The Impact of Modifying Empirical Antibiotic Therapy Based on Intestinal Colonization Status on Clinical Outcomes of Febrile Neutropenic Patients.

BACKGROUND: This paper aimed to inspect factors affecting febrile neutropenia patients with hematologic malignancies. The intestinal colonization rate of extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-E) and carbapenem-resistant Enterobacteriaceae (CRE) was assessed. The rate of subsequent ESBL-E and CRE bacteremia correlated with corresponding bacterial colonization was evaluated. Further, the risk factors for ESBL-E and CRE intestinal colonization were examined. Finally, the impact of rectal swab screening combined with adapted empirical antibiotic therapy on the mortality rate of patients with febrile neutropenia was assessed.
MATERIALS AND METHODS: Febrile neutropenia patients underwent rectal swabs and collection of blood culture specimens upon admission. Empirical treatment was subsequently modified according to rectal swab results if necessary. Bacteremia patients were treated according to blood culture results. Explorative forward-stepwise logistic regression analyses were used to identify risk factors for ESBL-E and CRE fecal carriage and mortality.
RESULTS: In total, 201 rectal swabs and 402 blood samples were collected from 163 patients during 201 febrile neutropenia episodes. Of these episodes, 38 (18.9%) were colonized with ESBL-E and 30 (14.92%) with CRE. Bloodstream infections developed in 29/201 (14.42%) episodes. Only bacteremia episodes caused by Gram-negative bacilli were included in our analysis. The development of Gram-negative-rod bacteremia was observed in eight out of 38 (21%) ESBL-E colonized episodes and four out of 30 (13.33%) CRE-colonized episodes. A BSI developed in three out of 38 (7.89%) ESBL-E colonized episodes, and two out of 30 (6.66%) CRE-colonized episodes developed BSI with the respective organism. Multivariate analysis identified previous quinolone use as the only independent risk factor for fecal colonization of multi-drug-resistant (MDR) Enterobacteriaceae (ESBL-E and CRE) (odds ratio, 17.09; 95%-confidence interval, 5.29 - 55.18; P <0.0001). No significant association was observed between ESBL-E and CRE carriage and increased risk of developing subsequent bacteremia. No significant differences were detected between groups receiving modified and non-modified treatments in duration of hospitalization or antibiotic therapy (univariate analysis) and 28-day mortality rate (logistic regression).
CONCLUSION: Quinolone exposure was a major risk factor for ESBL-E and CRE fecal carriage. Performing rectal swab screening for MDR Enterobacteriaceae and modifying empirical antibiotic therapy accordingly did not improve clinical outcomes of febrile neutropenia patients.

Introduction

Bloodstream infections (BSIs) remain the leading cause of mortality in patients with chemotherapy-induced neutropenia [1]. Bacterial penetration of mucosal abrasions or mucositis induced by chemotherapy in the mucosal barrier during neutropenia can cause BSIs [2]. Bacterial colonization is considered the initial step in infection development, followed by translocation of colonizing bacteria. Recurring hospitalization is a major risk factor for colonization by multi-drug-resistant (MDR) bacteria in the gut. Therefore, febrile neutropenia patients are considered a high-risk population due to their repetitive hospital admissions and administration of chemotherapy. This can lead to colonization by MDR bacteria and subsequent BSI development [2]. A prospective observational multicenter study in Italy that investigated carbapenem-resistant Klebsiella pneumoniae (CR-KP) BSI development in CR-KP rectal carriers reported that chemotherapy was an independent risk factor for CR-KP BSI development [3]. Furthermore, a higher BSI rate has been reported in colonized patients (50%) than in uncolonized patients (7.5%) [4]. Notably, the risk of infection is 38-fold higher in patients colonized by MDR pathogens than in non-colonized patients [5]. Moreover, a risk factor for infection and an indication to modify empirical antibiotic therapy is colonization by methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus (VRE), extended-spectrum β-lactamase (ESBL)-producing Gram-negative bacteria, and carbapenemase-producing organisms, including Klebsiella pneumoniae carbapenemase (KPC)[6]. Furthermore, MDR pathogens are considered one of the most significant threats to the successful treatment of infection. Understanding bacterial colonization may facilitate the production of an empirical regimen with improved therapeutic effects and minimize unfavorable outcomes [5]. Colonization by bacteria in the gut influences empirical antibiotic selection in febrile neutropenia patients. Hence, early colonization status-based empirical antibiotic treatment may reduce ESBL-E BSI-related mortality by preventing lethal outcomes [7].

