Background: Despite the widespread prescription of antibiotics for the treatment of chronic rhinosinusitis (CRS), their efficacy remains uncertain. Limited penetration of systemic antibiotics into the sinonasal mucosa has been reported previously by this group. This study aimed to investigate the short-term effects of antibiotics on the sinus and gut microbiota as well as any relationships these had with drug distribution.Methods: Thirty subjects undergoing functional endoscopic sinus surgery for CRS were randomized to one of three groups: (1) doxycycline (100 mg daily for 7 days); (2) roxithromycin (300 mg daily for 7 days); and (3) control (no antibiotics given). Sinonasal and stool samples collected before and after treatment were analyzed using 16S ribosomal RNA (rRNA) gene-targeted amplicon sequencing and Droplet Digital polymerase chain reaction (PCR) for bacterial community composition and the quantification of bacterial DNA, respectively.Results: There were no significant major bacterial community shifts or changes to bacterial diversity and load following the treatment period in all patient groups. Non-significant trend reductions were observed in gut microbial diversity with antibiotics. For the roxithromycin group, sinonasal bacterial diversity was negatively correlated with serum drug levels and reduced overall compared to controls (p < 0.05). The relative abundance of Staphylococcus ASV129 in sinonasal samples reduced with increasing mucus doxycycline levels (p = 0.01). Conclusion:Antibiotic prescription for CRS should be further investigated because of preliminary evidence of poor sinonasal drug penetration, unproven efficacy, and the potential impact of dysbiosis in the sinuses and off-target sites. Further studies should consider distinguishing the presence of DNA from viable and nonviable bacteria.

No abstract

27Background: Despite the widespread prescription of antibiotics for patients with 28 chronic rhinosinusitis (CRS), the extent to which drug distribution to the sinonasal 29 mucosa influences their efficacy remains largely undefined. 30Methods: Thirty subjects undergoing functional endoscopic sinus surgery (FESS) for 31 bilateral CRS were randomized to one of three groups: 1) doxycycline (100 mg daily 32 for seven days) 2) roxithromycin (300 mg daily for seven days) and 3) control (no 33 antibiotics given). Drug levels were measured using liquid chromatography-tandem 34 mass spectrometry in sinonasal secretions, sinonasal tissues and serum at steady 35 state. Nasal endoscopy (Modified Lund-Kennedy) and Gastrointestinal Symptom 36Rating Scale (GSRS) scores were recorded. 37Results: Antibiotic concentrations in the nasal secretions were significantly lower 38 compared to those in the serum and tissue (mean mucus/serum ratio at steady state 39 = 0.16 and 0.37 for doxycycline and roxithromycin respectively; p<0.01). A short 40 course of antibiotic intake did not correlate with any difference in clinical outcomes 41 except where slightly higher GSRS scores were reported in the roxithromycin group 42 (p=0.04). 43 Conclusions: Although the efficacy of doxycycline and roxithromycin in sinonasal 44 mucus in vivo cannot be predicted solely from reported minimum inhibitory 45 concentrations, given the added complication of bacterial biofilm antimicrobial 46 tolerance, these results suggest that low mucosal penetration of antibiotics may be 47 one of the factors contributing to the limited efficacy of these agents in the treatment 48 of CRS. 49 50 51 Despite the widespread use of antibiotics in the treatment of chronic rhinosinusitis 52 (CRS), their efficacy for this indication remains debatable. There is increasing 53 evidence that the repeated use of broad-spectrum antibiotics is associated with both 54 microbial dysbiosis and the emergence of resistant bacterial strains(1-6). The 55 changes that occur in the sinonasal microbiota during oral antibiotic treatment in 56 CRS patients are poorly understood, and the microbiological effect of antibiotics at a 57 molecular level have not been correlated with clinical outcome measures. 58 Chronic rhinosinusitis (CRS) represents a spectrum of disorders that result from a 59 variety of immunopathological mechanisms that lead to persistent inflammation of 60 the paranasal sinus mucosa. Its clinical classification in two broad groups: CRS with 61 nasal polyps (CRSwNP) and CRS without NPs (CRSsNP) provides insight into the 62 severity of disease, extensiveness of surgery required, and the efficacy of medical 63 therapies. On a cellular level, both of these phenotypes are characterized by 64 epithelial disruption, ciliary dysfunction, mucus gland hyperplasia, bacterial 65 overgrowth and the formation of biofilms(7). The role of microbes in the 66 pathogenesis of CRS is largely unknown, but bacteria probably contribute to the 67 persistence and severity of the disease(8). The Internation...