Immune dysregulation is ubiquitous in patients who are critically ill.1, 2, 3 Sepsis exemplifies this dysregulation, in which pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) expressed by microbes and released from damaged tissue, respectively, initiate a strong inflammatory response by the binding of pattern recognition receptors, including Toll-like receptors (TLRs) and Nod-like receptors (NLRs), resulting in organ failure.1 Immune suppression and exhaustion, occurring in parallel with hyperinflammation, predispose individuals to secondary infections and reactivation of latent viruses. Tissue damage in other critical illnesses—such as the acute respiratory distress syndrome (ARDS), polytrauma, and severe acute pancreatitis—induces a similar immune response. Those who survive this initial response often have severe long-term disturbances in immune function that are associated with increased mortality, including persistent inflammation, immunosuppression, and catabolism (known as post-intensive care syndrome).3 However, despite three decades of trials that have explored the potential of treatments to moderate and control this immune dysregulation, no therapy has reached clinical practice.2, 4
Macrolides are a class of bacteriostatic antibiotics that inhibit protein synthesis by binding to the bacterial ribosome, with a broad spectrum of activity against many gram-positive and some gram-negative bacteria. Erythromycin is a macrolide that also serves as a motilin receptor agonist and is therefore given in the intensive care unit (ICU) at lower doses to alleviate gastrointestinal dysmotility. Notably, macrolides also have potent and wide-ranging immunomodulatory potential, altering the immune response beyond simple suppression or stimulation.5 Macrolides appear to expedite the return to immune homoeostasis and preserve or even enhance crucial antimicrobial defences.
Perhaps the most striking example of the immunomodulatory potency of macrolides comes from diffuse panbronchiolitis—an idiopathic, progressively destructive disease of the bronchioles—which can be transformed from a fatal to a treatable disease with daily low-dose erythromycin.6 In addition to their well-established benefit in chronic airway diseases, including chronic obstructive pulmonary disease (COPD), cystic fibrosis, and bronchiectasis,5 accumulating evidence suggests a potential role for macrolides in correcting immune dysregulation in patients who are critically ill.
Key messages
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Excessive release of damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs) in critical illness can lead to severe and long-lasting immune dysregulation, characterised by concurrent hyperinflammation with organ failure and immune suppression associated with secondary infections
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Independent of their antimicrobial effects, macrolides modulate key pathways and mechanisms involved in this immune dysregulation, which improves survival and reduces tissue-destructive inflammation in animal models that are relevant to critical care
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The overall effect of macrolides is to dampen excessive and detrimental inflammation, and simultaneously to protect the host from secondary infections by enhancing specific immune functions and reducing bacterial virulence
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Clinical studies of the immunomodulatory effects of macrolides in critically ill patients are scarce, but these drugs show promise in improving survival and reducing the duration of symptoms in severely ill patients with pneumonia, sepsis, and acute respiratory distress syndrome
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Novel non-antibiotic macrolides with enhanced immunomodulatory capacity are in development and have been shown to alter the immune response and improve survival in preclinical studies
Strategies of immunomodulation in the ICU have received much attention in the past 30 years, but effective therapies remain unknown. In this Review, we discuss immunomodulation by macrolides in the acute setting, particularly relating to the ICU. We provide an overview of evidence from preclinical and clinical studies for the beneficial effects of macrolides in acute diseases relevant to critical care. We discuss the mechanisms underlying the immunomodulatory effects of macrolides, and conclude by exploring the potential of novel non-antibiotic macrolide derivatives.