Skip to main content Accessibility help

Measuring antibiotic levels and their relationship with the microbiome in chronic rhinosinusitis

  • J Siu (a1), M D Tingle (a2) and R G Douglas (a1)



The evidence supporting the efficacy of antibiotic therapy in the treatment of chronic rhinosinusitis is not compelling. A limited number of studies show that the changes in the nasal microbiome in patients following drug therapy are unpredictable and variable. The evidence for the impact of oral antibiotics on the gut microbiota is stronger, possibly as a result of differences in drug distribution to various sites around the body. There are few studies on sinus mucosal and mucus levels of oral antibiotics used in the treatment of chronic rhinosinusitis. The distribution dependent effects of antibiotics on the sinonasal microbiome is unclear.


This review highlights that relative drug concentrations and their efficacy on microbiota at different sites is an important subject for future studies investigating chronic rhinosinusitis.


Corresponding author

Author for correspondence: Prof Richard George Douglas Department of Surgery, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand E-mail: Fax: +64 9 377 9656


Hide All

Prof R G Douglas takes responsibility for the integrity of the content of the paper



Hide All
1Wallwork, B, Coman, W, Mackay-Sim, A, Greiff, L, Cervin, A. A double-blind, randomized, placebo-controlled trial of macrolide in the treatment of chronic rhinosinusitis. Laryngoscope 2006;116:189–93
2Stewart, PS, Costerton, JW. Antibiotic resistance of bacteria in biofilms. Lancet 2001;358:135–8
3Kennedy, J, Borish, L. Chronic rhinosinusitis and antibiotics: the good, the bad, and the ugly. Am J Rhinol Allergy 2013;27:467–72
4Zhang, N, Van Zele, T, Perez-Novo, C, Van Bruaene, N, Holtappels, G, DeRuyck, N et al. Different types of T-effector cells orchestrate mucosal inflammation in chronic sinus disease. J Allergy Clin Immunol 2008;122:961–8
5Foreman, A, Holtappels, G, Psaltis, AJ, Jervis-Bardy, J, Field, J, Wormald, PJ et al. Adaptive immune responses in Staphylococcus aureus biofilm-associated chronic rhinosinusitis. Allergy 2011;66:1449–56
6Van Zele, T, Gevaert, P, Holtappels, G, Beule, A, Wormald, PJ, Mayr, S et al. Oral steroids and doxycycline: two different approaches to treat nasal polyps. J Allergy Clin Immunol 2010;125:1069–76.e4
7Hoggard, M, Biswas, K, Zoing, M, Mackenzie B, Wagner, Taylor, MW, Douglas, RG. Evidence of microbiota dysbiosis in chronic rhinosinusitis. Int Forum Allergy Rhinol 2017;7:230–9
8Wagner Mackenzie, B, Waite, DW, Hoggard, M, Douglas, RG, Taylor, MW, Biswas, K. Bacterial community collapse: a meta-analysis of the sinonasal microbiota in chronic rhinosinusitis. Environ Microbiol 2017;19:381–92
9Lee, JT, Frank, DN, Ramakrishnan, V. Microbiome of the paranasal sinuses: update and literature review. Am J Rhinol Allergy 2016;30:316
10Antunes, MB, Feldman, MD, Cohen, NA, Chiu, AG. Dose-dependent effects of topical tobramycin in an animal model of Pseudomonas sinusitis. Am J Rhinol Allergy 2007;21:423–7
11Lim, M, Citardi, MJ, Leong, JL. Topical antimicrobials in the management of chronic rhinosinusitis: a systematic review. Am J Rhinol Allergy 2008;22:381–9
12Ha, KR, Psaltis, AJ, Butcher, AR, Wormald, PJ, Tan, LW. In vitro activity of mupirocin on clinical isolates of Staphylococcus aureus and its potential implications in chronic rhinosinusitis. Laryngoscope 2008;118:535–40
13Legent, F, Bordure, P, Beauvillain, C, Berche, P. A double-blind comparison of ciprofloxacin and amoxycillin/clavulanic acid in the treatment of chronic sinusitis. Chemotherapy 1994;40(suppl 1):815
