This retrospective before-after study was performed with a cohort of haematological patients treated from 2007-2014 at the haematology department of the UMCU. A new local protocol, promoting early discontinuation of EAT with carbapenems, was compared with the earlier protocol for patients receiving intensive treatment for AML or high-risk MDS.
All adult patients (≥ 18 years) with the diagnoses AML or high risk MDS, treated between January 1st 2007 and December 31st2014 in the UMCU with at least one period of prolonged and profound neutropenia were included. Of these patients, only neutropenic episodes related to intensive chemotherapy (including one of the following cytostatic agents: idarubicin, cytarabine, daunorubicin, vincristine, adriamycin, mitoxantrone or etoposide) or allogenic SCT were included. Neutropenic episodes following other chemotherapeutic regimens or unrelated to chemotherapy or allogenic SCT were excluded. The new protocol on restrictive EAT use was implemented on January 1st 2011. The period from October 1st2010 to April 1st 2011 was considered as transition period, therefore neutropenic episodes occurring within this interval were excluded. Neutropenic episodes between January 1st 2007 and October 1st 2010 (period I) were compared to neutropenic episodes between April 1st 2011 and December 31st 2014 (period II).
Definition of profound and prolonged neutropenia
Neutropenia was defined as at least two consecutive neutrophil measurements of < 0.5x109cells/L within 90 days. A single neutrophil count above 0.5x109cells/L was ignored, if flanked by neutrophil counts below < 0.5x109 cells/L within one week. Only prolonged neutropenic episodes, with a duration of seven days or more, occurring within fourteen days after start of chemotherapy or conditioning for allogenic SCT were taken into account. These neutropenic episodes are frequently accompanied by mucositis. If chemotherapy or allogenic SCT was started during a period of pre-existing neutropenia, the neutropenic episode was considered to be (at least partially) treatment- related if the neutropenia continued for at least seven days after start of treatment.
Prophylaxis and antimicrobial treatment
An overview of the old and new protocols is shown in figure 1. See supplement for more details on antimicrobial prophylaxis and treatment.
A primary database containing patient data extracted from hospital electronic patient record systems was set up using the Research Data Platform in the UMCU. This database consisted of all patients linked to the diagnosis or treatment of AML or MDS. Data of prescribed antibacterial therapy and cell-count data used to identify neutropenic episodes, were derived from the Utrecht Patient Oriented Database (UPOD) (10). Data of administered cytostatic agents and data concerning allogenic SCT in our patient selection was collected from the in-hospital pharmacy department of the UMCU and the treatment files of the haematology department, respectively. Data of positive blood cultures was derived from the General Laboratory Information Management System (GLIMS). This study was performed in accordance with the ethical standards of our centre.
The primary outcome was carbapenem use within neutropenic episodes following chemotherapy or conditioning for allogenic SCT in AML and high-risk MDS patients, expressed as total days on therapy (DOT). The median DOT with a carbapenem within neutropenia in period I was compared with the median DOT after implementation of the new protocol in period II. Carbapenem use in the transition period was not taken into account.
Antibiotic use was analysed for different antibiotics, expressed as DOT/100 neutropenic days. Antibiotics were grouped as prophylactic and therapeutic agents. Total antibiotic consumption consisted of the sum of DOT of the individual antibiotics, e.g. if a patient used 2 different antibiotics on a particular day this was counted as 2 DOT/neutropenic days. Cotrimoxazol was analysed when dosed in 960 mg BID, leaving out Pneumocystis jirovecii/Toxoplasma prophylaxis after allogenic SCT (480 mg QD).
Secondary outcomes were 30-day mortality, ICU-admittance within 30 days after start EAT and blood cultures positive for microorganisms sensitive to imipenem. These outcomes were measured for the neutropenic episodes in which EAT was started. Cases of mortality within 30 days after start of EAT with a carbapenem were reviewed separately by three of the authors (AN, AB and TVDB). Overall mortality, infection-related mortality and carbapenem preventable mortality were distinguished. Carbapenem preventable mortality was defined as infection-related mortality where continuing EAT possibly could have prevented the adverse outcome, because of a suspected or proven etiologic agent that was carbapenem sensitive.
Positive blood cultures within neutropenia drawn after discontinuation of EAT were analysed, because the goal was to study the possible adverse consequences of early discontinuation of carbapenems (e.g. infection/bacteraemia with carbapenem sensitive microorganisms).
Analysis was conducted at the level of the neutropenic episodes. Data-analysis was performed using SAS enterprise Guide 7.1. A descriptive statistical analysis was done using SPSS statistics 21. Continuous data are expressed in median (IQR) or mean (SD) depending on distribution.