Review
Immunomodulation by macrolides: therapeutic potential for critical care

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Summary

Critical illness is associated with immune dysregulation, characterised by concurrent hyperinflammation and immune suppression. Hyperinflammation can result in collateral tissue damage and organ failure, whereas immune suppression has been implicated in susceptibility to secondary infections and reactivation of latent viruses. Macrolides are a class of bacteriostatic antibiotics that are used in the intensive care unit to control infections or to alleviate gastrointestinal dysmotility. Yet macrolides also have potent and wide-ranging immunomodulatory properties, which might have the potential to correct immune dysregulation in patients who are critically ill without affecting crucial antimicrobial defences. In this Review, we provide an overview of preclinical and clinical studies that point to the beneficial effects of macrolides in acute diseases relevant to critical care, and we discuss the possible underlying mechanisms of their immunomodulatory effects. Further studies are needed to explore the therapeutic potential of macrolides in critical illness, to identify subgroups of patients who might benefit from treatment, and to develop novel non-antibiotic macrolide derivatives with improved immunomodulatory properties.

Introduction

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

  • 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

  • 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

  • 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

  • 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

  • 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.

Section snippets

Models of critical illness

The potential of immunomodulation by macrolides in the context of critical illness has been explored in numerous preclinical models pertaining to pneumonia, sepsis, and lung injury (appendix pp 2–3). The overall outcome can be summarised as follows: macrolides—either alone or in addition to an antibiotic that is effective against the pathogen—modulate the immune response to attenuate inflammation-induced tissue damage and improve survival, independent of bacterial load.7, 8, 9, 10, 11, 12, 13,

Clinical studies of critical illness

Few clinical studies have investigated the immunomodulatory effects of macrolides in acute critical illnesses. Completed studies were predominantly retrospective and observational and, similar to preclinical studies, mostly related to pneumonia, sepsis, and lung injury (table). Considering the substantial overlap in the immune pathways and clinical phenotypes associated with critical illnesses, the reported benefits could be relevant to other diseases characterised by immune dysregulation, such

Mechanisms of action relevant to critical illness

Although most in-vivo studies of the immunomodulatory activity of macrolides relate to lung inflammation, the cellular effects of macrolides suggest that they might also influence extrapulmonary inflammatory disorders. Figure 1 shows the clinically relevant effects of macrolides in the context of lung infection, and figure 2 provides an overview of reported effects for various immune cell types. In this Review, we consider only macrolides with 14-membered and 15-membered lactone rings (eg,

Novel non-antibiotic macrolide derivatives

Concerns about unintentional exacerbation of antimicrobial resistance might hinder the widespread use of macrolides for non-antibiotic indications. Fortunately, macrolides can be modified to eliminate their antibacterial effects while maintaining or enhancing their immunomodulatory capacity. EM703, a non-antibiotic erythromycin derivative, improved survival in mice following an airway infection caused by P aeruginosa, probably by reducing the release of pro-inflammatory cytokines.87

Conclusions and future directions

Macrolides profoundly modulate the immune response, inducing a multitude of pro-inflammatory and anti-inflammatory effects that have the potential to correct a distorted immune balance in patients who are critically ill. The immunomodulatory effects of macrolides are complex and appear to be dependent on time, dose, and the broader context (eg, severity of disease). Defining and delineating the extent and impact of these effects and separating cause from correlation remains challenging. Matters

Search strategy and selection criteria

We searched PubMed (MEDLINE) for all relevant studies published between Jan 1, 2008, and Jan 26, 2020, and identified older landmark studies by searching the reference lists of original research and review articles. The medical subject headings used were “macrolides” combined with “immunomodulation”, “immunity”, or “immune system”. In addition, we did a more detailed search comprising all antibiotic macrolides used in clinical practice and novel non-antibiotic macrolides combined with relevant

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