14Namyslowski, G, Misiolek, M, Czecior, E, Malafiej, E, Orecka, B, Namyslowski, P et al. Comparison of the efficacy and tolerability of amoxycillin/clavulanic acid 875 mg b.i.d. with cefuroxime 500 mg b.i.d. in the treatment of chronic and acute exacerbation of chronic sinusitis in adults. J Chemother 2002;14:508–17
15Sydnor, TA Jr, Scheld, WM, Gwaltney, J Jr, Nielsen, RW, Huck, W, Therasse, DG. Loracarbef (LY 163892) vs amoxicillin/clavulanate in bacterial maxillary sinusitis. Ear Nose Throat J 1992;71:225–32
16Orlandi, RR, Kingdom, TT, Hwang, PH, Smith, TL, Alt, JA, Baroody, FM et al. International Consensus Statement on Allergy and Rhinology: Rhinosinusitis. Int Forum Allergy Rhinol 2016;6(suppl 1):S22209
17Suzuki, H, Shimomura, A, Ikeda, K, Furukawa, M, Oshima, T, Takasaka, T. Inhibitory effect of macrolides on interleukin-8 secretion from cultured human nasal epithelial cells. Laryngoscope 1997;107:1661–6
18Pynnonen, MA, Venkatraman, G, Davis, GE. Macrolide therapy for chronic rhinosinusitis: a meta-analysis. Otolaryngol Head Neck Surg 2013;148:366–73
19Ambrose, PG, Anon, JB, Bhavnani, SM, Okusanya, OO, Jones, RN, Paglia, MR et al. Use of pharmacodynamic endpoints for the evaluation of levofloxacin for the treatment of acute maxillary sinusitis. Diagn Microbiol Infect Dis 2008;61:132010.1016/j.diagmicrobio.2008.01.010
20Ambrose, PG, Anon, JB, Owen, JS, VanWart, S, McPhee, ME, Bhavnani, SM et al. Use of pharmacodynamic end points in the evaluation of gatifloxacin for the treatment of acute maxillary sinusitis. Clin Infect Dis 2004;38:1513–20
21Axelsson, A, Brorso, JE. Concentration of antibiotics in sinus secretions. Doxycycline and spiramycin. Ann Otol Rhinol Laryngol 1973;82:44–810.1177/000348947308200111
22Cherrier, P, Tod, M, Gros, VL, Petitjean, O, Brion, N, Chatelin, A. Cefotiam concentrations in the sinus fluid of patients with chronic sinusitis after administration of cefotiam hexetil. Eur J Clin Microbiol Infect Dis 1993;12:211–1510.1007/BF01967115
23Dewever, M. Determination of roxithromycin concentration in the mucosa of the maxillary sinus. Br J Clin Pract 1988;42(suppl 55):81
24Dinis, PB, Monteiro, MC, Martins, ML, Silva, N, Morais, JG. Sinus tissue concentration of moxifloxacin after a single oral dose. Ann Otol Rhinol Laryngol 2004;113:142–6
25Dinis, PB, Monteiro, MC, Martins, ML, Silva, N, Gomes, A. Sinus tissue pharmacokinetics after oral administration of amoxicillin/clavulanic acid. Laryngoscope 2000;110:1050–5
26Ehnhage, A, Rautiainen, M, Fang, AF, Sanchez, SP. Pharmacokinetics of azithromycin in serum and sinus fluid after administration of extended-release and immediate-release formulations in patients with acute bacterial sinusitis. Int J Antimicrob Agents 2008;31:561–6
27Eneroth, CM, Lundberg, C, Wretlind, B. Antibiotic concentrations in maxillary sinus secretions and in the sinus mucosa. Chemotherapy 1975;21(suppl 1):17
28Fang, AF, Palmer, JN, Chiu, AG, Blumer, JL, Crownover, PH, Campbell, MD et al. Pharmacokinetics of azithromycin in plasma and sinus mucosal tissue following administration of extended-release or immediate-release formulations in adult patients with chronic rhinosinusitis. Int J Antimicrob Agents 2009;34:6771
29Fraschini, F, Scaglione, F, Pintucci, G, Maccarinelli, G, Dugnani, S, Demartini, G. The diffusion of clarithromycin and roxithromycin into nasal mucosa, tonsil and lung in humans. J Antimicrob Chemother 1991;27(suppl A):61–5
30Gehanno, P, Darantière, S, Dubreuil, C, Chobaut, JC, Bobin, S, Pages, JC et al. A prospective, multicentre study of moxifloxacin concentrations in the sinus mucosa tissue of patients undergoing elective surgery of the sinus. J Antimicrob Chemother 2002;49:821–6
