Relationship between Time to Clinical Response and Outcomes among Pneumonia Outcomes Research Team (PORT) Risk Class III and IV Hospitalized Patients with Community-Acquired Pneumonia Who Received Ceftriaxone and Azithromycin

Abstract

Recent Food and Drug Administration (FDA) guidance endorses the use of an early clinical response endpoint as the primary outcome for community-acquired bacterial pneumonia (CABP) trials. While antibiotics will now be approved for CABP, in practice they will primarily be used to treat patients with community-acquired pneumonia (CAP). More importantly, it is unclear how achievement of the new FDA CABP early response endpoint translates into clinically applicable real-world outcomes for patients with CAP. To address this, a retrospective cohort study was conducted among adult patients who received ceftriaxone and azithromycin for CAP of Pneumonia Outcomes Research Team (PORT) risk class III and IV at an academic medical center. The clinical response was defined as clinical stability for 24 h with improvement in at least one pneumonia symptom and with no symptom worsening. A classification and regression tree (CART) was used to determine the delay in response time, measured in days, associated with the greatest risk of a prolonged hospital length of stay (LOS) and adverse outcomes (in-hospital mortality or 30-day CAP-related readmission). A total of 250 patients were included. On average, patients were discharged 2 days following the achievement of a clinical response. In the CART analysis, adverse clinical outcomes were higher among day 5 nonresponders than those who responded by day 5 (22.4% versus 6.9%, P ‫؍‬ 0.001). The findings from this study indicate that time to clinical response, as defined by the recent FDA guidance, is a reasonable prognostic indictor of real-world effectiveness outcomes among hospitalized PORT risk class III and IV patients with CAP who received ceftriaxone and azithromycin.

Assessment of Time to Clinical Response, a Proxy for Discharge Readiness, among Hospitalized Patients with Community-Acquired Pneumonia Who Received either Ceftaroline Fosamil or Ceftriaxone in Two Phase III FOCUS Trials

“…On average, patients were dis- (14). Similar to the study by Zasowski and colleagues (15), they also observed a predictable lag between the achievement of stability and subsequent hospital discharge (14). There are also some indications that time to clinical stability and being dischargeable may be important determinants of subsequent hospital readmission and death.…”

“…Given the clear link between the time to clinical stability and hospital discharge (13)(14)(15), these findings may have implications for clinical practice, as ceftaroline may be associated with a shorter time to hospital discharge than that achieved with ceftriaxone among hospitalized patients with CAP, particularly those with only a Gram-positive pathogen(s) at the baseline. The methodology employed here also provides a framework from which to draw comparative effectiveness inferences from phase III CAP efficacy trials.…”

“…There are also some indications that time to clinical stability and being dischargeable may be important determinants of subsequent hospital readmission and death. Collectively, several recent studies (13)(14)(15) and the criteria for a dischargeable CAP patient in the ATS/IDSA CAP clinical management guidelines (4), which are nearly identical to the early clinical response outcome variable used in the FDA-specified day 4 clinical response analysis of ceftaroline versus ceftriaxone for CABP (12), lay the foundation for the clinical relevance of our post hoc adjudication analyses. Several issues should be taken into consideration when interpreting these findings.…”

“…to oral antibiotic therapy in hospitalized patients, as well as to judge appropriateness for hospital discharge (4). A number of studies have demonstrated that there is a clear link between the time to a clinical response (e.g., clinical stability and symptom improvement) and subsequent hospital discharge and outcomes among hospitalized patients with CAP (13)(14)(15). Using a definition of response nearly identical to our time to discharge readiness criterion, Zasowski and colleagues were able to conclusively demonstrate a monotonic relationship between the time to a clinical response and the hospital LOS among PORT risk class III and IV hospitalized adult CAP patients who received ceftriaxone and azithromycin (15).…”

Assessment of Time to Clinical Response in Patients with Sepsis Treated Before and After Implementation of a Matrix-Assisted Laser Desorption Ionization Time-of-Flight Blood Culture Identification Algorithm

“…Time to clinical response is an important outcome that has previously been associated with several important long-term outcomes. [27][28][29] In addition, we have proposed an efficient, low-resource method by which ASPs can implement rapid diagnostics within their health system. Lack of funding and/or personnel are often cited as barriers to functional and effective ASPs.…”