Recent Failures

One of the great disappointments during the past 30 years has been the failure to convert advances in our understanding of the underlying biologic features of sepsis into effective new therapies.60 Researchers have tested both highly specific agents and agents exerting more pleiotropic effects. The specific agents can be divided into those designed to interrupt the initial cytokine cascade (e.g., antilipopolysaccharide or anti–proinflammatory cytokine strategies) and those designed to interfere with dysregulated coagulation (e.g., antithrombin or activated protein C).61 The only new agent that gained regulatory approval was activated protein C.62 However, postapproval concern about the safety and efficacy of activated protein C prompted a repeat study, which did not show a benefit and led the manufacturer, Eli Lilly, to withdraw the drug from the market.11 All other strategies thus far have not shown efficacy. With the recent decision to stop further clinical development of CytoFab, a polyclonal anti–tumor necrosis factor antibody (ClinicalTrials.gov number, NCT01145560), there are no current large-scale trials of anticytokine strategies in the treatment of sepsis.

Among the agents with broader immunomodulatory effects, glucocorticoids have received the most attention. Intravenous immune globulin is also associated with a potential benefit,63 but important questions remain, and its use is not part of routine practice.23 Despite a large number of observational studies suggesting that the use of statins reduces the incidence or improves the outcome of sepsis and severe infection,64 such findings have not been confirmed in randomized, controlled trials, so the use of statins is not part of routine sepsis care. 23

Problems with Therapeutic Development

Faced with these disappointing results, many observers question the current approach to the development of sepsis drugs. Preclinical studies commonly test drugs in young, healthy mice or rats exposed to a septic challenge (e.g., bacteria or bacterial toxins) with limited or no ancillary treatment. In contrast, patients with sepsis are often elderly or have serious coexisting illnesses, which may affect the host response and increase the risk of acute organ dysfunction. Furthermore, death in the clinical setting often occurs despite the use of antibiotics, resuscitation, and intensive life support, and the disease mechanisms in such cases are probably very different from those underlying the early deterioration that typically occurs in animal models in the absence of supportive care. There are also large between-species genetic differences in the inflammatory host response.65

In clinical studies, the enrollment criteria are typically very broad, the agent is administered on the basis of a standard formula for only a short period, there is little information on how the agent changes the host response and host–pathogen interactions, and the primary end point is death from any cause. Such a research strategy is probably overly simplistic in that it does not select patients who are most likely to benefit, cannot adjust therapy on the basis of the evolving host response and clinical course, and does not capture potentially important effects on nonfatal outcomes.

New Strategies

Consequently, hope is pinned on newer so-called precision-medicine strategies with better preclinical models, more targeted drug development, and clinical trials that incorporate better patient selection, drug delivery, and outcome measurement. For example, options to enrich the preclinical portfolio include the study of animals that are more genetically diverse, are older, or have preexisting disease. Longer experiments with more advanced supportive care would allow better mimicry of the later stages of sepsis and multiorgan failure, permitting the testing of drugs in a more realistic setting and perhaps facilitating the measurement of outcomes such as cognitive and physical functioning. In addition, preclinical studies could be used to screen for potential biomarkers of a therapeutic response for which there are human homologues.

Activated protein C mutants that lack anticoagulant properties are examples of more targeted drug development and were shown to provide protection from sepsis-induced death in animals, without an increased risk of bleeding.66 Biomarkers such as whole-genome expression patterns in peripheral-blood leukocytes may aid in stratifying patients into more homogeneous subgroups or in developing more targeted therapeutic interventions.67 The insight that severe sepsis can cause immunosuppression raises the possibility of using immune-stimulatory therapy (e.g., interleukin-7, granulocyte–macrophage colony-stimulating factor,68 or interferon-γ69), but ideally, such therapy would be used only in patients in whom immunosuppression is identified or predicted. Thus, such therapies could be deployed on the basis of laboratory measures, such as monocyte HLA-DR expression. In addition, concern about accelerated neurocognitive decline in survivors of sepsis opens up avenues to explore agents currently being tested in patients with dementia and related conditions.

The designs of trials could be modified to more easily incorporate these ideas. For example, the considerable uncertainty at the beginning of a trial with regard to the appropriate selection of patients and drug-administration strategy and the possibility of treatment interactions may be better handled with the use of a Bayesian design. A trial could commence with multiple study groups that reflect the various uncertainties to be tested but then automatically narrow assignments to the best-performing groups on the basis of predefined-response adaptive randomization rules. Such designs could be particularly helpful when testing combination therapy or incorporating potential biomarkers of drug responsiveness.