Table 1.

Therapies for sepsis and septic shock: aims and major findings

Therapy aim	Drug/ therapy	Major findings in studies
Pathogen “killing” (bactericidal drugs)	Antibiotics Antimicrobial peptides (in association with antibiotics)	Observation studies: early antibiotics increased survival in human septic shock [28, 29] Talactoferrin-α: trend to decreased 28-day mortality in phase 2 trial [46]; negative in phase 3 trial
Endotoxin removal	Polymyxin B hemoperfusion Cytosorb® Nanobeads	Hemodynamics and organ dysfunction improvements in phase 2 trial; negative phase 3 trial in human septic shock [51, 52] Ongoing studies in human septic shock [NCT 02288975] Ongoing preclinical study [53]
Neutralization of pathogens or cytokines	Antimicrobial peptide MD54 Anakinra Eritoran (blocks LPS binding to TLR4) and monoclonal antibody against endotoxin (E5)	Interacts with LPS and promotes LPS aggregation [47] Decreased 28-day mortality in human septic shock and macrophage activation syndrome [48] Negative phase 3 trial in human septic shock [49, 50]
Attenuation of excessive inflammatory response induced by sepsis	Antimicrobial peptide MD54	Inhibition of proinflammatory cytokines transcription in in vitro studies; decreased IL-6 and TNF-α production in animal studies; increased survival in murine CLP model [47]
	GM-CSF	Normalization of monocyte HLA-DR expression; restoration of monocyte cytokine production; nonsignificant decreases in time of mechanical ventilation, ICU, and hospital length of stay; improvements in APACHE-II in human septic shock [67]
Attenuation of immune suppression induced by sepsis	IL-7 Monoclonal antibody against PD1 and PDL1	Induction of T and B cell growth; inhibition of lymphocyte apoptosis in preclinical studies [65] Improvements in lymphocyte function and reduction of apoptosis in vitro [66]
Intestinal barrier protection	IL-11, insulin-like growth factor	Protection against increased intestinal permeability and anti-apoptotic properties in preclinical studies [62, 63]
Microbiome reestablishment	Fecal microbiota transplant	Attenuation of colitis in patients with Clostridium difficile infection [59]
Pathogen clearance	Monoclonal antibody against PCSK9	Greater survival in murine CLP model [56]

APACHE-II, Acute Physiology and Chronic Health Evaluation II; LPS, lipopolysaccharide; TLR4, Toll-like receptor 4; CLP, cecal ligation and puncture; GM-CSF, granulocyte macrophage colony-stimulating factor; HLA-DR, human leukocyte antigen class 2; ICU, intensive care unit; IL, interleukin; PD1, programmed death-1; PDL1, programmed death ligand-1; PCSK9, proprotein convertase subtylisin/kexin type 9.