Impact of choice, timing, sequence and combination of broad-spectrum antibiotics on the outcome of allogeneic haematopoietic stem cell transplantation

Recent data link the incidence of intestinal GvHD (iGvHD) after allogeneic haematopoietic stem cell transplantation (aSCT) to exposure with piperacillin-tazobactam or imipenem-cilastatin. To assess relevance of timing, duration, sequence and combination of antibiotic treatment in this setting, we applied a time-dependent model to our aSCT cohort. Patients from the prospective Cologne Cohort of Neutropenic Patients (CoCoNut) undergoing aSCT from January 2007 to April 2013 were included into a time-dependent multivariate Cox proportional hazards regression model with backward-stepwise selection. In 399 eligible patients, cumulative antibiotic exposure (hazard ratio (HR) 2.46; 95% confidence interval (95% CI) 1.59-3.81; P < 0.001) and exposure to sequential treatment with penicillin derivatives and carbapenems (HR 6.22, 95% CI 1.27-30.31), but not to the individual classes, were associated with iGvHD at day 100. Glycopeptides were assessed as a risk factor (HR 3.73, 95% CI 1.51-9.19), but not considered independent, since their use was dependent on previous exposure to penicillin derivatives and carbapenems. Patients with iGvHD presented with increased non-relapse mortality at day 365 (HR 3.51; 95% CI 2.10-5.89; P < 0.001). We identified sequential exposure to penicillin derivatives and carbapenems as well as overall exposure to antibiotics as independent risk factors for iGVHD. Confirmation of these findings in larger, prospective cohorts is necessary

Potential biomarkers to predict outcome of faecal microbiota transfer for recurrent Clostridioides difficile infection

Background & Aims: Faecal microbiota transplantation (FMT) has proven high clinical efficacy in the management of recurrent Clostridioides difficile infection (rCDI) with cure rates of over 80% after a single treatment. Nevertheless, the reasons for failure in the remaining 20% remain elusive. The aim of the present study was to investigate different potential predictors of response to FMT. Methods: Faecal specimens of sixteen patients undergoing FMT for rCDI, as well as samples from the respective donors were collected and analyzed by 16S rRNA gene profiling, bile acid-inducible (baiCD) gene specific qPCR, and liquid chromatography tandem-mass spectrometry (LC-MS/MS) to quantify the concentrations of primary and secondary bile acids. Results: Using the faecal concentration of the secondary bile acid lithocholic acid (LCA) within the patient specimens, we were able to predict response to FMT (accuracy 95.2%, sensitivity 100%, specificity 90.9%). By combining the faecal LCA concentration with the urinary pCS concentration, an accuracy of 100% was achieved. Conclusion: LCA appears to be a promising marker candidate for prediction of clinical response to FMT. Other makers, such as urinary concentration of pCS, but not 3-IS, might be used to improve accuracy of prediction. Further studies are warranted to validate these candidate markers. (C) 2019 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved

Assessment of urinary 3-indoxyl sulfate as a marker for gut microbiota diversity and abundance of Clostridiales

Objectives: After allogeneic hematopoietic stem cell transplantation (allo-HCT), urinary levels of 3-indoxyl sulfate (3-IS) correlate with the relative abundance of bacteria from the class Clostridia (RAC), and antibiotic treatment is considered the major determinant of this outcome. A high RAC has been associated with favorable outcome after allo-HCT and protection from Clostridium difficile infection (CDI). We assessed correlations between alpha diversity, RAC and urinary 3-IS levels in a non-allo-HCT clinical cohort of antibiotic treated patients to further explore 3-IS as a biomarker of reduced diversity and predisposition to CDI. Methods: Fecal and urinary specimens were analyzed from 40 non-alto-HCT hospitalized patients before and 9 +/- 2 days after initiation of intravenous antibiotic treatment. Fecal microbiota were analyzed by 16s RNA sequencing and urinary 3-IS was analyzed by liquid chromatography-tandem mass spectrometry. Receiver operating characteristic (ROC) analysis was performed to assess the predictive value of 3-IS. Results: At a RAC cutoff of 2.5) was predictive with an accuracy of 82% (negative predictive value: 87%, positive predictive value 67%). Accuracy was improved by combing antibiotic history with 3-IS levels (accuracy 89%, npv 88%, ppv 92%). Conclusion: In conjunction with patient antibiotic history, 3-IS is a candidate marker to predict RAC

Phase II Dose Escalation Study of Caspofungin for Invasive Aspergillosis ▿ §

Our objective was to evaluate the maximum tolerated dose of caspofungin for invasive aspergillosis (IA). The safety and pharmacokinetics of escalating dosages of caspofungin were investigated in IA. Eight patients each received caspofungin 70, 100, 150, or 200 mg once a day (QD). Dose-limiting toxicity (DLT) was defined as the same non-hematological treatment-related adverse event of grade ≥4 in 2 of 8 patients or ≥3 in 4 of 8 patients in a cohort. A total of 46 patients (median age, 61 years; 21 female; 89% with hematological malignancies) received caspofungin (9, 8, 9, and 20 patients in the 70-, 100-, 150-, and 200-mg cohorts) for a median of 24.5 days. Plasma pharmacokinetics were linear across the investigated dosages and followed a two-compartment model, with weight as the covariate on clearance and sex as the covariate on central volume of distribution. Simulated peak plasma concentrations at steady state ranged from 14.2 to 40.6 mg/liter (28%), trough concentrations from 4.1 to 11.8 mg/liter (58%), and area under the concentration-time curve from 175 to 500 mg/liter/h (32%) (geometric mean, geometric coefficient of variation). Treatment was well tolerated without dose-limiting toxicity. The rate of complete or partial responses was 54.3%, and the overall mortality at 12-week follow-up was 28.3%. In first-line treatment of invasive aspergillosis, daily doses of up to 200 mg caspofungin were well tolerated and the maximum tolerated dose was not reached. Pharmacokinetics was linear. Response rates were similar to those previously reported for voriconazole and liposomal amphotericin