Relationship Between a PK/PD Parameter and Therapeutic Response of Ceftobiprole in Patients with Complicate Skin and Skin Structure Infection
H Kimko, B Murthy, RS Strauss, S Xu, P Bagchi, P Nandy, K Bush, GJ Noel
Johnson & Johnson Pharmaceutical R&D, LLC
Objectives: Ceftobiprole is an investigational cephalosporin with activity against Gram-negative and Gram-positive pathogens, including methicillin-resistant staphylococci. Two phase 3 studies have been conducted in patients with complicated skin and skin structure infection (cSSSI). The purpose of this analysis was to evaluate the relationship between % time above MIC (%T>MIC) and clinical and microbiologic responses in patients with cSSSI.
Methods: The dataset from the 312 patients in the microbiological Intent-To-Treat analysis with measured ceftobiprole concentrations and the baseline MIC values was used. The individual pharmacokinetic (PK) profiles were obtained from a population PK model to estimate individual %T>MIC. Pearson's chi2 test was used to test the independence of 2 variables: %T>MIC targets (>=30% or >=50%) and therapeutic responses (i.e., clinical cure/failure). The relationship was also investigated by logistic regression analyses using continuous %T>MIC by infection type and pathogen type.
Results: For the subjects with a %T>MIC below 30%, the clinical failure rate approached 32% (7 of 22 subjects), compared with the subjects with greater than 30% T>MIC, whose failure rate approximated 9% (27 of 290 subjects). There was a strong association (P < 0.005) between achieving the >=30% or >=50% T>MIC targets and the probability of achieving clinical success. The continuous variable, %T>MIC, demonstrated a positive trend on the probability of clinical success for both infection type and pathogen type.
Conclusions: There was a strong association between achieving the >=30% or >=50% T>MIC targets and the probability of achieving clinical or microbiological success with ceftobiprole. The logistic regression showed that the probability of therapeutic success increased with increasing %T>MIC.