This retrospective before-after study was performed with a cohort of haematological patients treated from 2007-2014 at the haematology department of the UMCU. The intervention consisted of the introduction of a new local protocol that, in contrast to the previous local protocol, promoted early discontinuation of EAT with carbapenems and discouraged standard empirical treatment with vancomycin. This new protocol was started on January 1st 2011.
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. 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, after starting the new protocol). The period from October 1st2010 to April 1st 2011 was considered a transition period, therefore neutropenic episodes occurring within this interval were excluded. Complete patient data was not available before 2007, therefore the maximal period that could be studied before the intervention was 45 months (taken into account the transition period). A similar length was chosen for study period II, i.e. 45 months, making the total study period eight years (2007-2014).
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 ensuing neutropenia 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; old protocol
Before January 2011, prophylaxis during an episode of prolonged neutropenia consisted of oral ciprofloxacin 500 mg BID and oral fluconazole 150 mg QD (figure 1). When patients were colonized with ciprofloxacin resistant Gram-negative bacteria, cotrimoxazole (960 mg BID orally) combined with colistin (200 mg TID orally) was used as prophylaxis. Streptococcal prophylaxis was added when patients received high dose cytarabine (clindamycin 300 mg TID orally) or busulfan/cyclophosphamide (cefazolin 1000 mg TID i.v.). In case of colonisation with Candida glabrata or Candida krusei, patients received amphotericin B deoxycholate orally (200 mg QID), instead of fluconazole. When a patient developed fever, defined as a single temperature measurement > 38.6°C or > 38.3°C for more than an hour, EAT with imipenem 500 mg QID i.v. was administered. Antibiotic prophylaxis was either stopped or continued during EAT depending on the preference of the treating physician. If fever persisted, empirical vancomycin was added according to the physician’s judgment. Imipenem was continued until patients were afebrile for at least five days. If blood cultures became positive, EAT was continued for at least ten days, and depending on the pathogen/clinical suspicion, targeted antibiotics were added (e.g. vancomycin). In case of neurological disease / neurological involvement or symptoms, patients received meropenem (1000 mg TID i.v.) instead of imipenem because of an increased probability of convulsions (11).
Prophylaxis and antibiotic treatment; new protocol
In January 2011, a protocol on restrictive EAT use was introduced, adapted from the protocol described by Slobbe et al (10). The new protocol was prepared by a subgroup of haematologists and medical microbiologists and subsequently discussed with the full haematology staff and the hospital antibiotic committee. The final protocol was endorsed by all parties and published on a haematology protocol site. Afterwards, during multidisciplinary meetings held twice weekly, the new protocol and the adherence was frequently brought to attention. Bacterial prophylaxis did not change except that streptococcal prophylaxis consisted of cefazolin only (1000 mg TID i.v.). Fluconazol was given, but in case of colonisation with C. glabrata or C. krusei no antifungal prophylaxis was administered. In case of febrile neutropenia, imipenem was started and discontinued after three days if blood cultures remained negative, irrespective of fever, on condition that the patient was hemodynamically stable and there was no suspicion of pulmonary infection with an (at that moment) unknown etiology (figure 1). The use of vancomycin as standard EAT was discouraged, except in case the patient was hemodynamically instable. When blood cultures became positive, therapy was targeted on the pathogen and EAT was discontinued. During EAT, antibacterial prophylaxis was discontinued. If a patient became febrile for a second time during the same neutropenic episode, imipenem was restarted (after collection of blood cultures and repeated physical examination) and stopped as described above. According to the protocol, EAT was not restarted for additional 3rd febrile episodes during the same neutropenic period, provided that the patient remained hemodynamically stable.
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) (12). 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 and vancomycin use within neutropenia following chemotherapy or conditioning for allogenic SCT in AML and high-risk MDS patients. Because neutropenia following chemotherapy or SCT was considered as the period that patients were most at risk for severe infections and the intervention involved a policy change regarding antibiotic use within this period of neutropenia, antibiotic use was expressed as total days of therapy (DOT) per 100 neutropenic days. Interrupted time series (ITS) analysis was performed to assess pre-existing trends, the immediate effect of intervention (step change) and the sustainability of this effect in period II. In addition, the overall use of carbapenems and vancomycin within period I, calculated as the sum of DOT divided by the sum of neutropenic days * 100, was compared to the overall use in period II.
As secondary outcome, the use of other antibiotic agents was analysed, expressed as DOT per 100 neutropenic days. Total antibiotic use consisted of the sum of DOT of all antibiotics combined. If a patient used 2 (or more) different antibiotics on a particular day this was counted as 2 (or more) DOT. Cotrimoxazole was analysed when dosed in 960 mg BID, leaving out Pneumocystis jirovecii/Toxoplasma prophylaxis after allogenic SCT (480 mg QD).
Other secondary outcomes were 30-day mortality, ICU-admission 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-associated mortality and carbapenem preventable mortality were distinguished. Infection-associated mortality was defined as clinical signs and/or microbiologically results compatible with infection at time of death. Carbapenem preventable mortality was defined as infection-associated 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. Changes in carbapenem use and vancomycin use were analysed by ITS. Effect of intervention was represented by a step change (representing the immediate effect). A segmented linear mixed regression model was used with a random intercept for individual patients to correct for multiple neutropenic episodes per patient. Analysis was not corrected for confounders. The 95% confidence interval was derived through bootstrapping with 20000 iterations. For all antibiotics included in this study, the overall use of different antibiotics within period I was compared to period II, expressed in DOT/100 neutropenic days. Data-analysis was performed using SAS enterprise Guide 7.1. Statistical analysis was done using R version 3.5.1.