Chronic rhinosinusitis (CRS) is an inflammatory disorder of the nose and paranasal sinuses of unknown cause and great individual and societal impact. CRS is currently defined by the presence of at least two of the following symptoms for greater than 12 weeks (hyposmia, nasal obstruction, facial pain/pressure and anterior/posterior nasal drainage) in addition to endoscopic or radiographic evidence of sinonasal inflammation . Symptoms of CRS can be debilitating, with patients reporting quality of life scores akin to those for patients with chronic obstructive pulmonary disease (COPD) and congestive heart failure . With an incidence of approximately one in seven adults in the United States , CRS has a prevalence three to four times greater than asthma, ulcer disease and chronic bronchitis . An estimated 4.7 million emergency room visits and 61.2 million lost workdays are estimated to be attributed to CRS . As a result, CRS is responsible for billions of dollars in healthcare-related costs with parallel losses resulting from absenteeism from work . The personal and public ramifications of CRS are significant, especially as the incidence of this chronic condition appears to be increasing steadily [1,6]. Despite this, our understanding of the pathogenesis of CRS remains incomplete, and therefore, our treatment options remain similarly compromised.
Although initially considered an infectious process driven by pathogenic bacteria, CRS is widely accepted as a syndrome of persistent sinonasal mucosal inflammation resulting from multiple causes  (Table 1). As in other multifactorial disease states with incompletely understood causes, a variety of treatment strategies are available. The goals of decreasing mucosal inflammation, improving mucociliary clearance and controlling infection are approached through a number of medical and surgical interventions. The role of oral antibiotics in CRS remains a surprising conundrum, as these medications are nearly universally prescribed yet largely unsupported by research.
ORAL ANTIBIOTICS IN CHRONIC RHINOSINUSITIS
Although the pathogenesis of CRS is incompletely understood, the disease state involves an interaction between genetic predisposition, innate immunity, inflammation, bacterial burden and allergic responsiveness. The role of oral antibiotics cannot be considered without an appreciation for developments in the understanding of the role of bacteria in CRS.
Although it is accepted that bacteria represent a component of the inflammatory process of CRS, the primacy of their role is increasingly called into question. In patients with unilateral CRS, Bhattacharyya  demonstrated no significant difference in the bacterial profiles between diseased and contralateral normal sides. Further clouding the pathogenic nature of bacteria in CRS and the concomitant need for antibiotics are studies of ethmoid biopsies that show no difference between the bacteriologic profiles of patients with CRS and control individuals [8,9]. Bacterial identification through culture techniques may omit pathogens within biofilms, an increasingly important consideration in CRS. Recent investigations suggest that biofilms, through varied laboratory techniques, can be demonstrated in a significantly greater percentage of CRS patients than in controls [10,11]. Future studies quantifying the amount of biofilm present may have implications for treatment . Similarly, the association of biofilms with abnormal epithelium has recently been reported and may help elucidate the relationship between biofilms and inflammation, whether causative or responsive . In CRS, antbiotics may exert their greatest effects by reducing the bacterial burden that contributes to inflammation or by treating acute, purulent exacerbations of CRS. Although methodologic difficulties are common in bacteriologic studies, the nebulous role of bacteria in CRS pathogenesis augurs future changes for the clinical use of antibiotics by physicians treating CRS.
At present, multiple surveys demonstrate that greater than 90% of otolaryngologists use oral antibiotics in the treatment of CRS [13,14]. Despite the near ubiquity of antibiotic use, there is none that is approved by the U.S. Food and Drug Administration for the treatment of CRS [6,15]. Furthermore, current review of the literature finds no high-level evidence to support antibiotic use in CRS [16,17,18▪,19▪▪,20,21,22▪▪,23▪▪,24]. The anecdotal nature of antibiotic prescribing practices in CRS and parallel need for further clinical research in this area is apparent.
The need for more stringent and evidence-based use of oral antibiotics in the management of CRS is made evident by the increasing prevalence of antibiotic resistance among bacteria commonly isolated from the nose and sinuses. Greater use of antibiotics leads to an increased potential for antibiotic resistance, and overprescription of broad-spectrum antibiotics for virally mediated infections or those without clear bacterial causes are concerning culprits for inappropriate use.