31Gnarpe, H, Lundberg, C. Preliminary report. L-phase organisms in maxillary sinus secretions. Scand J Infect Dis 1971;3:257–9
32Kuehnel, TS, Schurr, C, Lotter, K, Kees, F. Penetration of telithromycin into the nasal mucosa and ethmoid bone of patients undergoing rhinosurgery for chronic sinusitis. J Antimicrob Chemother 2005;44:591–4
33Liss, RH, Norman, JC. Visualization of doxycycline in lung tissue and sinus secretions by fluorescent techniques. Chemotherapy 1975;21(suppl 1):2735
34Lundberg, C, Gullers, K, Malmborg, AS. Antibiotics in sinus secretions. Lancet 1968;2:107–8
35Margaritis, VK, Ismailos, GS, Naxakis, SS, Mastronikolis, NS, Goumas, PD. Sinus fluid penetration of oral clarithromycin and azithromycin in patients with acute rhinosinusitis. Am J Rhinol 2007;21:574–8
36Pea, F, Marioni, G, Pavan, F, Staffieri, C, Bottin, R, Staffieri, A et al. Penetration of levofloxacin into paranasal sinuses mucosa of patients with chronic rhinosinusitis after a single 500 mg oral dose. Pharmacol Res 2007;55:3841
37Stoeckel, K, Harell, M, Dan, M. Penetration of cefetamet pivoxil and cefuroxime axetil into the maxillary sinus mucosa at steady state. Antimicrob Agents Chemother 1996;40:780–3
38Tolsdorff, P. Penetration of ofloxacin into nasal tissues. Infection 1993;21:6670
39Langdon, A, Crook, N, Dantas, G. The effects of antibiotics on the microbiome throughout development and alternative approaches for therapeutic modulation. Genome Med 2016;8:39
40Jakobsson, HE, Jernberg, C, Andersson, AF, Sjolund-Karlsson, M, Jansson, JK, Engstrand, L. Short-term antibiotic treatment has differing long-term impacts on the human throat and gut microbiome. PLoS One 2010;5:e9836
41Zaura, E, Brandt, BW, Teixeira de Mattos, MJ, Buijs, MJ, Caspers, MP, Rashid, MU et al. Same exposure but two radically different responses to antibiotics: resilience of the salivary microbiome versus long-term microbial shifts in feces. MBio 2015;6:e0169315
42Periti, P, Mazzei, T, Mini, E, Novelli, A. Clinical pharmacokinetic properties of the macrolide antibiotics. Effects of age and various pathophysiological states (Part I). Clin Pharmacokinet 1989;16:193214
43Agwuh, KN, MacGowan, A. Pharmacokinetics and pharmacodynamics of the tetracyclines including glycylcyclines. J Antimicrob Chemother 2006;58:256–65
44Mouton, JW, Theuretzbacher, U, Craig, WA, Tulkens, PM, Derendorf, H, Cars, O. Tissue concentrations: do we ever learn? J Antimicrob Chemother 2008;61:235–7
45US Food and Drug Administration. Bioanalytical method validation guidance for industry. In: [29 August 2018]
46Serralheiro, A, Alves, G, Falcao, AC. Bioanalysis of small-molecule drugs in nasal and paranasal tissues and secretions: current status and perspectives. Cent Eur J Chem 2012;10:686702
47Bimazubute, MA, Rozet, E, Dizier, I, Gustin, P, Hubert, P, Crommen, J et al. Liquid chromatographic determination of enrofloxacin in nasal secretions and plasma of healthy pigs using restricted access material for on-line sample clean-up. J Chromatogr A 2007;1189:456–66
48Levine, JM, D'Antonio, CM. Elton revisited: a review of evidence linking diversity and invasibility. Oikos 1999;87:1526
49Ramakrishnan, VR, Hauser, LH, Feazel, LM, Ir, D, Robertson, CE, Frank, DN. Sinus microbiota varies among chronic rhinosinusitis phenotypes and predicts surgical outcome. J Allergy Clin Immunol 2015;136:334–4210.1016/j.jaci.2015.02.008
50Turnbaugh, PJ, Ley, RE, Hamady, M. The human microbiome project. Nature 2007;449:804–1010.1038/nature06244
51Liu, CM, Soldanova, K, Nordstrom, L, Dwan, MG, Moss, OL, Contente-Cuomo, TL et al. Medical therapy reduces microbiota diversity and evenness in surgically recalcitrant chronic rhinosinusitis. Int Forum Allergy Rhinol 2013;3:775–8110.1002/alr.21195
