Patient characteristics
A total of 395 patients who underwent HSCT from September 2017 to April 2019 were evaluated. Two hundred and twenty-one (55.9%) were male, and 174 (44.1%) were female, with a median age of 36 years (range, 9-67). Table 1 shows the demographic and clinical characteristics of the patients. There was no significant difference between the two groups in age, sex, underlying disease or type of HSCT.
CRE detection rate, BSI incidence and clinical outcomes
During period 1, 3 patients (3/200, 1.5%) were identified as colonized with CRE in the gut; one died of septic shock, and the other two survived. Four patients who were screened negative for CRE colonization before HSCT later developed CRE BSIs (4/200, 2%) during the HSCT period. Two (50%) out of the 4 patients died, as one patient died of CRE-related septic shock and the other of CRE BSI-induced thrombotic microangiopathy. During period 2, 21 (10.8%) out of 195 patients were identified to be colonized with CRE, which was a significantly higher percentage than that identified by single screening (p<0.001). Among these patients, the median number of screening times performed in patients was 6 (ranging from 4 to 15 times): only 4 (19.0%) patients were identified as positive for CRE at the first screening, 5 (23.8%) at the second screening, and the remaining 12 (57.1%) at the third or more screening. One of these colonized patients with neutropenia subsequently developed CRE BSI (1/21, 4.8%) but survived (Table 2).
Targeted managements
Twenty-four patients (3 detected during period 1 and 21 detected during period 2) were identified to be colonized with CRE in the gut, and the clinical manifestations are summarized in Table 3. Among the 3 patients who received a single screening, 2 patients were positive for CRE screening before transplantation and developed fever at day +7 and day +5 after screening. They received tigecycline-based treatment within 24 hours of developing fever, and their body temperatures were controlled within 72 hours of fever onset. The other patient (patient 1) was negative for CRE screening before HSCT. However, due to symptoms of persistent neutropenic fever, abdominal pain, diarrhea and significantly increased CRP (over 100 mg/L) after HSCT, the stool swab of this patient was sent for another CRE screening, which indicated positive CRE colonization at 3 days after fever initiation. She was then treated with tigecycline but ultimately died of septic shock.
During period 2, febrile episodes did not occur after positive screening in 9 patients, and antibiotics were not used. For the other 12 colonized patients, they developed neutropenic fever, and the median time from colonization identification to fever was 9 days (1-17 days). They received treatment with tigecycline in the initial 24 hours of following fever onset (except patients 20 received tigecycline after 48 hours of fever onset) considering the emergence of neutropenic fever, accompanying clinical signs of infection and significantly increased inflammatory biomarkers: the body temperatures of 9 patients were controlled within 72 hours of fever onset. Three patients (patients 12, 20, and 23) continued to suffer high fever (over 38.5°C) 48 hours after tigecycline treatment and were additionally treated with polymyxin. Polymyxin was changed to ceftazidime-avibactam due to the nephrotoxicity in patient 20. The patient 20 was diagnosed CRE BSI three days after fever. The body temperatures of 3 patients returned to normal after the administration of targeted treatment. Finally, 21 colonized patients were discharged after successful hematopoietic reconstruction.
Microbiological data
CRE strains were isolated from 11 patients in blood cultures, including strains detected in the unscreened phase and 24 patients in stool swabs during the screening period (the first positive result was documented for samples from the same origin), revealing 22 K. pneumoniae and 13 E. coli. K. pneumoniae was predominant, accounting for 81.8% of CRE BSIs (9/11) and 54.2% (13/24) of CRE colonization. One patient with CRE colonization subsequently developed a CRE BSI, and the resistance to antibiotics was exactly consistent between blood culture and stool samples. The resistance rates to antibiotics of the 35 CRE isolates are shown in Table 4. Among the three carbapenems (meropenem, imipenem and ertapenem), there was a slight difference in the antibiotic resistance rate of the two strains, which cannot be ruled out for technical reasons. The resistance rates of tigecycline and amikacin were 0% and 28.6%, respectively.