Holistic Composite Endpoints With Strategic Analyses: Toward More Informed Clinical Decision-Making for Gram-Negative Bacterial Bloodstream Infections

Increasing resistance in common bacterial pathogens to available antibiotic treatment options is a slow-moving, ongoing, unrelenting global health crisis that impacts all fields of medicine. In gram-negative bacteria, 2 mechanisms of resistance are increasingly important and prevalent worldwide. First, enzymatically mediated resistance due to metallo-β-lactamases (MBLs) is on the rise. Of these, the New Delhi MBL (NDM) is the most important family. Recent epidemiologic trends suggest that NDM has now replaced the serine carbapenemase family of Klebsiella pneumoniae carbapenemase as the most common cause of enzymatic carbapenem resistance in Enterobacterales in the United States [1, 2]. A second concern involves Escherichia coli and Klebsiella pneumoniae strains with insert mutations in the gene encoding penicillin-binding protein 3 (PBP3) rendering them less susceptible to β-lactam antibiotics—including cefiderocol—that bind primarily to PBP3 [3]. In addition to antibiotic stewardship and infection prevention measures that decrease the spread of resistance, novel antibiotics and adjunctive therapies, such as bacteriophages and monoclonals, are needed to treat patients infected with these resistant bacteria. Cefiderocol was approved by the US Food and Drug Administration in 2019, with promisingly broad in vitro activity that includes the highest priority gram-negative bacteria. Seven years later, the question of how best to use this agent is not yet resolved. In this issue of Clinical Infectious Diseases, Hardy et al report a secondary analysis of the GAME CHANGER trial; an open-label randomized trial, in which cefiderocol was noninferior to standard of care for the primary endpoint of 14-day mortality in patients with gram-negative nosocomial bloodstream infection [4]. In the carbapenem-resistant subset, 14-day mortality was 14% (9/64) in the cefiderocol arm versus 10% (6/63) in the standard-of-care arm, with a notable difference in mortality (5/16 vs 0/11) in patients infected with MBL producers [4, 5]. While limited by small numbers, this suggests caution when considering the use of cefiderocol in patients infected with MBL producers. This effect appears primarily driven by bacteria that produce enzymes in the NDM family, which more effectively hydrolyze cefiderocol when compared to other MBL enzymes [5]. In the secondary analyses reported here in Clinical Infectious Diseases, 2 holistic composite endpoint assessments were applied: a 5-level desirability of outcome ranking (DOOR) outcome analyzed using the DOOR paradigm and a composite based on 6 hierarchical endpoints analyzed using generalized pairwise comparisons (GPCs). Importantly, the endpoints were defined before study results were known to investigators. These approaches allow for more granular and patient-centered assessment of patient status after antibiotic treatment and are increasingly used in antibiotic clinical trials (Table 1). For instance, the recently published DOTS and ANDROMEDA-SHOCK-2 trials had holistic composites as primary endpoints [8, 9]. In DOOR analysis, the 3 events of interest—treatment failure (recurrent positive blood cultures), infectious complications (multidrug-resistant bacteria colonization/infection and/or candidemia), and serious adverse events—all occurred in 12%–16% in both treatment arms. All-cause mortality at 90 days was also similar at ∼29%. The overall DOOR analysis indicated a 50.4% (46%–55%) probability that a patient treated with cefiderocol would have a more desirable outcome at day 90 when compared to a patient on standard-of-care antibiotics. The null hypothesis of no difference between groups cannot be rejected since the 95% CI includes 50%. A benefit of DOOR analysis is that in addition to all-cause mortality, some indication is provided on the likelihood of having a good outcome without any of the events of interest. In GAME CHANGER, this only occurred in slightly more than half of patients. It should be noted that both endpoints of treatment failure and infectious complications could be met by patients without necessarily resulting in a negative clinical impact. For instance, a participant colonized with methicillin-resistant S. aureus would meet the infectious complications endpoint. Generally, when constructing a DOOR outcome, investigators are encouraged to select endpoints that are clinically important and that indicate how patients feel, function, or survive [7]. The functional bloodstream infection score (FBIS) that was used as a tiebreaker for patients with identical DOOR ranks is a nice example of an outcome that reflects the patient's functional status. Principles of Holistic Composite Endpoints Composing information from individuals is patient centric and pragmatic, providing insights that separate analyses of component endpoints cannot. It is the only way to recognize the correlations among component endpoints and the cumulative nature of different outcomes in individual patients. Composites do not have to be binary, and components do not have to be treated with equal importance. Death may be the most important component Although binary endpoints are common, patient response is more finely graded. A mortality outcome does not distinguish the responses of patients who survive with morbidity and necessary organ support from those surviving without such conditions. A clinical failure endpoint does not distinguish the responses of patients who died from those that survive with another failure condition. Composing information does not imply abandonment of analyses of component outcomes. Component outcomes are analyzed to fully understand the nature of the effects. Composites and its components are analyzed and interpreted together. Analyses should be on a common scale, ie, absolute risk, such as the DOOR probability and net benefit, as relative risk measures cannot be simultaneously interpreted due to different baseline risks [6]. Different composite outcomes represent diff