Sub-Inhibitory Clindamycin and Azithromycin reduce S. aureus Exoprotein Induced Toxicity, Inflammation, Barrier Disruption and Invasion

Abstract

Background: Chronic rhinosinusitis (CRS) is defined as a chronic inflammation of the nose and paranasal sinus mucosa associated with relapsing infections—particularly with S. aureus. Long-term treatments with protein synthesis inhibitor antibiotics have been proposed to reduce inflammation in the context chronic severe inflammatory airway pathologies, including CRS. This study assessed the effect of subinhibitory clindamycin and azithromycin on S. aureus exoprotein induced inflammation, toxicity and invasiveness. Methods: S. aureus ATCC51650 and two clinical isolates grown in planktonic and biofilm form were treated with subinhibitory clindamycin and azithromycin. Exoproteins were collected and applied to primary human nasal epithelial cells (HNECs) in monolayers and at air-liquid interface. This was followed by lactate dehydrogenase (LDH), enzyme-linked immunosorbent assay (ELISA), Transepithelial Electrical Resistance (TEER) and paracellular permeability assays to assess the effect on cell toxicity, inflammatory cytokine production and mucosal barrier structure and function, respectively. The effect of these treatments was tested as well on the S. aureus invasiveness of HNECs. Results: Subinhibitory clindamycin reduced S. aureus exoprotein production in planktonic and biofilm form, thereby blocking exoprotein-induced toxicity, reversing its detrimental effects on mucosal barrier structure and function and modulating its inflammatory properties. Sub-inhibitory azithromycin had similar effects—albeit to a lesser extent. Furthermore, clindamycin—but not azithromycin—treated S. aureus lost its invasive capacity of HNECs. Conclusion: Subinhibitory clindamycin and azithromycin reduce S. aureus exoprotein production, thereby modulating the inflammatory cascade by reducing exoprotein-induced toxicity, inflammation, mucosal barrier disruption and invasiveness.

Azithromycin and ciprofloxacin inhibit interleukin‐8 secretion without disrupting human sinonasal epithelial integrity in vitro

“…The decreased production of IL‐8 from HSNECs treated with azithromycin corroborates other published studies showing the anti‐inflammatory effect of macrolides including azithromycin in vitro and in vivo 37 . Moreover, a recent study identified that sub‐inhibitory azithromycin may also reduce Staphylococcus aureus exoproteins that induce pro‐inflammatory cytokines from HSNECs 38 . In a study using primary nasal polyp epithelial cells, several macrolides reduced the production of IL‐8 under Escherichia coli serotype 055:85 LPS‐stimulation.…”

“…37 Moreover, a recent study identified that sub-inhibitory azithromycin may also reduce Staphylococcus aureus exoproteins that induce pro-inflammatory cytokines from HSNECs. 38 In a study using primary nasal polyp epithelial cells, several macrolides reduced the production of IL-8 under Escherichia coli serotype 055:85 LPS-stimulation. CRS patients with nasal polyps (CRSwNP) showed reduced polyp size and lower IL-8 levels in nasal lavage following treatment with macrolide antibiotics.…”

Virulence alterations in staphylococcus aureus upon treatment with the sub-inhibitory concentrations of antibiotics

“…Hu et al . found that 1/2 MIC of clindamycin (0.1 μg/mL) but not azithromycin (1 μg/mL) results in the loss of the invasive capacity of S. aureus ATCC® 51650™ to enter primary human nasal epithelial cells; the infection rate of antibiotic-treated bacteria is 6.3% ± 0.76%, whereas that of bacteria without antibiotic treatment is 49% ± 9.8% [36] . In some cases, the sub-MICs of antibiotics that promote S. aureus adhesion capacity do not correlate well with bacterial invasion capability.…”

“…S. aureus can invade and propagate in mammalian cells [36] . After adhesion, subsequent invasion may occur during the infection of suitable host cells by S. aureus .…”

Chronic Rhinosinusitis—An Update on Epidemiology, Pathogenesis and Management

“…It has been demonstrated that S. aureus is able to penetrate the barrier of the columnar epithelium of the paranasal sinuses, thus enhancing the inflammatory process [ 9 , 10 ]. In this issue of JCM, Hu et al [ 11 ] studied the effects of sub-inhibitory clindamycin and azithromycin on the production of S. aureus exoproteins and the ensuing effect of decreasing inflammation, epithelial barrier disruption and invasion. The study was performed on primary human nasal epithelial cells (HNECs) from patients undertaking endoscopic skull base techniques without clinical or radiological evidence of CRS.…”