous episode of FN.

Comparison of Empiric Antibiotic Escalation Therapy with Vancomycin (VAN) versus Linezolid (LIN) in Patients with Febrile Neutropenia.

BackgroundIn febrile neutropenia, either linezolid (LIN) or vancomycin (VAN) can be used if a gram-positive infection is suspected. Interestingly there is no literature in which both are compared in the setting of febrile neutropenia. Therefore, we provide here the results of a retrospective analysis of adding VAN versus LIN in patients with febrile neutropenia.MethodsPatients with haematological diseases and febrile neutropenia after myelosuppressive chemotherapy and no clearance of infection after the first empiric broad-spectrum antibiotic were escalated to VAN or LIN from 03/2010 to 03/2014 at the University Hospital Bonn were included in this retrospective analysis.ResultsOut of the 73 patients, 50 had received VAN and 23 LIN. The median hospitalisation time in the LIN cohort was significantly shorter than in the VAN cohort (LIN 16 days vs VAN 20 days p=0.046). Successful defervescence with the escalation to VAN or LIN could be detected in 76% of the LIN cases and 50% in the VAN group (p=0.052). This trend to better efficacy with LIN was also shown by a higher rate of discontinuation of VAN and escalation to another antibiotic scheme (54.2%) than in the LIN cohort (24%, p=0.052).ConclusionThe antibiotic therapy in febrile neutropenia with LIN showed a trend of better efficacy than therapy with VAN. However, because of the small sample size and the retrospective manner, VAN may still be considered a reasonable option in neutropenic fever, and randomised studies are needed in this field.

PAnTher Cub: procalcitonin-guided antibiotic therapy for febrile neutropenia in children and young people with cancer - a single-arm pilot study

BackgroundFebrile neutropenia (FN) is a common complication of cancer treatment in children and young people, and many episodes are over-treated. Procalcitonin, may be an appropriate tool to guide the stopping...

Commentary on Cefepime versus Cefoperazone/Sulbactam in Combination with Amikacin as Empirical Antibiotic Therapy in Febrile Neutropenia

Commentary on Cefepime versus Cefoperazone/Sulbactam in Combination with Amikacin as Empirical Antibiotic Therapy in Febrile Neutropenia

Real-world management of infection during chemotherapy for acute leukemia in Japan: from the results of a nationwide questionnaire-based survey by the Japan Adult Leukemia Study Group.

We conducted a nationwide questionnaire-based survey in 2019 following 2001, 2007 and 2013 surveys to clarify the real-world management of infection during chemotherapy for acute leukemia in Japan. An online questionnaire was sent through SurveyMonkey® to member institutions of the Japan Adult Leukemia Study Group in June 2019. The questionnaire consisted of 52 multiple-choice questions covering prophylactic measures, screening and diagnostic tests, empirical antibiotic therapy, antifungal management, the usage of granulocyte-colony stimulating factor, and vaccinations against influenza and pneumococcus during intensive chemotherapy for acute leukemia. Questions associated with antimicrobial stewardship were also included. Usable responses were received from 163 of 218 (74.8%) institutions. Approximately, half (52.2%) of the institutes did not have infectious disease department. As antibiotic prophylaxis, fluoroquinolones (62%) were most commonly used in induction chemotherapy for acute myeloid leukemia. No prophylaxis accounted for 19% of the institutions, which has gradually increased compared to previous surveys. In empirical antibiotic therapy for febrile neutropenia, monotherapy with β-lactam antibiotics was the most commonly used first-line therapy. De-escalation was not considered in 42.2% of the institutions. In conclusion, this study clarified the real-world management of infection during intensive chemotherapy for acute leukemia in 2019 and raised future issues in Japan.

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

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. 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. 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). 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.

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.

Clinical efficacy of cycling empirical antibiotic therapy for febrile neutropenia in pediatric cancer patients.

Febrile neutropenia (FN) is the main treatment-related cause of mortality among children with cancer, as the prolonged use of broad-spectrum antibiotics can lead to antibiotic resistance in these patients. Antibiotic cycling has been reported to limit the emergence of antibiotic-resistant bacteria among adult patients. However, no studies have evaluated pediatric patients with FN. Between September 2011 and February 2014, 126 pediatric cancer patients were admitted to our center for chemotherapy and/or hematopoietic stem cell transplantation and were included in this study. Retrospective and prospective data collection were performed before and after antibiotic cycling, respectively. Between September 2011 and November 2012 (before antibiotic cycling was implemented), intravenous cefpirome was used as the empirical therapy for FN. Between December 2012 and February 2014 (after antibiotic cycling was implemented), the monthly antibiotic cycling involved intravenous piperacillin-tazobactam (PIPC/TAZ), intravenous meropenem or ciprofloxacin (CPFX), and intravenous cefepime in that order. For children aged ≥13 years, the monthly cycling involved intravenous PIPC/TAZ, and CPFX was administered. The detection rates for extended-spectrum β-lactamase producers in blood and stool culture samples decreased significantly after the implementation of antibiotic cycling (0.33/1000 patient-days vs 0/1000 patient-days, p=0.03; 1.00/1000 patient-days vs 0/1000 patient-days, p<0.01; respectively). Antibiotic cycling was associated with a decreased emergence of multidrug-resistant microbes.

