Increased Mortality With Tigecycline as Adjunct Tx for Severe CDAD
SAN DIEGO, CA—Tigecycline used as adjunctive therapy for severe Clostridium difficile-associated diarrhea (CDAD) led to higher rates of colectomy and higher mortality, according to results of a multicenter study presented by Candace Marr, DO, from the Catholic Health System and The State University of New York at Buffalo, Buffalo, NY, at IDWeek 2015.
Tigecycline, a broad-spectrum glycylcycline antibiotic, was approved by the Food and Drug Administration (FDA) for the treatment of complicated skin and soft tissue infections and complicated intra-abdominal infections. It inhibits production and sporulation of C. difficile in vitro. Tigecycline has been used off-label for the treatment of refractory or severe CDAD; however, in September 2013, “the FDA issued a warning regarding increased risk of death when used for treatment of FDA-approved or non-approved uses,” she said.
However, to date, no study has compared outcomes for adjuvant tigecycline with standard CDAD therapies in patients with life-threatening C. difficile infection. Her team conducted a multicenter, retrospective cohort study (n=646) comparing patients with severe CDAD treated with standard antibiotics vs. adjuvant tigecycline with standard therapy.
Study patients were classified by illness severity assessed by a scoring system derived from the Hines VA C. difficile infection severity index. Among all patients, 79 had CDAD severity scores ≥3, of which 46 received standard antibiotic therapy and 31 received adjuvant tigecycline with standard therapy, 70% of whom were prescribed the agent within 48 hours of diagnosis.
Researchers looked at all-cause 30-day mortality between the cohorts as its primary endpoint. Secondary endpoints consisted of in-hospital mortality and colectomy incidence as treatment for C. difficile. Binary logistic regression analysis was used to compare outcomes, controlling for CDAD severity score.
Adjunctive tigecycline therapy was linked to significantly higher 30-day mortality vs. standard therapy for CDAD (odds ratio [OR] 2.89, 95% CI: 1.06–7.91; P=0.038). The adjunctive tigecycline group also showed significantly increased rates of adjusted in-hospital mortality (OR 2.77, 95% CI: 1.02–7.52; P=0.046) as well as higher colectomy rates (OR 11.3, 95% CI: 1.22–101.7; P=0.033).
In addition, mortality was higher in the 30% of patients who were prescribed tigecycline 48 hours or more (vs. within 48 hours) post-diagnosis; however, this difference was not significant (OR 0.70 vs. 0.52; P=0.45). Of the patients treated with tigecycline, 20 (61%) died; among those receiving standard therapy, 16 (35%) died.
“Despite tigecycline's in vitro activity against C. difficile, its broad spectrum activity may contribute to continued dysregulation of gut flora and promotion of a C. difficile-susceptible gut environment,” Dr. Marr said.
Limitations included the retrospective nature of the study, sample size, defining severe CDAD, and that the C. difficile assay did not identify NAP1 strains, she concluded, adding that a large multicenter study may help determine potential adverse outcomes related to tigecycline treatment for patients with severe CDAD.