Antimicrobial Stewardship: A Game Changer in the Fight against Carbapenem-Resistant <i>Enterobacteriaceae</i> (CRE) among Children with Cancer

Abstract                                   Background                   Carbapenem-resistant Enterobacteriaceae (CRE) is an emerging threat among pediatric cancer patients, with a high mortality rate. A previous study in our center reported that 254 patients with CRE BSI were diagnosed from (2013-2018) with mortality from CRE BSI being 30%. Previous colonization was reported in 35% of those patients. Time to start adequate antibiotics is an independent prognostic factor for patients with CRE BSI, (48%) of patients started active treatment after 48h from culture and associated with higher mortality when compared to patients who started treatment earlier. Our recommendations include antimicrobial stewardship for early detection through routine screening and timely adequate therapy that may impact the outcome for such high-risk patient groups.                                                   Methods                   This prospective study included all pediatric cancer patients with (CRE) bloodstream infections (BSI) at a children’s cancer hospital in Egypt (2020–2022) with adopting antimicrobial stewardship program goals by (1) applying routine screening by rectal swab for high-risk patients and starting active treatment for patients colonized by CRE. (2) Introduction of PCR-based method (Cepheid XpertCarba-R assay) is developed for detecting carbapenemase genes with the availability of results within one hour which can allow for rapid time to start active treatment in less than 48h.                                                   Results                   One hundred and fifty pediatric cancer patients with CRE BSI were identified; 83% had hematological malignancies, and 17% had solid tumors. Acute myeloid leukemia was the most common hematological malignancy (47%). The main clinical features for acquiring CRE-BSI were prolonged neutropenia &amp;gt; 7 days (62%), previous Carbapenem exposure (82%), Quinilone prophylaxis (44%), central venous catheter use (40%), previous colonization with a resistant pathogen (35%) and ICU admission within 90 days (18%).                   E. coli was the most common isolated pathogen (65%), followed by Klebsiella pneumoniae (31%). Documented site of infection was reported with pneumonia in (32%), typhlitis in 15% skin soft tissue infection (57%), CNS infection (18%), and urinary tract infection in (10%). Time to start active antibiotics in less than 48h was reported in 89% with clinical cure reported in 71% and microbiological clearance was reported in in less than 7 days in 70% of patients. The need for ICU admission as sepsis related to CRE was reported in 29/150 (19%). The Gentopyic profile for CRE in our study reported that class B (69%) with NDM reported in 98/150 (65%) and VIM 6/150 (4%) was the most common carbanamases followed by Oxa-48 in 89/150(59%) of patients while KPC enzyme reported only in 6/150(4%). Day 30 mortality was reported in 23/150(15%). Upon multivariate analysis, patients with Klebsiella pneumoniae BSI, NDM genotype carbapenemases, CRE with aminoglycosides resistance or associated with pneumonia, and CRE patients who developed septic shock with the need for ICU admission were predictors of poor outcome.                                                   Conclusion                   CRE-BSI is a major threat among pediatric cancer patients in limited-resource countries and is considered a barrier against better outcomes. Antimicrobial stewardship through routine screening for colonization detection and Rapid diagnosis by using gene expert with rapid time to start adequate active antibiotics treatment is associated with improvement of outcome and decreasing mortality.                   Table 1: Comparison between retrospective study and prospective study (after adopting antimicrobial stewardship goals)