Febrile Neutropenia Outcome in Hemato-Oncological Patients after the Implementation of an Adapted Therapeutic Protocol at a University Hospital in Uruguay
Authors: Grille Sofia , Matilde Boada , Guadagna Regina , Spangenber Maria Noel , Lemos Felipe , Stevenazzi Mariana , Diaz Lilian , Guillermo Cecilia 
Published: October 2019

Abstract
Background: Febrile neutropenia (FN) is among the leading causes of mortality and morbidity in hemato-oncologic patients undergoing cytotoxic chemotherapy.
The management of FN is typically algorithm-driven. The effectiveness in reducing FN related mortality of the antibacterial protocol proposed by the international guidelines is already reported. In this regard, most of the popular guidelines are based on clinical trials conducted in developed countries. Little is known about results in developing countries where patients delay consultation and have socio-cultural vulnerabilities. The aim of our study was to assess the results of the implementation of a local FN protocol in patients undergoing intensive chemotherapy regimens at Hospital de Clinicas in Uruguay.
Methods: We assessed a retrospective study with patients that have undergone intensive chemotherapy in our hemato-oncology service between 2011 and 2014. We included 127 neutropenia episodes (37 patients), with a median age of 37 years (18-79 years). Acute myeloid leukemia 26 (24.4%), acute lymphoblastic leukemia 12 (9.4%), non-Hodgkin lymphoma 74 (58.4%) and Hodgkin Lymphoma 15 (11.8%). Low risk patients were excluded. Additionally, episodes linked with high risk regimens as acute myeloid leukemia induction chemotherapy and alemtuzumab therapy were excluded from the analysis.
The initial antibiotic protocol consisted in piperacillin-tazobactam (4.5 gr every 6 hours). For patients with warning signs, more than one week of hospital stay, or having received in the last 30 days ciprofloxacin or 3er generation cephalosporin as prophylaxis meropenem (1gr every 8 hours) was indicated. Prophylactic antiviral (acyclovir) and antifungal (fluconazole) were given in every case. Modification of initial empirical treatment with piperacillin-tazobactam, changing to meropenem, was done if there was: a) deterioration in the clinical state, b) warning signs, hemodynamic instability or other organ dysfunction, c) persistent fever after 4 days of treatment, d) culture with antibiotic-resistant. In patients with hemodynamic instability, skin or soft tissue infection, suspected catheter-related infection or methicillin-resistant Staphylococcus aureus culture positive, vancomycin was added. Empirical antifungal coverage was considered in patients who had persistent fever after 6-7 days of antibiotic treatment without identified fever source.
Results: FN incidence was 33.1% (42 episodes). The presence of FN was associated with both the duration and severity of neutropenia. Median days of neutropenia (below 500/μL) in patients with FN was 10.0 ± 7.9 (standard deviation) vs 6.0 ± 3.7 (standard deviation) in patients without FN (p=0,001). Microbiological isolation from any source was achieved in 28.6% of the episodes and bacteremia was the most prevalent (77%). Multiple-antibiotic-resistant (MR) Gram-negative bacillus (GNB) were isolated in 58,3% of all microbiological documented infections, followed by GNB 25%. In 25 episodes the initial treatment was piperacilin/tazobactam (59%), while in 17 episodes Meropenem was. 15 episodes (35.7%) required vacomycin treatment. 32% of the episodes in which the initial treatment was piperacilin/tazobactam, needed to escalate to Meropenem. The mortality rate of febrile neutropenia episodes was 3.9% (40% related to sepsis).
Conclusions: In this work we observed high rate of microbiological documentation in FN episodes being bacteriemia the most frequent form and there was a predominance of MR-GNB. The high rate of GNB resistant to piperacilin/tazobactam, front line antibiotics in our protocol, and the early need to escalate to carbapenems raises the question whether it is necessary to change our antibiotic treatment protocol.

Disclosures
No relevant conflicts of interest to declare.