A retrospective review of culture results from 324 patients diagnosed with CRS over 5 years demonstrated Pseudomonas resistance rates near 13% for levofloxacin and 5% for ciprofloxacin . Kingdom and Swain  reviewed 101 patients with CRS undergoing endoscopic sinus surgery (ESS) and determined a higher resistance rate for quinolones among Pseudomonas (27%), as well as methicillin-resistant Staphylococcus aureus (MRSA) in 21% of isolates, and an overall resistance rate among isolates of 62% to at least one antibiotic. Bhattacharyya and Kepnes  reported similar rates of antibiotic resistance in their 5-year retrospective review; however, an increase in resistance over the course of the study was found only for erythromycin, to a peak of 69.7%. Earlier prospective studies by the same group did not demonstrate rising levels of resistance over time for individual CRS patients, yet the risk for increased community levels of antibiotic resistance was emphasized . Although MRSA prevalence is typically found in 15–20% of tertiary care isolates, the frequency in a large tertiary care Canadian study is dramatically lower, perhaps reflecting systemic differences in the use of oral antibiotics in CRS .
A two-pronged intervention is recommended to address both the individual patient with purulent disease and the larger community health issue of increasing prevalence of antibiotic resistance in common otolaryngologic conditions such as acute otitis media and CRS. Individual patients with purulent exacerbations of CRS should be treated on the basis of the antibiotic sensitivity results of endoscopically obtained cultures, thereby reducing the use of broad-spectrum empiric antibiotics [27–29]. A Cochrane review of patient and physician education efforts to reduce inappropriate broad-spectrum antibiotic use emphasized the difficulty of such endeavours, with the vast majority of studies failing to achieve their goals . The combination of public education campaigns and physician-oriented informational materials is suggested as multifaceted approaches to surmount local barriers to changing antibiotic practices . The published data regarding frequency of antibiotic use by otolaryngologists treating CRS suggest that further work must be done within our own ranks as well as in the larger community of physicians treating CRS.
The discussion of antibiotics can be compartmentalized into antibacterial effects and anti-inflammatory effects, with the former representing traditional treatment paradigms and the later reflective of long-term macrolide antibiotic therapy.
The former paradigm is consistent with the notion that CRS develops as a result of sinus ostial obstruction that leads to bacterial infection in the involved paranasal sinus. Although an appreciation for the inflammatory nature of CRS has supplanted this theory, it is in these cases of acute purulent exacerbation of CRS that antibiotics are most effective [17,18▪,19▪▪,20]. As our understanding has evolved to reflect CRS pathogenesis as an inflammatory process of the sinonasal mucosa, the need for and efficacy of antibiotics remains unclear. The most current consensus guidelines suggest, in addition to anti-inflammatory medications, that CRS be addressed with broader spectrum antibiotics and longer durations of treatment than in acute bacterial rhinosinusitis [20,21]. There is a dearth of high-level placebo-controlled studies that would enable physicians to make more informed decisions regarding their use of antibiotics in treating CRS. Over the past few years, only a single double-blind, placebo-controlled study of nonmacrolide antibiotics in CRS has been reported. Van Zele et al. demonstrated a significant reduction in polyp size that persisted for 12 weeks after treatment of CRS with nasal polyps in the doxycyline treated group as compared with controls receiving placebo. The reduction in polyp size was of longer duration in the oral antibiotic group than in the oral corticosteroid arm of the study . Despite widespread use, the antibacterial role of these medications in CRS remains without the support of high-level experimental data.
ORAL ANTIBIOTICS IN ENDOSCOPIC SINUS SURGERY FOR CHRONIC RHINOSINUSITIS
The conundrum of oral antibiotics in CRS extends to their use in the postoperative patient. Although 86.8% of otolaryngologists prescribe oral antibiotics as part of routine postoperative care following ESS, the literature supporting this role is scarce . Recent work by Albu and Lucaciu  demonstrates improved endoscopic appearance and symptom scores in postoperative patients receiving 2 weeks of postoperative antibiotic therapy. A review of evidence regarding postoperative antibiotic therapy recommends an optional role for antibiotics both to control early symptoms and prevent an acute infection from initiating further inflammation . In cases in which visible purulence can be cultured, antibiotics should be prescribed on the basis of identified sensitivities of the identified pathogen [15,18▪,33].
The macrolide antibiotics have become a focus of interest not only for their explicit antimicrobial properties but also increasingly as a result of their immunomodulatory and rheologic effects within the paranasal sinuses. Macrolides are polyketide compounds produced by actinomycetes with specific antibacterial properties by virtue of their preferential binding properties to eubacterial, and not eukaryotic, ribosomes . The clinically useful macrolides have 14, 15 and 16-membered lactone rings, though only the former two possess immunomodulatory properties that enhance their utility within the spectrum of inflammatory respiratory disease .
The immunomodulatory effects of long-term macrolide therapy were first appreciated clinically over 25 years ago in the management of diffuse panbronchiolitis (DPB), a lower respiratory inflammatory disease marked by profound neutrophilic inflammation . Given the current understanding of CRS as a multifactorial inflammatory process influenced by genetics, environment, immune status, anatomy, microbes and allergy, interventions that target final common pathway of mucosal inflammation have promoted macrolides to a position of significant interest. Macrolides have been demonstrated to decrease nasal mucous viscosity , improve transportability of nasal secretions  and decrease hypersecretion without impairing baseline levels of mucous secretion . Although the immunomodulatory effects of macrolides are promising, their antibiofilm properties deserve additional consideration in the pathogenesis of CRS. Macrolides impair bacterial adherence , interfere with the synthesis of bacterial quorum sensing molecules  and revert mucoid biofilm bacteria to the planktonic state , collectively impairing biofilm formation.
A more direct anti-inflammatory effect is exerted by the tendency for macrolide antibiotics to modulate the deleterious effects of prolonged neutrophil activity on the sinonasal mucosa. Production of interleukin-8, a strong neutrophil chemattractant, is suppressed by 14-membered macrolide antibiotics . Macrolides increase production of proinflammatory cytokines early in the microbial killing process before rapidly exerting a normalization of these cytokines through immunomodulatory effects . Furthermore, the collateral damage to sinonasal mucosa resulting from neutrophil oxidative killing is ameliorated by macrolides that limit free radical production . These immunomodulatory effects are demonstrable at macrolide concentrations below the minimum inhibitory concentration (MIC) for many of the targeted bacteria . The remarkable success of macrolide therapy in treating neutrophilic inflammation of lower respiratory disease processes has not been transposed to similar processes within the paranasal sinuses.
Observational studies of long-term macrolide antibiotics therapy in CRS patients have addressed both laboratory measures of inflammation and clinical benchmarks for responsiveness to treatment (Table 2) [46▪▪,47–49]. Cervin et al.'s  in-vivo studies demonstrated 12 weeks of clarithromycin to significantly decrease several markers of inflammation in response to a histamine challenge, although this study did not include correlation with symptom scores or radiographic/endoscopic evaluation. A recent, and more clinically oriented, study of long-term macrolide antibiotics therapy for CRS found medical therapy to be directly related to disease severity, with more severe disease being the least responsive, whereas lesser degrees of involvement or patients undergoing polypectomy had increased responsiveness to macrolide antibiotics . Although improvements are noted in both clinical and laboratory parameters of inflammation, these are modest and both aforementioned studies do not include either a placebo arm or a comparative medical therapy arm by which the degree of effectiveness can be assessed.
Macrolide therapy has been studied comparatively with both surgery and placebo. Ragab et al. found no difference in virtually all clinical endpoints and laboratory measures of inflammation between medically treated patients and those who underwent surgery. A 3-month course of erythromycin was studied in combination with nasal irrigations as well as oral and topical corticosteroids . Although the medical regimen was as well tolerated and effective as surgery, an independent effect of macrolide antibiotics cannot be assessed without a control group.
Towards this end, two placebo-controlled studies have sought to delineate the role of long-term macrolide therapy in CRS. Wallwork et al. found the macrolide antibiotics group to experience significant improvements in endoscopy and sinonasal outcomes test-20 (SNOT-20) scores over the placebo group; however, it is important to note that no patient reported a ‘complete improvement’. Conversely, Videler et al.[46▪▪] demonstrated no significant benefit in endoscopic appearance, nasal airflow testing, olfaction assessment or microbial profile after 3 months of low-dose azithromycin. The intensity of macrolide antibiotics effect on CRS symptoms remains a hurdle for future studies to clear. Improvements in the intensity of therapeutic effect have been addressed recently with a randomized prospective study comparing macrolide antibiotics monotherapy with combination therapy using a mucoactive agent (carbocisteine) with proven efficacy in reducing COPD exacerbations . A significant improvement in clinical efficacy was reported in the combination therapy group, although more adverse drug reactions were noted in the combination therapy group as well . Perhaps the most clinically relevant aspect of Wallwork et al.'s  study is a subgroup analysis demonstrating more robust and persistent symptomatic improvement in normal or low immunoglobulin E (IgE) patients treated with macrolide antibiotics when compared with the absence of SNOT-20 improvements in high IgE patients.
Clinical adoption of long-term macrolide therapy for CRS must address risks to treated patients as well as the implications for antibacterial resistance. In long-term treatment, the risk of adverse cardiovascular events remains vanishingly small, yet there can be significant macrolide resistance in patients treated for 3 or more years . Side effects of treatment including gastrointestinal symptoms and rash are common, while liver function abnormalities are rare [44,45,49,50]. The degree of benefit in CRS studies showing any improvement has been small, and these incremental gains must be weighed against the risks of long-term macrolide antibiotics therapy. The role for macrolide antibiotics in CRS, based on the most recent placebo-controlled studies, remains fairly limited. Patients with refractory CRS and low or normal IgE levels may be good candidates for long-term macrolide antibiotics therapy, provided they are counselled as to the modest and incomplete symptom improvement demonstrated by previous studies [16,23▪▪,24,52].
ODONTOGENIC INFECTIONS AND ANTIBIOTIC THERAPY
A sub-population of refractory CRS that typically receives multiple courses of oral antibiotics prior to a definitive diagnosis are those later discovered to have odontogenic maxillary CRS (OMCRS). An update of the recent literature [53,54,55▪▪,56] emphasizes that odontogenic sources should be considered in patients with maxillary disease that fails to respond to routine medical therapy or ESS (Table 3). The incidence of OMCRS was traditionally cited between 10 and 12% [57,58]; however, a recent report of ESS for maxillary CRS demonstrated 25% of this patient group to have an odontogenic origin for their disease . Although otolaryngologists tend to be mindful of OMCRS in the refractory patient, they are less cognizant of the optimal diagnostic modalities for this condition [53,55▪▪,59,60]. Computed tomography (CT) scans provide superior diagnostic yield and anatomic localization of odontogenic sources in comparison to conventional dental radiographs , with disease identified preoperatively by dental evaluation in only 14% of patients later demonstrated to have OMCRS [55▪▪]. Furthermore, the presentation can be confusing, as dentalgia was reported in only 29% of patients with OMCRS, whereas foul taste/smell is present in 48% and a unilateral disease on CT scan in 57% [55▪▪]. Otolaryngologists should review CT scans including the maxillary dentition to identify periapical infection, as appropriate dental management can resolve nearly all cases of OMCRS, particularly in those patients with disease refractory to prior medical therapy and ESS [55▪▪,57–60]. The role of oral antibiotics alone in the treatment of OMCRS is of limited efficacy. Conversely, dental procedures are highly successful in managing the periapical abscesses and periodontal disease that can serve as nidi of infection in OMCRS.
Given the incompletely understood multifactorial cause of the spectrum of disease that is CRS, it is not surprising that therapeutic options remain similarly unclear. Modalities as seemingly disparate, as ultrasound , photodynamic therapy  and thermotherapy  have been investigated as treatment strategies in CRS, yet consensus guidelines have not changed over the past 5–7 years [20,21,22▪▪,23▪▪,24]. Further research into the genetic predisposition of patients to infection, biofilm formation and innate immunity may provide a better understanding of the role of particular treatment strategies in individual patient subpopulations suffering from CRS. Both the antimicrobial effects on pathogens and the immunomodulatory effects of these medications on the patient may work in concert to ameliorate the symptoms of CRS. Discerning these effects may allow finer tuning of the inflammatory process in particular patient populations.
Although the role of oral antibiotics in management of CRS is controversial, and will remain so for the foreseeable future, there are some instances of clinical clarity. Empiric antibiotic therapy based on symptoms suggestive of CRS should be replaced by appropriate therapy supported by endoscopic or radiographic evidence of disease . The endoscopic appearance of purulence should be managed by culture-directed antibiotics, and antibiotics seem to be most effective in situations of acute exacerbations of CRS [17,18▪]. Purulent appearing secretions are more likely to be culture positive than nonpurulent ones and result in a change in antibiotic therapy in 51.4% of CRS patients . Broad-spectrum antibiotics are routinely prescribed in the treatment of CRS, although without the benefit of placebo-controlled trials to demonstrate their efficacy.
Low-dose macrolide antibiotics therapy may provide benefits through direct antimicrobial activity, the disruption of biofilm formation or through a modulation of the inflammatory response. The degree of benefit is thought to be small, with the greatest role for these medications in CRS patients with normal or low IgE levels. A suspicion for a dental source should be investigated with CT scans in refractory patients with maxillary disease as dentalgia is absent in the majority of patients with OMCRS, and dental surgery is the most effective treatment method.
There remains a critical need for clinical trials either to define the role for antibiotics in CRS or stratify patients for whom antibiotics will be most effective [22▪▪]. Antibiotics retain the risks of adverse medication effects, intervention costs and increased community bacterial resistance without a proven efficacy in CRS. Higher levels of evidence will allow physicians to balance the known risks and potential benefits of oral antibiotics in the management of CRS.
Conflicts of interest
The authors have no relevant conflicts of interest to disclose.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
- ▪ of special interest
- ▪▪ of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 89).
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