52Liu, CM, Kohanski, MA, Mendiola, M. Impact of saline irrigation and topical corticosteroids on the postsurgical sinonasal microbiota. Int Forum Allergy Rhinol 2015;5:185–90
53Jain, R, Hoggard, M, Zoing, M, Jiang, Y, Biswas, K, Taylor, MW et al. The effect of medical treatments on the bacterial microbiome in patients with chronic rhinosinusitis: a pilot study. Int Forum Allergy Rhinol 2018;8:890–9
54Cleland, EJ, Bassiouni, A, Vreugde, S, Wormald, PJ. The bacterial microbiome in chronic rhinosinusitis: richness, diversity, postoperative changes, and patient outcomes. Am J Rhinol Allergy 2015;30:3743
55Fokkens, WJ, Lund, VJ, Mullol, J, Bachert, C, Alobid, I, Baroody, F et al. EPOS 2012: European position paper on rhinosinusitis and nasal polyps 2012. A summary for otorhinolaryngologists. Rhinology 2012;50:11210.4193/Rhino50E2
56Hauser, LJ, Ir, D, Kingdom, TT, Robertson, CE, Frank, DN, Ramakrishnan, VR. Investigation of bacterial repopulation after sinus surgery and perioperative antibiotics. Int Forum Allergy Rhinol 2015;6:3440
57Shehab, N, Patel, PR, Srinivasan, A, Budnitz, DS. Emergency department visits for antibiotic-associated adverse events. Clin Infect Dis 2008;47:735–43
58Kiguba, R, Karamagi, C, Bird, S. Antibiotic-associated suspected adverse drug reactions among hospitalized patients in Uganda: a prospective cohort study. Pharmacol Res Perspect 2017;5:e00298
59Korpela, K, Salonen, A, Virta, LJ, Kekkonen, RA, Forslund, K, Bork, P et al. Intestinal microbiome is related to lifetime antibiotic use in Finnish pre-school children. Nat Commun 2016;7:10410
60Raymond, F, Deraspe, M, Boissinot, M, Bergeron, MG, Corbeil, J. Partial recovery of microbiomes after antibiotic treatment. Gut Microbes 2016;7:428–34
61Angelakis, E, Million, M, Kankoe, S, Lagier, JC, Armougom, F, Giorgi, R et al. Abnormal weight gain and gut microbiota modifications are side effects of long-term doxycycline and hydroxychloroquine treatment. Antimicrob Agents Chemother 2014;58:3342–7
62Becattini, S, Taur, Y, Pamer, EG. Antibiotic-induced changes in the intestinal microbiota and disease. Trends Mol Med 2016;22:458–78
63Ianiro, G, Tilg, H, Gasbarrini, A. Antibiotics as deep modulators of gut microbiota: between good and evil. Gut 2016;65:1906–15
64Mikkelsen, KH, Frost, M, Bahl, MI, Licht, TR, Jensen, US, Rosenburg, J et al. Effect of antibiotics on gut microbiota, gut hormones and glucose metabolism. PLoS One 2015;10:e0142352
65Yoon, MY, Yoon, SS. Disruption of the gut ecosystem by antibiotics. Yonsei Med J 2018;59:412
66Gevers, D, Kugathasan, S, Denson, LA, Vázquez-Baeza, Y, Van Treuren, W, Ren, B et al. The treatment-naïve microbiome in new-onset Crohn's disease. Cell Host Microbe 2014;15:382–92
67Slimings, C, Riley, TV. Antibiotics and hospital-acquired Clostridium difficile infection: update of systematic review and meta-analysis. J Antimicrob Chemother 2014;69:881–91
68Boursi, B, Mamtani, R, Haynes, K, Yang, YX. The effect of past antibiotic exposure on diabetes risk. Eur J Endocrinol 2015;172:639–48
69Villarreal, AA, Aberger, FJ, Benrud, R, Gundrum, JD. Use of broad-spectrum antibiotics and the development of irritable bowel syndrome. WMJ 2012;111:1720
70Lankelma, JM, Cranendonk, DR, Belzer, C, de Vos, AF, de Vos, WM, van der Poll, T et al. Antibiotic-induced gut microbiota disruption during human endotoxemia: a randomised controlled study. Gut 2017;66:1623–30


Measuring antibiotic levels and their relationship with the microbiome in chronic rhinosinusitis

  • J Siu (a1), M D Tingle (a2) and R G Douglas (a1)


Altmetric attention score

Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed