engleski

Empirical antibiotic therapy for neutropenic fever after allogeneic stem cell transplantation influences graft-versus-host disease-related mortality

Background: Neutropenic fever (NF) after allogeneic hematopoietic stem cell transplantation (allo- HSCT) is common and treated with a choice of clinically equivalent empirical antibiotics. However, treatment with antibiotics results in loss of bacterial diversity ; this loss has been shown to affect graft-versus-host disease (GVHD)- related outcomes. We hypothesized that the differences in the spectrum of activity of antibiotics given for NF can differently affect intestinal microbiota and modulate subsequent frequency and severity of GVHD and related outcomes. Aims: With the aim to evaluate the associations among individual antibiotic treatments and GVHD-related mortality, we retrospectively examined 340 consecutive adult recipients of allo-HSCT at our center. Methods: For each antibiotic, we stratified patients into two cohorts: those treated with a certain antibiotic, and those never receiving that antibiotic. We then compared the cumulative incidence of GVHD-related mortality for the two cohorts and evaluated them for potential differences using the Gray's test. The multivariate analysis was performed using the semi-parametric proportional hazards model of Fine and Gray. Results: Between January 2011 to December 2017, 198 male and 142 female patients underwent allo-HSCT at a median age of 47 years (range, 18–67). Among them, most patiens (67%) were treated for myeloid malignancies, while the rest had lymphoproliferative disorders (33%). The donors were related in 120 cases (35%), unrelated in 188 patients (55%) and haploidentical in 32 patients (10%). Most of the patients (69%) received peripheral blood stem cells after a reduced- intensity conditioning regimen (64%). Most frequently administered antibiotics given between days −7 to +28 relative to allo-HSCT were vancomycin in 57% patients, piperacillin- tazobactam in 47% of patients, meropenem in 44% of patients and cefepime in 37% of patients. We found that treatment of NF with piperacillin-tazobactam and vancomycin was associated with increased GVHD- related mortality at 5 years (17% in piperacillin- tazobactam - treated patients vs. 9% in untreated patients, p = 0.03, and 16% in vancomycin - treated patients vs. 8% in untreated patients, p = 0.02). The use of vancomycin was also associated with an increased incidence of grade 2–4 clinical GVHD (18% in vancomycin - treated patients vs. 11% in untreated patients, p = 0.02). On the contrary, two other antibiotics, cefepime and meropenem (usually used as second-line treatment), were not associated with GVHD-related mortality (p = 0.52 and p = 0.62, respectively). In the multivariate analysis, the use of vancomycin remained significantly correlated (p = 0.03) with GVHD- related mortality, after adjusting for other GVHD risk factors (age, disease risk, source of stem cells, conditioning regimen). Summary/Conclusion: Microbiota injury in allo-HSCT patients has been observed in several ways, including reduction in commensal anaerobes, expansion of commensal Enterococcus species and loss of overall diversity. Consistent with these reports, we demonstrate that use of antibiotics such as piperacillin-tazobactam and vancomycin leads to increased GVHD severity. A full explanation has yet to be revealed but one possible contribution could be the rise of antibiotic-resistant enterococci ; both directly with the use of vancomycin and indirectly through the use piperacillin-tazobactam and reduction of anaerobes. Our findings raise the question to the ideal choices of antibiotics for NF, causing a reappraisal of the manner in which antibiotics have been used in allo-HSCT so far.

neutropenic fever ; empirical antibiotic therapy ; allogeneic stem cell transplantation

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