Procalcitonin-guided protocol is not useful to manage antibiotic therapy in febrile neutropenia: a randomized controlled trial.

Febrile neutropenia (FN) requires immediate use of antibiotics (ATB), and procalcitonin (PCT) is proven to be useful in guiding antibiotic therapy in different settings. This study investigated the use of PCT as a guide for the duration of ATB in FN. A randomized controlled trial was carried out from January-December 2010. A total of 62 hematological adult patients with FN were randomized, in 1:1 ratio, into two groups: (1) PCT group: length of ATB guided by institutional protocol plus PCT dynamics, and (2) control group: duration of ATB in accordance with institutional protocol. There was no difference between groups regarding the use of ATB for the first episode of fever (HR 1.14, 95% CI 0.66-1.95, p = 0.641), with equivalent median duration of ATB therapy (PCT group 9.0days and control group 8.0days, p = 0.67), and median number of days without ATB (0days, IQR 0-2days for both groups, p = 0.96). We observed no difference in clinical cure rate (p = 0.68), infection relapse (p = 1.0), superinfection (p = 0.85), length of hospitalization (p = 0.64), and mortality at 28days (p = 0.39) and at 90days (p = 0.72). Considering the cut-off of 0.5ng/ml, PCT was correlated with bacteremia (sensitivity of 51.9% and specificity of 76.5%). In this randomized controlled trial, adding a PCT-guided protocol to the standard recommendations did not reduce the use of antibiotics in febrile neutropenia, although no apparent harm was caused. PCT proved to be a marker of bacteremia in this setting.

Response of First-Line Antibiotic Therapy in Patients with Febrile Neutropenia During Treatment of Hematological Disorders

Patients with hematological disorders develop febrile neutropenia (FN); most of these events remain undetermined in origin. We performed a prospective study to determine the microbiological characteristics of infections and their response to the first-line antibiotic therapy in FN. The study was conducted at National Institute of Blood Disease and Bone Marrow Transplant. Two-hundred episodes of FN were assessed for the bacterial growth, antimicrobial susceptibility pattern and response to the first-line treatment of FN. All patients were given Ceftazidime and Amikacin Bosch Pharmaceutical (Pvt. Ltd), as first-line antibiotic in FN. Out of 200 episodes we had 108 clinically and microbiologically documented infections. The isolated frequencies for gram negative and gram positive organisms were n=52 and 49 (48 and 45%) respectively. Among gram negative micro-organisms, Escherichia coli (E. coli) was isolated in 15 (28.8%), Klebsiella pneumonae in 4 (7.6%) and Pseudomonas aeruginosa in 10 (19.2%) were in highest frequencies. Methicillin sensitive staphylococci emerged as the frequently isolated gram-positive bacteria. Eight-one episodes (45.3%) responded to the first-line treatment and death reported in 20 cases (10%). Our study showed almost equal trend of gram positive and gram negative bacteria isolated from patients suffering from neutropenic fever. Empirical use of Ceftazidime and Amikacin as first-line antibiotics was able to cover the infection only in 45.3% of episodes suffering from FN.

Antimicrobial susceptibility of blood culture isolates of viridans streptococci: relationship to a change in empirical antibiotic therapy in febrile neutropenia.

This study investigated the antibiotic susceptibilities of 67 isolates of viridans streptococci from 61 cases of bacteraemia in immunocompromised paediatric patients with malignancy. The majority of patients (87%) had received prior courses of empirical antibiotic therapy, which consisted of ceftazidime plus amikacin during period 1 and piperacillin/tazobactam plus amikacin during period 2. Susceptibility to vancomycin and quinupristin/dalfopristin was 100%. Susceptibility to beta-lactam antibiotics varied. For period 1, the geometric mean MICs of all beta-lactams tested against blood culture isolates (n = 31) exceeded those against isolates (n = 36) collected from blood after the change in empirical therapy (by 3.3-fold for ceftazidime, 2.8-fold for piperacillin/tazobactam and 1.6-fold for penicillin). The selection of a beta-lactam antibiotic for empirical therapy must be made with care, as repeated courses of certain agents may be more likely to select for viridans streptococci with diminished susceptibility.

