Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to an infection [1]. Sepsis is still the most common cause of mortality in patients hospitalized in intensive care units (ICUs), despite advancements in antimicrobials and resuscitation techniques. Sepsis is the typical disease in terms of pathogenesis, when excessive inflammation being the likely cause. In fact, infection causes hyper-inflammatory responses, and sepsis is maintained by an overabundance of endogenous pro-inflammatory molecules (mostly cytokines), which results in a cytokine storm. Tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and interferon (IFN)-γ are considered prominent mediators of the “cytokine storm” and their primary role in sepsis pathogenesis are largely emphasized [2]. Particularly, TNF alpha is essential for the growth, activation, and differentiation of neutrophils and monocytes/macrophages [3]. Because of its ability to counteract the effects of IL-1 and TNF alpha and gamma, interleukin 10 (IL-10) is known to have an immunomodulatory role [3]. This is the reason we chose TNF-α and IL-10 as our two indicators of the imbalance between pro- and anti-inflammatory pathways.

Numerous immunomodulatory treatments are being considered in response to the immune response's dysregulation of pro- and anti-inflammatory cytokines. In addition to their antibacterial properties, macrolides have long been known to have an immunomodulatory effect [4]. This impact was first clearly demonstrated in diffuse panbronchiolitis and subsequently extended to a number of long-term inflammatory lung diseases, including cystic fibrosis, asthma, and chronic obstructive pulmonary disease (COPD) [5].

Around 10 years ago, the effects of macrolides in sepsis started to spark interest [[6], [7], [8]], with the main focus being on clinical indicators such as mortality. There is no impact on the immunological response. Here, we sought to assess the effects on immuno-inflammatory variables and on clinical outcome of the addition of erythromycin to conventional therapy in ICU septic patients. Specifically, we measured the TNF/IL-10 ratio in order to determine how well erythromycin controls excessive inflammation. Our hypothesis was that adding erythromycin to conventional therapy would allow a more significant decrease in the TNF-alpha/IL-10 ratio from D1 to D6, improving cytokine storm control and reducing mortality.