In vitro studies have shown that a primary mechanism by which macrolides act as an anti-inflammatory is through its ability to inhibit nuclear factor kappa B (NFκB). NFκB facilitates the transcription of the inflammatory genes that when expressed leads to the production of IL-2, IL-6, IL-8, TNF-α, GM-CSF, and other inflammatory mediators [23]. Various viruses and bacteria can activate the NFκB pathway of inflammation, and exposure to macrolides leads to a decrease in the expression of these inflammatory genes. The downregulation of the expression of certain inflammatory genes has been confirmed in vivo, where several studies have demonstrated a decrease in local sinonasal mucosal levels of IL-8 following macrolide therapy [13, 24, 25].

Macrolides have several other beneficial effects in the setting of CRS. First, it improves mucociliary function of the sinonasal cavity. This was shown in two animal models, whereby 2 weeks of roxithromycin increased mucociliary clearance [26, 27]. Second, macrolides have been found to normalize mucus production and consistency [28, 29]. Third, macrolides decrease neutrophil accumulation and encourage their apoptosis, which reduces the damage caused by the release of cytotoxic substances [24, 30, 31]. Finally, macrolides interfere with TGF-β function by blocking its receptor [32]. This decreases collagen deposition and the subsequent fibrosis that is seen in TGF-β upregulation. Figure 13.3 outlines the mechanisms of action for macrolides as anti-inflammatories.

Various studies have investigated the utility of macrolide use in the management of CRS; however, there are only two randomized controlled trials evaluating the effectiveness of prolonged macrolide therapy in patients with CRS. In 2006, Wallwork performed a randomized, double-blind placebo-controlled trial evaluating oral roxithromycin 150 mg daily for 3 months in CRSsNP [20]. The results demonstrated that macrolide therapy provided significant improvements in both quality of life (QoL) and endoscopic findings at the end of the treatment period. Quality of life, however, was no longer significantly improved at 3-month follow-up after stopping macrolide treatment. Additionally, they identified that patients with decreased serum IgE levels experienced greater benefit from macrolide therapy. In 2011, Videler et al. performed a randomized, double-blind placebo-controlled trial evaluating oral azithromycin 500 mg daily for 3 days followed by 500 mg once a week for 11 weeks [21]. In contrast to the study by Wallwork et al., their results failed to demonstrate a significant improvement in both QoL and endoscopic findings [21]. A possible explanation for the lack of significant results obtained by Videler et al. is that 500 mg given once a week was an underdose of the amount that would be required to improve symptoms.

There are ten observational studies that have investigated symptom improvement with macrolide therapy [33–42]. All studies report symptom improvement in over 50 % and endoscopic improvement in 40–70 % of study subjects; however, none used a validated instrument to evaluate sinus symptomatology. There are two studies that retrospectively examined the role of macrolide antibiotics following endoscopic sinus surgery. In both studies, a significant improvement in symptoms was found in the group that was treated with long-term macrolides [38].

In 2013, an evidence-based review with recommendations by Soler et al. summarized the evidence on prolonged macrolide therapy in CRS [43]. They identified 17 studies, both retrospective and prospective. They concluded that because a consistent benefit was seen in numerous observational studies and one controlled study, macrolide antibiotics would be a reasonable option in patients with CRS. Furthermore, macrolides should be especially considered in patients with low serum IgE levels.

Complications of macrolide antibiotics include hypersensitivity reactions, hepatotoxicity, and gastrointestinal upset. Other reported complications include ototoxicity and prolonged QT interval with subsequent dysrhythmia. There is also a risk of adverse drug-to-drug interactions with statins, antidepressants, antiepileptics, and methotrexate. Finally, there is the theoretical risk of antibiotic resistance; however, none of the abovementioned studies reported cases of bacterial resistance as a result of prolonged macrolide use.

At this time, available evidence suggests that a long course of at least 12 weeks of low-dose macrolide antibiotics may help alleviate symptoms of CRS that are refractory to conventional therapy. The evidence suggests that macrolide therapy is most effective in patients who have nonallergic CRS with low serum IgE levels. Those who have allergic disease and predominantly eosinophilic inflammation are less likely to experience clinical improvement.

In patients with refractory CRS, it is reasonable to consider trial therapy with a macrolide [44]. Furthermore, it may be prudent to obtain a serum IgE level to identify those individuals who would most likely benefit from macrolide therapy. Table 13.2 summarizes the macrolide antibiotics that have been used in CRS, their dosages, and contraindications.

There has been great interest in studying the non-antimicrobial properties of tetracyclines. One of the most well-known properties is its ability to inhibit matrix metalloproteinases (MMPs). Doxycycline decreases MMP activity by both direct inhibition of MMP molecules as well as the downregulation of their production [45]. MMPs mediate proteolysis of the extracellular matrix and play an important role in connective tissue remodeling. As such, MMPs are involved in the pathogenesis of wound healing, tumor invasion, and inflammation [46–50]; therefore, inhibiting MMPs may reduce the inflammatory response in the mucosa of patients with CRS.

Tetracyclines exert an anti-inflammatory effect through other mechanisms, including the stabilization of reactive oxygen specifies, inhibition of nitric oxide synthesis, and reduction of neutrophil chemotaxis [45, 51–53]. Additionally, tetracyclines have been implicated in decreasing IgE production, while levels of IgA, IgM, and IgG are unaffected [54, 55]. A possible explanation for this is that it interferes with terminal B lymphocyte differentiation and class switching [56]. By virtue of decreasing IgE, it also decreases IgE-mediated responses such as the mast cell-dominant late allergy phase [54]. Figure 13.4 outlines the mechanisms of action for tetracyclines as anti-inflammatories.