Vancomycin as part of initial empirical antibiotic therapy for febrile neutropenia in patients with cancer: pros and cons.

Gram-positive organisms predominate as the bacterial pathogens identified in episodes of febrile neutropenia. This has led to increased use of antibiotics with efficacy against gram-positive organisms (often vancomycin) as part of empirical antibiotic regimens for treating febrile neutropenia. Among 101 children randomized to receive amikacin, ticarcillin, and vancomycin or ticarcillin/clavulanate and amikacin along with vancomycin placebo, treatment success in those treated with vancomycin was higher (85% vs. 62%). In 1990, the European Organization for Research and Treatment of Cancer-National Cancer Institute of Canada Clinical Trials Group compared amikacin and ceftazidime with and without vancomycin and concluded that there was no need to include vancomycin in initial empirical antibiotic therapy. Results from another study and a retrospective review of a large clinical trial also support the previous conclusion. In 1999, most experts in the field recommend vancomycin not be part of the initial empirical therapy regimen for treating febrile neutropenia in patients with cancer.

Economic aspects of empiric antibiotic therapy for febrile neutropenia in children with cancer.

Several antibiotic regimens have been proposed worldwide for empiric treatment of febrile neutropenia in children with cancer, but none of them shows clear advantages in terms of clinical efficacy. Therefore, other parameters, including drug acquisition costs, should be considered in the selection of treatment. Children receive a "fraction" of a standard daily dose, and this fraction is generally calculated on the basis of body weight; therefore, the cost of each day of therapy is determined by the packages available for each single drug. We calculated the acquisition costs of various drugs proposed for the empiric treatment of febrile neutropenia in children with cancer, and then we estimated the daily cost of therapy referred to different patient weights. In general, the combination regimen with ceftriaxone plus aminoglycoside turned out to be less expensive than other regimens (including monotherapy with third-generation cephalosporins or carbapenems).

Empirical and subsequent use of antibacterial agents in the febrile neutropenic patient

The objective of this analysis were an assessment of the feasibility of a more individually tailored approach of empirical antibiotic therapy in febrile neutropenia and an exploration of the reasons to modify the initial regimen. The main source was a database on febrile neutropenic cancer patients from an unblinded large trial conducted in 35 centres world-wide. This was supplemented by data from patients enrolled in a consecutive series of randomized trials at the Department of Haematology, University Hospital Nijmegen. Diagnostic procedures were standardized, types of possible infections defined and the reasons for modifying an empirical regimen were recorded. Survival of the febrile neutropenic episode, development of microbiologically and clinically defined infection in relation to causative organisms, and results of modification. Monotherapy was as effective as combination therapy with an overall mortality of < or = 7%, with 21% of neutropenic episodes accompanied by a clinically defined infection proving fatal compared with only 4% of episodes without a focus. At the end of treatment the empirical regimen had been added to in 60% of cases in the multicentre trial, in contrast to 39% in our own institution, in many cases simply because of continuing fever. The development of local guidelines for individually tailoring antibiotic therapy by complementing the empirical regimen is a feasible option for achieving an optimal anti-infective strategy for febrile neutropenic cancer patients.

Infections in patients with hematological diseases: recent advances in serological diagnosis and empiric therapy.

Recent advances in the diagnosis and therapy of infections in patients with hematological diseases are reviewed. In general, 40-60% of febrile episodes lack clinical or microbiological evidence of infection and are thus treated empirically. Among the cases of microbiologically documented bacteremia treated in our department, the incidence of Gram-negative bacteria was high (47.1%) and the incidence of Gram-positive bacteremia is increasing. To improve the diagnostic rate of Gram-negative sepsis, the measurement of plasma endotoxin was performed. Of 147 febrile neutropenic episodes, endotoxemia was observed in 58 (39.5%) and the causative microorganisms of these infections were deemed Gram-negative bacteria. The measurement of plasma (1-->3)-beta-D-glucan, a ubiquitous component of fungi, was also performed for making early diagnosis of deep mycosis; the sensitivity of this assay was 90% and the specificity was 100%. The detection of (1-->3)-beta-D-glucan appears to be useful as a screening test of deep mycosis. The effects of the concomitant use of granulocyte-colony stimulating factor (G-CSF) and empiric antibiotic therapy for febrile neutropenia were studied in a randomized fashion. G-CSF did not affect the rate of the response to the empiric antibiotic therapy, although a significant effect of G-CSF on neutrophil recovery was observed. Guidelines for empiric antibiotic and antifungal therapy combined with serological diagnosis are proposed.