Length of therapy during a phase 3 study of eravacycline and meropenem for complicated intra-abdominal infection

Author(s):
Kenneth Lawrence; Erin Mathias; Ekaterina Efimova; Melanie Olesky; Patrick Horn; Philip Barie

Background:

The recent Study to Optimize Peritoneal Infection Therapy (STOP-IT) trial demonstrated that, for patients with complicated intra-abdominal infection (cIAI) after adequate surgical or interventional radiologic source control, short-duration antibiotic therapy (~ 4 d) was associated with similar outcomes compared to longer-duration therapy (~ 8 d). This study was performed to assess prescribing of antibiotic therapy for cIAI subsequent to STOP-IT with respect to duration, and to determine patient- or disease-related characteristics related to shorter treatment courses, regardless of patient severity of illness

Hypothesis:

Compared with enrollees into the Investigating Gram-Negative Infections Treated with Eravacycline (IGNITE)1 study (JAMA Surg 2017;152:224), patients enrolled into IGNITE4 have similar clinical outcomes while receiving shorter courses of antibiotics after adequate source control, regardless of risk factors for complications.

Methods:

Post-hoc analysis of IGNITE4, a randomized, double-blind, non-inferiority phase 3 trial, made to describe patient demographics and outcomes by duration of therapy (DoRx). Patients with documented cIAI were randomized (1:1) to either eravacycline 1 mg/kg IV q12h or meropenem 1g IV q8h. DoRx was up to 14 d at the clinician’s discretion. Clinical outcome at the test of cure (TOC) visit, ~ 28 d after randomization, was the primary efficacy endpoint in the microbiological-intent-to-treat (micro-ITT) population. Three groups were categorized based on DoRx: < 5 d, 5.5 to 8 d, and > 8 d, respectively. Statistical analysis assessed the association of several collected patient variables using multi-group Χ² to compare data among groups (p < 0.05). Ordinal logistic regression was performed using all variables having a univariate association with DoRx.

Results:

Patients who received longer DoRx had higher Acute Physiology and Chronic Health Evaluation (APACHE) II scores (p=0.016), were less likely to have a diagnosis of complicated appendicitis (p<0.001), and were more likely to have an open surgical procedure (p<0.001) compared to those receiving shorter DoRx.  Overall average DoRx was 7.4 d, and for the groups were 4.6 d, 7.2 d, and 12.3 d, respectively. Clinical success in the micro-ITT group for the three groups were 88.4%, 94.5%, and 87%, respectively (p=0.06)

Conclusions:

In IGNITE4, patients receiving longer courses of antibiotic treatment were sicker, had a diagnosis other than complicated appendicitis, and were more likely to have an open surgical procedure.   Average DoRx values exceeded that in the short-course treatment group in STOP-IT and were similar to those in IGNITE1. Clinical practice may not be evolving, but the clinical trial context may be constraining.