Narimatsub et al. demonstrated that screening for Pseudomonas aeruginosa colonization was predictive of the development of BSI after reduced-intensity cord blood transplantation [4]. In this study, 50% of colonized versus 7.5% of non-colonized patients developed P. aeruginosa BSI. Demiraslan et al. identified a significantly higher rate of bacteremia (33.3%) among patients colonized by carbapenem-resistant Gram-negative bacilli (CRGNB). In contrast, non CRGNB-colonized patients exhibited a lower bacteremia rate (9.1%) (P = 0.001) [8]. This highlights the importance of colonization by MDR bacteria prior to BSI development. However, no significant difference in mortality was noted between patients administered colistin and those who were not (P = 0.56).

Menzo et al. proposed a diagnostic and therapeutic algorithm to reduce BSI rates in neutropenic patients based on rectal swab cultures in order to identify patients infected with Klebisella pneumoniae carbapenemase (KPC) producing-bacteria. The authors suggested modifying the therapeutic regimen according to the rectal swab results [9]. Notably, this paper did not cite any evidence explaining the extent to which colonizing pathogens cause bacteremia, nor the effect of the adapted treatment on patient outcomes.

Our study was conducted in Syria, a country with a poor health system and high rate of antimicrobial resistance. Estimates of ESBL-E carriage in Syria range from 26 to 66% [1011]. Carbapenem-resistant Enterobacteriaceae (CRE) producer Syrian carriages vary between centers and range from 17 to 37% [1112]. At centers with high rates of colonization by MDR bacteria, it has been proposed that fecal screening in combination with consecutive adaption of empirical treatment may be useful in colonized patients [7]; however, this approach has not been formally assessed. Moreover, the implementation of rectal swab surveillance as a component of standard-of-care is solely based on expert opinion. Most febrile neutropenia patients in our centers received carbapenems or colistin as a component of empirical therapy when they had been identified to be hospitalized or had previous febrile neutropenia episodes. This practice increased the administration of carbapenems and colistin, thereby increasing selection pressure.

We conducted a prospective multicenter study to assess the intestinal colonization rate of ESBL-E and CRE. This was performed for multiple reasons. First, we aimed to delineate the clinical impact of colonization by MDR bacteria in patients affected by hematological diseases. Second, we aimed to better understand the risk factors associated with rectal colonization by MDR bacteria and subsequent BSIs in order to facilitate early recognition and reduce population mortality. Third, we aimed to evaluate the rate of subsequent ESBL-E and CRE bacteremia correlated with corresponding bacterial colonization. Fourth, we aimed to identify risk factors for ESBL-E and CRE intestinal colonization. Finally, we aimed to assess the impact of rectal swab screening in combination with adapted empirical antibiotic therapy on the mortality rate of patients with febrile neutropenia.

Materials and Methods

1. Setting, patients, and study design

All febrile neutropenia patients who received active chemotherapy treatment and provided informed consent were enrolled in this study. The patients were admitted to the infectious disease and hematology wards in two Damascus University-affiliated hospitals. This study was designed as an observational prospective multicenter cohort study and was conducted between February 1, 2018, and June 18, 2020. All subjects provided written informed consent. The study protocol was approved by the independent Ethical Review Committee of the Faculty of Medicine at Damascus University (IER no. 2018-01-011-025).

The cohort comprised adults older than 18 years of age with hematological malignancies who received chemotherapy and developed febrile neutropenia. We excluded patients who were not actively receiving chemotherapy or those who underwent total body irradiation and/or a major surgery within 1 month of admission. The same patient could be included more than once for different febrile neutropenia episodes. Information regarding baseline characteristics, clinical data, empirical antibiotic therapy, and clinical outcomes were documented. Surveillance culture results prior to first admission were not required. A rectal swab and two 15-mL specimens of blood culture, separated by 30 minutes, were obtained from all included patients at admission. A new rectal swab was obtained in cases of febrile neutropenia episode recurrence.

All patients were treated empirically prior to obtaining rectal culture results according to the local institutional guidelines (standard-of-care) with ceftazidime, cefepime, or piperacillin/tazobactam with an antipseudomonal aminoglycoside for the first 48 hours. Results from rectal swabs and blood cultures were obtained within 48 and 120 hours, respectively. An adapted empirical antibiotic therapy as defined by institutional guidelines was used based on rectal swab results. Additionally, escalated or deescalated antibiotic treatment was applied according to blood culture results if no other infection was detected (Fig. 1). Rectal swabs and blood specimens were processed at the local laboratories of the two Damascus University-affiliated hospitals. Chromogenic agar media such as CHROMID® ESBL and CHROMID® CARBA (both obtained from bioMérieux Deutschland GmbH, Nürtingen, Germany) and nonchromogenic, nonselective media were used to detect bacteria in rectal swabs. Species identification and susceptibility testing were performed according to the standards set by the Clinical Laboratory and Standards Institute (CLSI) using Becton Dickinson NMIC/ID-94 panels [13]. Baseline and demographic characteristics of colonized and non-colonized episodes were compared in order to assess risk factors for intestinal colonization by ESBL-E and CRE, and to assess the clinical outcomes of patients who underwent screening for intestinal colonization by MDR bacteria. Length of hospital stay, duration of antibiotic therapy, and 14-day and 28-day overall mortality rate were calculated.

Figure 1

Flow diagram of treatment strategy according to ESBL-E and CRE colonization.

aAccording to in vitro susceptibility test report.

ESBL-E, extended-spectrum beta-lactamase-producing Enterobacteriaceae; CRE, carbapenem-resistant Enterobacteriaceae.

2. Definitions

A febrile neutropenia episode was defined as a single oral temperature of ≥38.3°C or a temperature of ≥38.0°C (100.4°F) sustained over 1 hour with an absolute neutrophil count <500 cells/mm3. Prior antibiotic therapy was defined as the administration of any systemic antibiotic within 1 month prior to admission [14]. ESBL-E or CRE colonization was defined as the detection of the respective organism in at least one rectal swab. BSI was defined as the detection of the causative pathogen in at least one blood culture. Standard empirical antibiotic therapy constituted the administration of an antibiotic (typically ceftazidime, cefepime, or piperacillin-tazobactam and amikacin) against suspected infection without prior identification of the causative pathogen according to our local institutional guidelines. Adapted empirical antibiotic therapy was defined as the administration of antibiotics according to rectal swab results. For example, if a rectal swab yielded ESBL-E or CRE pathogens, then carbapenem or colistin, respectively, were administered as empirical antibiotic therapy according to in vitro susceptibility reports. Escalated and deescalated targeted therapy referred to a standard or adapted antibiotic regimen which was escalated or deescalated to antibiotics, which exhibited documented in vitro activity against bloodstream isolates. For instance, if a rectal swab yielded non-ESBL/non-CRE pathogens, standard empirical antibiotic therapy was continued. Inadequate empirical antibiotic therapy was defined as the absence of treatment of bacteremia patients with at least one empirical antibiotic with proven in vitro activity against bloodstream isolates.

3. Statistical Analysis

BSI incidence and percentages of intestinal ESBLE and CRE carriers among enrolled patients were calculated. Chi-square test for categorical variables, Fisher's exact test for sample numbers less than 30, and Student's t-test for continuous variables were used to compare colonized and non-colonized episodes. Multivariate logistic regression analysis was performed to determine the risk factors associated with ESBL-E and CRE intestinal colonization based on the combination of ESBL-E and CRE colonized episodes as a single category versus the reference category (non-ESBL-E/non-CRE carriage). The mortality rate and adequacy of the prescribed treatment for patients who developed BSIs (ESBL-E and CRE colonized and non-colonized) were compared. Univariate logistic regression analysis was used for categorical variables. Non-ESBL-E/non-CRE carriage was set as the reference group for binary outcome (BSI, mortality), whereas non-ESBL-E/non-CRE bacteremia was set as the reference group for bacteremia outcome, which is a multinomial variable. A general linear model-univariate analysis of variance (ANOVA) was used to compare continuous variables among the three groups (ESBL-E, CRE, and non-ESBL-E/non-CRE carriage groups). Binary logistic regression analysis was performed in order to determine potential risk factors associated with mortality. Multivariate logistic regression analysis of factors potentially associated with ESBL-E/CRE acquisition and mortality included all statistically significant variables in univariate analysis as well as gender and age regardless of statistical significance. Variables close to significance (0.05