P04 – The synergistic effect of Clostridium difficile toxins on the intestinal barrier and remote inflammatory responses
Author(s):
Lawrence Diebel, David Liberati, Wayne State University
Background: Toxin A and toxin B are the primary virulence factors for Clostridium difficile colitis. There is controversy about the relative importance and the specific roles of these two toxins in the severity of colonic disease and the development of systemic complications.
Hypothesis: We compared the relative effects of toxin A, toxin B and toxin A+B on toxin penetration of the intestinal epithelial barrier and subsequent PMN activation and lung microvascular injury in an in vitro model.
Methods: HT29-MTX mucus producing intestinal epithelial cell (IEC) monolayers were established in transwell plates. Toxin A, toxin B or toxins A and B were added to the apical chamber (at 10ng/ml each). IEC basal chamber supernatants were collected at intervals. Transepithelial passage of the toxins was determined using an ELISA. The effect of the basolateral supernatants following IEC exposure to toxin(s) vs. direct toxin exposure on PMN activation and lung microvascular injury (HMVEC) were determined.
Results: Mean ± S.D. (N = 5 for each group)
Conclusions: PMN activation and HMVEC injury were due to direct effects of C. difficile toxins and mediators produced after IEC exposure to these toxins. C. difficile toxin A facilitates the translocation of toxin B into the basal (systemic) side of IEC monolayers. The study supports the importance of both toxins in the pathogenesis of intestinal barrier injury and systemic inflammation in vivo.
Increased Incidence of Blood Product Transfusions Among Transplant Patients Treated with Linezolid Compared to Daptomycin
Author(s):
Background: Thrombocytopenia is a known complication of prolonged linezolid use although little data exist specifically in the transplant population who may be at higher risk secondary to ongoing immunosuppression. This study evaluates the hematological safety of linezolid for the treatment of infections in transplant recipients compared to transplant patients treated with a control antibiotic, daptomycin.
Hypothesis: The incidences of hematological toxicity are increased in transplant patients treated with linezolid compared to transplant patients treated with daptomycin.
Methods: We performed a retrospective study from 1/08 through 6/12 of transplant inpatients on immunosuppression treated with linezolid (LZD) or daptomycin (DAP) excluding patients: <18 years old, pre-engraftment after HSCT, relapsed cancer, aplastic anemia, or those who had received cytotoxic therapy or antibodies within 30 days preceding treatment. Outcomes included the incidences of anemia, leukopenia, or thrombocytopenia at the end of antimicrobial treatment, and blood product transfusions. Results: The LZD cohort included 126 incidences, while the DAP cohort included 130 incidences of treatment. The demographic and baseline clinical variables were similar between cohorts. DAP cohort were more likely to be treated for blood stream infections (46.15% vs 31.75%; P=.02), while LZD group received more linezolid doses (15.8 vs 9.74; P<0.0001) than daptomycin doses received by the DAP group. LZD patients were more likely to receive red blood cell (68% vs 50.8%; P=0.007) and platelet transfusions (38.4% vs 20.8%; P=0.002) during course of treatment. For patients receiving thrombocytopenic drugs, mycophenolate and/or chemotherapeutic agents, end of treatment (EOT) platelet <150K was not statistically significant in the LZD cohort compared to DAP (54.8% vs 40%; P=0.09). Conclusions: Transplant patients who received linezolid had a higher incidence of blood product transfusions, compared to transplant patients who received daptomycin. Although there was no statistically significant EOT thrombocytopenia between cohorts, LZD patients were more likely to receive platelet transfusion during the course of treatment. The difference may be related to greater drug exposure (number of doses) in the LZD cohort. Clinicians caring for transplant patients should account for the need for blood products when considering the use of linezolid.